- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01648205
Long-term Efficacy Study of Sodium Channel Blocker in LQT3 Patients
Efficacy of Ranolazine in LQT3 Patients
Study Overview
Status
Conditions
Intervention / Treatment
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.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
-
-
New York
-
Rochester, New York, United States, 14642
- University of Rochester
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Non-Randomized
- Interventional Model: Sequential Assignment
- Masking: Double
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Placebo followed by Ranolazine Administration
Placebo for 1 month and Ranolazine for 5 months.
|
Matching Placebo will be given for first month.
Patients will receive ranolazine 1000mg bid for subsequent 5 months.
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in QTc Duration at 2 Months
Time Frame: 1 month to 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 Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in QTc at 6 Months
Time Frame: 1 month to 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
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Wojciech Zareba, MD,PhD, University of Rochester
Publications and helpful links
General Publications
- 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.
- 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.
- 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.
- 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.
- 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.
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Pathologic Processes
- Heart Diseases
- Cardiovascular Diseases
- Congenital Abnormalities
- Arrhythmias, Cardiac
- Cardiac Conduction System Disease
- Heart Defects, Congenital
- Cardiovascular Abnormalities
- Long QT Syndrome
- Molecular Mechanisms of Pharmacological Action
- Membrane Transport Modulators
- Sodium Channel Blockers
- Ranolazine
Other Study ID Numbers
- IN-US-259-0128
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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