Prospective Cardiac Ultrasound Imaging Study With Demonstrator
Phase: NA
Conditions: Ventricular Tachycardia
Sponsor: Fondazione IRCCS Policlinico San Matteo di Pavia

Research Protocol 
Prospective Cardiac Ultrasound Imaging Study With Demonstrator 
 
 
Version 0.3, 31-mar-2021  
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Prospective Cardiac Ultrasound Imaging Study With Demonstrator 
 
 
 
 
Type of Research Project: 
Research project involving human subjects  
 
 
Risk Categorisation:  
Limited patient risk 
 
 
Project Leader: 
 Dr. Roberto Rordorf 
Responsabile UOS Aritmologia ed Elettrofisiologia 
Divisione di Cardiologia 
Fondazione IRCCS Policlinico S. Matteo, Pavia 
 
 
 
Statistics 
 
 
dr Catherine Klersy 
 
 
 
 
Responsabile UOS Epidemiologia Clinica e Biometria 
 
 
 
 
Fondazione IRCCS Policlinico S. Matteo, Pavia 
 
 

Research Protocol 
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PROTOCOL SIGNATURE FORM    
 
 
Study Title 
Prospective Cardiac Ultrasound Imaging Study With Demonstrator 
 
The project leader has approved the protocol Version 1, 31-mar-2021, and confirms hereby to 
conduct the project according to the protocol, the local legal requirements, current version of the 
World Medical Association Declaration of Helsinki [1] and the principles and procedures for 
integrity in scientific research involving human beings.  
 
Project leader: 
 
Site  
IRCCS Policlinico S. Matteo, Pavia 
Name: Dr. Roberto Rordorf 
Date: 
 _________________________ 
Signature:  ___________________________  
 
 
 
 
 

Research Protocol 
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TABLE OF CONTENTS 
TABLE OF CONTENTS 
3 
GLOSSARY OF ABBREVATIONS 
4 
1 BACKGROUND AND PROJECT RATIONALE 
5 
2 PROJECT OBJECTIVES AND DESIGN 
5 
2.1 Primary objective 
5 
2.2 Primary and additional endpoints 
5 
2.3 Project design 
7 
2.4 System in use 
7 
3 STUDY POPULATION AND PROCEDURES 
9 
3.1 Study population, inclusion and exclusion criteria 
9 
3.2 Recruitment, screening and informed consent procedure 
9 
3.3 Study procedures 
9 
3.1.1 
Demographics and cardiovascular history 
9 
3.1.2 
Cardiac Motion monitoring 
10 
3.4 Withdrawal and discontinuation 
10 
4 STATISTICS AND METHODOLOGY 
11 
4.1. Statistical analysis plan 
11 
4.2. Handling of missing data 
11 
4.3 Core laboratory 
11 
5 REGULATORY ASPECTS AND SAFETY 
11 
5.1 Local regulations / Declaration of Helsinki 
11 
5.2 Notification of safety and protective measures 
11 
5.3 Serious events 
11 
5.4 Amendments 
11 
5.5 End of project 
11 
5.6 Insurance 
12 
6   BENEFIT-RISK ASSESSMENT 
12 
7 QUALITY CONTROL DATA PROTECTION 
12 
7.1 Quality measures 
12 
7.2 Data recording and source data 
12 
7.3 Confidentiality and coding 
12 
7.4 Retention of study data 
12 
8  FUNDING / PUBLICATION / DECLARATION OF INTEREST 
12 
9 REFERENCES 
13 
10 APPENDIX 
13 
 
 

Research Protocol 
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GLOSSARY OF ABBREVATIONS 
 
CRF 
Case report form 
CT scan 
Computed Tomography scan 
 
 
 

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1 
BACKGROUND AND PROJECT RATIONALE  
 
Echocardiography is an established specialty with dedicated tools, which require a lot of know-
how both in manipulation and interpretation [1, 2]. Most cardiac patients who are prescribed a 
Computed Tomography scan (CT scan), or a Magnetic Resonance Imaging exam will undergo 
transthoracic echocardiography in the first place. The Prospective Cardiac Ultrasound Imaging 
Study aims at collecting cardiac ultrasound data from patients diagnosed with ventricular 
tachycardia. The research will analyse the ultrasound image data quality and establish if it is 
appropriate to develop a new medical device supporting automated cardiac ultrasound image 
interpretation during non-invasive cardiac procedures, i.e. ventricular tachycardia stereotactic 
radioablation. Such device would allow for a new way of monitoring patients during hospital 
procedures. 
This early research protocol will collect data from volunteer patients. The data will not be used 
for diagnostic nor treatment purposes and the protocol’s procedure duration is limited, hence 
the research is of very limited risk for the participants. The research has the potential to enable 
the creation of a medical device that will benefit patients with ventricular tachycardia and other 
cardiac pathologies in the future. 
2 
PROJECT OBJECTIVES AND DESIGN  
2.1 Primary objective 
The primary objective of the research is to evaluate the ultrasound image quality for arrythmia 
patients, to investigate potential echogenicity and artefact issues, which may arise from age, 
body composition, mechanical valves, leads from implanted devices, etc. in order to have a 
representative sample of the variety of ventricular tachycardia patients. 
2.2 Primary and additional endpoints 
 
Objectives 
The primary research objective is the proportion of subjects who have a positive evaluation in 
image interpretation metric and positive visual inspection of the ultrasound images. 
 
Secondary objective; Additionally, for patients for whom a full field of view CT scan is available, 
the theoretical impact of probe positioning during a CT scan is analysed for hypothetical 
treatment planning. 
 
Endpoints 
Primary 
The objective will be quantitatively assessed by scoring each patient as follows: 
- 
A) Cardiac motion analysis performance:  
o Score 1 if analysis of the ultrasound images with the EBAMed software gives 
a cardiac phase error (within R-R interval) < 0.1  
o Score 0 otherwise 
- 
B) Respiratory motion analysis performance:  
o Score 1 if analysis of the ultrasound images with the EBAMed software gives 
a motion amplitude lower than 30 mm and if the number of breathing cycles 
matches the one observed from the motion of the chest.  
o Score 0 otherwise 
 
 

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- 
C) Image quality performance: 
o Score 1 if visual inspection by a member of San Matteo team can identify in 
the ultrasound images at least one of these structures: left ventricular wall, 
interventricular septum, or heart valve. 
o Score 0 otherwise 
- 
D) Image quality performance : 
o Score 0 if visual inspection by a member of San Matteo team identifies that 
the heart becomes invisible for part of the time due to tissue motion linked to 
respiration. 
o Score 1 otherwise 
 
For each patient, scoring will be done for each imaging view (parasternal and apical). If the 
score is 2 (at least 1 point in A or B and 1 point in C or D)or higher for at least one of the 
imaging views, the outcome will be considered as positive. The final result will be the proportion 
(in %) of patients with a positive outcome defined as the number of patients with a positive 
evaluation divided by the total number of patients x 100.  
 
Secondary 
The objective will be quantitatively assessed by scoring each patient (only those with a CT 
available): 
- 
with Score 1: if a successful radio-ablation treatment plan respecting dose constraints 
can be created using a clinical treatment planning software (see details below) and, 
- 
with Score 0: if it is not possible to create such a treatment plan . 
 
The final result will be the proportion of patients (in %) with a 1 Score: number of patients with 
score 1 divided by the number of patients with Score 0 or 1 x 100.  
 
The treatment plan is performed with the Raystation clinical treatment planning software by a 
Medical Physicist from the EBAMed team. An electrophysiologist from the San Matteo team will 
draw on the CT the contours of a realistic ventricular tachycardia ablation treatment target and 
the contours of relevant organs-at-risk (including e.g. adjacent cardiac substructures, 
oesophagus, stomach and trachea). An additional virtual structure will be contoured on the CT, 
representing the position of the ultrasound probe (based on the best probe view as assessed by 
scoring for the primary endpoint). A successful treatment plan will need to accomplish all of the 
following:  
- 
radiation beams do not go through the ultrasound probe  
- 
treatment target receives at least 25 Gy (typical treatment dose) 
- 
organs at risk receive a dose below the thresholdsgiven in Table 1 
 
 
 

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Table 1: OARs and their relevant metrics (some taken from literature1, others from 
consultations with early implementers). 
OAR 
Relevant Metric 
Limit 
Whole heart  – PTV 
*D(50%Volume) 
< 5 Gy 
Non-involved myocardium = Left ventricular 
wall + right ventricular wall – PTV 
V(20Gy) 
Low as 
possible 
Left Atrium 
*Dmax 
< 4.4 Gy 
Mitral valve 
Dmax 
< 14 Gy 
Aortic valve 
Dmax 
< 14 Gy 
Left-anterior-descending coronary artery 
*Dmax 
< 14 Gy 
Aorta 
*Dmax 
< 20 Gy 
Superior Vena Cava 
*D(50%Volume) 
< 0.6 Gy 
Whole Lungs 
*V(total) – V(7Gy), 
D(5%Volume) 
> 1500 cc 
Spinal Canal 
*Dmax 
V(6Gy) 
< 7 Gy  
< 0.1cc 
Oesophagus 
*Dmax  
V(9Gy) 
< 14.5 Gy 
< 1cc 
Skin 
*Dmax 
V(10Gy) 
< 14.4 Gy 
< 10 cc 
Trachea 
*Dmax  
V(10Gy) 
< 15 Gy 
< 1 cc 
ICD (electronics) 
*Dmax 
< 0.5 Gy 
 
Data that may influence the results will be collected such as patient’s demographics and 
cardiovascular history. 
2.3 Project design  
This is a single center, one arm, feasibility study. The patients will undergo one Cardiac motion 
monitoring procedure to collect ultrasound imaging data via the Demonstrator 2 developed by 
EBAMed SA, Switzerland and there is no follow-up planned. 
 
2.4 System in use 
For this study, Demonstrator 2 and related components provide monitoring of the cardiac 
motion in all its components: cyclical heart-beat motion, cyclical respiratory motion and non-
cyclical heart position changes with the patient lying in supine position. 
 
                                                        
 
1 Radiosurgery for ventricular tachycardia: preclinical and clinical evidence and study 
design for a German multi‑center multi‑platform feasibility trial (RAVENTA). Oliver Blanck 
et al. Clinical Research in Cardiology (2020) https://doi.org/10.1007/s00392-020-01650-
9 
 

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The system encompasses Demonstrator 2 for ultrasound imaging and optical localization. The 
system offers non-invasive means for accurate and precise real-time monitoring of the patient’s 
heart position and cardiac motion management (see Figure 1 below).   
 
 
Figure 1 Schematic view of study system 
 
The system is comprised of the following functional components: 
- 
The Workstation, which integrates: 
• 
Consumer grade computer 
• 
Consumer grade screen 
• 
Consumer grade keyboard and mouse 
The Workstation is used for: 
▪ 
Communication with Optical localization system 
▪ 
Communication with Demonstrator 2 
▪ 
Graphical User Interface  
- 
The real-time data acquisition module of Demonstrator 2 (Appendix A - Demonstrator 
IFU), which controls data acquisition from: 
• 
ECG system (Appendix B – ECG Operator’s Guide) 
• 
Ultrasound imaging system (beamformer and probe) 
- 
The Optical localization system (Appendix C - Optical Localization System User Guide) 
 
 
The following additional components are provided to the users:  
- 
Disposable ECG electrodes 
- 
Re-usable reflective markers for optical localization 
- 
Disposable ultrasound probe holder strap 
- 
Re-usable ultrasound probe holder 
- 
Patient positioning board with grab bar and arm support (EagleBoard)  
 
The system provides the following output information: 
- 
User Interface with live ultrasound images, ECG signals including ECG R-waves, 
ultrasound probe localization data and metrics calculated during the data acquisition, 
as well as warnings.  
- 
Session records including ultrasound images, ECG data and ultrasound probe 
localization data.  
- 
Metrics calculated during the data acquisition, including warnings 

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3 
STUDY POPULATION AND PROCEDURES 
3.1 Study population, inclusion and exclusion criteria  
The study will enrol up to 24 adult patients diagnosed with ventricular tachycardia.  
Patients with cardiac or non-cardiac implants in the thorax area are of interest for the research. 
Patients of all relevant ages and gender should be represented in the final study population. 
 
Inclusion criteria: 
1. Patient with history of ventricular tachycardia 
2. Over 18 years old 
3. Ability and willingness to provide written informed consent 
 
Exclusion criteria:  
1. Patient in arrhythmic storm 
3.2 Recruitment, screening and informed consent procedure 
All consecutive adult patients diagnosed with ventricular tachycardia and visiting the site will be 
screened for the study by the study leader and his study team.  
After reviewing the information sheet, patients will be offered the opportunity to ask questions 
and they will be offered enough reflexion time before they sign the informed consent form. Two 
copies of the informed consent will be signed. One copy is for the patient, one copy will be 
maintained at the site. The data collection and study procedure will start after the signature of 
the informed consent by both parties and within a maximum of 30 days after the signature. 
Above 30 days, a new consent form needs to be collected before proceeding with the protocol.  
The patients will not receive compensation for their participation in the study. 
3.3 Study procedures 
Patient’s participation starts at informed consent signature and ends after completion of the 
study’s Cardiac Motion Monitoring procedure. 
 
The study will start as soon as the protocol is approved by ethics. The recruitment period is 
expected to last from May 2021 to August 2021. 
 
The table below describes the data collection and study procedures: 
Data Collection  
Information and 
informed consent form 
Procedure  
(within 30 days of consent) 
Signature 
X 
 
Demographics and 
cardiovascular history 
 
X 
Cardiac Motion Monitoring with 
Demonstrator 2 
 
X 
CTscan (if available) 
 
(X) 
Adverse Event 
 
X 
Deviations, technical issues 
 
X 
 
3.1.1 Demographics and cardiovascular history 

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The patient will be asked to confirm his/her demographics and cardiovascular history. 
 
3.1.2 Cardiac Motion monitoring 
The following procedure steps will take place: 
• 
The study system is installed in the room before patient arrival  
• 
The patient needs to fully undress the upper body before lying on the bed  
• 
The 3 ECG electrodes are placed 
• 
Ultrasound gel is applied on the ultrasound probe 
A – Apical view   
• 
The ultrasound probe is positioned for apical viewing and fixed with the probe holder and 
the probe holder strap around patient’s chest. Probe position is recorded on case report 
form. The relative position of the probe is automatically recorded via is optical 
localization system. 
• 
The cardiac motion monitoring can start. During data acquisition, the image quality of the 
ultrasound images is visually monitored. The following data sequences are acquired 
successively: 
1. Patient in free breathing, 5 minutes 
2. Next 5 minutes, the patient starts holding breath for 10 seconds, repeated every 
minute (total: 5 breath holds in 5 minutes) 
• 
Ultrasound probe, probe holder and strap are removed 
B – Parasternal view 
• 
The ultrasound probe is positioned for parasternal viewing and fixed with the probe 
holder – when available and stable - or held manually. 
• 
The following data sequences are acquired successively: 
1. Patient in free breathing, minimum 1 minute, goal: 5 minutes with fixed probe 
position 
2. Next 5 minutes, the patient starts holding breath for 10 seconds, repeated every 
minute (total: 5 breath holds in 5 minutes), with fixed probe position. Note: this 
step is required when probe holder is in use, and optional when probe is 
manually held. 
• 
The patient is offered tissues to remove ultrasound gel before dressing up 
• 
The patient is asked whether he/she experienced any discomfort during the procedure 
 
The procedure is performed by a trained investigator. The Cardiac Motion monitoring procedure 
will last for up to one (1) hour. 
 
3.4 Withdrawal and discontinuation 
Patient will be withdrawn from the study if they do not pertain the enrollment criteria, or in case 
of absence of a Cardiac Motion monitoring procedure by the time the study ends.  
Patients can withdraw their consent at any time. No additional data will be collected after patient 
withdrawal. As much as possible, the reason for patient withdrawal shall be collected. 
In case of a patient withdrawal before any data is collected, a new enrollment may take place to 
ensure enough data is collected in the study. 

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4 
STATISTICS AND METHODOLOGY 
4.1. Statistical analysis plan 
Sample Size. This is a feasibility study at early research stage. We plan to enroll 24 patients. 
We aim at a feasibility of 90% for the primary endpoint (success in 22/24 pts). With 24 patients 
and an expected proportion of 90%, the lower limit of the 95% confidence interval (95%CI)  will 
be 73% (precision 17%); with an expected proportion of 95% (success in 23/24 pts), the lower 
limit of the 95%CI would be 79% (precision 11%). 
Data Analysis. The number and proportion of success for the primary and secondary endpoint 
will be reported with their 95%CI. The proportion of success and 95%CI will also be reported by 
patients characteristics (for instance, but not limited to: age <=/>65; BMI overweight/normo-
underweight), gender, VT etiology)  
Descriptive statistics (mean and standard deviation/median and quartiles or counts and percent) 
will be reported for the population description.  
-  
4.2. Handling of missing data  
Patients with major deviation to the protocol, i.e. lack of ultrasound imaging data, will not be 
analyzed. 
4.3 Core laboratory 
The data will be shared with EBAMed SA to perform the analysis of the records upon their 
anonimization.  
5 
REGULATORY ASPECTS AND SAFETY 
5.1 Local regulations / Declaration of Helsinki 
This research project will be conducted in accordance with the protocol, the Declaration of 
Helsinki [3], the principles of Good Clinical Practice, and local relevant regulations. The Project 
Leader acknowledges his responsibilities as both the Project Leader and the Sponsor. 
5.2 Notification of safety and protective measures  
Although not expected, the project leader will promptly notify the Ethics Committee (within 24 
hours) if immediate safety and protective measures have to be taken during the conduct of the 
research project. 
5.3 Serious events  
If a serious adverse event occurs, the research project will be interrupted, and the Ethics 
Committee notified on the circumstances. 
5.4 Amendments 
Substantial changes to the project set-up, the protocol and relevant project documents will be 
submitted to the Ethics Committee for approval before implementation. Exceptions are 
measures that have to be taken immediately in order to protect the participants.  
5.5 End of project 
Upon project completion or discontinuation, the Ethics Committee is notified within 90 days.  

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5.6 Insurance 
For any damage caused by the trial, the IRCCS Policlinico San Matteo Foundation insurance 
policy is active to cover the civil liability of its employees.  
6   BENEFIT-RISK ASSESSMENT  
The study is set-up in order to minimize the burden on the patient, with a single non-invasive, 
short and simple Cardiac Motion monitoring procedure. The procedure bears no risk for the 
study participant. The participant will not get direct benefit from her/his participation in the study, 
but, as mentioned in 1 Background and project rationale, the research has the potential to 
enable the creation of a medical device, that will eventually benefit patients with ventricular 
tachycardia and other cardiac pathologies in the future. 
 
7 
QUALITY CONTROL DATA PROTECTION 
7.1 Quality measures  
Data will be collected on site and maintained in dedicated study files. Training and support will 
be provided by EBAMed SA on the use of the system (Demonstrator 2 and related 
components). 
For quality assurance the Ethics Committee may visit the research sites. Direct access to the 
source data and all project related files and documents must be granted on such occasions. 
7.2 Data recording and source data 
The source data is collected on paper Case Report Forms (CRF) and retained at study site. Any 
error or correction will be marked in a legible format, with initials and date of input by the 
corrector. CRF data is transferred to electronic format in a single database for further analysis. 
The Demonstrator 2 system session records are saved on the Workstation in electronic format.  
Demonstrator 2 system data is saved in an external hard drive for archiving. 
7.3 Confidentiality and coding 
Study data will be handled with uttermost discretion and is only accessible to authorized 
personnel who require the data to fulfil their duties within the scope of the research project. On 
the CRFs and other study specific documents, participants are only identified by a unique 
participant number.  
7.4 Retention of study data  
The source data will be maintained at the site and stored for a minimum of 5 years.  
The data may be pooled with additional future studies of similar interest to increase study 
power.  
8  FUNDING / PUBLICATION / DECLARATION OF INTEREST 
The site receives funding by EBAMed to undertake the study. The site and EBAMed have a 
contract in place that covers study data sharing. 
The investigators have no personal interest, financial or otherwise, in the conduct of the study. 
In the event of a publication, both the study leader, the study team and EBAMed will collectively 
participate. 

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9 
REFERENCES 
1. 
Guidelines for   Performing a Comprehensive Transthoracic Echocardiographic 
Examination in Adults: Recommendations from the American Society of Echocardiography, 
2018 (https://www.asecho.org/wp-content/uploads/2019/01/2019_Comprehensive-TTE.pdf) 
2. 
Malik et al, Transthoracic Echocardiography: Pitfalls and Limitations as Delineated at 
Cardiac 
CT 
and 
MR 
Imaging, 
RadioGraphics 
2017; 
37:383–406 
(https://pubs.rsna.org/doi/pdf/10.1148/rg.2017160105) 
3. 
Declaration of Helsinki  
(https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-
medical-research-involving-human-subjects ) 
10 APPENDIX 
Appendix A - Demonstrator IFU 
IFU_2021MAR23_OperationManualDemonstrator2IOCabinet_v1.0 
 
Appendix B – ECG Operator’s Guide 
Accusync42_OperatorGuide 
 
Appendix C - Optical Localization System User Guide 
20200811_EXP_HWB_NDI-PolarisVega-User-Guide