Long-term Efficacy Study of Sodium Channel Blocker in LQT3 Patients

Long QT Syndrome Clinical Trial

Official title:

Efficacy of Ranolazine in LQT3 Patients

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01648205
• Other study ID #: IN-US-259-0128
• Status: Completed
• Phase: Phase 2
• Start date: September 2012
• Est. completion date: July 20, 2018

Study information

• Verified date: March 2022
• Source: University of Rochester
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine whether late sodium channel blockade might be effective in shortening the QTc interval in various LQT3 mutations and be considered as a safe therapeutic option for LQT3 patients.

Description:

Long QT syndrome (LQTS) is a genetic disorder characterized by prolongation of the QT interval in the electrocardiogram (ECG) and a propensity to torsade de pointes ventricular tachycardia frequently leading to syncope, cardiac arrest, or sudden death usually in young otherwise healthy individuals. The long QT syndrome is caused by mutations of predominantly potassium and sodium ion channel genes or channel-related proteins. The most common types of LQTS affect: the slow delayed rectifier potassium repolarization channel (KCNQ1; LQT1) resulting in a reduction in IKs current; the rapid delayed rectifying potassium repolarization channel (KCNH2; LQT2) resulting in a reduction in IKr current; and the sodium channel (SCN5A; LQT3) resulting in an increase in late INa current. Among positively genotyped patients, LQT1 and LQT2 account for about 90% of LQTS cases, whereas LQT3 accounts for about 5% to 8% of cases. LQT3 patients represent a challenging cohort of patients. Unlike patients with LQT1 and LQT2 form of this disorder, the LQT3 patients have high lethality of cardiac events with 1 in 5 patients dying suddenly during their first syncopal or arrhythmic event. In childhood (age 0-18) in the analysis of 1,404 patients, LQT3 was found to be associated with significantly higher risk of aborted cardiac arrest or death than LQT1 and LQT2. A similar pattern is observed in LQTS patients after age 40 in whom LQT3 patients show the highest risk. Optimal therapy in LQT3 patients remains controversial. There are data showing that sodium current blockers including mexiletine and flecainide shorten QTc duration in LQT3 patients. Ranolazine is a selective late sodium current inhibitor that has been also showed to reduce QTc in DKPQ mutation and D1790G mutation patients. However, data on long-term effectiveness of ranolazine are limited.

This single-blinded study evaluated a long-term effects of ranolazine on QTc duration in LQT3 patients with various LQT3 mutations. Enrolled subjects are treated for 1 months with matching placebo and next for subsequent 5 months with ranolazine with ECG recorded at baseline, 1 , 2, and 6 months of follow-up.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 25
• Est. completion date: July 20, 2018
• Est. primary completion date: July 20, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 21 Years and older

Eligibility

Inclusion Criteria:

• Genotyped positive for LQT3 (SCN5A) mutation

• Age 21 years or older

• Not currently taking an antiarrhythmic drug (beta blockers are allowed)

• Enrolled in LQTS Registry

Exclusion Criteria:

• Age less than 21 years

• Not confirmed to have an LQT3 mutation

• Significant co-morbidity that would preclude subject's safe participation in this study

• Females who are pregnant or nursing

• Females of childbearing age who are not using acceptable method of birth control

• Evidence of prior sensitivity to ranolazine

• Hepatic or renal disease that might adversely affect ranolazine excretion

• Currently taking strong CYP3A inhibitors

• Currently taking P-gp inhibitors

• Currently taking CYP3A inducers

• In vitro studies of specific mutation show no effect of ranolazine on late sodium current kinetics or show repolarization prolongation

Related Conditions & MeSH terms

• Long QT Syndrome

Intervention

Drug:
• Placebo
Matching Placebo will be given for first month.
• Ranolazine
Patients will receive ranolazine 1000mg bid for subsequent 5 months.

Locations

Country	Name	City	State
United States	University of Rochester	Rochester	New York

Sponsors (2)

Lead Sponsor	Collaborator
University of Rochester	Gilead Sciences

Country where clinical trial is conducted

United States, 

References & Publications (5)

Benhorin J, Taub R, Goldmit M, Kerem B, Kass RS, Windman I, Medina A. Effects of flecainide in patients with new SCN5A mutation: mutation-specific therapy for long-QT syndrome? Circulation. 2000 Apr 11;101(14):1698-706. — View Citation

Moss AJ, Zareba W, Schwarz KQ, Rosero S, McNitt S, Robinson JL. Ranolazine shortens repolarization in patients with sustained inward sodium current due to type-3 long-QT syndrome. J Cardiovasc Electrophysiol. 2008 Dec;19(12):1289-93. doi: 10.1111/j.1540-8167.2008.01246.x. Epub 2008 Jul 25. — View Citation

Schwartz PJ, Priori SG, Locati EH, Napolitano C, Cantù F, Towbin JA, Keating MT, Hammoude H, Brown AM, Chen LS, Colatsky TJ. Long QT syndrome patients with mutations of the SCN5A and HERG genes have differential responses to Na+ channel blockade and to increases in heart rate. Implications for gene-specific therapy. Circulation. 1995 Dec 15;92(12):3381-6. — View Citation

Zareba W, Moss AJ, Locati EH, Lehmann MH, Peterson DR, Hall WJ, Schwartz PJ, Vincent GM, Priori SG, Benhorin J, Towbin JA, Robinson JL, Andrews ML, Napolitano C, Timothy K, Zhang L, Medina A; International Long QT Syndrome Registry. Modulating effects of age and gender on the clinical course of long QT syndrome by genotype. J Am Coll Cardiol. 2003 Jul 2;42(1):103-9. — View Citation

Zareba W, Moss AJ, Schwartz PJ, Vincent GM, Robinson JL, Priori SG, Benhorin J, Locati EH, Towbin JA, Keating MT, Lehmann MH, Hall WJ. Influence of the genotype on the clinical course of the long-QT syndrome. International Long-QT Syndrome Registry Research Group. N Engl J Med. 1998 Oct 1;339(14):960-5. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in QTc Duration at 2 Months	Change in QTc at 2 months on ranolazine vs. at 1 month on placebo. This was prespecified outcome.	1 month to 2 months
Secondary	Change in QTc at 6 Months	Change in QTc at 6 months on ranolazine vs. at 1 month on placebo. This was prespecified outcome.	1 month to 6 months