Verapamil as Therapy for Children and Young Adults With Dravet Syndrome

NCT01607073 | Completed Phase 2 Results DMC

• 1 other identifier: IND 113666
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 4

Brief 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.

Conditions

Dravet Syndrome

Keywords

Dravet; seizures; verapamil

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (2)

• Change in Number of Myoclonic Seizures From Week 8 (Baseline) to Week 12

  Week 8 (baseline) to Week 12

• Change in Number of Absence Seizures From Week 8 (Baseline) to Week 12

  Week 8 to Week 12

Study Arms (1)

open label adjunctive add on

OTHER

open label adjunctive add on of verapamil to existing medications. dosing begins at 1 mg/kg/d and increases weekly to target of 4 mg/kg/d in divided doses (three times/day)

Drug: Verapamil

Interventions

Verapamil DRUG

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.

Also known as: Calan, Covera, Isoptin, Verelan

open label adjunctive add on

Eligibility Criteria

• Age: 2 Years - 25 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Gillette Children's Specialty Healthcare: lead
• Mayo Clinic: collaborator
• Ann & Robert H Lurie Children's Hospital of Chicago: collaborator
• Dartmouth-Hitchcock Medical Center: collaborator

Study Sites (4)

Children's Memorial Hospital

Chicago, Illinois, 60614, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Gillette Children's Specialty Healthcare

Saint Paul, Minnesota, 55101, United States

Location

Mary Hitchcock Memorial Hospital

Lebanon, New Hampshire, 03756, United States

Location

Related Publications (36)

• 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.

  PMID: 21463290 BACKGROUND

• 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.

  PMID: 21463281 BACKGROUND

• 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.

  PMID: 19303743 BACKGROUND

• 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. doi: 10.1016/0002-8703(82)90192-2.

  PMID: 7102502 BACKGROUND

• Flynn JT, Pasko DA. Calcium channel blockers: pharmacology and place in therapy of pediatric hypertension. Pediatr Nephrol. 2000 Dec;15(3-4):302-16. doi: 10.1007/s004670000480.

  PMID: 11149130 BACKGROUND

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

  PMID: 6340050 BACKGROUND

• 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. doi: 10.1016/0002-9149(81)90325-8. No abstract available.

  PMID: 6795914 BACKGROUND

• 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. doi: 10.1016/s0895-7061(01)02218-x.

  PMID: 11724204 BACKGROUND

• 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. doi: 10.1097/00004872-199917050-00016.

  PMID: 10403616 BACKGROUND

• Forslund L, Bjorkander I, Ericson M, Held C, Kahan T, Rehnqvist N, Hjemdahl P. Prognostic implications of autonomic function assessed by analyses of catecholamines and heart rate variability in stable angina pectoris. Heart. 2002 May;87(5):415-22. doi: 10.1136/heart.87.5.415.

  PMID: 11997407 BACKGROUND

• May A, Leone M, Afra J, Linde M, Sandor 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. doi: 10.1111/j.1468-1331.2006.01566.x.

  PMID: 16987158 BACKGROUND

• Lampl C. Childhood-onset cluster headache. Pediatr Neurol. 2002 Aug;27(2):138-40. doi: 10.1016/s0887-8994(02)00406-x.

  PMID: 12213616 BACKGROUND

• 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.

  PMID: 19409754 BACKGROUND

• Ferri R, Curzi-Dascalova L, Arzimanoglou A, Bourgeois M, Beaud C, Nunes ML, Elia M, Musumeci SA, Tripodi M. Heart rate variability during sleep in children with partial epilepsy. J Sleep Res. 2002 Jun;11(2):153-60. doi: 10.1046/j.1365-2869.2002.00283.x.

  PMID: 12028480 BACKGROUND

• Yang TF, Wong TT, Chang KP, Kwan SY, Kuo WY, Lee YC, Kuo TB. Power spectrum analysis of heart rate variability in children with epilepsy. Childs Nerv Syst. 2001 Oct;17(10):602-6. doi: 10.1007/s003810100505.

  PMID: 11685522 BACKGROUND

• Chiron C, Marchand MC, Tran A, Rey E, d'Athis P, Vincent J, Dulac O, Pons G. Stiripentol in severe myoclonic epilepsy in infancy: a randomised placebo-controlled syndrome-dedicated trial. STICLO study group. Lancet. 2000 Nov 11;356(9242):1638-42. doi: 10.1016/s0140-6736(00)03157-3.

  PMID: 11089822 BACKGROUND

• 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.

  PMID: 19552653 BACKGROUND

• 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. doi: 10.1056/NEJM199712183372504.

  PMID: 9400037 BACKGROUND

• Neels HM, Sierens AC, Naelaerts K, Scharpe SL, Hatfield GM, Lambert WE. Therapeutic drug monitoring of old and newer anti-epileptic drugs. Clin Chem Lab Med. 2004;42(11):1228-55. doi: 10.1515/CCLM.2004.245.

  PMID: 15576287 BACKGROUND

• Brogden RN, Heel RC, Speight TM, Avery GS. Clobazam: a review of its pharmacological properties and therapeutic use in anxiety. Drugs. 1980 Sep;20(3):161-78. doi: 10.2165/00003495-198020030-00001.

  PMID: 6107238 BACKGROUND

• Greenblatt DJ, Divoll M, Puri SK, Ho I, Zinny MA, Shader RI. Clobazam kinetics in the elderly. Br J Clin Pharmacol. 1981 Nov;12(5):631-6. doi: 10.1111/j.1365-2125.1981.tb01281.x.

  PMID: 6120710 BACKGROUND

• Giraud C, Tran A, Rey E, Vincent J, Treluyer JM, Pons G. In vitro characterization of clobazam metabolism by recombinant cytochrome P450 enzymes: importance of CYP2C19. Drug Metab Dispos. 2004 Nov;32(11):1279-86.

  PMID: 15483195 BACKGROUND

• 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. doi: 10.1111/j.1365-2125.1984.tb02558.x.

  PMID: 6529527 BACKGROUND

• 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. doi: 10.1124/dmd.105.007237. Epub 2006 Jan 13.

  PMID: 16415114 BACKGROUND

• Contin M, Riva R, Albani F, Baruzzi AA. Effect of felbamate on clobazam and its metabolite kinetics in patients with epilepsy. Ther Drug Monit. 1999 Dec;21(6):604-8. doi: 10.1097/00007691-199912000-00004.

  PMID: 10604819 BACKGROUND

• Backman JT, Olkkola KT, Aranko K, Himberg JJ, Neuvonen PJ. Dose of midazolam should be reduced during diltiazem and verapamil treatments. Br J Clin Pharmacol. 1994 Mar;37(3):221-5. doi: 10.1111/j.1365-2125.1994.tb04266.x.

  PMID: 8198928 BACKGROUND

• Fleishaker JC, Sisson TA, Carel BJ, Azie NE. Pharmacokinetic interaction between verapamil and almotriptan in healthy volunteers. Clin Pharmacol Ther. 2000 May;67(5):498-503. doi: 10.1067/mcp.2000.106292.

  PMID: 10824628 BACKGROUND

• Kantola T, Kivisto KT, Neuvonen PJ. Erythromycin and verapamil considerably increase serum simvastatin and simvastatin acid concentrations. Clin Pharmacol Ther. 1998 Aug;64(2):177-82. doi: 10.1016/S0009-9236(98)90151-5.

  PMID: 9728898 BACKGROUND

• Lamberg TS, Kivisto KT, Neuvonen PJ. Effects of verapamil and diltiazem on the pharmacokinetics and pharmacodynamics of buspirone. Clin Pharmacol Ther. 1998 Jun;63(6):640-5. doi: 10.1016/S0009-9236(98)90087-X.

  PMID: 9663178 BACKGROUND

• 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. doi: 10.1016/0006-2952(85)90541-6.

  PMID: 4015695 BACKGROUND

• Wang YH, Jones DR, Hall SD. Prediction of cytochrome P450 3A inhibition by verapamil enantiomers and their metabolites. Drug Metab Dispos. 2004 Feb;32(2):259-66. doi: 10.1124/dmd.32.2.259.

  PMID: 14744949 BACKGROUND

• Edwards DJ, Lavoie R, Beckman H, Blevins R, Rubenfire M. The effect of coadministration of verapamil on the pharmacokinetics and metabolism of quinidine. Clin Pharmacol Ther. 1987 Jan;41(1):68-73. doi: 10.1038/clpt.1987.11.

  PMID: 3802708 BACKGROUND

• Abernethy DR, Egan JM, Dickinson TH, Carrum G. Substrate-selective inhibition by verapamil and diltiazem: differential disposition of antipyrine and theophylline in humans. J Pharmacol Exp Ther. 1988 Mar;244(3):994-9.

  PMID: 3252045 BACKGROUND

• Sirmans SM, Pieper JA, Lalonde RL, Smith DG, Self TH. Effect of calcium channel blockers on theophylline disposition. Clin Pharmacol Ther. 1988 Jul;44(1):29-34. doi: 10.1038/clpt.1988.108.

  PMID: 3391002 BACKGROUND

• 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. doi: 10.1007/BF02280751.

  PMID: 1505606 BACKGROUND

• Allen LV Jr, Erickson MA 3rd. Stability of labetalol hydrochloride, metoprolol tartrate, verapamil hydrochloride, and spironolactone with hydrochlorothiazide in extemporaneously compounded oral liquids. Am J Health Syst Pharm. 1996 Oct 1;53(19):2304-9. doi: 10.1093/ajhp/53.19.2304.

  PMID: 8893069 BACKGROUND

MeSH Terms

Conditions

Epilepsies, Myoclonic; Seizures

Interventions

Verapamil

Condition Hierarchy (Ancestors)

Epilepsy, Generalized; Epilepsy; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epileptic Syndromes; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Phenethylamines; Ethylamines; Amines; Organic Chemicals

Results Point of Contact

• Title: Beverly Wical, MD
• Organization: Gillette Children's Specialty Healthcare

BWical@gillettechildrens.com

(651) 229-3870

Study Officials

• Beverly S Wical, MD

  Gillette Children's Specialty Healthcare

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 24, 2012
• First Posted: May 28, 2012
• Study Start: April 1, 2012
• Primary Completion: January 1, 2015
• Study Completion: January 1, 2015
• Last Updated: April 13, 2021
• Results First Posted: March 23, 2021

Record last verified: 2021-03

Locations

US (4)