Can MRI-based Computational Modelling of the Heart be Used to Predict Critical Substrate in Scar-dependent Ventricular Tachycardia Ablation?
Conditions: Ventricular Tachycardia
Sponsor: St George's, University of London

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Research Protocol 
 
 
FULL/LONG TITLE OF THE STUDY 
 
Can MRI-based computational modelling of the 
heart be used to predict critical substrate in scar-
dependent ventricular tachycardia ablation? 
SHORT STUDY TITLE / ACRONYM 
 
Multimodality assessment of ventricular scar 
arrhythmogenicity. 
PROTOCOL VERSION NUMBER AND DATE 
 
Version 1.1 (12/02/2021) 
IRAS Number: 
284337 
JRES Reference Number 
2020.0237 
Funder Reference Number: 
RES 20 21 001 
ClinicalTrials.gov Reference Number 
NCT04632394 
This protocol has regard for the HRA guidance and order of content 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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SIGNATURE PAGE 
The undersigned confirm that the following protocol has been agreed and accepted and that the Chief 
Investigator agrees to conduct the study in compliance with the approved protocol and will adhere to the 
principles outlined in the Declaration of Helsinki, the Sponsor’s SOPs, and other regulatory requirement. 
I agree to ensure that the confidential information contained in this document will not be used for any other 
purpose other than the evaluation or conduct of the investigation without the prior written consent of the 
Sponsor 
I also confirm that I will make the findings of the study publically available through publication or other 
dissemination tools without any unnecessary delay and that an honest accurate and transparent account of the 
study will be given; and that any discrepancies from the study as planned in this protocol will be explained. 
 
 
Signature:   
  
 
 
 
Date: 04/12/2020 
 
Name (please print): Sam Hollingworth 
 
 
 
 
 
Position: Research Governance and Facilitation Officer, SGUL 
 
 
 
 
 
Chief Investigator: 
Signature:  
 
 
 
Date: 04/12/2020 
Name: (please print): Magdi Saba 
 
 
 
 
 
 
 
 
 
 

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LIST of CONTENTS 
GENERAL INFORMATION 
Page No. 
PROTOCOL COMPLIANCE DECLARATION  
1 
TITLE PAGE 
 
1 
RESEARCH REFERENCE NUMBERS 
 
1 
SIGNATURE PAGE 
2 
LIST OF CONTENTS 
 
3 
KEY STUDY CONTACTS 
4 
FUNDING 
 
5 
ROLE OF SPONSOR AND FUNDER 
5 
STUDY FLOW CHART  
6 
ABBREVIATIONS 
7 
1. BACKGROUND 
 
8 
2. RATIONALE  
9 
3. THEORETICAL FRAMEWORK 
9 
4. RESEARCH QUESTION/AIM(S)  
9 
5. STUDY DESIGN/METHODS 
10 
6. STUDY SETTING 
12 
7. SAMPLE AND RECRUITMENT 
13 
8. ETHICAL AND REGULATORY COMPLIANCE 
14 
9. DISSEMINATION  POLICY 
17 
10. REFERENCES 
18 
11. APPENDICIES 
20 
 
 

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KEY STUDY CONTACTS 
 
KEY STUDY CONTACTS 
Chief Investigator 
Dr Magdi Saba 
msaba@sgul.ac.uk 
07834351045 
Study Co-ordinator 
Dr Michael Waight 
Michaelwaight@nhs.net 
07929339359 
Sponsor 
St George’s University of London 
 
Name: Sam Hollingworth 
Position: Research Governance and Facilitation Officer 
Email:   researchgovernance@sgul.ac.uk 
St Georges Joint Research & Enterprise Service (JRES), Cranmer 
Terrace SW17 ORE 
Funder(s) 
The AVATAR program fund under the direction of Dr Magdi Saba 
– administered by The St. George’s Hospital Charity 
 
Key Protocol Contributors 
Dr Michael Waight 
Michaelwaight@nhs.net 
07929339359 
Dr Anthony Li 
Anthony.li@stgeorges.nhs.uk 
07957445834 
 
Dr Magdi Saba 
msaba@sgul.ac.uk 
07834351045 
 
Professor Natalya Trayanova 
ntrayanova@jhu.edu 
 
Dr Adityo Prakosa 
Adityo.Prakosa@jhu.edu 
Committees 
NA  
 
 
 
 
 

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FUNDING AND SUPPORT IN KIND 
FUNDER 
FINANCIAL AND NON FINANCIALSUPPORT 
GIVEN 
The AVATAR program fund under the direction of Dr 
Magdi Saba – administered by The St. George’s 
Hospital Charity. 
 
Contact: 
Ms. Vivien Gunn  
Grant Manager 
Vivien.Gunn@stgeorges.nhs.uk 
 
Full financial support to complete the MDRes 
degree in three years. 
 
ROLE OF FUNDER 
 
The funder will provide materials to facilitate the investigators in conducting the study, including access to 
computers for data storage and analysis and statistical analysis. The funder is paying the salary of the principal 
investigator – Dr Waight. The funder will not be involved in the design of the study, the collection or analysis of 
data, manuscript writing or dissemination of results. 
 
 
PROTOCOL CONTRIBUTORS 
The protocol was developed by the named investigators as above: 
• 
Dr Michael Waight 
• 
Dr Anthony Li 
• 
Dr Magdi Saba 
• 
Professor Natalya Trayanova 
• 
Dr Adityo Prakosa 
The funder did not contribute to the production of this protocol. 
 
 
 
 
 
 
 
 
 
 
 

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STUDY Schematic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-ablation 
 
Sustained, monomorphic 
scar-dependent VT. 
LGE cardiac MRI 
Computational model of 
predicted critical VT sites 
EP study 
Co-registration of 
computational model with 
electroanatomical map 
VT ablation 
Follow up at 3, 6 and 12 
months with rhythm analysis 
Post- ablation 
VT ablation 

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ABBREVIATIONS 
AE  
Adverse Event  
AR  
Adverse Reaction  
CI  
Chief Investigator  
CRF  
Case Report Form  
GCP  
Good Clinical Practice  
GP  
General Practitioner  
HRA 
Health Research Authority  
ICF  
Informed Consent Form  
ISF  
Investigator Site File  
NHS  
National Health Service  
NIHR  
National Institute for Health Research  
PI  
Principal Investigator  
REC 
Research Ethics Committee 
SAE 
Serious Adverse Event 
SGUL 
St Georges, University of London 
SGHFT 
St Georges, University Hospitals NHS 
Foundation Trust 
JRES 
(St Georges) Joint Research and Enterprise 
Services 
VT 
Ventricular tachycardia 
MRI 
Magnetic resonance imaging 
ICD 
Implantable cardioverter-defibrillator 
LAVA 
Locally abnormal ventricular activity 
LGE 
Late gadolinium enhancement 
LAT 
Local activation time 
LV 
Left ventricle 
RV 
Right ventricle 

V1.1 12.02.2021             8 
 
STUDY PROTOCOL 
Can MRI-based computational modelling of the heart be used to predict critical substrate in scar-dependent 
ventricular tachycardia ablation? 
 
1 
BACKGROUND 
Ventricular tachycardia (VT) is a life threatening rhythm disturbance of the heart, which is associated with a 
significant risk of mortality as well as morbidity. VT is particularly prevalent in patients with ischaemic heart 
disease. Over the past three decades, catheter directed ablation has emerged as an increasingly useful adjunct 
to the implantable cardioverter-defibrillator (ICD) as treatment for this rhythm disorder, especially if 
medications fail, or are prohibited by side effects or patient choice. Traditional catheter ablation of VT uses 
several different invasive mapping methods to analyse the ventricular myocardium in detail and aims to modify 
those areas which are thought to be critical for sustaining the arrhythmic circuit. Commonly used techniques 
include activation mapping, entrainment mapping, pace-mapping and substrate mapping. 
Activation mapping is a technique which, in cases of focal VT, records the earliest ventricular activation to find 
areas which are key in the generation of the arrhythmia, or in cases of re-entrant VT, to identify the diastolic 
pathway which allows the perpetuation of the arrhythmia1.  
Entrainment mapping is a technique whereby critical parts of the arrhythmia circuit can be identified by pacing 
at different locations, in an attempt to enter the excitable gap and capture the arrhythmia circuit. Once the 
critical isthmus utilised by the circuit is identified, ablation in this area can lead to termination of the 
arrhythmia.2 
Both activation and entrainment mapping require a stable VT which is haemodynamically tolerated, which is 
often not the case. Therefore other methods of invasively mapping VT have been devised, most notably 
substrate mapping. Substrate mapping can be performed with the patient in sinus rhythm and is based on the 
fact that arrhythmogenic substrate in the ventricle produces different EGM signals from healthy tissue. 
Features of interest include fractionated signals, low voltage, split or double potentials, mid-diastolic 
potentials, late potentials and locally abnormal ventricular activity (LAVA) 34. 
For some patients, particularly in those with non-ischaemic cardiomyopathy, scar is predominantly epicardial 
or mid-myocardial, meaning that endocardial mapping and ablation may be of limited efficacy5. In these cases, 
accessing the epicardium via a subxiphoid incision and performing additional ablation on the epicardial surface 
has been shown to be of benefit 6,7. 
Recently, data have emerged suggesting that computational modelling of a patient’s heart based on 3D MRI 
reconstructions can enable prediction of optimal targets for VT ablation non-invasively. This has been 
confirmed in both retrospective and prospective studies.8 This involves high resolution MRI imaging with late-
gadolinium enhancement (LGE) to assess the three-dimensional geometry of the scar, followed by 
reconstruction of the patient’s heart in silico9,10. Fibre orientation is established and overlaid onto this model11. 
Standard electrophysiological properties are applied to the different categories of tissue as defined by the LGE 
signal intensity, namely, normal tissue, scar and grey zone. Using computational modelling, this “virtual heart” 
is then analysed for different potential ventricular tachycardia circuits that are theoretically sustainable based 
on the information supplied. A virtual electrophysiology study with programmed stimulation is conducted by 
virtually pacing the heart model from various different locations9. An algorithm is used to predict optimal 
ablation sites to terminate all possible VT circuits in this model heart. The algorithm initially generates “primary 
sites”, which are the initial locations which have the potential to sustain ventricular tachycardia in the patient’s 
heart. The model then undergoes virtual VT ablation of these primary sites and the prediction algorithm is re-
run. This may generate a new VT-sustaining substrate and give predictions of “secondary sites” which can 
sustain VT in the post-ablation heart. The process is repeated until the heart is no longer VT-inducible. 12. In this 
way, not only should the patient’s clinical VT be ablated, but all future potential ventricular tachycardias 
supportable by the substrate in its current form should also be avoided, reducing the need for repeat VT 
ablation. 

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2 
RATIONALE  
Current invasive substrate mapping techniques are time and labour intensive. The ability to identify 
arrhythmogenic from non-arrhythmogenic areas within the same scar is limited, leading to prolonged 
procedure time and the potential overuse of ablative energy. Activation mapping during ventricular 
tachycardia, the gold standard for defining the critical isthmus sustaining the arrhythmia, is significantly limited 
by hemodynamic instability. 
Image-guided VT ablation has been shown to improve substrate definition and may underpin improved 
outcomes in certain patient populations13,14. Given the newly emerging field of personalised medicine and 
computation modelling this study will help to assess if an MRI-based, computer generated model accurately 
correlates to the invasive findings from an EP study with regards to targeting ablation in VT. If the model proves 
to be accurate, this will help to advance the process of in silico planning of VT ablation and potentially lead to 
improvements in outcomes of VT ablation, as well as reducing the need for repeated procedures. Results from 
the invasive studies can also be fed back into the computational model in an attempt to improve its accuracy. 
Furthermore, by assessing the electrophysiological properties of the computer generated predicted sites, we 
may learn which signals may indicate a critically important part of the VT circuit which traditional 
electroanatomical maps may miss.  
3 
THEORETICAL FRAMEWORK 
As outlined above 
4 
RESEARCH QUESTION/AIM(S) 
• 
To assess the accuracy of an MRI-based, computer-generated model of the heart in predicted sites 
which are particularly important in generating and sustaining ventricular tachycardia.  
• 
What are the invasive electrophysiological properties of the sites which are predicted by the MRI-based 
computational model?  
• 
Does ablation of the computer generated predicted sites lead to a change in the electrophysiological 
properties of distant sites?  
 
4.1 
Objectives 
 
• 
To perform high resolution cardiac MRI prior to undergoing catheter-based VT ablation in order to non-
invasively assess scar and provide data for computational modelling and prediction of likely VT circuits 
in silico. 
• 
To assess the accuracy of the in silico predicted sites when compared to invasively obtained 
electrophysiological data. 
• 
To assess the ventricular scar characteristics in patients with scar-dependent VT using high-definition 
invasive mapping. 
• 
To invasively assess the in silico predicted sites in order to ascertain the electrophysiological properties 
which likely lead to their prediction as key sites for arrhythmogenesis.  
• 
To corroborate the in silico predictions with the invasive findings during catheter-based VT ablation. 
 
4.2 
Outcome 
• 
Assessment of the degree of validation of in silico computational modelling by invasive ventricular scar 
interrogation to see if the predicted sites match those sites which would have been determined as 
important from invasive mapping.  
• 
Qualification of the electrophysiological characteristics of those sites which the computational model 
predicted in an attempt to see what it is about them that makes them likely to be key to maintaining 
the arrhythmia. With our mapping techniques, we can assess not only the amplitude and morphology 

V1.1 12.02.2021             10 
 
of the electrograms from these areas, but also the directionality of wavefronts to see if this is an 
important feature. With the additional benefit of the 3D computational model, we may be able to gain 
some insight into the 3D nature of channels which form part of the VT substrate. 
• 
Assessment of the change in the invasive electrophysiological characteristics of distant sites following 
ablation of the primary predicted in silico sites. By ablating the predicted areas, it is possible that when 
we re-map distant points, they may be a change in their electrophysiological properties. There may be 
a change in variables such as the stim-QRS latency, the QRS morphology, the capture threshold and the 
nature of the exit site (e.g. multiple-exit site changing to single-exit site). 
• 
Assessment of the frequency of ventricular arrhythmia, frequency of therapy delivered from an ICD (if 
applicable) and duration until first delivered therapy on serial heart rhythm monitors. Also assessment 
of patient’s symptoms and adverse effects on clinical consultation. 
5 
STUDY DESIGN and METHODS of DATA COLLECTION AND DATA ANALYIS 
 
The study will be a single centre, prospective study based at St George’s University Hospitals NHS Foundation 
Trust in London. Consecutive patients presenting to the hospital with an appropriate scar-dependent, 
sustained monomorphic ventricular tachycardia, requiring catheter ablation, will be screened for inclusion into 
the study. Full inclusion and exclusion criteria are listed below. Patients are likely to be predominantly 
outpatients, requiring elective VT ablation, however inpatients may also be included in the study. 
If found eligible for the study, the patient will be approached by one of the study investigators and a Patient 
Information Sheet (PIS) will be offered. Written consent will be obtained if the patient is willing to proceed.  
If included in the study, de-identified, anonymized MRI images from patient’s routine scan will be transferred 
to Johns Hopkins University, Baltimore Maryland, for computational analysis. The patient’s MRI images will be 
reconstructed, analysed and a 3D geometric model of the patient’s heart formed. From this, a computer-
generated model of the patient’s heart will be created. As described above, a virtual EP study, VT ablation and 
generation of both primary and secondary sites will be generated. The computation model as well as the 
locations of these primary and secondary sites will again be stored securely and transferred back to the 
primary research centre.  
The patient will then undergo traditional endocardial, and in appropriate cases, epicardial, mapping and 
ablation of ventricular tachycardia, using the techniques previously described 1–3,7,15. Patient preparation on the 
day of the procedure will be as for any other clinical VT ablation. Ablation technique will depend on whether or 
not there is a documented 12 lead ECG of the patient’s clinical VT and also whether or not the VT is 
haemodynamically tolerated (stable) or not (unstable). This will be decided by the operator and will follow 
usual practice for VT ablation. 
We will use a multipolar mapping catheter, in order to create a high-density map and gain as detailed 
information as possible about the substrate. Multipolar catheters are used as standard of care for VT mapping 
and ablation in our institution and most other high-volume specialised centres. The 3D computational model 
will be merged with the traditional 3D electroanatomical map generated during the VT ablation. Particular care 
will be taken when mapping the points of interest from the computational prediction to assess their particular 
electrophysiological properties. This will allow us to assess variables such as wavefront directionality, 
amplitude and morphology to see if they have a particular signal which marks them as important in sustaining 
the VT circuit and therefore conferring their importance in predicting potential sites for ablation. By overlaying 
the computer generated model onto the invasive map, we will be able to corroborate the predicted model’s 
findings with traditional mapping techniques. 
Ablation technique will be as per standard of care and the order of ablation will be guided by standard invasive 
mapping. However if we ablate at an area which the MRI-model also predicted to be important, we will re-map 
the surrounding myocardium to see if there has been an effect of the electrophysiological properties of these 
distant sites following ablation of the predicted sites.. The computer model will not alter the extent of ablation 
and will not lead to ablation of any areas which wouldn’t otherwise be ablated using traditional mapping.  

V1.1 12.02.2021             11 
 
 
The patients will be followed up as standard of care at 3, 6 and 12 months following their procedure with ICD 
interrogation, or in the case of absence of an ICD an extended ECG monitoring period. We will use this to 
assess frequency and duration of recorded arrhythmias time to recurrence of ventricular arrhythmia as well as 
frequency of therapy delivered by the device. We will also use data from their clinical consultation to evaluate 
their symptoms and response to the procedure including any adverse events. 
 
STUDY FLOW CHART 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6 
STUDY SETTING 
The study setting is a large tertiary centre hospital in London, St George’s University Hospitals NHS Foundation 
Trust which serves a population of around 1.3 million. It also receives referrals from district general hospitals 
around it including in London, Surrey and Sussex. The patient population is diverse and referrals are made to a 
 
 
Pre-ablation 
 
Post- ablation 
Sustained, monomorphic 
scar-dependent VT. 
LGE cardiac MRI 
Computational model of 
predicted critical VT sites 
EP study 
Co-registration of 
computational model with 
electroanatomical map 
VT ablation 
Follow up at 3, 6 and 12 
months with rhythm analysis 
and clinical consultation 
VT ablation 

V1.1 12.02.2021             12 
 
specialist arrhythmia clinic from which suitable patients can be identified. The majority of recruited patients 
are expected to be outpatients who are symptomatic from VT despite optimal medical therapy. This will allow 
sufficient time to perform the cardiac MRI and to generate the computational model. In some scenarios, 
emergency admissions with symptomatic VT may be included if they are suitable for inpatient VT ablation and 
there is sufficient time for the MRI and computation analysis to take place prior to the VT ablation. All patient 
recruitment, consent, imaging and ablation will be performed at the single study centre.  
 
The MRI images will be transferred to Johns Hopkins University in Baltimore, Maryland, USA for computational 
analysis and predictive modelling. This information will be securely transferred and on completion will be 
transferred back to the investigators for analysis. 
 
7 
SAMPLE AND RECRUITMENT 
7.1.1 
Inclusion criteria  
• 
Adult inpatients admitted to St George’s Hospital London with sustained ventricular tachycardia or 
outpatients identified from the arrhythmia clinic with significant monomorphic ventricular tachycardia 
noted on cardiac monitoring who: 
o Have sustained, monomorphic scar-dependent ventricular tachycardia 
o Are symptomatic 
o Failed, unable or unwilling to tolerate anti-arrhythmic medications 
o Able to have a cardiac MRI 
o Have a life expectancy > 1 year 
o At least 40 days following a myocardial infarction 
7.1.2 
Exclusion criteria  
• 
Patients under the age of 18 
• 
Patients who are unable to give informed consent 
• 
Pregnant patients 
• 
Unable to have cardiac MRI 
• 
Prohibitive procedural risk 
• 
Unable to tolerate the ablation procedure due to haemodynamic instability 
7.2.1  Size of sample 
We aim to recruit at least 20 consecutive patients. This is larger than any previous study in this area and will 
provide sufficient numbers to assess if the computational modelling is accurate in predicting sites of myocardium 
critical to sustaining ventricular tachycardia.  
The current frequency of ventricular tachycardia ablation is roughly one patient every two to three weeks. Allowing 
for incomplete patient uptake to the study, this should permit the required number of patients to be recruited 
within 20 months. This allows sufficient time for data analysis and writing up of the results. 
 
 
 
 
7.2.2  Sampling technique 
 

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Given the low volume of patients presenting with the appropriate ventricular arrhythmia, and the small sample 
size being targeted, the sampling technique will be of consecutive recruitment over a period estimated to be 20 
months.  
 
7.3.1 
 Recruitment 
Potential patients will be identified from two sources: first, those presenting to the arrhythmia clinic at the 
primary centre with findings of sustained ventricular tachycardia who are symptomatic despite medical 
therapy. Clinicians at this arrhythmia clinic will be members of the study team. Suitable patients identified in 
this way would be referred for ventricular tachycardia ablation as standard of care. These patients will be 
highlighted to the site research team who are also part of patient clinical team who will then proceed to 
perform eligibility screening using the inclusion / exclusion criteria. The patients will have the study discussed 
with them and if consent is gained, they will be enrolled. 
The second group of patients are those who present acutely to hospital (either directly to the primary study 
centre or referred from a different hospital for further management). The study investigators will be involved 
in the care of these patients as standard of clinical practice. However, if for any reason the study investigators 
are not involved in the care of the particular patient, the patient’s clinical team can highlight and approach 
these potential participants before referring them directly to the study investigators. The same inclusion / 
exclusion criteria would apply and the investigators may explain the study to them, offer enrolment and gain 
consent for inclusion whilst inpatients. 
The investigations and procedures, including the cardiac MRI and mapping and ablation of the tachycardia, are 
considered standard of care. Therefore no extra journeys, follow up appointments or costs will be incurred by 
the patients who choose to participate in the study. 
 
 
7.3.2 Consent 
 
Informed consent will be obtained in writing after full discussion of the Patient Information Sheet. If necessary, 
the consent process may be remote, for example if the patient’s initial consultation is via telephone. If this is 
the case, then the patient information sheet and consent form will be emailed or posted to patient and the PIS 
discussed by phone with patient. If happy, the patient will sign the consent form and consent will be 
documented in the notes. The patient will then email or post the partially signed consent form back to the 
study investigators, who will re-confirm consent over the phone and countersign the consent form. A copy of 
the fully signed consent form will be returned to the patient. 
Consent will be required for the use, storage and sharing of the data collected from the MRI as well as the 
mapping and ablation data obtained at the time of catheter ablation. Written information about the objectives, 
methods and aims of the study will be provided and sufficient time will be allowed for the patient to make an 
informed decision, ask questions and consult a legal representative if requested. Only those patients deemed 
to have capacity will be approached for inclusion into the study. 
Risks and benefits of the MRI as well as the ablation are obtained as standard of care for this group of patients by 
the clinical team.  
 
7.3.3 Data collection tool  
Each patient enrolled into the study will have a unique study trial ID number. This will allow the de-
identification of all subsequent data associated with that patient. All subsequent data collection will be 

V1.1 12.02.2021             14 
 
transcribed next to this trial ID number in electronic format, through Microsoft Excel spreadsheets. There will 
be an electronic link document which will contain the patient identifiable information and the trial ID numbers, 
but no other data. This will be electronic and kept secure on password protected computers at St George’s 
University, to which only the study investigators will have access. The link document will be kept until the 
results of the study have been analysed and written up. We anticipate that this will be complete within 3 years. 
The patient’s consent will be kept in a locked area in the University. 
Routine baseline demographics, risk factors and investigation results such as the patient’s ECG and 
echocardiogram findings will be collected, de-identified and added to the Excel sheet. Primary data generated 
by the study will include the 3D computational model generated from the patient’s cardiac MRI as well as data 
from the VT ablation including the baseline ECG, and electrograms during tachycardia and baseline rhythm. 
Individual data points from various endocardial and epicardial points will be collected by the mapping catheters 
which will contain information such as voltage, activation time, electrogram amplitude, directionality and 
morphology. Pacemaps and entrainment maps will be collected if these techniques are used. This data is 
generated by the cathlab software – Precision and Carto and will be de-identified, then transferred via USB 
stick to the password-protected excel spreadsheet with the appropriate trial ID number.  
The data generated from the study will be stored for the duration of the study (3 years) and then archived onto 
secure, password-protected hard-drives. Paper documents will be archived with Iron Mountain for 5 years. 
 
 
 
 
 
8 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
The aims and methods of the research minimise extra investigations or procedures to the participant as well as 
confer no extra perceived risk by participating in the study. We believe that by using our study design the 
procedure will be lengthened by around 10% in duration, however due to our design, there will be no 
additional dose of ionising radiation above standard of care. The extra 10% duration (roughly 30 minutes) may 
slightly increase the risk of standard anaesthetic complications such as venous thromboembolism, pneumonia, 
confusion and allergic reaction. This will be mentioned on the PIS. The computational model will not influence 
the ablation set that the patient receives. We have set out clear inclusion and exclusion criteria to ensure that 
enrolled patients are appropriate and not coerced into taking part in the study. The interventions that the 
patient undergoes fall within internationally recognised guidelines for treatment of these patients. It has the 
support of the wider multidisciplinary team at the centre where it is being carried out. 
 
 
 
 
8.1 
Assessment and management of risk 
 
The research protocol is predominantly within established standards for patients presenting with sustained 
monomorphic scar-dependent ventricular tachycardia. Undergoing a cardiac MRI and endocardial / epicardial 

V1.1 12.02.2021             15 
 
mapping and ablation for patients unresponsive to, intolerant of, or unwilling to use anti-arrhythmic therapy, is 
within the scope of international guidelines for these patients. Therefore, the protocol incurs no additional 
procedure for the patient. The extra time spent with co-registration of the computationally-generated virtual 
heart with the invasively-acquired 3D EAM, the extra mapping of the in silico predicted targets and remapping 
after ablation of the predicted sites, will mean that the procedure is only minimally extended beyond standard 
care, and by no more than a maximum of 10% of the usual duration. We propose that this does not generate a 
particular increase in risk compared to a standard VT ablation beyond the increased chance of complication 
from general anaesthetic. The overall goal of the ablation will remain the same whether the patient is included 
in the study or not – to render the patient non-inducible to VT. We will not ablate any area of the heart that 
wouldn’t warrant it during a standard VT ablation and no area that is deemed important will be left un-ablated 
if the model does not predict it to be important. Therefore there is no expectation that they will be at higher 
risk of recurrence from participating in this study. 
The data collection and sharing with Johns Hopkins University generates data protection requirements which 
will be met in accordance to the Data Protection Act of 2018. All patient information will be stored securely on 
restricted-access University storage and will be transferred securely only to the research team members 
directly involved in the study. 
 
 
8.2  
 Research Ethics Committee (REC) and other Regulatory review & reports 
Before the start of the study, a favourable opinion will be sought from an appropriate REC for the study 
protocol, informed consent forms and other relevant documents e.g. advertisements.  
For HRA- NHS REC reviewed research 
• 
Substantial amendments that require review by NHS REC will not be implemented until that 
review is in place and other mechanisms are in place to implement at site.   
• 
It is the Chief Investigator’s responsibility to produce the annual reports and submit the REC 
within 30 days of the anniversary date on which the favourable opinion was given, and 
annually until the study is declared ended. 
• 
The Chief Investigator will notify the REC of the end of the study within one year after the end 
of the study. 
If the study is ended prematurely, the Chief Investigator will notify the REC, including the reasons for the 
premature termination. 
Regulatory Review & Compliance  
The study has approval from the main study centre (St George’s Hospital NHS foundation Trust). 
For any amendment to the study, the Chief Investigator will submit information to the appropriate body in 
order for them to issue approval for the amendment. The Chief Investigator or designee will work with sites 
(R&D departments at NHS sites as well as the study delivery team) so they can put the necessary arrangements 
in place to implement the amendment to confirm their support for the study as amended. 
Amendments  
Any amendments will be brought up with the HRA and SGREC in accordance with their policy and in writing. 
The funding body will also be notified. The decision to amend the protocol and whether it is substantial or non-
substantial will be made by the chief investigator as well as the other contributors in the group in a 
collaborative fashion. The chief investigator will keep record of the amendment history.  

V1.1 12.02.2021             16 
 
8.3         Peer review 
The protocol has been reviewed and agreed upon by two expert reviewers – Professor Elijah Behr and Dr Michael 
Papadakis. 
 
 
8.4  
Patient & Public Involvement 
Other than patient participation, no public involvement is required in the design, management, undertaking, 
analysis or dissemination of this study. The trial is listed on ClinicalTrials.gov under trial ID: NCT04632394 
 
8.5 
Protocol compliance  
Protocol deviations, non-compliances, or breaches are departures from the approved protocol. 
All protocol deviations must be adequately documented on the relevant forms and reported to the Chief 
Investigator and Sponsor immediately.  
Deviations from the protocol which are found to frequently recur are not acceptable, will require immediate 
action and could potentially be classified as a serious breach. 
 
8.6 
Data protection and patient confidentiality  
Data within this study will be compliant with the 2018 Data Protection Act as well as the EU General Data 
Protection Regulation (GDPR). Study data will be collected solely by the study investigators. When an individual 
is recruited to the study, we will assign them a trial ID number, against which all data collection will be 
recorded as an Excel spreadsheet. No patient identifiable information will be contained in this document. A link 
document will be created which will contain the trial ID number as well as the patient name and medical record 
number but no other data from the study. This will be password-protected, stored on secure computers and 
only accessible by the study investigators. We will collect demographic data from their medical records 
including age, gender, and ethnicity. We will also collect date regarding the patient’s cardiovascular risk factors 
and pertinent cardiac investigations such as ECG and echocardiography results. Following the cardiac MRI, the 
files will be stored as DICOM (Digital Imaging and Communications in Medicine) images and de-identified image 
files will be sent with end-to-end encryption and stored securely at Johns Hopkins University. The computer 
generated model will be created and sent back to us with end-to-end encryption. Johns Hopkins University will 
securely retain the anonymised MRI-model for as long as is required to complete the study. The de-identified 
output from Johns Hopkins will be kept on secure, password protected computers. The outputs from the VT 
ablation (discussed above) will be downloaded from the cath lab software following the ablation. Again these 
will be stored in a database with the corresponding trial ID number assigned to the patient so that they remain 
anonymous. The results of the follow up 3, 6 and 12 month rhythm monitor will be added to the same 
database as well as an objective assessment of symptoms from the clinical consultation. Data will be stored 
securely on password protected University hard-drives to which only the study investigators will have access. 
Data will be sent and stored securely, with only necessary parties having access to the data. The data will only 
be stored as long as is necessary to complete the study, prior to being archived. The data custodian will be the 
Principal Investigator.  
8.7 
Indemnity 
 
St George’s University Hospitals NHS Foundation Trust sponsored research: 
St Georges University Hospitals NHS Foundation Trust is party to NHS Litigation Authority (NHSLA) / NHS 
Resolution. As an NHS body it is liable for clinical negligence and other negligent harm to individuals covered by 

V1.1 12.02.2021             17 
 
their duty of care. NHS Institutions employing researchers are liable for negligent harm caused by the design of 
studies they initiate. 
 
 
8.8 
Access to the final study dataset 
The study investigators will all have access to the final dataset. A secondary analysis is not envisaged, but if 
required, would only be undertaken with the consent of the participants. 
 
 
9 
DISSEMINIATION POLICY 
9.1  
Dissemination policy 
The data arising from the study will be owned by the study sponsor, who will have the right to publish the data. 
On completion of the study, the data will be analysed and tabulated and a Final Study Report generated, which 
will be accessible by means of peer-reviewed research articles as well as from the Chief Investigator. The 
funding body will be acknowledged within publication of the data. Participants in the study will be able to have 
access to the results of the study, once completed, if requested. 
Publication: “Any activity that discloses, outside of the circle of trial investigators, any final or interim data or 
results of the Trial, or any details of the Trial methodology that have not been made public by the Sponsor 
including, for example, presentations at symposia, national or regional professional meetings, publications in 
journals, theses or dissertations.” 
All scientific contributors to the Trial have a responsibility to ensure that results of scientific interest arising from 
Trial are appropriately published and disseminated. The Sponsor has a firm commitment to publish the results of 
the Trial in a transparent and unbiased manner without consideration for commercial objectives.  
To maximise the impact and scientific validity of the Trial, data shall be consolidated over the duration of the trial, 
reviewed internally among all investigators and not be submitted for publication prematurely. Lead in any 
publications arising from the Trial shall lie with the Sponsor in the first instance.  
Before the official completion of the Trial,  
All publications during this period are subject to permission by the Sponsor. If an investigator wishes to publish a 
sub-set of data without permission by the Sponsor during this period, the Steering Committee/the Funder shall 
have the final say.  
Exempt from this requirement are student theses that can be submitted for confidential evaluation but are subject 
to embargo for a period not shorter than the anticipated remaining duration of the trial.      
Up to 180 days after the official completion of the Trial  
During this period the Chief Investigator shall liaise with all investigators and strive to consolidate data and results 
and submit a manuscript for peer-review with a view to publication in a reputable academic journal or similar 
outlet as the Main Publication.  
• 
The Chief Investigator shall be senior and corresponding author of the Main Publication.  
• 
Insofar as compatible with the policies of the publication outlet and good academic practice, the other 
Investigators shall be listed in alphabetic order.  
• 
Providers of analytical or technical services shall be acknowledged, but will only be listed as co-authors 
if their services were provided in a non-routine manner as part of a scientific collaboration.  

V1.1 12.02.2021             18 
 
• 
Members of the Steering Group shall only be acknowledged as co-authors if they contributed in other 
capacities as well.   
• 
If there are disagreements about the substance, content, style, conclusions, or author list of the Main 
Publication, the Chief Investigator shall ask the Steering Group to arbitrate.     
 
Beyond 180 days after the official completion of the Trial  
After the Main Publication or after 180 days from Trial end date any Investigator or group of investigators may 
prepare further publications.  In order to ensure that the Sponsor will be able to make comments and suggestions 
where pertinent, material for public dissemination will be submitted to the Sponsor for review at least sixty (60) 
days prior to submission for publication, public dissemination, or review by a publication committee. Sponsor’s 
reasonable comments shall be reflected. All publications related to the Trial shall credit the Chief and Co-
Investigators as co-authors where this would be in accordance with normal academic practice and shall 
acknowledge the Sponsor and the Funders.    
 
9.2          Archiving Arrangements  
Each site will be responsible for their onsite level study archiving. The trial essential TMF along with any central 
trial database will be archived in accordance with the sponsor SOP 
 
9.3  
Authorship eligibility guidelines and any intended use of professional writers 
Authorship will be granted to those who have had a significant contribution to the design, implementation and 
analysis of the study. No professional writers are expected to be required. 
 
10 
REFERENCES 
1.  
Schalij MJ, van Rugge FP, Siezenga M, van der Velde ET: Endocardial Activation Mapping of Ventricular 
Tachycardia in Patients. Circulation, 1998; 98:2168–2179.  
2.  
Stevenson WG, Friedman PL, Sager PT, et al.: Exploring postinfarction reentrant ventricular tachycardia 
with entrainment mapping. Journal of the American College of Cardiology, 1997; 29:1180–1189.  
3.  
Josephson ME, Anter E: Substrate Mapping for Ventricular Tachycardia Assumptions and 
Misconceptions. JACC: Clinical Electrophysiology, 2015; 1:341–352.  
4.  
SACHER F, LIM HS, DERVAL N, et al.: Substrate Mapping and Ablation for Ventricular Tachycardia: The 
LAVA Approach. Journal of Cardiovascular Electrophysiology, 2015; 26:464–471.  
5.  
Wichter T, Paul M, Eckardt L, et al.: Arrhythmogenic right ventricular cardiomyopathy: Antiarrhythmic 
drugs, catheter ablation, or ICD? Herz. 2005, pp. 91–101.  
6.  
Cesario DA, Vaseghi M, Boyle NG, et al.: Value of high-density endocardial and epicardial mapping for 
catheter ablation of hemodynamically unstable ventricular tachycardia. Heart Rhythm, 2006; 3:1–10.  
7.  
Maccabelli G, Mizuno H, Della Bella P: Epicardial ablation for ventricular tachycardia. Indian Pacing and 
Electrophysiology Journal, 2012; 12:250–268.  
8.  
Prakosa A, Arevalo HJ, Deng D, et al.: Personalized virtual-heart technology for guiding the ablation of 
infarct-related ventricular tachycardia. Nature Biomedical Engineering, 2018; 2:732–740.  

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9.  
Arevalo HJ, Vadakkumpadan F, Guallar E, et al.: Arrhythmia risk stratification of patients after 
myocardial infarction using personalized heart models. Nature Communications, 2016; 7.  
10.  
Prakosa A, Malamas P, Zhang S, et al.: Methodology for image-based reconstruction of ventricular 
geometry for patient-specific modeling of cardiac electrophysiology. Progress in Biophysics and 
Molecular Biology, 2014; 115:226–234.  
11.  
Bayer JD, Blake RC, Plank G, Trayanova NA: A novel rule-based algorithm for assigning myocardial fiber 
orientation to computational heart models. Annals of Biomedical Engineering, 2012; 40:2243–2254.  
12.  
Zahid S, Whyte KN, Schwarz EL, et al.: Feasibility of using patient-specific models and the “minimum cut” 
algorithm to predict optimal ablation targets for left atrial flutter. Heart Rhythm, 2016; 13:1687–1698.  
13.  
Zghaib T, Ipek EG, Hansford R, et al.: Standard Ablation Versus Magnetic Resonance Imaging-Guided 
Ablation in the Treatment of Ventricular Tachycardia. Circulation: Arrhythmia and Electrophysiology, 
2018; 11:1–6.  
14.  
Dickfeld T, Tian J, Ahmad G, et al.: MRI-guided ventricular tachycardia ablation integration of late 
gadolinium-enhanced 3D scar in patients with implantable cardioverter- defibrillators. Circulation: 
Arrhythmia and Electrophysiology, 2011; 4:172–184.  
15.  
Shivkumar K: Catheter ablation of ventricular arrhythmias. New England Journal of Medicine, 2019; 
380:1555–1564.  
  
 
 
11.1 
Appendix 1- Required documentation  
CVs of research team – see separate attachment 
Patient Information Sheet – see separate attachment 
 
13 Appendix 3 – Amendment History 
Amendment 
No. 
Protocol 
version no. 
Date issued Author(s) of changes 
Details of changes made 
 
1.0 
04/12/2020 Michael Waight 
Magdi Saba 
Anthony Li 
First submission 
1 
1.1 
12/02/2021 Michael Waight 
Magdi Saba 
Anthony Li 
Revisions following REC meeting.  
Clarified that MRI-model does not alter 
order of ablation. 
Clarified that JHU will retain MRI model 
until study is complete. 
Clarified extra GA risks associated with 
longer procedure time