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Dravet SyndromePhase 2NCT01607073

Verapamil as Therapy for Children and Young Adults With Dravet Syndrome

A Phase 2 study testing Verapamil in people with Dravet Syndrome, run by Gillette Children's Specialty Healthcare at 4 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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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. Read more about this study

Who is it for?
Ages 2 to 25 years
Conditions the study is for
Dravet Syndrome
What is being tested?
Verapamil
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
2 participants
Where
4 sitesUnited States
Study dates
Apr 2012to Jan 2015
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 2 to 25 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • 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

Who cannot join

  • 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

Trial locations and contacts

4 sites in 1 country.

United States4 sites

  • Children's Memorial Hospital

    Chicago, Illinois, 60614

  • Mary Hitchcock Memorial Hospital

    Lebanon, New Hampshire, 03756

  • Mayo Clinic

    Rochester, Minnesota, 55905

  • Gillette Children's Specialty Healthcare

    Saint Paul, Minnesota, 55101

Other trials in United States

About this study

Official title: Verapamil as Adjunctive Seizure Therapy for Children and Young Adults With Dravet Syndrome

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.

Read the detailed 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.

Conditions
Dravet Syndrome
Being tested
Verapamil
Keywords
Dravet, seizures, verapamil
Medical subject headings
Epilepsies, Myoclonic, Seizures

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • VerapamilDrug

    Also called Calan, Covera, Isoptin, Verelan

    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.

Study groups in NCT01607073
Study groupRoleWhat they receive
open label adjunctive add onOtheropen 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)
Receives: Drug: Verapamil

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: Week 8 (baseline) to Week 12

Secondary outcomes (2)

  1. 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.

    Measured: Week 8 (baseline) to Week 12

  2. 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

    Measured: Week 8 to Week 12

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted28 May 2012 (estimated)
  2. Study startApr 2012
  3. Primary completionJan 2015
  4. Study completionJan 2015

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
2 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01607073
Sponsor's protocol ID
IND 113666
Status last verified
Mar 2021
First submitted
24 May 2012
Last updated
13 Apr 2021
Data monitoring committee
Yes

Publications

  • 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.

    PubMed 21463290

  • 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.

    PubMed 21463281

  • 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.

    PubMed 19303743

  • 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.

    PubMed 7102502

  • 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.

    PubMed 11149130

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

    PubMed 6340050

  • 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.

    PubMed 6795914

  • 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.

    PubMed 11724204

  • 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.

    PubMed 10403616

  • 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.

    PubMed 11997407

  • 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.

    PubMed 16987158

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

    PubMed 12213616

  • 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.

    PubMed 19409754

  • 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.

    PubMed 12028480

  • 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.

    PubMed 11685522

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Verapamil in people with Dravet Syndrome, run by Gillette Children's Specialty Healthcare at 4 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 8 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 13 Apr 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 4 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 23 Mar 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in Number of General Tonic-clonic Seizures From Week 8 (Baseline) Visit to Week 12 Visit (time frame: Week 8 (baseline) to Week 12). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01607073, which also lists 36 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Apr 2021.

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