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

NCT ID: NCT01648205

Last Updated: 2022-04-07

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 25 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-09-30
• Study Completion Date: 2018-07-20

Brief 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.

Detailed 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.

Conditions

Long QT Syndrome

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Placebo followed by Ranolazine Administration

Placebo for 1 month and Ranolazine for 5 months.

Group Type: EXPERIMENTAL

Placebo

Intervention Type: DRUG

Matching Placebo will be given for first month.

Ranolazine

Intervention Type: DRUG

Patients will receive ranolazine 1000mg bid for subsequent 5 months.

Interventions

Placebo

Matching Placebo will be given for first month.

Intervention Type: DRUG

Ranolazine

Patients will receive ranolazine 1000mg bid for subsequent 5 months.

Intervention Type: DRUG

Other Intervention Names

Ranexa

Eligibility Criteria

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

• Minimum Eligible Age: 21 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Gilead Sciences

INDUSTRY

Sponsor Role: collaborator

University of Rochester

OTHER

Sponsor Role: lead

Responsible Party

Wojciech Zareba

Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Wojciech Zareba, MD,PhD

Role: PRINCIPAL_INVESTIGATOR

University of Rochester

Locations

University of Rochester

Rochester, New York, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 18662191 (View on PubMed)

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. doi: 10.1056/NEJM199810013391404.

Reference Type: BACKGROUND

PMID: 9753711 (View on PubMed)

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. doi: 10.1016/s0735-1097(03)00554-0.

Reference Type: BACKGROUND

PMID: 12849668 (View on PubMed)

Schwartz PJ, Priori SG, Locati EH, Napolitano C, Cantu 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. doi: 10.1161/01.cir.92.12.3381.

Reference Type: BACKGROUND

PMID: 8521555 (View on PubMed)

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. doi: 10.1161/01.cir.101.14.1698.

Reference Type: BACKGROUND

PMID: 10758053 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

IN-US-259-0128

Identifier Type: -

Identifier Source: org_study_id