Diltiazem in Jervell and Lange-Nielsen Syndrome
Phase: PHASE4
Conditions: Jervell and Lange Nielsen Syndrome
Sponsor: Vanderbilt University Medical Center

Protocol Version #: 2 
 
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Protocol Date: 4/2/2024 
 
 
Diltiazem in Jervell and Lange-Nielsen Syndrome 
 
 
Principle Investigator: 
 
Prince Kannankeril, MD MSCI 
Professor of Pediatrics 
Division of Pediatric Cardiology 
Vanderbilt Center for Arrhythmia Research and Therapeutics (VanCART) 
Monroe Carell Jr. Children’s Hospital at Vanderbilt 
Vanderbilt University Medical Center 
 
Sub-Investigators: 
 
Frank A. Fish, MD  
Professor of Pediatrics and Medicine 
Vanderbilt Center for Arrhythmia Research and Therapeutics (VanCART) 
Monroe Carell Jr. Children’s Hospital at Vanderbilt 
Vanderbilt University Medical Center 
 
Dan Roden, MD 
Professor of Medicine, Pharmacology, and Biomedical Informatics 
Director, Oates Institute for Experimental Therapeutics 
Senior Vice President for Personalized Medicine 
Vanderbilt University Medical Center 
 
M. Benjamin Shoemaker, MD, MSCI 
Associate Professor of Medicine 
Division of Cardiovascular Medicine, Department of Medicine 
Vanderbilt Center for Arrhythmia Research and Therapeutics (VanCART) 
Vanderbilt University Medical Center 
 
Yuko Wada, MD 
Research Instructor, Clinical Pharmacology 
Vanderbilt Center for Arrhythmia Research and Therapeutics (VanCART) 
Vanderbilt University Medical Center 
 
 
 
 
 
 
 
 
 
 

Protocol Version #: 2 
 
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Protocol Date: 4/2/2024 
 
Table of Contents: 
 
Study Schema 
1.0 
Background 
2.0 
Rationale and Specific Aims 
3.0 
Animal Studies and Previous Human Studies 
4.0 
Inclusion/Exclusion Criteria 
5.0 
Enrollment/Randomization 
6.0 
Study Procedures 
7.0 
Risks of Investigational Agents/Devices (side effects) 
8.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk to Participants or 
Others 
9.0 
Study Withdrawal/Discontinuation 
10.0 Statistical Considerations 
11.0 Privacy/Confidentiality Issues 
12.0 Follow-up and Record Retention 

Protocol Version #: 2 
 
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Protocol Date: 4/2/2024 
 
1.0 
Background 
 
Jervell and Lange-Nielsen (JLN) syndrome is a rare inherited arrhythmia syndrome characterized by 
severe QT prolongation, bilateral sensorineural hearing loss and risk of ventricular arrhythmias and sudden 
death. It is a severe form of congenital long QT syndrome (LQTS) caused by homozygosity or compound 
heterozygosity in KCNQ1 or KCNE1, the 2 subunits of the slow delayed rectifier potassium current (IKs). Fifty 
percent of individuals with JLNS have cardiac events before 3 years of age and more than half of untreated 
children with JLN die before 15 years of age.1 
 
1. Tranebjærg L, Samson RA, Green GE. Jervell and Lange-Nielsen Syndrome. 2002 Jul 29 [updated 2017 Aug 17]. In: 
Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® 
[Internet]. Seattle (WA): University of Washington, Seattle; 1993–2024. PMID: 20301579. 
 
 
2.0 
Rationale and Specific Aims 
 
Beta-blockers are the cornerstone of therapy in LQTS, but have only partial efficacy in JLN, with 51% 
of JLN patients having arrhythmic events despite therapy and 27% on therapy who suffer cardiac arrest or 
sudden death.2 The median age at death on therapy was 8 years (IQR, 6 to 14). Additional therapies are 
clearly needed for this rare disease.  
 
Wada et al used induced pluripotent stem cell-derived cardiomyocytes from a JLN patient to 
demonstrate severe action potential duration (APD, the cellular correlate of the QT interval) prolongation.3 
While this is expected, due to genetic loss of IKs, pharmacologic block of IKs minimally prolonged APD in control 
cells. Dr. Wada has new evidence that L-type Ca channel (LTCC) current is significantly increased in JLN cells 
compared to control cells, and that the calcium channel blocker diltiazem significantly shortens APD at low 
therapeutic concentrations. Diltiazem does not block IKr at therapeutic concentrations unlike other calcium 
channel blockers like verapamil, which may prolong the QT interval. This suggests diltiazem may be a useful 
therapeutic agent specifically in JLN syndrome. Therefore, we aim to test the following hypothesis in humans: 
 
Specific Aim: To test the hypothesis that IV diltiazem acutely shortens the QT interval in 
human(s) with the Jervell-Lange Nielsen syndrome. 
 
2. Schwartz PJ, Spazzolini C, Crotti L, et al. The Jervell and Lange-Nielsen syndrome: natural history, molecular basis, and 
clinical outcome. Circulation. 2006 Feb 14;113(6):783-90. PMID: 16461811. 
3. Wada Y, Wang L, Hall LD, Yang T, Short LL, Solus JF, Glazer AM, Roden DM. The electrophysiologic effects of KCNQ1 
extend beyond expression of IKs: evidence from genetic and pharmacologic block. Cardiovasc Res. 2024 Epub ahead of 
print. PMID: 38442735. 
 
3.0 
Animal Studies and Previous Human Studies 
 
The ability of a drug to shorten the QT interval acutely has been successfully extrapolated to chronic 
beneficial effects in various forms of the long QT syndromes. Mexiletine IV shortened the QT interval by 116 
+/- 50 ms in 15 LQT3 patients, and the QT interval was also shortened by chronic oral mexiletine in a subset 
of patients.4 IV potassium was infused in 7 LQT2 patients, showing a 24% reduction in QTc (from 617 to 469 
ms),5 and chronic oral potassium shortens QTc in LQT2 patients.6 Both mexiletine and supplemental potassium 
are now used as additional therapies in LQT3 and LQT2 respectively. Here we propose a similar line of 
investigation for diltiazem in JLN syndrome.  
 
Diltiazem is an oral and parenteral nondihydropyridine calcium channel antagonist, approved by FDA 
for atrial arrhythmias, hypertension, and angina. Primarily, diltiazem inhibits the flow of calcium ions through 

Protocol Version #: 2 
 
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Protocol Date: 4/2/2024 
the LTCC into cardiac muscle during depolarization. Diltiazem is a negative inotrope and negative chronotrope. 
Along with coronary artery vasodilation, the combination decreases myocardial oxygen demand resulting in 
decreased heart rate. The standard initial IV dose is 0.25 mg/kg over 2 minutes. If needed, a repeat dose of 
0.35 mg/kg can be given after 15 minutes. No renal or hepatic dose adjustment is necessary.7  
 
4. Funasako M, Aiba T, Ishibashi K, et al. Pronounced Shortening of QT Interval With Mexiletine Infusion Test in Patients 
With Type 3 Congenital Long QT Syndrome. Circ J. 2016;80(2):340-5. PMID: 26632536. 
5. Compton SJ, Lux RL, Ramsey MR, et al. Genetically defined therapy of inherited long-QT syndrome. Correction of 
abnormal repolarization by potassium. Circulation. 1996 Sep 1;94(5):1018-22. PMID: 8790040. 
6. Etheridge SP, Compton SJ, Tristani-Firouzi M, Mason JW. A new oral therapy for long QT syndrome: long-term oral 
potassium improves repolarization in patients with HERG mutations. J Am Coll Cardiol. 2003 Nov 19;42(10):1777-82. 
PMID: 14642687. 
7. Talreja O, Cassagnol M. Diltiazem. 2023 Aug 28. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 
2024 Jan–. PMID: 30422532. 
 
4.0 
Inclusion/Exclusion Criteria 
 
Inclusion Criteria 
• 
Age > 18 years 
• 
Genetically confirmed diagnosis of Jervell and Lange-Nielsen syndrome 
o Homozygous or compound heterozygous for variants in KCNQ1/KCNE1 
o QT prolongation on ECG 
o Sensorineural hearing loss 
• 
Able to provide written informed consent 
 
Exclusion Criteria 
• 
Known hypersensitivity to diltiazem 
• 
Pregnancy 
• 
Congestive heart failure, angina, preexcitation, or COPD 
• 
Sick sinus syndrome or AV block in the absence of a pacemaker/defibrillator 
• 
Any clinically significant ongoing medical or surgical condition that might jeopardize the subject’s safety 
or interfere with the conduct of the study in the judgement of the investigator 
• 
Baseline systolic blood pressure <100 Hg or diastolic blood pressure < 60 Hg 
 
5.0 
Enrollment/Randomization 
 
Eligible subjects will be enrolled by study personnel. Due to the rarity of JLN syndrome, there are only 
2 eligible subjects currently followed at VUMC. We anticipate enrolling a single subject, but will seek approval 
for additional subjects.  
 
6.0 
Study Procedures 
 
General Approach: This is a prospective proof-of-concept trial that will enroll eligible patients with JLN and 
test the hypothesis that diltiazem IV will result in QT shortening. Subjects will be recruited by study personnel 
and will be scheduled for a single outpatient CRC visit. On the day of the visit, written informed consent will be 
obtained, a urine pregnancy test will be obtained for those subjects who are able to be pregnant, and the 
subject’s weight and blood pressure will be recorded. If baseline SBP is < 100 mm Hg or DBP < 60 mm Hg, 
the study will be terminated. Otherwise, a peripheral IV will be inserted and diltiazem doses ordered to the 
bedside. If an implanted cardiac device (pacemaker or ICD) is in place, it will be interrogated to ensure no 
recent rhythm abnormalities. Just prior to administering diltiazem, an ECG and BP will be obtained. A single 
dose of I.V. diltiazem (0.25 mg/kg over 2 minutes) will be administered with 12-lead ECG and BP obtained at 
2, 5, 7, 10, 15 and 20 minutes. If at 10 minutes there has been no QT shortening, and the SBP is stable 

Protocol Version #: 2 
 
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Protocol Date: 4/2/2024 
(<20% drop from baseline and > 100 mm Hg) a repeat dose (0.35 mg/kg) will be given at 15 minutes, with 
12-lead ECG and BP obtained at 17, 20, 22, 25, 30 and 35 minutes (see Table below). After 20 minutes (single 
dose) or 35 minutes (2 doses), the test will end and the subject will remain in the CRC monitored on 
continuous telemetry for 2 hours. Prior to CRC discharge the IV will be removed. The primary analysis will be a 
repeated measures (paired) comparison of the QTc at baseline and following diltiazem. As JLN is a very rare 
disease, we anticipate enrolling only 1 or perhaps 2 subjects, as that represents the total number of subjects 
followed at VUMC.  
 
Prior to 
Enrollment Patient recruited in clinic or by phone 
 
Patient will continue all outpatient medications prior to study. Specifically, beta-blocker 
therapy will not be stopped for this study. 
8:00 AM 
Arrive to Clinical Research Center (CRC) 
 
Sign consent form, obtain weight, BP, urine pregnancy test 
8:15 AM 
Place peripheral I.V., order diltiazem (0.25 mg/kg and 0.35 mg/kg doses) to bedside  
8:30 AM 
Interrogate Device if present 
 
Obtain baseline ECG and BP just prior to diltiazem 
 
Sample Timetable with 1 dose 
9:00 AM 
Administer IV diltiazem (0.25 mg/kg) over 2 minutes  
9:02 AM 
2 min ECG and BP 
9:05 AM 
5 min ECG and BP 
9:07 AM 
7 min ECG and BP 
9:10 AM 
10 min ECG and BP 
9:15 AM 
15 min ECG and BP 
9:20 AM 
20 min ECG and BP 
 
End test 
+2:00 hours Monitored rest period. Patient remains on the CRC 
 
 
 
Sample Timetable with 2 doses 
 
Obtain baseline ECG and BP just prior to diltiazem 
9:00 AM 
Administer IV diltiazem (0.25 mg/kg) over 2 minutes  
9:02 AM 
2 min ECG and BP 
9:05 AM 
5 min ECG and BP 
9:07 AM 
7 min ECG and BP 
9:10 AM 
10 min ECG and BP – If no QT shortening and BP stable, prepare second dose 
9:14 AM 
14 min ECG and BP 
9:15 AM 
Administer IV diltiazem (0.35 mg/kg) over 2 minutes 
9:17 AM 
17 min ECG and BP 
9:20 AM 
20 min ECG and BP 
9:22 AM 
22 min ECG and BP 
9:25 AM 
25 min ECG and BP 
9:30 AM 
30 min ECG and BP 
9:35 AM 
35 min ECG and BP 
 
End test 
+2:00 hours Monitored rest period. Patient remains on the CRC 
 
 
 
7.0 
Risks 
 
Risks associated with diltiazem include hypotension, bradycardia, dizziness, flushing, fatigue, 
headaches and edema. Many of these risks are mitigated by the IV dosing, with peak effect in 2-5 minutes 
after bolus dosing. We expect a slight decrease in blood pressure, as a decrease in SBP and DBP of 17 and 13 
mm Hg was observed in clinical studies. Hypotension was observed in 9-16% of individuals given diltiazem for 

Protocol Version #: 2 
 
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Protocol Date: 4/2/2024 
conversion of SVT or atrial fib/flutter.8,9 We expect less hypotension given to subjects in sinus rhythm. For 
safety, diltiazem will not be given if the baseline SBP is < 100 mm Hg, or DBP < 60 mmHg.  
 
8. Dougherty AH, Jackman WM, Naccarelli GV, Friday KJ, Dias VC. Acute conversion of paroxysmal 
supraventricular tachycardia with intravenous diltiazem. IV Diltiazem Study Group. Am J Cardiol. 1992 Sep 1;70(6):587-
92. PMID: 1510006. 
9. Goldenberg IF, Lewis WR, Dias VC, Heywood JT, Pedersen WR. Intravenous diltiazem for the treatment of 
patients with atrial fibrillation or flutter and moderate to severe congestive heart failure. Am J Cardiol. 1994 Nov 
1;74(9):884-9. PMID: 7977118. 
 
 
8.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk to Participants or 
Others 
 
Reporting of Adverse Events or Unanticipated Problems involving Risk to Participants or Others: 
 
Definitions of adverse events: an adverse event (AE) is any untoward medical occurrence in a patient 
or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a 
causal relationship with the treatment or study protocol. 
 
Adverse events include: 
o Worsening (change in nature, severity or frequency) of conditions present at the onset of the trial 
o Patient / subject deterioration due to the primary illness 
o Intercurrent illnesses 
o Drug interactions 
o Events related or possibly related to concomitant medications 
o Abnormal laboratory values or changes of vital signs, as well as significant shifts from baseline within 
the range of normal, which the Investigator considers clinically significant. 
 
Unexpected Adverse Drug Reaction: an unexpected Adverse Drug Reaction is an adverse reaction, the 
nature or severity of which is not consistent with the applicable product information. Definitions of serious 
adverse events or serious adverse drug reaction: during clinical investigations, adverse events may occur 
which, if suspected to be drug-related (adverse drug reactions), must be significant enough to lead to important 
changes in the way the medicinal product is developed (e.g., change in dose, population, needed monitoring, 
consent forms). This is particularly true for reactions, which, in their most severe forms, threaten life or 
function.  
 
A serious adverse event/experience (SAE) or reaction is any untoward medical occurrence that: 
 
1. results in death 
2. is life-threatening 
3. requires inpatient hospitalization or prolongation of existing hospitalization 
4. results in persistent or significant disability/ incapacity (as per reporter’s opinion) 
5. is a congenital anomaly/birth defect 
6. is another medically important condition 
7. The term "life-threatening" in the definition of "serious" refers to an event in which the patient is at risk 
of death at the time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe. 
 
Important medical conditions that may not result in death, be life-threatening, or require hospitalization may 
be considered as SAEs when, based upon appropriate medical judgment, they may jeopardize the patient or 
may require intervention to prevent one of the outcomes listed in the definition above. Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; or development of drug dependency or drug abuse.  

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Protocol Date: 4/2/2024 
 
Definition of severity of adverse events: 
 
Mild: 
 
Causing no limitation of usual activities; the subject / patient may experience slight discomfort. 
 
Moderate:  
Causing some limitation of usual activities; the subject / patient may experience annoying 
discomfort. 
 
Severe:  
Causing inability to carry out usual activities; the subject / patient may experience intolerable 
comfort or pain. 
 
Definition of adverse event causality: 
 
The Investigator will determine causality of each adverse event by using the classification criteria: 
unlikely, likely, or not assessable. 
 
Unlikely: 
The AE is considered by the Investigator to be due to a pre-existing condition, a known 
manifestation of the target disease, a recurrent condition, or is likely explained by environmental 
or diagnostic therapeutic factors or was pre-existing and did not deteriorate. 
 
Likely: 
The AE occurred during or after administration of the study treatment or a pre-existing event 
worsened within an appropriate period of time, and at least one of the following criteria is 
applicable:  
o the event could not be explained by the clinical condition or history of the subject, 
environmental or toxic factors, or other diagnostic or therapeutic measure; 
o was an expected ADR associated with study treatment or a class-labeled drug effect; 
o AE subsided or disappeared after withdrawal or dose reduction of study treatment; or 
o AE recurred after re-exposure to study treatment. 
 
Not assessable: There is insufficient or conflicting evidence for classifying the causality of the AE as likely or 
unlikely. Lack of information may apply for this situation. 
 
Note: AEs with causality 'likely' or 'not assessable' are considered to be 'possibly drug-related.' 
 
Adverse event reporting 
 
Any adverse events (AEs) will be reported to the PI within 72 hours of notification of the event. The PI 
will notify the IRB of any major adverse events. Any unanticipated problems involving risk to the participants or 
others will be discussed with the PI and IRB. Non-serious AEs and incidences of noncompliance with the 
protocol will be reported to the IRB at the time of annual review. 
 
Serious Adverse Events (SAEs) will be reported according to the following procedure: 
 
The occurrence of serious adverse events will be reported to the Investigator within 24 hours after 
notification of their occurrence. The Investigator will report SAEs to the Vanderbilt Institutional Review Board 
within 7 days of the Investigator’s notification of the event. 
 
In an unanticipated event of prolonged side effect, requiring prolongation of hospital stay, patients will 
be retained in the hospital until side effects have resolved. For minor side effects, where inpatient care is 
deemed unnecessary, follow- up will be maintained via phone or as outpatient if necessary. Patient and their 
families will be given the PI’s contact number for reporting any other effects of medication following discharge. 
 

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Protocol Date: 4/2/2024 
Any newly discovered information which may affect the subject or their caregiver’s decision to continue 
to participate in the study will be passed on to them as soon as possible. This may also result in a change to 
the consent form and review by the IRB. 
 
9.0 
Study Withdrawal/Discontinuation 
 
 
Participants may withdraw from the study at any time by informing the study staff verbally or in writing. If 
an individual withdraws their consent, we will withdraw the participant. Contact information for the PI and study 
staff will be made available to the participant upon enrollment in the consent document.  Any remaining 
biological samples and data will be destroyed. Any data or biological samples that have been used for 
research prior to their withdrawal request will not be withdrawn and destroyed. 
A participant may be withdrawn from the study by the PI if any of the following occurs: 
i. A procedural complication occurs prior to completion of the study protocol that requires the study 
procedure to be aborted, or precludes collection of study data. 
ii. The patient becomes hemodynamically unstable for any other reason that requires the study procedure to 
be cancelled prior to completion of the study protocol, or precludes the collection of study data 
iii. The primary operator determines it is in the patient’s best interest to forego completion of the study 
protocol  
 
10.0 Statistical Considerations 
 
This is a proof-of-concept study testing the hypothesis that diltiazem will shorten the QT interval in JLN 
syndrome, a very rare disease. It is likely we will recruit a single subject. Thus we anticipate simply presenting 
the heart rate, QT, and QTc before and after IV diltiazem. BP will be monitored for safety.  
 
11.0 Privacy/Confidentiality Issues 
 
We describe here mechanisms in place at Vanderbilt through IRB policy to protect against such risks; 
these apply to all studies described below.  All records are retained on password-protected computers 
accessible only to members of the study team. Computers containing these records are only connected to 
networks if they include appropriate firewalls and security measures. The identity of any individuals and their 
families are not to be revealed in any publication without their written informed consent. 
 
12.0 Follow-up and Record Retention 
 
The expected duration of this study is estimated to be 1 year. The study results will be retained for at 
least six years after the study is completed. At that time, the research information not already in the medical 
record will be destroyed.