Clinical trial NCT04134845: A Clinical Trial Utilizing Dantrolene in Patients With Ventricular Arrhythmias.
Official title: A Randomized Controlled Trial of RyR2 Inhibition With Dantrolene and Susceptibility to Ventricular Arrhythmias in Patients With Structural Heart Disease.
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
PHASE3
Conditions: Ventricular Tachycardia
Keywords: Ventricul Tachycardia ablation
Lead sponsor: Vanderbilt University Medical Center
Sponsor class: OTHER
First posted: 2019-10-22
Enrollment: 84
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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
Primary purpose: TREATMENT

Brief 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.

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 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.

Eligibility criteria: 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

Primary outcomes:
measure: Inducibility of sustained VT/VF by standardized ventricular stimulation protocol
timeFrame: 10 minutes post drug infusion
Secondary outcomes:
measure: Stage of inducibility by standardized ventricular stimulation protocol of the sustained VT/VF
timeFrame: 10 minutes post drug infusion
Other outcomes:
measure: Serial heart rate measurements
timeFrame: pre drug infusion, 1 minute, 5 minute, 10 minute and 20 minutes post infusion
measure: Serial Blood pressure measurements
timeFrame: pre drug infusion,1minute, 5 minute, 10 minute and 20 minutes post drug infusion
measure: Serial arterial O2 sats
timeFrame: pre drug, post drug 1 minute, 5 minute, 10 minute and 20 minutes
measure: Serial mixed venous O2 sats- measured from PA catheter
timeFrame: pre drug infusion, 1 minute , 5 minute, 10 minute and 20 minutes post drug infusion
measure: Serial PA measurements
timeFrame: pre drug infusion , 1 minute, 5 minute, 10 minute and 20 minutes post drug infusion
measure: Serial Pulmonary Cap. Wedge pressure measurements
timeFrame: pre drug infusion, 1 minute, 5 minute, 10 minute and 20 minutes post drug infusion
measure: Per the pharmacokinetics measurements that will be collected and measured offline-drug half life
timeFrame: 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
measure: Maximum observed plasma concentration
timeFrame: 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
measure: Time to reach maximum observed plasma concentration
timeFrame: 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
measure: Area under the concentration-time curve from zero to infinity
timeFrame: 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
measure: Ventricular effective refractory period pre/post Dantrolene
timeFrame: pre-drug infusion, post drug infusion at 5 minutes, 10 minutes,15 minutes and 20 minute post-drug
measure: Oxygen Saturation
timeFrame: pre-procedure, during procedure
measure: Respiratory Rate
timeFrame: pre-procedure, during procedure
measure: Minute Ventilation
timeFrame: during procedure
measure: Tidal Volume
timeFrame: during procedure
measure: Arterial Blood Gas - pH
timeFrame: pre-procedure, during procedure, two hours post procedure
measure: Arterial Blood Gas - pO2
timeFrame: Pre-procedure, during procedure, two hours post procedure
measure: Arterial Blood Gas - pCO2
timeFrame: pre-procedure, during procedure, two hours post procedure
measure: Arterial Blood Gas - base excess
timeFrame: pre-procedure, during procedure, two hours post procedure
measure: Muscle Strength
timeFrame: pre-procedure, two hours post procedure
measure: Neuromuscular twitch height
timeFrame: During procedure, post drug infusion at 0, 5, 10, 15, 20 minutes
measure: Respiratory support
timeFrame: pre-procedure, during procedure, and two hours post procedure
measure: Negative Inspiratory Force
timeFrame: pre-procedure and two hours post procedure
measure: Neuromuscular train of four
timeFrame: pre-procedure, during procedure, post drug infusion at 0, 5, 10, 15, 20 minutes, and continuous
measure: Blood chemistry
timeFrame: pre-procedure, during procedure, two hours post procedure
Locations:
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
Study officials:
affiliation: Vanderbilt University Medical Center
name: William Stevenson, MD
role: PRINCIPAL_INVESTIGATOR
References: