Clinical trial NCT01648205
Conditions: Long QT Syndrome
Keywords: ranolazine clinical trial
Sponsor: University of Rochester
Start date: 2012-09-01; Completion date: 2018-07-20
Enrollment: 25 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

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.

Arms: arm 1: Placebo for 1 month and Ranolazine for 5 months.
Interventions: intervention 1: Placebo intervention 2: Ranolazine
Intervention descriptions: intervention 1: Matching Placebo will be given for first month. intervention 2: Patients will receive ranolazine 1000mg bid for subsequent 5 months.

Protocol documents:
Prot_SAP_000.pdf: 
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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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10.24.16 RSRB # 40975
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
1.
Moss AJ, Schwartz PJ, Crampton RS, et al. The long QT syndrome. Prospective longitudinal 
study of 328 families. Circulation 1991;84:1136-44.
2.
Zareba W. Cygankiewicz I. Long QT syndrome and short QT syndrome. Progr Cardiovasc Dis 
3.
Zareba W, Moss AJ, Schwartz PJ, et al. Influence of genotype on the clinical course of the long-
QT syndrome. International Long-QT Syndrome Registry Research Group. N Engl J Med 
1998;339:960-5.
4.
Priori SG, Schwartz PJ,Napolitano C, et al. Risk stratification in the long-QT syndrome. N Engl 
J Med. 2003;348:1866-74
5.
Antzelevitch C, Shimizu W. Cellular mechanisms underlying the long QT syndrome: Curr Opin 
Cardiol 2002;17:43–51
6.
El Sherif N, Caref EB, Chinushi M et al. Mechanism of arrhythmogenicity of the short-long 
cardiac sequence that precedes ventricular tachyarrhythmias in the long QT syndrome. Journal 
of the American College of Cardiology. 1999;33:1415-1423.
7.
Splawski I, Thimoty, K, Tateyama M, et al. Variant of SCN5A sodium channel impicated in risk 
of cardiac arrhythmia. Science 2002;297:1333-6
8.
Tester DJ, Will ML, Haglund CM, Ackerman MJ. Compendium of cardiac channel mutations in 
541 consecutive unrelated patients referred for long QT syndrome genetic testing. Heart 
Rhythm 2005;2:507-17.
9.
Couderc JP, Zareba W, Burattini L, Moss AJ. Beat-to-beat repolarization variability in LQTS 
patients with SCN5A sodium channel gene mutation. Pacing Clin Electrophysiol. 1999;22:1581-
1592
10. Zareba W, Sattari MN, Rosero S, et al. Altered atrial, atrio-ventricular, and ventricular 
conduction in patients with the long QT syndrome caused by the KPQ SCN5A sodium channel 
gene mutation. Am J Cardiol 2001;88:1311-15
11. Benhorin J, Taub R, Goldmit M, et al. Effects of flecainide in patients with new SCN5A 
mutation: mutation-specific therapy for long-QT syndrome? Circulation 2000;101:1698-706.
12. Schwartz PJ, Priori SG, Spazzolini C, et al. Genotype-phenotype correlation in the long-QT 
syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation 2001;10389–95.
13. Zareba W, Moss AJ, Locati EH et al. Modulating effects of age and gender on the clinical 
course of long QT syndrome by genotype. J Am Coll Cardiol 2003;42:103-9.
14. Goldenberg I, Zareba W, Moss AJ. Long QT Syndrome. Curr Probl Cardiol 2008;33:629-94.
15. Moss AJ, Zareba W, Hall WJ, et al. Effectiveness and limitations of beta-blocker therapy in 
congenital long QT syndrome. Circulation 2000;101:616-623
16. Schwartz PJ, Spazzolini C, Crotti L et al. All LQT3 patients need an ICD: true or false? Heart 
Rhythm. 2009;6:113-120.
17. Schwartz PJ, Priori SG, Locati EH et al. 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;92:3381-3386.


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18. Moss AJ, Windle JR, Hall WJ, et al. Safety and efficacy of flecainide in subjects with long QT 3 
Syndrome (DeltaKPQ mutation): A randomized, double-blind, placebo-controlled clinical trial. 
Ann Noninvasive Electrocardiol. 2005;4:59-66.
19. Priori SG, Napolitano C, Schwartz PJ et al. The elusive link between LQT3 and Brugada 
syndrome: the role of flecainide challenge. Circulation. 2000;102:945-947.
20. Moss AJ, Zareba W, Schwarz KQ et al. Ranolazine shortens repolarization in patients with 
sustained inward sodium current due to type-3 long-QT syndrome. Journal of Cardiovascular 
Electrophysiology. 2008;19:1289-1293.
21. Antzelevitch C, Belardinelli L, Zygmunt AC, et al. Electrophysiologic effects of ranolazine: a 
novel anti-anginal agent with antiarrhythmic properties. Circulation 2004;110:904–910.
22. Rivolta I, Clancy CE, Tateyama M, et al. A novel SCN5A mutation associated with long QT-3: 
altered inactivation kinetics and channel dysfunction. Physiological Genomics. 2002;10:191-
197.
23. Rajamani S, El-Bizri N, Shryock JC, et al. Use-dependent block of cardiac late Na(+) current by 
ranolazine. Heart Rhythm 2009;6:1625-31.
 

ICF_001.pdf: 
265 Crittenden Blvd., CU 420653. Rochester, NY 14642-0653 
      RSRB# 40975           08.15.12 
585.275.5391 · 585.273.5283 fax · www.urmc.rochester.edu 
 
SCHOOL OF MEDICINE & DENTISTRY                                                                                
 
Heart Research Follow-Up Program 
 
LQTS Study Phone Numbers: 
585-276-0016 · Toll free 888-543-3469 
 
 
 
 
           MEDICINE of THE HIGHEST ORDER
  
 
 
 
 
 
 
 
 
 
 
CONSENT FORM 
 
Title of Study:  Ranolazine in LQT3 (Study 2, Long Term) 
Principal Investigator:  Wojciech Zareba, M.D., PhD  
Clinical Principal Investigator:  Spencer Rosero, M.D. 
 
This consent form describes a research study, what you may expect if you decide to 
take part and important information to help you make your decision.  Please read 
this form carefully. 
 
The study staff will explain this study to you. Please ask questions about anything that is 
not clear before you agree to participate. You may take this consent form home to think 
about and discuss with family or friends. 
 
 Being in this study is voluntary – it is your choice. 
 If you join this study, you can change your mind and stop at any time. 
 If you choose not to take part, your routine medical care will not be changed in any way.   
 There are risks from participating and you should understand what these mean to you. 
 
Introduction 
 
You are being asked to take part in this study because you have been found to have a 
genetic mutation that causes Long QT Syndrome. The effect of ranolazine has been 
studied on one or more individuals with the same mutation that you have through our 
Ranolazine in LQT3 (Study 1, Short Term) research study and or/ in a prior study of 
intravenous ranolazine done here in the past, and the data has been analyzed for safety. 
 
If you currently take a beta-blocker, that medication will not be changed. 
  
This study is being conducted by Wojciech Zareba, M.D., PhD, and Spencer Rosero, M.D. 
of the University of Rochester’s Department of Cardiology. 
 
Purpose of Study 
 
Research is designed to benefit society by gaining new knowledge. The purpose of the 
study is to determine the benefits of a medicine called ranolazine (known as Ranexa).   
Ranolazine is thought to be an effective way to protect the heart against arrhythmias that 
are common in Long QT Syndrome.  Early studies have shown ranolazine to shorten the 
QT interval in LQT3. 
 
Ranolazine (known as Ranexa) has been approved by the United States Food and Drug 
Administration (FDA) for the treatment of patients with chronic angina (pain or discomfort in 
the chest, jaw, shoulder, back, or arm that keeps coming back), a symptom of a heart 


265 Crittenden Blvd., CU 420653. Rochester, NY 14642-0653 
      RSRB# 40975           08.15.12 
585.275.5391 · 585.273.5283 fax · www.urmc.rochester.edu 
 
problem called coronary heart disease.  It has not been approved for the prevention and 
treatment of long QT syndrome.  
 
Ranolazine may improve the heart beat rhythm, and the level of oxygen in cells that are not 
receiving enough oxygen, which happens in patients with heart disease. Its use in this 
study is for testing purposes only. 
 
Background 
 
Long QT Syndrome (LQTS) is a genetic disorder characterized by prolongation of the QT 
wave in the electrocardiogram (ECG).  People with LQTS are at risk of developing an 
arrhythmia that may cause dizziness, fainting, seizure or even sudden death.  There are 
different types of LQTS.  People with Long QT-3 (LQT3) are at a greater risk of developing 
sudden death during their first arrhythmic event than Long QT-1 (LQT1) and Long QT-2 
(LQT2). 
 
Schedule of Procedures 
 
The University of Rochester has contracted with a company called Examination 
Management Services, Inc. (EMSI) to do home visits for administering ECGs and Holter 
monitors (and to collect a baseline blood sample from all participants and a blood specimen 
for pregnancy testing from female participants) for this study. 
 
If you decide to take part in this research, a study representative will visit you to perform the 
following: 
 
 An ECG and 24-hour Holter recording will be done.  If you are female, a pregnancy 
test will be done. If you did not have a blood test for kidney function recently done, a 
blood sample (one teaspoon) will be drawn.  
 The same (with the exception of the blood test and pregnancy test) will be done at 
the one-month, 5 weeks, two-month and six-month intervals. 
 
A supply of study drug will be shipped to you from the University of Rochester at the 
beginning of the study and instructions about when to begin taking study drug will be 
provided by the study nurse after baseline laboratory results have been reviewed. On the 
first day, you will be given a supply of study medication or a placebo (placebo is a drug that 
looks like the study medication but has no active ingredients).  During the six month study 
you will be taking both ranolazine and placebo, but you will not be told which you are on at 
any given time. 
 
Description of Procedures 
 
Electrocardiogram (ECG) & Holter Monitor  
You will have an electrocardiogram (ECG) performed and recorded.  An ECG is an 
electrical recording of your heart rate and rhythm.  You will be asked to lie down and 
patches called electrodes connected to wires are affixed to your body. This requires 
cleaning the site where the electrode is attached, and if necessary, shaving or clipping of 
hair may occur. No electricity is sent through your body, and there is no possibility of 
receiving an electrical shock.  You will be asked to remain still while the test is performed. 
The results will be recorded on graph paper. 


265 Crittenden Blvd., CU 420653. Rochester, NY 14642-0653 
      RSRB# 40975           08.15.12 
585.275.5391 · 585.273.5283 fax · www.urmc.rochester.edu 
 
A Holter monitor records electrical signals from the heart via a series of electrodes attached 
to your chest. These electrodes are connected to a small piece of equipment about the size 
of a cell phone that is then attached to your belt or worn with a shoulder strap, and is 
responsible for keeping a log of your heart’s electrical activity throughout the recording 
period.  No electricity is sent through your body, and there is no possibility of receiving an 
electrical shock. 
 
Blood Test 
At your first visit, you will have blood drawn (1 teaspoon) for testing your kidney function. 
 
Pregnancy Test 
If you are female and are able to have children, a pregnancy test will be performed to make 
sure that you are not pregnant at the start of the study. This test will be done from a blood 
specimen (1 teaspoon). 
Information about your participation in this study will be included in your electronic medical 
record. 
 
Number of Subjects 
 
We expect 30 subjects to participate in this study.   
 
Duration of the Study 
 
Your participation in the study will last approximately 6 months. 
 
Risks of Participation  
 
Risk of Ranolazine  
 
Ranolazine has been studied in both healthy volunteers and people with heart disease. The 
side effects are discussed below.  Common side effects have usually gone away after the  
drug was stopped, and no long-term side effects have been reported. There may be side 
effects that we don’t know about at this time. 
 
We will ask you to stop taking the drug if the side effects become severe. The most 
commonly reported side effects in both healthy volunteers and patients have been: 
dizziness, headache, nausea, fatigue, constipation, indigestion, leg or ankle swelling, chest 
pain, coughing, breathlessness, palpitations (awareness of a racing heart beat), 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.  
 
 
 


265 Crittenden Blvd., CU 420653. Rochester, NY 14642-0653 
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585.275.5391 · 585.273.5283 fax · www.urmc.rochester.edu 
 
Ranolazine has also caused small changes in the electrical activity of the heart, as 
measured by the ECG.  These effects, known as “QT prolongation,” appeared as small 
changes in the ECG readings, but were not felt by the study participants taking ranolazine.  
Higher blood levels of ranolazine increased these effects.  Other drugs that cause these 
effects have also caused a serious disturbance of the heart rhythm and sudden death, in 
rare cases.  This has not happened in previous studies with ranolazine.  Early studies have 
shown ranolazine to shorten the QT value in LQT3 patients. 
 
If you are taking digoxin, you 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. 
 
If you are taking simvastatin, you will be instructed to limit the dose of simvastatin to 20 mg 
once daily as the plasma levels of simvastatin are increased when ranolazine is taken 
together with this drug. 
 
If, during the study you would require treatment with moderate CYP3A inhibitors you should 
reduce your dosage of the drug to 500 mg twice a day (instead of 1000 mg twice a day), 
including: 
 for your heart: verapamil, diltiazem  
 for nausea and vomiting: aprepitant (Emend®)  
 for bacterial infection: erythromycin 
 for fungus infection: fluconazole  (Diflucan®)  
 grapefruit juice or grapefruit-containing products  
 
 If, during the study you would require treatment with strong CYP3A inhibitors or CYP3A 
inducers, your study drug would need to be stopped for the period of treatment with these 
drugs including: 
 for fungus infection: ketoconazole (Nizoral®), itraconazole (Sporanox®, Onmel) 
 for infection: clarithromycin (Biaxin®) 
 for depression: nefazodone 
 for HIV: nelfinavir (Viracept®), ritonavir (Norvir®), lopinavir and ritonavir (Kaletra®) 
indinavir (Crixivan®), saquinavir (Invirase®) 
 for tuberculosis (TB): rifampin (Rifadin®), rifabutin (Mycobutin®), rifapentin (Priftin®) 
 for seizures: phenobarbital, phenytoin (Phenytek®, Dilantin® Dilantin-125®), 
carbamazepine (Tegretol®), 
 St. John’s wort (Hypericum perforatum) 
 
If, during the study you develop liver problems and/or scarring (cirrhosis) of your liver your 
study drug would need to be stopped. If, during the study you would require treatment with 
CYP2D6 substrates, such as tricyclic antidepressants and antipsychotics, the dose of study 
drug may need to be adjusted, as these drugs may increase your exposure to study drug. 
 
Please inform us right away if you have any side effects or unusual health events, even if 
they don't disrupt your daily life, regardless of whether you think the study medication 
caused them or not. 
 
 
 
 


265 Crittenden Blvd., CU 420653. Rochester, NY 14642-0653 
      RSRB# 40975           08.15.12 
585.275.5391 · 585.273.5283 fax · www.urmc.rochester.edu 
 
 
Risk of Electrocardiogram (ECG) and Holter Monitor 
There is minimal risk from ECG monitoring and Holter monitoring. The sticky patches 
(electrodes) placed on your skin detect only the electrical signals from your heart. No 
electricity is sent through your body, and there is no possibility of receiving an electric 
shock. There may be skin irritation (redness and itchiness) from the electrode gel or 
adhesive. 
 
Pregnancy 
 
There may be risks to the mother (or to an embryo, fetus or nursing infant) that are 
currently unknown or unanticipated. If you are a woman capable of having children, you 
must use a medically approved method of birth control, i.e., oral contraceptives; barrier 
method (condom AND diaphragm combined with spermicide); implants; injections; IUD or 
abstinence.  A diaphragm or condom alone is not considered adequate contraception. 
 
Risks associated with the Home Visits 
The researchers are required to report information reported by you, your partner, or your 
child, regarding potential child abuse or neglect.  The researcher will also report if there is a 
reasonable suspicion, based on information provided by you, your partner, or your child, 
that you may present a danger of harm to others or that you may harm yourself unless 
protective measures are taken. 
 
Potential Loss of Confidentiality:  The risk associated with this study also includes loss of 
privacy and confidentiality because we will collect data from your medical record. Protected 
health data will be kept as confidential as it can be but complete confidentiality cannot be 
assured. 
 
Compensation for Injury: 
 
If you are directly injured by the drug that is being studied, or by clinical procedures solely 
required to participate in the study, you may need to pay for treatment of your injuries, but 
you will be reimbursed for the reasonable and necessary medical expenses for such 
treatment. You will not be required to pay for emergency medical treatment provided at 
Strong Memorial Hospital or Highland Hospital. The University may seek payment for 
treating study-related injuries from your health insurer or the study sponsor. 
 
Benefits of Participation 
 
You might not benefit from being in this research study.  The potential benefit to you from 
being in this study might be identifying an effective treatment for your Long QT syndrome 
 
New Study Findings  
  
If we discover anything that might make you change your mind about continuing in the 
study, we will let you know. 
 
 
 
 
 
 


265 Crittenden Blvd., CU 420653. Rochester, NY 14642-0653 
      RSRB# 40975           08.15.12 
585.275.5391 · 585.273.5283 fax · www.urmc.rochester.edu 
 
 
Sponsor Support 
 
The University of Rochester is receiving payment from Gilead Sciences, Inc. for conducting 
this research study. 
 
Costs  
 
There will be no cost to you to participate in this study. 
 
Payments  
 
You will be paid $200/month ($1200 maximum) for participating in this study. 
 
Confidentiality of Records and Authorization to Use and Disclose Information for 
Research Purposes  
The University of Rochester makes every effort to keep the information collected from you 
private.  In order to do so, we will use coded identifiers on records we create.  Password-
protected electronic records are accessible only to authorized study personnel.  Sometimes, 
however, researchers need to share information that may identify you with people that work 
for the University, regulators or the study sponsor.   
 
If you have never received a copy of the University of Rochester Medical Center (URMC) 
and Affiliates Notice of Privacy Practices, please ask the investigator for one. 
 
What information may be used and given to others? 
The study doctor will get your personal and medical information.  For example:  
 Research records 
 Records about phone calls made as part of this research 
 Records about your study visits 
 Past and present medical records related to the study  
 Results of medical tests done as part of this study 
 
Who may use and give out information about you? 
 The study doctor and the study staff 
 URMC and Affiliates 
 
Your information may be given to:  
 The Department of Health and Human Services;  
 The University of Rochester;  
 The U.S. Food and Drug Administration (FDA) may also need to inspect study records 
at some point during the study or even after it has been completed.  In the event that 
this should occur, every effort will be made to keep identifying information about you 
private.  
 The study sponsor, Gilead Science, Inc. and its study monitors 
 Examination Management Services, Inc. (EMSI) will be given your name and contact 
information in order to schedule home visits according to our study contract 
 Other LQTS researchers collaborating with the University of Rochester 
Your name will not be provided unless required. 
 
 


265 Crittenden Blvd., CU 420653. Rochester, NY 14642-0653 
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585.275.5391 · 585.273.5283 fax · www.urmc.rochester.edu 
 
Why will this information be used and/or given to others? 
 to do the research,  
 to study the results, and  
 to see if the research was done right.   
 
If the results of this study are made public, information that identifies you will not be used. 
 
What if I decide not to give permission to use and give out my health information? 
Then you will not be able to be in this research study. 
 
May I review or copy my information? 
Yes, but only after the research is over. 
 
 
 
How long will this be permission be valid? 
This permission will last indefinitely. Records will be maintained for a minimum of seven 
years and for as long as University of Rochester researchers deem the records to be 
important to keep. 
 
May I cancel my permission to use and disclose information? 
You may cancel your permission to use and disclose your health information at any time.  
You do this by sending written notice to the study doctor.  Upon receiving the written notice, 
the study team will no longer use or disclose your health information and you will not be 
able to stay in this study.  Information that has already been gathered may need to be used 
and given to others for the validity of the study.   
 
May I withdraw from the study? 
If you withdraw your permission to be in the study, no new health information identifying 
you will be gathered after that date.  Information that has already been gathered may still be 
used and given to others.   
 
Is my health information protected after it has been given to others? 
There is a risk that your information will be given to others without your permission. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law.  This website will not include information that can identify you.  At 
most, the website will include a summary of the results.  You can search this website at any 
time. 
 
 
Contact Persons 
 
For more information concerning this research or if you believe that you have suffered a 
research related injury, emotional or physical discomfort, please contact: 
Spencer Rosero, M.D. 
School of Medicine and Dentistry 
601 Elmwood Ave, Box 679 
Rochester, New York 14642 
(585) 275-4775 


265 Crittenden Blvd., CU 420653. Rochester, NY 14642-0653 
      RSRB# 40975           08.15.12 
585.275.5391 · 585.273.5283 fax · www.urmc.rochester.edu 
 
Please contact the University of Rochester Research Subjects Review Board at 265 
Crittenden Blvd., CU 420315, Rochester, NY 14642-8315, Telephone (585) 276-0005 or 
(877) 449-4441 for the following reasons: 
 
You wish to talk to someone other than the research staff about your rights as a 
research subject; 
 
To voice concerns about the research; 
 
To provide input concerning the research process; 
 
In the event the study staff could not be reached. 
 
Voluntary Participation 
 
Taking part in this study is voluntary.  You are free not to take part or to withdraw at any 
time, for whatever reason.  No matter what decision you make, there will be no penalty or 
loss of benefit to which you are entitled.  In the event that you do withdraw from this study, 
the information you have already provided will be kept in a confidential manner. 
 
******************************************************************************************** 
 
SIGNATURE/DATES 
 
After reading and discussing the information in this consent form you should understand: 
 
Why this study is being done; 
 
What will happen during the study; 
 
Any possible risks and benefits to you; 
 
Other options you may have instead of being in the study;  
 
How your personal information will be protected; 
 
What to do if you have problems or questions about this study. 
 
Subject Consent 
I have read (or have had read to me) the contents of this consent form and have been 
encouraged to ask questions.  I have received answers to my questions.  I agree to 
participate in this study.  I have received (or will receive) a signed copy of this form for my 
records and future reference. 
 
 
 
 
 
 
 
 
 
Subject Name (Printed by Subject) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Subject 
 
 
 
 
 
Date 
 
 
Person Obtaining Consent 
I have read this form to the subject and/or the subject has read this form.  I will provide the 
subject with a signed copy of this consent form.  An explanation of the research was given 
and questions from the subject were solicited and answered to the subject’s satisfaction.  In 
my judgment, the subject has demonstrated comprehension of the information.  I have 
given the subject adequate opportunity to read the consent before signing. 
 
 
 
 
 
 
 
 
 
Name and Title (Print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Person Obtaining Consent  
 
 
Date