Does VNS Interact With the Serotonergic and Immune System in Children With Intractable Epilepsy?
Primary Purpose
Refractory Epilepsy in Children
Status
Unknown status
Phase
Phase 2
Locations
Netherlands
Study Type
Interventional
Intervention
Vagus Nerve Stimulator: Neurocybernetic prothesis NCP, Cyberonics Inc., Webster, TX, USA
Sponsored by
About this trial
This is an interventional treatment trial for Refractory Epilepsy in Children focused on measuring intractable childhood epilepsy, VNS, immune system
Eligibility Criteria
Inclusion Criteria:
- Seizures not adequately controlled by anti-epileptic drugs of first or second choice with adequate and stable serum anticonvulsant concentrations
- Acceptable seizure regulation but intolerable side effects with adequate and stable serum anticonvulsant concentrations
- Not eligible for epilepsy surgery
- Age between 4 and 18 years
- Informed consent
Exclusion Criteria:
- Evidence of a progressive cerebral lesion, degenerative disorder, malignancy or a history with malignancy in the past 5 years
- Unstable medical disease (i.e. cardiovascular, hepatic, renal, musculoskeletal, gastrointestinal, metabolic, endocrine) in the last 2 years
- Documented history with generalized status epilepticus in the past three months
- High risks for complications (obstructive respiratory disease, gastric disorders, cardiac I disorders)
- A history of alcohol or drug abuse, of psychiatric disorder requiring electroconvulsive therapy, chronic use of major tranquillisers (neuroleptics, antidepressants, or MAO inhibitors) in the past 6 months
- Regularly treatment with antihistamines, metoclopramide or CNS-active compounds
- Treatment with an experimental drug during the past 30 days
- Subjects who are schizophrenic or have exhibited any psychotic symptomatology
Sites / Locations
- Maastricht University Medical Center
- Epilepsiecentrum Kempenhaeghe
Arms of the Study
Arm 1
Arm 2
Arm Type
Placebo Comparator
Experimental
Arm Label
active control group
treatment group
Arm Description
The active control group is stimulated with: Output current 0.25 milliampere, Pulse width 0.1 milliseconds, Frequency 1 Hz, Duty cycle: 14 sec on 60 min off (duty cycle <0.5%)
The high stimulation group is stimulated with output current 0.25 milliampere, Pulse width 0.5 milliseconds, Frequency 30 Hz, Duty cycle: 30 sec on 5 min off in the treatment group the current was stepwise increased with two week intervals to the maximally tolerated output current (maximum 1.75 mA).
Outcomes
Primary Outcome Measures
seizure frequency reduction of 50% or more
Seizure frequency is measured by using seizure diaries
Secondary Outcome Measures
Full Information
NCT ID
NCT01378611
First Posted
June 14, 2011
Last Updated
June 28, 2011
Sponsor
Epilepsiecentrum Kempenhaeghe
Collaborators
Maastricht University Medical Center
1. Study Identification
Unique Protocol Identification Number
NCT01378611
Brief Title
Does VNS Interact With the Serotonergic and Immune System in Children With Intractable Epilepsy?
Official Title
Does VNS Interact With the Serotonergic and Immune System in Children With Intractable Epilepsy? A Randomized Clinical Study.
Study Type
Interventional
2. Study Status
Record Verification Date
June 2011
Overall Recruitment Status
Unknown status
Study Start Date
March 2006 (undefined)
Primary Completion Date
March 2012 (Anticipated)
Study Completion Date
March 2013 (Anticipated)
3. Sponsor/Collaborators
Name of the Sponsor
Epilepsiecentrum Kempenhaeghe
Collaborators
Maastricht University Medical Center
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
Clinical randomized controlled observer blinded add-on design. Additionally there will be a non-controlled follow-up phase of the study. Children (Age 4-18 years) with intractable epilepsy, and not eligible for resective surgery will be treated with VNS.
Aim of the study:
To evaluate tolerability and effectiveness of VNS in children with intractable epilepsy and cognitive and behavioural problems in a controlled study.
To evaluate the effect of VNS on the immune system which, in its turn, will lead to changes in the serotonin metabolic pathway
To link the therapeutic effect of VNS to changes in the serotonin (5HT) metabolic pathway.
In addition the investigators hope to detect some markers of immune and neurotransmitter function that enable us to predict 1) Neuronal cell loss in relation to cognitive decline 2) the response to therapeutic treatment of VNS.
Hypothesis:
The investigators aim to explore neuronal correlates for cognitive morbidity in children with intractable epilepsy and to relate this to morphologic changes, biochemical markers, and to epilepsy characteristics.
Correction of the "stressed" pro-inflammatory status of monocytes/macrophages via an electrical stimulation of the vagus nerve will prevent/ameliorate seizures as well as behavioural mood symptoms in children with refractory epilepsy, characterized by the "pro-inflammatory monocyte signature"
Detailed Description
Background information:
Repetitive seizures lead to an increase of pro-inflammatory cytokines in the peripheral blood. Experimentally it has been shown that activation of inflammatory cytokines by the peripheral administration of a toxic agents causes sickness behaviour. Pro-inflammatory cytokines interfere with the catabolisation of a precursor of Serotonin (Tryptophan). Tryptophan is catabolised to an endogen NMDA receptor agonist. NMDA (an excitatory neurotransmitter) can lead to neuronal damage.
The Vagus Nerve (VN) plays an important role in the interaction between the neurotransmitter and immune system in which cytokines are crucial. Vagus nerve stimulation (VNS) has an effect on various amino-acid pools in the brain. Patients who respond to VNS show significantly increased serotonin metabolites in their cerebrospinal fluid. VNS is also associated with marked peripheral increases in pro-, and anti-inflammatory circulating cytokines. Given the complexity of the serotonergic system and its interaction with multiple neurotransmitter systems in the human brain it is not surprising to find that serotonin plays a role in the etiology and the course of affective disorders. It is to be expected that the serotonin-immune pathway also plays a role in the course of epilepsy.
Study population:
Children (Age 4-18 years) with intractable epilepsy, and not eligible for resective surgery
Study design:
Clinical randomized controlled observer blinded add-on design. Additionally, and as a non-controlled follow-up of the study, the active control group will receive therapeutic stimulation parameters. In a secondary analysis both VNS groups will be compared with the pre-surgical period (baseline)
Intervention: VNS The generator is implanted beneath the subcutaneous tissue in the upper chest region. The electrode is tunneled from the generator to the stimulation site in the neck. The system is programmed with a computer. The pulse width, output current, signal frequency and stimulation time are programmed telemetrically.
The study group is stimulated with the following parameters: Output current 0.25 milliampere (to be ramped up to max. 1.75 milliampere), Pulse width 0.5 milliseconds, Frequency 30 Hz, Duty cycle: 30 sec on 5 min off (duty cycle 10%).
The active control group is stimulated with: Output current 0.25 milliampere, Pulse width 0.1 milliseconds, Frequency 1 Hz, Duty cycle: 14 sec on 60 min off (duty cycle <0.5%)
Primary endpoint:
Seizure frequency reduction of 50% or more.
Main variables:
Demographics Epilepsy specific data (Seizure frequency (diary), Medication) Biochemical and neuro-immunological assessments in in peripheral blood and CSF(serotonin metabolites, Noradrenalin, GABA, Glutamate, pro-, and anti-inflammatory cytokines).
Neuropsychologic variables (mood, cognition, QoL )
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Refractory Epilepsy in Children
Keywords
intractable childhood epilepsy, VNS, immune system
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
45 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
active control group
Arm Type
Placebo Comparator
Arm Description
The active control group is stimulated with: Output current 0.25 milliampere, Pulse width 0.1 milliseconds, Frequency 1 Hz, Duty cycle: 14 sec on 60 min off (duty cycle <0.5%)
Arm Title
treatment group
Arm Type
Experimental
Arm Description
The high stimulation group is stimulated with output current 0.25 milliampere, Pulse width 0.5 milliseconds, Frequency 30 Hz, Duty cycle: 30 sec on 5 min off in the treatment group the current was stepwise increased with two week intervals to the maximally tolerated output current (maximum 1.75 mA).
Intervention Type
Device
Intervention Name(s)
Vagus Nerve Stimulator: Neurocybernetic prothesis NCP, Cyberonics Inc., Webster, TX, USA
Other Intervention Name(s)
vagus nerve stimulation
Intervention Description
The study group is stimulated with the following parameters: Output current 0.25 milliampere (to be ramped up to max. 1.75 milliampere), Pulse width 0.5 milliseconds, Frequency 30 Hz, Duty cycle: 30 sec on 5 min off (duty cycle 10%).
Primary Outcome Measure Information:
Title
seizure frequency reduction of 50% or more
Description
Seizure frequency is measured by using seizure diaries
Time Frame
after 3 and 6 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
4 Years
Maximum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Seizures not adequately controlled by anti-epileptic drugs of first or second choice with adequate and stable serum anticonvulsant concentrations
Acceptable seizure regulation but intolerable side effects with adequate and stable serum anticonvulsant concentrations
Not eligible for epilepsy surgery
Age between 4 and 18 years
Informed consent
Exclusion Criteria:
Evidence of a progressive cerebral lesion, degenerative disorder, malignancy or a history with malignancy in the past 5 years
Unstable medical disease (i.e. cardiovascular, hepatic, renal, musculoskeletal, gastrointestinal, metabolic, endocrine) in the last 2 years
Documented history with generalized status epilepticus in the past three months
High risks for complications (obstructive respiratory disease, gastric disorders, cardiac I disorders)
A history of alcohol or drug abuse, of psychiatric disorder requiring electroconvulsive therapy, chronic use of major tranquillisers (neuroleptics, antidepressants, or MAO inhibitors) in the past 6 months
Regularly treatment with antihistamines, metoclopramide or CNS-active compounds
Treatment with an experimental drug during the past 30 days
Subjects who are schizophrenic or have exhibited any psychotic symptomatology
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
A.P. Aldenkamp, Prof
Organizational Affiliation
Epilepsie centrum Kempenhaeghe
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
EMJ Cornips, MD,
Organizational Affiliation
Maastricht University Medical Center
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
J. Hulsman, PhD
Organizational Affiliation
Epilepsie centrum Kempenhaeghe
Official's Role
Study Chair
Facility Information:
Facility Name
Maastricht University Medical Center
City
Maastricht
State/Province
Limburg
ZIP/Postal Code
6229HX
Country
Netherlands
Facility Name
Epilepsiecentrum Kempenhaeghe
City
Heeze
State/Province
Noord-Brabant
ZIP/Postal Code
5591VE
Country
Netherlands
12. IPD Sharing Statement
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Does VNS Interact With the Serotonergic and Immune System in Children With Intractable Epilepsy?
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