Dravet Syndrome
Conditions
Keywords
Dravet, seizures, verapamil
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.
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.
Interventions
DRUGVerapamil
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.
Sponsors
Mayo Clinic
Ann & Robert H Lurie Children's Hospital of Chicago
Dartmouth-Hitchcock Medical Center
Gillette Children's Specialty Healthcare
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 25 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Number of General Tonic-clonic Seizures From Week 8 (Baseline) Visit to Week 12 Visit | Week 8 (baseline) to Week 12 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Number of Myoclonic Seizures From Week 8 (Baseline) to Week 12 | 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. |
| Change in Number of Absence Seizures From Week 8 (Baseline) to Week 12 | Week 8 to Week 12 | The secondary outcome measure is the change in number of absence seizures from Week 8 (Baseline) to Week 12 |
Countries
United States
Participant flow
Recruitment details
One participant was recruited from the principal investigator's medical clinic. The other participant contacted us through clincialtrials.gov to participate in this study, and was subsequently recruited because he fit all inclusion/exclusion criteria.
Participants by arm
| Arm | Count |
|---|---|
| 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)
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. | 2 |
| Total | 2 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
Baseline characteristics
| Characteristic | Open Label Adjunctive Add on |
|---|---|
| Age, Categorical <=18 years | 1 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants |
| Age, Continuous | 16.5 years STANDARD_DEVIATION 1.5 |
| Region of Enrollment United States | 2 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 2 / 2 |
| serious Total, serious adverse events | 1 / 2 |
Outcome results
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.
Time frame: Week 8 (baseline) to Week 12
Population: Change in number of general tonic-clonic seizures between Week 8 (baseline) and Week 12 visits.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Week 8 Baseline | Change in Number of General Tonic-clonic Seizures From Week 8 (Baseline) Visit to Week 12 Visit | 39 General tonic-clonic seizures |
| Week 12 Verapamil 4mg/kg/Day | Change in Number of General Tonic-clonic Seizures From Week 8 (Baseline) Visit to Week 12 Visit | 14 General tonic-clonic seizures |
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
Time frame: Week 8 to Week 12
Population: Number of Abscence seizures from Week 8 (baseline) to Week 12 visits.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Week 8 Baseline | Change in Number of Absence Seizures From Week 8 (Baseline) to Week 12 | 165 Abscence seizures |
| Week 12 Verapamil 4mg/kg/Day | Change in Number of Absence Seizures From Week 8 (Baseline) to Week 12 | 101 Abscence seizures |
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.
Time frame: Week 8 (baseline) to Week 12
Population: Participant's collected number of myoclonic seizures at Week 8 visit (baseline) prior to taking verapamil and at Week 12 after 4 weeks of taking verapamil. This participant was the only participant who had seizure types other than general tonic-clonic seizures.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Week 8 Baseline | Change in Number of Myoclonic Seizures From Week 8 (Baseline) to Week 12 | 116 Myoclonic seizures |
| Week 12 Verapamil 4mg/kg/Day | Change in Number of Myoclonic Seizures From Week 8 (Baseline) to Week 12 | 175 Myoclonic seizures |