A Clinical Trial Utilizing Dantrolene in Patients With Ventricular Arrhythmias.

Ventricular Tachycardia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04134845
• Other study ID #: 190797
• Status: Active, not recruiting
• Phase: Phase 2/Phase 3
• Start date: August 21, 2020
• Est. completion date: June 2024

Study information

• Verified date: February 2024
• Source: Vanderbilt University Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 84
• Est. completion date: June 2024
• Est. primary completion date: June 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Tachycardia
• Tachycardia, Ventricular
• Ventricular Tachycardia

Intervention

Drug:
• Dantrolene/Ryanodex
muscle relaxant
• Placebo
Controlled placebo of saline administered Intravenous; 1 mg/kg IV over 3 minutes, one time dose

Locations

Country	Name	City	State
United States	Vanderbilt University Medical Center	Nashville	Tennessee

Sponsors (1)

Lead Sponsor	Collaborator
Vanderbilt University Medical Center

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Serial heart rate measurements	Heart rate- BPM	pre drug infusion, 1 minute, 5 minute, 10 minute and 20 minutes post infusion
Other	Serial Blood pressure measurements	BP - mmHg	pre drug infusion,1minute, 5 minute, 10 minute and 20 minutes post drug infusion
Other	Serial arterial O2 sats	O2 sats %, percent of Hgb	pre drug, post drug 1 minute, 5 minute, 10 minute and 20 minutes
Other	Serial mixed venous O2 sats- measured from PA catheter	mixed venous O2 sats % percent of Hgb	pre drug infusion, 1 minute , 5 minute, 10 minute and 20 minutes post drug infusion
Other	Serial PA measurements	PA- mmHg	pre drug infusion , 1 minute, 5 minute, 10 minute and 20 minutes post drug infusion
Other	Serial Pulmonary Cap. Wedge pressure measurements	PCWP- mmHg	pre drug infusion, 1 minute, 5 minute, 10 minute and 20 minutes post drug infusion
Other	Per the pharmacokinetics measurements that will be collected and measured offline-drug half life	half-life (h)	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	Maximum observed plasma concentration	Cmax (ng/ml)	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	Time to reach maximum observed plasma concentration	Tmax (h)	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	Area under the concentration-time curve from zero to infinity	AUC- h ng/ml	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	Ventricular effective refractory period pre/post Dantrolene	VERP measured at 500 ms	pre-drug infusion, post drug infusion at 5 minutes, 10 minutes,15 minutes and 20 minute post-drug
Other	Oxygen Saturation	Oxygen saturation measured by pulse oximeter, %	pre-procedure, during procedure
Other	Respiratory Rate	Rate of respiration, respiration per minute	pre-procedure, during procedure
Other	Minute Ventilation	Ventilator measured L/min of ventilation	during procedure
Other	Tidal Volume	Volume of ventilated air, measured as L/breath	during procedure
Other	Arterial Blood Gas - pH	Blood gas, obtained from arterial blood supply, pH measurement	pre-procedure, during procedure, two hours post procedure
Other	Arterial Blood Gas - pO2	Blood gas, obtained from arterial blood supply, mmHg of O2 concentration	Pre-procedure, during procedure, two hours post procedure
Other	Arterial Blood Gas - pCO2	Blood gas, obtained from arterial blood supply, mmHg of CO2 concentration	pre-procedure, during procedure, two hours post procedure
Other	Arterial Blood Gas - base excess	Blood gas, obtained from arterial blood supply, mmHg of CO2 concentration	pre-procedure, during procedure, two hours post procedure
Other	Muscle Strength	Handgrip strength using a dynamometer; measured in pounds of force	pre-procedure, two hours post procedure
Other	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
Other	Respiratory support	Bag/mask ventilation, CPAP, BiPAP, LMA, or tracheal intubation	pre-procedure, during procedure, and two hours post procedure
Other	Negative Inspiratory Force	measured in cm H20	pre-procedure and two hours post procedure
Other	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
Other	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
Primary	Inducibility of sustained VT/VF by standardized ventricular stimulation protocol	Post drug ventricular stimulation with RV ventricular catheter in the RV apex with increasing extra stimuli with planned decrement stimuli by 10 ms to ERP. Outcome is measured as Ventricular inducibility yes/no.	10 minutes post drug infusion
Secondary	Stage of inducibility by standardized ventricular stimulation protocol of the sustained VT/VF	measured as ordinal variable for stage of ventricular stimulation protocol;specific step by step V-stim research protocol will be followed with single extra stimuli up to six extra stimuli added to VERP. What stage of Inducible VT will be recorded.	10 minutes post drug infusion