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

• Sponsor: University of Rochester (Other)
• Overall Status: Completed
• CT.gov ID: NCT01648205
• Collaborator: Gilead Sciences (Industry)
• Enrollment: 25
• Location: 1
• Arm: 1
• Duration (Months): 70.6
• Patients Per Site Per Month: 0.4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Long QT Syndrome	Drug: Placebo; Drug: Ranolazine	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 25 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: Patients will receive placebo for 1 month and subsequently ranolazine 1000mg twice a day for 5 months.Patients will receive placebo for 1 month and subsequently ranolazine 1000mg twice a day for 5 months.
• Masking: Double (Participant, Outcomes Assessor)
• Masking Description: Matching placebo and ranolazine pills were used. Patients were blinded regarding administration of medication. ECG Core Lab reading ECGs was blinded regarding drug assignment.
• Primary Purpose: Treatment
• Official Title: Efficacy of Ranolazine in LQT3 Patients
• Study Start Date: Sep 1, 2012
• Actual Primary Completion Date: Jul 20, 2018
• Actual Study Completion Date: Jul 20, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Placebo followed by Ranolazine Administration Placebo for 1 month and Ranolazine for 5 months.	Drug: Placebo; Matching Placebo will be given for first month.; Drug: Ranolazine; Patients will receive ranolazine 1000mg bid for subsequent 5 months.; Other Names: Ranexa

Outcome Measures

Primary Outcome Measures

1. Change in QTc Duration at 2 Months [1 month to 2 months]

   Change in QTc at 2 months on ranolazine vs. at 1 month on placebo. This was prespecified outcome.

Secondary Outcome Measures

1. Change in QTc at 6 Months [1 month to 6 months]

   Change in QTc at 6 months on ranolazine vs. at 1 month on placebo. This was prespecified outcome.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Rochester	Rochester	New York	United States	14642

Sponsors and Collaborators

• University of Rochester
• Gilead Sciences

Investigators

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

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 24, 2016
• Informed Consent Form - Aug 15, 2012

More Information

Publications

• 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.
• 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.
• 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.
• 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.
• 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.

• Responsible Party: Wojciech Zareba, Professor of Medicine, University of Rochester
• ClinicalTrials.gov Identifier: NCT01648205
• Other Study ID Numbers: IN-US-259-0128
• First Posted: Jul 24, 2012
• Last Update Posted: Apr 7, 2022
• Last Verified: Mar 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• 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
• Keywords provided by Wojciech Zareba, Professor of Medicine, University of Rochester: ranolazine; clinical trial
• Additional relevant MeSH terms: Long QT Syndrome; Ranolazine

Study Results

Participant Flow

Arm/Group Title	Placebo
Arm/Group Description	There were 25 subjects enrolled receiving placebo for 1 month with ECG to be obtained at baseline and at 1 month.
Period Title: Placebo
STARTED	25
COMPLETED	21
NOT COMPLETED	4
Period Title: Placebo
STARTED	23
COMPLETED	18
NOT COMPLETED	5

Baseline Characteristics

Arm/Group Title	All Participants
Arm/Group Description	There were 25 subjects that started the study receiving placebo for 1 month.
Overall Participants	25
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	22 88%
>=65 years	3 12%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	49 (14)
Sex: Female, Male (Count of Participants)
Female	13 52%
Male	12 48%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	25 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	25 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	25 100%
QTc duration (miliseconds) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [miliseconds]	493 (55)

Outcome Measures

1. Primary Outcome

Title	Change in QTc Duration at 2 Months
Description	Change in QTc at 2 months on ranolazine vs. at 1 month on placebo. This was prespecified outcome.
Time Frame	1 month to 2 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Ranolazine at 2 Months
Arm/Group Description	Placebo was administered for 1 month.	Ranolazine was administered after 1 month
Measure Participants	25	23
Mean (Standard Deviation) [miliseconds]	503 (46)	497 (47)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Ranolazine at 2 Months
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7958
	Comments
	Method	t-test, 2 sided
	Comments	Paired t-test was used
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.6
	Confidence Interval	(2-Sided) 95%; -14.1 to 11.0
	Parameter Dispersion	Type: Standard Deviation; Value: 26.8
	Estimation Comments

2. Secondary Outcome

Title	Change in QTc at 6 Months
Description	Change in QTc at 6 months on ranolazine vs. at 1 month on placebo. This was prespecified outcome.
Time Frame	1 month to 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Ranolazine at 6 Months
Arm/Group Description	Placebo administered at first month.	Ranolazine was administered for 5 months following 1 month on placebo.
Measure Participants	23	21
Mean (Standard Deviation) [miliseconds]	504 (53)	501 (49)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Ranolazine at 2 Months
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3369
	Comments
	Method	t-test, 2 sided
	Comments	Paired t-test was used
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	8.4
	Confidence Interval	(2-Sided) 95%; -9.5 to 26.2
	Parameter Dispersion	Type: Standard Deviation; Value: 35.9
	Estimation Comments

Adverse Events

Time Frame	Adverse events data were collected for 1 month on placebo and for up to 5 months on ranolazine.
Arm/Group Title	Ranolazine		Placebo
Arm/Group Description	During 5 months on ranolazine following adverse events were reported: Ventricular fibrillation successfully treated with shock from implantable cardioverter-defibrillator (n=1) Ventricular fibrillation unsuccessfully treated with shock from implantable cardioverter-defibrillator with subsequent death (n=1) Bundle branch block (n=1) Dizziness/unsteadiness (n=3) Headache (n=1) Constipation (n=1) Hematuria (n=1) Hemorrhoids (n=1)		During 1 month on placebo following adverse events were reported: Pregnancy (n=1) Gastritis (n=1) Generalized weakness (n=1)
All Cause Mortality
	Ranolazine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/25 (4%)		0/25 (0%)
Serious Adverse Events
	Ranolazine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/25 (8%)		0/25 (0%)
Cardiac disorders
Ventricular Fibrillation	2/25 (8%)	2	0/25 (0%)	0
Other (Not Including Serious) Adverse Events
	Ranolazine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/25 (12%)		0/25 (0%)
Nervous system disorders
Dizziness	3/25 (12%)	3	0/25 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.