Next Generation X-ray Imaging System
Conditions: Stroke, Acute
Sponsor: Philips Clinical & Medical Affairs Global

NCT number: 
         NCT04571099

 
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Clinical Research Protocol 
 
Next Generation X-ray Imaging System (NEXIS) 
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Controlled Document is approved when all approvers have signed. Approval and effective date is the date of the latest signature. 
 
Revision History 
Revision 
Revision Date 
Author 
Changes/Comments 
00 
2019 nov 05 
 
 
Initial version 
01 
2020 Feb 27 
 
 
Revision to incorporate changes in response to 
questions of MPA: 
- 
Summary & section 6.6.3: Removed 
exclusion criteria (eGFR prior to 
investigational scan lower than 45 or relevant 
risk factors excludes iodine contrast 
injection) because patients can still be 
included, but will not receive a contrast 
enhanced scan. 
- 
Section 3.4: added that before enrollment of 
subjects, the study will be registered in the 
ClinicalTrials.gov database. 
- 
Section 6.6.1: clarified which subject will be 
replaced: Subjects will be replaced if they or 
the investigator withdraws the patient for any 
reason described in 6.4.1 or if image quality 
is too low due to movement during exam. 
- 
Section 6.6.2.1: Clarified that patients that 
fail to return on day 2 for examination will not 
be replaced. 
- 
Section 7.2 & Appendix IV: Clarified the 
meaning of immediately based on MEDDEV 
2.7 / 3 rev.3, which the sponsor is stated to 
follow (page 27): The Sponsor shall report 
immediately, but no later than 2 calender 
days after awareness by sponsor of a new 
reportable event or new information in 
relation with an already reported event 
- 
Section 8.1: In response to the comment that 
the procedure for evaluating image 
endpoints was not clearly described, we 
have rewritten this section to clarify that 
readers will not be involved in the study and 
will have no information regarding the 
acquisition type (e.g. CBCT, CT, DE-CBCT). 
- 
Section 14: Added extra information 
regarding the termination of the study: (1) 
After the last patient has been included and 
investigated with the investigational device 
the clinical investigator and Sponsor will 
inform the EC and regulatory authority about 
end of inclusion. (2) An early termination 
and/or study termination of the clinical 
investigation will be documented and shared 
with the EC and regulatory authority. 
- 
Section 15: added “This clinical investigation 
will be recorded on ClinicalTrials.gov.” 
 

 
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Open Issues 
None 
 

 
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Table of Contents 
 
Approval ..............................................................................................................................................................1 
Revision History ..................................................................................................................................................2 
Open Issues ........................................................................................................................................................3 
Table of Contents ...............................................................................................................................................4 
1. 
Document Introduction ................................................................................................................................7 
1.1. 
Purpose ...............................................................................................................................................7 
1.2. 
Scope ..................................................................................................................................................7 
1.3. 
References..........................................................................................................................................7 
1.4. 
Definitions & Abbreviations .................................................................................................................7 
Summary ............................................................................................................................................................9 
2. 
State of the art in stroke treatment .............................................................................................................9 
2.1. 
Stroke prevalence and associated costs ......................................................................................... 13 
2.2. 
Current standard of care .................................................................................................................. 14 
2.3. 
Stroke Imaging ................................................................................................................................. 14 
2.4. 
Computed Tomography (CT) ........................................................................................................... 14 
2.5. 
Computed Tomography Angiography (CTA) ................................................................................... 14 
2.6. 
Computed Tomography Perfusion (CTP) ........................................................................................ 14 
2.7. 
Multiphase CT Angiograpy (mCTA) ................................................................................................. 15 
2.8. 
Flat panel detector imaging including Cone Beam CT (CBCT) ....................................................... 15 
2.9. 
Spectral CT / Dual Energy Computed Tomography (DECT) ........................................................... 15 
2.10. 
Spectral Cone Beam CT / Dual Energy Cone Beam CT (DE-CBCT) ......................................... 16 
2.11. 
Stroke treatment .......................................................................................................................... 16 
2.11.1. 
Thrombolysis (IVT) .................................................................................................................. 16 
2.11.2. 
Endovascular treatment ........................................................................................................... 16 
2.12. 
Patient outcome ........................................................................................................................... 17 
3. 
Device description ................................................................................................................................... 17 
3.1. 
Summary description of the investigational device and comparator ............................................... 17 
3.2. 
Detailed description of the investigational device ............................................................................ 17 
3.2.1. 
Intended Purpose .................................................................................................................... 18 
3.2.2. 
Necessary training and experience needed to use the research device ................................. 18 
3.2.3. 
Materials that will be in contact with tissues or body fluids ..................................................... 18 
3.2.4. 
Device Traceability .................................................................................................................. 18 
3.2.5. 
The Allura NEXIS Investigational Device ................................................................................ 18 
3.2.6. 
Limitations of the investigational device .................................................................................. 20 
3.3. 
Evaluation of preclinical testing ....................................................................................................... 20 
3.4. 
Evaluation of clinical testing ............................................................................................................. 21 
4. 
Risks and benefits of the investigational device and clinical research .................................................... 21 
5. 
Objectives ................................................................................................................................................ 21 
5.1. 
Primary objective ............................................................................................................................. 21 
5.2. 
Secondary objective ........................................................................................................................ 21 
5.3. 
Additional objectives – 3D diagnostic imaging ................................................................................ 22 
5.4. 
Additional objectives – 3D image quality parameters ...................................................................... 22 
5.5. 
Justification for the design of the study ........................................................................................... 22 
6. 
Study Design ........................................................................................................................................... 23 
6.1. 
General ............................................................................................................................................ 23 
6.2. 
Screening and procedures............................................................................................................... 23 
6.2.1. 
Computed tomography (CT) .................................................................................................... 23 
6.2.2. 
Procedural angiography ........................................................................................................... 24 
6.2.3. 
Iodine contrast agent eligibility test .......................................................................................... 24 
6.2.4. 
DE-CBCT without (w/o) and with (w) contrast agent ............................................................... 24 
6.3. 
Enrollment and duration ................................................................................................................... 24 
6.4. 
Informed consent process ............................................................................................................... 24 
6.4.1. 
Subject withdrawal or discontinuation ..................................................................................... 25 
6.5. 
Investigational device exposure and comparators .......................................................................... 25 

 
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6.6. 
Subjects ........................................................................................................................................... 27 
6.6.1. 
Number of subjects .................................................................................................................. 27 
6.6.2. 
Procedure for the replacement of subjects .............................................................................. 27 
6.6.3. 
Inclusion and exclusion criteria ................................................................................................ 27 
6.7. 
Follow Up ......................................................................................................................................... 28 
6.8. 
Adverse Events ................................................................................................................................ 28 
7. 
Adverse event reporting ........................................................................................................................... 28 
7.1. 
Definitions ........................................................................................................................................ 28 
7.2. 
Reporting ......................................................................................................................................... 29 
7.3. 
Anticipated adverse device effects .................................................................................................. 32 
7.4. 
Unavoidable adverse events ........................................................................................................... 33 
8. 
Statistical considerations ......................................................................................................................... 33 
8.1. 
Image data management ................................................................................................................. 33 
8.2. 
Sample size justification .................................................................................................................. 33 
8.3. 
Statistical methods ........................................................................................................................... 34 
8.4. 
Subject Disposition .......................................................................................................................... 34 
8.5. 
Demographics and Baseline Characteristics ................................................................................... 34 
8.5.1. 
Study characteristics ................................................................................................................ 34 
8.6. 
Primary objective ............................................................................................................................. 35 
8.6.1. 
Ischemic stroke diagnostic accuracy ....................................................................................... 35 
8.7. 
Secondary objectives ....................................................................................................................... 35 
8.7.1. 
Vessel tree visibility ................................................................................................................. 35 
8.7.2. 
Intracranial hemorrhage detection accuracy ........................................................................... 36 
8.8. 
Additional Objectives – 3D diagnostic imaging................................................................................ 36 
8.8.1. 
Ischemic stroke diagnostic accuracy, vessel tree visibility and hemorrhage detection accuracy 
compared to regular CBCT ...................................................................................................................... 36 
8.8.2. 
Characterization of brain tissue as normally perfused, at risk (penumbra) or infarcted .......... 37 
8.8.3. 
Characterization of intracranial hemorrhage ........................................................................... 37 
8.8.4. 
Characterization of intracranial thrombus ................................................................................ 37 
8.8.5. 
Separation of grey and white matter, and iodine from blood and calcium .............................. 38 
8.8.6. 
Assessment of novel segmentation and reconstruction techniques ........................................ 38 
8.9. 
Additional Objectives – 3D image quality parameters ..................................................................... 38 
8.9.1. 
Objective image quality parameters ........................................................................................ 38 
8.9.2. 
Subjective image quality parameters ....................................................................................... 39 
8.9.3. 
Image artefacts, especially near bony structures .................................................................... 39 
8.10. 
Additional objectives - Safety ....................................................................................................... 40 
8.10.1. 
Radiation exposure and iodine contrast agent dose ............................................................... 40 
8.10.2. 
Adverse events ........................................................................................................................ 40 
8.10.3. 
Adverse Device Effects ............................................................................................................ 40 
8.10.4. 
Device Deficiencies that could have led to Serious Adverse Event ........................................ 41 
9. 
Data management ................................................................................................................................... 41 
9.1.1. 
Confidentiality .......................................................................................................................... 42 
9.1.2. 
Source Documentation ............................................................................................................ 42 
9.2. 
Monitoring Plan ................................................................................................................................ 42 
9.3. 
Retention period .............................................................................................................................. 43 
9.4. 
AUDITS/INSPECTIONS .................................................................................................................. 43 
10. 
Amendments to the Clinical Research Protocol .................................................................................. 43 
11. 
Deviations from the clinical Research protocol .................................................................................... 43 
12. 
Device accountability ........................................................................................................................... 43 
13. 
Statements of compliance ................................................................................................................... 44 
14. 
(Early) termination or suspension of the Research ............................................................................. 44 
15. 
Publication policy ................................................................................................................................. 44 
16. 
STUDY FINANCES ............................................................................................................................. 45 
17. 
STUDY REPORT ................................................................................................................................. 45 
18. 
Literature .............................................................................................................................................. 45 
Appendix I: List of Investigators and sites ....................................................................................................... 48 
Appendix II: List of monitor(s)/Clinical Study Manager .................................................................................... 49 

 
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Appendix III: DECLARATION OF HELSINKI................................................................................................... 50 
A. 
INTRODUCTION ................................................................................................................................. 50 
B. 
PRINCIPLES FOR ALL MEDICAL RESEARCH ................................................................................. 51 
C. 
ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH MEDICAL CARE ....... 53 
Appendix IV: Reporting requirements to MEC and Competent Authority ....................................................... 55 
Appendix V: Study Scales ............................................................................................................................... 57 
 

 
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1. 
Document Introduction 
1.1. 
Purpose 
This template shall be used as a basis of a clinical Research protocol for clinical Research. The document 
describes the minimum amount of information to be included in the clinical Research protocol based on the 
regulations to ensure safety and wellbeing of human subjects and users. 
1.2. 
Scope 
This clinical research protocol applies to study: Next Generation X-ray Imaging System (NEXIS) 
1.3. 
References 
Reference 
Identification 
Title / additional remarks 
[REF-1] 
XCY607-130522 
Investigator Brochure - NEXIS 
[REF-2] 
XCY607-130561 
Monitoring Plan - NEXIS 
 
1.4. 
Definitions & Abbreviations 
 
Term 
Description 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
AICA 
Anterior inferior cerebellar artery 
AIS  
Acute Ischemic Stroke 
ASPECTS 
Alberta Stroke Program Early CT Score (See Appendix V for details) 
CBCT  
Cone beam computed tomography 
CE 
Conformité Européenne (European Conformity) 
CEC 
Clinical Events Committee 
CFR 
Code of Federal Regulation 
CRF 
Case Report Form 
CNR 
Contrast-to-noise ratio 
CT  
Computed tomography 
CTA  
CT Angiography 
CTP  
CT Perfusion 
DE-CBCT  
Dual energy CBCT 
DECT  
Dual energy CT 
DL 
Dual Layer (detector) 
e-CRF 
Electronic Case Report Form 
e-GFR 
Estimated Global Filtration Rate 
EPX 
Examination, Patient, X-ray information 
EU-MDD 
Medical Device Directive (EEC) 93/42 of the European  Council of 14 June 1993 
as amended 
EU-MDR 
Medical Device Regulation (EU) 2017/745 of the European Parliament and of the 
Council of 5 April 2017 
FDA 
Food Drug Administration 
HE 
High Energy layer of the detector, also known as the second layer 
ICA  
Internal carotid artery 
ICF 
Informed Consent Form 
IFU 
Instructions for Use 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization 
IW 
Interventional Workspot: Philips product that enables advanced applications 
LE 
Low Energy layer of the detector, also known as the first layer 
LVO  
Large vessel occlusion 

 
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Term 
Description 
MCA  
Middle cerebral artery 
mCTA  
Multiphase CTA (See Appendix V for details) 
MEC 
Medical Ethic Committee 
mTICI 
modified thrombolysis in cerebral infarction (TICI) score (See appendix V for 
details) 
neCT 
Non-contrast enhanced CT 
NEXIS 
Next Generation X-ray Imaging System 
PICA 
Posterior inferior cerebellar artery 
SAE 
Serious Adverse Event 
SCA 
Superior cerebellar artery 
SNR 
Signal-to-noise ratio 
USADE 
Unanticipated Serious Adverse Device Effect 
 
 
 

 
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Summary 
Identification of investigational device 
 
 
 
 
 
 
 
Study design 
The study is prospective, open label, single centre. This is a first in man study of a novel dual energy flat 
panel detector technique, which also entails new reconstruction and segmentation algorithms. 
 
With this trial, we aim to evaluate the diagnostic capabilities of a novel flat panel detector capable of 
acquiring and processing multi energy photon information. The Allura NEXIS Investigational Device 
emplys a flat panel detector system having novel energy separation capabilities. Consequently, we see a 
need to study and assert the diagnostic capabilities of our new detector in a relevant patient population. 
 
The study serves as a proof of concept and, given results are satisfactory, would have substantial impact 
on treatment time for patients eligible for thrombectomy. If patients are diagnosed and treated for ischemic 
stroke in the same room, we would expect a significant reduction in neuron loss due to ischemia and thus 
have a positive impact on patient outcome. 
 
Objective 
The objective of this study is to evaluate the capability of DE-CBCT to render an accurate diagnosis by 
defining the diagnostic performance of DE-CBCT compared to gold/reference standard. 
 
 
 

 
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Primary and secondary objectives  
Primary objective 
Ischemic stroke diagnostic accuracy 
Accuracy of DE-CBCT to determine the extent and localization of ischemic stroke changes in brain tissue, 
using neCT as the reference standard.  
Secondary objective 
Vessel tree visibility 
Proportion of contrast-enhanced DE-CBCT rated non-inferior (i.e. equal or superior) vessel visibility 
compared to CTA (reference standard). 
 
Intracranial hemorrhage detection accuracy  
Accuracy of DE-CBCT to determine the presence of intracranial hemorrhage, using neCT as the 
reference standard. 
Additional objectives – 3D diagnostic imaging 
 
Ischemic stroke diagnostic accuracy, vessel tree visibility and hemorrhage detection accuracy 
compared to regular CBCT. 
 
Characterization of brain tissue as normally perfused, at risk (penumbra) or infarcted. 
 
Characterization of intracranial hemorrhage. 
 
Characterization of intracranial thrombus. 
 
Separation of grey and white matter, and iodine from blood and calcium. 
 
Assessment of novel segmentation and reconstruction techniques. 
Additional objectives – 3D image quality parameters 
 
Objective image quality parameters. 
 
Subjective image quality parameters. 
 
Image artefacts, especially near bony structures. 
 
Main inclusion criteria 
1. The patient has signed and dated the Informed Consent Form (ICF) 
2. Age ≥ 50 years old  
3. Clinical and radiological signs consistent with acute stroke 
I. Patient diagnosed with ischemic stroke of the anterior circulation and not eligible for thrombectomy.  
II. Patient diagnosed with ischemic stroke of the anterior circulation and subjected to thrombectomy.  
III. Patient diagnosed with hemorrhagic stroke.  
 
Main exclusion criteria 
1. Pregnant or breastfeeding women. 
2. Previous stroke or parenchymal damage/defects in anterior circulation territories (only applicable 
for subjects included by criterion 3.I or 3.II). 
3. Subject participates in a potentially confounding drug or device trial during the course of the study.  
4. Participation in the study exposes the subject to risk, as assessed at the discretion of the treating 
physician. 
5. All subjects who meet an exclusion criteria according to national law. 
6. Subject or subject family member is a known Philips employee. 
No. of subjects 

 
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In total, the minimum sample size required is 20 subjects, of which two-thirds have ischemia, one-
third have intracranial hemorrhage, and at least half must have done a contrast enhanced DE-CBCT. 
Our estimated necessary sample size is 29 subjects, taking algorithm optimization and potential 
invalid data into account. 
Study procedures 

 
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Screening and procedures 
Subjects will be screened regarding the study inclusion/exclusion criteria to determine their initial 
eligibility. A member of the research team (hospital/institution personnel assigned to the Study) should 
review their eligibility. All screened subjects will be documented in the Screening/Enrolment log, 
including the reason for non-participation for subjects who do not enrol. The only procedures imposed 
by the study is imaging without and if eligible, with iodine contrast agent. 
Computed tomography (CT)  
Computed tomography (CT), including DECT, obtained directly prior to and during the study will be 
used for comparison. 
Procedural angiography 
For patients undergoing thrombectomy (criterion 3.II). Post thrombectomy angiogram result will be 
determined according to the mTICI score as assessed by the treating interventional radiologist. 
Iodine contrast agent eligibility test 
Kidney function by means of aGFR and non-renal risk factors for CI-AKI will be determined day 1 
(criteria 3.I and 3.III) and/or day 2 (3.I and 3.II), before imaging with the investigational device.  
 
Sufficient renal clearance is determined as aGFR equal to or over 45 ml/min. Non-renal risk factors 
for CI-AKI are determined as diabetes, chronic heart failure (NYHA III/IV), dehydration, sepsis, 
hypoxia, liver cirrhosis and regular intake of NSAID or nephrotoxic substances such as antibiotics, 
chemotherapy and immunosuppressive agents.  
 
A sufficient renal clearance and absence of multiple non-renal risk factors for CI-AKI will be required 
to perform contrast enhanced scans according the following dosage (32): Gram iodine / GFR ratio ≤ 
1,0. This dosage ratio also applies for consecutive scans with iodine contrast agent, such as day 1 
subjects included by criterion 3.I (already investigated with standard of care mCTA and CTP). 
DE-CBCT without (w/o) and with (w) contrast agent 
Depending on inclusion criterion 3.I, 3.II or 3.III, the research protocol differs as depicted in Figure 4. 
Investigational device exposure and comparators 
As per clinic standard, patients with suspected ischemic stroke are evaluated with neCT, mCTA and 
CTP upon admission. Patients arriving from another hospital with a confirmed LVO can optionally be 
imaged with only neCT and CTP.  Also, as per clinic standard, ischemic stroke patients treated in any 
way (thrombolysis and/or thrombectomy) undergoes DECT 12-36 hours after treatment to assess the 
presence and extent of hemorrhage and ischemia. Patients diagnosed with hemorrhagic stroke will 
typically be evaluated with neCT and mCTA/CTA upon admission. 
 
This study will investigate the performance of DE-CBCT in comparison to regular 
neCT/mCTA/CTA/CTP imaging at admission and subsequent DECT (DECT only for subjects in 3.I and 
3.II). Table 1 provides an overview of the devices each subject is exposed to depending on inclusion 
criterion. 
 
  
Day 1 
  
  
  
Day 2 
  
  
  
Inclusion 
criterion 
Standard 
imaging (CT-
based) 
Iodine 
contrast 
eligibility 
test 
DE-CBCT w/o 
contrast 
agent 
DE-CBCT 
w 
contrast 
agent 
Iodine 
contrast 
eligibility 
test 
Standar
d 
imaging 
(DECT) 
DE-CBCT 
w/o 
contrast 
agent 
DE-CBCT 
w 
contrast 
agent 
3.I 
X 
X 
X 
 X 1 
X 
X 2 
X 
X 1 
3.II 
X 
  
  
X 
X 
X 
X 1 

 
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3.III 
X 
X 
X 
X 1 
  
  
  
  
Table 1. Overview of the devices the subject is exposed to depending on inclusion criterion. Timeline: left to right. 
1 No iodine contrast agent will be administered if deemed ineligible 
2 Only if subject has been treated with thrombolysis 
Italics depicts standard diagnostic protocol 
 
Subjects presenting with acute stroke will be evaluated by the physician in accordance with the 
institutional practice, to establish an appropriate treatment plan based on the subject's medical 
condition and available diagnostic screening procedures prior to recruitment in the Study. The 3rd 
inclusion criterion will define the investigational device exposure for the subjects: 
 
3.I subjects will be imaged with DE-CBCT without and with contrast agent day 1 after standard diagnostic 
CT imaging. If subject is still hospitalized at Karolinska on day 2, an additional DE-CBCT without and with 
contrast agent will be made. 
 
3.II subjects will be imaged with DE-CBCT without and with contrast agent day 2 directly after their 
standard diagnostic DECT scan. 
 
3.III subjects will be imaged with DE-CBCT without and with contrast agent day 1 after standard diagnostic 
CT imaging. 
 
The figure below provides an overview of the study flow, consisting of a combination of standard of 
care scans and scans with the NEXIS investigational device. 
 
Figure 1: Study flow chart according to inclusion criterion met. Timeline: left to right. 
 
Follow up 
Patient departs from the investigation at end of investigation day 1 (group III) or day 2 (group I and II). 
 
Duration of the study 
The total duration of the study is expected to be 4-6 months for subject recruitment and investigation 
2. 
State of the art in stroke treatment 
2.1. 
Stroke prevalence and associated costs 
Stroke is the third most common cause of death in the developed world and the leading cause of acquired 
neurological disability.   
The World Health Organisation (WHO) estimates that cardiovascular diseases are the leading cause of 
death globally, causing 17.3 million deaths in 2008. Of these, stroke caused an estimated 6.2 million deaths 
in 2008 and was the second leading cause of global death. Cerebrovascular disease is the most common 

 
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cause of neurological disability in older adults (1) and contributes substantially to other late complications 
such as dementia and epilepsy. Stroke incidence rates are increasing rapidly in low-income and middle-
income countries (2, 3). In high-income countries, substantial increases in the absolute numbers of 
individuals affected by stroke are projected due to increasing population life-expectancy, even if stroke 
incidence rates are reduced or maintained at current levels (2). Stroke is also a substantial contributor to 
healthcare costs.  The American Heart Association estimates that annual total (direct and indirect) costs of 
stroke were $34 Billion in 2011. In Ireland, a collaboration between clinicians and the Economic and Social 
Research Institute estimated total stroke-related costs of 0.5-0.7 Billion Euro in 2007, with costs projected to 
exceed 1 Billion Euro by 2020 (4).  
2.2. 
Current standard of care 
Ischemic stroke is caused by acute occlusion of an artery leading to immediate reduction in blood flow within 
the corresponding cerebrovascular territory. The size and site of the occlusion, and the efficiency of 
compensatory collateral blood flow, determine the extent of impaired blood flow and resulting neurological 
symptoms from “at risk‟ (ischemic) and/or dead (infarcted) brain. Early spontaneous re-canalisation may 
occur from the endogenous release of tPA, a serine protease of the fibrinolytic system which converts the 
zymogen plasminogen into the active protease plasmin, leading to cleavage of fibrin and the dissolving of 
newly formed thrombin “clot‟. However, for most patients, and particularly in those with large occlusions (5), 
this natural physiological function is inadequate to avoid the outcome of infarcted cerebral tissue from the 
occluded vessel. 
2.3. 
Stroke Imaging 
Multiple imaging protocols are used together to diagnose patients presenting with symptoms consistent with 
acute stroke, such as focal disabling neurological deficit or loss of consciousness. A reliable diagnosis is 
essential to determine the most beneficial treatment strategy for the patient. 
Studies that established the efficacy of modern endovascular recanalization (6) most commonly use non-
contrast agent enhanced CT (neCT) and vessel tree visualization such as CT angiography (CTA) combined 
with dynamic information through a brain perfusion scan for patient selection.  
2.4. 
Computed Tomography (CT) 
Currently, Computed Tomography (CT) is the preferred diagnostic imaging technique because of high 
contrast resolution, good availability and quick scan time. A neCT scan is the first diagnostic investigation to 
be done in order to exclude the presence of intracranial hemorrhage (i.e. hemorrhagic stroke) and extensive 
infarction, as both are contraindications for intravenous thrombolytic therapy. Today, neCT provides sub-
millimeter resolution in x, y as well as z direction (3D). 
2.5. 
Computed Tomography Angiography (CTA) 
CTA serves the purpose of mapping the cerebral vascular anatomy as well as identifying any present 
occlusion, stenosis or vessel anomaly which could have implications on treatment strategy. Computed 
tomography angiography (CTA) is performed with and synchronized to intravenous iodine contrast agent 
administration. With CTA, the radiologist can identify the thrombus in the case of an ischemic stroke. 
Currently, there is substantial evidence (6) that it is possible to access and extract large vessel occlusions 
(LVOs) located in proximal anterior circulation vessels such as the internal carotid artery (ICA) and middle 
cerebral artery (MCA) M1 and M2 section. Also, LVOs in the posterior circulation located in the vertebral 
artery, basilar artery and posterior cerebral artery (PCA) segment P1 are accessible. Approximately 80% of 
all ischemic strokes occur in the anterior circulation.  
 
The majority of ischemic stroke patients presenting with severe focal neurological deficit have a LVO on 
CTA. At Karolinska, the CTA also includes the aortic arch and neck vessels and thus provide anatomical 
information and determines the presence of stenosis or dissection, which can have implications on catheter 
selection and treatment strategy. 
2.6. 
Computed Tomography Perfusion (CTP)  
Using dynamic information provided by CT Perfusion (CTP), early manifest infarctions not visible on neCT 
can be detected. This information is crucial as manifest ischemia increases risk and decreases potential 

 
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benefit from endovascular recanalization therapies. Equally important, dynamic imaging also visualizes 
tissue with decreased blood flow at risk of manifest ischemia (penumbra) that could potentially be salvaged 
by endovascular recanalization. Similar to CTA, CTP is performed with and synchronized to intravenous 
iodine contrast agent administration. However, CTP involves repeated scans over the head (usually 17-35 
sweeps) over the course of 40-60 seconds. The assessment of CTP involves a “mismatch” concept where 
an intact cerebral blood volume in an area of decreased blood flow and/or blood transit time is thought to 
indicate a penumbra, and a corresponding area with decreased cerebral blood volume is thought to indicate 
manifest ischemia. Multiple software tools are available to assess CTP parameters, with some agreement 
differences (7).  
The HERMES collaboration (6) indicated that dynamic imaging was beneficial in selecting patients for 
thrombectomy, and subsequent large studies such as DAWN and DEFUSE 3 (8, 9) both used dynamic 
imaging for patient selection in an extended time window (up to 24 hrs from symptom onset). Similarly, 
patient selection by perfusion imaging for thrombolysis in an extended time frame (4.5 - 9 hrs) has also been 
proven to correlate with beneficial outcome (10, 11). 
Accordingly, CTP has rapidly become established practice at most comprehensive stroke centres worldwide 
when assessing patients with suspected acute ischemic stroke (AIS).  
2.7. 
Multiphase CT Angiograpy (mCTA) 
An alternative or complement to CTP to assess vessel perfusion dynamics is to use Multiphase CT 
Angiography (mCTA). This technique usually involves three consecutive CTA scans performed on the same 
patient, approximately 8 seconds apart. mCTA has been shown to correlate with functional outcome in 
patients better than a single-phase CTA (12) and determined a reliable tool for imaging selection in patients 
with AIS (13). Moreover, mCTA has been shown to predict tissue fate similar to CTP in patients with AIS 
(14). The assessment of mCTA does not necessarily involve additional software tool analysis (which is 
required for CTP), and thus makes mCTA easier to use and less dependent on advanced processing 
algorithms. 
2.8. 
Flat panel detector imaging including Cone Beam CT (CBCT) 
Endovascular recanalization is done with X-ray guidance in an interventional suite equipped with a flat panel 
detector C-arc system. The flat panel detector is predominantly used for 2D image guidance during 
interventional procedures. However, it can also be used for diagnostic 3D imaging by rotating the detector 
around the patient and reconstructing the resulting 3D volume. This imaging technique is known as Cone 
Beam CT (CBCT) and enables important diagnostic information, usually in conjunction with an interventional 
procedure. Most often, CBCT is used for anatomical assessment such as bone morphology and 
characterization of iodine contrast enhanced blood vessels, peri- and postprocedural information such as 
stent/graft placement, as well as detection of important procedure related complications such as intracranial 
hemorrhage. However, due to detector limitations, flat panel detector systems currently lack the possibility of 
detailed low contrast tissue discrimination, such as soft tissue and brain tissue characterization. 
2.9. 
Spectral CT / Dual Energy Computed Tomography (DECT) 
Photons (X-rays) interact with matter in different ways dependent on atomic number (AN) and electron 
density (ED) of the material. The main photon interactions in the energy range used for diagnostic imaging 
are through Compton Scattering (CS) and Photoelectric Effect (PE). Essentially, the composition of the 
tissue or material (AN and ED) determines the probability of a photon with a certain energy to interact by 
either CS or PE. Especially the PE interaction component shows great energy dependency. Photons that are 
not absorbed (by PE) or scattered away from the imaging detector (by CS) are registered and quantified. The 
differences in PE interaction can be used to separate different tissues and materials, as well as to improve 
image contrast resolution.  
Imaging techniques to separate photon energy (spectral imaging) have emerged and gained much attention 
over the last decade due to great technical advances and an increasing number of clinical applications. The 
rationale for how diagnostic CT scans are performed and interpreted is changing with the availability of 
added spectral information. Today, the readily available technique is interchangeably referred to as Spectral 
CT or Dual Energy CT (DECT). Several spectral techniques exists and yet more promising ones are under 
development. 
Spectral CT / DECT can add significant value to a diagnostic investigation, for example by offering the 
potential of improved tissue characterization through reconstruction of virtual monoenergetic images (VMI) 

 
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as well as material separation and iodine quantification (15-17). Today, DECT is widely used within 
neuroradiology, for example to separate blood from iodine contrast leakage after an interventional procedure 
(18). Recent studies show promising results using DECT for acute stroke imaging (19-21), indicating a 
possibility of higher diagnostic sensitivity and specificity to detect early ischemic changes. 
2.10. 
Spectral Cone Beam CT / Dual Energy Cone Beam CT (DE-CBCT) 
As of yet, photon energy separation is most commonly utilized in CT scanners to improve image quality and 
to extract additional image information. Applying this concept to flat panel detectors placed in interventional 
suites would theoretically render CBCT images with improved tissue and anatomical characterization, as well 
as an increased iodine detectability. This technique has been termed Spectral CBCT or Dual Energy CBCT 
(DE-CBCT).  
A technically sophisticated approach to enable energy separation is to superimpose detector layers on each 
other. Using this technique, the first detector layer captures low energy photons, and the second detector 
layer captures photons of higher energy. This enables a separation of photon energy spectra, which is 
utilized to improve image information content. Improved detector properties could also make it feasible to 
lower the necessary radiation dose to the patient and health care personnel involved in a wide range of 
interventional procedures. 
Preclinical studies have provided insights on the possibilities of energy separating flat panel detectors, and 
our trial aims to evaluate this technique in a diagnostic application. In order to assess the images, new 
reconstruction algorithms are developed. 
2.11. 
Stroke treatment 
Acute ischemic stroke (AIS) can be treated either by administering a thrombolytic drug (thrombolysis), or by 
thrombectomy where the blocking thrombus is retrieved from the occluded vessel with a endovascular 
device. Commonly, both treatment strategies are used together in the case of a LVO. 
2.11.1. 
Thrombolysis (IVT) 
Clot-dissolving drugs such as intravenous recombinant tissue plasminogen activator (IV rtPA) can 
significantly improve the prognosis for a patient with AIS by restoring blood flow to a region of the brain 
blocked by an arterial clot/thrombus. Until 2015, this was the only scientifically proven treatment for any type 
of AIS. However important, it has been shown that IVT has a very small likelihood of successful 
recanalization when the thrombus measures 8 mm or more (5). Large thrombi commonly occlude the 
proximal intracranial arteries, usually termed large vessel occlusions (LVO). The proximal location of a LVO 
typically leads to substantial neurological deficits and a poor prognosis without successful treatment. 
2.11.2. 
Endovascular treatment 
A blood clot/thrombus in a proximal intracranial artery can be removed by an endovascular procedure termed 
thrombectomy. The thrombectomy aims to achieve arterial recanalization and thus restoration of blood flow 
and oxygen delivery to brain tissue. Typically, the femoral artery is punctured with a needle and the 
intracranial arterial vasculature is subsequently accessed using a catheter system under X-ray guidance. 
Endovascular treatment for patients with AIS and LVO using second-generation devices (primarily stent 
retrievers (SRs)) have demonstrated to be beneficial across five large randomized clinical trials (RCTs) (6). 
The addition of endovascular thrombectomy to standard medical care also resulted in better 24-h 
recanalization rates (71% of successful recanalization rate)(6). In these five RCTs, mechanical 
thrombectomy was performed in more than 80% of cases with a SR, a self-expanding stent used to retrieve 
thrombi (6). These studies provided compelling evidence for the beneficial results of mechanical 
thrombectomy in patients with LVO of the anterior circulation presenting within 6 hours of symptom onset 
and has since 2015 been established practice world wide. 
Furthermore, RCTs DAWN and DEFUSE 3 published in 2018 provided insights that thrombectomy can be a 
beneficial treatment option up to 24 hours after symptom onset, thus making endovascular recanalization a 
possible treatment option for an even larger patient group (8, 9). These studies both used “mismatch” 
concepts separating irreversible ischemic tissue from potentially salvageable tissue to select patients for 
thrombectomy. 

 
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3.2.1. 
Intended Purpose 
The intended medical purpose of the Allura NEXIS Investigational Device is to perform neurovascular 
imaging applications, including diagnostic, interventional and minimally invasive procedures on human 
patients. It is intended to support cerebral angiography, as well as PTAs, stent placements, embolization and 
thrombolysis. 
 
It can be used for all human patients, subject to the inclusion criteria, for the goal described in this research 
protocol. Patient weight is limited to the specification of the patient table. 
3.2.2. 
Necessary training and experience needed to use the research device 
The Allura NEXIS Investigational Device is intended to be used and operated by: adequately trained, 
qualified, and authorized health care professionals who have understanding of the safety information and 
emergency procedures as defined by local laws and regulations for radiation workers and staff. 
 
To facilitate safe and efficacious operation of the system by a trained healthcare professional, instructions for 
use are provided as part of the device labelling, as well as a basic training at system handover The 
Instruction for Use (IFU) contains safety precautions and handling of the investigational device. 
3.2.3. 
Materials that will be in contact with tissues or body fluids 
No materials of the Allura NEXIS Investigational Device will be in contact with tissue or body fluids. 
3.2.4. 
Device Traceability 
Records shall be kept to document when the device is received, installed or returned/uninstalled/disposed at 
the hospital. 
3.2.5. 
The Allura NEXIS Investigational Device 
 
 
 
 
 
 
 

 
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Figure 2 Allura FD20/15 biplane product 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 

 
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3.4. 
Evaluation of clinical testing 
As no commercially available flat panel detector system has energy separation capabilities today, the 
investigation NEXIS devices has not been tested clinically. This study will collect the first clinical data. Before 
enrollment of subjects, the study will be registered in the ClinicalTrials.gov database. 
 
 
4. 
Risks and benefits of the investigational device and clinical 
research 
The NEXIS system is not CE marked and is referred to as an investigational device that needs approval 
from both the Swedish Medical Products Agency (MPA, Läkemedelsverket) and the Ethics committee 
(Etikprövningsmyndigheten) before it can be used in this clinical trial.  
Clinical benefits 
No direct benefit will be added for the patients. However, their participartion in this study will provide 
valuable scientific information and guidance towards an improved diagnostic and treatment approach for 
future patients with the same diagnosis. Our strategy of diagnosing and treating stroke in the same 
room has the potential to lower the time elapsed before treatment and thus give patients a better chance 
of successful reperfusion of brain tissue (25). 
 
Risk assessment 
The risk assessment process that Philips follows is in accordance with ISO 14971.This will ensure that the 
level of risk is acceptable prior to the start of the study. A detailed overview of the risk assessment can be 
found in the Investigator Brochure section 5 [REF-1]. 
 
The Overall Conclusion of the risks vs benefits analysis is that: 
 
Both device related risks and the study related risks have been considered and mitigation controls in 
place are effective 
o 
All device related risks have been reduced as far as possible and individual residual risks after 
mitigation are classified as acceptable. 
o 
Risks to the subject associated with the clinical procedure required by the study plan are limited 
to additional X-ray dose and iodine contrast and can be justified. 
 
The overall residual risk is acceptable; 
 
Based on the overall safety profile, AlluraNEXIS Investigational Device can be safely used in clinical 
practice. 
5. 
Objectives 
This study aims to assess the diagnostic imaging properties as well as image quality properties in 
subjects presenting with suspected ischemic stroke. Infarcted stroke tissue, white and grey matter 
discrimination, thrombus characteristics, separation of blood, iodine and calcium as well as artifacts 
near the skull base and posterior fossa will be evaluated, among others. As initial stroke imaging must 
be able to identify or exclude intracranial bleeding, subjects with hemorrhagic stroke will be included. 
For detailed information about evaluation of endpoints and statistics, please see chapter 8. 
5.1. 
Primary objective 
Ischemic stroke diagnostic accuracy 
Accuracy of DE-CBCT to determine the extent and localization of ischemic stroke changes in brain tissue, 
using neCT as the reference standard.  
5.2. 
Secondary objective 
Vessel tree visibility 
Proportion of contrast-enhanced DE-CBCT rated non-inferior (i.e. equal or superior) vessel visibility 
compared to CTA (reference standard). 
 

 
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Intracranial hemorrhage detection accuracy  
Accuracy of DE-CBCT to determine the presence of intracranial hemorrhage, using neCT as the 
reference standard. 
5.3. 
Additional objectives – 3D diagnostic imaging 
 
Ischemic stroke diagnostic accuracy, vessel tree visibility and hemorrhage detection accuracy 
compared to regular CBCT. 
 
Characterization of brain tissue as normally perfused, at risk (penumbra) or infarcted. 
 
Characterization of intracranial hemorrhage. 
 
Characterization of intracranial thrombus. 
 
Separation of grey and white matter, and iodine from blood and calcium. 
 
Assessment of novel segmentation and reconstruction techniques. 
 
5.4. 
Additional objectives – 3D image quality parameters 
 
Objective image quality parameters. 
 
Subjective image quality parameters. 
 
Image artefacts, especially near bony structures. 
 
5.5. 
Justification for the design of the study 
Despite recent advancements in the treatment of ischemic stroke, time management for patients potentially 
eligible for thrombectomy remains far from ideal. When the patient arrives at the hospital, he/she must first 
be transported to the CT scanner for diagnosis and then further to the interventional suite for thrombectomy. 
This consumes a substantial amount of time and resources, and any delay to proper treatment may lead to 
additional manifest brain ischemia. It is estimated that about 2 million neurons are lost per minute during an 
acute ischemic stroke caused by a large vessel occlusion (26). Earlier diagnosis of the stroke cause followed 
by immediate treatment is quintessential to save brain tissue. The concept of diagnosing and treating 
ischemic stroke in the same room would be revolutionary, with similarities to modern management of acute 
coronary syndrome. In recent years, this concept of stroke diagnosis and treatment in the same room has 
been proven feasible in small studies, minimizing time to recanalization of occluded intracranial arteries (27, 
28) 
 
With this study, we aim to evaluate the diagnostic capabilities of a novel flat panel detector capable of 
acquiring and processing multi energy photon information. The Allura NEXIS Investigational Device employs 
a flat panel detector system having novel energy separation capabilities. Consequently, there is a need to 
study and evaluate the diagnostic capabilities of our new detector in a relevant patient population. All 
subjects included in the study will receive standard protocol healthcare. The only intervention imposed 
on study participants is additional imaging and intravenous iodine contrast agent administration. 
The study is designed to provide a proof of concept and, given results are satisfactory, could have 
substantial impact on time to treatment for patients eligible for thrombectomy. If patients are diagnosed and 
treated for ischemic stroke in the same room, we would expect a significant reduction in neuron loss due to 
ischemia and thus have a positive impact on patient outcome. 
 
In order to evaluate relevant diagnostic quality and image quality in the acute stroke setting, we will 
include subjects with ischemic stroke of the anterior circulation coming to the comprehensive stroke 
center at Karolinska University Hospital (inclusion criteria 3.I and 3.II). As initial imaging must be able to 
identify or exclude intracranial hemorrhage, subjects determined to have a hemorrhagic stroke will also 
be included in the study (3.III). For stroke patients, an additional contrast enhanced scan is relevant to 
delineate the intracranial vessels in order to identify relevant pathology. 
  
Even though no additional radiation dose compared to a standard CBCT is anticipated, subjects will 
receive an additional radiation dose compared to standard diagnostic protocol due to the additional 
image acquisition. However, the brain is quite insensitive to radiation exposure (weighting factor of 0.01 

 
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when calculating effective organ doses (29), and sensitivity to stochastic radiation effects decreases 
with age (30). The great majority of stroke patients in Sweden are 65 years or older (31). To ensure that 
the risks of additional radiation is minimized, no subject under the age of 50 will be included in the study. 
No gender specific safety considerations have been identified for subjects aged 50 and over. However 
unlikely, women included in the study will be asked about current pregnancy. 
Usage of iodine contrast agents poses a small risk of contrast-induced acute kidney injury (CI-AKI). We 
will follow Swedish national guidelines, recommending that the total amount of iodine (in grams) 
administered for a contrast enhanced scan should not exceed the calculated aGFR in mL/min (32), 
given that the patient has a sufficient renal clearance and does not have multiple risk factors. For more 
information, see section 6.2.3. 
Subjects not eligible for thrombectomy (criterion 3.I) receive less iodine contrast agent and radiation 
exposure compared to patients undergoing thrombectomy, where iodine is used to navigate during the 
procedure under X-ray image guidance. Investigational DE-CBCT of these subjects on day 1 imposes 
varying extent of residual iodine intracranially (from previous standard of care imaging). However, these 
subjects typically show very relevant imaging features, as hyperacute ischemic changes are challenging 
yet crucial to visualize. Moreover, DE-CBCT imaging potentially enables iodine removal/suppression. If 
still hospitalized day 2, an additional DE-CBCT enables diagnostic information about stroke progression. 
Subjects that have undergone thrombectomy (inclusion criteria 3.II) will be included one day after 
admission (day 2), when most of the iodine typically has been filtered out by the kidneys. An absolute 
GFR (aGFR) and non-renal risk factors for CI-AKI will be assessed before administering iodine contrast 
agent. These measures will ensure that the risks associated with iodine contrast agents will be 
minimized. 
Similar to above, subjects with a verified intracranial hemorrhage (inclusion criteria 3.III) will be imaged 
without and with iodine contrast agent day one after assessment of aGFR and non-renal risk factors.  
 
If the subject is deemed inappropriate to receive iodine contrast agent, only imaging without iodine 
contrast agent will be done. In addition to above, other individual or healthcare aspects may select 
subjects to undergo only imaging without injection of iodine contrast agent. 
 
 
6. 
Study Design  
6.1. 
General 
The study is prospective, open label, single centre. This is a first in man study of a novel dual energy flat 
panel detector technique, which also entails new reconstruction and segmentation algorithms. The study will 
be run in Karolinska University Hospital, Solna. Radiographers and selected physicians will be trained in the 
use of the Allura NEXIS Investigational Device protocols before any subject investigation.  
6.2. 
Screening and procedures 
Subjects will be screened regarding the study inclusion/exclusion criteria to determine their initial 
eligibility. A member of the research team (hospital/institution personnel assigned to the Study) should 
review their eligibility. All screened subjects will be documented in the Screening/Enrolment log, 
including the reason for non-participation for subjects who do not enrol. The only procedures imposed 
by the study is imaging without and if eligible, with iodine contrast agent. 
6.2.1. 
Computed tomography (CT)  
Computed tomography (CT), including DECT, obtained directly prior to and during the study will be used 
for comparison. 

 
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6.2.2. 
Procedural angiography 
For patients undergoing thrombectomy (criterion 3.II). Post thrombectomy angiogram result will be 
determined according to the mTICI score as assessed by the treating interventional radiologist. 
6.2.3. 
Iodine contrast agent eligibility test 
Kidney function by means of aGFR and non-renal risk factors for CI-AKI will be determined day 1 
(criteria 3.I and 3.III) and/or day 2 (3.I and 3.II), before imaging with the investigational device.  
 
Sufficient renal clearance is determined as aGFR equal to or over 45 ml/min. Non-renal risk factors for 
CI-AKI are determined as diabetes, chronic heart failure (NYHA III/IV), dehydration, sepsis, hypoxia, 
liver cirrhosis and regular intake of NSAID or nephrotoxic substances such as antibiotics, chemotherapy 
and immunosuppressive agents.  
 
A sufficient renal clearance and absence of multiple non-renal risk factors for CI-AKI will be required to 
perform contrast enhanced scans according the following dosage (32): Gram iodine / GFR ratio ≤ 1,0. 
This dosage ratio also applies for consecutive scans with iodine contrast agent, such as day 1 subjects 
included by criterion 3.I (already investigated with standard of care mCTA and CTP). 
6.2.4. 
DE-CBCT without (w/o) and with (w) contrast agent 
Depending on inclusion criterion 3.I, 3.II or 3.III, the research protocol differs as depicted in Figure 4. 
 
6.3. 
Enrollment and duration 
Subjects are considered to be enrolled in the Research after they have signed the informed consent form. No 
study procedures will be performed before this moment.  
 
We will enrol adults admitted with suspected acute stroke that have undergone standard diagnostic imaging 
upon admission. The study process will not affect the standard of care, only provide additional imaging data. 
Images will be processed retrospectively. All consecutive patients who meet the inclusion criteria and not 
the exclusion criteria will be enrolled, in accordance with investigational device availability. 
 
The total duration of the study is expected to be 4-6 months for subject recruitment and investigation. The 
subject will only be actively involved in the study when acquiring images, other parameters will be 
documented as regular standard of care and accessed retrospectively. Thus, that part of the study is purely 
observational. 
6.4. 
Informed consent process 
Informed consent will be obtained from every subject in writing by the Investigator or his authorized designee 
before the clinical Research is started. The subject will be informed both orally and in writing about all 
aspects that are relevant to the subject’s decision to participate in the trial, including the trial procedures and 
risks and benefits of participation in the clinical Research. The informed consent will include an explanation 
of the study, duration, explanation of medical record access and patient anonymity, and how their coded 
data may be transferred, used for publications or in submissions for reimbursement support. The 
informed consent form will contain language that is non-technical and understandable to the patient. 
Ample time should be provided for the subject to read and understand the informed consent form and to 
consider participation. The informed consent will include personally dated signatures of the subject and the 
principal investigator or an authorized designee responsible for conducting the informed consent process. 
The investigator or an appropriately designated member of the study staff shall co-sign the consent 
form, indicating they believe the subject has understood the nature and risks of the study and, in their 
estimation, the subject clearly understands the scope of the consent. The investigator must inform 
subjects that they are in a clinical trial, apprise them of their rights as set forth in the informed consent 
document, and make written documentation that such a discussion took place. The subject will receive a 
copy of the signed informed consent and any other written information. 
 

 
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If new information becomes available that might significantly affect the subject’s future health and medical 
care, it shall be provided to the subjects in written form. If relevant, subject shall be asked to reconfirm their 
continuing informed consent in writing. In this trial only patients that can give informed consent themselves 
will be included. 
 
The procedure around how the informed consent is collected will be recorded in each subjects' medical 
record. The signed consent forms will be retained by the investigator and made available (for review 
only) to the study monitor and auditor on request. 
 
The Investigation site will maintain a log of all screened patients detailing the reasons for any 
subsequent patient exclusions or non-participation in the study.  
6.4.1. 
Subject withdrawal or discontinuation 
Participation in this investigation is voluntary, and the subject may withdraw at any time. All enrolled 
subjects will be included in data analysis, unless they withdraw permission for their data to be used. The 
Sponsor will retain and continue to use any data collected prior to the withdrawal of consent, unless 
specified by the Subject. 
In the event the subject chooses to withdraw, he/she will be instructed to contact the Investigator 
immediately. Withdrawal from the investigation will not affect the subject's standard of care. The subject 
will be informed of any significant information regarding new findings that may develop during the 
course of the research study that may relate to his or her willingness to continue participation as a study 
subject. 
Subjects will participate in their routine follow-up (day 2, when applicable) and allow this data to be 
gathered. If their participation is terminated, any of their data which has been already gathered will 
continue to be included. The completion of a subject's participation in the study or early departure from 
the study must be fully documented in the subject's study progress notes. 
Subjects will be considered discontinued from the study if any of the following occur: 
 
Subject voluntarily withdraws from the study: A subject may withdraw consent from study 
participation at any time. 
 
Subject withdrawn from the study by the investigator. An investigator may withdraw an enrolled 
subject from the study for the following reason: 
If participation in the study is life threatening for the subject or at the investigators own discretion. 
 
6.5. 
Investigational device exposure and comparators 
As per clinic standard, patients with suspected ischemic stroke are evaluated with neCT, mCTA and CTP 
upon admission. Patients arriving from another hospital with a confirmed LVO can optionally be imaged 
with only neCT and CTP.  Also, as per clinic standard, ischemic stroke patients treated in any way 
(thrombolysis and/or thrombectomy) undergoes DECT 12-36 hours after treatment to assess the 
presence and extent of hemorrhage and ischemia. Patients diagnosed with hemorrhagic stroke will 
typically be evaluated with neCT and mCTA/CTA upon admission. 
 
This study will investigate the performance of DE-CBCT in comparison to regular neCT/mCTA/CTA/CTP 
imaging at admission and subsequent DECT (DECT only for subjects in 3.I and 3.II). Table 3 provides 
an overview of the devices each subject is exposed to depending on inclusion criterion. 
 
 

 
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Day 1 
  
  
  
Day 2 
  
  
  
Inclusion 
criterion 
Standard 
imaging (CT-
based) 
Iodine 
contrast 
eligibility 
test 
DE-CBCT w/o 
contrast 
agent 
DE-CBCT 
w 
contrast 
agent 
Iodine 
contrast 
eligibility 
test 
Standard 
imaging 
(DECT) 
DE-CBCT 
w/o 
contrast 
agent 
DE-CBCT 
w 
contrast 
agent 
3.I 
X 
X 
X 
 X 1 
X 
X 2 
X 
X 1 
3.II 
X 
  
  
X 
X 
X 
X 1 
3.III 
X 
X 
X 
X 1 
  
  
  
  
Table 3. Overview of the devices the subject is exposed to depending on inclusion criterion. Timeline: left to right. 
1 No iodine contrast agent will be administered if deemed ineligible 
2 Only if subject has been treated with thrombolysis 
Italics depicts standard diagnostic protocol 
 
Subjects presenting with acute stroke will be evaluated by the physician in accordance with the 
institutional practice, to establish an appropriate treatment plan based on the subject's medical condition 
and available diagnostic screening procedures prior to recruitment in the Study. The 3rd inclusion 
criterion will define the investigational device exposure for the subjects: 
 
3.I subjects will be imaged with DE-CBCT without and with contrast agent day 1 after standard diagnostic CT 
imaging. If subject is still hospitalized at Karolinska on day 2, an additional DE-CBCT without and with 
contrast agent will be made. 
 
3.II subjects will be imaged with DE-CBCT without and with contrast agent day 2 directly after their standard 
diagnostic DECT scan. 
 
3.III subjects will be imaged with DE-CBCT without and with contrast agent day 1 after standard diagnostic 
CT imaging. 
 
Figure 4 provides an overview of the study flow, consisting of a combination of standard of care scans 
and scans with the NEXIS investigational device. 
 
 
Figure 4. Study flow chart according to inclusion criterion met. Timeline: left to right. 
 

 
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6.6. 
Subjects 
6.6.1. 
Number of subjects 
In total, the minimum sample size required is 20 subjects, of which two-thirds have ischemia, one-third 
have intracranial hemorrhage, and at least half must have done a contrast enhanced DE-CBCT. Our 
estimated necessary sample size is 29 subjects, taking algorithm optimization and potential invalid data 
into account. 
 
The number of subjects are necessary to collect sufficient data for the evaluation of the primary and 
secondary endpoints, taking algorithm optimization and potential invalid data into account. Subjects will be 
replaced if they or the investigator withdraws the patient for any reason described in 6.4.1 or if image quality 
is too low due to movement during exam. The enrollment period is expected to last for 4-6 months.  
 
See Section 8 (Statistical considerations) for more details on the subject sample size. 
6.6.2. 
Procedure for the replacement of subjects 
Subjects in the study will be replaced in case of withdrawal of consent or if subject is found ineligible for the 
study after signing of the informed consent and before the measurement. Subject will also be replaced if 
patient movement during image acquisition significantly affect assessment of the image material, as judged 
by the investigator. If only the second scan for subjects included according to 3.I is invalid, they will not be 
replaced. 
6.6.2.1. 
Lost to follow-up 
If a subject enrolled by inclusion criterion 3.I fails to return for their day 2 examination, their first study 
examination will still be included in the study. Thus, these subjects will not be replaced. 
 
6.6.3. 
Inclusion and exclusion criteria 
Subjects participating in the study will be carefully selected based on the next inclusion and exclusion 
criteria. 
6.6.3.1. 
Inclusion criteria 
1. The patient has signed and dated the Informed Consent Form (ICF) 
2. Age ≥ 50 years old  
3. Clinical and radiological signs consistent with acute stroke 
I. Patient diagnosed with ischemic stroke of the anterior circulation and not eligible for thrombectomy.  
II. Patient diagnosed with ischemic stroke of the anterior circulation and subjected to thrombectomy.  
III. Patient diagnosed with hemorrhagic stroke.  
 
6.6.3.2. 
Exclusion criteria 
1. Pregnant or breastfeeding women. 
2. Previous stroke or parenchymal damage/defects in anterior circulation territories (only applicable for 
subjects included by criterion 3.I or 3.II). 
3. Subject participates in a potentially confounding drug or device trial during the course of the study.  
4. Participation in the study exposes the subject to risk, as assessed at the discretion of the treating 
physician. 
5. All subjects who meet an exclusion criteria according to national law. 
6. Subject or subject family member is a known Philips employee. 

 
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6.7. 
Follow Up 
Subject participation is terminated at the end of investigation day 1 (criterion 3.III) or day 2 (criterion 3.I 
and 3.II). 
6.8. 
Adverse Events 
Any adverse events that occur during the investigation (day 1 or day 2) will be recorded. 
7. 
Adverse event reporting 
The proposed study will be started under the MDD, however as of 26 May 2020, the reporting of serious 
adverse events and device deficiencies shall be carried out in accordance with the Medical Device 
Regulation.  
Adverse event reporting under MDD is done according to ISO14155:2011 and MEDDEV 2.7/3 revison 3. 
7.1. 
Definitions 
Adverse Event (AE) 
ISO14155: Any untoward medical occurrence, unintended disease or injury, or untoward clinical signs 
(including abnormal laboratory findings) in subjects, users or other persons, whether or not related to the 
investigational medical device 
NOTE 1 This definition includes events related to the investigational medical device or the comparator. 
NOTE 2 This definition includes events related to the procedures involved. 
NOTE 3 For users or other persons, this definition is restricted to events related to investigational medical 
devices. 
 
EU-MDR: An Adverse Event (AE) is defined as any untoward medical occurrence, unintended disease or 
injury or any untoward clinical signs, including an abnormal laboratory finding, in subjects, users or other 
persons, in the context of a clinical research, whether or not related to the investigational device. 
 
 
Serious Adverse Event (SAE) 
ISO14155: Adverse event that led to any of the following:  
a) death  
b) serious deterioration in the health of the subject, that resulted in any of the following: 
1) a life-threatening illness or injury, or 
2) a permanent impairment of a body structure or a body function, or 
3) hospitalisation or prolongation of patient hospitalization, or 
4)   in medical or surgical intervention to prevent life-threatening illness or injury or permanent 
impairment to a body structure of a body function. 
5) a chronic disease  
c) foetal distress, foetal death or a congenital physical or mental impairment or birth defect 
 
EU-MDR: Any adverse event that led to any of the following:  
(a) death,  
(b) serious deterioration in the health of the subject, that resulted in any of the following:  
(i) life-threatening illness or injury,  
(ii) permanent impairment of a body structure or a body function,  
(iii) hospitalisation or prolongation of patient hospitalisation,  
(iv) medical or surgical intervention to prevent life-threatening illness or injury or permanent impairment to 
a body structure or a body function,  
(v) chronic disease,  
(c) foetal distress, foetal death or a congenital physical or mental impairment or birth defect 
 
Device Deficiency  
ISO14155: Inadequacy of a medical device with respect to its identity, quality, durability, reliability, safety or 
performance 
NOTE Device deficiencies include malfunctions, use errors, and inadequate labelling. 

 
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EU-MDR: Any inadequacy in the identity, quality, durability, reliability, safety or performance of an 
investigational device, including malfunction, use errors or inadequacy in information supplied by the 
manufacturer. 
 
Adverse Device Effect (ADE) 
ISO14155: Adverse event related to the use of an investigational medical device. Note This includes any 
adverse event resulting from insufficient or inadequate instructions for use, deployment, implantation, 
installation, or operation, or any malfunction of the investigational medical device, and any event resulting 
from use error or from intentional misuse of the investigational medical device. 
 
Serious Adverse Device Effect (SADE) 
MEDDEV 2.7/3 rev 3: Adverse device effect that has resulted in any of the consequences characteristic of a 
serous adverse event. 
 
Unanticipated Serious Adverse Device Effect (USADE) 
ISO14155: Unanticipated Serious Adverse Device Effect is a serious adverse device effect which by its 
nature, incidence, severity or outcome has not been identified in the current version of the risk analysis 
report 
NOTE Anticipated serious adverse device effect (ASADE) is an effect which by its nature, incidence, severity 
or outcome has been identified in the risk analysis report. 
 
7.2. 
Reporting 
 
It is the responsibility of the Investigator to comply with 1) his/her Ethical Committee requirements for 
reporting safety event, and 2) any country specific regulatory/CA Investigator requiremnts for safety events. 
 
All adverse events shall be recorded. The safety assessments will consist of Adverse Events (AE) from the 
time the ICF is signed through departure from study for those patients enrolled, and to discharge or 24 hours 
for those patients identified as screening failures by inclusion/exclusion criteria.  
The AEs will be categorized using MedDRA Coding of Adverse Events Nomenclature Standardized 
nomenclature. 
 
The investigator shall report to Sponsor any related or unrelated serious adverse (device) event and device 
deficiencies that could have led to a Serious Adverse Device Effect (SADE) if a) suitable action had not been 
taken or b) intervention had not been made or c) if circumstances had been less fortunate via the adverse 
event form or device deficiency form in the e-CRF. The investigator shall supply the Sponsor, upon 
Sponsor’s request, with any additional information related to the safety reporting of a particular event.  
The investigator should report to the MEC and/or competent authority these serious adverse events and 
device deficiencies that might have led to a serious adverse device effect, if required by MEC or competent 
authority, as further detailed in Appendix IV.  
 
The reporting requirement from investigational site to the sponsor is: 
 
Type of Adverse Event 
Reporting Requirements 
 
SAE 
 
SADE 
 
USADE 
 
Death 
 
Any study device deficiency that could have 
led to an SADE 
Report to Sponsor immediately upon awareness of 
event but no later than 24 hours (In written within 5 
days). 
 
All other Adverse Events 
 
All other study device deficiencies 
Report to Sponsor immediately upon awereness  of 
event, but no later than 14 calender days. 
 

 
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Non-serious adverse (device) events shall be recorded on the adverse event forms. Device Deficiencies 
shall be recorded on the device deficiency form. The Sponsor and Monitor can request access to this 
information at any time. The event reporting is done via the electroic data capture system (EDC). If the 
electroic data capture system (EDC) is unavaible the AE can be notified via email to the study mailbox: 
 
 
The study site personnel must seek information on Adverse Events by specific questioning and, as 
appropriate, by examination. Information  on each Adverse Event should be recorded immediately in relevant 
source documents, and also on the appropriate eCRF (in the EDC). The following attributes must be 
assigned by the Investigator for adverse events: 
 
 
Description of the event 
 
Actions taken 
 
Date of onset and resolution 
 
Determination if event is serious 
 
Determination if the event is anticipated – in the even of an SADE 
 
Determination of event severity 
 
Determination of the causal relationship to study device and study procedure 
 
Information collected for device deficiencies are:  
 
Date of device deficiency 
 
Whether this could have led to a Serious Adverse Device Effect (SADE) if  
o 
a) suitable action had not been taken or  
o 
b) intervention had not been made or  
o 
c) if circumstances had been less fortunate.  
 
 
The clinical course of each event will be followed until resolution or stabilization. 
 
The investigator shall supply the Sponsor, upon Sponsor’s request, with any additional information related to 
the safety reporting of a particular event. 
 
The investigator should report to the MEC and/or competent authority these serious adverse events and 
device deficiencies that might have led to a serious adverse device effect, if required by MEC or competent 
authority, as described below and summarized in Appendix IV: Reporting requirements to MEC and 
Competent Authority. 
 
 
Adverse Events (AE) and Adverse Device Effects (ADE) 
All adverse events shall be recorded. The safety assessments will consist of Adverse Events (AE) from the 
time the ICF is signed through departure from study for those patients enrolled, and to discharge or 24 hours 
for those patients identified as screening failures by inclusion/exclusion criteria.  
The AEs will be categorized using MedDRA Coding of Adverse Events Nomenclature Standardized 
nomenclature. 
 
The sponsor is: 
 Responsible for the classification of adverse events and ongoing safety evaluation of the clinical 
research and shall review the investigator's assessment (done by the CEC) of all adverse events and 
determine and document in writing their seriousness and relationship to the investigational device; in 
case of disagreement between the sponsor and the principal investigator(s), the sponsor shall 
communicate both opinions to MEC and Competent authorities 
 Review all device deficiencies and determine and document in writing whether they could have led to 
a serious adverse device effect; in case of disagreement between the sponsor and the principal 
investigator(s), the sponsor shall communicate both opinions to MEC and competent authority. 
 Report or ensure the reporting, to the MEC by the principal investigator(s), of all serious adverse 
events and device deficiencies that could have led to a serious adverse device effect,  

 
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 In case of serious adverse device effects and device deficiencies that could have led to serious 
adverse device effects, determine whether the risk analysis needs to be updated and assess whether 
corrective or preventive action is required. 
 
Competent Authorities: 
The Sponsor shall report immediately, but no later than 2 calender days after awareness by sponsor of a 
new reportable event or new information in relation with an already reported event to the competent 
authorities the following Serious Adverse events and device deficiency that occur at any of the involved trial 
sites: 
 
Serious Adverse Events and  
 
Device Deficiencies that could have led to a Serious Adverse Device Effect (SADE) if  
a) suitable action had not been taken or  
b) intervention had not been made or  
c) if circumstances had been less fortunate 
A causal relationship between the SAE and the investigational device(s), or procedures performed as part of 
the clinical trial or other conditions of the trial conduct cannot be excluded. 
 
 
 
7.2.1 Adverse Event Severity 
 
The intensity or severity of each Adverse event must be assessed according to the following classifications: 
 
Mild 
Awareness of signs, symptoms, or events that are otherwise easily tolerated that may result 
in minimal transient impairment of body function or damage to a body structure, but do not 
require intervention other than monitoring. 
Moderate 
Any event that results in moderate transient impairment of body function or damage to a body 
structure that causes interference with usual activities, or that warrants possible intervention, 
such as the administration of medication, to prevent permanent impairment of body function 
or damage to body structure. 
Severe 
Any event that is incapacitating (an inability to do usual activities) or is life-threatening and 
results in permant impairment of body function or damage to a body structure, or requires 
intervention, such as major surgery, to prevent permanent impairment of body function or 
damage to a body structure. 
 
 
7.2.2 Adverse Event Causality Assessment 
 
The clinician who examines and evaluates the enrolled subject will determine the AE’s causality based on 
temporal relationshil and his/her clinical judgment . The degree of certainty about causality will be graded 
using the categories below. 
 
Causality 
Defintion of causality 
Causal 
relationship 
The event is associated with the investigational device beyond reasonable doubt. 
Probable 
The relationship with the use of the investigational device seems relevant and/or the event 
cannot reasonably be explained by another cause, but additional information may be 
obtained. 
Possible 
The relationship with the use of the investigational device is week but cannot be ruled out 
completely. 
Unlikely 
The relationship with the use of the investigational device seems not relevant and/or the 
event can be reasonably explained by another cause, but additional information may be 
obtained. 
Not related 
Relationship to the investigational device can be excluded. 
 
 

 
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7.2.3 Adverse Event Outcome 
 
The outcome of each Adverse Event must be assessed according to the following classification. 
 
Outcome classification 
Definition 
Recovered/Resolved 
Subject fully recovered with no observable residual effects 
Recovered/Resolved with sequelae 
Subject recovered with observable residual effect 
Recovering/Resolving 
Subject’s condition improving, but residual effects remain 
Not Recoverering/Not Resolved 
AE is ongoing without improvement in the overall condition 
Fatal 
Subject died as a result of the AE (whether or not the AE is related 
to the investigational device) 
Unknown 
AE outcome is unknown (e.g., subject is lost to follw-up) 
 
 
 
7.3. 
Anticipated adverse device effects 
Anticipated adverse device effects are described below in Table 4 
 
Anticipated adverse device 
effects 
Likely incidence 
Mitigation or treatment 
Side effects of additional X-ray 
dose 
PoH 1 
The brain is quite insensitive to radiation 
exposure: weighting factor of 0.01 when 
calculating effective organ doses (29), and 
sensitivity to stochastic radiation effects 
decreases with age (30).  
To ensure that the risks of additional 
radiation is minimized, no subject under the 
age of 50 will be included in the study. 
Side effects of additional Iodine 
contrast 
PoH 1 
An absolute GFR (aGFR) and non-renal risk 
factors for CI-AKI will be assessed before 
administering iodine contrast agent. These 
measures will ensure that the risks 
associated with iodine contrast agents will be 
minimized. 
Dose control functionality fails, 
causing more radiation than 
expected 
PoH 2 
Tests are implemented 
Poor scan quality if slower 
XperCT scan results in motion 
artifacts 
PoH 2 
Add guidance in the IFU to guide scan 
selection in case a fast scan is required. The 
Allura product also has a 20s neuro scan and 
the user can use a faster non-spectral scan 
when needed.  
Table 4 Aniticipated adverse device effects. 
 
 
7.3 Clinical Event Committee (CEC) 
 
Clinical Events Committee (CEC) & Event notification 
An independent board consisting of radiologists, hospital physicists and stroke physicians who are not 
participating in the study will adjudicate serious adverse events in the trial. 
The role of the CEC will be to: 
• 
Adjudicate any SAE that could be attributable to ionizing radiation. 

 
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• 
Adjudicate whether an SAE is deemed attributable to the procedure or is from the natural course of 
the standard research protocol or stroke illness. 
• 
Continuous evaluation of available external data and/or knowledge, as presented at major 
congresses and /or published in peer-reviewed journals, which may have an impact on the study or 
be considered a protocol violation. 
• 
The CEC role does not interfer with the sponsor’s responsibility to classify and report adverse events 
to competent authorities. 
7.4. 
Unavoidable adverse events 
Not applicable since only a scan will be acquired. 
 
8. 
Statistical considerations 
Any departure or deviation from these planned statistical methodologies will be documented and 
discussed in the Statistical Analysis Plan that will include the statistical rationale for change. 
8.1. 
Image data management 
The raw image data with added dual energy properties (DE-CBCT) will be processed using novel 
reconstruction and segmentation techniques. During the intervention only the product reconstruction 
algorithm is available for raw image data acquired by the first layer of the detector and images reconstructed 
in this fashion will be identical to current CBCT. 
 
After the intervention the DE-CBCT raw image data will be reconstructed with the novel spectral 
reconstruction software and then evaluated by three independent neuroradiologists (not involved in the 
clinical investigation) for subjective outcome variables. The first cases will also be used to iterate and 
optimize reconstruction algorithms. Images will be processed on-site and off-site. For ordinal outcome 
variables comparing the subjective performance of DE-CBCT and CBCT to CT, CTA and CTP (such as the 
first secondary objective), neuroradiologists will have access to both DE-CBCT and reference image data 
concurrently. For the primary and second secondary objective DE-CBCT and reference image, data will be 
cleaned from any information regarding acquisition technique and evaluated randomly and separated in time, 
in order to limit the possibility of bias. 
 
A secure image data repository will be set up at Karolinska University Hospital, the access to which will be 
provided through IntelliSpace Discovery (ISD) that will serve as the interfacing client for managing and logging 
the access of data by authorized personnel involved in this study. No additional software will be required by the 
user to access the data as the ISD client runs in chrome web browser with a zero footprint i.e., no data will be 
stored on user’s computer while using the ISD interface. 
8.2. 
Sample size justification 
Statistical analyses will be performed by Karolinska University Hospital. This is a prospective, open label 
single centre study. A diagnostic study using DE-CBCT on confirmed acute ischemic or hemorrhagic 
stroke has not been done before. The sample size estimations aims to prove diagnostic quality non-
inferiority compared to CT according to performance goals below. 
 
The sample size for the primary endpoint is trait-based, using ten [10] ASPECTS regions for each 
subject. To evaluate the diagnostic accuracy of DE-CBCT compared to CT, it is estimated that a sample 
size of 137 is required to render a power of 90% (target accuracy of 0.90, performance goal lower 
boundary of 0.80, one-sided alpha of 0.025). For this endpoint, a minimum sample size of 14 subjects is 
required. 
 
The first secondary endpoint (vessel tree visibility) is also trait-based, using eleven [11] arterial regions 
for each subject. To evaluate the proportion of regions rated equal or superior to CT, it is estimated that 
a sample size of 126 is required to render a power of 80% (target proportion of 0.90, performance goal 
lower boundary of 0.80, one-sided alpha of 0.0125, adjusted for multiple secondary endpoints). For this 
endpoint, a minimum sample size of 12 subjects is required. 

 
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The second secondary endpoint is defined as diagnostic accuracy to determine the presence of 
intracranial hemorrhage, comparing DE-CBCT to CT (reference). The endpoint is subject-based and it is 
estimated that a sample size of 20 is required to render a power greater than 95% (target accuracy of 
0.9999, performance goal lower boundary of 0.80, one-sided alpha of 0.0125, adjusted for multiple 
secondary endpoints). The sample size includes both subjects with hemorrhage and negative controls, 
preferably with 0.5 hemorrhage prevalence, with a threshold of at least a third of our subjects to have an 
intracranial hemorrhage. For this endpoint, a minimum sample size of 20 is required. 
 
In total, the minimum sample size required is 20 subjects, of which two-thirds have ischemia, one-third 
have intracranial hemorrhage, and at least half must have done a contrast enhanced DE-CBCT. Our 
estimated necessary sample size is 29 subjects, taking algorithm optimization and potential invalid data 
into account. 
8.3. 
Statistical methods 
All variables will be summarized by descriptive statistics  The statistics for continuous variables includes 
mean, median, standard deviation, 95% confidence interval for the means, and the number of observations.  
For categorical variables, number of events, event rate, and 95% confidence interval for the event rate will be 
presented. 
 
For categorical variables, the Fisher’s Exact or chi-squared test will be used. For numerical variables, 
Student's t-test will be applied for image quality parameters such as signal-to-noise ratio (SNR) and 
contrast-to-noise ratio (CNR). For ordinal rank variables concerning radiologist interpretation, the 
Wilcoxon test will be used. The decision to use non-parametric or parametric tests will be based on the 
result from Shapiro-Wilk test as well as the distribution of the data on a P-P plot.  
 
Receiver operating characteristic (ROC) curves will be constructed and accuracy as well as area under 
the curve (AUC) will be used to assess image diagnostic performance, where applicable. Sensitivity, 
specificity, negative and positive predictive value will be assessed with optimal cut off, where applicable. 
The DeLong test will be applied when comparing ROC curves. The Kappa coefficient will be used to 
evaluate interrater and within-observer agreement, where applicable. Additional statistical methods may 
be used in accordance with relevant literature (33). A biostatistician is involved in planning and 
executing the statistical analyses. 
8.4. 
Subject Disposition 
A subject disposition chart will be presented.  
8.5. 
Demographics and Baseline Characteristics 
Basic subject characteristics such as age, gender, height and weight etc., will be collected and described 
descriptively in a publication format.  
8.5.1. 
Study characteristics 
Subject characteristics 
 
Sex 
 
Age 
 
Iodine contrast agent dose received before investigation (during the previous 72 hrs) 
 
 
Treatment and diagnostic characteristics 
 
Time stamps for admission CT, follow-up DECT and study investigation 
 
Time of symptom onset, if available 
 
Thrombolysis yes/no (at least bolus) 

 
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 
Thrombectomy yes/no 
 
mTICI score at the end of thrombectomy procedure rated by treating neurointerventionalist 
 
Time from symptom onset to start of thrombolysis 
 
Time from symptom onset to end result of endovascular therapy (thrombectomy) 
 
Any deviation from the planned analysis described below will be documented with justification in the final 
clinical report. 
8.6. 
Primary objective  
8.6.1. 
Ischemic stroke diagnostic accuracy 
 
Endpoint 
Accuracy of DE-CBCT ASPECTS to determine the extent and localization of ischemic stroke changes in 
brain tissue, using neCT ASPECTS as the reference standard.  
 
 
Applicable subjects 
Subjects diagnosed with ischemic stroke on CT. 
 
Data 
 
ASPECTS 
o 
Left / Right 
o 
1 to 10 
o 
Location - L, C, IC, I, M1, M2, M3, M4, M5, M6 
 
Analysis 
Images are evaluated by radiologists using neCT as reference standard and the ASPECTS diagnostic 
accuracy is defined. 
 
Hypothesis: 
 
H0: π1 ≤ 0.80 
H1: π1 > 0.80 
 
Where π1 is the observed ASPECTS accuracy and 0.80 is the performance goal. 
8.7. 
Secondary objectives 
8.7.1. 
Vessel tree visibility 
 
Endpoint (1st Secondary endpoint) 
Proportion of contrast-enhanced DE-CBCT rated non-inferior (i.e. equal or superior) vessel visibility 
compared to CTA (reference standard). 
 
Applicable subjects 
All subjects with a contrast enhanced DE-CBCT scan and diagnostic CT angiography. 
 
Data 
 
Radiologist rating 
o 
Inferior/Equal/Superior 
 
Distal ICA (dICA) 
 
A1-A2 
 
Lenticulostriate arteries 

 
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 
M1  
 
M2  
 
M3-M4 
 
Distal Vertebrals 
 
Basilar 
 
Basilar perforating branches  
 
AICA-PICA-SCA 
 
P1-P2 
 
Analysis 
Images are evaluated by radiologists using CT angiography as reference standard and the proportion of 
equal or superior vessel visibility rating in abovementioned vessel territories is defined. 
 
Hypothesis: 
 
H0: π2 ≤ 0.80 
H1: π2 > 0.80 
 
Where π2 is the observed proportion of equal or superior vessel visibility and 0.80 is the performance 
goal. 
8.7.2. 
Intracranial hemorrhage detection accuracy 
 
Endpoint (2nd Secondary endpoint) 
Accuracy of DE-CBCT to determine the presence of intracranial hemorrhage using neCT as the 
reference standard. 
 
Applicable subjects 
All subjects in the study. 
 
Data 
 
Intracranial hemorrhage 
 
Yes / No 
 
Analysis 
Images are evaluated by radiologists using neCT as reference standard and the hemorrhage detection 
accuracy is defined. 
 
 
Hypothesis: 
 
H0: π3 ≤ 0.80 
H1: π3 > 0.80 
 
Where π3 is the observed intracranial hemorhage accuracy and 0.80 is the performance goal. 
8.8. 
Additional Objectives – 3D diagnostic imaging 
8.8.1. 
Ischemic stroke diagnostic accuracy, vessel tree visibility and 
hemorrhage detection accuracy compared to regular CBCT 
 
Applicable subjects, data and analysis same to that of primary and secondary endpoints, but using 
conventional CBCT image data (acquired from the top layer of the investigational device) as reference. 
 

 
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8.8.2. 
Characterization of brain tissue as normally perfused, at risk (penumbra) 
or infarcted 
 
Applicable subjects 
Subjects diagnosed with ischemic stroke. 
 
Data 
 
mCTA collateral score 
o 
Side: Left / Right 
o 
Score: 1 to 5  
 
ASPECTS score - CBV, MTT, CBF, TTP, Tmax or exploratory measurements 
o 
Side: Left / Right 
o 
Score: 1 to 10 
o 
Location - L, C, IC, I, M1, M2, M3, M4, M5, M6 
 
Infarct, penumbra and normally perfused tissue 
o 
Volume segmentation in ml 
 
Analysis  
Images are evaluated by radiologists using mCTA or CTP as reference standard. This is an exploratory 
objective. 
 
8.8.3. 
Characterization of intracranial hemorrhage 
 
Applicable subjects 
Subjects diagnosed with intracranial hemorrhage. 
 
Data 
Extraaxial or Intraaxial 
 
Extraaxial: SAH / SDH / EDH 
o 
Small, medium or extensive (SAH) 
o 
Maximum width (SDH/EDH) 
 
Intraaxial: Contusion/deep/lobar/cerebellum/brainstem/intraventricular 
o 
Volume segmentation in ml 
 
Hemorrhagic transformation of ischemic stroke 
 
HI – HI1 or HI2 
 
PH – PH1 or PH2 
 
Iodine vs blood – Majority/Minority or Equal 
 
Analysis 
Images are evaluated by radiologists using CT and/or DECT as reference standard.  
 
8.8.4. 
Characterization of intracranial thrombus 
 
Applicable subjects 
Subjects with an intracranial thrombus on CT. 
 
Data 
Localisation 
 
Side: Left / Right 
 
Localisation of thrombus: dICA, M1-M2, M3-M4, A1-A2 
 
Attenuation of thrombus (HU) 
 
Homogenous/heterogenous attenuation 

 
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 
Size: In mm as seen in maximum intensity projection (MIP) 
o 
Non contrast scan 
o 
Contrast enhanced scan (perceived filling defect) 
Inferior, Equal or Superior 
 
Perceived ability to identify thrombus 
 
Analysis 
Images are evaluated by radiologists using CT and/or DECT as reference standard.  
 
 
8.8.5. 
Separation of grey and white matter, and iodine from blood and calcium  
 
Applicable subjects 
All subjects. 
 
Data 
Possible / Not possible 
Inferior, equal or superior  
 
Grey vs white matter (insula, basal ganglia, cortex, cerebellum) 
 
Blood vs iodine 
 
Calcium vs iodine 
 
Blood vs calcium 
 
Analysis 
Images are evaluated by radiologists using CT and/or DECT as reference standard. Proportion rated 
“possible” as well as equal or superior compared to reference standard is defined. 
 
8.8.6. 
Assessment of novel segmentation and reconstruction techniques 
 
Applicable subjects 
All subjects. 
 
Data 
 
Separate, delineate infarcted and viable brain tissue 
 
Identify thrombus location 
 
Separate, delineate infarcted tissue from tissue at risk and normally perfused tissue 
 
Analysis 
This is an exploratory objective. Reference standards include commercially available CT segmentation 
software from concurrent CT. 
 
8.9. 
Additional Objectives – 3D image quality parameters 
8.9.1. 
Objective image quality parameters 
 
Applicable subjects 
All subjects. 
 
Data 
HU (or equivalent), standard deviations, CNR and SNR 
 
Central vs peripheral location in the image 
 
Water 

 
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 
Fat 
 
Grey matter 
 
White matter 
 
Blood 
 
Iodine 
 
Calcium (bone) 
 
 
Analysis 
Absolute numerical variables, mean and standard deviations of image quality indexes will be compared 
to reference standards (CT, DECT, CBCT). 
 
8.9.2. 
Subjective image quality parameters 
 
Applicable subjects 
All subjects. 
 
Data 
Yes / No: Visualization of 
 
Whole cerebrum 
 
Whole cerebellum 
 
Whole skull base 
 
Vessels after intravenous contrast media 
Inferior, equal or superior 
 
Sharp reproduction of the border between white and grey matter 
o 
Supratentorial 
o 
Infratentorial 
 
Sharp reproduction of the basal ganglia 
 
Sharp reproduction of the ventricular system 
 
Sharp reproduction of the cerebrospinal fluid space around the mesencephalon 
 
Sharp reproduction of the cerebrospinal space over the brain (subcalvarial space) 
 
Sharp reproduction of the great vessels and choroid plexuses after iv contrast media 
o 
Sharpness of large arteries (smoothness of vessel wall) 
o 
Visibility of small arteries (side branches) 
o 
Discrimination of crossing arteries/perforators 
o 
Venous filling 
 
Analysis 
This assessment is based on the European Guidelines on Quality Criteria for Computed Tomography 
(34). Images are evaluated by radiologists using CT, CBCT and/or DECT as reference standard.  
 
8.9.3. 
Image artefacts, especially near bony structures 
 
Applicable subjects 
All subjects. 
 
Data 
More, equal or less 
 
Near skull base 
 
Near convexity 
 
Posterior fossa 
 
Artifacts from metal devices, coils, clips, embolization material 
 

 
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Analysis 
Images are evaluated by radiologists and compared to reference standards (CT, DECT, CBCT).  
 
8.10. 
Additional objectives - Safety 
8.10.1. 
Radiation exposure and iodine contrast agent dose 
 
Endpoint 
Reported radiation exposure and iodine contrast agent dose compared to reference standards. 
 
Applicable subjects 
All subjects. 
 
Data 
 
Radiation dose in relevant exposure measures 
o 
Patient radiation exposure – radiation exposure index (e.g. air kerma and CTDI) 
o 
Dose-related data (e.g. tube kilovoltage) will be collected. 
 
Iodine dose in ml 
 
Analysis 
The patient radiation dose exposure (absorbed organ dose and effective dose) is estimated based on the 
radiation-dose related data registered by the x-ray machine during the performed clinical procedures. Values 
are compared with reference standards. 
 
 
8.10.2. 
Adverse events 
 
Objective 
Report all adverse events.  
 
Endpoint 
Adverse events, including information of the seriousness, treatment needed, resolution and relevant 
judgment concerning the causal relationship with the investigational devices, comparator or procedure will be 
summarized for safety information. 
 
Analysis 
The objective is descriptive with no performance requirements and no sample size has been calculated. 
All subjects will be included in this analysis. 
 
All adverse events will be presented in a tabular format. 
8.10.3. 
Adverse Device Effects 
 
Objective 
Adverse device effects, including information of the seriousness, treatment needed, resolution and relevant 
judgment concerning the causal relationship with the investigational devices or procedure will be 
summarized for safety information. 
 
Endpoint 
Adverse device effects, including information of the seriousness, treatment needed, resolution and relevant 
judgment concerning the causal relationship with the investigational devices or procedure will be 
summarized for safety information. 
 

 
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Analysis 
The objective is descriptive with no performance requirements and no sample size has been calculated. All 
subjects will be included in this analysis. 
 
All adverse device effects will be presented in a tabular format. 
8.10.4. 
Device Deficiencies that could have led to Serious Adverse Event 
 
Objective 
Device deficiencies that could have led to Serious Adverse Events, including any corrective actions taken 
during the study, if any, will be summarized for safety information. 
 
Endpoint 
Device deficiencies that could have led to Serious Adverse Events, including any corrective actions taken 
during the study, if any, will be summarized for safety information. 
 
Analysis 
The objective is descriptive with no performance requirements and no sample size has been calculated. All 
subjects will be included in this analysis. 
 
All device deficiency that could have led to a serious adverse device effect will be presented in tabular 
format. 
9. 
Data management 
The handling of data, including data quality assurance, will comply with regulatory guidelines (for example 
GCP and ISO 14155) and the sponsor’s SOPs and work instructions. All steps and actions taken regarding 
data management and quality assurance will be documented in the sponsor’s SOPs and data handling 
guidelines.  
A secure image data repository will be set up at Karolinska University Hospital, the access to which will be 
provided through IntelliSpace Discovery (ISD) that will serve as the interfacing client for managing and logging 
the access of data by authorized personnel involved in this study. No additional software will be required by the 
user to access the data as the ISD client runs in chrome web browser with a zero footprint i.e., no data will be 
stored on user’s computer while using the ISD interface. 
Electronic Case Report Form (e-CRF) will be used to collect medical history, subjects demographics, 
procedure related informaton, protocol deviations, adverse events and device deficiencies. The e-CRF will 
be used for data review, data cleaning and issuing and resolving queries. This e-CRF is a web-based e-CRF 
which is password protected and is CFR part 11 compliant. At the end of the study the data will be stored as 
a frozen dataset and will be retained. 
The e-CRF data from the subjects will be key-coded (pseudo anonymized). The information related to the 
subjects (like name) is kept separately in the enrollment log at the hospital. Date and time of the procedure 
and date of discharge will be collected. Patient dose data will not contain any patient names or numbers.  
Procedure date and time will be used to link the dose data to the corresponding CRF data. 
Exported (image) data will be de-identified. The remaining data will be de-identified. 
The data will be collected and stored in a secure location. 
 
Completed report forms will be verified against source data and visually checked by the study monitor for 
completeness, consistency, and legibility. 
All adverse event terms recorded on the report forms will be entered into the safety database. All data on the 
adverse events will be entered into a validated database. Edit checks will be implemented to ensure data 
quality and accuracy. Responses to requests for further clarification of data recorded in the reports will be 
answered, dated, and electronically signed by the investigator. Changes will be implemented in the database 
and the data review and validation procedures will be repeated as needed. 

 
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At the end of the study, the database will be locked and the data will be released for reporting and statistical 
analysis. 
9.1.1. 
Confidentiality 
The investigator and institution involved in this study will only provide direct access to source data and 
documents to the steering committee, and to appropriate authorities for the purposes of monitoring, 
audit, ethics committee review or regulatory inspection. Each subject taking part in the study will have agreed 
explicitly to such access in writing. 
All subject data will always be treated with strict adherence to professional standards of confidentiality. All 
reports and communications relating to subjects in the study will identify the subjects by their subject ID 
number only. 
9.1.2. 
Source Documentation 
Investigators are required to prepare and maintain adequate and accurate case histories, recording all 
observations and other data pertinent to the research on each subject. 
9.2. 
Monitoring Plan 
Monitoring will be performed by a trained person appointed by Philips to ensure compliance with the Clinical 
Research protocol, applicable national regulations and international standards, patient safety and data 
validity. Details of the Monitoring Plan can be found in the Monitoring Plan [REF-2]. The Sponsor may 
designate one or more individuals to monitor the progress of a clinical study. The Sponsor may also delegate 
the monitoring responsibilities to a third party. However, the Sponsor remains ultimately responsible for the 
conduct of the study. The Institution is responsible for the appropriate de-identification of subject data. The 
Investigation site should provide access to the source data of the subjects. 
 
The first visit will occur as soon as possible after the first subject is enrolled at the study site. The monitoring 
schedule is based on the following considerations: enrollment rate, study compliance at the center, 
magnitude of data corrections required, complexity of the Research, IRB/MEC request, audit/inspection. 
 
 The monitor activities include: 
 
Check that the study is conducted, recorded and reported in compliance with this research protocol, , 
the good clinical practice, and applicable regulations. Acts to oversee the progress of the study. 
 
Check signed and dated informed consent of the subjects and check that this is signed before any 
study-related procedures are undertaken. 
 
Ensure that essential documents (e.g. contract, MEC/IRB approval) are maintained in the Site 
Regulatory File. 
 
Ensure recording of deviations from protocol and store in Site Regulatory File or CRF. 
 
Ensure that all adverse events and device deficiencies are reported to the sponsor, and all serious 
adverse events and device deficiencies that could have led to a serious adverse device effect are 
reported to the sponsor without unjustified delay. 
 
Ensure that adverse event and device deficiency are reported to the MEC/IRB and Competent 
Authority within the required timeframe, if required. 
 
Ensure that the principal investigator is informed and knowledgeable of all relevant document 
updates concerning the clinical research (e.g. research protocol and Investigator Brochure). Ensure 
that amendments to the protocol and/or Investigators Brochure are provided to the MEC/IRB and/or 
Competent Authority by the principal investigator.  
 
Ensure device accountability. 
 
No structural source data verification is anticipated. 
 
Names of the monitor(s) can be found inAppendix II of this protocol. An update of this list can be provided to 
the site under separate cover.  

 
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9.3. 
Retention period 
The investigator shall maintain the records related to this study during the investigation and for a period 
according to the national regulation. 
Philips will maintain the records for a period of device End of Life (EoL) plus 15 years.  
 
The sponsor and principal investigator shall take measures to prevent accidental or premature destruction of 
these documents. 
9.4. 
AUDITS/INSPECTIONS 
An independent audit by external regulatory agencies from the investigator’s own country or from abroad 
may take place at any time during or after the study. This may include on- site inspections and source data 
verification at the investigator’s hospital. 
 
10. 
Amendments to the Clinical Research Protocol 
Non-significant changes of the Clinical Reasearch protocol may be included (minor logistical or 
administrative changes not effecting the rights, safety and well being of human subjects or not related to the 
clinical Research objectives or endpoints), without prior approval. A simple notification to the MEC and where 
appropriate regulatory authorities will be made by the Sponsor. Significant changes (such as device 
modifications, study procedures) shall be discussed with the principal investigator and steering committee 
prior approval. All changes will be documented with a justification and described in the latest version of the 
Clinical Research Protocol. Significant changes shall be authorized by the MEC and the Competent Authority 
before implementation. Exempt from this requirement are measures which have to be taken immediately in 
order to protect the participants. In such circumstances, the investigator must notify the EC or IRB and 
steering committee and must describe the conditions necessitating the departure from the protocol and 
the outcome of the emergency intervention in a written report. The steering committee will determine 
whether the subject is to continue in the study or be considered a protocol violation. 
11. 
Deviations from the clinical Research protocol 
 
The Investigator is not allowed to deviate from the Clinical Research Protocol or to enroll subjects that do not 
comply with all inclusion and exclusion criteria.  
 
Under emergency circumstances, deviations from the Clinical Research Protocol to protect the rights, safety 
and well-being of human subjects may proceed without prior approval of the sponsor and the MEC. Such 
deviations shall be documented and reported to the sponsor and the MEC as soon as possible  
Reporting requirements are further specified in section 14.2. 
 
All deviations from the Clinical Research Protocol will be documented with date, subject, reason, actions 
taken and if the deviation affects subject's rights, safety and well being or the scientific integrity of the clinical 
Research. The deviation shall be notified to the Sponsor as soon as possible via the e-CRF. Deviations will 
be reviewed by the sponsor and in case of serious or repetitive deviations a corrective action plan may 
represent a need to initiate a corrective action plan with the principal investigator. In some cases, necessitate 
suspension of enrollment at the site or ultimately the principal investigator will be disqualified. 
12. 
Device accountability 
Access to the investigational device shall be controlled and the investigational devices shall be used only in 
the clinical Research and according to the Clinical Research Protocol. 
 
The sponsor shall keep records to document the physical location of all investigational devices from 
shipment of investigational device to the Investigation sites until return or disposal. 
 

 
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The principal investigator shall keep records documenting the receipt, installation, use, return and disposal of 
the investigational device, including date of receipt, identification of each investigational device and date on 
which the investigational device was returned. 
13. 
Statements of compliance 
This clinical Research shall be conducted in accordance with the clinical Research protocol, and with the 
ethical principles that have their origin in the Declaration of Helsinki and all applicable regional and/or 
national regulations. Furthermore, clinical research conducted in the European Union shall be conducted in 
accordance with the International Standards SS- EN ISO 14155: 2011 Clinical research of medical devices 
for human subjects – Good clinical practice and the Medical Device Directive (MDD).  As of 26 May 2020 the 
reporting of serious adverse events and device deficiencies shall be carried out in accordance with the Medical 
Device Regulation (MDR). 
 
This clinical Research shall not be started prior to obtaining a favorable opinion from a Medical Ethics 
Committee (MEC)/Institutional Review Board (IRB) and Regulatory authority, if required. Any additional 
requirements imposed by the MEC/IRB and/or regulatory authority shall be followed. 
. 
Insurance shall be provided for the subjects participating in this clinical trial according to local law. 
14. 
(Early) termination and Study termination 
There are no provisions or interim analyses planned that can result in an early termination of the trial. The 
principal investigator, EC, or regulatory authority may suspend or prematurely terminate participation in the 
clinical research at the Investigation sites for which they are responsible.  
Any signs of unknown or increased risks for the subjects will be discussed by the sponsor and investigator to 
assess the impact on the subjects and clinical research. If suspicion of an unacceptable risk to subjects 
arises during the clinical research, or when so instructed by the EC or regulatory authorities, the sponsor 
shall suspend the clinical research while the risk is assessed. 
 
The sponsor shall terminate the clinical research if an unacceptable risk is confirmed.  
If suspension or premature termination occurs, the terminating party shall justify its decision in writing and 
promptly inform the other parties with whom they are in direct communication. The principal investigator and 
sponsor shall keep each other informed of any communication received from either the EC or the regulatory 
authority.  
 
Serious or repetitive occurrence of deviations from study protocol or non-compliance with regulations may 
also be reason for early termination or suspension of a study site.  
 
After the last patient has been included and investigated with the investigational device the clinical 
investigator and Sponsor will inform the EC and regulatory authority about end of inclusion.  
 
An early termination and/or study termination of the clinical investigation will be documented and shared with 
the EC and regulatory authority. 
 
15. 
Publication policy 
It is the joint responsibility of the investigator and sponsor to submit the clinical Research data for publication. 
Approximately two publications in peer reviewed journals such as Stroke, Radiology or AJNR. Each 
investigator is allowed to publish their results. All investigators that contributed to the content of the 
publication should be included in the author list. 
 
This clinical investigation will be recorded on ClinicalTrials.gov.  
 
 

 
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16. 
 STUDY FINANCES 
The NEXIS project has received funding from the European Union's Horizon 2020 research and innovation 
programme under grant agreement No 780026. The funding covers salary for involved personnel during 
planning and conduction of the clinical trial. This is defined for all participating members in the grant 
agreement No 780026. 
 
17. 
STUDY REPORT 
Study report will be written by the sponsor according to ISO 14155: 2011. 
After completion of the investigation, the sponsor will provide a study report approved and signed by the 
principal investigator. 
18. 
Literature 
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34. Bongartz G GS, Jurik AG, et al. European Guidelines on Quality Criteria for Computed 
Tomography. EUR (Luxembourg). 1999. 
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AJNR American journal of neuroradiology. 2001;22(8):1534-42. 
36. Tan IY, Demchuk AM, Hopyan J, Zhang L, Gladstone D, Wong K, et al. CT angiography clot 
burden score and collateral score: correlation with clinical and radiologic outcomes in acute middle 
cerebral artery infarct. AJNR American journal of neuroradiology. 2009;30(3):525-31. 
37. Berkhemer OA, Jansen IG, Beumer D, Fransen PS, van den Berg LA, Yoo AJ, et al. Collateral 
Status on Baseline Computed Tomographic Angiography and Intra-Arterial Treatment Effect in 
Patients With Proximal Anterior Circulation Stroke. Stroke. 2016;47(3):768-76. 
38. Zaidat OO, Yoo AJ, Khatri P, Tomsick TA, von Kummer R, Saver JL, et al. Recommendations 
on angiographic revascularization grading standards for acute ischemic stroke: a consensus 
statement. Stroke. 2013;44(9):2650-63. 
39. Gerber JC, Miaux YJ, von Kummer R. Scoring flow restoration in cerebral angiograms after 
endovascular revascularization in acute ischemic stroke patients. Neuroradiology. 2015;57(3):227-
40. 
 
 
 

 
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Appendix III: DECLARATION OF HELSINKI 
 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964  and amended  by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 35th WMA General Assembly, Venice, 
Italy, October 1983 41st WMA General Assembly, Hong Kong, September 1989 48th WMA General 
Assembly, Somerset West, South Africa, October 1996 52nd WMA General Assembly, Edinburgh, 
Scotland, October 2000 53rd WMA General Assembly, Washington, DC, USA, October 2002 (Note of 
Clarification on paragraph 29 added) 55th  WMA  General Assembly, Tokyo, Japan, October 2004 
(Note of Clarification on Paragraph 30  added) 59th WMA General Assembly, Seoul, Korea, October 
2008 
 
A. INTRODUCTION 
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of ethical 
principles for medical research involving human subjects, including research on identifiable human material 
and data. The Declaration is intended to be read as a whole and each of its constituent paragraphs should 
not be applied without consideration of all other relevant paragraphs. 
2. Although the Declaration is addressed primarily to physicians, the WMA encourages other participants 
in medical research involving human subjects to adopt these principles. 
3. It is the duty of the physician to promote and safeguard the health of patients, including those who are 
involved in medical research. The physician's knowledge and conscience are dedicated to the fulfilment of 
this duty. 
4. The Declaration of Geneva of the WMA binds the physician with the words, "The health of my patient will 
be my first consideration," and the International Code of Medical Ethics declares that, "A physician shall act 
in the patient's best interest when providing medical care." 
5. Medical progress is based on research that ultimately must include studies involving human subjects. 
Populations that are underrepresented in medical research should be provided appropriate access to 
participation in research. 
 
6. In medical research involving human subjects, the well-being of the individual research subject must take 
precedence over all other interests. 
7. The primary purpose of medical research involving human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic interventions 
(methods, procedures and treatments). Even the best current interventions must be evaluated continually 
through research for their safety, effectiveness, efficiency, accessibility and quality. 
 
8. In medical practice and in medical research, most interventions involve risks and burdens. 
  
9. Medical research is subject to ethical standards that promote respect for all human subjects and protect 
their health and rights. Some research populations are particularly vulnerable and need special protection. 

 
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These include those who cannot give or refuse consent for themselves and those who may be vulnerable 
to coercion or undue influence. 
10. Physicians should consider the ethical, legal and regulatory norms and standards for research involving 
human subjects in their own countries as well as applicable international norms and standards. No 
national or international ethical, legal or regulatory requirement should reduce or eliminate any of the 
protections for research subjects set forth in this Declaration. 
 
B. PRINCIPLES FOR ALL MEDICAL RESEARCH 
11. It is the duty of physicians who participate in medical research to protect the life, health, dignity, 
integrity, right to self-determination, privacy, and confidentiality of personal information of research subjects. 
12. Medical research involving human subjects must conform to generally accepted scientific principles, be 
based on a thorough knowledge of the scientific literature, other relevant sources of information, and 
adequate laboratory and, as appropriate, animal experimentation. The welfare of animals used for research 
must be respected. 
13. Appropriate caution must be exercised in the conduct of medical research that may harm the 
environment. 
14. The design and performance of each research study involving human subjects must be clearly described 
in a research protocol. The protocol should contain a statement of the ethical considerations involved and 
should indicate how the principles in this Declaration have been addressed. The protocol should include 
information regarding funding, sponsors, institutional affiliations, other potential conflicts of interest and 
incentives for subjects and provisions for treating and/or compensating subjects who are harmed as a 
consequence of participation in the research study. The protocol should describe arrangements for post-
study access by study subjects to interventions identified as beneficial in the study or access to other 
appropriate care or benefits. 
15. The research protocol must be submitted for consideration, comment, guidance and approval to a 
research ethics committee before the study begins. This committee must be independent of the researcher, 
the sponsor and any other undue influence. It must take into consideration the laws and regulations of the 
country or countries in which the research is to be performed as well as applicable international norms and 
standards but these must not be allowed to reduce or eliminate any of the protections for research subjects 
set forth in this Declaration. The committee must have the right to monitor ongoing studies. The researcher 
must provide monitoring information to the committee, especially information about any serious adverse 
events. The committee may make no change to the protocol without consideration and approval. 
16. Medical research involving human subjects must be conducted only by individuals with the appropriate 
scientific training and qualifications. Research on patients or healthy volunteers requires the supervision 
of a competent and appropriately qualified physician or other health care professional. The responsibility for 
the protection of research subjects must always rest with the physician or other health care professional 
and never the research subjects, even though they have given consent. 
17. Medical research involving a disadvantaged or vulnerable population or community is only justified if 
the research is responsive to the health needs and priorities of this population or community and if there is 
a reasonable likelihood that this population or community stands to benefit from the results of the research. 
18. Every medical research study involving human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and communities involved in the research in comparison 

 
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with foreseeable benefits to them and to other individuals or communities affected by the condition under 
investigation. 
19. Every clinical trial must be registered in a publicly accessible database before recruitment of the first 
subject. 
20. Physicians may not participate in a research study involving human subjects unless they are confident 
that the risks involved have been adequately assessed and can be satisfactorily managed. Physicians must 
immediately stop a study when the risks are found to outweigh the potential benefits or when there is 
conclusive proof of positive and beneficial results. 
21. Medical research involving human subjects may only be conducted if the importance of the objective 
outweighs the inherent risks and burdens to the research subjects. 
22. Participation by competent individuals as subjects in medical research must be voluntary. Although 
it may be appropriate to consult family members or community leaders, no competent individual may be 
enrolled in a research study unless he or she freely agrees. 
23. Every precaution must be taken to protect the privacy of research subjects and the confidentiality of 
their personal information and to minimize the impact of the study on their physical, mental and social 
integrity. 
24. In medical research involving competent human subjects, each potential subject must be adequately 
informed of the aims, methods, sources of funding, any possible conflicts of interest, institutional affiliations 
of the researcher, the anticipated benefits and potential risks of the study and the discomfort it may entail, 
and any other relevant aspects of the study. The potential subject must be informed of the right to refuse 
to participate in the study or to withdraw consent to participate at any time without reprisal. Special 
attention should be given to the specific information needs of individual potential subjects as well as to 
the methods used to deliver the information. After ensuring that the potential subject has understood the 
information, the physician or another appropriately qualified individual must then seek the potential 
subject's freely-given informed consent, preferably in writing. If the consent cannot be expressed in writing, 
the non-written consent must be formally documented and witnessed. 
25. For medical research using identifiable human material or data, physicians must normally seek consent 
for the collection, analysis, storage and/or reuse. There may be situations where consent would be 
impossible or impractical to obtain for such research or would pose a threat to the validity of the research. 
In such situations the research may be done only after consideration and approval of a research ethics 
committee. 
26. When seeking informed consent for participation in a research study the physician should be particularly 
cautious if the potential subject is in a dependent relationship with the physician or may consent under 
duress. In such situations the informed consent should be sought by an appropriately qualified individual 
who is completely independent of this relationship. 
27. For a potential research subject who is incompetent, the physician must seek informed consent 
from the legally authorized representative. These individuals must not be included in a research study that 
has no likelihood of benefit for them unless it is intended to promote the health of the population 
represented by the potential subject, the research cannot instead be performed with competent persons, 
and the research entails only minimal risk and minimal burden. 
28. When a potential research subject who is deemed incompetent is able to give assent to decisions 

 
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about participation in research, the physician must seek that assent in addition to the consent of the legally 
authorized representative. The potential subject's dissent should be respected. 
29. Research involving subjects who are physically or mentally incapable of giving consent, for example, 
unconscious patients, may be done only if the physical or mental condition that prevents giving informed 
consent is a necessary characteristic of the research population. In such circumstances the physician 
should seek informed consent from the legally authorized representative. If no such representative is 
available and if the research cannot be delayed, the study may proceed without informed consent provided 
that the specific reasons for involving subjects with a condition that renders them unable to give informed 
consent have been stated in the research protocol and the study has been approved by a research ethics 
committee. Consent to remain in the research should be obtained as soon as possible from the subject 
or a legally authorized representative. 
30. Authors, editors and publishers all have ethical obligations with regard to the publication of the results 
of research. Authors have a duty to make publicly available the results of their research on human subjects 
and are accountable for the completeness and accuracy of their reports. They should adhere to accepted 
guidelines for ethical reporting. Negative and inconclusive as well as positive results should be published 
or otherwise made publicly available. Sources of funding, institutional affiliations and conflicts of interest 
should be declared in the publication. Reports of research not in accordance with the principles of this 
Declaration should not be accepted for publication. 
 
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE 
31. The physician may combine medical research with medical care only to the extent that the research 
is justified by its potential preventive, diagnostic or therapeutic value and if the physician has good reason to 
believe that participation in the research study will not adversely affect the health of the patients who serve 
as research subjects. 
32. The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of 
the best current proven intervention, except in the following circumstances: 
 
The use of placebo, or no treatment, is acceptable in studies where no current proven intervention 
exists; or 
 
Where for compelling and scientifically sound methodological reasons the use of placebo is 
necessary to determine the efficacy or safety of an intervention and the patients who receive 
placebo or no treatment will not be subject to any risk of serious or irreversible harm. Extreme care 
must be taken to avoid abuse of this option. 
33. At the conclusion of the study, patients entered into the study are entitled to be informed about the 
outcome of the study and to share any benefits that result from it, for example, access to interventions 
identified as beneficial in the study or to other appropriate care or benefits. 
34. The physician must fully inform the patient which aspects of the care are related to the research. 
The refusal of a patient to participate in a study or the patient's decision to withdraw from the study must 
never interfere with the patient-physician relationship. 
In the treatment of a patient, where proven interventions do not exist or have been ineffective, the physician, 
after seeking expert advice, with informed consent from the patient or a legally authorized representative, 
may use an unproven intervention if in the physician's judgment it offers hope of saving life, re-
establishing health or alleviating suffering. Where possible, this intervention should be made the object of 

 
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research, designed to evaluate its safety and efficacy. In all cases, new information should be recorded and, 
where appropriate, made. 
 
 

 
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Sponsor shall report to Competent Authority: 
 
 
all serious (assured or suspected) adverse events, known as SAE (see MEDDEV 2.7/3) 
 
substantial changes to the investigation plan  
 
changes regarding the coordinating investigator or principal investigator 
 
changes regarding participating investigation sites  
 
interruptions for reasons of safety in the investigation with an explanation  
 
restart of interrupted investigation with a justification  
 
if the investigation was terminated prematurely with a justification 
 
when the clinical investigation was completed 
All serious adverse events must be fully recorded and immediately reported, but no later than 2 calender 
days after awareness by sponsor of a new reportable event or new information in relation with an already 
reported event to all the competent authorities in the Member States where the clinical investigation is being 
conducted. The sponsor and the principal investigator must notify each other on an ongoing basis in 
accordance with SS-EN ISO 14155:2011 and the applicable investigation plan. 
All reports of serious adverse events (SAE/SADE) for medical devices should be submitted to the MPA in 
electronic format by using the online e-service (see link to the right). 
 
In the e-service drop down menu for Recipient, please choose the “SAE Report Clinical Investigation of 
Medical Device”option 
 
Add your name and e-mail address in the mandatory fields 
 
Attach the file with the report 
 
Please indicate both the MPA reference number and CIV ID of the clinical investigation in the message 
field. 
The notification of amendments made to the investigation plan and the participating investigator(s) must be 
dated and signed by the sponsor and the relevant principal /coordinating investigator. 
Use online e-service (see Notification of clinical investigations) to also electronically submit notifications of 
amendments. When using the e-service it is required that the notification form is resubmitted, specify in a 
cover letter if the form is updated to a new version. 
 
 
 
 
 
 
 

 
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Appendix V: Study Scales 
The following measurement scales will be used in this clinical study: 
ASPECTS - Alberta Stroke Program Early CT Score (35). This is a 10-point quantitative ordinal score 
used to assess early ischemic changed on non-contrast enhanced CT. It is used as a reproducible 
grading system in patients with suspected large vessel occlusion as part of the assessment of patients 
that might be eligible for thrombectomy. 
mCTA Collateral Score (13, 36, 37) - Scoring system used for evaluation of collateral circulation in the 
case of a large vessel occlusion, which correlates with functional outcome and is used in combination 
with other markers to select patients that could benefit from thrombectomy. 
mTICI - modified thrombolysis in cerebral infarction (TICI) score. This parameter will be reported using 
the mTICI (inclusive of the 2C rating) scale (38, 39). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Philips’ proprietary information. Unauthorized use is proh bited.