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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT01607073
Other study ID # IND 113666
Secondary ID
Status Completed
Phase Phase 2
First received
Last updated
Start date April 2012
Est. completion date January 2015

Study information

Verified date March 2021
Source Gillette Children's Specialty Healthcare
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

This study will assess how well the drug verapamil can improve control of seizures and dysautonomia symptoms in children and young adults diagnosed with Dravet syndrome. The safety of verapamil when given with all concomitant medications will also be assessed.


Description:

Dravet syndrome (DS) is a devastating form of pediatric seizure disorder (epilepsy), often related to abnormalities of one of the genes that controls sodium channel function in the brain (SCN1A). Most children with DS experience continued seizures even with optimal treatment of currently available anti-seizure therapies [1]. Many of these seizures are prolonged, and can be life threatening. This pilot study will assess the efficacy of verapamil in improving control of seizures in children and young adults DS. This will be done by adding verapamil as open label adjunctive therapy to medications already being given. Investigators will assess the effect of verapamil therapy on seizure control and on signs of autonomic dysfunction observable to the parents/guardians. Signs of autonomic function include body temperature regulation, sweating, heart rate, pupil size, and flushing of the skin. Iannetti, et al reported treating 2 children with clinical DS (one with an SCN1A mutation) with verapamil as adjunctive therapy [2]. Both children had a positive clinical response persisting for a number of months. No adverse effects were noted. We have treated an additional 4 children with DS with verapamil. There have been no significant adverse effects; 3 of 4 have experienced improved seizure control for months also. Verapamil has been shown to affect autonomic tone in patients with cardiac disorders (eg. high blood pressure, heart attack). It alters the balance between parts of the autonomic nervous system's function (called sympathetic and parasympathetic function) with a shift toward decreased sympathetic tone and increased parasympathetic (vagus nerve) tone [8, 9, 10]. Verapamil is used as an effective agent to treat certain types of autonomic headaches in both adults and children. In cluster headaches, autonomic symptoms (tearing, nasal congestion, facial sweating, papillary constriction) are prominent; verapamil is an accepted treatment [11, 12]. Intense emotion triggers seizures in a subset of children with DS. Modulation of autonomic function is likely an integral part of seizure threshold in those so affected. Children with DS have a higher rate of signs of abnormal autonomic function than do controls [13]. Cardiac autonomic control is also altered in these children, with a shift in the balance between sympathetic (relatively overactive) and parasympathetic (relatively less active) tone [14]. Similar findings have been identified in adults with intractable epilepsy and children with partial epilepsy [15, 16, 17]. Verapamil's action in stabilizing the balance of sympathetic and parasympathetic tone may play a role altering autonomic tone abnormalities in children with DS as well. This may be a part of the mechanism that leads to improved seizure control. Verapamil has been in clinical use for ~ 25 years. The FDA has granted an Investigational New Drug approval for use of this medication in this population of children and young adults. Investigators propose to add it to the patient's existing medications, and evaluate potential improvement in seizure control. Potential side effects will be screened. Investigators will monitor liver function with blood tests as well as concentrations of anti-seizure medications. Verapamil and nor-verapamil levels will be assessed twice also. Testing of heart rhythm (EKG) will be done before the study starts and twice more during the study.


Recruitment information / eligibility

Status Completed
Enrollment 2
Est. completion date January 2015
Est. primary completion date January 2015
Accepts healthy volunteers No
Gender All
Age group 2 Years to 25 Years
Eligibility Inclusion Criteria: - 2 to 25 years old - Onset of seizures in first year of life - seizure type usually generalized tonic-clonic, clonic, or hemiclonic, often prolonged (>10 minutes) - myoclonic jerks/myoclonic seizures - history of normal development at seizure onset with subsequent developmental delay or regression which occurs after seizure onset - presence of documented abnormality on the SCN1A gene - medically intractable epilepsy: must have been on at least 2 prior antiepileptic medications without adequate control of epilepsy - subject is capable of giving informed consent (or assent if possible) or has an acceptable surrogate capable of giving informed consent on the subject's behalf Exclusion Criteria: - use of clonidine, propranolol, carbamazepine, oxcarbazine, stiripentol, lamotrigine, or cyclosporine - Abnormalities of cardiac conduction or rhythm (excluding sinus arrhythmia) on screening EKG - significant use of grapefruit juice - ketogenic diet - pregnancy

Study Design


Related Conditions & MeSH terms


Intervention

Drug:
Verapamil
Verapamil will be prepared as a solution. A 50mg/ml oral suspension may be made with immediate release tablets and either a 1:1 mixture of Ora-Sweet and Ora-Plus or a 1:1 mixture of Ora-Sweet SF and Ora-Plus will be used. Children will start on a 4 weeks titration period: Week 1: 1mg/kg/day divided BID Week 2: 2mg/kg/day divided BID or TID Week 3: 3mg/kg/day divided BID or TID Week 4: 4mg/kg/day divided TID In event of adverse events, and in consultation with the family and treating physician, the dosage may be decreased to 2mg/kg/day and remain at that dose for the remainder of the study.

Locations

Country Name City State
United States Children's Memorial Hospital Chicago Illinois
United States Mary Hitchcock Memorial Hospital Lebanon New Hampshire
United States Mayo Clinic Rochester Minnesota
United States Gillette Children's Specialty Healthcare Saint Paul Minnesota

Sponsors (4)

Lead Sponsor Collaborator
Gillette Children's Specialty Healthcare Ann & Robert H Lurie Children's Hospital of Chicago, Dartmouth-Hitchcock Medical Center, Mayo Clinic

Country where clinical trial is conducted

United States, 

References & Publications (36)

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Delogu AB, Spinelli A, Battaglia D, Dravet C, De Nisco A, Saracino A, Romagnoli C, Lanza GA, Crea F. Electrical and autonomic cardiac function in patients with Dravet syndrome. Epilepsia. 2011 Apr;52 Suppl 2:55-8. doi: 10.1111/j.1528-1167.2011.03003.x. — View Citation

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Giraud C, Treluyer JM, Rey E, Chiron C, Vincent J, Pons G, Tran A. In vitro and in vivo inhibitory effect of stiripentol on clobazam metabolism. Drug Metab Dispos. 2006 Apr;34(4):608-11. Epub 2006 Jan 13. — View Citation

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Iannetti P, Parisi P, Spalice A, Ruggieri M, Zara F. Addition of verapamil in the treatment of severe myoclonic epilepsy in infancy. Epilepsy Res. 2009 Jul;85(1):89-95. doi: 10.1016/j.eplepsyres.2009.02.014. Epub 2009 Mar 20. — View Citation

Inoue Y, Ohtsuka Y, Oguni H, Tohyama J, Baba H, Fukushima K, Ohtani H, Takahashi Y, Ikeda S. Stiripentol open study in Japanese patients with Dravet syndrome. Epilepsia. 2009 Nov;50(11):2362-8. doi: 10.1111/j.1528-1167.2009.02179.x. Epub 2009 Jun 22. — View Citation

Jawad S, Richens A, Oxley J. Single dose pharmacokinetic study of clobazam in normal volunteers and epileptic patients. Br J Clin Pharmacol. 1984 Dec;18(6):873-7. — View Citation

Kantola T, Kivistö KT, Neuvonen PJ. Erythromycin and verapamil considerably increase serum simvastatin and simvastatin acid concentrations. Clin Pharmacol Ther. 1998 Aug;64(2):177-82. — View Citation

Lamberg TS, Kivistö KT, Neuvonen PJ. Effects of verapamil and diltiazem on the pharmacokinetics and pharmacodynamics of buspirone. Clin Pharmacol Ther. 1998 Jun;63(6):640-5. — View Citation

Lampl C. Childhood-onset cluster headache. Pediatr Neurol. 2002 Aug;27(2):138-40. — View Citation

Lefrandt JD, Heitmann J, Sevre K, Castellano M, Hausberg M, Fallon M, Fluckiger L, Urbigkeit A, Rostrup M, Agabiti-Rosei E, Rahn KH, Murphy M, Zannad F, de Kam PJ, van Roon AM, Smit AJ. The effects of dihydropyridine and phenylalkylamine calcium antagonist classes on autonomic function in hypertension: the VAMPHYRE study. Am J Hypertens. 2001 Nov;14(11 Pt 1):1083-9. — View Citation

May A, Leone M, Afra J, Linde M, Sándor PS, Evers S, Goadsby PJ; EFNS Task Force. EFNS guidelines on the treatment of cluster headache and other trigeminal-autonomic cephalalgias. Eur J Neurol. 2006 Oct;13(10):1066-77. — View Citation

Motte J, Trevathan E, Arvidsson JF, Barrera MN, Mullens EL, Manasco P. Lamotrigine for generalized seizures associated with the Lennox-Gastaut syndrome. Lamictal Lennox-Gastaut Study Group. N Engl J Med. 1997 Dec 18;337(25):1807-12. Erratum in: N Engl J Med 1998 Sep 17;339(12):851-2. — View Citation

Mukherjee S, Tripathi M, Chandra PS, Yadav R, Choudhary N, Sagar R, Bhore R, Pandey RM, Deepak KK. Cardiovascular autonomic functions in well-controlled and intractable partial epilepsies. Epilepsy Res. 2009 Aug;85(2-3):261-9. doi: 10.1016/j.eplepsyres.2009.03.021. Epub 2009 May 5. — View Citation

Neels HM, Sierens AC, Naelaerts K, Scharpé SL, Hatfield GM, Lambert WE. Therapeutic drug monitoring of old and newer anti-epileptic drugs. Clin Chem Lab Med. 2004;42(11):1228-55. Review. — View Citation

Petretta M, Canonico V, Madrid A, Mickiewicz M, Spinelli L, Marciano F, Vetrano A, Signorini A, Bonaduce D. Comparison of verapamil versus felodipine on heart rate variability in hypertensive patients. J Hypertens. 1999 May;17(5):707-13. — View Citation

Porter CJ, Garson A Jr, Gillette PC. Verapamil: an effective calcium blocking agent for pediatric patients. Pediatrics. 1983 May;71(5):748-55. Review. — View Citation

Renton KW. Inhibition of hepatic microsomal drug metabolism by the calcium channel blockers diltiazem and verapamil. Biochem Pharmacol. 1985 Jul 15;34(14):2549-53. — View Citation

Sapire DW, O'Riordan AC, Black IF. Safety and efficacy of short- and long-term verapamil therapy in children with tachycardia. Am J Cardiol. 1981 Dec;48(6):1091-7. — View Citation

Schwartz JB, Keefe DL, Kirsten E, Kates RE, Harrison DC. Prolongation of verapamil elimination kinetics during chronic oral administration. Am Heart J. 1982 Aug;104(2 Pt 1):198-203. — View Citation

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Skluzacek JV, Watts KP, Parsy O, Wical B, Camfield P. Dravet syndrome and parent associations: the IDEA League experience with comorbid conditions, mortality, management, adaptation, and grief. Epilepsia. 2011 Apr;52 Suppl 2:95-101. doi: 10.1111/j.1528-1167.2011.03012.x. — View Citation

Stringer KA, Mallet J, Clarke M, Lindenfeld JA. The effect of three different oral doses of verapamil on the disposition of theophylline. Eur J Clin Pharmacol. 1992;43(1):35-8. — View Citation

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* Note: There are 36 references in allClick here to view all references

Outcome

Type Measure Description Time frame Safety issue
Primary Change in Number of General Tonic-clonic Seizures From Week 8 (Baseline) Visit to Week 12 Visit The primary study endpoint is the change in number of seizures from baseline. Since we only had one participant finish the study, the endpoint was changed to Week 12 visit. Participants were on verapamil for 4 weeks at Week 12. Week 8 (baseline) to Week 12
Secondary Change in Number of Myoclonic Seizures From Week 8 (Baseline) to Week 12 The secondary outcome is the change in number of myoclonic seizures between baseline Week 8 visit and Week 12 visit. Week 8 (baseline) to Week 12
Secondary Change in Number of Absence Seizures From Week 8 (Baseline) to Week 12 The secondary outcome measure is the change in number of absence seizures from Week 8 (Baseline) to Week 12 Week 8 to Week 12
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