EEG Controlled Triage in the Ambulance for Acute Ischemic Stroke
Phase: NA
Conditions: Stroke, Ischemic
Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

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ELECTRA-STROKE 
EEG controlled triage in the ambulance for acute ischemic stroke 
RESEARCH PROTOCOL 
 
 
 
 
 
 
 

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PROTOCOL TITLE: ‘ELECTRA-STROKE: EEG controlled triage in the 
ambulance for acute ischemic stroke’ 
 
Protocol ID 
NL65939.018.18 
Short title 
ELECTRA-STROKE 
EudraCT number  
Not applicable 
Version 
10.0 
Date 
20-04-2022 
Coordinating investigator 
Laura C.C. van Meenen, PhD-candidate 
Amsterdam University Medical Centers 
Location AMC 
Department of Neurology, room H2-225 
Meibergdreef 9, 1105 AZ Amsterdam 
The Netherlands  
Telephone: +31 20 5663447 
Email: l.c.vanmeenen@amsterdamumc.nl 
 
Project leaders 
 
 
Dr. Jonathan Coutinho, neurologist 
Amsterdam University Medical Centers 
Location AMC 
Department of Neurology, room H2-260 
Meibergdreef 9, 1105 AZ Amsterdam 
The Netherlands 
Telephone: +31 20 566 2004 
Email: j.coutinho@amsterdamumc.nl 
 
Dr. Wouter Potters, technical physician 
Amsterdam University Medical Centers 
Location AMC 
Dept. of Clin. Neurophysiology, room D2-127 
Meibergdreef 9, 1105 AZ Amsterdam 
The Netherlands 
Telephone: +31 20 5663515 
Email: w.v.potters@amsterdamumc.nl 
 
Principal investigator coordinating center (in 
Dutch: hoofdonderzoeker/ uitvoerder) 
 
Dr. Jonathan Coutinho, neurologist 
 
Study staff other participating centers 
VUMC  
Marieke Visser, neurologist 
Amsterdam UMC, location VUMC 
Department of neurology 

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De Boelelaan 1117, 1081 HV Amsterdam 
Telephone: 020-4442834 
Email: mc.visser@vumc.nl 
 
OLVG West 
Renske van den Berg, neurologist 
OLVG, location West 
Department of Neurology 
Jan Tooropstraat 164, 1061 AE Amsterdam 
Telephone: 020-5108780 
Email: r.vandenberg-vos@olvg.nl 
 
Noordwest Ziekenhuisgroep, location 
Alkmaar 
Patricia Halkes, neurologist 
Noordwest Ziekenhuisgroep, location 
Alkmaar 
Wilhelminalaan 12, 1815 JD Alkmaar 
Telephone: 0725484444 
Email: p.h.a.halkes@nwz.nl 
 
Ambulance Amsterdam 
Arjen Siegers, anesthesiologist and medical 
manager ambulance care Ambulance 
Amsterdam 
Ambulance Amsterdam 
Karperweg 19-25, 1075 LB Amsterdam 
Telephone: 020-5709500 
Email: asiegers@ambulanceamsterdam.nl 
 
Witte Kruis Noord-Holland Noord 
Martin Smeekes, director Safety Region 
Noord-Holland Noord, director Regional 
Ambulance Service Noord-Holland Noord 
Hertog Aalbrechtweg 22, 1823 DL Alkmaar 
Telephone: 072-5675010 
Email: msmeekes@vrnhn.nl 
 
Sponsor (in Dutch: verrichter/opdrachtgever) 
Amsterdam University Medical Centers 
Location AMC 
Meibergdreef 9, 1105AZ Amsterdam 
The Netherlands 
 
Subsidising party 
AMC Innovation Grant 
Independent expert 
Vincent Odekerken, neurologist 
Amsterdam University Medical Centers 
Location AMC 

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Department of Neurology, room H2-228 
Meibergdreef 9, 1105 AZ Amsterdam 
The Netherlands 
Telephone: +31 20 5663445 
Email: v.j.odekerken@amc.nl 
Laboratory sites 
Not applicable 
Pharmacy 
Not applicable 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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PROTOCOL SIGNATURE SHEET 
 
 
               Signature 
     Date 
Head of Department 
Prof. dr. B.M.J. Uitdehaag, neurologist 
 
 
Project leader 
Dr. J. Coutinho, neurologist AMC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
 
PROTOCOL TITLE ........................................................................................................................................... 2 
PROTOCOL SIGNATURE SHEET ...................................................................................................................... 5 
TABLE OF CONTENTS ..................................................................................................................................... 6 
LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS ................................................................................ 8 
SUMMARY ..................................................................................................................................................... 9 
1. INTRODUCTION AND RATIONALE ........................................................................................................... 12 
2. OBJECTIVES ............................................................................................................................................. 14 
3. STUDY DESIGN ......................................................................................................................................... 14 
4. STUDY POPULATION ............................................................................................................................... 16 
4.1 Population (base) .............................................................................................................................. 16 
4.2 Inclusion criteria ................................................................................................................................ 17 
4.3 Exclusion criteria ............................................................................................................................... 18 
4.4 Sample size calculation ..................................................................................................................... 18 
5. TREATMENT OF SUBJECTS ...................................................................................................................... 20 
6. INVESTIGATIONAL PRODUCT .................................................................................................................. 21 
7. NON-INVESTIGATIONAL PRODUCT ......................................................................................................... 21 
7.1 Name and description of non-investigational product ..................................................................... 21 
7.2 Summary of findings from non-clinical studies................................................................................. 21 
7.3 Summary of findings from clinical studies ........................................................................................ 22 
7.4 Summary of known and potential risks and benefits ....................................................................... 22 
8. METHODS ................................................................................................................................................ 22 
8.1 Study parameters/end points ........................................................................................................... 22 
8.1.1 Main study parameter/end point .............................................................................................. 22 
8.1.2 Secondary study parameters/end points .................................................................................. 22 
8.2 Blinding ............................................................................................................................................. 23 
8.3 Study procedures .............................................................................................................................. 23 

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8.4 Withdrawal of individual subjects .................................................................................................... 24 
8.5 Replacement of individual subjects after withdrawal ...................................................................... 24 
9. SAFETY REPORTING ................................................................................................................................. 24 
9.1 Temporary halt for reasons of subject safety ................................................................................... 24 
9.2 AEs, SAEs and SUSARs ....................................................................................................................... 25 
9.2.1 Adverse Events (AEs) .................................................................................................................. 25 
9.2.2 Serious Adverse Events (SAEs) ................................................................................................... 25 
9.3 Follow up of adverse events ............................................................................................................. 26 
9.4 Safety committee .............................................................................................................................. 26 
10. STATISTICAL ANALYSIS AND ALGORITHM DEVELOPMENT ................................................................... 26 
11. ETHICAL CONSIDERATIONS ................................................................................................................... 27 
11.1 Regulation statement ..................................................................................................................... 27 
11.2 Recruitment and consent ................................................................................................................ 27 
11.3 Incapacitated subjects .................................................................................................................... 30 
11.4 Benefits and risk assessment, group relatedness ........................................................................... 31 
11.5 Compensation for injury ................................................................................................................. 31 
11.6 Incentives ........................................................................................................................................ 31 
12. ADMINISTRATIVE ASPECTS AND MONITORING .................................................................................... 31 
12.1 Handling and storage of data and documents ................................................................................ 31 
12.2 Monitoring and Quality Assurance ................................................................................................. 31 
12.3 Amendments ................................................................................................................................... 32 
12.4 Annual progress report ................................................................................................................... 32 
12.5 Temporary halt and (premature) end of study report .................................................................... 32 
13. RISK ANALYSIS ....................................................................................................................................... 33 
14. REFERENCES .......................................................................................................................................... 33 
 
 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS 
AE 
Adverse event 
AIS 
Acute ischemic stroke 
AMC 
Academic Medical Center, 1 of 2 Amsterdam UMC locations 
Amsterdam UMC 
Amsterdam University Medical Centers 
AVG 
General Data Protection Regulation (in Dutch: Algemene Verordening 
Gegevensbescherming) 
CT 
Computed Tomography 
EEG 
Electroencephalography 
EMS 
Emergency medical service 
EVT 
Endovascular thrombectomy 
ER 
Emergency room 
METC  
Medical research ethics committee (MREC); in Dutch: medisch ethische 
toetsingscommissie (METC) 
MRI 
Magnetic Resonance Imaging 
mRS 
Modified Rankin Scale 
NIHSS 
National Institute of Health Stroke Scale 
OLVG West 
Onze Lieve Vrouwe Gasthuis, locatie Amsterdam West 
SAE 
Serious adverse event  
Sponsor 
The sponsor is the party that commissions the organisation or performance of the 
research, for example a pharmaceutical company, academic hospital, scientific 
organisation or investigator. A party that provides funding for a study but does not 
commission it is not regarded as the sponsor, but referred to as a subsidising party. 
VUMC 
Vrije Universiteit Medisch Centrum, 1 of 2 Amsterdam UMC locations 
WMO 
 
Medical Research Involving Human Subjects Act (in Dutch: Wet Medisch-
wetenschappelijk onderzoek met mensen) 
 

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SUMMARY 
RATIONALE 
Endovascular thrombectomy (EVT) is standard treatment for acute ischemic stroke (AIS) if there is a 
large vessel occlusion in the anterior circulation (LVO-a). Because of its complexity, EVT is performed in 
selected hospitals only. Currently, approximately half of EVT eligible patients are initially admitted to 
hospitals that do not provide this therapy. This delays initiation of treatment by approximately an hour, 
which decreases the chance of a good clinical outcome. Direct presentation of all patients with a 
suspected AIS in EVT capable hospitals is not feasible, since only approximately 7% of these patients are 
eligible for EVT. Therefore, an advanced triage method that reliably identifies patients with an LVO-a in 
the ambulance is necessary. Electroencephalography (EEG) may be suitable for this purpose, as 
preliminary studies suggest that slow EEG activity in the delta frequency range correlates with lesion 
location on cerebral imaging. Use of dry electrode EEG caps will enable relatively unexperienced 
paramedics to perform a reliable measurement  without the EEG preparation time associated with ‘wet’ 
EEGs. Combined with algorithms for automated signal analysis, we expect the time of EEG recording and 
analysis to eventually be below five minutes, which would make stroke triage in the ambulance by EEG 
logistically feasible. 
HYPOTHESIS 
We hypothesize that dry electrode cap EEG can be used in patients with a suspected AIS to identify 
patients with an LVO-a in the ambulance.  
OBJECTIVE 
To determine the diagnostic accuracy of dry electrode cap EEG for diagnosis of LVO-a, when performed 
by paramedics in the ambulance in patients with a suspected AIS.  
STUDY DESIGN 
This diagnostic study consists of four phases: 
Phase 1: Optimization of measurement time and software settings of the dry electrode cap EEG in a non-
emergency setting in patients in whom a regular EEG is/will be performed for standard medical care. 

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Phase 2: Optimization of measurement time and software settings of the dry electrode cap EEG in 
patients close to our target population in a non-emergency setting. 
Phase 3: Validation of several existing algorithms and development of one or more new algorithms for 
LVO-a detection, as well as optimization of logistics and software settings of the dry electrode EEG cap in 
patients close to our target population in an in-hospital emergency setting. 
Phase 4: Validation of several existing algorithms and algorithms developed in phase 3 for LVO-a 
detection in patients with a suspected AIS in the ambulance, as well as assessment of technical and 
logistical feasibility of performing EEG with dry electrode caps in patients with a suspected AIS in the 
ambulance.  
STUDY POPULATION 
Phase 1: Patients in the outpatient clinic of the Clinical Neurophysiology department of the AMC, in 
whom a regular EEG has been/will be performed for standard medical care.  
Phase 2: Patients with an AIS admitted to the Neurology ward of the coordinating hospital with an LVO-a 
(after reperfusion therapy).  
Phase 3: Patients with a suspected AIS in the emergency room (ER) of the coordinating hospital (before 
reperfusion therapy). 
Phase 4: Patients with a suspected AIS in the ambulance. 
INTERVENTION 
Performing a dry electrode cap EEG (in phase 1 in the outpatient clinic, in phase 2 during hospital 
admission, in phase 3 in the ER and in phase 4 in the ambulance).  
MAIN END POINTS 
- 
Primary end point: the area under the receiver operating characteristics (ROC) curve of the 
theta/alpha ratio for diagnosis of LVO-a, based on dry electrode EEG performed by paramedics 
in the ambulance in suspected AIS patients; 
- 
Secondary end points:  

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o Sensitivity, specificity, positive predictive value (PPV) and negative predictive value 
(NPV) of the theta/alpha ratio, and test characteristics of other existing EEG data based 
algorithms for LVO-a detection (e.g. Weighted Phase Lag Index, delta/alpha ratio); 
o Logistical and technical feasibility of paramedics performing dry electrode cap EEG in 
the ambulance in suspected AIS patients ; 
o Developing one or more novel EEG data based algorithms with optimal diagnostic 
accuracy for LVO-a detection in suspected AIS patients with ambulant dry electrode cap 
EEG. 
NATURE AND EXTENT OF THE BURDEN AND RISKS ASSOCIATED WITH PARTICIPATION, 
BENEFIT AND GROUP RELATEDNESS 
A single EEG is performed on each patient. The EEG is a safe, non-invasive and painless procedure that is 
used regularly in standard medical practice. It does not involve electromagnetic radiation. The use of dry 
electrodes makes the procedure less time-consuming. After optimization of measurement time in phase 
1 and 2, the procedure will take less than five minutes in total. Therefore, when the measurements are 
performed in an emergency setting in phases 3 and 4, the procedure can be completed within the time 
it takes the treating physician or paramedic to perform their regular work-up. This way, initiation of 
treatment will not be delayed. We expect the dry electrode cap to cause no to minimal discomfort, and 
only during the measurement. We will use CE marked products for performing the dry electrode cap 
EEGs. The results of the EEG will only be analyzed after admission or discharge, and will therefore not 
influence the choice of hospital by the paramedic. As soon as feasible, preferably within 72 hours after 
arrival at the hospital or at discharge (whichever comes first), deferred informed consent will be asked. 
If informed consent is given, a CRF will be filled out containing information on patient characteristics, 
medical history, medication use, physical and neurological examination performed by the treating 
physician, results of imaging studies, diagnosis and treatment as well as logistical and technical 
information, obtained from the patient, the treating physician and the ambulance service. There are no 
follow up visits. For the patient, there is no benefit of participation in the study.  
 
 

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1. INTRODUCTION AND RATIONALE 
 
Acute ischemic stroke (AIS) is a major cause of mortality and morbidity worldwide, affecting 
approximately 1 per 1000 people per year1. In the Netherlands, 20.000 people are hospitalized with AIS 
each year, of whom 25-30% die because of the stroke2,3. Since the 1990’s, intravenous thrombolysis 
(IVT) has been standard treatment for AIS4.  In 2015, there was a breakthrough in treatment of AIS with 
the publication of 5 large randomized controlled trials showing the effectiveness of endovascular 
thrombectomy (EVT) in patients with a large vessel occlusion in the anterior circulation (LVO-a)5. Since 
then, EVT has been become standard therapy for this population until 6 hours after stroke onset, and as 
of recently, for a selected population, up to 24 hours5-7. It is important to initiate treatment as soon as 
possible, as this increases the chance of a good clinical outcome8.  
Because of its complexity, EVT is performed only in selected hospitals. Currently, approximately half of 
EVT eligible patients are initially admitted to a hospital that does not provide this therapy. After the 
initial work-up, these patients are transferred to an EVT capable hospital. This delays initiation of 
treatment by approximately an hour, which decreases the absolute chance of functional independence 
3 months after the stroke by 5-8%8,9. An advanced triage method that reliably identifies patients with an 
LVO-a in the ambulance is necessary, so that these patients can be directly transported to an EVT 
capable stroke center.  
A triage method for this purpose needs to have both high specificity and high sensitivity for LVO-a. The 
sensitivity of the diagnostic method is important, because a false negative test result means that the 
patient would be transported to a non EVT capable hospital, delaying his/her treatment. However, we 
deem the specificity of the method even more important, for the following reasons.  Currently, EVT 
capable hospitals are overburdened because many patients with a suspected stroke are directly brought 
to these hospitals, as paramedics often do not want to take the chance of bringing a patient to the 
‘wrong’ hospital. However, only a small part of these patients, circa 7%, is eligible for EVT. This causes 
EVT capable hospitals to have low capacity for admission of patients that do need specialized care. 
Additionally, patients with expected stroke currently are first evaluated in the emergency room where 
they undergo diagnostic procedures, and are then brought to the angiography room to undergo EVT. 
This takes approximately an hour from entering the hospital to the start of treatment (not all this time is 
due to diagnostic procedures, but also to other logistical issues that are not addressed in this study). 
Currently, the angiography room is not being prepared for every patient that is presented to the 

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emergency room with a suspected stroke, because of the low a priori chance of eligibility for EVT in 
patients with a suspected stoke.  A diagnostic method with high specificity will make it possible, in 
patients in whom a high likelihood of an LVO-a has been determined in the ambulance, to minimize (or 
maybe even leave out) diagnostic procedures in the emergency room and to present these patients 
directly to the angiography room, in order to save time. Several methods for determining the likelihood 
of an AIS with an LVO-a have been proposed. However, none of these have been found to be suitable for 
prehospital triage. Clinical scales, containing items for scoring the severity of neurological deficit, are 
difficult to be reliably applied by paramedics and have low diagnostic accuracy10. Another option for pre-
hospital stroke triage that has been explored, is equipping ambulances with an imaging system for 
performing non-contrast CT and CT angiography to diagnose LVO-a and, in some studies, give IVT. 
However, its efficacy has not been proven and there are concerns regarding the safety and cost-
effectiveness of this method11. An effective and safe prehospital triage method for stroke that can be 
reliably performed and analyzed by paramedics has not yet been found. 
Electroencephalography (EEG) may be suitable for prehospital triage, as preliminary studies suggest that 
slow EEG activity in the delta frequency range correlates with lesion location on cerebral imaging12,13. 
Another study has suggested using (a)symmetry in brain activity for monitoring of stroke patients14. EEG 
is already being used in clinical practice for monitoring for signs of cerebral ischemia during carotid 
surgery while the carotid artery is clamped, and can predict the likelihood of postoperative neurological 
deficit with high specificity (84-92%)15,16. This suggests that the occlusion of a large artery, similar to 
clamping of the carotid artery in its effect on cerebral blood supply, could also be predicted by EEG. One 
case-control study found that in patients with a recent AIS, the Brain Symmetry Index – an index that 
expresses EEG asymmetry (the higher the index, the more asymmetrical is the EEG signal) – positively 
correlated with severity of neurological deficits17. Other case-control studies have shown that ratios 
between slow and fast EEG activity, such as the delta/alpha ratio, can be used to discriminate between 
AIS patients and healthy controls with high sensitivity and specificity18,19. The Weighted Phase Lag Index, 
a measure for functional connectivity between different areas of the brain, has also been proposed for 
this purpose19. Although a regular EEG measurement takes approximately an hour, mostly due to 
preparation time, using dry electrode EEG caps decreases preparation time dramatically20. Combined 
with algorithms for automated signal analysis, we expect the time of a single EEG recording and analysis 
to be below 5 minutes, which will make stroke triage in the ambulance by EEG logistically feasible. 
Automated analysis would make it unnecessary for paramedics to be schooled in EEG interpretation; 

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combined with the easily applicable dry electrode cap, this should enable relatively unexperienced 
paramedics to perform a reliable measurement. 
To our knowledge, no study of the diagnostic accuracy of EEG for LVO-a has been performed. We 
hypothesize that EEG can accurately predict the likelihood of the presence or absence of an LVO-a in 
patients with a suspected AIS when performed in the ambulance by paramedics. If this is indeed true, 
then EEG could be used for triage for patients with a suspected AIS, in a similar way the 
electrocardiography (ECG) is currently used for triage in patients with suspected myocardial infarction in 
the ambulance: by bringing patients with a high likelihood of necessity of endovascular therapy directly 
to an EVT capable center.  
 
2. OBJECTIVES 
 
The primary objective of this diagnostic study is to determine the diagnostic accuracy of dry electrode 
cap EEG for diagnosis of LVO-a, when performed by paramedics in the ambulance in patients with a 
suspected AIS.  
The secondary objectives of this study are: 
- Determining the diagnostic accuracy for LVO-a detection of several existing EEG data based algorithms 
(e.g. Weighted Phase Lag Index, delta/alpha ratio); 
- Assessing the logistical and technical feasibility of paramedics performing dry electrode cap EEG in the 
ambulance in suspected AIS patients; 
- Developing one or more novel EEG data based algorithms with an optimal diagnostic accuracy for LVO-
a detection in suspected AIS patients with ambulant dry electrode cap EEG. 
 
3. STUDY DESIGN 
The ELECTRA-STROKE is an investigator-initiated, diagnostic study, that consists of four phases (see 
below). 

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STUDY PHASE 1: OPTIMIZING MEASUREMENT TIME, SOFTWARE SETTINGS AND 
DATA TRANSFER LOGISTICS IN PATIENTS IN WHOM A REGULAR EEG HAS BEEN/WILL 
BE PERFORMED FOR STANDARD MEDICAL CARE IN A NON-EMERGENCY SETTING 
This phase will be carried out in the outpatient clinic of the department of Clinical Neurophysiology of a 
single center (Amsterdam UMC, location AMC). We will perform dry electrode cap EEGs on patients in 
whom a regular EEG has been/will be performed for standard medical care. We will compare the regular 
EEG to the dry electrode cap EEG and this way try to optimize the dry electrode cap EEG measurement, 
software settings, data transfer logistics and measurement time in a population of patients less 
vulnerable than our target population, in a non-emergency setting.  
STUDY PHASE 2: OPTIMIZING MEASUREMENT TIME, SOFTWARE SETTINGS AND 
DATA TRANSFER LOGISTICS IN PATIENTS CLOSE TO TARGET POPULATION IN A NON-
EMERGENCY SETTING. 
This phase will be carried out in the brain care unit of a single center (Amsterdam UMC, location AMC). 
We will perform dry electrode cap EEGs in a population close to our target population – patients that 
have been admitted with an AIS and an LVO-a – in a non-emergency setting. We will test technical 
feasibility of the dry electrode cap EEG in patients that are, in part, unable to cooperate with the 
procedure (e.g. patients that because of lowered consciousness or agitation will not keep their head 
still).  
STUDY PHASE 3: VALIDATION OF EXISTING ALGORITHMS AND DEVELOPMENT OF 
NEW ALGORITHM(S) IN PATIENTS IN THE EMERGENCY ROOM 
This phase will be carried out in the ER of a single center (Amsterdam University Medical Centers, 
location AMC). In this phase, we will perform dry electrode cap EEGs in patients that are presented to 
the ER of the coordinating hospital with a clinically suspected AIS, according to the paramedic that 
presents the patient, or with a known LVO-a. The last category of patients have undergone an initial 
work-up in a primary stroke center, where the diagnosis LVO-a has been made, and are transferred to 
our hospital to undergo EVT. The EEG data of this ‘enriched’ population, with a higher incidence of LVO-
a compared to the primary target population, will be used to validate several existing algorithms and to 
develop one or more new algorithms for diagnosis of LVO-a. 
STUDY PHASE 4: VALIDATION OF ALGORITHMS IN THE AMBULANCE 

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This phase is the only multi-center phase of this study. It will be carried out in the ambulances of one 
ambulance station in Amsterdam and one ambulance station in Alkmaar. These ambulances bring 
patients with a suspected acute stroke to the following hospitals: AMC, VUMC and OLVG West and 
Noordwest Ziekenhuisgroep, location Alkmaar. These will therefore be the centers participating in this 
study phase, as well as the Ambulance Amsterdam. The EEG data will be used to validate several existing 
algorithms (among which is the Brain Symmetry Index) and the algorithm(s) developed in phase 3. 
Technical and logistical feasibility of performing ambulant EEGs in patients with a suspected AIS in the 
ambulance will also be assessed. 
Phase 4 will start with a ‘run in’ phase. The objective of this phase is to assess technical and logistical 
feasibility of performing ambulant EEGs in patients with a suspected AIS, before commencing inclusion 
of the prespecified study population. Inclusion will not be consecutive at this stage. 
The four phases will not necessarily run consecutively; they may also, in part, run simultaneously. Each 
phase consists of performing a single dry electrode cap EEG per patient and collecting information on 
patient characteristics, medical history, medication use, physical and neurological examination 
performed by the treating physician, imaging studies, diagnosis and treatment as well as logistical and 
technical information, obtained from the patient, the Emergency Medical Service (EMS) and the treating 
physician. There are no follow up visits. The study will run until the number of patients required 
according to the sample size calculation have been included for each phase. 
 
4. STUDY POPULATION 
4.1 POPULATION (BASE) 
STUDY PHASE 1 
We will recruit patients in whom a regular EEG has been/will be performed for standard medical care in 
the outpatient clinic of the Clinical Neurophysiology department of the AMC, who meet the criteria 
described in chapter 4.2 and 4.3. 
STUDY PHASE 2 
We will recruit patients with a that have been admitted to the hospital with an LVO-a, who meet the 
criteria described in chapter 4.2 and 4.3. 

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STUDY PHASE 3 
We will recruit patients with a suspected AIS or a known LVO-a in the ER, who meet the criteria 
described in chapter 4.2 and 4.3.  
STUDY PHASE 4 
We will recruit patients with a suspected AIS in the ambulance, who meet the criteria described in 
chapter 4.2 and 4.3. 
4.2 INCLUSION CRITERIA 
STUDY PHASE 1 
- Age of 18 years or older; 
- Patient is in the outpatient clinic of the Clinical Neurophysiology department of the AMC, because a 
regular EEG has been/will be performed on him/her for standard medical care; 
- Written informed consent by patient. 
STUDY PHASE 2 
- A diagnosis of acute ischemic stroke caused by a large vessel occlusion in the anterior circulation 
(intracranial carotid artery or proximal (M1/M2) middle cerebral artery confirmed by neuro-imaging 
(CTA or MRA); 
- Stroke onset <72 hours before expected time of performing EEG; 
- Age of 18 years or older; 
- Written informed consent by patient or legal representative. 
STUDY PHASE 3 
- Suspected acute ischemic stroke, as judged by the paramedic presenting the patient to the ER or 
known AIS with an LVO-a; 
- Onset of symptoms or, if onset was not witnessed, last seen well <24 hours ago; 

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- Age of 18 years or older; 
- Written informed consent by patient or legal representative (deferred). 
STUDY PHASE 4 
- Suspected acute ischemic stroke as judged by the attending paramedic; 
- Onset of symptoms or, if onset not witnessed, last seen well <24 hours ago; 
- Age of 18 years or older; 
- Written informed consent by patient or legal representative (deferred). 
4.3 EXCLUSION CRITERIA 
STUDY PHASE 1 
- Injury or active infection of electrode cap placement area. 
STUDY PHASE 2 
- Injury or active infection of electrode cap placement area. 
STUDY PHASE 3 
- Injury or active infection of electrode cap placement area. 
STUDY PHASE 4 
- Injury or active infection of electrode cap placement area. 
4.4 SAMPLE SIZE CALCULATION 
STUDY PHASE 1 
For study phase 1, where we aim to optimize measurement time, software settings and data transfer 
logistics in patients in the outpatient clinic of the Clinical Neurophysiology department of the AMC, we 

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plan to include 20 patients or less, depending on the judgement of the investigators of when the optimal 
settings and logistics have been found.  
STUDY PHASE 2 
For study phase 2, where we aim to optimize measurement time, software settings and data transfer 
logistics in a population of patients with an AIS in a non-emergency setting, we plan to include 20 
patients or less, depending on the judgement of the investigators of when the optimal settings and 
logistics have been found.  
STUDY PHASE 3 
For study phase 3, where we aim to validate existing algorithms and to develop one or more new  
algorithms, we plan to include 60 patients with an LVO-a. Because the coordinating center, where this 
phase will be conducted, is the only hospital in its region performing EVT, many patients with an LVO-a 
are transported here. In the population of suspected ischemic stroke patients in this hospital’s ER, 
including patients transferred for EVT, the incidence of LVO-a is approximately 20% based on data from 
our own stroke database. Therefore, we aim to include 300 patients in this phase (approximately 60 
patients with an LVO-a and 240 patients without an LVO-a) or less, depending on the judgement of the 
investigators of when the goal of this study phase is achieved. 
STUDY PHASE 4 
For study phase 4, where we aim to validate existing algorithms and one or more new algorithms for 
LVO-a detection, our primary outcome measure is the specificity of the dry electrode cap EEG in a 
population of patients with a suspected AIS. Sample size calculation is based on an expected specificity 
of 70% for LVO-a. Originally, sample size calculation was based on an expected LVO-a rate of 7% and a 
dropout rate of 20%. However, an interim analysis, based on 137 suspected stroke patients in whom an 
EEG was performed in the ambulance, showed an actual incidence of LVO-a of 5% and a dropout rate of 
58%. Patients considered as a ‘drop out’ had insufficient EEG data quality (n=72), onset of symptoms 
>24 hours before EEG registration (n=4) or did not give consent for participation in the study (n=3). The 
EEG data quality increased over the course of the study, so we expect a lower dropout rate for future 
EEG registrations. Based on these interim data, we adjusted the sample size for phase 4 of the study as 
follows.  

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With an incidence of LVO-a of 5% among patients with a clinically suspected AIS in the ambulance, an 
alpha of 0.05, and a maximum margin of error of 7%, 174 patients with a suspected AIS are required21. 
Assuming a dropout rate of 55%, we intend to recruit 386 patients with a suspected AIS. A patient is 
considered a ‘drop out’ if no informed consent is/can be obtained, if no information on the diagnosis 
made by the treating physician is/can be obtained, or if the EEG measurement is of insufficient technical 
quality, as judged by the clinical neurophysiologist. Patients included in the ‘run in’ phase are excluded 
from the primary analysis and thus not included in our sample size calculation. In the ‘run in’ phase, we 
will additionally include 50 patients or less.  
 
5. TREATMENT OF SUBJECTS 
STUDY PHASE 1 
After informed consent is obtained, a single dry electrode cap EEG (see chapter 6) will be performed in 
each patient. We will compare the regular EEG to the dry electrode cap EEG and  collect information on 
patient characteristics, medical history and medication use. There are no follow up visits.  
STUDY PHASE 2 
After informed consent is obtained, a single dry electrode cap EEG (see chapter 6) will be performed in 
each patient. Additionally we will collect information on patient characteristics, medical history, 
medication use, physical and neurological examination performed by the treating physician, imaging 
studies, diagnosis and treatment, obtained from the patient and the treating physician. There are no 
follow up visits.  
STUDY PHASE 3 
Directly at presentation in the ER, a single dry electrode cap EEG (see chapter 6) will be performed in 
each patient. As soon as feasible, preferably within 72 hours after arrival at the hospital or at discharge 
(whichever comes first), informed consent is asked (deferred consent, see chapter 10). If informed 
consent is obtained, we will collect information on patient characteristics, medical history, medication 
use, physical and neurological examination performed by the treating physician, imaging studies, 
diagnosis and treatment as well as logistical and technical information, obtained from the patient, the 
EMS and the treating physician. There are no follow up visits. 

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STUDY PHASE 4 
In the ambulance, a single dry electrode cap EEG (see chapter 6) will be performed in each patient. As 
soon as feasible, preferably within 72 hours after arrival at the hospital or at discharge (whichever 
comes first), informed consent is asked (deferred consent, see chapter 10). If informed consent is 
obtained, we will collect information on patient characteristics, medical history, medication use, physical 
and neurological examination performed by the treating physician, imaging studies, diagnosis and 
treatment as well as logistical and technical information, obtained from the patient, the EMS and the 
treating physician. There are no follow up visits. 
6. INVESTIGATIONAL PRODUCT 
This is not applicable, since no investigational product(s) will be used in this study. 
 
7.NON-INVESTIGATIONAL PRODUCT 
7.1 NAME AND DESCRIPTION OF NON-INVESTIGATIONAL PRODUCT 
We plan to use the WaveguardTM dry electrode EEG cap and compatible eegoTM amplifiers, developed by 
ANT Neuro B.V. Netherlands and all CE marked as medical devices in the European Union (see 
appendices 1 and 2). The dry electrode cap records the EEG signal; the amplifier is used to amplify the 
EEG signal and reduce artefacts. All products will be used within the intended use as described in the 
user manuals (see appendices 5, 6, 7, 8 and 9). We will use CE marked NeuroCenter® EEG software (CE 
class IIa) from Clinical Science Systems (ISO 9001 and ISO 13485 certified) and CE marked eegoTM 
software (CE class IIa) from ANT Neuro B.V. to acquire the signals from the eegoTM compatible amplifiers 
(see appendix 3 and 4).  
In a subgroup of patients, who will be included in study phase 3, we plan to use Ambu® Neuroline 720 
electrodes together with the Refa multichannel amplifier by TMSi (Twente Medical Systems 
International B.V. Netherlands), which are CE marked as medical devices in the European Union (see 
appendices 10 and 11). The electrodes record the EEG signal; the amplifier is used to amplify the EEG 
signal and reduce artefacts. All products will be used in accordance with the intended use as described 
in the user manuals (see appendices 12 and 13).   
7.2 SUMMARY OF FINDINGS FROM NON-CLINICAL STUDIES 

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This is not relevant for the WaveguardTM dry electrode cap, eegoTM amplifier, Neuroline 720 electrodes 
and Refa amplifier as they are all CE marked products that have been safely used in clinical studies (see 
chapter 7.3). NeuroCenter® EEG software and the eegoTM software are both a CE class IIa product.  
7.3 SUMMARY OF FINDINGS FROM CLINICAL STUDIES 
The WaveguardTM dry electrode cap, eegoTM amplifier, Neuroline 720 electrodes and Refa amplifier have 
all been safely used in several clinical studies, with no reported adverse events22-31. A small clinical study 
has shown that the Waveguard’s signal quality is similar to that of the conventional 128-channel wet 
(gel/paste) EEG22. However, to our knowledge, no study of the diagnostic accuracy of dry electrode cap 
EEG (or EEG in general) for LVO-a has been performed. 
7.4 SUMMARY OF KNOWN AND POTENTIAL RISKS AND BENEFITS 
The benefit of using either a dry electrode EEG cap or Neuroline 720 electrodes is that they are easily 
applicable and drastically reduce preparation time, which makes them suitable for use in an emergency 
setting. Since EEG is a safe, non-invasive and painless procedure that is used regularly in standard 
medical practice and we will use CE marked products for our measurements, we expect no health risks 
and no to minimal discomfort during a short period of time associated with participation32. The dry 
electrode EEG caps will be cleaned and disinfected as recommended in the user manual (appendix 5) 
and the disposable Neuroline 720 electrodes will be for single use only.  
 
 8. METHODS 
8.1 STUDY PARAMETERS/END POINTS 
8.1.1 MAIN STUDY PARAMETER/END POINT 
The primary end point of the study is the area under the ROC curve of the theta/alpha ratio for diagnosis 
of LVO-a, based on dry electrode EEG performed by paramedics in the ambulance in suspected AIS 
patients.  
8.1.2 SECONDARY STUDY PARAMETERS/END POINTS 
Secondary end points of this study are: 

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- Sensitivity, specificity, PPV and NPV of the theta/alpha ratio, and test characteristics of other existing 
EEG data based algorithms for LVO-a detection (e.g. Weighted Phase Lag Index, delta/alpha ratio); 
- Logistical and technical feasibility of paramedics performing dry electrode cap EEG  in the ambulance in 
suspected AIS patients; 
- Developing one or more novel EEG data based algorithms with an optimal diagnostic accuracy for LVO-
a detection in suspected AIS patients with ambulant dry electrode cap EEG. 
8.2 BLINDING 
In this diagnostic accuracy study, the treating clinical team (in all phases) and the paramedics (in phase 
4) are blinded for the outcome of the EEG.  
8.3 STUDY PROCEDURES 
All collected data and study procedures are listed per study phase in the following table. There are no 
follow up visits. Items that are not part of standard medical procedure/treatment are bold.  
 
Phase 1 
Phase 2 
Phase 3 
Phase 4 
Patient 
characteristics* 
At baseline 
At baseline 
<24 hours after 
arrival in hospital or 
at discharge 
(whichever comes 
first) 
<24 hours after 
arrival in hospital or 
at discharge 
(whichever comes 
first) 
Past medical history 
At baseline 
At baseline 
<24 hours after 
arrival in hospital or 
at discharge 
(whichever comes 
first) 
<24 hours after 
arrival in hospital or 
at discharge 
(whichever comes 
first) 
Medication use 
At baseline 
At baseline 
<24 hours after 
arrival in hospital or 
at discharge 
(whichever comes 
first) 
<24 hours after 
arrival in hospital or 
at discharge 
(whichever comes 
first) 
Pre-stroke modified 
Rankin Scale score 
NA 
At baseline 
<24 hours after 
arrival in hospital or 
at discharge 
(whichever comes 
first) 
<24 hours after 
arrival in hospital or 
at discharge 
(whichever comes 
first) 
Physical and 
neurological 
examination by 
treating physician 
NA 
At arrival in ER, data 
collected 
retrospectively at 
baseline 
At arrival in ER 
At arrival in ER 
National Institute of 
NA 
At arrival in ER, data 
At arrival in ER 
At arrival in ER 

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Health Stroke Scale 
(NIHSS) score 
collected 
retrospectively at 
baseline 
Brain imaging results, 
if available 
NA 
At arrival in ER, data 
collected 
retrospectively at 
baseline 
At arrival in ER (if 
necessary, as judged 
by treating 
physician) 
At arrival in ER (if 
necessary, as judged 
by treating 
physician) 
Dry electrode cap EEG 
At baseline 
At baseline 
At arrival in ER 
At arrival of 
ambulance 
Final diagnosis, as 
judged by treating 
physician 
NA 
At baseline 
At discharge 
At discharge 
Treatment with IVT 
and/or EVT 
NA 
Data collected 
retrospectively at 
baseline 
At arrival in ER (if 
necessary, as judged 
by treating 
physician) 
At arrival in ER (if 
necessary, as judged 
by treating 
physician) 
Times regarding 
stroke logistics** 
NA 
Data collected 
retrospectively at 
baseline 
Collected during 
first 24 hours after 
symptom onset 
Collected during 
first 24 hours after 
symptom onset 
*Age, sex, right/left-handedness, estimated quantity and length of hair on the head of the participant. 
**Time of: last seen well or witnessed stroke onset, 112-call, ambulance arrival on site, ambulance departure to hospital, 
ambulance arrival at hospital, start neuro-imaging (if any), start IVT/EVT (if any), transfer times from other primary hospital (if 
applicable).  
 
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. 
8.5 REPLACEMENT OF INDIVIDUAL SUBJECTS AFTER WITHDRAWAL 
Since our sample size calculation includes an expected dropout rate, we will not replace subjects that 
have withdrawn from the study. Record will be kept of all reasons for withdrawal and these will be 
reported along with the study results. 
 
9. SAFETY REPORTING 
9.1 TEMPORARY HALT FOR REASONS OF SUBJECT SAFETY 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the study if there is 
sufficient ground that continuation of the study will jeopardise subject health or safety.  The sponsor 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. 

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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 investigational product or the intervention. All adverse events 
reported spontaneously by the subject or observed by the investigator or his/her staff will be recorded. 
9.2.2 SERIOUSADVERSE 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; 
- 
any other important medical event that did not result in any of the outcomes listed above due to 
but could have been based upon appropriate judgement by the investigator. 
The sponsor will report the SAEs through the web portal ToetsingOnline to the accredited METC that 
approved the protocol, within 15 days of first knowledge of the SAE. 
Stroke often results in complications such as infections, delirium, constipation, decubitus wounds, 
swallowing difficulties and falls, as well as in hospitalization and death. Because we expect no health risk 
related to participation in this study, these events will be reported to the accredited METC that 
approved the protocol in a yearly line listing until the last patient has completed the study.  
Furthermore, the following situations will not be reported as (S)AEs: 
- 
Elective hospitalization for pre-existing conditions that have not been exacerbated by study 
treatment as judged by the clinical investigator and where admission did not take longer than 
anticipated; 
- 
Admission for diagnosis or therapy of a condition that existed before inclusion to this study and 
has not increased in severity or frequency as judged by the clinical investigator; 
- 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present at the start 
of the study that do not worsen. 

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9.3 FOLLOW UP OF ADVERSE EVENTS 
All AEs will be followed until they have abated, or until a stable situation has been reached. Depending 
on the event, follow up may require additional tests or medical procedures as indicated, and/or referral 
to the general physician or a medical specialist. SAEs will be reported if they occur within 1 hour after 
completion of the EEG-measurement.  
9.4 SAFETY COMMITTEE 
Installation of a safety committee is not deemed necessary, considering that EEG is a safe, non-invasive 
and painless procedure that is used regularly in standard medical practice and we are using CE marked 
products only. 
 
10. STATISTICAL ANALYSIS AND ALGORITHM DEVELOPMENT 
STUDY PHASE 1 AND 2 
For phase 1 and 2 of this study, the obtained data will not be statistically analyzed, for these phases are 
meant to gain technical and logistical information on the products being used in a non-emergency 
setting. 
STUDY PHASE 3 
For phase 3 of this study, we will determine the diagnostic accuracy of several existing and one or more 
self-developed EEG data based algorithms for LVO-a detection by comparing the proportions of patients 
with and without an LVO-a as predicted by EEG to the proportion of patients with and without an LVO-a 
as diagnosed by the treating physician. A receiver operating characteristic (ROC) curve will be plotted for 
each algorithm and the optimal cut-off value for each algorithm will be determined. For these cut off 
values, the sensitivity, specificity, negative predictive value and positive predictive value will be reported 
with 95% confidence intervals. 
ALGORITHM DEVELOPMENT 
Data of phase 3 and phase 4 will be used to develop one or more new EEG based algorithms for LVO-
detection. We will create artificial intelligence (AI) based algorithm(s). First, we will create a logistic 

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regression model based on standard EEG features, e.g. time domain characteristics, power spectral 
density in different frequency bands, coherence measures, and entropy measures. This will be the 
reference to assess the improvement of the novel AI based models. Second, we will work on EEG 
classification algorithms based on random forests and support vector machines, using the same EEG 
features as input. Finally, to support future studies, we will explore new methods that use raw EEG data 
as input, such as convolutional or recurrent neural networks33-35. 
STUDY PHASE 4 
For phase 4 of this study, we will determine the diagnostic accuracy of several existing and one or more 
self-developed EEG data based algorithms for LVO-a detection  by comparing the proportions of patients 
with and without an LVO-a as predicted by EEG to the proportion of patients with and without an LVO-a 
as diagnosed by the treating physician. An ROC curve will be plotted for each algorithm and the optimal 
cut-off value will be determined. For this cut off value, the sensitivity, specificity, negative predictive 
value and positive predictive value will be reported with 95% confidence intervals. 
11. ETHICAL CONSIDERATIONS 
11.1 REGULATION STATEMENT 
This study will be conducted according to the principles of the Declaration of Helsinki (October 2013) 
and in accordance with the Medical Research Involving Human Subjects Act (WMO). 
11.2 RECRUITMENT AND CONSENT 
STUDY PHASE 1 
For phase 1 of this study, patients will be recruited by the investigators and physicians of the 
departments of Neurology and Clinical Neurophysiology of the coordinating hospital. Patients fulfilling 
the in- and exclusion criteria will be given the study information letter and, after having been giving time 
to read, think about and ask questions regarding the content of the letter, will be asked for written 
informed consent. After informed consent is obtained, the patient will be included in the study. 
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For phase 2 of this study, patients will be screened by the investigators and physicians of the 
department of Neurology. Patients fulfilling the in- and exclusion criteria of this study, or their legal 
representative (see chapter 10.3), will be given the study information letter and, after having been 
giving time to read, think about and ask questions regarding the content of the letter, will be asked for 
written informed consent. After informed consent is obtained, the patient will be included in the study. 
STUDY PHASE 3 
For phase 3 of this study, patients will be screened for eligibility in the ER by the investigators. In 
patients fulfilling the in- and exclusion criteria, an EEG will be performed before obtaining informed 
consent, and the diagnosis made by the treating physician will be registered. We will withhold any 
further study procedures until informed consent is obtained. Afterwards, as soon as feasible and 
preferably within 72 hours after arrival at the hospital or at discharge (whichever comes first), the 
patient or legal representative (see chapter 10.3) is informed and asked for informed consent by the 
investigator. If informed consent is granted, we will use the data that have already been obtained and 
continue the study procedures. If informed consent is not granted, we will ask the patient or legal 
representative for consent to use the data that have been collected up to that point for this study. If this 
is granted, we will use the data that have already been obtained but will not proceed with further study 
procedures. If this is denied, the obtained data will be destroyed. Figure 1 shows the procedure of 
obtaining deferred consent. If the patient is deceased before informed consent can be asked from the 
patient or the legal representative, the data that have been collected will be used for the study without 
having obtained informed consent.  
STUDY PHASE 4 
For phase 4 of this study, patients will be screened for eligibility in the ambulance by the first responding 
paramedic. In patients fulfilling the in- and exclusion criteria, an ambulant EEG will be performed before 
obtaining informed consent, and the diagnosis made by the treating physician will be registered. We will 
withhold any further study procedures until informed consent is obtained. As soon as feasible and 
preferably within 72 hours after arrival at the hospital or at discharge (whichever comes first), the 
patient or legal representative (see chapter 10.3) is informed and asked for informed consent by the 
investigator. If informed consent is granted, we will use the data that have already been obtained and 
continue the study procedures. If informed consent is not granted, we will ask the patient or legal 

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representative for consent to use the data that have been collected up to that point for this study. If this 
is granted, we will use the data that have already been obtained but do not proceed with further study 
procedures. If this is denied, the obtained data will be destroyed. Figure 1 shows the procedure of 
obtaining deferred consent. If the patient is deceased before informed consent can be asked from the 
patient or the legal representative, the data that have been collected will be used for the study without 
having obtained informed consent. 
ETHICAL CONSIDERATIONS REGARDING DEFERRED CONSENT 
Informed consent is fundamental for patient participation in any type of research. However, in acute 
stroke research, the ‘time is brain’ principle conflicts with this. For study procedures that need to be 
performed in the acute setting, asking informed consent in a way that the patient or legal representative 
has the time to calmly consider the information and ask questions means losing valuable time: an hour 
delay in initiation of reperfusion therapy (IVT or EVT) in AIS causes a 5-8% decrease in chance of 
functional independence 3 months after the stroke8,9. Also, asking for informed consent in the acute 
setting is unlikely to result in a decision that is well thought through, because the patient or legal 
representative may be overwhelmed and under psychological stress36. Finally, many patients with an AIS 
are unable to comprehend information regarding study participation due to lowered consciousness, 
aphasia or anosognosia (not realizing the severity of one’s own disease, often due to a lesion of the non-
dominant cerebral hemisphere). Only including patients that are capable of giving informed consent 
would mean selecting a sub group of patients with relatively mild neurological symptoms that is not 
representative of the population of patients with an LVO-a. A legal representative is often not present in 
the acute phase37. For the above mentioned reasons, several acute stroke trials have been conducted 
where informed consent was not required prior to randomization38. According to the Medical Research 
Human Subjects Act (in Dutch: WMO), for research that can only be conducted in an emergency setting 
it is allowed to perform study procedures without prior informed consent, if inclusion in the study may 
benefit the person in urgent need of medical treatment, for as long as the circumstances preventing the 
giving of consent exist.  
Performing an EEG in patients with a suspected AIS in the short time window prior to initiation of 
treatment is necessary in this study, because the objective is to study the diagnostic accuracy of the 
ambulant EEG for LVO-a. As soon as the occlusion is being treated (by IVT and/or IAT), this is no longer 
possible. Although participation in this study does not benefit the patient, it is very important that a 

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reliable stroke triage method is found for stroke patients in the long term, as described in chapter 1. 
Considering that EEG is a safe, non-invasive and painless procedure that is used regularly in standard 
medical practice and does not involve electromagnetic radiation, alongside the above mentioned 
reasons, we deem it ethical to perform the EEG and register the diagnosis prior to asking informed 
consent, while withholding all other study procedures until informed consent is obtained. We will ask 
informed consent as soon as feasible, preferably within 72 hours after arrival at the hospital or at 
discharge (whichever comes first). If informed consent is not granted, we will ask the patient or legal 
representative for consent to use the earlier obtained data for this study. If this is granted, we will use 
the data that have already been obtained but will not proceed with further study procedures. If this is 
denied, the obtained data will be destroyed. Figure 1 shows the procedure of obtaining deferred 
consent. 
 
Figure 1: Flow chart showing process of obtaining deferred consent for phase 3 and 4 of the study. Acute setting is in the ER for 
phase 3 and in the ambulance for phase 4. 
 
11.3 INCAPACITATED SUBJECTS 
Due to lowered consciousness, aphasia or anosognosia (not realizing the severity of one’s own disease, 
often due to a lesion of the non-dominant cerebral hemisphere), patients with an AIS frequently are 

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unable to comprehend information regarding study participation. Therefore, they are often not able to 
give or to deny informed consent. It is essential that these patients are included in the study, as 
excluding them would mean selecting a sub group of patients with relatively few neurological symptoms 
that is not representative of the population of patients with an LVO-a. If a patient is incapacitated, their 
legal representative (according to the WMO) will be asked for informed consent. If an incapacitated 
patient becomes capable of considering informed consent during admission, informed consent will be 
asked. If denied, the patient will be excluded at that point. Incapacitated patients that object to 
participation, will not be included in the study. Incapacitated patients that object during participation, 
will immediately be excluded at that moment. The patient or, if he/she is incapacitated, the legal 
representative, can refuse informed consent without any consequences for further treatment and can 
withdraw informed consent at any time during the study, which is stated in the information letter.  
11.4 BENEFITS AND RISK ASSESSMENT, GROUP RELATEDNESS 
EEG is a safe, non-invasive and painless procedure that is used regularly in standard medical practice 
and does not involve electromagnetic radiation. The WaveguardTM dry electrode cap and the eegoTM 
amplifier are both CE marked and have been safely used in several clinical studies (see chapter 6.3). We 
expect no health risks and no to minimal discomfort (only during measurement) associated with 
participation. For patients, there is no benefit of participation in the study. 
11.5 COMPENSATION FOR INJURY 
As we do not expect  any risks related to participation in this study, we deem exemption from the 
requirement to insure cover for damage to research subjects caused by this study applicable. 
11.6 INCENTIVES 
For the patient, there is no benefit of participation in the study.  
 
12. ADMINISTRATIVE ASPECTS AND MONITORING 
12.1 HANDLING AND STORAGE OF DATA AND DOCUMENTS 
EEG data within phase 1 and 2 will be stored locally. After an ambulant EEG is performed in phase 3 
and 4, the EEG data will be sent to a secure external server, containing only EEG data, date and time 
of the EEG recording and an assigned patient identification code. These data will be sent from the 

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secure external server to the coordinating investigator. The paramedic that has performed the EEG 
will fill out a predesigned form with patient characteristics and patient identification code and send 
it to the local coordinating investigator per mail. A log with all identification codes and identifying 
information will be kept digitally by the local coordinating investigator, separate from the study 
database. This log will be password encrypted and saved on the secured drive system of the 
participating center, only being accessible to the local research staff. Other study data, as described 
in chapter 7.3, will in part be retrieved from the ambulance service and from the electronic patient 
file. All study data, apart from identifying information, imaging data and EEG data, will be stored in 
a digital database (Castor), also password encrypted and only accessible to the research staff of the 
participating center and the coordinating hospital. EEG and imaging data will finally be stored on a 
network drive within the AMC, accessible only to authorized research staff of the coordinating 
hospital. Handling of data will comply with the General Data Protection Regulation (in Dutch: 
Algemene Verordening Gegevensbescherming). 
12.2 MONITORING AND QUALITY ASSURANCE 
Not applicable. 
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 investigator will submit a summary of the progress of the study 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, amendments and other 
problems.  
12.5 TEMPORARY HALT AND (PREMATURE) 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 

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ended prematurely, the investigator will notify the accredited METC within 15 days, including the 
reasons for the premature termination. Within one year after 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.  
 
13. RISK ANALYSIS 
EEG is a safe, non-invasive and painless procedure that is used regularly in standard medical practice. It 
does not involve electromagnetic radiation. We will use CE marked products only for measurements. We 
expect no health risks and no to minimal discomfort (only during the measurement) associated with 
participation. 
14. REFERENCES 
1. Thrift AG, Thayabaranathan T. Global stroke statistics. Int J Stroke. 2017 Jan;12(1):13-32. 
2. Vaartjes I, O'Flaherty M, Capewell S, Kappelle J, Bots M. Remarkable decline in ischemic stroke 
mortality is not matched by changes in incidence. Stroke. 2013;44(3):591-7. 
3. Centraal Bureau voor de Statistiek, StatLine (online database).  
4. National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen 
activator for acute ischemic stroke. N Engl J Med. 1995 Dec 14;333(24):1581-7. 
5. HERMES collaborators. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-
analysis of individual patient data from five randomised trials. Lancet. 2016 Apr 23;387(10029):1723-31. 
6. Nogueira RG, Jadhav AP et al. Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between 
Deficit and Infarct. N Engl J Med. 2018 Jan 4;378(1):11-21. 
7. Albers GW, Marks MP et al. Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion 
Imaging. N Engl J Med. 2018 Feb 22;378(8):708-718. 
8. Saver JL, Goyal M et al. Time to Treatment With Endovascular Thrombectomy and Outcomes From 
Ischemic Stroke: A Meta-analysis. JAMA. 2016 Sep 27;316(12):1279-88. 

NL65939.018.18  
 
 
 
 
          ELECTRA-STROKE version 10.0, d.d. 20-04-2022 
 
 
34 
 
9. Froehler MT, Saver JL et al. Interhospital Transfer Before Thrombectomy Is Associated With Delayed 
Treatment and Worse Outcome in the STRATIS Registry (Systematic Evaluation of Patients Treated With 
Neurothrombectomy Devices for Acute Ischemic Stroke). Circulation. 2017 Dec 12; 136(24): 2311–2321. 
10. Turc G, Maïer B et al. Clinical scales do not reliably identify acute ischemic stroke patients with large-
artery occlusion. Stroke. 2016;47:1466–1472. 
11. Fassbender K, Grotta JC et al. Mobile stroke units for prehospital thrombolysis, triage, and beyond: 
benefits and challenges. Lancet Neurol. 2017 Mar;16(3):227-237. 
12. Finnigan SP, Rose SE et al. Correlation of quantitative EEG in acute ischemic stroke with 30-day 
NIHSS score: comparison with diffusion and perfusion MRI. Stroke. 2004 Apr;35(4):899-903. 
13. Finnigan S, Van Putten MJ et al. EEG in ischaemic stroke: quantitative EEG can uniquely inform (sub-
)acute prognoses and clinical management. Clin Neurophysiol. 2013 Jan;124(1):10-9. 
14. Van Putten MJ, Tavy DL et al. Continuous Quantative EEG monitoring in hemispheric stroke patients 
using the brain symmetry index. Stroke. 2004 Nov;35(11):2489-92. 
15. Lam AM et al, Manninen PH et al. Monitoring electrophysiologic function during carotid 
endarterectomy: 
a 
comparison 
of 
somatosensory 
evoked 
potentials 
and 
conventional 
electroencephalogram. Anesthesiology. 1991 Jul;75(1):15-21. 
16. Thirumala PD, Thiagarajan K et al. Diagnostic accuracy of EEG changes during carotid 
endarterectomy in predicting perioperative strokes. J Clin Neurosci. 2016 Mar;25:1-9. 
17. Anastasi AA, Falzon O et al. Brain Symmetry Index in healthy and stroke patients for assessment of 
prognosis. Stroke Res Treat. 2017;2017:8276136.  
18. Finnigan S, Wong A et al. Defining abnormal slow EEG activity in acute ischaemic stroke: Delta/alpha 
ratio as an optimal QEEG index. Clin Neurophysiol. 2016 Feb;127(2):1452-1459. 
19. Van Kaam RC, Van Putten MJAM et al. Contralesional Brain Activity in Acute Ischemic Stroke. 
Cerebrovasc Dis. 2018;45(1-2):85-92. 

NL65939.018.18  
 
 
 
 
          ELECTRA-STROKE version 10.0, d.d. 20-04-2022 
 
 
35 
 
20. Lopez-Gordo MA, Sanchez Morillo D. Dry EEG Electrodes. Sensors (Basel). 2017 Jul; 14(7): 12847-
12870.  
21. Hajian-Tilaki K. Sample size estimation in diagnostic test studies of biomedical informatics. J 
Biomedical Inform. 2014 Apr; 48:193-204.  
22. Fiedler P, Pedrosa P et al. Novel Multipin Electrode Cap System for Dry Electroencephalography. 
Brain Topogr. 2015 Sep;28(5):647-656. 
23. Zhongxiang D, De Souza S et al. EEG Cortical Connectivity Analysis of Working Memory Reveals 
Topological Reorganization in Theta and Alpha Bands. Front Hum Neurosci. 2017; 11:237. 
24. Yang Y, Guliyev B et al. Dynamic Causal Modeling of the Cortical Responses to Wrist Pertubations. 
Front Neurosci. 2017; 11:518. 
25. Ehinger BV, Fischer P et al. Kinesthetic and vestibular information modulate alpha activity during 
spatial navigation: a mobile EEG study. Front Hum Neurosci. 2014; 8:71.  
26. Stone DB, Tamburro G et al. Automatic removal of physiological artifacts in EEG: the optimized 
fingerprint method for sports science applications. Front Hum Neurosci. 2018; 12:96. 
27. Barzegaran E, Vildavski VY. Fine structure of posterior alpha rhythm in human EEG: frequency 
components, their cortical sources and temporal behavior. Sci Rep. 2017; 7:8249. 
28. Bashford J, Wickham A et al. Preprocessing surface EMG data removes voluntary muscle activity and 
enhances SPiQE fasciculation analysis. Clinical Neurophysiology. 2020 Jan; 131(1): 265–273.  
29. Tamborska A, Bashford J et al. Non-invasive measurement of fasciculation frequency demonstrates 
diagnostic accuracy in amyotrophic lateral sclerosis. Brain Communications. 2020 Sep; 2(2): fcaa141. 
30. Kamavuako E, Scheme E et al. Determination of optimum threshold values for EMG time domain 
features; a multi-dataset investigation. J. Neural Eng. 2016 Jun; 13(4): 46011.  

NL65939.018.18  
 
 
 
 
          ELECTRA-STROKE version 10.0, d.d. 20-04-2022 
 
 
36 
 
31. Rezaie R, Schiller K et al. The Clinical Utility of Transcranial Magnetic Stimulation in Determining 
Hemispheric Dominance for Language: A Magnetoencephalography Comparison Study. Journal of 
Clinical Neurophysiology. 2020 Mar; 37 (2): 90-103. 
32. Fiedler P, Muhle R et al. IEEE Trans Neural Syst Rehabil Eng. 2018 Apr;26(4):750-757.  
33. Roy Y, Banville H et al. Deep learning for electroencephalogram (EEG) classification tasks: a review. J. 
Neural Eng. 2019 Jun;16(3):031001.  
34. Wang P, Jiang A et al. LSTM-Based EEG Classification in Motor Imagery Tasks. IEEE Transactions on 
Neural Systems and Rehabilitation Engineering. 2018 Nov;26(11):2086-2095. 
35. Kumar S, Sharma A et al. Brain wave classification using long shortterm memory network based 
OPTICAL predictor. Sci Rep. 2019 9:9153. 
36. Jansen TC, Kompanje EJ et al. Deferred proxy consent in emergency critical care research: ethically 
valid and practically feasible.  2009 Jan;37:S65-8. 
37. Annane D, Outin H et al. The effect of waiving consent on enrollment in a sepsis trial. Intensive Care 
Med. 2004 Feb;30(2):321-324. 
38. Feldman WB, Kim AS et al. Effect of waivers of consent on recruitment in acute stroke trials. 
Neurology. 2016 Apr; 86(16):1543-1551.