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Verapamil as Therapy for Children and Young Adults With Dravet Syndrome

Sponsor
Gillette Children's Specialty Healthcare (Other)
Overall Status
Completed
CT.gov ID
NCT01607073
Collaborator
Mayo Clinic (Other), Ann & Robert H Lurie Children's Hospital of Chicago (Other), Dartmouth-Hitchcock Medical Center (Other)
2
Enrollment
4
Locations
1
Arm
33
Duration (Months)
0.5
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 2

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.

Study Design

Study Type:
Interventional
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 :
Apr 1, 2012
Actual Primary Completion Date :
Jan 1, 2015
Actual Study Completion Date :
Jan 1, 2015

Arms and Interventions

Arm Intervention/Treatment
Other: 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)

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:
  • Calan
  • Covera
  • Isoptin
  • Verelan

    		•

    Outcome Measures

    Primary Outcome Measures

    1. 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 Outcome Measures

    1. 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.

    2. 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

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    2 Years to 25 Years
    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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Children's Memorial Hospital Chicago Illinois United States 60614
    2 Mayo Clinic Rochester Minnesota United States 55905
    3 Gillette Children's Specialty Healthcare Saint Paul Minnesota United States 55101
    4 Mary Hitchcock Memorial Hospital Lebanon New Hampshire United States 03756

    Sponsors and Collaborators

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

    Investigators

    • Principal Investigator: Beverly S Wical, MD, Gillette Children's Specialty Healthcare

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    Gillette Children's Specialty Healthcare
    ClinicalTrials.gov Identifier:
    NCT01607073
    Other Study ID Numbers:
    • IND 113666
    First Posted:
    May 28, 2012
    Last Update Posted:
    Apr 13, 2021
    Last Verified:
    Mar 1, 2021
    Keywords provided by Gillette Children's Specialty Healthcare
    Dravet
    seizures
    verapamil
    Additional relevant MeSH terms:
    Epilepsies, Myoclonic
    Syndrome
    Verapamil

    Study Results

    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.
    Pre-assignment Detail
    Arm/Group Title Adjunctive Verapamil
    Arm/Group Description Participants taking verapamil for Dravet syndrome
    Period Title: Overall Study
    STARTED 2
    COMPLETED 1
    NOT COMPLETED 1

    Baseline Characteristics

    Arm/Group Title Open Label Adjunctive Add on
    Arm/Group Description 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.
    Overall Participants 2
    Age (Count of Participants)
    <=18 years
    1
    50%
    Between 18 and 65 years
    1
    50%
    >=65 years
    0
    0%
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    16.5
    (1.5)
    Sex: Female, Male (Count of Participants)
    Female
    1
    50%
    Male
    1
    50%
    Region of Enrollment (participants) [Number]
    United States
    2
    100%

    Outcome Measures

    1. Primary Outcome
    Title Change in Number of General Tonic-clonic Seizures From Week 8 (Baseline) Visit to Week 12 Visit
    Description 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

    Outcome Measure Data

    Analysis Population Description
    Change in number of general tonic-clonic seizures between Week 8 (baseline) and Week 12 visits.
    Arm/Group Title Week 8 Baseline Week 12 Verapamil 4mg/kg/Day
    Arm/Group Description Week 8 visit - 8 weeks of baseline seizure data collected Participants have titrated up to 4mg/kg/day of verapamil
    Measure Participants 2 2
    Number [General tonic-clonic seizures]
    39
    14
    2. Secondary Outcome
    Title Change in Number of Myoclonic Seizures From Week 8 (Baseline) to Week 12
    Description 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

    Outcome Measure Data

    Analysis Population Description
    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/Group Title Week 8 Baseline Week 12 Verapamil 4mg/kg/Day
    Arm/Group Description Collected number of seizures at baseline before participants were taking verapamil. Participants taking verapamil for 4 weeks post baseline.
    Measure Participants 1 1
    Number [Myoclonic seizures]
    116
    175
    3. Secondary Outcome
    Title Change in Number of Absence Seizures From Week 8 (Baseline) to Week 12
    Description 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

    Outcome Measure Data

    Analysis Population Description
    Number of Abscence seizures from Week 8 (baseline) to Week 12 visits.
    Arm/Group Title Week 8 Baseline Week 12 Verapamil 4mg/kg/Day
    Arm/Group Description Collected number of seizures at baseline before participants were taking verapamil. Participants taking verapamil for 4 weeks post baseline.
    Measure Participants 1 1
    Number [Abscence seizures]
    165
    101

    Adverse Events

    Time Frame Up to 35 weeks
    Adverse Event Reporting Description Adverse event data was collected from time of consent to end of study participation.
    Arm/Group Title Open Label Adjunctive Add on
    Arm/Group Description 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.
    All Cause Mortality
    Open Label Adjunctive Add on
    Affected / at Risk (%) # Events
    Total / (NaN)
    Serious Adverse Events
    Open Label Adjunctive Add on
    Affected / at Risk (%) # Events
    Total 1/2 (50%)
    Nervous system disorders
    Seizure 1/2 (50%) 1
    Other (Not Including Serious) Adverse Events
    Open Label Adjunctive Add on
    Affected / at Risk (%) # Events
    Total 2/2 (100%)
    Nervous system disorders
    Insomnia 1/2 (50%) 1
    Drooling 1/2 (50%) 1
    Skin and subcutaneous tissue disorders
    Rash 1/2 (50%) 1

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Beverly Wical, MD
    Organization Gillette Children's Specialty Healthcare
    Phone (651) 229-3870
    Email BWical@gillettechildrens.com
    Responsible Party:
    Gillette Children's Specialty Healthcare
    ClinicalTrials.gov Identifier:
    NCT01607073
    Other Study ID Numbers:
    • IND 113666
    First Posted:
    May 28, 2012
    Last Update Posted:
    Apr 13, 2021
    Last Verified:
    Mar 1, 2021