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Sodium Channel Splicing in Heart Failure Trial (SOCS-HEFT) Prospective Study

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ClinicalTrials.gov Identifier: NCT02738749
Recruitment Status : Recruiting
First Posted : April 14, 2016
Last Update Posted : April 12, 2017
Sponsor:
Information provided by (Responsible Party):
Rhode Island Hospital

Tracking Information
First Submitted Date  ICMJE April 7, 2016
First Posted Date  ICMJE April 14, 2016
Last Update Posted Date April 12, 2017
Study Start Date  ICMJE June 2014
Estimated Primary Completion Date July 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 12, 2016)
The levels of sodium channel splicing variants measured by gene expression that are related to arrhythmic events, change every 3 months from baseline to one 1 year after ICD therapy. [ Time Frame: baseline, 3-month, 6-month, 9-month, and 12-month after ICD therapy ]
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02738749 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: April 12, 2016)
The levels of sodium channel splicing variants measured by gene expression that are related to the type of ICD implanted, change every 3 months from baseline to one 1 year after ICD therapy. [ Time Frame: baseline, 3-month, 6-month, 9-month, and 12-month after ICD therapy ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Sodium Channel Splicing in Heart Failure Trial (SOCS-HEFT) Prospective Study
Official Title  ICMJE Sodium Channel Splicing in Heart Failure Trial (SOCS-HEFT) Prospective Study
Brief Summary

Congestive heart failure (CHF) represents a major health care concern in the United States. Currently, risk stratification of sudden cardiac death and the need for implantable cardioverter-defibrillator (ICD) placement are essentially dependent upon assessment of left ventricular ejection fraction (LVEF). Nevertheless, the predictive value of LVEF is suboptimal, alternative testing for risk assessment for the development of sudden cardiac death in the heart failure population is desirable.

At the genome level, the investigator has focused on the role of SCN5A gene mutations in arrhythmogenesis. Lymphocyte SCN5A mRNA processing may serve as a surrogate marker to assess SCN5A function at the cardiac level and may correlated with arrhythmic risk in high risk populations. This study will determine if SCN5A variant levels are predictive of appropriate ICD therapies in patients with a newly implanted ICD.

Detailed Description

Scientific Background and Significance Introduction

Congestive heart failure (CHF) represents a major health care concern in the United States. It has been estimated that approximately 5 million patients in the U.S. have CHF, and nearly 550,000 people are diagnosed with this disease annually. It is known that sudden cardiac death occurs more frequently in the setting of structural heart disease. Moreover, the risk for sudden cardiac death is 6 to 9 times greater in the heart failure population, and cardiac arrhythmias are perhaps the leading cause of death in CHF patients. Currently, both the American College of Cardiology and the American Heart Association endorse the placement of implantable cardioverter-defibrillators (ICDs) in patients with ischemic cardiomyopathy, reasonable life expectancy, and reduced ejection fraction below 40% (class I, level of evidence A). Additionally, placement of ICDs is recommended in non-ischemic cardiomyopathy patients who meet similar requirements with an ejection fraction of less than 35% (class I, level of evidence B). Despite these recommendations for primary prevention of sudden death by way of ICD implantation, more than half of the patients receiving a device are likely to not experience an arrhythmic event that necessitates ICD therapy delivery. ICD devices, on average, cost $20,000-50,000 exclusive of operative and follow up costs. Currently, risk stratification of sudden cardiac death and the need for ICD placement are essentially dependent upon assessment of left ventricular ejection fraction. Other methods employed for risk stratification are signal averaged electrocardiogram (ECG) and another electrocardiographic technique known as T-wave alternans. Although these methods are FDA approved for risk prediction of cardiac death, such techniques are not widely employed in the U.S. given equipment and personnel costs to implement them. Thus, alternative testing for risk assessment for the development of sudden cardiac death in the heart failure population is desirable.

Role of Sodium Channels and the SCN5A Gene

The cardiac voltage-gated sodium (Na+) channel, SCN5A, is the main channel generating current for electrical propagation in heart muscle and is the target of many antiarrhythmic drugs. Defective expression of the cardiac Na+ channel results in increased arrhythmic risk as evidenced by sudden death in the Brugada Syndrome. SCN5A mutations have also been implicated in the inherited long-QT syndrome, which can result in the development of the fatal dysrhythmias like ventricular fibrillation and torsades de pointes. Additionally, mutations in the SCN5A gene have also been proposed to exist and enhance risk for drug-induced dysrhythmias.

Many studies have been done to shed light on the role of this tetrodotoxin-insensitive sodium channel in disease states. It has been demonstrated that mutated sodium channels in dilated cardiomyopathy may function differently depending upon the specific mutation type of the principal Na+ channel. Specifically, Nguyen et al have demonstrated that these mutations may lead to changes in physiological function such as slower action potential rise time, enhanced late sodium current during steady state, or impaired inactivation. Additional mutations in the SCN5A gene have been linked to shifts in voltage dependence of Na+ channel inactivation in patients with idiopathic ventricular fibrillation. Prior research has suggested that decreased inactivation of late sodium currents may contribute to action potential prolongation. A different SCN5A gene abnormality has been shown to lead to decreased sodium current density and an positive shift in the cell membrane half-maximal activation potential. Therefore, mutations of the Na+ channel can cause altered channel behavior and arrhythmias.

Previous study showed that disruptions in sodium handling may result in change in calcium homeostasis via action of the Na+/Ca2+ exchanger. Overall, such changes in sodium current (INa) are likely to significantly contribute to arrhythmia in the setting of failing myocardium.

At the genome level, research has focused on the role of SCN5A gene mutations in arrhythmogenesis. Nevertheless, the investigators have recently described acquired defects in Na+ channel messenger RNA (mRNA) that result in reduced Na+ current and occur only in failing hearts. Three 3'-terminal SCN5A mRNA splicing variants were identified and characterized in failing human heart ventricles. Additional measurements suggested that the truncation mutants could cause electrical abnormalities severe enough to contribute to arrhythmic risk. Also, the investigators showed that lymphocytes process sodium channels similarly to cardiomyocytes. Thus, lymphocyte SCN5A mRNA processing may serve as a surrogate marker to assess SCN5A function at the cardiac level and may correlated with arrhythmic risk in high risk populations. This study will determine if SCN5A variant levels are predictive of appropriate ICD therapies in patients with a newly implanted ICD.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
Condition  ICMJE Death, Sudden, Cardiac
Intervention  ICMJE Device: Implantable cardioverter-defibrillator (ICD)
Patients with newly implanted implantable cardioverter-defibrillators (ICDs) for primary prevention will be enrolled.
Study Arms  ICMJE ICD group
Adult patients with newly implanted ICD devices for primary prevention will be enrolled. At baseline, 3-, 6-, 9-, and 12-month followup visit, the medial information and blood samples will be collected.
Intervention: Device: Implantable cardioverter-defibrillator (ICD)
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 12, 2016)
450
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 2020
Estimated Primary Completion Date July 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. All patients must be greater than 18 years of age.
  2. All patients must be able to give informed consent.
  3. Patients must receive an ICD within 10 days for primary prevention.

Exclusion Criteria:

  1. Patients less than 18 years of age.
  2. History of congenital heart disease.
  3. History of congenital electrophysiological disorders like the long-QT syndrome or Brugada disease.
  4. Patients have an ICD implanted for secondary prevention.
  5. Patients taking immunosuppressive medications, have chronic infection, or have an acute or chronic inflammatory illness that might alter white cell mRNA expression.
  6. Patients with any illness expected to result in death within 18 months of enrollment.
  7. Patients with white blood cell dyscrasia or cancers.
  8. Patients with end-stage renal disease (ESRD) on hemodialysis or peritoneal dialysis
  9. Current illicit drug use.
  10. Inability to give informed consent.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Lori-Ann DeSimone, RN,BSN (401) 793-5554
Contact: Michael Orlov, MD 401-793-4107
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02738749
Other Study ID Numbers  ICMJE 426228-16
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Rhode Island Hospital
Study Sponsor  ICMJE Rhode Island Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Michael Orlov, MD Rhode Island Hospital
PRS Account Rhode Island Hospital
Verification Date April 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP