Refractory Epilepsy in ChildrenPhase 2/3NCT01378611
Does VNS Interact With the Serotonergic and Immune System in Children With Intractable Epilepsy?
A Phase 2/3 study testing Vagus Nerve Stimulator: Neurocybernetic prothesis NCP, Cyberonics Inc., Webster, TX, USA in people with Refractory Epilepsy in Children, run by Epilepsiecentrum Kempenhaeghe at 2 sites in Netherlands.
Trial 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: 1. Read more about this study
- Who is it for?
- Ages 4 to 18 years
- Conditions the study is for
- Refractory Epilepsy in Children
- What is being tested?
- Vagus Nerve Stimulator: Neurocybernetic prothesis NCP, Cyberonics Inc., Webster, TX, USA
- Type of treatment
- Medical device
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 45 participants
- Where
- 2 sitesNetherlands
- Study dates
- Mar 2006to Mar 2013
- Phase
- Phase 2/3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 4 to 18 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
2 sites in 1 country.
Netherlands2 sites
Epilepsiecentrum Kempenhaeghe
Heeze, North Brabant, 5591VE
Maastricht University Medical Center
Maastricht, Limburg, 6229HX
About this study
Official title: Does VNS Interact With the Serotonergic and Immune System in Children With Intractable Epilepsy? A Randomized Clinical Study.
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:
Read more
- 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"
Read the 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 )
- Conditions
- Refractory Epilepsy in Children
- Being tested
- Vagus Nerve Stimulator: Neurocybernetic prothesis NCP, Cyberonics Inc., Webster, TX, USA
- Keywords
- intractable childhood epilepsy, VNS, immune system
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Vagus Nerve Stimulator: Neurocybernetic prothesis NCP, Cyberonics Inc., Webster, TX, USADevice
Also called vagus nerve stimulation
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%).
| Study group | Role | What they receive |
|---|---|---|
| active control group | Placebo comparator | 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%) Receives: Device: Vagus Nerve Stimulator: Neurocybernetic prothesis NCP, Cyberonics Inc., Webster, TX, USA |
| treatment group | Experimental | 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). Receives: Device: Vagus Nerve Stimulator: Neurocybernetic prothesis NCP, Cyberonics Inc., Webster, TX, USA |
What is being measured
The primary outcome is the main question the study is designed to answer.
seizure frequency reduction of 50% or more
Seizure frequency is measured by using seizure diaries
Measured: after 3 and 6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Jun 2011 (estimated)
- Study startMar 2006
- Primary completionMar 2012 (estimated)
- Study completionMar 2013 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Refractory Epilepsy in ChildrenStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 45 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Epilepsiecentrum Kempenhaeghe
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Maastricht University Medical Center
- Investigators
- A.P. Aldenkamp, Prof, Study chair, Epilepsie centrum KempenhaegheEMJ Cornips, MD,, Study chair, Maastricht University Medical CenterJ. Hulsman, PhD, Study chair, Epilepsie centrum Kempenhaeghe
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01378611
- Sponsor's protocol ID
- MEC 05-232 (PF 218)
- Status last verified
- Jun 2011
- First submitted
- 14 Jun 2011
- Last updated
- 29 Jun 2011
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 29 Jun 2011. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Does VNS Interact With the Serotonergic and Immune System in Children With Intractable Epilepsy? A Randomized Clinical Study.
- ClinicalTrials.gov ID
- NCT01378611
- Acronym / sponsor ID
- MEC 05-232 (PF 218)
- Conditions
- Refractory Epilepsy in Children
- Keywords
- intractable childhood epilepsy, VNS, immune system
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 45 participants (estimated)
- Lead sponsor
- Epilepsiecentrum KempenhaegheIndustry (pharma, biotech, devices)
- Collaborators
- Maastricht University Medical Center
- Study start
- Mar 2006
- Primary completion
- Mar 2012 (estimated)
- Study completion
- Mar 2013 (estimated)
- First posted
- 22 Jun 2011 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 )
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| active control group | Placebo comparator | Device: Vagus Nerve Stimulator: Neurocybernetic prothesis NCP, Cyberonics Inc., Webster, TX, USAThe 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%) |
| treatment group | Experimental | Device: Vagus Nerve Stimulator: Neurocybernetic prothesis NCP, Cyberonics Inc., Webster, TX, USAThe 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). |
Who may qualify
- Ages
- 4 to 18 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (5 listed)
- 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
Key exclusion criteria (8 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Vagus Nerve Stimulator: Neurocybernetic prothesis NCP, Cyberonics Inc., Webster, TX, USAAlso: vagus nerve stimulationThe 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%). | Device | active control group, treatment group |
Primary outcome
seizure frequency reduction of 50% or more
Time frame: after 3 and 6 months
Seizure frequency is measured by using seizure diaries
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Jun 2011.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
A.P. Aldenkamp, Prof study chair
Epilepsie centrum Kempenhaeghe
EMJ Cornips, MD, study chair
Maastricht University Medical Center
J. Hulsman, PhD study chair
Epilepsie centrum Kempenhaeghe
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing Vagus Nerve Stimulator: Neurocybernetic prothesis NCP, Cyberonics Inc., Webster, TX, USA in people with Refractory Epilepsy in Children, run by Epilepsiecentrum Kempenhaeghe at 2 sites in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 29 Jun 2011. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
seizure frequency reduction of 50% or more (time frame: after 3 and 6 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Jun 2011.