Validation of 3D Synthetic MRI for Neuroimaging - Prospective, Multicenter, Multireader Investigation
Phase: NA
Conditions: Clinical Indication for Brain MRI, Healthy Volunteers
Sponsor: SyntheticMR

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CONFIDENTIAL 
 
CLINICAL INVESTIGATION PLAN (CIP) 
 
Clinical Investigation Title: 
Validation of 3D Synthetic MRI for neuroimaging – 
prospective, multicenter, multireader investigation 
Clinical Investigation Code: 
CIP-003 
Code Name: 
Curie 
Investigational Device(s): 
SyMRI 15 (3D) 
Coordinating Investigator: 
Dr. Jeffrey Miller 
Phoenix Children's Hospital 
1919 East Thomas Road 
Phoenix, AZ 85016 
USA 
Sponsor: 
SyntheticMR AB (publ) 
Storgatan 11 
582 23 Linköping 
Sweden 
 
Date: 
21-December-2023 
 
 
Revision 
Version History 
K 
Investigational Device renamed 
J 
Update of intended purpose and claims of investigational device, handling of 
incidental findings, statistical design, method and analytical procedure 
I 
Recruitment of healthy adult controls added and update of pediatric total 
H 
Intended purpose of device updated, endpoints changed accordingly. 
G 
Internal version, never released.  
F 
Inclusion criterion number 5 updated (subject information can be given in 
English or Spanish). Table 6 with acquisition parameters updated. 
E 
Internal version, never released. Not used in CIP-003 study and not distributed 
to sites. 
D 
Pediatric population divided in two sub-groups (Anesthesia and No-Anesthesia) 
C 
Updated according to IRB request 27-May-2022 

 
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B 
Updated according to IRB request 23-May-2022 
A 
First release 
 
 
This clinical investigation will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki. Furthermore, the clinical investigation will be performed in compliance with ISO 
14155:2020, Regulation (EU) 2017/745 and applicable regional or national US regulations. 
 
CONFIDENTIAL 
This Clinical Investigation Plan contains privileged or confidential information, which is the property of the Sponsor. 
Information may not be disclosed to a third party without written authorization from the Sponsor 

 
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1 
SYNOPSIS 
 
NAME OF THE SPONSOR: 
SyntheticMR AB (publ) 
Storgatan 11 
582 23 Linköping 
Sweden 
CLINICAL INVESTIGATION TITLE: 
Validation of 3D Synthetic MRI for neuroimaging – prospective, multicenter, multireader investigation 
CLINICAL INVESTIGATION CODE: 
CIP-003 
INVESTIGATIONAL DEVICE(S): 
SyMRI 15 (3D) 
OVERALL CLINICAL INVESTIGATION DESIGN: 
This is a pre-market, prospective, multicenter, reader clinical investigation in which multiple blinded readers will 
assess accuracy and image quality of synthetic and conventional 3D MR images to evaluate the performance of the 
SyMRI 15 (3D) software when used for visualization of the brain. The investigation consists of two parts, the image 
acquisition and the image review.  
 
For the image acquisition part, subjects will be recruited at up to 6 sites in the US. Subjects will consist of patients 
aged 0-99 years, scheduled for MRI of the brain, and healthy controls. In total 180 evaluable subjects will be 
included. Approximately 120 will be patients, whereof 65 adult subjects (age 18-99 years) and 55 pediatric subjects 
(age 0-17 years). The pediatric population will consist of two groups, one with subjects receiving anesthesia (Sub-
group Anesthesia) and one with subjects not receiving anesthesia (Sub-group No-anesthesia). In addition, a group 
of approximately 60 evaluable, healthy adult controls will be included. The aim is to include subjects covering a 
broad range of pathologies reflecting the intended use population.  
 
All subjects will undergo an MRI scan of the brain, using a fixed set of scanning parameters on a 3T MRI scanner 
from Philips. From each subject, the following sequences will be acquired for the investigation:  
• 
3D T1w (conventional image) 
• 
3D T2w (conventional image) 
• 
3D T2w FLAIR (conventional image) 
• 
3D-QALAS (data for generation of synthetic images) 
 
For the image review part of the investigation, the software SyMRI 15 (3D) will be used to post-process data from 
the 3D-QALAS acquisition to generate synthetic T1w and T2w images. For each subject, conventional and synthetic 
images will then be assessed by 5 blinded, experienced neuroradiologists who will assess the images with regards to 
image quality, legibility of anatomical structures, artifacts, and radiological findings. The readings will be separated 
into two reading sessions with a 4-week memory-washout period.  
 
Results will be analyzed for the whole cohort, a pediatric sub-population (subjects aged 0-17 years) and an adult 
sub-population (subjects aged 18-99 years). 
INCLUSION AND EXCLUSION CRITERIA: 
Inclusion Criteria 
The subjects have to meet all of the following criteria to be eligible to participate in the clinical investigation: 
 
 
INCLUSION CRITERIA 
1 
Any gender, aged 0-99 years 
2 
Subject scheduled for MRI of the brain 
OR 
Healthy control with passed screening form 
3 
Subject suitable for MRI as judged by investigator 
4 
Subject agrees to 5-20 min extra MRI scan time 
5 
Subject able to understand written and verbal information in English or Spanish 
6 
Provision of informed consent (and assent if applicable) 

 
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Exclusion Criteria 
Subjects meeting any of the following criteria will not be permitted to participate in the clinical investigation: 
 
 
EXCLUSION CRITERIA 
1 
Have contraindication(s) to MRI scanning per the routine MR Safety Screening policy of the 
investigational site 
2 
Have severe trauma, disability or pre-existing pathology that is expected to interfere with normal conduct 
of MRI scanning or complete scanning of the brain 
3 
Have medical condition(s) such as those requiring urgent medical care that, in the opinion of a physician 
investigator, would prevent safe participation in the study 
4 
Adult subjects (aged 18-99 years) in need of anesthesia during MRI scanning 
5 
Pregnancy at time of enrollment determined according to the clinic’s MR Safety Screening policy 
6 
Previous enrollment in this investigation 
 
OBJECTIVES: 
Primary Objective 
The primary objective is to: 
• 
demonstrate non-inferiority of synthetic 3D MR images compared to conventional MR images with 
respect to sensitivity and specificity of pathological findings. 
 
Secondary Objective(s) 
The secondary objectives are to demonstrate non-inferiority of synthetic 3D MR images compared to conventional 
MR images with respect to: 
• 
classification of pathological findings, 
• 
diagnostic accuracy in an adult population, and 
• 
diagnostic accuracy in a pediatric population 
 
Other exploratory objectives are to evaluate: 
• 
legibility of anatomical structures. 
• 
frequency and type of artifacts. 
• 
inter-rater and inter-method agreement, and  
• 
image quality for T1w and T2w images, synthetic 3D MR images compared to conventional MR 
images 
 
PERFORMANCE AND SAFETY ENDPOINTS: 
Primary Performance Endpoint  
• 
Difference in sensitivity of pathological findings (pathological vs normal/no finding) between 
synthetic and conventional MR images on the full analysis set.  
• 
Difference in specificity of pathological findings (pathological vs normal/no finding) between 
synthetic and conventional MR images on the full analysis set. 
 
Secondary Performance Endpoints 
• 
Difference in diagnostic accuracy of radiological findings (radiological finding class) between 
synthetic and conventional MR images on the subgroup of pathological patients. The ground truth 
is the site-determined diagnosis (radiological finding class).   
• 
Primary and secondary endpoints (sensitivity, specificity, accuracy) in adults (18–99 years). 
• 
Primary and secondary endpoints (sensitivity, specificity, accuracy) in pediatrics (0–17 years). 
 
Exploratory Endpoints 

 
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• 
Legibility of anatomical structures, per structure. 
• 
Presence and type of artifacts, per contrast weighting (T1w, T2w). 
• 
Inter-rater agreement (agreement, kappa coefficient and Gwet’s AC1 coefficient) with regards to 
radiological finding classes. 
• 
Inter-method agreement (agreement, kappa coefficient and Gwet’s AC1 coefficient) with regards to 
radiological finding classes. 
• 
Image quality score per contrast weighting (T1w, T2w). 
 
Safety Endpoints 
• 
Incidence of Adverse Events (AE), Adverse Device Effects (ADE), Serious Adverse Events (SAE), 
Serious Adverse Device Effects (SADE), Unanticipated Adverse Device Effect (UADE), 
Unanticipated Serious Adverse Device Effect (USADE) and Device Deficiencies (DD). 
 
STATISTICAL METHODS: 
Performance Analysis 
Descriptive statistics of subject demographics, characteristics of readers, and performance endpoints will be 
summarized descriptively at the patient, reader and image level. Continuous variables will be described with mean, 
standard deviation, median, minimum, and maximum value, and categorical variables with numbers and 
percentages.  
 
Statistical analyses will be performed on the patient level. Comparisons between conventional and synthetic MR 
images will be conducted using non-inferiority testing procedures.                                                                              
 
 
 
 
 
 
 
                                                                                                                The mean difference will be presented 
with corresponding two-sided 95% confidence interval. Non-inferiority will be established if the lower limit of the 
two-sided 95% confidence interval for the mean difference (i.e., intercept) is strictly greater than a pre-specified 
non-inferiority margin. The primary analyses will be performed on the full analysis set. Separate analyses on adult 
and pediatric sub-populations, and separate analyses by reader, will also be performed.  
 
For the primary and secondary endpoints, a non-inferiority margin of -0.05 will be used. All tests will be one-sided 
and conducted at significance level α=0.025. In case of a successful non-inferiority test for the two primary 
performance endpoints, the entire probability mass α=0.025 will be transferred to the secondary performance 
endpoints in the order specified in Section 10.2.2 Secondary performance endpoints. Non-inferiority will then be 
declared for all secondary performance endpoints with a successful non-inferiority test until the first encounter of 
a non-successful non-inferiority test. Estimates and confidence intervals of remaining performance endpoints will 
be presented descriptively but not considered as confirmatory findings. 
 
Safety Analysis 

 
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Safety variables will be summarized descriptively. 
 
Power and sample size 
A total of 180 evaluable subjects (90 pathological, 90 controls) and 5 readers will be included in the study to obtain 
80% simultaneous power in both primary endpoints using one-sided test, significance level α=0.025, non-inferiority 
margin -0.05. The calculations are based on the following assumptions: 
 
 
 
 
 
 
 
 
 
All tests will be one-sided and conducted at significance level α=0.025. The power for each of the primary endpoints 
is 90% and power for both primary endpoints simultaneously is 80%. No multiplicity adjustment is needed for the 
primary endpoints since non-inferiority in both primary endpoints is required to declare non-inferior diagnostic 
accuracy (sensitivity/specificity) with synthetic MR images compared to conventional MR images. Secondary 
performance endpoints will be evaluated using a hierarchical testing procedure only if the pass criteria for the 
primary endpoints is fulfilled. 
 
 
 
 
 

 
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2 
SPONSOR CIP APPROVAL PAGE 
The undersigned, hereby confirms that they have read and understood the content of this Clinical 
Investigation Plan (CIP) and further approves its content. 
 
 
 
 
______________________________  
______________________ 
Ulrik Harrysson 
 
 
Date (dd-Mmm-yyyy) 
CEO, SyntheticMR 
 
 
 

 
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3 
TABLE OF CONTENTS 
1 
SYNOPSIS ................................................................................................................................................... 3 
1.1 
Power and sample size ...................................................................................................................................6 
2 
SPONSOR CIP APPROVAL PAGE ..................................................................................................... 7 
3 
TABLE OF CONTENTS ........................................................................................................................ 8 
4 
ABBREVIATIONS AND ACRONYMS ........................................................................................... 11 
5 
INTRODUCTION ................................................................................................................................ 12 
5.1 
Background .................................................................................................................................................. 12 
6 
IDENTIFICATION AND DESCRIPTION OF THE INVESTIGATIONAL DEVICE ... 14 
6.1 
Manufacturer ................................................................................................................................................ 14 
6.2 
Identification of Investigational Medical Device ................................................................................... 14 
6.3 
Device Traceability ...................................................................................................................................... 14 
6.4 
Intended Purpose ........................................................................................................................................ 15 
6.5 
Indication and Population .......................................................................................................................... 15 
6.6 
Technical and Functional Features ........................................................................................................... 15 
6.7 
Manufacturing and Materials ..................................................................................................................... 15 
6.8 
Training and Experience ............................................................................................................................ 15 
6.9 
Installation and Use ..................................................................................................................................... 16 
7 
JUSTIFICATION OF CLINICAL INVESTIGATION DESIGN ............................................. 17 
7.1 
Identification of pathologies to cover in the clinical investigation ...................................................... 17 
7.2 
Justification of clinical investigation design ............................................................................................ 19 
8 
BENEFITS AND RISKS OF THE INVESTIGATIONAL DEVICE, CLINICAL 
PROCEDURE, AND CLINICAL INVESTIGATION ......................................................................... 21 
8.1 
Anticipated Clinical Benefits ..................................................................................................................... 21 
8.2 
Residual Risks and Anticipated Adverse Device Effects ...................................................................... 21 
8.3 
Risks Associated with Participating in the Clinical Investigation ........................................................ 22 
8.4 
Possible interactions with concomitant medical treatments ................................................................. 23 
8.5 
Risk Control ................................................................................................................................................. 23 
8.6 
Benefit-to-Risk Rationale ........................................................................................................................... 23 
9 
OBJECTIVES AND HYPOTHESES OF THE CLINICAL INVESTIGATION ................. 24 
9.1 
Primary Objective ........................................................................................................................................ 24 
9.2 
Secondary Objectives .................................................................................................................................. 24 
9.3 
Exploratory objectives ................................................................................................................................ 24 
9.4 
Hypothesis .................................................................................................................................................... 24 
9.5 
Claims and Intended Performance of the Investigational Device ....................................................... 24 
9.6 
Risks and Anticipated Adverse Device Effects ...................................................................................... 24 
10 
DESIGN OF THE CLINICAL INVESTIGATION ..................................................................... 25 
10.1 
General ..................................................................................................................................................... 25 
10.2 
Investigation Endpoints ........................................................................................................................ 25 
10.2.1 
Primary performance endpoint .................................................................................................. 25 

 
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10.2.2 
Secondary performance endpoints ............................................................................................ 25 
10.2.3 
Exploratory endpoints ................................................................................................................. 25 
10.2.4 
Safety endpoints ............................................................................................................................ 26 
10.3 
Investigational Device(s) and Comparator(s) .................................................................................... 26 
10.3.1 
Investigational device - SyMRI 15 (3D) .................................................................................... 26 
10.3.2 
Other medical device to be used during the clinical investigation ....................................... 26 
10.4 
Subjects .................................................................................................................................................... 26 
10.4.1 
Inclusion Criteria .......................................................................................................................... 26 
10.4.2 
Exclusion Criteria ......................................................................................................................... 26 
10.4.3 
Relationship of Investigation Population to Target Population ........................................... 27 
10.4.4 
Number of Subjects ..................................................................................................................... 27 
10.4.5 
Methods of Assigning Subjects to Different Treatment Arms ............................................. 28 
10.4.6 
Subject Withdrawal, Discontinuation, or Lost to Follow-up ................................................ 28 
10.4.7 
Subject Follow-up and Care ....................................................................................................... 28 
10.5 
Readers ..................................................................................................................................................... 28 
10.6 
Clinical Investigation Duration ............................................................................................................ 28 
10.7 
Clinical Investigation Procedures ......................................................................................................... 29 
10.7.1 
Schedule of Clinical Investigation Procedures /Assessments ............................................... 30 
10.7.2 
Image Acquisition ......................................................................................................................... 30 
10.7.3 
Image Review ................................................................................................................................ 33 
10.7.4 
Data collected during Visit 1 – MR exam ................................................................................ 34 
10.7.5 
Performance Variables and Measurements .............................................................................. 34 
10.7.6 
Safety Variables and Measurements .......................................................................................... 36 
10.7.7 
Activities Performed by Sponsor ............................................................................................... 36 
10.7.8 
Potential Confounding Factors .................................................................................................. 36 
10.7.9 
Future use of data obtained from subject ................................................................................ 36 
11 
MONITORING PLAN ......................................................................................................................... 37 
11.1 
Subject Records and Source Data ........................................................................................................ 37 
11.2 
Access to Source Data and Documentation ...................................................................................... 37 
12 
STATISTICAL CONSIDERATIONS ............................................................................................... 38 
12.1 
Statistical Design, Method and Analytical Procedures ..................................................................... 38 
12.1.1 
Analysis populations .................................................................................................................... 38 
12.1.2 
General Statistical Methodology ................................................................................................ 38 
12.1.3 
Primary Performance Analysis ................................................................................................... 38 
12.1.4 
Secondary Performance Analyses .............................................................................................. 39 
12.1.5 
Exploratory Analyses ................................................................................................................... 39 
12.1.6 
Safety Analysis............................................................................................................................... 40 
12.1.7 
Justification of choice of non-inferiority margin ..................................................................... 40 
12.2 
Sample size .............................................................................................................................................. 40 

 
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12.3 
Drop-out Rates ....................................................................................................................................... 40 
12.4 
Level of Significance and Power .......................................................................................................... 40 
12.5 
Pass / Fail Criteria .................................................................................................................................. 41 
12.6 
Interim Analysis ...................................................................................................................................... 41 
12.7 
Reporting of Deviations from the Original Statistical Analysis Plan (SAP) ................................. 41 
12.8 
Subgroups for Analysis .......................................................................................................................... 41 
12.9 
Procedures that Take into Account all the Data ............................................................................... 41 
12.10 
Missing, Unused or Spurious Data ...................................................................................................... 41 
12.11 
Exclusion of Particular Information from the Testing of the Hypothesis ................................... 41 
13 
DATA MANAGEMENT ...................................................................................................................... 42 
13.1 
Data Management – Image acquisition part ...................................................................................... 42 
13.2 
Data Management – Image review part .............................................................................................. 42 
13.3 
Data Retention ........................................................................................................................................ 43 
13.4 
Monitoring, Audits and Inspections .................................................................................................... 43 
14 
AMENDMENTS TO THE CIP ......................................................................................................... 44 
15 
DEVIATIONS FROM THE CIP ....................................................................................................... 45 
16 
DEVICE ACCOUNTABILITY .......................................................................................................... 46 
17 
STATEMENTS OF COMPLIANCE ................................................................................................ 47 
17.1 
Institutional Ethics Review ................................................................................................................... 47 
17.2 
Insurance .................................................................................................................................................. 47 
18 
INFORMED CONSENT PROCESS ................................................................................................ 48 
19 
ADVERSE EVENTS, ADVERSE DEVICE EFFECTS AND DEVICE DEFICIENCIES 49 
19.1 
Definitions ............................................................................................................................................... 49 
19.2 
Non-reportable adverse events ............................................................................................................ 50 
19.3 
Methods for discovering and documenting AE/ADE .................................................................... 50 
19.3.1 
Severity ........................................................................................................................................... 51 
19.3.2 
Causality ......................................................................................................................................... 51 
19.4 
Methods for Discovering and Documenting Device Deficiencies ................................................ 53 
19.5 
Reporting of USADE/UADE ............................................................................................................. 53 
19.6 
Foreseeable adverse events and anticipated adverse device effects ............................................... 54 
19.7 
Data Monitoring Committee ................................................................................................................ 54 
20 
VULNERABLE POPULATION .................................................................................................. 55 
21 
SUSPENSION OR EARLY TERMINATION OF THE CLINICAL INVESTIGATION . 56 
21.1 
Subject Follow-up .................................................................................................................................. 56 
22 
PUBLICATION POLICY .............................................................................................................. 57 
23 
REFERENCES ................................................................................................................................. 58 
24 
APPENDICES ................................................................................................................................... 60 
24.1 
Appendix A – Clinical Investigation Plan Agreement Form .......................................................... 60 
24.2 
Appendix B – Clinical Investigation Contact List ............................................................................. 61 

 
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24.3 
Appendix C – Declaration of Helsinki ............................................................................................... 64 
 
4 
ABBREVIATIONS AND ACRONYMS 
 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
ASADE 
Anticipated Serious Adverse Device Effect 
CIP 
Clinical Investigation Plan 
CIR 
Clinical Investigation Report 
CRO 
Contract Research Organization 
DMC 
Data Monitoring Committee 
DMP 
Data Management Plan 
DMR 
Data Management Report 
DVP 
Data Validation Plan 
eCRF 
Electronic Case Report Form 
EU 
European Union 
FDA 
Food and Drug Administration 
GDPR 
General Data Protection Regulation 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
ISO 
International Organization for Standardization 
LAR 
Legally Authorized Representative  
MDR 
Medical Device Regulation – Regulation (EU) 2017/745 
MRI 
Magnetic Resonance Imaging 
PI 
Principal Investigator 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SDV 
Source Data Verification 
SMF 
Study Master File 
SOP 
Standard Operating Procedure 
TBD 
To Be Decided 
UADE 
Unanticipated Adverse Device Effect 
USADE 
Unanticipated Serious Adverse Device Effect 
WMA 
World Medical Association 
 
 

 
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5 
INTRODUCTION 
This investigation is funded by SyntheticMR AB. A clinical trial agreement is set between the sponsor 
and each investigational site, detailing roles, and responsibilities. 
5.1 Background  
Magnetic Resonance Imaging (MRI) is a highly versatile, non-invasive, and widely used medical imaging 
technique intended for acquiring detailed anatomical information, thereby contributing to the study of 
the mechanistic underpinnings of both body function and dysfunction. The principle of MRI relies 
upon every tissue having its own intrinsic physical properties(1). Briefly, MRI employs powerful 
magnets that generate a strong magnetic field forcing protons in the body to align with it. Pulsing 
thereupon a radiofrequency current through the patient triggers the stimulation of the protons, causing 
them to spin out of equilibrium. The MRI sensors can thereafter detect the resulting release of energy 
as the protons realign with the magnetic field, striving towards returning to their original position, in a 
phase called relaxation. This measurable energy imbalance differs depending on the physical and 
chemical properties of the tissue and/or lesion(2). In general, one MRI acquisition is done for each 
contrast setting, implying that the patient often undergoes several imaging passes if several contrast 
settings are needed for the examination. A typical MRI exam takes about 30 to 45 minutes, depending 
on how many different contrast settings are required. The images are visually examined by the physician 
post-acquisition. Nowadays, MRI is the gold standard for investigating most affections of the central 
nervous system and its indications for use are therefore wide-ranging: stroke, epilepsy, brain tumors, 
infections and inflammation, multiple sclerosis (MS), dementia, metabolic disorders, post-trauma, 
nerve palsies, and vascular diseases, to name a few(3).  
 
The technology surrounding MRI is developing steadily, and newer quantitative techniques are now 
available to complement qualitative imaging, altogether resulting in more specific anatomical 
information(4). Recent progress in quantitative MRI makes it possible to measure physical properties 
of the human soft tissue, such as R1 and R2 relaxation rates and proton density (PD), on an absolute 
scale, altogether in a reasonable acquisition time(1). In other words, contrast varying synthetic MR 
images can be produced upon a single acquisition by calculating the expected image intensity with 
virtual contrast settings(1). Therefore, this technique may contribute to shortening the duration of the 
MRI exam(5). In addition, quantitative MRI approaches allow for a more objective and reproducible 
evaluation of the tissue than does conventional MRI, the assessment of which is based on the arbitrary 
signal contrast between tissues(6, 7). However, the extensive acquisition time deployed to quantify these 
tissue parameters(1), and the potential emergence of motion artifacts(8) are limitations that deserve to 
be considered. In this regard, motion artifacts could arise owing to the fact that the quality of synthetic 
MR images hinges on that of a single acquisition(8) and that the patient’s comfort may be impacted by 
long MR acquisition times(9). 
 
The generation of synthetic MR images using SyMRI, which is most commonly based on the two-
dimensional (2D) multi-dynamic multi-echo (MDME) sequence(6, 10), has been previously validated for 
the brain and proven to be non-inferior to conventional MR images(8). For example, the MDME 
sequence has been used for the assessment of different brain diseases, including MS(6, 11), brain 
infarctions(12), and meningitis(13), among others. However, this sequence, owing to its 2D properties, 
has a relatively low resolution in the slice direction compared to three-dimensional (3D) acquisition, 
fact that has likely hampered its use in routine clinical examination.  
 
More recently, efforts have been made to improve the spatial resolution of existing mapping techniques 
by acquiring the whole-brain data in 3D instead. Compared with a 2D approach, 3D acquisitions enable 
thinner slices, which are contiguous and easier to interpolate in the slice direction. Furthermore, a 3D 
acquisition allows visualization of the subject from any orientation, thus enhancing depiction of 
structures and subsequent more refined characterization of the pathologies(14). One of these techniques, 
the so-called 3D-quantification using an interleaved Look-Locker acquisition sequence with a T2 
preparation pulse (3D-QALAS) sequence, has been successfully applied to both the heart(15-17) and 
brain(7, 10, 14, 18, 19) structures, with high-level accuracy, precision, repeatability and reproducibility. In 

 
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their study, Fujita et al7 assessed the reliability of 3D-QALAS sequence-derived parameters values and 
compared them with those obtained using the MDME sequence. The authors concluded that the 
method’s reliability was high, and was likewise accompanied by high spatial resolution, which enabled 
the collection of detailed morphological information of the whole brain. In another study by the same 
authors(18), 3D-QALAS was shown to be reliable for measuring cortical thickness and subcortical 
volumes in most brain regions. Despite the potential of the 3D-QALAS relaxometry method, current 
3D quantitative imaging techniques require long acquisition times, thereby limiting its clinical use. The 
studies by Fujita et al(14) and Murata et al(10) investigated the addition of the compressed sensing (CS) 
reduction factor to the process and assessed whether it impacted the 3D-QALAS output quality in the 
brain. In both studies, the use of CS accelerated the 3D-QALAS scan while preserving tissue 
quantitative values and the quality of the resulting synthetic images.  
 
SyMRI is a post-processing software medical device intended for use in visualization of soft tissue in 
the head. The device analyzes input data from MRI systems and utilizes data from supported MR 
sequences to generate synthetic MR images with multiple contrasts, which can be subsequently adjusted 
by the user post-acquisition. A 3D version of SyMRI has been developed under research agreement 
since 2013 when the first feedback related a 3D version of SyMRI was received from the market. 
 
The aim of this prospective, multicenter, multireader clinical investigation is to evaluate the 
performance of the SyMRI 15 (3D) software compared to conventional 3D MRI when used for 
visualization of the brain. The objectives are to compare image quality, legibility of anatomical 
structures, artifact prevalence and inter method agreement of synthetic 3D MR images with 
conventional 3D images.  
 
The clinical investigation will be conducted in compliance with Declaration of Helsinki, the most 
current version of ISO 14155 and applicable regional or national regulations. The clinical data retrieved 
from this clinical investigation will be evaluated and incorporated in the product Clinical Evaluation 
Report (CER). 
 
 

 
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6 
IDENTIFICATION AND DESCRIPTION OF THE INVESTIGATIONAL 
DEVICE 
SyMRI allows the user to generate multiple image contrasts from a single acquisition. This is 
accomplished by post-processing a multi-delay, multi-echo acquisition (M2D-MDME or 3D-QALAS) 
into parametric maps. The parametric maps are R1, R2 relaxation rates, and proton density (PD). The 
inverse relaxation parameters, T1 relaxation time (1/R1), and T2 relaxation time (1/R2) are also 
provided as parametric maps. The parametric maps can be visualized as contrast weighted MR images, 
such as T1, T2, PD, and Inversion Recovery (IR) weighted images (including T1-FLAIR, T2-FLAIR, 
STIR, Double IR, and PSIR weighted images). SyMRI calculates the pixel signal intensity as a function 
of R1, R2, PD, and desired MR scanner settings, such as echo time (TE), repetition time (TR), and 
inversion delay time (TI). A number of default settings for TE, TR, and TI are provided, but the user 
has the ability to change the contrast of the images. SyMRI generates all the different image contrasts 
from the same parametric maps, derived from the same acquisition. This leads to enhanced image slice 
registration, owing to the absence of inter-acquisition patient movement. SyMRI provides the user the 
ability to change the contrast of the images after the acquisition. This is performed by adjusting the 
TE, TR, and/or TI parameters post-acquisition, to generate the specific contrast desired. 
 
SyMRI also enables the users to obtain volumetric information in the head, including white matter 
(WM), grey matter (GM), cerebrospinal fluid (CSF), Myelin correlated (MyC) partial volume, brain 
parenchyma (BP) and intracranial cavity (IC). This is accomplished by using tissue definitions based 
on the parametric maps. The tissue definitions provide tissue partial volume, or tissue fraction, per 
voxel. SyMRI also provides image processing tools to extract the values of the parametric maps, and 
tissue partial volume, per individual pixel, per region of interest, or the entire imaging volume. 
 
SyMRI is intended to be used on data produced by any of the following acquisition sequences: 
• 
M2D-MDME sequence data from GE MAGiC 
• 
M2D-MDME sequence data from Philips SyntAc 
• 
M2D-MDME sequence data from Siemens TSE_MDME 
• 
3D-QALAS sequence data from Philips 3D-QALAS 
 
In this investigation, the 3D-QALAS sequence created by Philips Healthcare will be used. The 3D-
QALAS technique is based on a 3D spoiled Turbo Field Echo sequence that contains multiple 
dynamics which are preceded by pre-pulses, T2-prep and inversion RF pulses. The signal amplitude 
per pixel in the raw data generated by the 3D-QALAS sequence is then used to calculate the PD, T1 
and T2 values by SyMRI and can subsequently be transformed into routine imaging contrasts. 
6.1 Manufacturer 
SyntheticMR AB (publ) 
Storgatan 11 
SE-582 23 Linköping, Sweden 
 
6.2 Identification of Investigational Medical Device 
SyMRI 15 (3D) 
 
6.3 Device Traceability 
Device traceability is maintained in the clinical investigation by creating a new version of SyMRI that 
is used specifically in the clinical investigation. All contrast weighted images that will be used in the 
investigation are generated by SyntheticMR with this version after all subjects has been recruited and 
before the image reading can start. When the contrast weighted images are exported from SyMRI to 
DICOM format, the SyMRI software store relevant version information in DICOM tag SyntheticMR 
private group (3005), thus ensuring full traceability on the contrast weighted images back to the 

 
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investigational device. The SyMRI software is not sent to the readers or sites for the purpose of the 
investigation.  
 
6.4 Intended Purpose 
SyMRI is a post-processing software medical device intended for use in visualization of soft tissue. 
SyMRI analyzes input data from MR imaging systems. SyMRI utilizes data from supported MR 
sequences to generate parametric maps of R1, R2 relaxation rates, and proton density (PD). SyMRI 
can generate multiple image contrasts from the parametric maps. SyMRI enables post-acquisition 
image contrast adjustment. SyMRI is indicated for head imaging. 
 
SyMRI is also intended for automatic labeling, visualization and volumetric quantification of 
segmentable brain tissues from a set of MR images. Brain tissue volumes are determined based on 
modeling of parametric maps from SyMRI. 
 
When interpreted by a trained physician, SyMRI images can provide information useful in determining 
diagnosis. SyMRI is intended to be used in combination with at least one other, conventional MR 
acquisition (e.g. T2-FLAIR). 
 
6.5 Indication and Population 
SyMRI is a post-processing software medical device intended for use in visualization of soft tissue and 
is indicated for head imaging. The intended population is patients of all ages with clinical indications 
for MR imaging of the head. 
 
6.6 Technical and Functional Features 
In essence, SyMRI has the following technical and functional features 
1. Generate parametric maps (T1, T2, PD) based on the absolute tissue properties. 
2. Generate several contrast weighted images.  
3. Visualize the image in three planes (Ax, Cor, Sag). 
4. Allow the user to adjust time parameters (TE/TR/TI) post scan. 
5. Provide volumetric information for brain, e.g. WM, GM, CSF, MyC. 
6. Show the volumetric information compared to a healthy population (reference curves). 
7. Export images and information to DICOM or Structured Report. 
 
This investigation covers the use of the contrast weighted images generated from the 3D-QALAS 
sequence for the brain imaging. 
6.7 Manufacturing and Materials 
Not applicable since the investigational device is a pure Software Medical Device. 
 
6.8 Training and Experience 
There is no specific training required from a regulatory point of view in order to use SyMRI. The 
output from SyMRI is contrast weighted images, which, when interpreted by a trained radiologist can 
be used to assist in diagnosing patients according to the intended purpose of the product. SyntheticMR 
do offer training and guidance to all end-users but these are not mandatory from a safety perspective 
and focus more on improving the user experience and provide best practice. 
 
For this clinical investigation no specific training of the SyMRI software is planned. The radiologists 
participating in the study will not use SyMRI directly but only interpret and analyze the contrast 
weighted images generated from SyMRI. All radiologist participating in the investigation are 
experienced in neuro imaging and have all the necessary training to interpret the images. 
 

 
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6.9 Installation and Use 
No specific medical or surgical procedures are involved in the use of the investigational device. 

 
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7 
JUSTIFICATION OF CLINICAL INVESTIGATION DESIGN 
A 3D version of SyMRI has been developed under research agreement since 2013 when the first 
feedback relating a 3D version of SyMRI was received from the market. Since then, extensive software 
system tests of SyMRI have been performed to confirm that specified software requirements are 
fulfilled. In addition, 5 articles have been published on SyMRI with the use of 3D-QALAS sequence 
on brain in human subjects(7, 10, 14, 18, 19). These publications have mainly focused on quantitative 
measurements (brain volume and cortical thickness) and/or qualitative comparisons between synthetic 
and conventional MR images in adult healthy volunteers and MS patients. Since SyMRI 15 (3D) is 
intended to be used in patients of all ages with clinical indications for MR imaging of the head, 
SyntheticMR has identified that a clinical investigation validating the use of SyMRI 15 (3D) in clinical 
neuroimaging in individuals of different ages and a broad range of pathologies is needed to support 
the intended purpose of SyMRI 15 (3D). Thus, the clinical investigation is aiming at confirming the 
clinical usability and safety of SyMRI 15 (3D), when used according to its proposed labelling, to create 
support for the current claims and intended purpose. The clinical data retrieved from this clinical 
investigation will be evaluated and incorporated in the product Clinical Evaluation Report (CER).  
 
7.1 Identification of pathologies to cover in the clinical investigation 
As described above, the aim is to include subjects covering a broad range of pathologies seen in brain 
MRI. The distribution of the pathologies included in the investigation should also reflect the real-life 
prevalence of the different pathologies in the target population. This means that the aim will be to 
include a higher number of subjects with the most frequent pathologies and a lower number of subjects 
with the less frequent pathologies. 
 
 
 

 
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Table 1: Pathology groups and prevalence in adult population. 
 
Prevalence 
Pathology group 
Example of pathology or disease 
1 
Infectious/Inflammatory/ 
Demyelinating 
MS and other demyelinating disorders  
Infectious (bacterial, viral, fungi)  
Vasculitis  
Autoimmune-mediated encephalitis 
1 
Vascular Disorders of the Brain 
Ischemia/infarcts 
Hemorrhagic 
Small vessel disease  
Venous thrombosis  
Aneurysm 
1 
Neuro Degenerative Disorders and 
Hydrocephalus 
Alzheimer’s and other primary neurodegenerative disorders 
Movement disorders, e.g. Parkinson 
Communicating hydrocephalus 
Non-communicating incl. normal pressure hydrocephalus 
2 
Intracranial Neoplasms 
Primary Brain tumors  
Metastasis  
Extra-axial tumors 
Cystic lesions  
Sellar tumors 
2 
Traumatic Lesions 
Intra-axial Hematomas  
Extra-axial Hematomas  
Diffuse axonal injury 
2 
 
Congenital Malformations 
 
 
Brain developmental malformations 
3 
Toxic and Metabolic conditions 
Exogenous toxins 
Drug-induced neurotoxic disorders 
Radiation and chemotherapy induced injuries 
Acquired metabolic diseases 
Leukodystrophies and inherited metabolic conditions 
Prevalence rated as 1=most common, 2=common, 3=least common 
 
Table 2: Pathology groups and prevalence in pediatric population.  
 
Prevalence  
Pathology group 
Example of pathology or disease 
2 
Infectious/Inflammatory/ 
Demyelinating 
MS and other demyelinating disorders  
Infectious (bacterial, viral, fungi)  
Vasculitis  
Autoimmune-mediated encephalitis 
2 
Vascular Disorders of the Brain 
Ischemia/infarcts 
Hemorrhagic 
Venous thrombosis  
Aneurysm 
2 
Neuro Degenerative Disorders and 
Hydrocephalus 
Communicating hydrocephalus 
Non-communicating incl. normal pressure hydrocephalus 
1 
Intracranial Neoplasms 
Low Grade Astrocytomas 
High Grade Astrocytomas 
Brain Stem Gliomas 
Medulloblastomas 
Ependymomas 
Sellar tumors 
1 
Traumatic Lesions 
Intra-axial Hematomas  
Extra-axial Hematomas  
Diffuse axonal injury 
2 
 
Congenital Malformations 
 
 
Brain developmental malformations 
3 
Toxic and Metabolic conditions 
Exogenous toxins 
Drug-induced neurotoxic disorders 
Radiation and chemotherapy induced injuries 
Acquired metabolic diseases 
Leukodystrophies and inherited metabolic conditions 
Prevalence rated as 1=most common, 2=common, 3=least common 
 
 

 
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7.2 Justification of clinical investigation design 
This premarket investigation is designed as a prospective, multicenter, multireader clinical investigation 
in which blinded, multiple readers will assess the image quality of synthetic and conventional 3D MR 
images to determine the clinical usability and performance of synthetic images when used for 
visualization of the brain. 
 
Since SyMRI 15 (3D) is intended to be used in patients of all ages with clinical indications for MR 
imaging of the head, subjects from the age of 0 to 99 years, with a broad range of pathologies will be 
included in the investigation. Among the pathologies listed in Table 1 and Table 2, there are conditions 
that may involve cognitive impairment, such as Alzheimer’s disease. Both children and mentally 
disabled persons are considered vulnerable according to FDA regulations (21 CFR 56.111) and 
additional safeguards have been included in the study to protect the rights and welfare of these subjects 
(see Section 18). The research part for the subject is limited to 5-20 additional minutes in the MRI 
scan. This is considered to involve no greater than minimal risk to the subjects. 
 
Healthy controls (adults) will also be recruited in order to evaluate potential false positive. 
 
The imaging appearance of a child’s brain can appear different than that of an adult. Additionally, 
images of a child’s brain appear different between children of different age groups and different 
development stages. There are also a number of neurological diseases that are more common in 
children than adults. MRI protocols and imaging techniques designed and validated in adults are not 
always applicable to the imaging of a child’s brain. This justifies a pediatric population of a broad age 
span. The sites recruiting children were selected based on well-experienced, leading principal 
investigators within the field of pediatric neuroradiology. There are no anticipated direct benefits for 
the subject. However, the results from this research study might help to reduce the scan time for future 
children. 
 
Sedation and general anesthesia are sometimes utilized, most frequently in children less than 6 years, 
in order to minimize the motion artifacts that can accompany children and lead to reduced diagnostic 
efficacy of MRI examinations. The risks of sedation and general anesthesia themselves are very low 
when managed by providers with appropriate training and experience. Children having anesthesia will 
be carefully monitored by trained and experienced health care providers throughout the whole MR 
procedure. These subjects will be included in the sub-group Anesthesia. 
 
A prerequisite for the generation of synthetic MR images with SyMRI 15 (3D) is MRI data acquired 
using the 3D-QALAS sequence. To date, there are no MRI scanners which are FDA-cleared for the 
3D-QALAS sequence available and therefore the access to retrospective data is limited. Thus, a 
prospective design has been chosen for this investigation. In addition, this enables the use of a 
standardized MRI protocol ensuring comparable MR images from the different sites. Although the 
MR images are collected prospectively, the MR images acquired for the investigation will not be used 
for diagnostic reasons or treatment decisions which means that the subjects will not be affected by the 
use of SyMRI 15 (3D). 
 
A multicenter approach has been chosen to assure timely inclusion of the pathology groups listed in 
section 7.1. Furthermore, the sites will consist of a mix of university hospitals and private imaging 
centers since it is expected that the university hospitals will handle the more unusual pathologies while 
the private imaging centers will handle larger volumes of the more common pathologies.  
 
The image quality of the synthetic MR images will be evaluated by multiple readers and compared with 
conventional MR images. A number of 5 readers evaluating all cases in the investigation was deemed 
sufficient and feasible. The readers will be blinded to image type (i.e. synthetic versus conventional) 
and the cases will be read in a randomized order to eliminate potential sources of bias. 
 

 
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The three contrast weightings T1w, T2w and T2w FLAIR were chosen for this investigation since 
these are commonly used in conventional neuroimaging. Since the purpose is to test SyMRI according 
to its intended used, only the T1w and T2w images will be evaluated, and a conventional FLAIR will 
be included in all readings of the synthetic images. Conventional 3D images were chosen as the 
comparator for all three contrast weighted images to allow a robust comparison of the image quality 
with all three planes with similar resolution available to the readers for all images. 
 
 
 

 
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8 
BENEFITS AND RISKS OF THE INVESTIGATIONAL DEVICE, CLINICAL 
PROCEDURE, AND CLINICAL INVESTIGATION 
When discussing risks and benefits of a new medical device, there are different aspects that have to be 
considered, including the potential risks and benefits for the subjects participating in the clinical 
investigation and for future patients with clinical use of the new device. 
 
The risk management related to the device has been conducted in accordance with ISO 14971 and 
included risk analysis and risk evaluation, risk control and pre-production and post-production review. 
 
8.1 Anticipated Clinical Benefits 
The anticipated clinical benefits of SyMRI 15 (3D) are: 
• 
Thinner slices and no slice gap compared to SyMRI 2D using the M2D-MDME sequence. 
• 
Ability to visualize the anatomy in three planes (Ax, Cor, Sag). 
• 
Provides valuable volumetric information in the head, including white matter, grey matter, 
cerebrospinal fluid, Myelin correlated partial volume, brain parenchyma and intracranial cavity. 
• 
Allow the user to adjust time parameters (TE/TR/TI) post acquisition. 
 
8.2 Residual Risks and Anticipated Adverse Device Effects 
Entering the MR scanner will follow the sites standard procedure and safety protocols. MR scanners 
are considered safe since they do not emit ionizing radiation. 
 
After review of risk documentation for SyMRI 15 (3D), the remaining clinical risks after risk control 
that have been employed are summarized in Table 3 (RMR-8 Risk Management Report(23)). Some of 
the problems identified in the risk analysis are also well-known issues in conventional images which is 
a well-tried MRI method with established routines and clinical practices. New users of the product will 
be informed of the identified risks. When the device is used in accordance with the intended use and 
recommended system requirements, SyMRI 15 (3D) is considered safe and effective based on the risk-
benefit analysis. 
 
Table 3 Residual risks identified for SyMRI14 
POTENTIAL CLINICAL EFFECT 
HAZARDOUS SITUATION 
EXPLANATION 
MISINTERPRETATION AND 
POTENTIAL MISDIAGNOSIS 
Image artifacts due to 
patient movements 
Image artifacts due to patient movements (fuzzy images with 
blurry edges). This kind of image artifacts are common for 
conventional MR as well, and are well known within currently 
accepted clinical practices. 
Image artifacts specific to 
SyMRI 
• Images with black blood features due to suppressed 
signal in image acquisition (due to blood flow or 
accumulated contrast agents in the tissue), 
• Ghosting artifacts caused by flow (flow sensitivity), 
• Small features may disappear and will not be visible in 
the image if the resolution is too low for the particular 
feature of interest. 
Quantitative analysis not 
accurate or reproducible 
Inaccurate or irreducible quantitative analysis may lead to 
incorrect information to support diagnosis, and to incorrect 
diagnosis. Precision of quantitative measurements depends 
on all parameters, and scanner setting and magnetic   field 
tolerances for different MR scanner manufacturers may thus 
reduce the precision. Follow up exams on different MR 
scanner make and model may lead to   small differences in 

 
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the quantitative analysis, and thus to reduced precision of 
the analysis. 
Incorrect patient data or 
patient data mix-up 
Incorrect patient data may lead to potential incorrect 
diagnosis. This may be due to: 
• data transfer to and from PACS system 
• data security issues (such as corrupt data, tampering 
with data, network security breach) 
LOSS OF FUNCTIONALITY 
Tool unavailability 
In case SyMRI s not available for use (such as software crash, 
data transfer errors or network issues, the analysis cannot be 
performed as intended. 
The diagnosis will in such cases have to be based on 
conventional MR. 
 
In this clinical investigation, SyMRI 15 (3D) will be used by Sponsor to generate synthetic MR images 
after subject has completed the investigation. Site will not have access to the synthetic MR images and 
diagnoses and treatment decisions will be based on the conventional MR images according to site’s 
clinical routines. Therefore, the use of SyMRI 15 (3D) will not involve any risks to, or affect the care 
of, the subjects participating in the investigation.  
 
The MRI devices used in the investigation, including the investigational 3D-QALAS sequence, will be 
within FDA specified parameters and considered to involve no greater than minimal risk to the 
subjects.  
 
There are no anticipated adverse device effects for the investigational devices, neither for SyMRI 15 
(3D) nor for the 3D-QALAS sequence. 
 
8.3 Risks Associated with Participating in the Clinical Investigation 
For patients, only subjects scheduled for an MRI of the brain, either according to clinical routine care 
or as part of other clinical investigation/research study, will be asked to participate in this clinical 
investigation. Participation will involve 5-20 minutes extra time in the MRI scanner to acquire the 
investigational MR images. There will be no greater than minimal risk from the additional imaging, but 
subjects may experience discomfort due to the additional time in the scanner. 
 
For the healthy control group, participation will involve 20 to 30 minutes of scan time in the MRI with 
no greater than minimal risk for the MRI procedure. Standard site MRI safety procedures will be 
followed and all images will be reviewed to rule out incidental findings. Site will follow up with subjects 
where incidental findings occur and guidance for seeking clinical care will be provided. If an 
abnormality is found, the subject will be informed of the finding and instructed to schedule a follow-
up as soon as possible with the appropriate care provider as recommended by the site medical director 
or his/her primary care provider (PCP). If the incidental finding is considered severe or urgent, 
immediate intervention/admission to a hospital may be required. If a severe incidental finding is noted 
by the MRI technician and/or study physician, they will seek immediate internal opinion by a physician. 
If deemed life threatening the subject will be sent to the appropriate hospital otherwise the appropriate 
information will be provided to the subject to schedule a follow-up as soon as possible with the 
appropriate care provider as recommended by the site medical director or his/her PCP. 
 
Anesthesia will be utilized in some of the pediatric subjects. Extended anesthesia is considered to 
constitute a greater than minimal risk for the subjects. Therefore, these subjects will be included in a 
separate sub-group (Anesthesia) and additional safety measures will be taken. Children scheduled for 
MRI under anesthesia will only be included in the study if the physician investigator and the 
anesthesiologist deem it safe to extend the scan time under anesthesia with 5-20 minutes. The children 

 
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will be carefully monitored by licensed anesthesiologists throughout the whole MR procedure. For the 
informed consent process, see section 18. 
 
Risks associated with MRI scan in general (not specific for the clinical investigation): 
• 
MRI uses a powerful magnet to make images; therefore, persons with metal implants, such as 
certain types of surgical clips or pacemakers, should not have an MRI.  
• 
Other metal objects such as keys, pocketknives, credit cards, cell phones, and some types of 
cosmetics or jewelry must be removed prior to entrance to the magnet room. The MRI scanner 
also uses radio frequency waves that can, on rare occasions, cause a mild warming sensation.  
• 
The MRI scanner makes loud banging noises during the scanning session. Subject will be 
provided with earplugs/ ear protection to reduce the noise heard from the scanner.  
• 
It is also possible, but rare, that the magnetic fields in the scanner can cause mild twitching in 
the arms and legs.  
• 
Some people feel uncomfortable and/or claustrophobic when lying inside the MRI scanner. 
If subject feels nervous or upset during the MRI, the procedure may be stopped. 
 
The risks presented above are associated with the MRI scan and are not predicted to increase due to 
the additional time in the MRI scanner. 
 
8.4 Possible interactions with concomitant medical treatments 
Gadolinium-based contrast agents may affect the appearance of the MR images and therefore, the 
investigational sequences should be taken before gadolinium is administrated in this clinical 
investigation. 
8.5 Risk Control 
The MRI devices used in the investigation, including the 3D-QALAS sequence, will be within FDA 
specified parameters. Careful attention will be paid to safety procedures to prevent the potential risks 
associated with MRI scan. 
 
For the pediatric population, anesthesia will be allowed if needed for the scheduled MRI. Inclusion in 
the investigation will mean an extension of the scan time under anesthesia of 5-20 minutes. FDA 
classifies prolonged anesthesia as greater than 3 hours(25). Prolonged anesthesia is not anticipated as 
part of this study since a single MRI exam never exceeds 2 hours and >99% of all MRI exams at 
Phoenix Children's Hospital (Site 1) are 1 hour or less. Only subjects without medical condition(s) that, 
in the opinion of a physician investigator, would prevent safe participation in the study will be included 
(see exclusion criterion no. 3). This means that only children where the physician investigator and the 
anesthesiologist deem it safe to extend the scan time under anesthesia with 5-20 minutes will be 
included in the study. All sites recruiting children are specialized in pediatric neuroradiology and are 
experienced in performing and monitoring MRI under anesthesia. The sites will follow their clinical 
routines in terms of pediatric anesthesia. 
 
Risks related to the processing of subjects’ personal data, and in particular data concerning health, will 
be mitigated by use of pseudonymization, whereby the personal data will no longer be attributable to 
a specific subject without the use of a key which will be kept separately and securely by the PI. 
8.6 Benefit-to-Risk Rationale 
This investigation is considered a non-significant risk study since the output from the investigational 
device will not be used for any patient treatment or diagnosis. The subject discomfort for the extra 
scan time is considered small. The potential benefit for future patients outweighs the risks. 

 
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9 
OBJECTIVES AND HYPOTHESES OF THE CLINICAL INVESTIGATION 
9.1 Primary Objective 
The primary objective is to demonstrate non-inferiority of synthetic 3D MR images compared to 
conventional MR images with respect to sensitivity and specificity of pathological findings. 
9.2 Secondary Objectives 
The secondary objectives are to demonstrate non-inferiority of synthetic 3D MR images compared to 
conventional MR images with respect to: 
• 
classification of pathological findings, 
• 
diagnostic accuracy in an adult population, and 
• 
diagnostic accuracy in a pediatric population. 
9.3 Exploratory objectives 
Other exploratory objectives are to evaluate: 
• 
legibility of anatomical structures, 
• 
frequency and type of artifacts, 
• 
inter-rater and inter-method agreement, and 
• 
image quality for T1w and T2w images, with synthetic 3D MR images compared to 
conventional MR images. 
 
9.4 Hypothesis 
The null hypothesis (H0) is that the difference in sensitivity and specificity of pathological findings 
(pathology vs normal/no finding) with synthetic 3D MR images compared to conventional MR images 
is less than or equal to -0.05. 
 
The alternative hypothesis (H1) is that the difference in sensitivity and specificity of pathological 
findings (pathology vs normal/no finding) with synthetic 3D MR images compared to conventional 
MR images is greater than -0.05. 
 
Each of the two one-sided hypotheses will be tested at significance level α=0.025. 
 
9.5 Claims and Intended Performance of the Investigational Device  
When interpreted by a trained physician, the information from SyMRI can provide information useful 
in determining diagnosis. 
 
T1w and T2w images from SyMRI can replace conventional T1w and T2w images of similar resolution 
and provide the same determination of radiological findings. 
 
9.6 Risks and Anticipated Adverse Device Effects 
One risk from the risk analysis will be assessed during the clinical investigation: the risk for 
misinterpretation and potential misdiagnosis due to possible novel image artifacts specific to SyMRI 
or synthetic MR images. Image artifacts in conventional MR are well-known and can be easily identified 
by a trained radiologist or MR technician. This clinical investigation will assess the risk for possible 
novel image artifacts that could arise when using SyMRI. 
 
 

 
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10 DESIGN OF THE CLINICAL INVESTIGATION 
10.1 General 
This is a pre-market, prospective, multicenter, reader clinical investigation in which blinded, multiple 
readers will assess the image quality of synthetic and conventional 3D MR images to evaluate the 
performance of the SyMRI 15 (3D) software when used for visualization of the brain. The investigation 
consists of two parts, the image acquisition and the image review.  
 
For the image acquisition part, subjects will be recruited at 5-10 sites in the US. Subjects will consist of 
individuals aged 0-99 years, who either are patients scheduled for MRI of the brain or healthy controls. 
The aim is to include subjects covering a broad range of pathologies reflecting the intended use 
population. All subjects will undergo an MRI scan of the brain, using a fixed set of scanning parameters 
on a 3T MRI scanner from Philips. From each subject, the following sequences will be acquired for 
the investigation:  
• 
3D T1w (conventional image) 
• 
3D T2w (conventional image) 
• 
3D T2w FLAIR (conventional image) 
• 
3D-QALAS (data for generation of synthetic images) 
 
For the image review part of the investigation, SyMRI 15 (3D) will be used to post-process data from 
the 3D-QALAS acquisition to generate synthetic T1w and T2w images. For each subject, the reader 
will either have synthetic T1w and T2w plus a conventional FLAIR, or will have only conventional 
images. The images will be assessed by 5 blinded, experienced neuroradiologists who will assess the 
images with regards to image quality, legibility of anatomical structures, artifacts, and radiological 
findings. The readings will be separated into two reading sessions with a 4-week memory-washout 
period.  
 
Results will be analyzed for the whole cohort, a pediatric sub-population (subjects aged 0–17 years) 
and an adult sub-population (subjects aged 18–99 years).  
 
10.2 Investigation Endpoints 
10.2.1 Primary performance endpoint 
• 
Difference in sensitivity of pathological findings (pathological vs normal/no finding) between 
synthetic and conventional MR images on the full analysis set.  
• 
Difference in specificity of pathological findings (pathological vs normal/no finding) between 
synthetic and conventional MR images on the full analysis set.  
The ground truth is the site-determined diagnosis (pathological vs. normal/no finding).  
 
10.2.2 Secondary performance endpoints 
• 
Difference in diagnostic accuracy of radiological findings (radiological finding class) between 
synthetic and conventional MR images on the subgroup of pathological patients. The ground 
truth is the site-determined diagnosis (radiological finding class).   
• 
Primary and secondary endpoints (sensitivity, specificity, accuracy) in adults (18–99 years). 
• 
Primary and secondary endpoints (sensitivity, specificity, accuracy) in pediatrics (0–17 years).  
10.2.3 Exploratory endpoints 
• 
Legibility of anatomical structures, per structure. 
• 
Presence and type of artifacts, per contrast weighting (T1w, T2w). 
• 
Inter-rater agreement (agreement, kappa coefficient and Gwet’s AC1 coefficient) with 
regards to radiological finding classes. 

 
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• 
Inter-method agreement (agreement, kappa coefficient and Gwet’s AC1 coefficient) with 
regards to radiological finding classes. 
• 
Image quality score per contrast weighting (T1w, T2w). 
10.2.4 Safety endpoints 
• 
Incidence of Adverse Events (AE), Adverse Device Effects (ADE), Serious Adverse Events 
(SAE), Serious Adverse Device Effects (SADE), Unanticipated Adverse Device Effect 
(UADE), Unanticipated Serious Adverse Device Effect (USADE) and Device Deficiencies 
(DD). 
 
10.3 Investigational Device(s) and Comparator(s) 
10.3.1 Investigational device - SyMRI 15 (3D) 
SyMRI 15 (3D) will be used to post-process data from the 3D-QALAS acquisition to generate synthetic 
contrast weighted images with virtual scanner settings corresponding to the conventional images and 
thus generate synthetic T1w and T2w images. The post-processing will be carried out by the Sponsor 
and thus, neither the subjects nor the readers will be exposed to or handle the investigational device.  
 
The comparator is conventional 3D MR images, which will be considered as ground truth in the 
investigation. 
10.3.2 Other medical device to be used during the clinical investigation  
All scanning will be done on 3.0T MRI machines from Philips. An investigational pulse sequence called 
3D-QALAS from Philips will be used to generate the data necessary for SyMRI. This sequence is not 
yet cleared by FDA and will be provided to each site prior to investigation start via a research agreement 
between site and Philips. 
10.4  Subjects 
10.4.1 Inclusion Criteria 
The subjects must meet all of the following criteria to be eligible to participate the investigation: 
 
 
INCLUSION CRITERIA 
1 Any gender, aged 0-99 years 
2 Subject scheduled for MRI of the brain 
OR 
Healthy control with passed screening form 
3 Subject suitable for MRI as judged by investigator 
4 Subject agrees to 5-20 min extra MRI scan time 
5 Subject able to understand written and verbal information in English or Spanish 
6 Provision of informed consent (and assent if applicable) 
 
10.4.2 Exclusion Criteria 
Subjects meeting any of the following criteria will not be permitted to participate in the investigation: 
 
 
EXCLUSION CRITERIA 
1 
Have contraindication(s) to MRI scanning per the routine MR Safety Screening policy of the 
investigational site 
2 
Have severe trauma, disability or pre-existing pathology that is expected to interfere with normal 
conduct of MRI scanning or complete scanning of the brain 
3 
Have medical condition(s) such as those requiring urgent medical care that, in the opinion of a 
physician investigator, would prevent safe participation in the study 
4 
Adult subjects (aged 18-99 years) in need of anesthesia during MRI scanning 

 
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5 
Pregnancy at time of enrollment determined according to the clinic’s MR Safety Screening policy 
6 
Previous enrollment in this investigation 
10.4.3 Relationship of Investigation Population to Target Population 
SyMRI 15 (3D) is indicated for head imaging. The investigation population has been selected to 
represent the most common pathologies and abnormalities in the brain examined by MRI in the target 
population (see Section 7). Since SyMRI 15 (3D) is intended to be used in patients of all ages, subjects 
ranging from 0 to 99 years of age will be included in the investigation (see Section 20). 
10.4.4  Number of Subjects 
In total 180 evaluable subjects will be recruited.  
 
Approximately 120 will be patients, whereof 65 adult subjects (age 18-99 years) and 55 pediatric 
subjects (age 0-17 years). The pediatric population will consist of two groups, one with subjects 
receiving anesthesia (Sub-group Anesthesia) and one with subjects not receiving anesthesia (Sub-group 
No-anesthesia). 
 
In addition, a group of approximately 60 evaluable, healthy adult controls will be included in the clinical 
investigation to be able to evaluate the specificity of the investigational device. 
 
The aim is to include 5-14 subjects in each pathology group as specified in Table 4. The number of 
subjects per pathology groups is based on the prevalence of these pathologies (see Section 7.1). For 
the adult population, the aim is to include ≥10 subjects in the most common groups, ≥5 subjects in 
the intermediate group and ≥3 subjects in the least common groups. Corresponding figures for the 
pediatric group are ≥7 subjects in the most common groups, ≥4 subjects in the intermediate group 
and ≥2 subjects in the least common groups. 
 
Prevalence was rated from 1 to 3 (1=most common, 2=common, 3=least common) as seen in Table 
1 and Table 2. 
 
Table 4: Target number of subjects per pathology group and sub-population 
 
 
Pediatric population 
Adult population 
 
Pathology group 
Prevalence 
Target number 
of subjects 
Prevalence 
Target number 
of subjects 
Total 
Infectious/Inflammatory/Demyelinating 
2 
≥ 4 
1 
≥ 10 
≥ 14 
Vascular Disorders of the Brain 
2 
≥ 4 
1 
≥ 10 
≥ 14 
Neuro Degenerative Disorders and Hydrocephalus 
2 
≥ 4 
1 
≥ 10 
≥ 14 
Intracranial Neoplasms 
1 
≥ 7 
2 
≥ 5 
≥ 12 
Traumatic Lesions 
1 
≥ 7 
2 
≥ 5 
≥ 12 
Congenital Malformations 
2 
≥ 4 
2 
≥ 5 
≥ 9 
Toxic and Metabolic conditions 
3 
≥ 2 
3 
≥ 3 
≥ 5 
Normal/no findings 
 
N/A 
 
N/A 
 
 
A Normal/no findings-category exists because some subjects are expected to present without any 
clinical findings.  
 
Recruitment to the different pathology groups will be monitored during recruitment period. When the 
number of subjects in a pathology group is deemed sufficient by the Sponsor, recruitment to this 
specific group will be stopped to avoid overrepresentation of that pathology in the investigation 
population compared to the target population.  
 
Each investigational site is estimated to recruit 20-30 patients. The healthy controls will be recruited 
by one of the investigational sites. 
 

 
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A subject is defined as evaluable in the study if they have completed the necessary scans as described 
in this protocol. If a sequence is missing, or if settings did not follow the acquisition parameters (e.g 
resolution), or if the subject did not complete all scans, the subject images will be excluded from the 
image review. 
10.4.5  Methods of Assigning Subjects to Different Treatment Arms 
Not applicable since all subjects will undergo the same investigational procedures and no treatment is 
given to the subjects.  
10.4.6 Subject Withdrawal, Discontinuation, or Lost to Follow-up 
Subjects are free to discontinue participation in the clinical investigation at any time and are not 
required to give a reason for their decision. However, subjects who discontinue the investigation should 
always be asked about the reason(s) for their discontinuation and about the presence of any adverse 
event (AE) /adverse device effect (ADE) and, if possible, be assessed by an investigator. 
Discontinuation from the clinical investigation will not affect the future treatment/care of the subject. 
 
If the subject will withdraw his/her consent no further data will thereafter be recorded. Data collected 
up to the date of withdraw of informed consent will be used in the data analysis and for the Clinical 
Investigation Report (CIR). In case of withdrawal, all AEs/ADEs should be followed up.  
 
Subjects may be withdrawn from the clinical investigation and assessments at any time, if deemed 
necessary by the Principal Investigator. 
 
Specific reasons for withdrawal of subjects from this clinical investigation are:  
a) The decision of a subject to withdraw from the investigation (including if the subject 
withdraws informed consent); 
b) The Principal Investigator deems the subject unfit for the investigation or suspects poor CIP 
compliance; 
c) The subject is not able to lay still in the MRI, causing poor quality of the MRI scans; 
d) The Principal Investigator deems it is in the subject’s best interest to be taken out of this 
investigation, e.g. due to claustrophobia. 
 
Incorrectly enrolled subjects will be withdrawn from further assessments.  
10.4.7 Subject Follow-up and Care 
After completed MRI scan, there is no follow-up of the subjects within the investigation. Instead, 
subjects will be treated according to site’s clinical routine. 
 
10.5  Readers 
All readers participating in the image review part of the study will have more than 10 years of post-
graduate experience within neuroradiology. All readers will be US ABR and CAQ certified neuro-
radiologists. 
 
The readers will be blinded to site-determined diagnosis to reduce information bias. 
 
The following information will be collected from all readers: Name, Country, Job Title, Fellowship 
status, Practice focus, Years of experience (post-graduate), CV and Certificates. 
 
10.6 Clinical Investigation Duration 
 
Recruitment of patients: 
Point of enrolment: 
June 2022 
Enrolment period: 
June 2022-December 2023 

 
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Expected duration of each 
subject’s participation: 
1 day 
Total expected duration of 
the clinical investigation: 
18 months 
 
Recruitment of healthy controls:  
Enrolment period: 
August 2023-December 2023 
Expected duration of each 
subject’s participation: 
1 day 
 
10.7  Clinical Investigation Procedures 
The assessments and procedures that will be performed during the clinical investigation are shown in 
the table below. 
 

 
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10.7.1  Schedule of Clinical Investigation Procedures /Assessments 
 
Table 5: Schedule of the Clinical Investigation procedures 
Assessment 
Image 
Acquisition 
Image Review 
Visit 1 
MR exam 
Generation of 
Synthetic Images 
Image Review 
Part I2 
Image Review 
Part II 
Transfer of Image 
Review data 
Responsible 
Site 
Sponsor 
Reader 
Reader 
Sponsor 
eCRF1 
Viedoc 
Viedoc 
CARPL 
CARPL 
Viedoc 
Subject visit 
X 
 
 
 
 
Informed consent 
X 
 
 
 
 
Subject Eligibility 
Verification 
X 
 
 
 
 
Demography 
X 
 
 
 
 
MR Scanning 
X 
 
 
 
 
Use of 3D-QALAS 
X 
 
 
 
 
Anonymization of MRI 
X 
 
 
 
 
Upload of MR images in 
eCRF 
X 
 
 
 
 
Adverse events 
X 
 
 
 
 
Device Deficiencies 
X 
X 
 
 
 
Site-determined diagnosis 
X 
 
 
 
 
Subject termination 
X 
 
 
 
 
Use of Investigational Device 
SyMRI 
 
X 
 
 
 
Image review by readers 
 
 
X 
X 
 
Transfer of image review 
data from CARPL eCRF to 
Viedoc eCRF 
 
 
 
 
X 
1 Two eCRFs will be used in this clinical investigation; Viedoc eCRF for subject-related data and CARPL eCRF for image review data. When image review is complete, 
image review data will be extracted from CARPL and uploaded in Viedoc for archiving purposes. 
2 The image review will be conducted over 2 sessions (Part I and Part II) with a 4-week memory washout period in-between to minimize recall bias. The blinded 
reader will evaluate the synthetic MR images of a case in one session and the conventional MR images of the same case in the other session. 
10.7.2 Image Acquisition 
10.7.2.1 Visit 1 – MR exam  
Before any investigation-related procedures are initiated, the informed consent (and if applicable 
assent) must be signed and dated by the subject (or their legally acceptable representative and/or 
witness, as applicable) and by the Investigator who gave the subject the verbal and written information. 
The original document will be retained in the Investigator Site File (ISF) and a copy provided to the 
subject. For further details on the informed consent process please see section 18. 
 
After written informed consent has been obtained and it has been confirmed that the subject fulfills 
all the inclusion criteria and none of the exclusion criteria, the subject will be considered enrolled in 
the clinical investigation. The subject will be allocated to a unique subject identification number and 
demographic data will be collected.  

 
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The subject will then undergo an MRI scan which will consist of: 
1. the MRI scan that the subject was originally scheduled for, and 
2. the additional investigational MRI scan (=1-4 additional pulse sequences depending on 
subject’s routine protocol, corresponding to an addition of 5-20 minutes to the length of the 
subject’s scheduled scan) 
 
For the healthy controls, a screening form will be used to identify eligible subjects. Subjects interested 
in participating in the study will be interviewed over phone according to the screening form by PI or 
delegate. The screening form is designed to rule out subjects with important medical history that could 
interfere with the study’s objective to include healthy controls.  
 
Healthy controls that pass the screening will be scheduled for an MRI. On the day of the MRI the 
informed consent form will be signed and dated by the subject and investigator or delegate. 
 
For the healthy controls, only the investigational scans specified in Table 6 below will be performed. 
 
NB: MRI scans for the investigation should be performed before any gadolinium-based contrast agent 
is given to the subject. 
 
For the pediatric population, anesthesia is allowed if needed for the scheduled MRI and should follow 
site’s clinical routines. These subjects will be included in the sub-group with pediatric subjects receiving 
anesthesia (Sub-group Anesthesia). Children having anesthesia will be carefully monitored by licensed 
anesthesiologists throughout the whole MR procedure. Sedation and general anesthesia are sometimes 
utilized, most frequently in children less than 6 years, in order to minimize the motion artifacts that 
can accompany children. 
Use of contrast agents and anesthesia will be collected in the Viedoc eCRF. 
10.7.2.1.1 MRI Protocol 
All MRI scans will be performed on a 3.0T MRI from Philips. For the investigation, images will be 
acquired using a fixed set of scanning parameters according to Table 6. The resolution will be similar 
for all sequences or as close as possible depending on MRI scanner.  
 
Table 6: Acquisition parameters for 3D-QALAS and conventional sequences 
Imaging Parameters 
3D T1w 
3D T2w 
3D T2w FLAIR 
3D-QALAS 
FOV (mm) 
220-250 
220-250 
220-250 
220-250 
Resolution 
0.9-1.2 mm iso 
0.9-1.2 mm iso 
0.9-1.2 mm iso 
1.2 mm iso 
TR 
Site dependent 
Site dependent 
Site dependent 
Shortest 
TE 
2.3 
TI 
- 
ETL 
150 
Bandwidth (Hz/px) 
393 
Acceleration technique  
SENSE or CS-SENSE 
SENSE or CS-SENSE 
SENSE or CS-SENSE 
CS-SENSE 
Scan time (estimate) 
2-4 min 
2-4 min 
3-6 min 
5-6 min 
 
Since this is a multi-site study with six sites, some difference in the image acquisition between the 
conventional images will need to be accepted. For example, resolution is allowed to range between 0.9-
1.2 mm isotropic for the conventional images. FOV can vary depending on patient head size. 
Acceleration technique and amount of acceleration may also be different for conventional images from 
the different sites. 
 
If any of these sequences are available in the standard protocol, with the requested resolution, this will 
be used as input for this clinical investigation. It is likely that some of these sequences with the specified 
resolution will need to be added after the routine clinical scan. This means that depending on the 
standard protocol used by the site for the specific clinical question, this may add an extra 1-4 sequences 

 
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for the subject. The conventional 3D images can be generated with either Turbo Spin Echo sequences 
or Gradient Echo sequences, therefore all imaging parameters are not specified beforehand. 
 
After completed MRI scan, subject ends his/her participation in the clinical investigation. 
10.7.2.1.2 Anonymization of MRI files 
Before DICOM images are uploaded to the Viedoc eCRF the images need to be anonymized. For the 
sites that have processes and tools in place for how to correctly anonymize DICOM images this process 
can be used.  
 
SyMRI requires certain DICOM tags to work properly. A DICOM Conformance Statement is available 
from SyntheticMR specifying the requirements. To make sure these are not removed during 
anonymization, a test scan matching the study protocol should be acquired, anonymized and evaluated. 
If required tags are removed the anonymization process will need to be adjusted. 
 
If necessary, the Sponsor can recommend site with tools and guide for how to safely and efficiently 
anonymize DICOM images. 
10.7.2.1.3 Labelling and uploading of MRI files 
After anonymization, a zip file should be created, containing all DICOM images from all four 
investigational sequences (3D-T1w, 3D-T2w, 3D-T2w FLAIR and 3D-QALAS). The zip file should 
be named with site number and subject ID as in the example below. The zip file can then be uploaded 
in the Viedoc eCRF. 
 
Example file name 
01-101 
 
 
02-003 
10.7.2.1.4 Site-determined diagnosis 
MR images acquired during the MRI scan will be sent to a radiologist for evaluation as per site’s clinical 
routines. The site will decide the site-determined diagnosis for each subject on the basis of the results 
from MR imaging studies and work-up performed according to the standard of care by clinical 
neuroradiologists. This means that the radiologist will have access to the subject’s medical records, and 
that the site-determined diagnosis will be based on more information than what is available for the 
readers in this clinical investigation, e.g. for the site determined diagnosis the neuroradiologist may also 
have access to DWI or SWI which will not be available in this clinical investigation. 
 
For the healthy control group, the site determined diagnosis will be considered normal/no finding if 
the PI determine that no pathology is identified in the brain on the conventional MRI. Minor non-
exclusionary incidental findings will be allowed for the healthy control group in order to take into 
consideration normal variance that is typically seen in MR imaging and normal ageing. The following 
list is used to categorize incidental findings: 
 
Non-exclusionary incidental findings 
1. Non-neoplastic cysts: small (<2cm) arachnoid cyst, pineal gland cyst, enlarged perivascular 
spaces 
2. Vascular encephalopathy, defined as Fazekas grade 0 or 1, in patients older than 18 years old 
Exclusionary incidental findings 
3. Cysts that are larger than 2cm 
4. Intracranial tumors: intra-axial (tumors in brain parenchyma); extra-axial (tumors in bone 
and meninges)  
5. Vascular malformations 
6. Major developmental disorders  
7. Chronic brain injury and acquired focal or diffuse loss of normal parenchyma regardless of 
the etiology with the exception of age-related cerebral volume loss (e.g., prior stroke, brain 

 
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surgery, trauma, atrophy due to neurodegenerative disease such as frontotemporal 
degeneration; or other causes) 
8. Vascular encephalopathy, defined as Fazekas grade 2 or 3, in patients older than 18 years old 
 
The site-determined diagnosis is considered the ground truth. 
 
The sites report the site-determined diagnosis by using the same scale as the study readers will, see 
Table 7. The site should also add a summary of the radiological findings in free text with more 
information about type of pathology or diagnosis seen in the subject. 
 
The site-determined diagnosis and radiological findings will be entered into the Viedoc eCRF by site 
personnel. 
 
Table 7: Site-determined diagnosis is reported on the following groups 
RADIOLOGICAL FINDING CLASSES 
Infectious/Inflammatory/Demyelinating  
Vascular Disorders of the Brain 
Neuro Degenerative Disorders and Hydrocephalus 
Intracranial Neoplasms 
Traumatic Lesions 
Congenital Malformations 
Toxic and Metabolic conditions 
Normal / No findings 
 
A subject can only belong to one pathology group. If there are more than one pathology (or pathology 
options) in one case, the site-determined diagnosis will be based on the most appropriate or significant 
pathology group. 
10.7.3 Image Review 
When all subjects have been included and the image acquisition part of the investigation has been 
completed the image review can begin.  
10.7.3.1 Generation and upload of synthetic images 
Sponsor will download the MRI files from the Viedoc eCRF. By using SyMRI 15 (3D), Sponsor will 
post-process data from the 3D-QALAS acquisition to generate synthetic contrast weighted images 
with virtual scanner settings corresponding to the conventional images and thus generate synthetic 3D 
T1w and T2w images. 
 
Table 8: Settings for Repetition time, Echo time and Inversion time used in SyMRI to generate synthetic images. 
 
T1w 
T2w 
TR 
650 
6000 
TE 
10 
100 
TI1 
- 
150 
 
Sponsor will then upload the conventional and the synthetic MR images into the online imaging 
platform CARPL (Mahajan Imaging, India) on which the images will be evaluated by the readers. 
CARPL contains full DICOM viewing functionalities including windowing/level, pan, zoom, ability to 
show multiple series and synchronized scroll. In this investigation the readers will also use the MPR 
functionality (Multi Plane Reformat) to view the images in three planes. The platform also contains 
ability to create survey questions. A survey with questions for the investigation endpoints will be 
prepared by Sponsor and answered by the readers during the image review.  
 
 

 
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10.7.3.2 Image Review part 1 + memory washout-period + Image Review part 2. 
During the image review the readers will either read the synthetic T1w and T2w images plus a 
conventional FLAIR, or only read the three conventional images. 
 
Synthetic 
Conventional 
Synthetic T1w  
Conventional T1w  
Synthetic T2w  
Conventional T2w 
Conventional T2w FLAIR  
Conventional T2w FLAIR  
 
The image quality will be evaluated by 5 blinded neuroradiologist by using the online imaging platform 
CARPL. The image review will be conducted over 2 sessions with a 4-week memory washout period 
in-between to minimize recall bias. Images from the same subject will be separated and read across the 
2 sessions, meaning that the reader will evaluate the synthetic MR images of a case in one session and 
the conventional MR images of the same case in another session. To minimize bias, the reader will be 
blinded to the type of image being reviewed (i.e., conventional vs synthetic), and the conventional and 
synthetic images will be mixed in a randomized order within a reading session. All readers will evaluate 
all images in the investigation. 
10.7.4 Data collected during Visit 1 – MR exam 
• 
Eligibility 
• 
Signed Informed Consent / Assent 
• 
Demographics 
o Age 
o Sex 
• 
MRI Examination 
o Use of anesthesia 
o Use of contrast agents during  investigational sequences 
o MRI performed according to CIP 
o Upload of MRI files  
• 
Site-determined diagnosis 
o Primary Pathology Group 
o Summary of radiological findings 
• 
Adverse Events 
• 
Device Deficiencies 
 
10.7.5 Performance Variables and Measurements 
10.7.5.1 Radiological findings 
The radiologist will be asked to interpret the case based on T1w, T2w, and T2w FLAIR images and 
choose the primary radiological finding class that they think is the reason behind the radiological 
findings in the images. There may be more than one pathology (or pathology options) in each case so 
the reader is asked to choose the most appropriate or significant pathology group. Not all patients are 
expected to have clinical findings, so a normal/no finding category is also included. 
 
RADIOLOGICAL FINDING CLASSES 
Infectious/Inflammatory/Demyelinating  
Vascular Disorders of the Brain 
Neuro Degenerative Disorders and Hydrocephalus 
Intracranial Neoplasms 
Traumatic Lesions 
Congenital Malformations 

 
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Toxic and Metabolic conditions 
Normal / No findings 
 
The ground truth will be the site-determined diagnosis on the basis of the results of conventional MR 
images and standard of care by neuroradiologist. This means that the ground truth may be based on 
more information than what will be available for the readers in this clinical investigation, e.g. for the 
site determined diagnosis the neuroradiologist may also have access to DWI or SWI which will not be 
available in this clinical investigation.  
 
10.7.5.2 Image Quality 
The radiologist will be asked to rate the image quality for the T1w and T2w images. A 5-point Likert 
scale will be used. Ratings of ≥3 will be considered clinically useable.  
 
RATE IMAGE QUALITY 
5 - Excellent 
4 - Good 
3 - Acceptable 
2 - Poor 
1 - Unacceptable 
 
10.7.5.3 Legibility of anatomical structures 
The radiologist will be asked to evaluate the legibility of anatomical structures in the T1w and T2w 
images. The anatomical structures are defined in the list below. Each anatomical structure will be rated 
on a binary scale (legible/illegible). Legibility is defined as the ability to see structures and margins 
associated with the key anatomic/morphologic feature to the extent necessary to be clinically usable. 
 
ANATOMICAL STRUCTURES 
Central sulcus 
Cerebral peduncle 
Corticomedullary junction 
Head of caudate nucleus 
Middle cerebellar peduncle 
Posterior limb of internal capsule 
10.7.5.4 Artifacts 
The radiologist will be asked to record presence and type of artifacts per contrast weighting. Type of 
artifact can be chosen from the pre-defined list below. If the artifact is not defined in the list the reader 
is asked to describe the artifact. 
 
ARTIFACTS 
Motion 
In-folding and wrap-around 
Flow or phase-encoding 
Magic angle effect 
Water-fat shift / chemical shift 
Magnetic susceptibility artifact 
Low resolution 
Low Signal to Noise 

 
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Low tissue contrast 
Other, please specify 
 
10.7.6  Safety Variables and Measurements 
The safety measurement will be the onset, severity, duration and frequency of AEs (anticipated and 
unanticipated), including determination of causality. Only events, which are new after the consent has 
been signed or have increased in severity after the consent has been signed, will be recorded. All AEs 
will be recorded and reported, and all data required both to assess the safety and to comply with the 
IRB and FDA requirements will be collected. All events will be followed up until resolved or judged 
as clinically stable according to the investigator or designee, if possible. 
10.7.7  Activities Performed by Sponsor 
The Sponsor will provide instructions to site personnel on how to perform the investigational pulse 
sequences. This will take place during site initiation and thereafter as required, e.g. if new site personnel 
or any re-training is required. 
10.7.8 Potential Confounding Factors 
No potential confounding factors have been identified. 
10.7.9 Future use of data obtained from subject 
The anonymized MR images collected from the subjects may be used for future research, product 
development, and inventions by the Sponsor, hospitals, universities and other businesses. 
 
 
 

 
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11 MONITORING PLAN 
A detailed description of monitoring activities will be provided in a separate, investigation-specific risk-
based monitoring plan. 
11.1 Subject Records and Source Data 
Subject data recorded directly in electronic case report form (eCRF) (and not into the medical record) 
will be considered source data. It is the responsibility of the PI to record essential information in the 
medical records, in accordance with regional and national regulations and requirements. The origin of 
source data in this clinical investigation will be further specified in a separate document (“Source Data 
Location Agreement”). 
 
In general the following information should be recorded in the medical records: 
• 
Investigation code, and or investigational title 
• 
Subject ID 
• 
That informed consent for participating in the clinical investigation was obtained, and the date 
of collection 
• 
Diagnosis 
• 
Visit number and visit date 
• 
All AEs 
• 
Treatments and medications 
• 
Subject health service identification number, if applicable  
 
The PI is responsible for ensuring the accuracy, completeness, legibility and timeliness of the data 
recorded in the eCRFs. Signed sections of eCRFs will be monitored on a regular basis. 
 
11.2 Access to Source Data and Documentation 
The PI should guarantee access to source documents for the monitor and auditors as well as for 
inspection by appropriate Regulatory Agencies, and Institutional Review Boards (IRBs), if required. 
 
 

 
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12 STATISTICAL CONSIDERATIONS 
12.1  Statistical Design, Method and Analytical Procedures 
12.1.1 Analysis populations 
• 
The full analysis set consists of all subjects with at least one pair of synthetic-conventional MR 
image readings from at least one reader. 
• 
The pathological subgroup consists of all subjects with a pathological finding according to 
site-determined diagnosis.  
• 
The control group consists of all non-pathological subjects, including both healthy volunteers 
and subjects classified as normal/no-finding according to site-determined diagnosis.   
• 
The adult sub-population consists of all subjects aged 18–99 years. 
• 
The pediatric sub-population consists of all subjects aged 0–17 years.  
12.1.2 General Statistical Methodology 
Descriptive statistics of subject demographics, characteristics of readers, and performance endpoints 
will be summarized descriptively at the patient, reader and image level. Continuous variables will be 
described with mean, standard deviation, median, minimum, and maximum value, and categorical 
variables with numbers and percentages.  
 
Statistical analyses will be performed on the patient level. Comparisons between conventional and 
synthetic MR images will be conducted using non-inferiority testing procedures.  
 
 
 
 
 
 
 
 
 
The mean difference will be presented with corresponding two-sided 95% confidence interval. Non-
inferiority will be established if the lower limit of the two-sided 95% confidence interval for the mean 
difference (i.e., intercept) is strictly greater than a pre-specified non-inferiority margin. The primary 
analyses will be performed on the full analysis set. Separate analyses on adult and pediatric sub-
populations, and separate analyses by reader, will also be performed. 
 
For the primary and secondary endpoints, a non-inferiority margin of -0.05 will be used. All tests will 
be one-sided and conducted at significance level α=0.025. In case of a successful non-inferiority test 
for the two primary performance endpoints, the entire probability mass α=0.025 will be transferred to 
the secondary performance endpoints in the order specified in Section 10.2.2 Secondary performance 
endpoints. Non-inferiority will then be declared for all secondary performance endpoints with a 
successful non-inferiority test until the first encounter of a non-successful non-inferiority test. 
Estimates and confidence intervals of remaining performance endpoints will be presented descriptively 
but not considered as confirmatory findings.  
12.1.3 Primary Performance Analysis 
 
Sensitivity of pathological findings 
The sensitivity of pathological findings will be calculated as the sample proportion of true positive 
(pathological) findings across all patients and readers. The difference in sensitivity between synthetic 

 
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and conventional MR will be evaluated using non-inferiority testing procedures with GEE for binary 
variables as described in Section 12.1.1 General Statistical Methodology. A non-inferiority margin of -0.05 
will be used. 
  
Specificity of pathological findings 
The specificity will be calculated as the sample proportion of true negative (non-pathological) findings 
across all patients and readers. The difference in specificity between synthetic and conventional MR 
will be evaluated using non-inferiority testing procedures with GEE for binary variables as described 
in Section 12.1.1 General Statistical Methodology. A non-inferiority margin of -0.05 will be used. 
 
Both primary endpoints will be tested at significance level α=0.025, one-sided test. Non-inferiority of 
diagnostic accuracy with synthetic MR images compared to conventional MR images will be declared 
if non-inferiority is demonstrated in both primary endpoints.  
12.1.4 Secondary Performance Analyses 
 
Diagnostic accuracy of radiological findings  
The accuracy of radiological findings will be calculated as the sample proportion of correctly identified 
radiological findings (radiological finding class) across all patients and readers. The difference in 
accuracy between synthetic and conventional MR will be evaluated using non-inferiority testing 
procedures  
A non-inferiority margin of -0.05 will be used, significance level α=0.025, one-sided test. The 
radiological finding classes will be cross-tabulated for synthetic and conventional images vs site-
determined diagnosis (ground truth). 
 
Other secondary endpoints 
The remaining secondary performance endpoints will be evaluated according to the methodology 
above in the following order: 
• 
Sensitivity of pathological findings in adult sub-population 
• 
Specificity of pathological findings in adult sub-population 
• 
Diagnostic accuracy of radiological findings in adult sub-population 
• 
Sensitivity of pathological findings in pediatric sub-population 
• 
Specificity of pathological findings in pediatric sub-population  
• 
Diagnostic accuracy of radiological findings in pediatric sub-population 
 
In case of a successful non-inferiority test for the two primary performance endpoints, the entire 
probability mass α=0.025 will be transferred to the secondary performance endpoints in the order 
listed above. Non-inferiority will be declared for all primary and secondary performance endpoints 
with a successful non-inferiority test until the first encounter of a non-successful non-inferiority test. 
Estimates and confidence intervals of remaining performance endpoints will be presented descriptively 
but not considered as confirmatory findings.  
12.1.5 Exploratory Analyses 
 
Legibility 
The percentage of legibility for each of the anatomic structures will be cross-tabulated for synthetic vs 
conventional for the contrast weighted images (T1w, T2w).  
 
Artifacts 
Each of the artifacts will be cross-tabulated synthetic vs conventional per contrast weighting (T1w, 
T2w). Any novel or previously unforeseen artifacts will be listed and described.  
 

 
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Inter-rater and inter-method agreement of radiological findings 
Each of the radiological finding classes will be cross-tabulated for synthetic vs conventional images, 
followed by calculation of percent agreement, Cohen’s kappa coefficient, and Gwet’s AC1 coefficient 
between methods and readers. Inter-method agreement will be analyzed to evaluate agreement between 
synthetic and conventional images, i.e., if the readers draw the same general conclusions regardless of 
image type. Inter-rater agreement will be calculated to evaluate how well the different readers agree 
with each other on the radiological findings when either synthetic or conventional images are used.  
 
Image quality of T1w and T2w images 
The difference in image quality score will be analyzed using linear mixed effects models as described 
in Section 12.1.1 General Statistical Methodology.  
12.1.6 Safety Analysis 
Safety variables will be summarized descriptively. 
 
12.1.7 Justification of choice of non-inferiority margin 
A non-inferiority margin of -0.05 for the mean difference in sensitivity, specificity and diagnostic 
accuracy will be used. 
 
12.2 Sample size 
A total of 180 evaluable subjects (90 pathological, 90 controls) and 5 readers will be included in the 
study to obtain 80% simultaneous power in both primary endpoints using one-sided test, significance 
level α=0.025, non-inferiority margin -0.05. The calculations are based on the following assumptions: 
 
 
 
 
 
 
 
 
12.3 Drop-out Rates 
No drop-out is expected from the evaluable subjects. 
 
For the healthy controls, a 10% drop-out is estimated considering incidental findings which will exclude 
subjects after scan, and some subjects not showing up the scheduled appointment. 
 
12.4 Level of Significance and Power 
All tests will be one-sided and conducted at significance level α=0.025. The power for each of the 
primary endpoints is 90% and power for both primary endpoints simultaneously is 80%. No 
multiplicity adjustment is needed for the primary endpoints since non-inferiority in both primary 
endpoints is required to declare non-inferior diagnostic accuracy (sensitivity/specificity) with synthetic 
MR images compared to conventional MR images. Secondary performance endpoints will be evaluated 
using a hierarchical testing procedure only if the pass criteria for the primary endpoints is fulfilled.  
 

 
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12.5  Pass / Fail Criteria 
The study will be passed if non-inferiority of synthetic compared to conventional MR images can be 
established with respect to both primary performance endpoints Sensitivity of pathological findings and 
Specificity of pathological findings on the full analysis set using one-sided test, non-inferiority margin –0.05 
and significance level α=0.025. 
  
12.6  Interim Analysis 
No interim analysis will be performed. 
 
12.7  Reporting of Deviations from the Original Statistical Analysis Plan (SAP) 
Any deviations discovered throughout the study from the original Statistical Analysis Plan (SAP) 
described in this CIP, will be described with justification in a CIP amendment to the final report, as 
deemed appropriate. 
 
12.8  Subgroups for Analysis 
Separate analyses for adult and pediatric sup-populations will be performed. Separate analyses across 
readers will also be performed.  
 
12.9  Procedures that Take into Account all the Data 
Outliers will be included in summary tables and listings, and will not be handled separately. 
 
12.10  Missing, Unused or Spurious Data 
Available data from prematurely withdrawn subjects will be included in the analysis as far as possible. 
Only pairs of synthetic and conventional images evaluated by the same reader will be included in the 
analysis. 
 
12.11  Exclusion of Particular Information from the Testing of the Hypothesis 
If only one type of image (either synthetic or conventional) of an image pair is evaluated by a reader, 
this image read will be excluded from the analysis. 
 

 
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13 DATA MANAGEMENT 
Two eCRFs will be used in this clinical investigation; Viedoc eCRF for image acquisition data and 
CARPL eCRF for image review data. When image review is complete, image review data will be 
extracted from CARPL and uploaded in Viedoc for longtime storage. 
13.1 Data Management – Image acquisition part 
Data management and handling will be conducted according to the investigation specific Data 
Management Plan (DMP) in accordance with applicable guidelines and CRO’s Standard Operating 
Procedures (SOPs). Any deviations, i.e. discrepancies and additions from the process defined in the 
DMP will be described in an investigation specific Data Management Report (DMR). 
 
Data will be collected in an eCRF specifically designed in Viedoc for this clinical investigation. The PI 
or an authorized person will record subject data in the Viedoc eCRF in a precise and accurate manner. 
Abbreviations should not be used. The PI is responsible for the data entered in the Viedoc eCRF and 
for signing-off at the end of the clinical investigation. The data should be recorded as soon as they are 
generated. 
 
The person entering data into the database is not allowed to attempt any personal interpretation or to 
make any decisions on the data other than self-evident corrections as listed in the investigation data 
entry instructions or data handling report. Data for screening failures (not included subjects) will not 
be collected in the eCRF. 
 
Data validation/data cleaning procedures are designed to assure validity and accuracy of clinical data. 
These procedures consist of manual review during data entry and computerized edit checks and queries 
for identifying data values that are outside the allowed range, incomplete or inconsistent, and CIP 
deviations. The Data Validation Plan (DVP) specifies the checks that are to be performed on subject 
data for the clinical investigation. All investigation-specific and standard data validation programming 
will be tested in a separate testing environment prior to use in the clinical investigation. 
 
When all data from all endpoints have been entered, discrepancies solved and all reconciliation with 
the safety database is complete, the Viedoc eCRF will be locked and the data will be analyzed. 
 
13.2 Data Management – Image review part 
The following work will be done by the sponsor during the image review part of the investigation: 
 
DICOM images and information about site-determined diagnosis will be downloaded from Viedoc 
eCRF and stored in a suitable structure. Sponsor will then generate synthetic contrast weighted images 
using investigational device SyMRI 15 (3D) with an automated script. Some DICOM tags (e.g. study 
and series description) need to be adjusted on both conventional and synthetic images in order to 
completely blind readers to the type of image they review. The images will be given a new identifier to 
be used for the Image Review part. 
 
The contrast weighted images will then be upload to CARPL. Sponsor will assign the cases to the 
readers for Image Review part 1. When all readers have completed the reading, the access to the images 
from part 1 will be removed. Sponsor will then assign the cases to the readers for Image Review part 
2. After the memory washout period the readers can start Image Review part 2. 
 
When part 2 of the Image Review is completed, the Sponsor will download the answers from image 
review part 1 and part 2 from CARPL and will incorporate the answers with the original Subject ID 
and site-determined diagnosis. This data will be transferred to Viedoc eCRF for long-term storage and 
will be analyzed according to the SAP. 
 
 

 
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13.3 Data Retention 
The medical records of clinical investigation subjects must be retained in accordance with local 
legislation and in accordance with the maximum period of time permitted by the hospital, institution 
or private practice. 
 
The PI shall retain all clinical investigation records during the investigation and for the period required 
by the applicable regulatory requirements or for at least 10 years after the premature termination or 
completion of the clinical investigation, whichever ever is the longest. The PI must take measures to 
prevent accidental or premature destruction of these documents. The PI should contact the Sponsor 
prior to destruction of any records or reports pertaining to the clinical investigation in order to ensure 
they no longer need to be retained. In addition, if the PI leaves the hospital, he/she should provide the 
Sponsor with the name and address of the person who will look after and be responsible for the clinical 
investigation-related records. If the records will be transferred to another person/party, the transfer 
will be documented at the investigation site or at the Sponsor.  
 
The Sponsor will retain the Study Master File (SMF) in line with applicable regulations or for at least 
10 years after the clinical investigation has ended, or, in the event that the device is subsequently placed 
on the market, at least 10 years after the last device has been placed on the market. 
 
13.4 Monitoring, Audits and Inspections 
During the clinical investigation, the monitor will have regular contacts with the investigation site. 
These contacts will include visits to confirm that the facilities remain adequate to specified standards 
and that the investigation team is carrying out the procedure stated in the CIP. All data must be 
accurately recorded in the eCRF. Source data verification (SDV), a comparison of data in the eCRF 
with the subject’s medical records and other records at the investigation site, will also be performed. 
The eCRF and source documents and records must be made accessible during the monitoring visit. 
 
The monitor or other Sponsor personnel will be available between visits if the PI or other investigation 
staff at the site needs information and/or advise. Authorized representatives of the Sponsor and/or 
international Regulatory Agencies may visit the site to perform audits/inspections, including SDV. 
 
 
 

 
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14 AMENDMENTS TO THE CIP 
Any change to the approved clinical investigation documents will be documented and include a written 
justification. Any effects of the implemented changes on other clinical investigation documents shall 
be evaluated and documented. If deemed necessary, affected documents shall be properly updated and 
relevant parties notified. The version number and date of amendments shall be documented. 
 
All amendments to the CIP will be documented in an amendment log and communicated to relevant 
parties. 
 
Proposed amendments to the CIP shall be agreed upon between the Sponsor and PI, or the 
Coordinating Investigator. The amendments to the CIP shall be notified to, or approved by, the IRB 
and Regulatory Agencies, if required. 
 
 

 
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15 DEVIATIONS FROM THE CIP 
A CIP deviation is a failure to follow, intentionally or unintentionally, the requirements of the CIP. 
Every effort should be made to comply with the requirements of the CIP and the investigator is not 
allowed to deviate from the CIP. Furthermore, waivers from the CIP is prohibited. 
 
As required by national regulations or guidelines, requests for deviations and reports of deviations will 
be provided to the IRB if the deviation affects subject’s rights, safety and well-being, or the scientific 
integrity of the clinical investigation. 
 
Under emergency circumstances deviations from the CIP may proceed without prior approval by the 
Sponsor and favorable opinion of the IRB if the rights, safety and well-being of human subjects need 
to be protected. Such deviations will be documented and reported to the Sponsor and IRB as soon as 
possible in accordance with national regulations. 
 
When the monitor or Sponsor identifies that the PI is out of compliance, this will be notified to the PI 
in writing, with a request to correct the source of the deviation immediately. Corrective action will be 
implemented to avoid repeated non-compliance, which will usually include re-training and may include 
terminating the clinical investigation at the site. 
 
The Sponsor is responsible for analyzing deviations and assessing their significance. Corrective 
action(s) will be implemented to avoid repeated deviations, which may include suspending the clinical 
investigation at the investigation site or disqualify the PI. 
 
 
 

 
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16 DEVICE ACCOUNTABILITY 
Device accountability at site is not applicable since the Investigational Device, the software SyMRI will 
not be distributed to site in the clinical investigation. Instead, the Sponsor will use SyMRI to generate 
the synthetic contrast weighted images which will be sent to the readers for evaluation during the image 
review part. The Sponsor will store relevant software version information in DICOM tag SyntheticMR 
private group (3005). 
 
Regarding the 3D-QALAS sequence, a research agreement between site and Philips will regulate site’s 
access to the sequence.  
 
 

 
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17 STATEMENTS OF COMPLIANCE 
This clinical investigation will be conducted in accordance with the ethical principles that have their 
origin in the Declaration of Helsinki (Appendix C). Furthermore, the clinical investigation will be 
conducted in compliance with ISO 14155:2020 and applicable regional or national regulations.  
 
17.1 Institutional Ethics Review 
The final CIP, including the final version of the ICF, must be approved or given a favorable opinion 
in writing by an IRB and Regulatory Agency before enrolment of any subject into the clinical 
investigation. The PI is responsible for informing the IRB of any amendment to the CIP as per local 
requirements. 
 
Any additional requirements imposed by the IRB or Regulatory Agency shall be followed. 
 
17.2 Insurance 
The Sponsor will purchase insurance to cover its liability under applicable tort law for bodily injury 
sustained by a clinical investigation participant. 
 
 

 
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18 INFORMED CONSENT PROCESS 
All subjects will receive written and verbal information regarding the clinical investigation prior to any 
investigation-related procedures take place. This information will emphasize that participation in the 
clinical investigation is voluntary and that the subject may withdraw from the investigation at any time 
and for any reason. All subjects will be given the opportunity to ask questions about the investigation 
and will be given sufficient time to decide whether to participate in the investigation or not. If any new 
important information arise during the clinical investigation the subject will be informed both orally 
and in writing.  
 
The written subject information explains that data will be collected and compiled maintaining 
confidentiality in accordance with national data legislation, and that authorized representatives of the 
Sponsor, international Regulatory Agencies or IRBs may require direct access to those parts of the 
medical records relevant to the investigation, including medical history, for verification of data. 
Additionally, the written subject information specifies that data will be recorded, collected, processed 
and may be transferred (within the US and to non-US countries). In accordance with the Health 
Insurance Portability and Accountability Act of 1996 (HIPAA) and the General Data Protection 
Regulation (GDPR) 2016/679, the data will not identify any subjects taking part in the investigation. 
 
Before any investigation-related procedures, the Informed Consent Form will be signed and dated by 
the subject (or their legally acceptable representative and/or witness, as applicable) and by the 
Investigator who gave the subject the verbal and written information.  
 
If a child is to be enrolled in the clinical investigation, the parent(s) or guardian must provide 
permission, with the assent of the child when appropriate, as described in 21 CFR part 50, subpart D.  
 
The child and the parent(s) or guardian(s) will be given adequate time and an adequate place to read 
and review the Informed Consent Form and Assent form. The Assent form is a shorter, more 
understandable consent form that is given to the child for them to agree to the study on. The study 
will be explained to the child in an age-appropriate language that the child can understand. The child 
will be given an opportunity to ask questions about the study (without the presence of the parent or 
guardian, if requested and appropriate) before signing.  
 
Age-appropriate Assent Forms for children will be used in this clinical investigation. The Assent forms 
should be signed by the child and the Informed Consent Form should be signed by the parent(s) or 
guardian(s). For children who are deemed too young to give assent (age defined by reviewing IRB), no 
signature is required by the child. The sub-group Anesthesia will have a higher risk determination than 
children not receiving anesthesia and consent will therefore be required from both parents/legal 
guardians. For children not receiving anesthesia (Sub-group No-anesthesia), consent will be required 
from one parent/legal guardian. 
 
If a child, who understands the procedures of the investigation, do not want to participate in the 
investigation, this decision must be respected. 
 
For vulnerable adult subjects, e.g. subjects with Alzheimer’s disease, an altered informed consent 
process will take place. The study will be explained using appropriate, simplified language, and the 
subject will be given ample time to ask question and to involve family member(s), significant other(s) 
and/or a Legally Authorized Representative (LAR). If needed, the LAR will sign the Informed Consent 
Form on behalf of the vulnerable subject. The LAR must provide consent prior to subject participation 
in the study. 
 
 
 

 
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19 ADVERSE EVENTS, ADVERSE DEVICE EFFECTS AND DEVICE 
DEFICIENCIES 
The definitions and procedures for reporting Adverse Events (AE), Adverse Device Effects (ADE), 
Serious Adverse Events (SAE), Serious Adverse Device Effects (SADE), Unanticipated Serious 
Adverse Device Effects (USADE) and Unanticipated Adverse Device Effects (UADE) are presented 
in the subsections below. It is of utmost importance that all staff involved in the investigation is familiar 
with the definitions and procedures and it is the responsibility of the Principal Investigator to ensure 
this. 
 
19.1 Definitions 
Adverse Device Effect (ADE) [ISO 14155:2020] 
Adverse event related to the use of an investigational medical device. 
 
Note 1: This definition includes adverse events resulting from insufficient or inadequate instructions 
for use, deployment, implantation, installation, or operation, or any malfunction of the investigational 
medical device. 
 
Note 2: This definition includes any event resulting from use error or from intentional misuse of the 
investigational medical device. 
 
Note 3: This includes ‘comparator’ if the comparator is a medical device. 
 
Adverse Event (AE) [ISO 14155:2020] 
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 and whether anticipated or unanticipated. 
 
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 the use of 
investigational medical devices or comparators. 
 
Device Deficiency [ISO 14155:2020] 
Inadequacy of an investigational medical device related to its identity, quality, durability, reliability, 
safety or performance. This may include malfunctions, use error, or inadequacy in the information 
supplied by the manufacturer. 
 
Note 1: Device deficiencies include malfunctions, use errors, and inadequacy in the information 
supplied by the manufacturer including labelling. 
 
Note 2: This definition includes device deficiencies related to the investigational medical device or the 
comparator. 
 
Serious Adverse Device Effect (SADE) [ISO 14155:2020] 
Adverse device effect that has resulted in any of the consequences characteristic of a serious adverse 
event.  
 
Serious Adverse Event (SAE) [ISO 14155:2020] 
Adverse event that led to any of the following: 
a) death,  

 
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b) serious deterioration in the health of the subject, users, or other persons as defined by one or 
more of the following: 
i. A life-threatening illness or injury, or 
ii. A permanent impairment of a body structure or a body function including chronic 
diseases, or 
iii. In-patient or prolonged hospitalization, or 
iv. medical or surgical intervention to prevent life-threatening illness or injury, or 
permanent impairment to a body structure or a body function, 
c) foetal distress, foetal death, a congenital abnormality, or birth defect including physical or 
mental impairment. 
 
Note: Planned hospitalization for pre-existing condition, or a procedure required by the CIP, without 
serious deterioration in health, is not considered a serious adverse event. 
 
Serious Health Threat [ISO 14155:2020] 
Signal from any adverse event or device deficiency that indicates an imminent risk of death or a serious 
deterioration in the health in subjects, users or other persons, and that requires prompt remedial action 
for other subjects, users or other persons. 
 
Note: This would include events that are of significant and unexpected nature such that they become 
alarming as a potential serious health hazard or possibility of multiple deaths occurring at short 
intervals. 
 
Unanticipated Serious Adverse Device Effect (USADE) [ISO 14155:2020] 
Serious adverse device effect which by its nature, incidence, severity or outcome has not been identified 
in the current risk assessment. 
 
Note: Anticipated Serious Adverse Device Effect (ASADE) is an effect which by its nature, incidence, 
severity or outcome has been identified in the risk assessment. 
 
Unanticipated Adverse Device Effect (UADE) [21 CFR 812.3(s)] 
Any serious adverse effect on health or safety or any life-threatening problem or death caused by, or 
associated with, a device, if that effect, problem, or death was not previously identified in nature, 
severity, or degree of incidence in the investigational plan or application (including a supplementary 
plan or application), or any other unanticipated serious problem associated with a device that relates 
to the rights, safety, or welfare of subjects. 
 
19.2 Non-reportable adverse events 
Not applicable 
19.3 Methods for discovering and documenting AE/ADE 
All subjects will be carefully monitored for the occurrence of AEs throughout the clinical investigation. 
Events prior to inclusion will be considered medical history. The Principal Investigator will collect 
safety information using non-leading questions such as “have you experienced any new health 
problems or worsening of existing conditions?”. Events directly observed or spontaneously 
volunteered by subjects will also be recorded throughout the clinical investigation. 
 
Clearly related signs, symptoms and abnormal diagnostic procedure results should be grouped together 
and reported as a single diagnosis or syndrome whenever possible. 
 
All AEs, including but not limited to events reported by the subject or reported in response to an open 
question by the Principal Investigator or member of the investigation team, which fall into any of the 

 
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previously defined definitions must be recorded as an AE in the Viedoc eCRF and should include the 
following information: 
• 
Brief description of the event (diagnosis) 
• 
Date of event onset  
• 
Date of event resolution 
• 
Severity 
• 
Seriousness 
• 
Causality assessment (i.e. relationship to medical device and/or procedure) 
• 
Unanticipated ADE (Yes, No) 
• 
Event treatment 
• 
Event outcome / resolution 
 
If the AE is classified as an Unanticipated ADE and meets the seriousness criteria, i.e. an 
USADE/UADE, it should be subject to expedited reporting as described in 19.5. 
 
A system generated e-mail notification to Sponsor and CRO will be triggered whenever an SAE or a 
USADE/UADE is entered or updated in the Viedoc eCRF, allowing immediate monitoring of the 
event. 
 
19.3.1  Severity 
Severity describes the intensity of an AE and will be assessed as: 
• 
Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention 
not indicated. 
• 
Moderate: minimal, local or non-invasive intervention indicated, limiting age-appropriate 
instrumental activities of daily living. 
• 
Severe or medically significant but not immediately life-threatening: hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. 
• 
Life-threatening consequences; urgent intervention indicated. 
• 
Death related to AE. 
 
If an AE changes in severity, it should be reported as an AE of new severity but with the same 
description and identifier. 
 
19.3.2  Causality 
Causality is the relationship between the use of the medical device (including the investigational device, 
the comparator and the medical – surgical procedure) and the occurrence of each AE.  
 
During the causality assessment, clinical judgment shall be used and the relevant documents, such as 
the CIP or the risk analysis report shall be consulted, as all the foreseeable AEs and the potential risks 
are listed and assessed there. The presence of confounding factors, such as concomitant 
medication/treatment, the natural history of the underlying disease, other concurrent illness or risk 
factors shall also be considered.  
 
For the purpose of harmonizing reports, each AE will be classified according to four different levels 
of causality. The Sponsor and the Principal Investigator will use the following definitions to assess the 
relationship of the AE to the investigational medical device, the comparator, or the medical – surgical 
procedures: 
• 
Not related: relationship to the device or procedures can be excluded when: 
o The event has no temporal relationship with the use of the investigational device or 
the procedures related to the investigational device; 

 
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o The serious event does not follow a known response pattern to the medical device (if 
the response pattern is previously known) and is biologically implausible; 
o The discontinuation of medical device application or the reduction of the levels of 
activation/exposure – when clinically feasible – and reintroduction of its use (or 
increase of the level of activation/exposure), do not impact on the serious event; 
o The event involves a body-site or an organ than cannot be affected by the device or 
procedure; 
o The serious event can be attributed to another cause (e.g. an underlying or concurrent 
illness/clinical condition, an effect of another device, drug, treatment or other risk 
factors); 
o The event does not depend on a false result given by the investigational device used 
for diagnosis, when applicable; 
In order to establish the non-relatedness, not all the criteria listed above might be met at the 
same time, depending on the type of device/procedures and the serious event. 
• 
Possible: the relationship with the use of the investigational device or comparator, or the 
relationship with procedures, is weak but cannot be ruled out completely. Alternative causes 
are also possible (e.g. an underlying or concurrent illness/clinical condition or/and an effect 
of another device, drug or treatment). Cases were relatedness cannot be assessed or no 
information has been obtained should also be classified as possible. 
• 
Probable: the relationship with the use of the investigational device or comparator, or the 
relationship with procedures, seems relevant and/or the event cannot bereasonably be 
explained by another cause. 
• 
Causal relationship: the serious event is associated with the investigational device, 
comparator or with procedures beyond reasonable doubt when: 
o The event is known side effect of the product category the device belongs to or of 
similar devices and procedures; 
o The event has a temporal relationship with investigational device use/application or 
procedures; 
o The event involved a body-site or organ that: 
▪ 
The investigational device or procedures are applied to; 
▪ 
The investigational device or procedures have an effect on; 
o The serious event follows a known response pattern to the medical device (if the 
response pattern is previously known); 
o The discontinuation of medical device application (or reduction of the level of 
activation/exposure) 
and 
reintroduction 
of 
its 
use 
(or 
increase 
of 
activation/exposure), impact on the serious event (when clinically feasible); 
o Other possible causes (e.g. an underlying or concurrent illness/clinical condition 
or/and an effect of another device, drug or treatment) have been adequately ruled 
out; 
o Harm to the subject is due to error in use; 
o The event depends on a false result given by the investigational device used for 
diagnosis, when applicable; 
In order to establish the relatedness, not all the criteria listed above might be met at the same 
time, depending on the type of device/procedures and the serious event. 
The Sponsor and the PI will distinguish between AEs related to the investigational device and those 
related to the procedures (any procedure specific to the clinical investigation). An AE can be related to 
both the procedures and the device. Complications of procedures are considered not related if the said 
procedures would have been applied to the subjects also in the absence of device use/application. 
 
Particular attention shall be given to the causality evaluation of USADE/UADE, since the occurrence 
of USADE/UADE could suggest that the clinical investigation places subjects at increased risk of 
harm than was expected beforehand. 
 

 
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In case of disagreement between the Sponsor and the PI assessments of the AE, both opinions shall 
be communicated to concerned parties. 
 
19.4 Methods for Discovering and Documenting Device Deficiencies 
Inadequacy of a medical device with respect to its identity, quality, durability, reliability, safety or 
performance shall be reported as a device deficiency without unnecessary delay to the Sponsor by using 
the device deficiency form. It is the PI’s responsibility to record every observed device deficiency 
together with an assessment. The Sponsor shall review all device deficiencies and determine and 
document in writing whether they could have led to an SADE. Device deficiencies that are assessed to 
or have SADE potential should be subjected to expedited reporting as described in Section 19.5. 
 
A system generated e-mail notification to Sponsor and CRO will be triggered whenever a DD is entered 
or updated in the Viedoc eCRF, allowing immediate monitoring of DDs. 
 
19.5 Reporting of USADE/UADE 
Since the US IDE definition of a UADE is very similar to the ISO 14155 definition of a USADE, any 
serious adverse device effect which by its nature, incidence, severity or outcome has not been identified 
in the current risk assessment will be classified as a USADE in this clinical investigation. 
 
USADEs must be reported by the PI to the Sponsor and the reviewing IRB, as described below: 
• 
PI is required to submit a report of a USADE to the Sponsor and the reviewing IRB as soon 
as possible, but in no event later than 10 working days after the investigator first learns of 
the event (21 CFR 812.150(a)(1)). 
• 
Sponsor must immediately conduct an evaluation of a USADE and must report the results of 
the evaluation to FDA, all reviewing IRBs, and all participating PIs within 10 working days 
after the Sponsor first receives notice of the effect (21 CFR 812.46(b), 812.150(b)(1)). 
 
The initial report should contain as much information as possible, but as a minimum the following 
information: 
• 
Subject ID 
• 
Adverse Event ID 
• 
Date of procedure/first use 
• 
Date of event onset 
• 
Age (years) 
• 
Patient gender (female, male, other, unknown) 
• 
Classification of event: 
o death, 
o life-threatening illness or injury, 
o permanent impairment/chronic disease, 
o hospitalization, 
o medical or surgical intervention, 
o fetal distress, fetal death or congenital physical or mental or birth defect, 
o not applicable1 
• 
Description of event: 
 
 
 
 
 
 
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o Nature of the observed symptoms 
o Duration and severity of the symptoms 
o Date of onset of first signs of the event (before it became a SAE) 
o Medical background of the patient 
o Medical care of the patient 
o Comments on the event in relation to already known safety data 
• 
Action/treatment/outcome 
• 
Relationship to procedure (not related, possible, probable, causal) 
• 
Relationship to the device (not related, possible, probable, causal) 
• 
Unanticipated SADE (Yes, No) 
• 
Investigation arm (test group, comparison group, blinded, not applicable) 
• 
Event status (resolved, resolved with sequelae, ongoing, death) 
• 
Date of event resolution (if ongoing enter not applicable) 
 
SAE/SADE EMERGENCY CONTACT DETAILS 
Name: Madeleine Enström, QA/RA Manager, SyntheticMR 
Phone: +4673-0690490 
Email: madeleine.enstrom@syntheticmr.com 
 
19.6 Foreseeable adverse events and anticipated adverse device effects 
Foreseeable adverse events associated with MRI: 
• 
the MRI scanner uses radio frequency waves that can, on rare occasions, cause a mild warming 
sensation similar to what you feel on a warm day  
• 
the MRI scanner makes loud banging noises during the scanning session  
• 
the magnetic fields in the scanner can cause mild twitching in the arms and legs  
• 
some people feel uncomfortable and/or claustrophobic when lying inside the MRI scanner  
 
There are no anticipated adverse device effects in the clinical investigation. 
19.7 Data Monitoring Committee 
Establishment of a Data Monitoring Committee (DMC) is not considered necessary for this pre-market 
clinical investigation since 1) the Magnetic Resonance Imaging (MRI) devices used in the investigation, 
including the 3D-QALAS sequence, will be within FDA specified parameters and 2) the MR images 
acquired for the investigation will not be used for diagnostic reasons or treatment decisions which 
means that the subjects will not be affected by the use of the Investigational Device SyMRI 15 (3D). 
In case data retrieved during the clinical investigation contradicts this decision, it will be reconsidered. 
 
 

 
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20 Vulnerable Population 
The investigation population has been selected to represent the most common pathologies and 
abnormalities seen in brain MRI of the target population. 
 
For the adult population, this means that vulnerable subjects with e.g. Alzheimer’s disease and other 
disorders which could involve cognitive impairment, may be included in the investigation. For this 
group of patients, a modified informed consent process will be used including the possible use of a 
Legally Authorized Representative (LAR), see Section 18. 
 
For the pediatric population, subjects aged 0-17 years will be included. Pediatric subjects are per se 
described as a vulnerable population according to ISO 14155:2020 and FDA regulations provide 
additional safeguards for children enrolled in clinical investigations (21 CFR part 50, subpart D). 
Therefore, also the potential subjects’ legal representative(s) will receive information both verbally and 
written about the study prior any decision about the subjects’ participation. The subject will be 
informed about the clinical investigation within his/her ability to understand, i.e. additional versions 
of the subject information have been developed to target different ages. If the subject will have 
difficulties to understand the contents of participating in the clinical investigation, i.e. as a child may 
have, additional time will be given for questions regarding the investigation as well as consent 
procedure. For more information on the consent process for pediatric subjects, see Section 18. 
 
 
 
 

 
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21 SUSPENSION OR EARLY TERMINATION OF THE CLINICAL 
INVESTIGATION 
If the clinical investigation is terminated early or suspended due to reasons of safety, the Sponsor will 
promptly inform the PI(s) and the investigation site(s) of the termination or suspension and the 
reason(s) thereof. The IRB will also be informed promptly and provided with the reason(s) for the 
termination or suspension by the Sponsor or by the PI(s) / investigation site(s). 
 
In addition, CIP violations may result in termination of the Clinical Investigation at a site. 
CIP violations are deviations made without permission as a result of error or fraud/misconduct. Where 
the monitor or Sponsor identifies that the Principal Investigator is out of compliance, this will be noted 
to the PI in writing, with a request to correct the source of the deviation immediately. Corrective 
actions will be implemented to avoid repeated non-compliance, including re-training. However, in case 
of repeated non-compliance despite implemented corrective actions, the clinical investigation will be 
terminated at the site. 
 
21.1 Subject Follow-up 
If the clinical investigation is prematurely terminated, the Sponsor and the PI(s) will assure that 
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22 PUBLICATION POLICY 
The clinical investigation will be registered in a publicly accessible database before recruitment of the 
first subject. 
 
A final report of the clinical investigation (CIR) will be completed, even if the investigation is 
prematurely terminated. The report will be prepared by the Sponsor according to the guideline 
presented in Annex D of ISO 14155:2020. 
 
All information supplied by the Sponsor in connection with this investigation will remain the sole 
property of the Sponsor and is to be considered confidential information. No confidential information 
will be disclosed to others without obtaining prior written consent from the Sponsor and will not be 
used except in the conduct of this investigation. 
 
The Sponsor may choose to publish or present data from this clinical investigation. If a Principal 
Investigator is offered first authorship, he/she will be asked to comment and approve the publication. 
The Sponsor has the right to use the results for registration and internal presentation and for 
promotion. 
 
Following completion of the entire investigation at all sites, Sponsor shall use reasonable endeavors to 
encourage appropriate publication or other dissemination based on the data collected in the 
investigation. The aim is to create two multi-center publications, one for the pediatric sub-population 
and one for the adult population. Co-authorship will be given to one person per site that contributed 
with data for the specific population. 
 
Institution shall not publish data/results derived from the individual institution site until such 
appropriate publication or other dissemination has been published in a multi-center publication. 
 
Sponsor will make the entire (anonymized) data collected in the Study available to all participating 
Principal Investigators and their Institutions for further research purposes after the investigation is 
concluded. In case publications are created based on the investigation data the Principal Investigator 
agrees to give credit to the original Institution and Investigator that participated in the Image 
Acquisition in accordance with good academic practice. 
 

 
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23 REFERENCES 
 
1. Warntjes JB, Leinhard OD, West J, Lundberg P. Rapid magnetic resonance quantification on the 
brain: Optimization for clinical usage. Magn Reson Med. 2008;60(2):320-9. 
 
2. Radue EW, Weigel M, Wiest R, Urbach H. Introduction to Magnetic Resonance Imaging for 
Neurologists. Continuum (Minneap Minn). 2016;22(5, Neuroimaging):1379-98. 
 
3. Skinner S. MRI brain imaging. Aust Fam Physician. 2013;42(11):794-7. 
 
4. de Mello R, Ma Y, Ji Y, Du J, Chang EY. Quantitative MRI Musculoskeletal Techniques: An Update. 
AJR Am J Roentgenol. 2019;213(3):524-33. 
 
5. Vargas MI, Drake-Pérez M, Delattre BMA, Boto J, Lovblad KO, Boudabous S. Feasibility of a 
Synthetic MR Imaging Sequence for Spine Imaging. AJNR Am J Neuroradiol. 2018;39(9):1756-63. 
 
6. Hagiwara A, Warntjes M, Hori M, Andica C, Nakazawa M, Kumamaru KK, et al. SyMRI of the 
Brain: Rapid Quantification of Relaxation Rates and Proton Density, With Synthetic MRI, Automatic 
Brain Segmentation, and Myelin Measurement. Invest Radiol. 2017;52(10):647-57. 
 
7. Fujita S, Hagiwara A, Hori M, Warntjes M, Kamagata K, Fukunaga I, et al. Three-dimensional high-
resolution simultaneous quantitative mapping of the whole brain with 3D-QALAS: An accuracy and 
repeatability study. Magn Reson Imaging. 2019;63:235-43. 
 
8. Tanenbaum LN, Tsiouris AJ, Johnson AN, Naidich TP, DeLano MC, Melhem ER, et al. Synthetic 
MRI for Clinical Neuroimaging: Results of the Magnetic Resonance Image Compilation (MAGiC) 
Prospective, Multicenter, Multireader Trial. AJNR Am J Neuroradiol. 2017;38(6):1103-10. 
 
9. Yi J, Lee YH, Song HT, Suh JS. Clinical Feasibility of Synthetic Magnetic Resonance Imaging in the 
Diagnosis of Internal Derangements of the Knee. Korean J Radiol. 2018;19(2):311-9. 
 
10. Murata S, Hagiwara A, Fujita S, Haruyama T, Kato S, Andica C, et al. Effect of hybrid of 
compressed sensing and parallel imaging on the quantitative values measured by 3D quantitative 
synthetic MRI: A phantom study. Magn Reson Imaging. 2021;78:90-7. 
 
11. Granberg T, Uppman M, Hashim F, Cananau C, Nordin LE, Shams S, et al. Clinical Feasibility of 
Synthetic MRI in Multiple Sclerosis: A Diagnostic and Volumetric Validation Study. AJNR Am J 
Neuroradiol. 2016;37(6):1023-9. 
 
12. Wallaert L, Hagiwara A, Andica C, Hori M, Yamashiro K, Koshino S, et al. The Advantage of 
Synthetic MRI for the Visualization of Anterior Temporal Pole Lesions on Double Inversion Recovery 
(DIR), Phase-sensitive Inversion Recovery (PSIR), and Myelin Images in a Patient with CADASIL. 
Magn Reson Med Sci. 2018;17(4):275-6. 
 
13. Andica C, Hagiwara A, Nakazawa M, Kumamaru KK, Hori M, Ikeno M, et al. Synthetic MR 
Imaging in the Diagnosis of Bacterial Meningitis. Magn Reson Med Sci. 2017;16(2):91-2. 
 
14. Fujita S, Hagiwara A, Takei N, Hwang KP, Fukunaga I, Kato S, et al. Accelerated Isotropic 
Multiparametric Imaging by High Spatial Resolution 3D-QALAS With Compressed Sensing: A 
Phantom, Volunteer, and Patient Study. Invest Radiol. 2021;56(5):292-300. 
 
15. Kvernby S, Rönnerfalk M, Warntjes M, Carlhäll CJ, Nylander E, Engvall J, et al. Longitudinal 
changes in myocardial T(1) and T(2) relaxation times related to diffuse myocardial fibrosis in aortic 
stenosis; before and after aortic valve replacement. J Magn Reson Imaging. 2018. 

 
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16. Kvernby S, Warntjes M, Engvall J, Carlhäll CJ, Ebbers T. Clinical feasibility of 3D-QALAS - Single 
breath-hold 3D myocardial T1- and T2-mapping. Magn Reson Imaging. 2017;38:13-20. 
 
17. Kvernby S, Warntjes MJ, Haraldsson H, Carlhäll CJ, Engvall J, Ebbers T. Simultaneous three-
dimensional myocardial T1 and T2 mapping in one breath hold with 3D-QALAS. J Cardiovasc Magn 
Reson. 2014;16(1):102. 
 
18. Fujita S, Hagiwara A, Hori M, Warntjes M, Kamagata K, Fukunaga I, et al. 3D quantitative synthetic 
MRI-derived cortical thickness and subcortical brain volumes: Scan-rescan repeatability and 
comparison with conventional T(1) -weighted images. J Magn Reson Imaging. 2019;50(6):1834-42. 
 
19. Fujita S, Hagiwara A, Takei N, Fukunaga I, Hagiwara Y, Ogawa T, et al. Rigid real-time prospective 
motion-corrected three-dimensional multiparametric mapping of the human brain. Neuroimage. 
2022:119176. 
 
20. Osborn A, Hedlund G, Salzman K. Osborn’s Brain - 2nd Edition. Elsevier; 2017. 
 
21. Jhaveri M. Diagnostic Imaging: Brain – 4th Edition. Elsevier; 2020. 
 
22. Barkhof F, Jäger HR, Thurnher MM, Rovira A. Clinical Neuroradiology: The ESNR Textbook. 
Springer; 2020. 
 
23. SyntheticMR, RMR-8 Risk management Report for Curie Clinical Investigation, Internal document. 
 
24. Wollman DE, Prohovnik I. Sensitivity and specificity of neuroimaging for the diagnosis of 
Alzheimer's disease. Dialogues Clin Neurosci. 2003 Mar;5(1):89-99. PMID: 22033599; PMCID: 
PMC3181708. 
 
25. U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA review results in 
new warnings about using general anesthetics and sedation drugs in young children and pregnant 
women. Silver Spring (MD): FDA; 2016. Available at: 
http://www.fda.gov/Drugs/DrugSafety/ucm532356.htm. Retrieved May 26, 2022. 
 

 
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24 APPENDICES 
24.1 Appendix A – Clinical Investigation Plan Agreement Form 
 
Investigation code: CIP-003 
 
CIP version: K 
 
 
I agree to the terms of this CIP. I will conduct the investigation according to the procedures specified 
herein.  
 
 
Site No.:  
 
Coordinating/Principal Investigator 
 
Name:  
 
 
 
Signature: _____________________ 
 
 
 
Date (dd-Mmm-yyyy): ______________ 
 
 
 
 
 

 
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24.2 Appendix B – Clinical Investigation Contact List 
 
COORDINATING INVESTIGATOR 
Name: Dr. Jeffrey Miller 
Professional position: Chief of Radiology at Phoenix Children’s Hospital and Clinical Assistant 
Professor of Radiology at University of Arizona College of Medicine 
Address: Phoenix Children's Hospital, 1919 East Thomas Road, Phoenix, AZ 85016, USA 
Phone: +1 602 933-1213 
E-mail: jhmiller@phoenixchildrens.com 
 
 
CLINICAL INVESTIGATION SITES 
A separate contact list of all principal investigators, investigation sites, and institutions will be available 
in the Study Master File (SMF). 
 
Site 1 
Name: Phoenix Children's Hospital 
Address: 1919 East Thomas Road, Phoenix, AZ 85016, USA 
 
Site 2 
Name: Diagnostic Imaging Sciences Center, University of Washington Medical Center 
Address: Box 357115, 1959 NE Pacific St, Seattle, WA 98195, USA 
 
Site 3 
Replaced by Site 7 
 
Site 4 
Name: SimonMed Imaging – Streeterville 
Address: 446 E. Ontario Street Suite 106, Chicago, Il 60611-7110, USA 
 
Site 5 
Name: Nemours Children’s Health, Nemours Children’s Hospital, Florida 
Address: 6535 Nemours Pkwy, Orlando, FL 32827, USA 
 
Site 6 
Name: ProScan Imaging 
Address: 1020 Crosspointe Dr Suite 103, Naples, FL 34110, USA 
 
Site 7 
Name: DENT Neurologic Institute 
Address: 3980 Sheridan Drive, Amherst, New York, 14226, USA 
 
 

 
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SPONSOR REPRESENTATIVE 
Name: Ulrik Harrysson 
Address: Storgatan 11, 582 23 Linköping, Sweden 
E-mail: ulrik.harrysson@syntheticmr.com 
 
SPONSOR PROJECT MANAGER: 
Name: Erik Lange 
Address: Storgatan 11, 582 23 Linköping, Sweden 
Phone: +46(0)70-331 56 78 
E-mail: erik.lange@syntheticmr.com 
 
CONTRACT RESEARCH ORGANIZATION (CRO) 
Name: Veranex Sweden AB 
Address: GoCo House, Gemenskapens gata 9, 431 53 Mölndal, Sweden 
Phone: +46 300 177 94 
 
CRO PROJECT MANAGER: 
Name: Anna Rydberg 
Address: GoCo House, Gemenskapens gata 9, 431 53 Mölndal, Sweden  
Phone: +46(0) 73-806 17 97 
E-mail: anna.rydberg@veranex.com 
 
BIOSTATISTICIAN 
Name: Statistiska Konsultgruppen 
Address: Thorild Wulffsgatan 1, SE-413 19 Göteborg 
E-mail: info@stat-grp.se 
 
SAFETY OFFICER 
Name: Madeleine Enström, QA/RA Manager 
Address: Storgatan 11, 582 23 Linköping, Sweden 
Phone: +46 (0)73-069 04 90 
E-mail: madeleine.enstrom@syntheticmr.com 
 
CLINICAL DATA MANAGER: 
Name: Matina Starck 
Address: GoCo House, Gemenskapens gata 9, 431 53 Mölndal, Sweden  
Phone: +46 (0) 72-551 57 02 
E-mail: matina.starck@veranex.com 
 
CLINICAL INVESTIGATION MONITORS 
Designated monitor(s): 
Address: TBD 
Phone: 
E-mail: 
 
CLINICAL INVESTIGATION PLAN AUTHOR(S) 
Name: Erik Lange 
Address: Storgatan 11, 582 23 Linköping, Sweden 
Phone: +46 (0)70-331 56 78 
E-mail: erik.lange@syntheticmr.com 
 
Name: Anna Rydberg 
Address: GoCo House, Gemenskapens gata 9, 431 53 Mölndal, Sweden  
Phone: +46 (0)73-806 17 97 

 
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E-mail: anna.rydberg@veranex.com 
 
Name: Henrik Imberg 
Address: Thorild Wulffsgatan 1, SE-413 19 Göteborg 
E-mail: info@stat-grp.se 
 
Name: Erica Swahn 
Address: Storgatan 11, 582 23 Linköping, Sweden 
E-mail: erica.swahn@syntheticmr.com 
 
Name: Peter Johansson 
Address: Storgatan 11, 582 23 Linköping, Sweden 
E-mail: peter.johansson@syntheticmr.com 
 
 
 

 
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24.3 Appendix C – Declaration of Helsinki 
 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 
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, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000  
53rd WMA General Assembly, Washington, DC, USA, October 2002 (Note of Clarification added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008  
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
 
PREAMBLE 
 
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 be 
applied with consideration of all other relevant paragraphs. 
 
2. 
Consistent with the mandate of the WMA, the Declaration is addressed primarily to physicians. The 
WMA encourages others who are involved in medical research involving human subjects to adopt 
these principles. 
 
 
GENERAL PRINCIPLES 
 
3. 
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.” 
4. 
It is the duty of the physician to promote and safeguard the health, well-being and rights of patients, 
including those who are involved in medical research. The physician's knowledge and conscience are 
dedicated to the fulfillment of this duty. 
5. 
Medical progress is based on research that ultimately must include studies involving human subjects. 
6. 
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 proven interventions must be evaluated 
continually through research for their safety, effectiveness, efficiency, accessibility and quality. 
7. 
Medical research is subject to ethical standards that promote and ensure respect for all human subjects 
and protect their health and rights. 
8. 
While the primary purpose of medical research is to generate new knowledge, this goal can never take 
precedence over the rights and interests of individual research subjects. 
9. 
It is the duty of physicians who are involved in medical research to protect the life, health, dignity, 
integrity, right to self-determination, privacy, and confidentiality of personal information of research 
subjects. The responsibility for the protection of research subjects must always rest with the physician 
or other health care professionals and never with the research subjects, even though they have given 
consent. 
10. Physicians must consider the ethical, legal and regulatory norms and standards for research involving 

 
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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. 
11. Medical research should be conducted in a manner that minimises possible harm to the environment. 
12. Medical research involving human subjects must be conducted only by individuals with the appropriate 
ethics and scientific education, training and qualifications. Research on patients or healthy volunteers 
requires the supervision of a competent and appropriately qualified physician or other health care 
professional. 
13. Groups that are underrepresented in medical research should be provided appropriate access to 
participation in research. 
14. Physicians who combine medical research with medical care should involve their patients in research 
only to the extent that this 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. 
15. Appropriate compensation and treatment for subjects who are harmed as a result of participating in 
research must be ensured. 
 
RISKS, BURDENS AND BENEFITS 
 
16. In medical practice and in medical research, most interventions involve risks and burdens. 
 
Medical research involving human subjects may only be conducted if the importance of the objective 
outweighs the risks and burdens to the research subjects. 
 
17. All medical research involving human subjects must be preceded by careful assessment of predictable 
risks and burdens to the individuals and groups involved in the research in comparison with 
foreseeable benefits to them and to other individuals or groups affected by the condition under 
investigation. 
 
Measures to minimise the risks must be implemented. The risks must be continuously monitored, 
assessed and documented by the researcher.  
 
18. Physicians may not be involved in a research study involving human subjects unless they are confident 
that the risks have been adequately assessed and can be satisfactorily managed. 
 
When the risks are found to outweigh the potential benefits or when there is conclusive proof of 
definitive outcomes, physicians must assess whether to continue, modify or immediately stop the 
study.  
 
VULNERABLE GROUPS AND INDIVIDUALS 
 
19. Some groups and individuals are particularly vulnerable and may have an increased likelihood of being 
wronged or of incurring additional harm. 
 
All vulnerable groups and individuals should receive specifically considered protection. 
 
20. Medical research with a vulnerable group is only justified if the research is responsive to the health 
needs or priorities of this group and the research cannot be carried out in a non-vulnerable group. In 
addition, this group should stand to benefit from the knowledge, practices or interventions that result 
from the research 
 
SCIENTIFIC REQUIREMENTS AND RESEARCH PROTOCOLS 
 
21. Medical research involving human subjects must conform to generally accepted scientific principles, 

 
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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. 
 
22. The design and performance of each research study involving human subjects must be clearly 
described and justified 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, potential conflicts of interest, incentives for 
subjects and information regarding provisions for treating and/or compensating subjects who are 
harmed as a consequence of participation in the research study. 
 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial provisions 
 
RESEARCH ETHICS COMMITTEES 
 
23. The research protocol must be submitted for consideration, comment, guidance and approval to the 
concerned research ethics committee before the study begins. This committee must be transparent in 
its functioning, must be independent of the researcher, the sponsor and any other undue influence and 
must be duly qualified. 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. No 
amendment to the protocol may be made without consideration and approval by the committee. After 
the end of the study, the researchers must submit a final report to the committee containing a summary 
of the study’s findings and conclusions.  
 
PRIVACY AND CONFIDENTIALITY 
 
24. Every precaution must be taken to protect the privacy of research subjects and the confidentiality of 
their personal information. 
 
INFORMED CONSENT 
 
25. Participation by individuals capable of giving informed consent as subjects in medical research must 
be voluntary. Although it may be appropriate to consult family members or community leaders, no 
individual capable of giving informed consent may be enrolled in a research study unless he or she 
freely agrees. 
26. In medical research involving human subjects capable of giving informed consent, 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, post-study provisions 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, 
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formally documented and witnessed.       
 
All medical research subjects should be given the option of being informed about the general outcome 
and results of the study. 
 
27. When seeking informed consent for participation in a research study the physician must 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 must be sought by an appropriately qualified individual 
who is completely independent of this relationship. 
28. For a potential research subject who is incapable of giving informed consent, the physician must seek 
informed consent from the legally authorised 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 group represented by the potential subject, the research cannot instead be performed with 
persons capable of providing informed consent, and the research entails only minimal risk and minimal 
burden. 
29. When a potential research subject who is deemed incapable of giving informed consent is able to give 
assent to decisions about participation in research, the physician must seek that assent in addition to 
the consent of the legally authorised representative. The potential subject’s dissent should be respected. 
30. 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 group. In such circumstances the 
physician must seek informed consent from the legally authorised 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 must be obtained 
as soon as possible from the subject or a legally authorised representative. 
31. The physician must fully inform the patient which aspects of their 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 adversely affect the patient-physician relationship. 
32. For medical research using identifiable human material or data, such as research on material or data 
contained in biobanks or similar repositories, physicians must seek informed consent for its collection, 
storage and/or reuse. There may be exceptional situations where consent would be impossible or 
impracticable to obtain for such research. In such situations the research may be done only after 
consideration and approval of a research ethics committee. 
 
USE OF PLACEBO 
 
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of 
the best proven intervention(s), except in the following circumstances: 
 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or 
 
Where for compelling and scientifically sound methodological reasons the use of any intervention less 
effective than the best proven one, the use of placebo, or no intervention is necessary to determine 
the efficacy or safety of an intervention  
 
and the patients who receive any intervention less effective than the best proven one, placebo, or no 
intervention will not be subject to additional risks of serious or irreversible harm as a result of not 
receiving the best proven intervention.  
 
Extreme care must be taken to avoid abuse of this option 
 
POST-TRIAL PROVISIONS 

 
Clinical Investigation Code: 
Date 
CIP-003, Version K 
2023-12-21 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 68 of 68 
 
 
 
34. In advance of a clinical trial, sponsors, researchers and host country governments should make 
provisions for post-trial access for all participants who still need an intervention identified as beneficial 
in the trial. This information must also be disclosed to participants during the informed consent 
process. 
 
RESEARCH REGISTRATION AND PUBLICATIONS AND DISSEMINATION OF 
RESULTS 
 
35. Every research study involving human subjects must be registered in a publicly accessible database 
before recruitment of the first subject. 
36. Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard to the 
publication and dissemination of the results of research. Researchers 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. All parties should adhere to accepted guidelines for ethical reporting. 
Negative and inconclusive as well as positive results must be published or otherwise made publicly 
available. Sources of funding, institutional affiliations and conflicts of interest must be declared in the 
publication. Reports of research not in accordance with the principles of this Declaration should not 
be accepted for publication. 
 
UNPROVEN INTERVENTIONS IN CLINICAL PRACTICE 
 
37. In the treatment of an individual patient, where proven interventions do not exist or other known 
interventions have been ineffective, the physician, after seeking expert advice, with informed consent 
from the patient or a legally authorised representative, may use an unproven intervention if in the 
physician's judgement it offers hope of saving life, re-establishing health or alleviating suffering. This 
intervention should subsequently be made the object of research, designed to evaluate its safety and 
efficacy. In all cases, new information must be recorded and, where appropriate, made publicly 
available.