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
Phase: NA
Conditions: Focal Epilepsy
Sponsor: Eindhoven University of Technology

Priming the epileptic Brain (PREP) 
 
 
 
 
 
 
 
 
 
 
 
 
Priming the Epileptic brain (PREP) 
Version May 2021 
 
- 
July 2020: Adaptation section 2, 3, 4.3, 4.4, 6.1, 6.3, 6.4, 7.8, 8.1, 8.2, 8.3, 8.5, 8.7, 
10, 11.1, 11.2, 12.1, 12.2, 13.2 and 14. 
- 
August 2020: Adaptation section 4.4 and 10 
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October 2020: Adaptation section 3, 4.1, 4.2, 4.3, 8.3, 8.5, 11.2, 12.1 and 13.1 
- 
May 2021: Adaptation section 3, 4.2, 4.3, 8.1.2, 8.3, 9.2.1 and 11.6 
 
 
 

Priming the epileptic Brain (PREP) 
 
 
 
PROTOCOL TITLE Priming the Epileptic Brain (PREP) 
 
Protocol ID 
Priming the Epileptic brain 
Short title 
PREP 
EudraCT number  
N.A. 
Version 
4.0 
Date 
19-05-2021 
Practical 
investigator/PhD 
student 
Drs. A. Remmers, Elisabeth Tweesteden Hospital, 
Eindhoven University of Technology TU/E & 
Academic Centre for Epileptology Kempenhaeghe 
Principal investigator (in Dutch: 
hoofdonderzoeker) 
 
Prof. Dr. H.J.M. Majoie, Academic Centre for 
Epileptology Kempenhaeghe 
 
Investigators 
Dr. G.L. Wagner, Academic Centre for Epileptology 
Kempenhaeghe 
Dr. R.P.W. Rouhl, Maastricht UMC+ 
Drs. J.H. van Tuijl, Elisabeth Tweesteden Hospital 
Dr. J.F.A. Jansen, Maastricht UMC+ 
Prof. dr. A.P. Aldenkamp, Academic Centre for 
Epileptology Kempenhaeghe & Department of 
neurology MUMC & Eindhoven University of 
Technology TU/e 
Project coordinator 
Dr. Ir. R.M.C. Mestrom, Eindhoven University of 
Technology TU/e 
Sponsor 
(in 
Dutch: 
verrichter/opdrachtgever) 
Eindhoven Technical University TU/e  
Subsidising party 
Health Holland, UCB & HOBO Heeze BV 

Priming the epileptic Brain (PREP) 
 
 
 
Independent expert (s) 
Dr. M.H.J.A. Debeij-van Hall, Academic Centre for 
Epileptology Kempenhaeghe 
Laboratory sites  
N.A. 
Pharmacy  
N.A. 

Priming the epileptic Brain (PREP) 
 
 
 
PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Head of Department: 
Drs. J.C. van Wevelingen 
 
19-05-2021 
Principal Investigator: 
Prof. Dr. H.J.M. Majoie 
 
19-05-2021 
 

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TABLE OF CONTENTS 
 
1. 
INTRODUCTION AND RATIONALE .............................................................................10 
2. 
OBJECTIVES ................................................................................................................12 
3. 
STUDY DESIGN ...........................................................................................................12 
4. 
STUDY POPULATION ..................................................................................................13 
4.1 
Population (base) ...................................................................................................13 
4.2 
Inclusion criteria .....................................................................................................13 
4.3 
Exclusion criteria ....................................................................................................13 
4.4 
Sample size calculation ..........................................................................................14 
5. 
TREATMENT OF SUBJECTS .......................................................................................14 
5.1 
Investigational product/treatment ............................................................................14 
5.2 
Use of co-intervention (if applicable) ......................................................................14 
5.3 
Escape medication .................................................................................................14 
6. 
INVESTIGATIONAL PRODUCT ....................................................................................15 
6.1 
Name and description of investigational  product(s) ...............................................15 
6.2 
Summary of findings from non-clinical studies ........................................................16 
6.3 
Summary of findings from clinical studies ...............................................................16 
6.4 
Summary of known and potential risks and benefits ...............................................16 
6.5 
Description and justification of route of administration and dosage .........................16 
6.6 
Dosages, dosage modifications and method of administration ...............................17 
6.7 
Preparation and labelling of Investigational Medicinal Product ...............................17 
6.8 
Drug accountability .................................................................................................17 
7. 
NON-INVESTIGATIONAL PRODUCT ...........................................................................17 
7.1 
Name and description of non-investigational product(s) .........................................17 
7.2 
Summary of findings from non-clinical studies ........................................................17 
7.3 
Summary of findings from clinical studies ...............................................................18 
7.4 
Summary of known and potential risks and benefits ...............................................18 
7.5 
Description and justification of route of administration and dosage .........................18 
7.6 
Dosages, dosage modifications and method of administration ...............................18 
7.7 
Preparation and labelling of Non-Investigational Medicinal Product ........................19 
7.8 
Drug accountability .................................................................................................19 
8. 
METHODS ....................................................................................................................19 
8.1 
Study parameters/endpoints ...................................................................................19 
8.1.1 
Main study parameter/endpoint .......................................................................19 
8.1.2 
Secondary study parameters/endpoints ..........................................................20 
8.1.3 
Other study parameters (if applicable) .............................................................20 
8.2 
Randomisation, blinding, and treatment allocation .................................................21 
8.3 
Study procedures ...................................................................................................21 
8.4 
Withdrawal of individual subjects ............................................................................23 
8.5 
Replacement of individual subjects after withdrawal ...............................................23 
8.6 
Follow-up of subjects withdrawn from treatment .....................................................24 
8.7 
Premature termination of the study .........................................................................24 

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9. 
SAFETY REPORTING ..................................................................................................24 
9.1 
Temporary halt for reasons of subject safety ..........................................................24 
9.2 
AEs, SAEs and SUSARs ........................................................................................24 
9.2.1 
Adverse events (AEs) ......................................................................................24 
9.2.2 
Serious adverse events (SAEs) .......................................................................24 
9.2.3 
Suspected unexpected serious adverse reactions (SUSARs) .........................25 
9.3 
Annual safety report ...............................................................................................25 
9.4 
Follow-up of adverse events ...................................................................................25 
9.5 
Data Safety Monitoring Board (DSMB) / Safety Committee] ...................................26 
10. 
STATISTICAL ANALYSIS ..........................................................................................26 
11. 
ETHICAL CONSIDERATIONS ...................................................................................26 
11.1 
Regulation statement .............................................................................................26 
11.2 
Recruitment and consent........................................................................................26 
11.3 
Objection by minors or incapacitated subjects ........................................................27 
11.4 
Benefits and risks assessment, group relatedness .................................................27 
11.5 
Compensation for injury .........................................................................................27 
11.6 
Incentives (if applicable) .........................................................................................27 
12. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .........................27 
12.1 
Handling and storage of data and documents ........................................................27 
12.2 
Monitoring and Quality Assurance ..........................................................................28 
12.3 
Amendments ..........................................................................................................28 
12.4 
Annual progress report ...........................................................................................28 
12.5 
Temporary halt and (prematurely) end of study report ............................................28 
12.6 
Public disclosure and publication policy ..................................................................28 
13. 
STRUCTURED RISK ANALYSIS...............................................................................28 
13.1 
Potential issues of concern .....................................................................................28 
13.2 
Synthesis ...............................................................................................................30 
14. 
REFERENCES ..........................................................................................................31 
15. 
APPENDIX ................................................................................................................35 
15.1 
QL-VAS ..................................................................................................................35 
15.2 
NHS3 .....................................................................................................................36 
15.3 
POMS-SF ...............................................................................................................37 
15.4 
SIDAED ..................................................................................................................38 
 
 
 
 
 
 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
AE 
AED 
Adverse Event 
Anti-epileptic drug 
AR 
BOLD 
BKT 
BRV 
BS 
CE 
CVST 
CYP 
Adverse Reaction 
Blood Oxygen Level Dependent 
Binary choice reaction test 
Brivaracetam 
Brain Stimulation 
Conformité Européenne 
Computerized visual searching task 
Cytochrome P450 
DSMB 
DTI 
EEG 
Data Safety Monitoring Board 
Diffuse Tensor Imaging 
Electroencephalography 
EudraCT 
fMRI 
GMP 
European drug regulatory affairs Clinical Trials  
Functional Magnetic Resonance Imaging 
Good Manufacturing Practice 
ICA 
METC  
Independent Component Analysis 
Medical research ethics committee (MREC); in Dutch: medisch ethische 
toetsing commissie (METC) 
MRI 
NHS3 
POMS-SF 
QL-VAS 
QOL 
RS-fMRI 
(S)AE 
Magnetic Resonance Imaging 
National hospital seizure severity scale 
Short form of profile of mood states 
Quality of life visual analog scale 
Quality of Life 
Resting state fMRI 
(Serious) Adverse Event  
SD 
SIDAED 
Sponsor 
Standard deviation 
Side effect of anti-epileptic drugs questionnaire 
The sponsor is the party that commissions the organization or performance 
of the research, for example a pharmaceutical company, academic hospital, 
scientific organization, or investigator. A party that provides funding for a 

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study but does not commission it is not regarded as the sponsor but referred 
to as a subsidising party. 
SV2A 
SUDEP 
SUSAR 
tDCS 
TEA 
T1 
TMS 
tVNS 
Synaptic Vesicle glycoprotein 2A 
Sudden unexpected death in epilepsy 
Suspected Unexpected Serious Adverse Reaction 
Transcranial Direct-Current Stimulation 
Treatment Adverse Events 
Telephone call 1 
Transcranial Magnetic Stimulation (TMS) 
Transcutaneous Vagal Nerve Stimulation 
Wbp 
Personal Data Protection Act (in Dutch: Wet Bescherming Persoonsgevens)
WMO 
 
WMA 
V1 
VNS 
VRT 
QL-VAS 
Medical Research Involving Human Subjects Act (in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 
World medical association 
Visit 1 
Vagal Nerve Stimulation 
Visual reaction time 
Quality of Life Visual Analogue Scale 
 
 

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SUMMARY 
Rationale: One of 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. We 
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: 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, we 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: One group receives transcutaneous vagal nerve stimulation (tVNS) 4 hours daily 
for the first 3 months of brivaracetam treatment. 
Main study parameters/endpoints: scoring on a composite index combining seizure 
reduction, improvement of cognition and quality of life.  
Nature and extent of the burden and risks associated with participation, benefit, and 
group relatedness: Besides minor temporary side effects no risk is attributed to tVNS. Because 
of the study one extra visit could be 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 benefit can be enormous if this treatment regime is able to provide control of disease 
earlier and more effective, since seizures have a tremendous impact on patient lives. Moreover, 
possibly necessary invasive treatments, and the corresponding risks, can be avoided. 
 

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1. INTRODUCTION AND RATIONALE 
Epilepsy is one of the most prevalent neurological disorders in the Netherlands, affecting 
roughly 180.000 individuals. The impact of the disorder is considerable for patients, especially 
if epilepsy is refractory to treatment. The condition pharmacoresistant or refractory epilepsy is 
met when complete control is not achieved after the use of two anti-epileptic drugs (AEDs), 
which is the case in approximately 30 percent of patients. In current practice, the next step is 
treatment with a newer AED, for example BRV which is registered as add-on treatment for 
focal epilepsy. Nevertheless, the development of novel AEDs in recent decades has not resulted 
in an improvement of the total amount of patients who become seizure free. Alternatively, 
epilepsy surgery and brain stimulation (BS) can be used in this group of patients. These 
treatments are however last-resort tools because of their invasive character and are also not 
sufficient for everybody. A new treatment regime that controls disease more effective in an 
earlier stage is desperately needed. 
In recent years, the insight into the neuronal mechanisms of epilepsy has changed 
towards a paradigm in which pathologic brain networks are considered important. Accordingly, 
a powerful modifier of these pathological networks might be the key in successful epilepsy 
treatment. For BS it is known that there is a mode of action through network modulation, as 
specific and long-lasting cerebral plasticity have been described after stimulation in recent 
animal and human studies, including Vagus Nerve Stimulation (VNS) [Hays 2013]. In addition, 
even in diseased brain effectiveness of VNS-based targeted plasticity therapies has been 
demonstrated, for example when paired with rehabilitation therapy [Hays 2015]. Given these 
results, BS might alter pathological epileptogenic networks beneficially as well, what could be 
a more plausible and constructive approach than pharmacological suppression of seizures. 
As mentioned before, BS also gained status as a so-called priming tool in the treatment 
of various brain diseases [Rumi 2005, Perez 2014, Hays 2015]. Priming can be described as 
augmenting the sensitivity of the brain to therapy by applying techniques that change the 
excitability of the cortex. Diverse non-invasive brain stimulation techniques such as 
transcranial magnetic stimulation (TMS), transcranial direct-current stimulation (tDCS) and 
VNS have been used to prime the brain in order to maximize the effects of further therapy, such 
as motor rehabilitation therapy in stroke or chemical treatment in depression and schizophrenia 
[Hays 2015, Rumi 2005, Zheng 2016]. Even though the exact mechanisms of BS priming 
remain unknown, there is evidence suggesting that priming facilitates network modulation 
[Hays 2015]. Notably, these effects persisted after discontinuation of therapy.  

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All data considered, there are reasons to believe that there is a role for the use of BS at 
an earlier stage in the treatment of epilepsy. One might hypothesise that by directing neural 
plasticity in pathological epileptic networks using VNS techniques, the epileptic brain can 
possibly be “primed” (prepared) for consecutive AED treatment. The limitation of testing this 
hypothesis is the invasive aspect of classic VNS treatment and most other BS techniques. The 
stimulation electrode is irreversibly attached at the stimulation site, and the implanted device 
has a battery which requires frequent replacement [Klooster 2016]. Recent development of a 
non-invasive vagus nerve stimulation technique offers possibilities. Transcutaneous auricular 
VNS (tVNS) applies stimulation via the auricular branch of the vagal nerve in the concha of 
the ear. In a recent randomized clinical trial, the beneficial effects of tVNS in drug resistant 
epilepsy were described [Bauer 2016]. However, the included patients already had a long 
history of epilepsy (average of 23.6 years), while we hypothesize that tVNS earlier in the 
disease course might be more effective. For example, because of the experience in clinical 
practice that persistent epilepsy is increasingly more difficult to treat. Moreover, Bauer et al left 
the AED treatment regimen unchanged, while we hypothesize that the combination of tVNS 
and a new AED could work synergistic. Last but not least, if the priming theory also goes for 
epilepsy treatment, it encompasses a temporary intervention instead of the current chronic use 
of VNS. 
 
To determine whether an epileptic brain has been primed or not, suitable measures needs 
to be defined. Besides clinical parameters, functional MRI (fMRI) also provides a non-invasive 
window into brain activity. In addition to traditional task-based fMRI, resting-state fMRI (RS-
fMRI) allows for visualizing baseline activity of the human brain by focusing on spontaneous 
fluctuations in the BOLD (blood oxygen level-dependent) signal. These fluctuations in brain 
activity form highly correlated patterns, so-called resting state networks (RSNs), which, in 
principle, reflect the full functional repertoire of the brain. A popular approach to spatially 
identify these RSNs is based on a mathematical technique called independent component 
analysis (ICA) [Lee 2013]. In patients with epilepsy, connectivity abnormalities have been 
found in RSNs such as the epileptogenic, cognitive, and sensory processing networks [Centeno 
2014]. In this way, fMRI can be used to identify changes in these RSNs as a result of treatment, 
that might be a read-out of successful therapy and possibly give more insight in the exact 
working mechanism of tVNS and priming. 
 
To conclude, the availability of tVNS as an unobtrusive method of VNS makes 
combining chemical and electrical modulation techniques more obvious and more feasible, 
especially in the earlier course of disease. In this study we propose a protocol in which the 

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epileptic brain is shortly treated by electrical modulation using tVNS, in order to prime the 
epileptic brain for chemical treatment using Brivaracetam.  
 
2. OBJECTIVES 
The main objective is: 
To determine the effect of tVNS as an electrical neuromodulation technique on priming the 
epileptic brain for add-on AED treatment with Brivaracetam, in terms of clinical improvement. 
 
The secondary objectives are: 
 To determine which clinical measures (e.a. seizures, cognition, quality of life, mood 
state) contribute to the possible clinical improvement.  
 To determine the underlying mechanism of the effect of tVNS by assessing differences 
in network-organization between patients ‘primed’ with short-term tVNS versus 
patients who have not been ‘primed’. 
 
Hypothesis: We hypothesize that pharmacotherapeutic treatment of refractory epilepsy can be 
more successful after “priming” the brain using tVNS as a temporary neuromodulation 
treatment. Furthermore, we expect that successful priming can be visualised by changes in 
network-organization. 
 
3. STUDY DESIGN 
We will use a cohort of 66 patients with refractory focal onset epilepsy, that starts add-on 
treatment with a new generation AED, Brivaracetam (BRV). They will be randomised in a 
study comparing i) 6 months of pharmacological treatment, of which the first 3 months 
combined with tVNS (intervention group), versus ii) 6 months of pharmacological treatment 
with BRV alone (control group). In each group a total of 33 patients will be included. A placebo-
controlled study is not possible because of the lack of a true sham stimulation. Besides clinical 
endpoints like quality of life and seizure frequency, additional cognitive tests will be performed 
at baseline, 3 months, and 6 months, to assess the effect and working mechanism of tVNS and 
its durability. An MRI scan will be done at baseline and 3 months. 
 
 
 
 

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Figure 1 Patient inclusion (n=66) 
 
 
 
 
 
 
 
 
              
 
     BRV + tVNS               
        BRV 
 
        
 
 
 Baseline 
  
 
 
 
 
                      
 
 
 
 
         
      
 
      
 
              
            BRV 
                   
        BRV 
 
 
 
 
            
       
      T2          T3  
 
 T4             T5 
 
 
 
 
4. STUDY POPULATION 
4.1 Population (base)  
Adults with a refractory focal epilepsy will be included in the study. Patients will be 
recruited from the outpatient clinics of the Academic centre for Epileptology 
Kempenhaeghe, Maastricht UMC+ and Elisabeth Tweesteden Hospital. The likelihood that 
the planned number of patients can be recruited is high, because of the large influx of new 
patients with refractory epilepsy every week.  
 
4.2 Inclusion criteria 
In order to be eligible to participate in this study, a subject must meet all the following 
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 
 
4.3 Exclusion criteria 
A potential subject who meets any of the following criteria will be excluded from 
participation in this study: 
- 
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 
3  m o n t h s
3  m o n t h s
V3
Cognition 
V2
MRI  
Cognition 
V1
MRI 
Cognition 
T1
B1
Start BRV 
Max 2 weeks

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- 
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 
 
4.4 Sample size calculation 
Based on  previous studies with both tVNS and with BRV a power calculation (Δ=0.0002, 
SD=0.00023) is performed with G*Power software aiming to distinguish an improvement 
on the composite index of > 2/3rd SD (seizure reduction, cognitive improvement, 
improvement of quality of life (QOL)), as this is a difference which is considered to have a 
potentially clinical relevance (Cohen 1977.). The power calculation, using a Mann-Whitney 
U test, showed that a sample size of 30 per group is required to reach a statistical power of 
80% (i.e. β=20% risk of type II errors) at α=0.05 (i.e. 5% risk of type I errors). Furthermore, 
a subject drop-out of 10% is estimated. Therefore, in total 66 subjects are needed. 
 
5. TREATMENT OF SUBJECTS 
5.1 Investigational product/treatment 
Patients in the intervention group will be additionally treated with tVNS for the first 3   
months of BRV treatment. 
 
5.2 Use of co-intervention (if applicable) 
Not applicable 
 
5.3 Escape medication 
Therapy intended for the acute treatment of seizures can be used as normal, such as 
benzodiazepines. This also applies to the treatment of a status epilepticus where current 
guidelines are leading. 
 

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6. INVESTIGATIONAL PRODUCT  
6.1 Name and description of investigational  product(s) 
The intervention group will receive 3 months of treatment with transcutaneous vagal nerve 
stimulation (tVNS). Vagal Nerve Stimulation (VNS) is the most used neurostimulation 
technique for the treatment of refractory epilepsy and has been used for more than 20 years. 
This traditional VNS method uses an implantable device with an electrode wrapped around 
the vagus nerve in the neck. Transcutaneous vagus nerve stimulation (tVNS) can stimulate 
the auricular branch of the vagus nerve through the skin of the outer ear. The study will use 
the CE certificated t-VNS device NEMOS® (tVNS technologies GmbH, previously 
Cerbomed GmbH, Erlangen, Germany), and the intended study population is within the 
approved indication for use, since it is intended for the treatment of epilepsy, depression 
and anxiety. The system includes an external pulse generator, roughly the size and weight 
of a cellular telephone, with a cutaneous contact electrode that is placed in the auricular 
tract. Placement of the electrode is designed to be a simple process, and patients are 
instructed on proper technique prior to using the device. A rechargeable Lithium battery 
powers the pulse generator, and the electrode is connected to the pulse generator via a 
connector cable. The rechargeable battery, battery charging station, and connector cables 
are included with the device. The used device settings are described in table 1. The technical 
support will be provided by the department of electrical engineering at TU Eindhoven. All 
personnel involved with the device will be appropriately trained in the requirements specific 
to this product. 
 
Figure 2: t-VNS device NEMOS ® with extern stimulator, placed in the auricular tract. 
 
 
Table 1: tVNS device parameters 
Pulse duration 
200-300 µs 
Duty cycle 
30 seconds on, 30 seconds off 
Current 
Set just below the threshold for painful stimulation (subject dependent) 
On / 24 hours 
4 hours (subject dependent which hours) 

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6.2 Summary of findings from non-clinical studies 
Animal studies showed no significant difference between VNS and tVNS for treatment of 
pentylenetrazole induced epilepsy rats [He 2009, He 2013]. In both treatment groups seizure 
activity measured with epidural EEG traces was significantly reduced, moreover the effects 
outlasted the period of stimulation. 
 
6.3 Summary of findings from clinical studies 
In addition to the well-known effect of the implanted VNS device (Panebianco 2015), 
preliminary studies show an equivalent effect of tVNS, with the advantage that the therapy 
can be easily stopped when in-effective. Moreover, the therapy has fewer side effects. The 
evidence that supports the use of tVNS was initiated by a small pilot study by Stefan et al 
[Stefan 2012]. Rong et al found a significant seizure reduction of 42.6 versus 11.5% in the 
control group in a randomized controlled trial in 144 patients [Rong 2014]. They also found 
a significant improvement in quality of daily life. Another recent randomized controlled 
trial by Bauer et al. in 70 patients showed a seizure reduction of 23 percent in the treatment 
group compared to -2.9 percent in the active control group, which was however not 
statistically significant. Side effects of tVNS include dizziness, headache and local pain, 
dysesthesia and itching and skin irritation at the stimulation site. All the side effects were 
reversible and disappeared soon after discontinuation of the stimulation [Bauer 2016, Rong 
2014, Song 2018].  
 
6.4 Summary of known and potential risks and benefits 
To date t-VNS has been well tolerated, without any serious adverse events. The most 
common side effects are headache or local pain at the stimulus site (11-32%), dizziness (7-
13%) and skin irritation (4-8%). All reported side effects disappeared soon after 
discontinuation of stimulation. 
 
6.5 Description and justification of route of administration and dosage 
 
According to the intended use, the stimulation is transcutaneous at the site of the external 
ear. The device parameters correspond to the advised settings by the producer and used in 
the published trials [Bauer 2016, Stefan 2012]. 
 

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6.6 Dosages, dosage modifications and method of administration 
The device will be used in the condition, and with the settings as supplied by the producer. 
The subject only has the ability to adjust the applied current. The current is set just below 
the threshold value for painful stimulation (paraesthesia) according to intended use which 
is also applied in previous trials.  
 
6.7 Preparation and labelling of Investigational Medicinal Product 
Since the investigational product is not pharmaceutical, the GMP guidelines are not relevant 
for this study. 
 
 
6.8 Drug accountability 
Not applicable. 
 
7. NON-INVESTIGATIONAL PRODUCT 
All patients will receive standard medical care for refractory focal epilepsy, in this case 
treatment with add-on Brivaracetam 2dd 50mg in accordance to guidelines. 
 
7.1 Name and description of non-investigational product(s) 
Brivaracetam (BRV, Briviact. UCB Pharma, Belgium) is a ligand of the synaptic vesicle 
protein SV2A and approved for adjunctive treatment of focal seizures. SV2A is a membrane 
glycoprotein and galactose transporter, present throughout the central nervous system in 
both GABA-ergic and glutaminergic neurons. It has been suggested that SV2A regulates 
several steps in the neurotransmitter release in the synaptic vesicle cycle. The anticonvulsant 
properties of BRV are thought to be a result of binding to SV2A and thus modulating 
neurotransmitter release [Klein 2018]. 
 
7.2 Summary of findings from non-clinical studies 
In phase I studies BRV was well tolerated and had a favourable pharmacokinetic profile 
over a wide dose range [Klein 2018]. BRV is highly lipid soluble and knows a rapid brain 
penetration. After oral administration, BRV is rapidly absorbed with a time to maximum 
concentration of approximately 1 hour. The maximum tolerated dose in healthy volunteers 
was 1,000 mg. Pharmacokinetics were not affected by age in healthy volunteers. Most 
patients with refractory epilepsy will use one or more AEDs. Brivaracetam does not 

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influence the CYP system, thus little interaction is expected with other AEDs the patient is 
already using. Furthermore, BRV did not significantly affect steady-state plasma 
concentration levels of concomitant AED’s in a large study of epilepsy patients [Benbadis 
2018]. Treatment initiation can take place at target dose, without a titration period.  
 
7.3 Summary of findings from clinical studies 
Safety, tolerability, and efficacy has been proven in 3 phase III prospective, multicentre, 
randomized, double-blind, placebo-controlled trials using a dose range of 50-200 mg/day in 
the adjunctive treatment of refractory focal seizures [Klein 2018]. A pooled analysis of these 
trials showed a significant reduction over placebo in focal seizure frequency/28 days and 
≥50% responder rates respectively of 19.5% and 34.2% for BRV 50mg/day, 24.4% and 
39,8% for 100mg/day, and 24% and 37,8% for 200mg/day. In a significant percentage of 
patients efficacy is seen as early as the first week of treatment and the effect continues to 
exist in the long-term.  
 
7.4 Summary of known and potential risks and benefits 
Treatment adverse effects (TEA) of BRV were studied using a pooled long term follow up 
of the 3 phase III clinical studies, investigating a total BRV exposure of 5,339 patient years. 
Most frequent TEA’s were headache (20.9%), dizziness (17.5%), somnolence (15.2%), 
nasopharyngitis (13.2%), fatigue (11.3%) and convulsions (10.6%) [Klein 2018]. Suicidal 
ideation was present in 0.5%. Discontinuation because of TEA’s was seen in 5.0%, 7.6% 
and 6.8% of patients treated with 50, 100, and 200mg BRV per day. Suicidal ideation was 
seen in 0.2% of patients taking BRV versus 0.7% in the placebo-group, with no reports of 
suicide attempts.  
 
7.5 Description and justification of route of administration and dosage 
Brivaracetam will be administered orally according to the intended use. 
 
7.6 Dosages, dosage modifications and method of administration 
The starting dosage is 50mg two times daily and the dose adjustments, up to a maximum of 
200mg daily, will be done by the treating neurologist corresponding to standard medical 
care. 
 

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7.7 Preparation and labelling of Non-Investigational Medicinal Product 
Not applicable, as the medication is prescribed and supplied outside the study. 
 
7.8 Drug accountability 
The medication will be prescribed by the treating neurologist, who is also responsible for 
any dose changes according to standard treatment protocol. The supply will be handled by 
the patient’s own pharmacy, as well as return and destruction of medication in case of 
discontinuation. A log will be used to track medication use, which will be evaluated every 
contact. This log includes brand, start date, dose and date of dose changes. 
 
8. METHODS 
8.1 Study parameters/endpoints 
8.1.1 Main study parameter/endpoint 
The success of therapy in epilepsy is not only determined by the amount of seizures, 
but by a combination of factors, for example cognitive disturbances, quality of life, the 
amount of side effects of treatments and society participation [Blond 2016, Baker 
2011, Chaplin 1998]. Moreover, vagus nerve stimulation has a direct effect on 
cognitive performance, mood and quality of life, independent of epilepsy [Groves & 
Brown 2005, Vonck et al 2014, Assenza 2020]. Not to mention the complex interaction 
of all these different factors, with for example stress inducing seizures. Therefore, we 
chose to use a composite index to determine the degree of success of therapy (Table 
1). Composite indexes are used before in epilepsy research, for example in drug 
research to combine the effect of seizure frequency and the burden of side effects 
[Cramer 1993]. While cognition is influenced by both epileptic seizures and tVNS 
treatment itself, and quality of life by even more factors, they are weighted as less 
important accordingly. Success of tVNS treatment is defined as a significant difference 
in total score between both groups in favour of the tVNS group. Based on the known 
effects of add-on brivaracetam and (t)VNS we expect the scores to be pseudo-
continuous. 
 
 
 
 

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Table 1 
 
8.1.2 Secondary study parameters/endpoints 
Compared between both groups: 
 
 Seizure frequency reduction in % at 3 and 6 months in respect to baseline  
 Seizure freedom rates, defined as the percentage of subjects with 100%  
reduction from baseline seizure frequency. It is calculated over the period 0-3 
months and 0-6 months by means of a per protocol and an intention-to-treat 
analysis with two methodologies, considering seizure-free drop-outs a success 
or failure. This is because the used method is widespread among different 
clinical epilepsy trials [Leppik 2006]. 
 Seizure severity assessed by the National Hospital Seizure Severity Scale – 
NHS3 [O’Dhonogue 1996], appendix 2 
 Profile of Mood State short form (POMS-SF) questionnaire to assess mood 
state, appendix 3 
 (Improvement in) cognitive functioning assessed by computerised cognitive 
tasks 
 Number of adverse events ascribed to tVNS and brivaracetam measured with 
the SIDAED questionnaire to include subjective complaints [Uijl 2006], 
appendix 6, and additional use of subjects’ report. 
 Required dose of Brivaracetam at 3 and 6 months 
 Change in network properties at 3 months 
 
8.1.3 Other study parameters (if applicable) 
By using randomisation, we hope to reduce the effect of confounding. Expected 
confounders are age, drug load and compliance of brivaracetam, extraordinary 
Composite index
 
Seizure reduction ≥50% 
3p 
Processing speed improvement ≥2/3 SD 
2p 
QL-VAS improvement (appendix 1) 
 ≥ 2 points 
1p 

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circumstances such as illness or stress, and comedication, for example for attention 
deficit disorders. These parameters will be registered.  
 
8.2 Randomisation, blinding, and treatment allocation 
Subjects are randomised by the investigators using randomisation software. The 
randomisation order is blinded, but because of the lack of a true sham stimulation protocol 
further blinding of patient, investigator and treating neurologist is not possible.  
 
8.3 Study procedures 
Screening Visit  
Prior to formal enrolment, the treating neurologist will screen interested subjects and 
determine if they meet inclusion, and no exclusion criteria. With the subject’s permission 
the treating neurologist will inform the investigator or trial nurse. They will provide eligible 
subjects with study information and informed consent documents in compliance with the 
local regulatory and legal requirements. Conform regular treatment, subjects are educated 
by their neurologist about brivaracetam, and the medication is started. Only study related 
visits will be at the participating centre, the Academic Centre for Epileptology 
Kempenhaeghe. The regular treatment is continued in the hospital of recruitment and the 
treating neurologist remains the same. 
 
Baseline Visit (V1)  
The investigator or trial nurse will read the informed consent and discusses the study 
information with the subject once more. If the subject meets inclusion and exclusion criteria, 
and agrees to participate, the patient will be included by the investigator or trial nurse. Their 
signature will be obtained in duplicate on the informed consent. The subject will be educated 
on how to classify seizures and maintain a seizure calendar. Questionnaires (NHS3, QOL-
VAS, and POMS-SF) will be completed. MRI scan and neuro cognitive tests will be 
performed. Randomisation will be performed. The tVNS group will be educated about the 
device which will also be demonstrated. 
 
Telephone call 1 (T1) for tVNS group 
The week following the start of the tVNS, usability issues are evaluated. 
 

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Seizure frequency and severity 
Patients will track and record their seizures by means of the epilepsy module in the mobile 
device application MedApp co-developed by Nationaal epilepsiefonds. In absence of a 
mobile device patients will use a paper seizure diary. Unfortunately, a seizure calendar is 
no guarantee of complete accuracy, but in this research setting more reliable options are not 
available. We hope to reduce this uncertainty by using a digital form and by means of 
frequent evaluation of the diary. The diary  and compliance to therapy will be evaluated 
every four weeks through either telephone calls (T2-5) or the visits (V1-3). Assessment of 
adequate treatment with brivaracetam and possible dose adjustments of brivaracetam as a 
consequence will be carried out by the treating neurologist in accordance to normal health 
care at visit 2 and 3 (V2-3). This will also be registered every contact. The seizure severity 
questionnaire will be completed during the visits (V1-3). 
 
Questionnaires 
Besides seizure severity (NHS3), the quality of life (QOL-VAS) and mood questionnaires 
(POMS-SF) will be completed during the visits (V1-3). 
 
Adverse events and side effects 
This data will also be evaluated all contact moments (by means of the SIDAED 
questionnaire), and patients are also able to mark them in MedApp. Any change in the 
treatment policy because of these effects is up to the treating neurologist. 
 
MRI protocol 
At baseline and 3 months patients will undergo an MRI scan with sequences for structural 
imaging (3D T1), diffuse tensor imaging (DTI) and resting state fMRI to display structural 
and functional connectivity. Contra-indications for MRI imaging are included in the 
exclusion criteria for the study. The duration of the MRI scan is approximately 30 minutes. 
Contrast agents or narcosis will not be used. 
 
Neuro cognitive tests 
The cognitive test battery comprises five cognitive tasks of which one is displayed on a 
Tobii computer with integrated eye tracker that records the performance. A big advantage 
over classical neuropsychological tests is the objectivity of the measurement. The cognitive 
tasks that will be used:  

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1. Computerized visual searching task (CVST) (Aldenkamp 2004): Subjects must 
compare a centred grid pattern with 24 surrounding patterns, one of which is identical 
to the target pattern. The test consists of 24 trials. Conventional output score is the 
total average searching time in seconds. 
2. Binary choice reaction test (BKT): Subjects must react differentially to a red square, 
presented on the left side of the screen than to a green square, presented on the right 
side. The score is the reaction time in milliseconds. 
3. Visual reaction time (VRT): Subjects must react as quickly as possible to a simple 
visual stimulus (white square on the screen) that is presented at random intervals, by 
pressing on the spacebar.  
4.  Visual reaction time Tobii: Subjects must react as quickly as possible to a simple 
visual stimulus (white square on the screen) that is presented at random intervals, by 
looking at the stimulus. The integrated eye tracker will record the time to first fixation. 
5.  The Rey auditory verbal learning task is used to assess memory function. 
The first four tests measure different components of central information processing, which 
is considered the most important cognitive function to assess in epilepsy patients [Grevers 
2016]. Memory is also an important determinant, especially in temporal lobe epilepsy. 
The total duration of the tests is 25 minutes. 
 
8.4 Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without any 
consequences. The investigator can decide to withdraw a subject from the study for urgent 
medical reasons. For instance, in case of prolonged hospitalization or seizure exacerbation 
with needs of addition of antiepileptic medication (except rescue medication) the subject 
will receive the necessary medical treatment but will be withdrawn from the study. For 
ethical reasons, if the subject wishes to continue t-VNS after withdrawal from the study this 
is allowed for the specified period. 
 
8.5 Replacement of individual subjects after withdrawal 
For every drop-out a new subject will be included to reach the intended group of 66 patients 
that complete follow-up. 
 

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8.6 Follow-up of subjects withdrawn from treatment 
Special follow-up for participants who are withdrawn from treatment is not considered 
necessary.  
 
8.7    Premature termination of the study 
We expect no serious adverse effects other than the known mild side effects of treatment 
with BRV or t-VNS which could cause a premature termination of the study. 
 
9. SAFETY REPORTING 
9.1 Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO, the investigators will suspend the 
study if there is enough ground that continuation of the study will jeopardise subject health 
or safety. The investigators will notify the accredited METC without undue delay of a 
temporary halt including the reason for such an action. The study will be suspended pending 
a further positive decision by the accredited METC. The investigator will take care that all 
subjects are kept informed. 
 
9.2 AEs, SAEs and SUSARs 
9.2.1 Adverse events (AEs) 
Adverse events are defined as any undesirable experience occurring to a subject during 
the study, whether or not considered related to the tVNS. All adverse events reported 
spontaneously by the subject or observed by the investigator or his staff will be 
recorded. The paresthesia due to electrical stimulation at the tVNS stimulation site are 
an adverse event, but because of the occurrence in all subjects and its clinical 
insignificance, this adverse event will not be reported to the ethical committee. A list 
of subjects reporting this adverse event will be kept. 
9.2.2 Serious adverse events (SAEs) 
A serious adverse event is any untoward medical occurrence or effect that  
- 
results in death; 
- 
is life threatening (at the time of the event); 
- 
requires hospitalisation or prolongation of existing inpatients’ hospitalisation; 
- 
results in persistent or significant disability or incapacity; 

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- 
is a congenital anomaly or birth defect; or 
- 
any other important medical event that did not result in any of the outcomes 
listed above due to medical or surgical intervention but could have been based 
upon appropriate judgement by the investigator. 
               An elective hospital admission will not be considered as a serious adverse event. 
 
We expect no SAEs in this study. In the unlikely case a SAE will occur, the study will     
be aborted until a possible connection between the SAE and our study is ruled out.  
 
We will report the SAEs through the webportal ToetsingOnline to the accredited 
METC that approved the protocol, within 7 days of first knowledge for SAEs that result 
in death or are life threatening followed by a period of maximum of 8 days to complete 
the initial preliminary report. All other SAEs will be reported within a period of 
maximum 15 days after the investigator has first knowledge of the serious adverse 
events. 
9.2.3 
Suspected unexpected serious adverse reactions (SUSARs) 
SUSARs will be handled conform SAEs. 
 
9.3 Annual safety report 
In addition to the expedited reporting of SUSARs, the investigators will submit, once a year 
throughout the clinical trial, a safety report to the accredited METC, competent authority, 
and competent authorities of the concerned Member States. 
This safety report consists of: 
- 
a list of all suspected (unexpected or expected) serious adverse reactions, along with 
an aggregated summary table of all reported serious adverse reactions, ordered by 
organ system, per study; 
- 
a report concerning the safety of the subjects, consisting of a complete safety 
analysis and an evaluation of the balance between the efficacy and the harmfulness 
of the medicine under investigation. 
 
9.4 Follow-up of adverse events 
All AEs will be followed until they have abated, or until a stable situation has been reached. 
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indicated, and/or referral to the general physician or a medical specialist. SAEs need to be 
reported till end of study within the Netherlands, as defined in the protocol.  
 
9.5 Data Safety Monitoring Board (DSMB) / Safety Committee] 
Not applicable. 
 
10. STATISTICAL ANALYSIS 
The analysis will be performed using SPSS, using a  Mann-Whitney U test. For further 
explanatory analysis we will use linear regression and discriminant analysis. Regarding the 
exploratory nature of the study, results will be evaluated with both intention-to-treat and per 
protocol analyses. 
 
11. ETHICAL CONSIDERATIONS 
11.1 Regulation statement 
This study will be conducted according to the principles of the Declaration of Helsinki (as 
adopted by the 64th WMA General Assembly, Fortaleza, Brazil October 2013), and is in 
accordance with the medical Research Involving Human Subjects Act (WMO) as well as 
common practice of Academic Center of Epilepsy Kempenhaeghe, when applicable for 
this study. 
 
11.2 Recruitment and consent 
Oral and written information about the aims of the study and the procedures will be provided 
by the investigators during the baseline visit when BRV is started. They will have the 
possibility to contact an investigator during working hours, and there will be an opportunity 
for questions during the first visit. Because inclusion within 2 weeks after start of 
brivaracetam is required, we have chosen for a minimal reflection period of 3 days. An 
example of the patient information letter and informed consent can be found in the 
attachments. Despite the fact that study visits take place at the Academic Centre for 
Epileptology Kempenhaeghe, the regular epilepsy treatment will be continued in the 
hospital of recruitment. They will not be referred to another hospital just because of the 
study. 
 
 

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11.3 Objection by minors or incapacitated subjects 
No minors or incompetent adults will be included in this study. 
 
11.4 Benefits and risks assessment, group relatedness 
If the treatment with tVNS is effective at this stage of treatment this potentially prevents 
burden of more additional anti-epileptic drugs, invasive methods of BS or surgery. The 
increase of quality of life and decrease of seizures, or even achieving seizure freedom, has 
an immense value because of medical, emotional, social, and economic consequences. And 
above all, this is then applicable to tens of thousands of patients in the Netherlands alone. 
Moreover, because tVNS is not only used for epilepsy, the increase of information about its 
working mechanism might be beneficial for other brain disorders as well. 
Equally important, to this point no severe harm is demonstrated because of tVNS use. If the 
known mild side effects occur, these are temporary in nature and will disappear after 
discontinuation of tVNS.  
 
11.5 Compensation for injury 
The investigator has a liability insurance which is in accordance with the legal requirements 
in the Netherlands (article 7 of the WMO). It provides cover for damage to research subjects 
through injury or death caused by the study. 
 
11.6 Incentives (if applicable) 
Patients may declare the costs made for travelling to and from Kempenhaeghe.  
 
12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
12.1 Handling and storage of data and documents 
Data are handled confidentially and is encrypted. Where it is necessary to be able to trace 
data to an individual subject, a subject identification code list can be used to link the data 
to the subject. The code will contain an unique number and the abbreviation of the 
including center. The principle investigator will safeguard the key to the code. The data 
will be stored for a period of 15 years. The handling of personal data complies with the 
Dutch Personal Data Protection Act (in Dutch: De Wet Bescherming Persoonsgegevens, 
Wbp). Unsuspected relevant findings on MRI will always be communicated with the 
general practitioner. 

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12.2 Monitoring and Quality Assurance  
      There is no DSMB. 
 
12.3 Amendments  
Amendments are changes made to the research after a favourable opinion by the accredited 
METC has been given. All amendments will be notified to the METC that gave a favourable 
opinion.  
 
12.4 Annual progress report 
The sponsor/investigator will submit a summary of the progress of the trial to the accredited 
METC once a year. Information will be provided on the date of inclusion of the first subject, 
numbers of subjects included and numbers of subjects that have completed the trial, serious 
adverse events/ serious adverse reactions, other problems, and amendments.  
 
12.5 Temporary halt and (prematurely) end of study report 
The investigator will notify the accredited METC of the end of the study within a period of 
8 weeks. The end of the study is defined as the last patient’s last visit. The investigator will 
notify the METC immediately of a temporary halt of the study, including the reason of such 
an action. In case the study is ended prematurely, the investigator will notify the accredited 
METC within 15 days, including the reasons for the premature termination. 
Within one year of the end of the study, the investigator will submit a final study report with 
the results of the study, including any publications/abstracts of the study, to the accredited 
METC. 
 
12.6 Public disclosure and publication policy 
We intend to publish the findings from the current study in international, peer-reviewed 
journals. Publication will not be limited to positive findings.  
 
13. STRUCTURED RISK ANALYSIS  
13.1 Potential issues of concern 
 
a. Level of knowledge about mechanism of action 

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The exact working mechanism of tVNS and VNS is not known yet (see chapter 1 and 6). 
So far, different hypotheses have been suggested for the working mechanism of BS in 
general or VNS, of which none have been proven by this day. Both actions at neuron and 
network level are described. Moreover, if the working mechanism of tVNS corresponds to 
invasive VNS is not known either, but the first studies at least do not prove otherwise. 
Except for the different side effects due to the stimulation site. 
 
b. Previous exposure of human beings with the test product(s) and/or products with a similar 
biological mechanism 
tVNS is already tested in multiple trials with epilepsy patients (see chapter 6). Additionally, 
tVNS is used in multiple healthy subjects and patients with other diseases, for example 
tinnitus, headache disorders or psychiatric diseases (Van Leusden et al 2015, Ben Menachem 
et al 2015, Wu et al 2018, Yakunina 2018). Furthermore, there are many years of experience 
with VNS and there is no reason to believe that tVNS has a very different working 
mechanism based on the so far published trials (see chapter 6).  
 
c. Can the primary or secondary mechanism be induced in animals and/or in ex-vivo human 
cell material? 
There are animal studies describing the effect of tVNS (see chapter 6), but those studies are 
not sufficient to answer the objectives because the differences in animal brain and behaviour 
compared to humans, among other things.  
 
d. Selectivity of the mechanism to target tissue in animals and/or human beings 
Besides the diseased part of the brain other brain areas are targeted too, of which no 
disadvantageous effects are known and expected. On the contrary, the reported positive 
effects on cognition might be partly caused by this. Target organs of the vagal nerve, for 
example the heart, possibly experience an effect of tVNS. However, so far no systemic side 
effects are reported in tVNS (see chapter 6). To be sure, patients with known cardiac 
arrhythmias are excluded. 
 
e. Analysis of potential effect 
The known side effects are mild and temporary of nature and disappear immediately after 
discontinuation of tVNS (see chapter 6). 
 

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f. Pharmacokinetic considerations 
Not applicable. 
 
g. Study population 
Subjects are patients suffering from refractory focal epilepsy which is usually not life-
threatening. There is a chance of so called sudden unexpected death in epilepsy (SUDEP) 
which is estimated at 9 in 1000 patient years in epilepsy patients in general, but is more 
prevalent in patients with nocturnal and generalised seizures which occur less frequently in 
focal epilepsy. 
 
h. Interaction with other products 
We hypothesize that the effect of BRV is strengthened by tVNS, but this expectation is 
mostly theoretical and partly based on studies in patients with other (in particular psychiatric) 
brain diseases with different medication and/or stimulation protocols, so the exact 
mechanism is not known. 
 
i. Predictability of effect 
Since the exact mechanism is not known we investigate multiple outcome measures in both 
seizure reduction, cognitive improvement, and quality of life, based on previous trials (see 
chapter 6). Since many outcome measures are subjective to reporting by patients, we also 
look for quantitative measures with MRI and computerized cognitive tests. 
 
j. Can effects be managed? 
No direct antagonist of tVNS is known, besides stopping the stimulation. In case of acute 
seizure exacerbation, which is not expected, management is possible with different fast 
working medicaments such as benzodiazepines. 
 
13.2 Synthesis 
Although the exact working mechanism of (t)VNS is not known yet, there is already 
extensive experience with the treatment and its attributed risks. So far, no risks are attributed 
to tVNS besides mild temporary side effects. Measures taken in this study to reduce potential 
risks are: the exclusion of patients with contra-indications for MRI, the exclusion of patients 
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in contrast to patients treated with invasive VNS), the use of the tVNS device within the 
indication of use and with the advised settings, the withdrawal of patients with a serious 
seizure exacerbation and the temporary halt of the study in case of serious adverse events. 
Even though no risks are known this far, the potential benefit of this treatment regime to 
control disease earlier and more effective would make many remaining risks acceptable in 
our opinion. Both better control of disease, with associated medical, emotional, social, and 
economic consequences, as well as prevention of burden of more additional anti-epileptic 
drugs or invasive treatments, are equally important. 
 
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15. APPENDIX 
 
15.1 QL-VAS 
 
 
 

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15.2 NHS3 
 
 
 

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15.3 POMS-SF 
 
 

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15.4 SIDAED