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Verapamil as Therapy for Children and Young Adults With Dravet Syndrome

Primary Purpose

Dravet Syndrome

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Verapamil
Sponsored by
Gillette Children's Specialty Healthcare
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Dravet Syndrome focused on measuring Dravet, seizures, verapamil

Eligibility Criteria

2 Years - 25 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Children's Memorial Hospital
  • Mayo Clinic
  • Gillette Children's Specialty Healthcare
  • Mary Hitchcock Memorial Hospital

Arms of the Study

Arm 1

Arm Type

Other

Arm Label

open label adjunctive add on

Arm 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)

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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

Full Information

First Posted
May 24, 2012
Last Updated
March 22, 2021
Sponsor
Gillette Children's Specialty Healthcare
Collaborators
Mayo Clinic, Ann & Robert H Lurie Children's Hospital of Chicago, Dartmouth-Hitchcock Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT01607073
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
Study Type
Interventional

2. Study Status

Record Verification Date
March 2021
Overall Recruitment Status
Completed
Study Start Date
April 2012 (undefined)
Primary Completion Date
January 2015 (Actual)
Study Completion Date
January 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Gillette Children's Specialty Healthcare
Collaborators
Mayo Clinic, Ann & Robert H Lurie Children's Hospital of Chicago, Dartmouth-Hitchcock Medical Center

4. Oversight

Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Dravet Syndrome
Keywords
Dravet, seizures, verapamil

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
2 (Actual)

8. Arms, Groups, and Interventions

Arm Title
open label adjunctive add on
Arm Type
Other
Arm 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)
Intervention Type
Drug
Intervention Name(s)
Verapamil
Other Intervention Name(s)
Calan, Covera, Isoptin, Verelan
Intervention Description
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.
Primary Outcome Measure Information:
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
Secondary Outcome Measure Information:
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
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
2 Years
Maximum Age & Unit of Time
25 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Beverly S Wical, MD
Organizational Affiliation
Gillette Children's Specialty Healthcare
Official's Role
Principal Investigator
Facility Information:
Facility Name
Children's Memorial Hospital
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60614
Country
United States
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
Gillette Children's Specialty Healthcare
City
Saint Paul
State/Province
Minnesota
ZIP/Postal Code
55101
Country
United States
Facility Name
Mary Hitchcock Memorial Hospital
City
Lebanon
State/Province
New Hampshire
ZIP/Postal Code
03756
Country
United States

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Verapamil as Therapy for Children and Young Adults With Dravet Syndrome

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