Efficacy of Ranolazine in LQT3 Patients
Phase: PHASE2
Conditions: Long QT Syndrome
Sponsor: University of Rochester

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Ranolazine in LQT3 Patients
I. PURPOSE OF THE STUDY AND BACKGROUND 
Purpose of the study. 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. 
Background.  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 (1,2). The long QT syndrome is caused by mutations of predominantly 
potassium and sodium ion channel genes or channel-related proteins leading to positive 
overcharge of myocardial cell with consequent heterogeneous prolongation of repolarization in 
various layers and regions of the myocardium (3-5). These conditions facilitate the early 
afterdepolarization and reentry phenomena underlying development of polymorphic ventricular 
tachycardia observed in patients with LQTS (6).
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 (7,8). Among positively 
genotyped patients, LQT1 and LQT2 account for about 90% of LQTS cases, whereas LQT3 
accounts for about 5% to 8% of cases (7,8). The remaining types of LQTS are extremely rare, 
although they contribute tremendously to our knowledge of the repolarization process. The 
significant number of LQT1 and LQT2 patients among LQTS patients contributed to more 
advanced understanding of phenotypic characterization and phenotype-genotype associations. The 
number of patients with the LQT3 form of the disease is proportionally smaller and studies 
conducted to date are rather small and focused predominantly on single gene mutation or single 
pedigree (9-12). Nevertheless, increased awareness of the LQTS among physicians and patients 
leads to a growing number of patients who are evaluated for the diagnosis of the LQTS and 
therefore the number of LQT3 patients is increasing too (8).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/arrhythmic event (Figure 1) (3,13).
Figure 1. The lethality of cardiac events analyzed by sex 
in long QT syndrome (LQTS) family members with known 
genotype. Open bars - males; black bars - females. 
P<0.001 when comparing LQT3 males and females to 
LQT1 and LQT2 males and females, respectively (Zareba 
2003; reference 13).
 
As shown in Figure 2 for childhood (age 0-18) in the analysis of 1404 patients, LQT3 was 
found to be associated with significantly higher risk of aborted cardiac arrest or death than LQT1 
and LQT2 (14). A similar pattern is observed in LQTS patients after age 40 in whom LQT3 patients 
show the highest risk. 

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Figure 2. The cumulative probability of aborted cardiac 
arrest or death in LQTS children (age 0-18 years) by 
genotype (Goldenberg 2008; reference 14).
Optimal therapy in LQT3 patients remains 
controversial. Data published in 2000 from the 
International LQTS Registry (15) did not support 
beneficial effects of beat-blockers in LQT3 patients, 
although only 28 LQT3 patients were available for 
analysis at that time. Recent analysis by Schwartz et al. 
(16) of 33 LQT3 patients (of whom 18 where on therapy) 
provide further indication that beta-blockers do not seem beneficial and that an implantable 
cardioverter-defibrillator (ICD) is not the solution for all LQT3 patients. There is a need for 
establishing criteria for determining which LQT3 patients might benefit from prevention of sudden 
death with ICD. At the same time further investigations toward use of sodium current blockers in 
LQT3 patients seem justified. 
There are preliminary data showing that sodium current blockers shorten QTc duration in 
LQT3 patients. Several sodium current blockers were tested: Schwartz et al. (17) demonstrated 
that mexiletine could be an option for LQT3 patients but gastro-intestinal side effects limit long-term 
use of this compound. We tested flecainide (18) documenting that low doses of these drugs are 
effective in shortening QT and subsequently we showed long-term effectiveness of this drug in QT 
shortening. However, as documented in a study by Benhorin et al. (11), QRS widening was 
observed in LQT3 patients receiving flecainide. Priori et al. (19) showed that flecainide may induce 
ST segment elevation in LQT3 patients, further raising concerns about the safety of flecainide 
therapy. 
Figure 3. Effect of ranolazine intravenous 
administration on QTc in LQT3 patients (Moss 
2008). 
Our recent data from a pilot study conduced in 5 patients with delta-KPQ mutation 
demonstrated that late sodium current blockade with ranolazine, a compound that does not affect 
sodium peak current and therefore does not changes QRS duration and morphology, is very 
effective in shortening QTc in LQT3 patients (20). This innovative therapy might serve as potential 
solution for treatment of LQT3 patients. However, there are very limited data on their effectiveness 
and long-term safety. Late sodium current blockade with ranolazine might be a safer option since 
peak sodium current and QRS duration are not affected by this class of the drugs. However, apart 
from a 5-patient study with acute intravenous administration of ranolazine (20), there are no data 
on long-term benefits and safety of oral use of this compound.   
 
Expression Studies with Ranolazine Administration
As non-clinical part of the project we will determine in in vitro expression studies whether the 
functional defects caused by the LQT3 mutations can be reversed by ranolazine mutation (21). We 
will test 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 

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effect of each individual mutation.  We expect that for mutations that show an increase in late 
sodium current this increase will be blocked by the drug without an increase in peak current.  For 
the I1768V mutant, no increase in persistent current was observed in previous functional studies 
(22). Nonetheless, because ranolazine is thought to act in the inactive state of the channel (22, 23), 
we expect the faster recovery from inactivation caused by this and other mutations to be reversed 
by the drug as shown for the R1623Q mutant channel (23).  For two of the mutants (F1617del and 
T370M), the functional defect is not known and ranolazine may not be able to reverse their effect. A 
dose response of ranolazine (1-300 M) will be measure for each of the mutants to test for 
mutation specific changes in the efficacy of the drug. 
II. CHARACTERISTICS OF THE RESEARCH POPULATION 
Number of subjects. The expected enrollment in Study 1 is 30 subjects.  The expected enrollment 
in Study 2 is 30 subjects.  Subjects are welcome to participate in both studies, if interested and 
eligible.
Gender of Subjects.   There are no gender-based enrollment restrictions. 
Age of Subjects.   The age range of subjects is 21 years of age and older
Racial and Ethnic Origin. There are no racial or ethnic restrictions.  
Inclusion Criteria:  

≥ 21 years of age

Genotyped positive for an LQT3 gene mutation

Not currently taking an antiarrhythmic drug (beta blockers are 
allowed)
Exclusion Criteria:

Age at enrollment is < 21 years of age

Has not had genetic confirmation of LQT3 mutation

Significant co-morbidity that would preclude the subject’s safe 
participation in this study

Pregnancy or women of child-bearing age not using an acceptable 
method of birth control (i.e.:  oral contraceptives, barrier method 
(condom AND diaphragm combined with spermicide.  A diaphragm or 
condom alone is not considered adequate contraception.) implants; 
injections; IUD or abstinence)

Nursing mothers

Evidence of prior sensitivity to ranolazine

Hepatic or renal disease that might adversely affect ranolazine 
excretion

Currently taking Strong CYP3A Inhibitors (including:  ketoconazole, 
itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir 
and saquinavir)   

Currently taking CP-gp inhibitors (including: cyclosporine) 

Currently taking CYP3A Inducers (including: rifampin, rifabutin, 
rifapentin, phenobarbital, phenytoin, carbamazepine and St. John’s 
wort)

Evidence for no effect of ranolazine on late sodium current kinetics in 
in vitro testing for specific mutation or evidence for repolarization 

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prolongation in in vitro testing of specific mutation.
 
Therapeutic modifications:

Moderate CYP3A inhibitors (including: diltiazem, verapamil, and 
erythromycin):  Limit ranolazine to 500 mg twice daily

CYP3A substrates: Limit simvastatin to 20 mg when used with 
ranolazine. 

Drugs transported by P-gp or metabolized by CYP2D6 (e.g. digoxin, 
tricyclic antidepressants):  May need reduced doses of these drugs 
when used with ranolazine 
Vulnerable Subjects. This study may involve some elderly subjects.  Extra care will be paid in 
order to ensure their understanding of this research.
 
III. METHODS AND PROCEDURES 
Study 1:  Short-term Ranolazine Administration.  We will administer this drug orally to 
determine the effect of ranolazine on QTc duration as well as other ECG, echocardiogram and 
Holter-derived parameters. 
The patients will be invited to stay at the General Clinical Research Center (GCRC).
On day 1, the subject will have baseline ECGs recorded hourly, an echocardiogram and 24-hour 
Holter recording as well as bedside ECG monitoring continuously. Laboratory test will be performed 
to determine creatinine clearance.  On day 2, the subject will receive 1000 mg of ranolazine orally 
and will have repeat ECG recordings, an echocardiogram 4-6 hours after dosage is given, and 
Holter monitoring and bedside monitoring continuously as well as hourly sampling of plasma 
concentration of ranolazine. Ranolazine reaches peak plasma concentration after oral 
administration in about 4-6 hours.  We will also evaluate the effects of ranolazine on novel ECG, 
echo and Holter-derived markers to determine whether they could be even more sensitive 
regarding effects of drug on repolarization and its dynamics. 
The study will remain under scrutiny of the Data Safety Monitoring Board (Sabu Thomas M.D. 585-
275-2475).  The Clinical Principal Investigator or representative will monitor the safety of the 
subject as well as any adverse events (Clinical P.I. Spencer Rosero, M.D. 585-275-4775).  
All ECGs and Holter recordings will be read blindly by the central ECG Core Lab.  
Remaining conservative, we expect that recruitment and testing of these patients will be scheduled 
to occur over 2 years. 
Study 2:  Long-term Ranolazine Administration.  The long-term effectiveness of ranolazine will 
be investigated in 30 subjects representing at least 3 different LQT3 mutations, by administering 
matching placebo for 30 days and ranolazine 2x1000mg for 150 days. Subjects will have ECG and 
Holter recording at baseline, 1 month, 3-7 days after start of ranolazine, 2 month, and 6-month time 
points. At baseline, laboratory test will be performed to determine creatinine clearance, unless this 
result is already available if subject participated in the Study 1. Data regarding possible side effects 
of the drug as well as clinical events will be collected.
Enrollment in Study 2 will be limited to subjects with mutations for which the effect of ranolazine 
has been studied, and the data analyzed for safety, in either Study 1 or in our prior IV ranolazine 
drug study.  In practice this will involve enrolling one subject with an unstudied mutation into Study 

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1, testing the effects and safety of ranolazine on that mutation, and then moving on to enrolling that 
subject or other subjects with that specific mutation into Study 2.
Exam One has been contracted by the University of Rochester to perform home visits for 
administering ECGs and Holter monitors and to collect baseline blood specimens (for creatinine 
testing for all participants and for pregnancy testing for women of reproductive age) for research 
purposes.  All Exam One personnel have been trained in HIPAA compliance and are bound by the 
privacy practices of that company.  NIH human subject protection training will be required of all 
personnel who have contact with study participants. Study-specific procedural training will be 
provided, including specific instructions for lead placement for ECGs and Holters and for reporting 
of safety concerns.  Exam One can insure via their event management system that every examiner 
that performs services for this study has their standard training, NIH human subject protection 
training, and reviews protocols specific to the related assessment services.  A schedule of regular 
conference calls and a reporting system will be established for monitoring of study visits including 
any problems encountered.
 
The study will remain under scrutiny of the Data Safety Monitoring Board (Sabu Thomas, M.D. 585-
275-2475).  The Clinical Principal Investigator or representative will monitor the safety of the 
subject as well as any adverse events (Clinical P.I. Spencer Rosero, M.D. 585-275-4775).  
All ECGs and Holter recordings will be read blindly by central ECG Core Lab.  
Shortening of QTc observed at 2 and 6 months in comparison to baseline and 1-month time points 
will be the primary endpoint of the study. We will also evaluate long-term effect of ranolazine on 
several novel ECG parameters reflecting repolarization morphology and dynamics, as mentioned 
above.  
It is hypothesized that the difference between the 2-month and baseline ECG as well as the 6-
month and baseline ECG will be significantly different compared to the difference between the 1-
month (placebo) ECG and baseline.  Assuming a 40ms standard deviation in studied LQT3 
patients, sample size of 30 patients will provide 90% power to detect at least 18 ms difference in 
QTc between ranolazine and baseline. It will provide 98% power if the difference is in the order of 
40 ms as observed in our prior study.   
DATA MANAGEMENT.  Data will be entered into our web-based, password-protected clinical data-
management system.   This data will be verified via a system of checks, queries and ranges to 
ensure accuracy. Some data checks are implemented during data entry, preventing some errors 
altogether and immediately prompting for resolution of other errors.  Other checks are performed 
daily and weekly yielding high quality data within strict timelines.
DATA ANALYSIS.  Routine patient clinical data, data forms, questionnaires, consent forms and 
any other correspondence will be maintained using our existing data management systems in the 
Heart Research Follow-up Program
DATA STORAGE.  All study documents will be kept in a locked file room.  All computers are 
password-protected and kept in a locked area.
IV. RISK/BENEFIT ASSESSMENT 
Risk Category. This research is of greater than minimal risk. 
Potential Risk. The potential risks associated with the study are: 

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Ranolazine
The most commonly reported side effects in both healthy volunteers and patients have been: 
dizziness, headache, nausea, fatigue, constipation, indigestion, peripheral leg or ankle swelling, 
chest pain, coughing, breathlessness, palpitations, abdominal pain, vomiting, and dry mouth.
The following serious side effects may be related to ranolazine and have occurred in people with 
heart disease: heart attack; fatal or life-threatening heart beat or rhythm (irregular, fast or slow); 
fainting or loss of consciousness, a spinning sensation; sweating; ringing/buzzing noise in the ear; 
abnormal lab tests related to the kidney, and involuntary muscle contractions. Higher doses of 
ranolazine have caused low blood pressure particularly when people rise from a lying or sitting 
position. Fainting, changes in vision, a burning or tingling feeling – in the legs, drowsiness, and 
confusion and disorientation have also been reported.
If the subject is taking digoxin, he will be instructed to decrease the dose of digoxin in half since 
ranolazine increases the level of digoxin in blood. The increase of blood level of digoxin might be 
associated with cardiac arrhythmias.
Electrocardiogram (ECG) & Holter Monitor Risks and Discomforts
There may be skin irritation from the gel or adhesive used to apply the electrodes.
Echocardiogram (ECHO)
Subjects will undergo two separate echocardiograms. Images will be digitized and stored
to optical disk for subsequent analysis off-line. The following views will be obtained:
•
Parasternal long axis (including zoom frame of LV outflow tract)
•
Parasternal short axis (papillary muscle level)
•
Apical 4-chamber
•
Apical 2-chamber
•
Apical 3-chamber
•
Color Tissue Doppler imaging in the apical 4, 2, and 3 chamber views, (one 3-
beat loop of each)
•
Pulsed-wave Doppler of mitral inflow from apical 4-chamber view
•
Pulsed-wave Doppler of pulmonary venous flow from apical 4-chamber view
•
Pulsed wave Doppler from the L VOT
•
Tissue Doppler tissue imaging of septal and lateral mitral annulus from apical
4-chamber view
The following parameters will be measured or calculated at each time point:
•
LV End-diastolic Volume/Index
•
LV End-systolic Volume/Index
•
Calculated L VEF = 1- LV End-systolic Volume/ LV End-diastolic Volume
ratio
•
LV Stroke Volume = LV Diastolic Volume - LV Systolic Volume
•
Visually estimated LV Ejection fraction
•
L V Global Strain (calculated from 2D strain images)
•
Myocardial Performance Index
•
Mitral E wave Velocity
•
Mitral A wave Velocity
•
Mitral E/ A ratio

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•
Mitral E wave deceleration time
•
LV Isovolumic Relaxation Time (LV IVRT)
•
Mitral Annular Velocity (Myocardial relaxation velocity (E')
•
Mitral E wave Velocity/Mitral Annular Velocity ratio (EIE')
•
Systolic Annular Velocity
•
Pulmonary Vein S wave Velocity
•
Pulmonary Vein D wave Velocity
•
Pulmonary Vein S wave/ D wave velocity ratio (SID)
•
LV Dyssynchrony score (ms)
An echocardiogram will be performed at the following time points:
•
Day 1
•
Day 2:  4-6 hours after ranolazine dose is given
Intravenous (IV) Line
An intravenous (IV) line will be inserted for the purpose of blood sampling.  There may be some 
minor discomfort, pain, redness, bruising or bleeding at the site of the needle puncture. 
Pregnancy
There may be risks to the mother (or to an embryo, fetus or nursing infant) that are currently 
unknown or unanticipated. The subject must use a medically approved method of birth control, (i.e.:  
oral contraceptives; barrier method (condom AND diaphragm combined with spermicide.  A 
diaphragm or condom alone is not considered adequate contraception.) implants; injections; IUD or 
abstinence).
Risks associated with Home Visits
Any evidence of child abuse or neglect or suspicion that a person may present a danger of harm to 
others or self that is observed during home visits is required to be reported to the appropriate 
authorities.
Potential Benefits to the Subjects. The subject may or may not benefit from this study.
Alternatives to Participation. The alternative is not to participate.
V. SUBJECT IDENTIFICATION, RECRUITMENT AND CONSENT/ASSENT 
Method Of Subject Identification And Recruitment. Most subjects will be recruited from the 
Long QT Registry at the University of Rochester.
Process of Consent. Study 1:  Subjects will be consented in the GCRC by a study team member.  
Study 2:   If the subject participated in Study 1, he may be consented into Study 2 before he is 
discharged.  Otherwise, subjects will be consented by a team member at/near the subject’s home 
or by mail.  
In both studies, the subject will sign two identical consent forms.  He will retain one for his records 
and the other will be kept in the locked file-room in the Heart Research Follow-Up Program.
Costs to the Subject. Study 1:  The subject may incur some nominal costs in his travels to the 
University of Rochester.  These costs may include:  driving to the airport, parking, meals on 
traveling days.  He will be reimbursed for these expenses upon supplying receipts.  Airline tickets, 

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possible hotel stay while in Rochester, and travel to/from the Rochester International Airport as well 
as travel from the hotel to/from the University of Rochester will be provided.  Study 2:  There are no 
expected costs to the subject.
Payment for Participation. Study 1:  $300/day ($600 maximum); Study 2:  $200/month ($1200 
maximum)
REFERENCES
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2.
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