Long QT Syndrome
Conditions
Keywords
ranolazine, clinical trial
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.
Interventions
DRUGPlacebo
Matching Placebo will be given for first month.
DRUGRanolazine
Patients will receive ranolazine 1000mg bid for subsequent 5 months.
Sponsors
Gilead Sciences
University of Rochester
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, 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.
Intervention model description
Patients will receive placebo for 1 month and subsequently ranolazine 1000mg twice a day for 5 months.
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Participants There were 25 subjects that started the study receiving placebo for 1 month. | 25 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Placebo | Pregnancy | 1 |
| Placebo | Protocol Violation | 2 |
| Placebo | Withdrawal by Subject | 1 |
| Ranolazine | Death | 1 |
| Ranolazine | Protocol Violation | 3 |
| Ranolazine | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 3 Participants |
| Age, Categorical Between 18 and 65 years | 22 Participants |
| Age, Continuous | 49 years STANDARD_DEVIATION 14 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 25 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| QTc duration | 493 miliseconds STANDARD_DEVIATION 55 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 25 Participants |
| Region of Enrollment United States | 25 participants |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 25 | 0 / 25 |
| other Total, other adverse events | 3 / 25 | 0 / 25 |
| serious Total, serious adverse events | 2 / 25 | 0 / 25 |
Outcome results
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.
Time frame: 1 month to 2 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in QTc Duration at 2 Months | 503 miliseconds | Standard Deviation 46 |
| Ranolazine at 2 Months | Change in QTc Duration at 2 Months | 497 miliseconds | Standard Deviation 47 |
p-value: 0.795895% CI: [-14.1, 11]t-test, 2 sided
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.
Time frame: 1 month to 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in QTc at 6 Months | 504 miliseconds | Standard Deviation 53 |
| Ranolazine at 2 Months | Change in QTc at 6 Months | 501 miliseconds | Standard Deviation 49 |
p-value: 0.336995% CI: [-9.5, 26.2]t-test, 2 sided