A Randomized Controlled Study to Evaluate the Reliability of Electrographic Flow™ (EGF) Mapping Algorithm Technology to Identify Sources of Atrial Fibrillation and Guide Ablation Therapy in Patients With Persistent Atrial Fibrillation
Phase: NA
Conditions: Atrial Fibrillation, Persistent
Sponsor: Cortex

 
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FLOW-AF  
Clinical Study Protocol 
A randomized, controlled study to evaluate the reliability of the Ablacon Electrographic FLOW 
(EGF) algorithm technology (Ablamap® Software) to identify AF sources and guide ablation 
therapy in patients with persistent atrial fibrillation 
 
 
Brief Title 
FLOW-AF: A Study to Evaluate the Ablacon Electrographic 
FLOW EGF Technology 
 
Clinicaltrials.gov identifier 
NCT04473963 
 
Device Name:  
Ablamap® Electrographic Flow Algorithm Technology 
 
Protocol No 
CP-001/CP-002 
 
Revision Number 
REV C 
 
Release Date:   
09 November 2020 
 
 

 
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Sponsor 
Ablacon 
 
Business Address 
Ablacon, Inc. 
4800 Wadsworth Blvd, Suite 310 
80033 Wheat Ridge, CO 
USA  
 
Principal Investigator(s): 
Petr Neuzil, MD 
Na Homolce Hospital 
Roentgenova 37/2 
150 00 Prague 5 
Czech Republic 
 
 
 
 
 

 
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1 
PROTOCOL SUMMARY 
Objective 
The objective of this study is to evaluate the reliability of the 
Ablacon Electrographic Flow (EGF) algorithm technology 
(Ablamap® Software) to identify AF sources and guide ablation 
therapy in patients with persistent atrial fibrillation 
Test Device 
Ablacon Electrographic Flow Algorithm Technology (Ablamap® 
Software) 
Study Design 
The study is a prospective, randomized, controlled multi-center 
study.  
Planned Subject Sample 
Size 
A maximum of 100 subjects will be enrolled in this study. 
No. of Sites 
Subjects will be enrolled at up to five (5) investigational sites in 
Europe. 
Primary Safety Endpoint 
Freedom from serious adverse events (SAEs) related to the 
procedure through 7 days following the Randomization procedure.    
Primary Efficacy 
Endpoint 
Acute procedure success defined as the ability to successfully ablate 
AF sources identified by the Ablacon EGF algorithm  
Secondary Efficacy 
Endpoints 
• Consistency of sources identified by the Ablacon EGF 
algorithm between the randomization procedure and any 
applicable subsequent EGF-guided ablation procedures as 
assessed by remapping of the atria and the algorithm's 
ability to reproduce sources identified by a previous 
procedure 
• Freedom from documented episodes of atrial fibrillation 
recurrence following the blanking period (90 days post 
procedure through 12 months). 
• Total number of EGF source ablations  
• Total time of EGF source ablations 
• Total fluoroscopy time and dose  
• Overall procedure time  
Inclusion Criteria 
 
1. Suitable candidate for intra-cardiac mapping and ablation of 
atrial arrhythmias. 
2. Above eighteen (18) years of age or of legal age to give 
informed consent specific to state and national law.   
3. Subjects with a history of documented symptomatic, 
persistent or longstanding persistent atrial fibrillation < 36 
months. 
4. Subject agrees to comply with study procedures and be 
available (geographically stable) for follow-up visits for at 
least 12 months. 

 
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5. Treatment of atrial fibrillation with ablation therapy 
presenting with recurrent symptoms of AF (not applicable to 
De Novo subjects) 
Exclusion Criteria 
1. LA diameter > 5.5 cm. 
2. Left ventricular ejection fraction (LVEF) < 35%. 
3. Presence of intramural thrombus, tumor or abnormality that 
precludes vascular access, catheter introduction or 
manipulation. 
4. Coagulopathy, bleeding diathesis or suspected procoagulant 
state. 
5. Known allergies or intolerance to anticoagulant and 
antiplatelet therapies to be used in conjunction with the 
study or contrast sensitivity that cannot be adequately pre-
treated prior to the ablation procedure. 
6. Positive pregnancy test results for female patients of 
childbearing potential or breast feeding. 
7. Acute or chronic medical condition that in the judgment of 
the investigator would increase risk to the patient or deem 
the patient inappropriate to participate in the study. 
8. Mitral valve stenosis and/or severe mitral regurgitation. 
9. Valvular atrial fibrillation. 
10. Prosthetic valves. 
11. NYHA Class IV. 
12. History of MI within 3 months prior to procedure. 
13. Atrial septal defect (ASD) or left atrial appendage (LAA) 
closure device. 
14. Atrial fibrillation from a reversible cause (e.g., surgery, 
hyperthyroidism, sarcoidosis or pericarditis). 
15. Life expectancy < 12 months based on medical history or 
the medical judgement of the investigator.  
16. Presence of any transvenous pacing, ICD or CRT leads. 
Follow-up Visit Schedule 
Subject Visit Description 
Timeframe / Visit Window 
Randomization Procedure 
Day 0 
Pre-Discharge  
Prior to discharge from hospital 
following ablation procedure 
7 days Follow-Up (Phone) 
7 ± 3 days 
3 Month Follow-Up 
90 ± 15 days 
6 Month Follow-Up 
180 ± 30 days 
12 Month Follow-up 
365 ± 45 days 
Unscheduled Visits 
As needed/necessary 
 

 
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1 INTRODUCTION 
Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with increased 
mortality, morbidity and impaired quality of life. Catheter ablation has become the standard of 
care for symptomatic patients with drug-refractory AF and the cornerstone of ablation is the 
electrical isolation of the pulmonary veins (pulmonary vein isolation = PVI).1 Long-term 
effectiveness of an approach based on PVI as the sole ablation strategy is reported to be high for 
patients with paroxysmal AF (81.6% at 12 months, 73.8% at 24 months, and 68.1% at 36 months).2 
However, the success rate of PVI is significantly lower with only up to 51% in patients with 
persistent AF.3 It is assumed that this is due to the fact that persistent AF is often driven by focal 
and reentrant activity in the atrial substrate rather than in the pulmonary veins.4 Accurate, enhanced 
mapping techniques that can localize those extra PV sources are essential to identify and guide 
ablation of these sources independently from PVI.  
Narayan, et al., used a 64 pole-basket catheter to map AF using unipolar electrograms recorded in 
the right and the left atrium to construct spatiotemporal source maps.5 The technology was called 
Focal Impulse and Rotor Modulation (FIRM). Compared with patients undergoing conventional 
AF ablation, FIRM guided ablation initially seemed to be associated with a higher acute success 
and a better outcome as demonstrated in non-randomized studies. However, in randomized multi-
center studies, significant benefit of FIRM guided ablation was not confirmed.6 
Since Narayan’s pioneer work several other systems were developed to invasively map rotational 
activities: Biosense Webster Carto Finder uses phase mapping applied to 64-pole basket catheter 
unipolar electrograms to identify rotors in the atrial wall.7 Acutus medical uses dipole density 
mapping with a 48-pole non-contact basket catheter to identify sources of excitation; CardioNXT 
uses small spiral catheters to search for AF-sources based on typical source pattern cross-
correlation with coronary sinus catheter signals; Volta Medical detects dispersion of activation 
maps in bipolar electrogram signals recorded using the PentaRay catheter with five splines and 20 
poles.8,9,10 However, none of these newer mapping systems have demonstrated the clinical 
relevance of these extra-pulmonary vein sources of excitation in the atrial myocardium over a 
period longer than a few seconds. As such, the ability to identify and ablate relevant non-
pulmonary vein foci/triggers to improve freedom from AF post-ablation has not been achieved to 
date.   
The recently developed Electrographic Flow (EGF) Mapping system (Ablamap® Software, 
Ablacon, Wheat Ridge, CO) is a technology based on a novel algorithm being able to 1) 
discriminate between active sources of excitation and passive rotations, which do not generate 
action potentials; and 2) estimate the average activity of such a source during a time interval such 
as one minute.11 It has been shown that only those sources that are generating excitation and that 
are active more than a quarter of the time are significant predictors for AF recurrence after PVI.12 
The EGF system uses a velocity vector matrix created through an optical flow analysis applied on 
surface voltage movies created using a minimal energy algorithm from endocardial unipolar 
electrograms. The analysis is conducted with the 64-electrode mapping basket catheter, which was 
also used for FIRM-guided rotor mapping.  
The goal of this clinical trial is to evaluate this novel mapping software for identifying AF sources 
in humans with persistent AF to optimize ablation success in this challenging and heterogeneous 
patient population. To date no EGF-guided ablation of AF sources has been performed in a 
controlled trial. 

 
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1.1 
Test Device Description 
The Ablacon, Inc. Ablamap® Software is an electrophysiological mapping software application 
designed to analyze the flow of excitation in cardiac tissue. The software uses an optical flow 
algorithm to process recorded files of electrocardiogram (ECG) signals from multiple-electrode 
mapping catheters (e.g. basket catheters) by transforming the time domain waveform information 
from all electrodes into space domain information and calculating velocity vectors of the 
electrographic action potential flow (EGF) for each point in space.  
 
The output is a set of files that graphically depict flow directions (velocity vectors) and sources 
where the flow is generated. The software discriminates between sources that may be focal or 
rotational and passive rotations that are not sources; detects spatial and temporal stability of 
sources; and defines the activity of sources as the percentage of time a source is at its maximum 
stability.  
 
The Ablamap® Software is stand-alone software installed on a standard, commercially available 
desktop or laptop computer. The software processes ECG data files that have been saved on a USB 
memory device, the computer, or a data server. The software does not control or interface with any 
medical device. There is no user or patient contact.  
 
The Ablamap® Software is an innovative AF mapping device compared with current devices on 
the market in that it can quantify the activity of rotors or focal impulses, which are sources of atrial 
fibrillation and distinct from passive rotors, which are not. It also identifies focal impulses, which 
are sources that break across/through the atrium wall. Other system(s) cannot quantitatively 
analyze active and passive rotations and struggle to consider focal impulses because they do not 
rotate.  The quantitative analysis allows monitoring of AF source behavior during therapy guidance 
and ultimately verification of successful ablations (Bellmann et al 2019). 
1.2 
Intended Treatment Population 
The Ablamap® Software is intended to treat patients with atrial fibrillation for whom 
electrophysiology procedures have been prescribed.   
 
2 STUDY PROTOCOL 
2.1 
Objective 
The objective of this study is to evaluate the reliability of the Ablacon Electrographic Flow (EGF) 
algorithm technology (Ablamap® Software) to identify AF sources and guide ablation therapy in 
patients with persistent atrial fibrillation. 
2.2 
Primary Endpoints 
The primary endpoint events for this trial to assess the safety and effectiveness of the Ablamap® 
Software System to guide therapy for the treatment of persistent atrial fibrillation are as follows: 
 

 
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• Primary Safety Endpoint: Freedom from serious adverse events (SAEs) related to the 
procedure through 7 days following the Randomization procedure.      
• Primary Effectiveness Endpoint: Acute procedure success defined as the ability to 
successfully ablate AF sources identified by the EGF algorithm. 
2.3 
 Secondary Endpoints 
• Consistency of sources identified by the Ablacon EGF algorithm between the 
Randomization procedure and any applicable subsequent EGF-guided ablation 
procedures 
• Freedom from documented episodes of AF recurrence following the blanking period (90 
days post-ablation) through 12 months. 
• Total number of EGF source ablations  
• Total time of EGF source ablations 
• Total fluoroscopy time and dose  
• Overall procedure time  
 
2.4 
Study Design 
The FLOW-AF study is a prospective, multi-center study conducted to assess the safety and 
efficacy of the Ablamap® Software System for patients with a history of persistent atrial 
fibrillation. This study will enroll up to 100 subjects.  Patients that present with persistent atrial 
fibrillation, meet eligibility, and have had a previous ablation procedure prior to being enrolled in 
the study will be eligible for enrollment.  All subjects must be in AF at the time of the procedure.   
 
2.5 
Enrollment/Screen Failures 
A subject is considered enrolled after signing the informed consent.  All enrolled subjects will then 
proceed to complete the screening and baseline tests. If they do not meet the eligibility criteria, 
they will be exited from the study and will not count towards the treated study population. 
 
2.6 
Randomization   
A 1:1 blocked randomization scheme stratified by site will be used for randomization.  Subjects 
will be randomized based on the results of the pre-procedure EGF mapping procedure.  If the 
subject has identifiable AF sources above a pre-specified threshold, the subject will be randomized 
to either: 1) immediate EGF-guided radiofrequency ablation with the Ablamap® Software System; 
or 2) EGF mapping followed by a cardioversion procedure, if required.  If the subject is 
randomized to no treatment, the investigator may choose to cardiovert the subject prior to ending 
the procedure.  Subjects that have no identifiable sources or sources below the threshold will not 
be randomized.  The investigator may choose to ablate those subjects per their standard ablation 
practices.   
 

 
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2.7 
Statistical Analysis 
Continuous variables will be reported as mean ± standard deviation and where appropriate as 
median ± interquartile range. Continuous variables were compared with unpaired t-test, and 
proportions were compared with the chi-square test. A two-sided p-value of < .05 was considered 
to indicate a statistically significant difference. For the secondary effectiveness endpoint of 
freedom from AF from the 90-day post-procedure blanking period through 12 months of follow-
up, the length of time to recurrence of AF in each group was analyzed using Kaplan-Meier 
curves. Data were managed using Microsoft Excel and statistical analyses calculated using 
Microsoft Excel or Matlab. 
 
3 SUBJECT SELECTION 
3.1 
Patient Selection-Criteria for Eligibility 
Subjects enrolled in the FLOW-AF Study should be selected from the investigators’ general patient 
population with a history of persistent atrial fibrillation that meet eligibility criteria.  Patient 
selection may also be performed by review of the medical records of those subjects whom have 
had prior AF treatment with ablation therapy.  Investigators are responsible for screening all 
potential subjects and selecting those who meet the eligibility criteria for the study.   
3.1.1 Study Inclusion Criteria 
 Subjects must have met ALL of the following criteria: 
1. Suitable candidate for intra-cardiac mapping and ablation of arrhythmias. 
2. Above eighteen (18) years of age or of legal age to give informed consent specific to state 
and national law.   
3. Subjects with a history of documented symptomatic, persistent or longstanding AF < 36 
months. 
4. Subject agrees to comply with study procedures and be available (geographically stable) 
for follow-up visits for at least 12 months 
5. Treatment of AF with ablation therapy presenting with recurrent symptoms of AF (not 
applicable to De Novo subjects). 
3.1.2 Study Exclusion Criteria 
Candidates were excluded from the study if any of the following applied: 
• LA diameter > 5.5 cm. 
• Left ventricular ejection fraction (LVEF) < 35% 
• Presence of intramural thrombus, tumor or abnormality that precludes vascular access, 
catheter introduction or manipulation 
• Coagulopathy, bleeding diathesis or suspected procoagulant state 
• Known allergies or intolerance to anticoagulant and antiplatelet therapies to be used in 
conjunction with the study or contrast sensitivity that cannot be adequately pre-treated prior 
to the ablation procedure 

 
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• Positive pregnancy test results for female patients of childbearing potential or breast 
feeding 
• Acute or chronic medical condition that in the judgment of the investigator would increase 
risk to the patient or deem the patient inappropriate to participate in the study 
• Mitral valve stenosis and/or severe mitral regurgitation  
• Valvular AF 
• Prosthetic valves 
• NYHA Class IV 
• History of MI within 3 months prior to procedure 
• ASD or LAA closure device. 
• AF from a reversible cause (e.g., surgery, hyperthyroidism, sarcoidosis or pericarditis) 
• Life expectancy < 12 months based on medical history or the medical judgement of the 
investigator 
• Presence of any transvenous pacing ICD or CRT leads. 
 
3.2 
Study Assessments 
The tests and measurements that were conducted at baseline, during the treatment procedure, and 
during follow-up visits are illustrated in Table 1.    
Table 1. Study Assessments 
Study 
Assessment 
Baseline 
Assessment 
Randomi-
zation 
Procedure 
Discharge 
7 Days 
( +/-3 
Days) 
3 Months 
(+/- 15 
Days) 
6 Months 
(+/- 30 
Days) 
12 Months 
(+/- 45 
Days) 
Informed 
Consent 
X 
-- 
-- 
-- 
-- 
-- 
-- 
Eligibility 
Criteria 
X 
-- 
-- 
-- 
-- 
-- 
-- 
Medical 
history and 
Demographics 
X 
-- 
-- 
-- 
-- 
-- 
-- 
Baseline 
Physical  
X 
-- 
 
 
 
 
 
Medication 
Assessment 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
-- 
X 
 
X 
X 
X 

 
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Study 
Assessment 
Baseline 
Assessment 
Randomi-
zation 
Procedure 
Discharge 
7 Days 
( +/-3 
Days) 
3 Months 
(+/- 15 
Days) 
6 Months 
(+/- 30 
Days) 
12 Months 
(+/- 45 
Days) 
Inclusion/exclu
sion 
X 
-- 
-- 
-- 
-- 
-- 
-- 
Holter Monitor 
 
 
 
 
 
X 
X 
Adverse 
Events 
-- 
X 
X 
X 
X 
X 
X 
Procedural 
Data 
-- 
X 
-- 
-- 
-- 
-- 
-- 
Protocol 
Deviations 
X 
X 
X 
X 
X 
X 
X 
3.3 
Subject Lost to Follow-Up 
The investigator will attempt to contact a subject at least three times prior to designating them as 
lost-to-follow-up subjects; two of these attempts should include attempting to contact subject via 
registered mail.  The investigator will document the date and type of attempted communication 
and will complete the Study Exit/Completion Form when a subject is lost to follow-up.  
3.4 
Subject Withdrawals and Discontinuation 
Subjects have the right to withdraw from the clinical investigation at any time and for any reason 
without prejudice to their future medical care by the investigation team or investigation site. The 
investigator will ask for the reason for their withdrawal and will record all information regarding 
the subject discontinuation on the Study Exit/Completion Case Report Form.  
A subject may be withdrawn from the clinical investigation for the following reasons:  
• Subjects may choose to withdraw from the clinical investigation under the terms of the 
Declaration of Helsinki and their consent documentation without having to give a 
reason;  
• Any unanticipated adverse reaction which is, in the opinion of the Investigator, related 
to the treatment and will endanger the well-being of the subject if treatment is 
continued;  
• Development of any intercurrent illness(es), infection or condition(s) that might 
interfere with the Clinical Investigational Plan;  
• Non-compliance with the clinical investigation procedures deemed by the Investigator 
to be sufficient to cause discontinuation;  
• Any problem deemed by the Investigator to be sufficient to cause discontinuation.  

 
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Investigator will treat all subjects discontinued from the investigation due to an unanticipated 
adverse reaction, directly related to the investigation, until the reaction resolves. 
3.5 
Ethics 
This study will be conducted in conformity with the ethical principles stated in the latest version 
of the Declaration of Helsinki, the applicable guidelines for good clinical practices, MEDDEV 
2.7/4 (Guidelines on Clinical investigations: a guide for manufacturers and notified bodies) and 
2.7/3 (Clinical investigations: serious adverse event reporting), ISO 14155:2011 (Clinical 
Investigation of Medical Devices for Human Subjects – Good Clinical Practice), or the applicable 
local and international regulations, whichever provide the greater protection of the individual.  The 
clinical investigation plan and other relevant documentation shall be submitted to the appropriate 
Ethics Committee for review.  In countries in which additional requirements apply (e.g., 
notification to, or approval from the Competent Authority), the study may start only after all 
regulatory requirements are fulfilled. 
3.6 
Regulatory Considerations 
The study will be reviewed by the relevant Ethics Committees, and by the relevant Competent 
Authority, as applicable. The study will not start without the written approval of the Ethics 
Committee and, where needed, the Competent Authority approval and after the completion of 
any other local regulation requirement. 
3.7 
Confidentiality and Data Protection 
Health data will be recorded and forwarded to the sponsor of the study, and to participating Ethics 
Committees and Competent Authorities, for evaluation as required.  Any information that is 
obtained in connection with this study that can be identified with the subjects will remain 
confidential.  Any data that may be published in scientific journals will not reveal the identity of 
the study participants.   
 
4 
ABBREVIATIONS AND DEFINITIONS 
4.1 
Table of Abbreviations  
Abbreviation 
Definition  
AF 
Atrial Fibrillation 
CA 
Competent Authority 
EC 
Ethics Committee 
EP 
Electrophysiologist 
ICF 
Informed Consent Form 
IFU 
Instructions for use 
IV 
Intra-venous 
LA 
Left Atrium 
LVEF 
Left Ventricular Ejection Fraction 
NYHA 
New York Heart Association 
RA 
Right Atrium 

 
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SAE 
Serious Adverse Event 
 
5 
REFERENCES 
 
1. 
Kirchhof, P., et al., 2016 ESC guidelines for the management of atrial fibrilation 
developed in collaboration with EACTS. Eur Heart J, 2016. 37(38): p. 2893-962. 
2. 
Knight, B.P., et al., Long-term outcomes after ablation for paroxsymol atrial fibrilation 
using the second-generation cryoballon. JACC Clin Electrophysiol, 2018. 11(6). 
3. 
Wouter, R.B., et al., Persistent atrial fibrilation: a systematic review and meta-analysis 
of invasive strategies. Int J Cardiol, 2019. 278: p. 137-43. 
4. 
Cheniti. G., et al., Atrial fibrilation mechanisms and implications for catheter ablation. 
Front Physiol, 2018. 9: p. 1458. 
5. 
Narayan, S.M., et al., Clinical mapping approach to diagnose electrical rotors and focal 
impulse sources for human atrial fibrilation, 2012. 23(5): p. 447-54. 
6. 
Brachmann, J., REAFFIRM: an interim analysis. Cardiac Rhythm News, 2018.  
7. 
Daoud, E.D., et al., Identification of repetative activation patterns using novel 
computational analysis of multielectrode recording during atrial fibrilation and flutter in 
humans. JACC Clin Electrophysiol, 2017. 3(3): p. 207-16. 
8. 
Grace, A., et al., Dipole density mapping of atrial fibrilation. Eur Heart j, 2017. 1(1): p. 
5-9. 
9. 
Kurian, T., et al., Rotors in patients with persistent atrial fibrilation. Card Electrophysiol 
Clin, 2011. 7(1): p. 157-63. 
10. 
Seitz, J., et al., AF ablation guided by Spatiotemporal Electrogram Dispersion Without 
Pulmonary Vein Isolation: A Wholly Patient-Tailored Approach. JACC, 2017. 69(25): p. 
3121-2. 
11. 
Bellmann, B., et al., Velocity characteristics of atrial fibrillation sources determined by 
electrographic flow mapping before and after catheter ablation. Int J Cardiol, 2019. 286: 
p. 56-60. 
12. 
Rillig et al., 2019; https://onlinelibrary.wiley.com/doi/full/10.1111/jce.13869