Clinical trial NCT05180916: Priming the Epileptic Brain: tVNS to Improve Efficacy of add-on AED in Patients With Focal Epilepsy
Official title: Priming the Epileptic Brain - Determining the Effect of Temporarily Addition of Transcutaneous Vagal Nerve Stimulation When Starting an add-on AED (in This Case Brivaracetam) in Patients With Refractory Focal Epilepsy
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Focal Epilepsy
Keywords: vagus nerve stimulation
Lead sponsor: Eindhoven University of Technology
Sponsor class: OTHER
Collaborators: name: Clinical Trial Center Maastricht B.V.
First posted: 2022-01-06
Enrollment: 66
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized Controlled trial
Primary purpose: TREATMENT

Brief summary: The most prevalent neurological disorder with also immense burden of disease, epilepsy, is in over 30 percent of patients difficult to treat. The ideal treatment regime would give complete control of disease in an early stage, not only for patient well-being, but also to prevent the onset of persistent pathologic epileptic networks in the brain. The first step in treatment is the trial, and error, of multiple anti-epileptic drugs (AEDs), while invasive brain stimulation (BS) techniques with network modulating properties are saved as a last resort. The investigators hypothesize that pharmacotherapeutic treatment of epilepsy can be more successful after "priming" (preparing) the brain using BS as a short-term neuromodulation treatment. The limitation of testing this hypothesis is the invasive aspect of the most used classic vagal nerve stimulation (VNS) treatment for epilepsy, but the recent development of transcutaneous vagal nerve stimulation (tVNS) offered a possibility to combine chemical and electrical modulation in an earlier stage of disease, which is not tested before. The investigators want to determine the priming effect on the epileptic brain of tVNS, to make it more susceptible to add-on treatment with Brivaracetam (BRV), an AED. In addition, the investigators aim to visualize these changes in the brain because of priming, possibly altered network-organisation.

Detailed description: Background of the study: The most prevalent neurological disorder with also immense burden of disease, epilepsy, is in over 30 percent of patients difficult to treat. The ideal treatment regime would give complete control of disease in an early stage, not only for patient well-being, but also to prevent the onset of persistent pathologic epileptic networks in the brain. The first step in treatment is the trial, and error, of multiple anti-epileptic drugs (AEDs), while invasive brain stimulation (BS) techniques with network modulating properties are saved as a last resort. The investigators hypothesize that pharmacotherapeutic treatment of epilepsy can be more successful after "priming" (preparing) the brain using BS as a short-term neuromodulation treatment. The limitation of testing this hypothesis is the invasive aspect of the most used classic vagal nerve stimulation (VNS) treatment for epilepsy, but the recent development of transcutaneous vagal nerve stimulation (tVNS) offered a possibility to combine chemical and electrical modulation in an earlier stage of disease, which is not tested before.

Objective of the study: Determine the priming effect on the epileptic brain of tVNS, to make it more susceptible to add-on treatment with Brivaracetam (BRV), an AED. In addition, the investigators aim to visualize these changes in the brain because of priming, possibly altered network-organisation.

Study design: Randomized Controlled Trial. Study population: Adults with a refractory (continuing of seizures despite 2 tried AEDs) focal epilepsy and therefore have an indication for start of Brivaracetam. Intervention (if applicable): One group receives transcutaneous vagal nerve stimulation (tVNS) 4 hours daily for the first 3 months of brivaracetam treatment. Primary study parameters/outcome of the study: Scoring on a composite index combining seizure reduction, improvement of cognition and quality of life. Secondary study parameters/outcome of the study (if applicable): Seizure reduction, seizure freedom rates, seizure severity, cognition, mood state, adverse events tVNS and brivaracetam, change in brain network properties.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness (if applicable): Besides minor temporary side effects no risk is attributed to tVNS. Because of the study one extra visit is necessary, besides regular clinical follow-up. The 3 visits do require some more time than usual because of the questionnaires, MRI and short cognitive tests. The burden of the telephone calls is very limited, since it only consists of a few short questions. Patients with claustrophobia are excluded, but the requirement of lying still can be somewhat uncomfortable. The eye tracking device uses a camera in the video screen, with no burden at all.

Eligibility criteria: Inclusion Criteria:

* Focal epilepsy which is refractory (at least 2 different AEDs tried) and therefore has an indication for start of brivaracetam
* Age ≥ 18 years.
* IQ \> 70 defined as any form of secondary education

Exclusion Criteria:

* - Inclusion not possible within 2 weeks after start of brivaracetam
* History of a progressive cerebral disorder (neurodegenerative diseases, tumours)
* History of psychogenic nonepileptic seizures (PNES)
* Inability to provide informed consent
* Any contra-indication for brivaracetam
* Current or recent use (exposed ≤ 90 days)
* Current or recent use (exposed ≤ 90 days) of levetiracetam
* Current treatment with neurostimulation
* Inability of handling the tVNS device personally
* Subjects that have a current diagnosis of cardiac arrhythmic disease
* Any contraindication for tVNS: pregnancy, active implants (such as cardiac pacemakers of cochlear implants) or cerebral shunts (e.g. ventriculo-peritoneal shunts with valve)
* Any contraindication for MRI: metallic foreign body, pacemaker, claustrophobia, pregnancy

Primary outcomes:
measure: Epilepsy frequency
timeFrame: 6 months
measure: Epilepsy frequency
timeFrame: 6 months
measure: Seizure severity
timeFrame: 6 months
Secondary outcomes:
measure: Brain networks
timeFrame: 3 months
Other outcomes:
Locations:
city: Heeze
country: Netherlands
facility: Stichting Kempenhaeghe
state: Noord Brabant
Study officials:
affiliation: ACE Kempenhaeghe
name: Marian M Majoie, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References: