Ventricular Tachycardia
Conditions
Keywords
Ventricul Tachycardia ablation
Brief summary
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.
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.
Interventions
DRUGDantrolene/Ryanodex
muscle relaxant
DRUGPlacebo
Controlled placebo of saline administered Intravenous; 1 mg/kg IV over 3 minutes, one time dose
Sponsors
Vanderbilt University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, 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.
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
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Inducible Sustained Ventricular Tachycardia/ Ventricular Fibrillation (VT/VF) Utilizing Standardized Stimulation Protocol. | 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
| Measure | Time frame | Description |
|---|---|---|
| Stage of Inducibility of Ventricular Tachycardia/Ventricular Fibrillation (VT/VF) by Standardized Ventricular Stimulation Protocol Pre and Post Drug/Placebo. | 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. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORWilliam Stevenson, MD
Vanderbilt University Medical Center
Participant flow
Recruitment details
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.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| Dantrolene/Ryanodex Dantrolene/Ryanodex; intravenous administration of dantrolene; 1 mg/ kg IV over 3 minute, one time dose
Dantrolene/Ryanodex: muscle relaxant | 29 |
| 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 | 22 |
| Total | 51 |
Baseline characteristics
| Characteristic | Placebo | Total | Dantrolene/Ryanodex |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 15 Participants | 34 Participants | 19 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 17 Participants | 10 Participants |
| Age, Continuous | 67.0 years | 67.8 years | 68.2 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 5 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 20 Participants | 45 Participants | 25 Participants |
| Region of Enrollment United States | 22 participants | 51 participants | 29 participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 1 Participants |
| Sex: Female, Male Male | 21 Participants | 49 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 29 | 0 / 22 |
| other Total, other adverse events | 5 / 29 | 2 / 22 |
| serious Total, serious adverse events | 0 / 29 | 0 / 22 |
Outcome results
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.
Time frame: 10 minutes post drug infusion
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dantrolene/Ryanodex | Number of Participants With Inducible Sustained Ventricular Tachycardia/ Ventricular Fibrillation (VT/VF) Utilizing Standardized Stimulation Protocol. | 4 Participants |
| Placebo | Number of Participants With Inducible Sustained Ventricular Tachycardia/ Ventricular Fibrillation (VT/VF) Utilizing Standardized Stimulation Protocol. | 9 Participants |
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.
Time frame: 10 minutes post drug infusion
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dantrolene/Ryanodex | Stage of Inducibility of Ventricular Tachycardia/Ventricular Fibrillation (VT/VF) by Standardized Ventricular Stimulation Protocol Pre and Post Drug/Placebo. | Single extra beats/ pre drug/placebo | 0 Participants |
| Dantrolene/Ryanodex | Stage of Inducibility of Ventricular Tachycardia/Ventricular Fibrillation (VT/VF) by Standardized Ventricular Stimulation Protocol Pre and Post Drug/Placebo. | Single extra beats/post drug/placebo | 0 Participants |
| Dantrolene/Ryanodex | Stage of Inducibility of Ventricular Tachycardia/Ventricular Fibrillation (VT/VF) by Standardized Ventricular Stimulation Protocol Pre and Post Drug/Placebo. | Double extra beats/pre drug/placebo | 2 Participants |
| Dantrolene/Ryanodex | Stage of Inducibility of Ventricular Tachycardia/Ventricular Fibrillation (VT/VF) by Standardized Ventricular Stimulation Protocol Pre and Post Drug/Placebo. | Double extra beats/post drug/placebo | 1 Participants |
| Dantrolene/Ryanodex | Stage of Inducibility of Ventricular Tachycardia/Ventricular Fibrillation (VT/VF) by Standardized Ventricular Stimulation Protocol Pre and Post Drug/Placebo. | Triple extra beats/pre drug/placebo | 10 Participants |
| Dantrolene/Ryanodex | Stage of Inducibility of Ventricular Tachycardia/Ventricular Fibrillation (VT/VF) by Standardized Ventricular Stimulation Protocol Pre and Post Drug/Placebo. | Triple extra beats/post drug/placebo | 3 Participants |
| Placebo | Stage of Inducibility of Ventricular Tachycardia/Ventricular Fibrillation (VT/VF) by Standardized Ventricular Stimulation Protocol Pre and Post Drug/Placebo. | Triple extra beats/pre drug/placebo | 5 Participants |
| Placebo | Stage of Inducibility of Ventricular Tachycardia/Ventricular Fibrillation (VT/VF) by Standardized Ventricular Stimulation Protocol Pre and Post Drug/Placebo. | Single extra beats/ pre drug/placebo | 1 Participants |
| Placebo | Stage of Inducibility of Ventricular Tachycardia/Ventricular Fibrillation (VT/VF) by Standardized Ventricular Stimulation Protocol Pre and Post Drug/Placebo. | Double extra beats/post drug/placebo | 3 Participants |
| Placebo | Stage of Inducibility of Ventricular Tachycardia/Ventricular Fibrillation (VT/VF) by Standardized Ventricular Stimulation Protocol Pre and Post Drug/Placebo. | Single extra beats/post drug/placebo | 1 Participants |
| Placebo | Stage of Inducibility of Ventricular Tachycardia/Ventricular Fibrillation (VT/VF) by Standardized Ventricular Stimulation Protocol Pre and Post Drug/Placebo. | Triple extra beats/post drug/placebo | 5 Participants |
| Placebo | Stage of Inducibility of Ventricular Tachycardia/Ventricular Fibrillation (VT/VF) by Standardized Ventricular Stimulation Protocol Pre and Post Drug/Placebo. | Double extra beats/pre drug/placebo | 4 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.
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
Other Pre-specified
Arterial Blood Gas - Base Excess
Blood gas, obtained from arterial blood supply, mmHg of CO2 concentration
Time frame: pre-procedure, during procedure, two hours post procedure
Other Pre-specified
Arterial Blood Gas - pCO2
Blood gas, obtained from arterial blood supply, mmHg of CO2 concentration
Time frame: pre-procedure, during procedure, two hours post procedure
Other Pre-specified
Arterial Blood Gas - pH
Blood gas, obtained from arterial blood supply, pH measurement
Time frame: pre-procedure, during procedure, two hours post procedure
Other Pre-specified
Arterial Blood Gas - pO2
Blood gas, obtained from arterial blood supply, mmHg of O2 concentration
Time frame: Pre-procedure, during procedure, two hours post procedure
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.
Time frame: pre-procedure, during procedure, two hours post procedure
Other Pre-specified
Maximum Observed Plasma Concentration
A pharmacokinetic measure to determine the highest concentration of the drug.
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
Other Pre-specified
Minute Ventilation
Ventilator measured L/min of ventilation
Time frame: during procedure
Other Pre-specified
Muscle Strength
Handgrip strength using a dynamometer; measured in pounds of force
Time frame: pre-procedure, two hours post procedure
Other Pre-specified
Negative Inspiratory Force
Measured by bedside breathing test.
Time frame: pre-procedure and two hours post procedure
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)
Time frame: pre-procedure, during procedure, post drug infusion at 0, 5, 10, 15, 20 minutes, and continuous
Other Pre-specified
Neuromuscular Twitch Height
Twitch amplitude; measured as a % of the baseline calibration twitch amplitude (unitless, % change)
Time frame: During procedure, post drug infusion at 0, 5, 10, 15, 20 minutes
Other Pre-specified
Number of Participants With a Change of Blood Pressure
Change in serial blood pressure at specified time points.
Time frame: 1 minute, 5 minute,10 minute, 15 minute and 20 minutes post infusion.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dantrolene/Ryanodex | Number of Participants With a Change of Blood Pressure | 1 minute | 0 Participants |
| Dantrolene/Ryanodex | Number of Participants With a Change of Blood Pressure | 5 minutes | 0 Participants |
| Dantrolene/Ryanodex | Number of Participants With a Change of Blood Pressure | 10 minutes | 0 Participants |
| Dantrolene/Ryanodex | Number of Participants With a Change of Blood Pressure | 15 minutes | 0 Participants |
| Dantrolene/Ryanodex | Number of Participants With a Change of Blood Pressure | 20 minutes | 0 Participants |
| Placebo | Number of Participants With a Change of Blood Pressure | 20 minutes | 0 Participants |
| Placebo | Number of Participants With a Change of Blood Pressure | 15 minutes | 0 Participants |
| Placebo | Number of Participants With a Change of Blood Pressure | 5 minutes | 0 Participants |
| Placebo | Number of Participants With a Change of Blood Pressure | 1 minute | 0 Participants |
| Placebo | Number of Participants With a Change of Blood Pressure | 10 minutes | 0 Participants |
Other Pre-specified
Oxygen Saturation
Oxygen saturation measured by pulse oximeter, %
Time frame: pre-procedure, during procedure
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.
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
Other Pre-specified
Respiratory Rate
Rate of respiration, respiration per minute
Time frame: pre-procedure, during procedure
Other Pre-specified
Respiratory Support
Bag/mask ventilation, CPAP, BiPAP, LMA, or tracheal intubation
Time frame: pre-procedure, during procedure, and two hours post procedure
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).
Time frame: pre drug, post drug 1 minute, 5 minute, 10 minute and 20 minutes
Other Pre-specified
Serial Heart Rate Measurements
Heart rate measurement performed by standard heart rate monitors in the Electrophysiology lab.
Time frame: pre drug infusion, 1 minute, 5 minute, 10 minute and 20 minutes post infusion
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).
Time frame: pre drug infusion, 1 minute , 5 minute, 10 minute and 20 minutes post drug infusion
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).
Time frame: pre drug infusion , 1 minute, 5 minute, 10 minute and 20 minutes post drug infusion
Other Pre-specified
Serial Pulmonary Cap. Wedge Pressure Measurements
Measuring the Pulmonary Capillary Wedge pressure by the hemodynamic pulmonary cathether
Time frame: pre drug infusion, 1 minute, 5 minute, 10 minute and 20 minutes post drug infusion
Other Pre-specified
Tidal Volume
Volume of ventilated air, measured as L/breath
Time frame: during procedure
Other Pre-specified
Time to Reach Maximum Observed Plasma Concentration
Tmax (h) Time to maximum concentration by 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
Other Pre-specified
Ventricular Effective Refractory Period Pre/Post Dantrolene
Ventricular effective refractory period measured via electrophysiology catheter.
Time frame: pre-drug infusion, post drug infusion at 5 minutes, 10 minutes,15 minutes and 20 minute post-drug