Priming the Epileptic Brain: tVNS to Improve Efficacy of add-on AED in Patients With Focal Epilepsy (PREP)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Focal Epilepsy
• Intervention / Treatment: Device: TVNS

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.

• Study Type: Interventional
• Enrollment (Anticipated): 66
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Angelique A Stuurman, Msc; Phone Number: 0031402279777; Email: prep@tue.nl
• Study Contact Backup: Name: Rob R Mestrom, Dr; Phone Number: 0031402279777; Email: prep@tue.nl

Study Locations

• Netherlands
  • Noord Brabant
    • Heeze, Noord Brabant, Netherlands, 5590 AB
      • Recruiting
      • Stichting Kempenhaeghe
      • Contact: Angelique Stuurman; Phone Number: 0031 0402279777; Email: prep@tue.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Brivaracetam + Transcutaneous vagal nerve stimulation; Start of Brivaracetam (treatment as usual), combined with tVNS in the first 3 months of treatment	Device: TVNS; Cerbomed NEMOS
No Intervention: Brivaracetam; Start of Brivaracetam (treatment as usual)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Epilepsy frequency	Seizure reduction (in % at 3 and 6 months in respect to baseline)	6 months
Epilepsy frequency	Seizure freedom rates (defined as the percentage of subjects with 100% reduction from baseline seizure frequency)	6 months
Seizure severity	Assessed by the National Hospital Seizure Severity Scale - NHS3, comparing scores at 3 and 6 months to baseline). Score range 1-27 (higher score = more severe).	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brain networks	Detect changes in network properties by comparing fMRI (functional MRI) data at 3 months with baseline (independent component analysis)	3 months

Collaborators and Investigators

• Sponsor: Eindhoven University of Technology
• Collaborators: Clinical Trial Center Maastricht B.V.
• Investigators: Principal Investigator: Marian M Majoie, Prof. Dr., ACE Kempenhaeghe

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2021
• Primary Completion (Anticipated): July 1, 2023
• Study Completion (Anticipated): July 1, 2023

Study Registration Dates

• First Submitted: July 2, 2021
• First Submitted That Met QC Criteria: December 17, 2021
• First Posted (Actual): January 6, 2022

Study Record Updates

• Last Update Posted (Actual): January 6, 2022
• Last Update Submitted That Met QC Criteria: December 17, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Keywords: vagus nerve stimulation
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epilepsy; Epilepsies, Partial
• Other Study ID Numbers: PREP_001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No