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

March 15, 2022 updated by: Wojciech Zareba, University of Rochester

Efficacy of Ranolazine in LQT3 Patients

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.

Study Overview

Status

Completed

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

Interventional

Enrollment (Actual)

25

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • New York
      • Rochester, New York, United States, 14642
        • University of Rochester

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

21 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

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:
  • Ranexa

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

This is where you will find people and organizations involved with this study.

Collaborators

Investigators

  • Principal Investigator: Wojciech Zareba, MD,PhD, University of Rochester

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

September 1, 2012

Primary Completion (Actual)

July 20, 2018

Study Completion (Actual)

July 20, 2018

Study Registration Dates

First Submitted

July 18, 2012

First Submitted That Met QC Criteria

July 19, 2012

First Posted (Estimate)

July 24, 2012

Study Record Updates

Last Update Posted (Actual)

April 7, 2022

Last Update Submitted That Met QC Criteria

March 15, 2022

Last Verified

March 1, 2022

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

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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