Efficacy Study of Sodium Channel Blocker in LQT3 Patients

LQT3 mutations in the LQTS Registry will be studied using in vitro expression studies to
determine whether ranolazine causes a decrease in late sodium current, slower recovery from
inactivation and/or changes in time course of inactivation, ameliorating the causative
functional effect of each individual mutation.

Individuals with select LQT3 mutations already studied in vitro will be invited to
participate in a short term (2 day) study in the Clinical Research Center studying the
effects of an oral dose of ranolazine on QTc duration and other ECG, echocardiogram and
Holter-derived parameters.

The same individuals, as well as other individuals with the same mutation, will be invited to
participate in a 6-month study involving ranolazine and matched placebo, to help evaluate the
long-term effectiveness of ranolazine in the population. Periodic ECGs and 24-hour Holter
recordings will be obtained for evaluation of QTc duration and other ECG and Holter-derived
parameters.

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