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Feasibility of Dantrolene to Study RyR2 Inhibition to Prevent Ventricular Arrhythmias

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04134845
Recruitment Status : Completed
First Posted : October 22, 2019
Last Update Posted : April 9, 2020
Sponsor:
Information provided by (Responsible Party):
William Stevenson, Vanderbilt University Medical Center

Brief Summary:
This is an open label trial (N=5 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.

Condition or disease Intervention/treatment Phase
Ventricular Tachycardia Drug: Dantrolene Early Phase 1

Detailed Description:
Dantrolene inhibits RyR2-mediated Ca leak but does not block the Na channel. By reducing spontaneous Ca leak, dantrolene may reduce Ca mediated Na channel inactivation thereby reversing slowed conduction in abnormal tissues. It also may reduce SK channel activation thereby reversing shortened refractoriness in abnormal tissues. The investigators will test the idea that selective RyR2 inhibition with dantrolene will reduce VT/VF in structural heart disease by reversing proarrhythmic changes in conduction and refractoriness that promote scar-related reentry.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 5 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Pilot Trial to Demonstrate the Feasibility of Using Dantrolene to Study RYR2 Inhibition to Prevent Ventricular Arrhythmias
Actual Study Start Date : October 7, 2019
Actual Primary Completion Date : February 10, 2020
Actual Study Completion Date : February 10, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Arrhythmia

Arm Intervention/treatment
Experimental: Dantrolene
intravenous administration of dantrolene; 1 mg/ kg IV over 1 minute, one time dose
Drug: Dantrolene
muscle relaxant
Other Name: Dantrium, Ryanodex




Primary Outcome Measures :
  1. Inducibility of sustained VT/VF by standardized ventricular stimulation protocol [ Time Frame: 10 minutes post drug infusion ]
    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.


Secondary Outcome Measures :
  1. Inducibility of sustained VT/VF by standardized ventricular stimulation protocol [ Time Frame: 10 minutes ]
    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.


Other Outcome Measures:
  1. Serial heart rate measurements [ Time Frame: pre drug x 1, 5 minute, 10 minute and 20 minutes ]
    Heart rate- BPM

  2. Serial Blood pressure measurements [ Time Frame: pre drug x 1, 5 minute, 10 minute and 20 minutes ]
    BP - mmHg

  3. Serial arterial O2 sats [ Time Frame: pre drug x 1, 5 minute, 10 minute and 20 minutes ]
    O2 sats %, percent of Hgb

  4. Serial mixed venous O2 sats- measured from PA catheter [ Time Frame: pre drug x 1, 5 minute, 10 minute and 20 minutes ]
    mixed venous O2 sats % percent of Hgb

  5. Serial PA measurements [ Time Frame: pre drug x 1, 5 minute, 10 minute and 20 minutes ]
    PA- mmHg

  6. Serial Pulmonary Cap. Wedge pressure measurements [ Time Frame: pre drug x 1, 5 minute, 10 minute and 20 minutes ]
    PCWP- mmHg

  7. Per the pharmacokinetics measurements that will be collected and measured offline-drug half life [ Time Frame: 5, 10, 15, 20 minutes, 1-4 hours, 6-12 hours,16-24 hours and optional 28-36 hours ]
    half-life (h)

  8. Maximum observed plasma concentration [ Time Frame: 5, 10, 15, 20 minutes, 1-4 hours, 6-12 hours,16-24 hours and optional 28-36 hours ]
    Cmax (ng/ml)

  9. Time to reach maximum observed plasma concentration [ Time Frame: 5, 10, 15, 20 minutes, 1-4 hours, 6-12 hours,16-24 hours and optional 28-36 hours ]
    Tmax (h)

  10. Area under the concentration-time curve from zero to infinity [ Time Frame: 5, 10, 15, 20 minutes, 1-4 hours, 6-12 hours,16-24 hours and optional 28-36 hours ]
    AUC- h ng/ml

  11. Ventricular effective refractory period pre/post Dantrolene [ Time Frame: Pre-drug, 5, 10,15 and 20 minute post-drug ]
    VERP measured at 500 ms



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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)

Exclusion Criteria:

  • Mechanical ventricular support (e.g. LVAD, ECMO)
  • NYHA class IV heart failure
  • LVEF < 20%
  • Morbid obesity (BMI > 40 kg/m2)
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04134845


Locations
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United States, Tennessee
Vanderbilt University Medical Center
Nashville, Tennessee, United States, 37232
Sponsors and Collaborators
Vanderbilt University Medical Center
Investigators
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Principal Investigator: William Stevenson, MD Vanderbilt University Medical Center
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Responsible Party: William Stevenson, Professor of Medicine, Vanderbilt University Medical Center
ClinicalTrials.gov Identifier: NCT04134845    
Other Study ID Numbers: 190797
First Posted: October 22, 2019    Key Record Dates
Last Update Posted: April 9, 2020
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by William Stevenson, Vanderbilt University Medical Center:
Ventricul Tachycardia ablation
Additional relevant MeSH terms:
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Tachycardia
Tachycardia, Ventricular
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Pathologic Processes
Cardiac Conduction System Disease
Dantrolene
Muscle Relaxants, Central
Physiological Effects of Drugs
Neuromuscular Agents
Peripheral Nervous System Agents