Verapamil as Therapy for Children and Young Adults With Dravet Syndrome
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| ClinicalTrials.gov Identifier: NCT01607073 |
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Recruitment Status :
Completed
First Posted : May 28, 2012
Last Update Posted : March 25, 2015
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Dravet Syndrome | Drug: Verapamil | Phase 2 |
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.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 2 participants |
| Allocation: | N/A |
| Intervention Model: | Single Group Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Verapamil as Adjunctive Seizure Therapy for Children and Young Adults With Dravet Syndrome |
| Study Start Date : | April 2012 |
| Actual Primary Completion Date : | January 2015 |
| Actual Study Completion Date : | January 2015 |
| Arm | Intervention/treatment |
|---|---|
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open label adjunctive add on
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)
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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. Other Names:
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- Seizure Frequency [ Time Frame: Baseline, 8 weeks, 12 weeks, 16 weeks, 24 weeks, and 35 weeks ]The primary study endpoint is GTCS seizure frequency. A reduction in the number and severity of seizures is anticipated.
- Frequency of myoclonic/absence/atypical absence seizures [ Time Frame: Baseline, 8 weeks, 12 weeks, 16 weeks, 24 weeks, and 35 weeks ]We anticipate a reduction in myoclonic, absence, and atypical absence seizures as well.
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| Ages Eligible for Study: | 2 Years to 25 Years (Child, Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01607073
| United States, Illinois | |
| Children's Memorial Hospital | |
| Chicago, Illinois, United States, 60614 | |
| United States, Minnesota | |
| Mayo Clinic | |
| Rochester, Minnesota, United States, 55905 | |
| Gillette Children's Specialty Healthcare | |
| St. Paul, Minnesota, United States, 55101 | |
| United States, New Hampshire | |
| Mary Hitchcock Memorial Hospital | |
| Lebanon, New Hampshire, United States, 03756 | |
| Principal Investigator: | Beverly S Wical, MD | Gillette Children's Specialty Healthcare |
| Responsible Party: | Beverly S. Wical, M.D., Pediatric Neurologist, Gillette Children's Specialty Healthcare |
| ClinicalTrials.gov Identifier: | NCT01607073 |
| Other Study ID Numbers: |
IND 113666 |
| First Posted: | May 28, 2012 Key Record Dates |
| Last Update Posted: | March 25, 2015 |
| Last Verified: | March 2015 |
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Dravet seizures verapamil |
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Epilepsies, Myoclonic Syndrome Disease Pathologic Processes Epilepsy, Generalized Epilepsy Brain Diseases Central Nervous System Diseases Nervous System Diseases |
Epileptic Syndromes Verapamil Anti-Arrhythmia Agents Calcium Channel Blockers Membrane Transport Modulators Molecular Mechanisms of Pharmacological Action Calcium-Regulating Hormones and Agents Physiological Effects of Drugs Vasodilator Agents |