Verapamil as Therapy for Children and Young Adults With Dravet Syndrome

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Brief Title

Verapamil as Therapy for Children and Young Adults With Dravet Syndrome

Official Title

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

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.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Change in Number of General Tonic-clonic Seizures From Week 8 (Baseline) Visit to Week 12 Visit

Secondary Outcome

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

Condition

Dravet Syndrome

Intervention

Verapamil

Study Arms / Comparison Groups

 open label adjunctive add on
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)

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

2

Start Date

April 2012

Completion Date

January 2015

Primary Completion Date

January 2015

Eligibility Criteria

        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
      

Gender

All

Ages

2 Years - 25 Years

Accepts Healthy Volunteers

No

Contacts

Beverly S Wical, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT01607073

Organization ID

IND 113666


Responsible Party

Sponsor

Study Sponsor

Gillette Children's Specialty Healthcare

Collaborators

 Mayo Clinic

Study Sponsor

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


Verification Date

March 2021