PROOF: Evaluating the Performance of the KODEX-EPD CRyOballoon Occlusion Feature in Patients With Atrial Fibrillation
Conditions: Atrium; Fibrillation, Ablation
Sponsor: EPD Solutions, A Philips Company

 
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PROOF: Evaluating the Performance of the KODEX-EPD 
CRyOballoon Occlusion Feature in patients with atrial 
fibrillation (CLN-KODEX-0019) 
Clinical Investigation Plan 
 
 
Protocol version: 
4 
Clinicaltrials.gov 
NCT04293198 
Issue Date: 
15-Jul-20 
Clinical Study Sponsor: 
EPD Solutions (a/k/a Philips Medical Systems Nederland B.V.) 
Veenpluis 6 
5684 PC, Best 
The Netherlands 
(Revision History); 
Version 1.0  
2019 Dec 10 
 
Version 2.0 
2020 Jan 21 
 
Version 3.0 
2020 Jul 15 
 
Version 4.0  
2022 Jan 31 
 
 
 
 
 
 

 
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Investigator Protocol Agreement Page 
 
 I confirm agreement to conduct the study in compliance with the protocol. 
 I agree to conduct the study in compliance with the protocol, International Conference on 
Harmonization (ICH) Guidelines for Good Clinical Practice (GCP), patient privacy regulations and 
other applicable regulatory requirements. 
 I acknowledge that I am responsible for overall study conduct. I agree to personally conduct or 
supervise the described clinical study. 
 I agree to ensure that all associates, colleagues and employees assisting in the conduct of the study are 
informed about their obligations. Mechanisms are in place to ensure that site staff receive the 
appropriate information throughout the study. 
 I agree to provide all required data and agree to source document verification of study data with 
patient’s medical records.   
 I agree to report serious and/or unanticipated and/or device related adverse events to Sponsor within 24 
hours from occurrence. 
 
 
Site Name 
 
 
 
 
 
Principal Investigator Name 
 
 
 
 
 
 
Signature 
 
Date 
 
 
 
 

 
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 STUDY COLLABORATORS 
 
 
 
Coordinating Investigators 
Ronald Berger 
Johns’ Hopkins University 
600 North Wolfe Street 
Halsted 570 
Baltimore, MD 21287, USA 
Carlo De Asmundis 
UZ Brussel 
Laarbeeklaan 101 
1090 Jette Brussel, Belgium 
 
rberger@jhmi.edu 
+1 410 614 2751 
Carlo.Deasmundis@uzbrussel.be  
+32(0)494 92 05 84 

 
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TABLE OF CONTENTS 
 
 
 
Study Collaborators................................................................................................................................... 3 
Table of Contents ...................................................................................................................................... 4 
Study Synopsis .......................................................................................................................................... 7 
1. 
Background and Rationale .............................................................................................................. 11 
 
Overview of Disease ................................................................................................................ 11 
 
Arrhythmias ............................................................................................................ 11 
 
Current Treatment Options ..................................................................................... 11 
 
Cryoballoon Ablation Therapy and Technology .................................................... 12 
 
KODEX-EPD System .............................................................................................................. 12 
 
Description of the KODEX-EPD System ............................................................... 12 
 
Intended Use ........................................................................................................... 14 
 
Limitations for use .................................................................................................. 14 
 
Exposure to Study Device ....................................................................................... 14 
 
Study design justification ......................................................................................................... 15 
 
(Pre)Clinical Studies with the KODEX-EPD System ............................................. 15 
 
Relevant Clinical Studies ........................................................................................ 15 
2. 
Experimental Plan ........................................................................................................................... 16 
 
Study Objectives....................................................................................................................... 16 
 
Study Design ............................................................................................................................ 16 
 
Study Schematic ...................................................................................................... 16 
 ............................................................................................................................................... 16 
 ............................................................................................................................................... 16 
 
Primary Endpoints................................................................................................... 17 
 
Secondary and Exploratory Endpoints .................................................................... 17 
 
Study Duration ........................................................................................................ 17 
 
Study Centers ........................................................................................................................... 17 
 
Number of patients ................................................................................................................... 17 
 
Subject Selection and Enrollment ............................................................................................ 17 
 
Study Population and Eligibility ............................................................................. 17 
 
Inclusion Criteria..................................................................................................... 18 
 
Exclusion Criteria ................................................................................................... 18 
 
Withdrawal .............................................................................................................. 18 
 
Study Procedures ...................................................................................................................... 18 
 
Screening and Informed Consent ............................................................................ 18 
 
Intervention ............................................................................................................. 19 

 
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Follow up ................................................................................................................ 21 
 
Discharge & End of Study ...................................................................................... 21 
 
After End of Study .................................................................................................. 21 
 
Schedule of Assessments ........................................................................................ 21 
 
Standardization of Study Procedures ...................................................................... 22 
3. 
Risk/Benefit Analysis ..................................................................................................................... 23 
 
Potential Risk to the Subject .................................................................................................... 23 
 
Potential Benefits to the Subject .............................................................................................. 23 
 
Benefit-Risk Rationale ............................................................................................................. 23 
4. 
Safety Data Collection, Recording and Reporting .......................................................................... 24 
 
Definitions ................................................................................................................................ 24 
 
Adverse Events (AE) .............................................................................................. 24 
 
Adverse Device Effect (ADE) ................................................................................ 24 
 
Serious Adverse Event (SAE) ................................................................................. 24 
 
Serious Adverse Device Effect (SADE) ................................................................. 25 
 
Unanticipated Serious Adverse Device Event (USADE) ....................................... 25 
 
Device Deficiencies ................................................................................................ 25 
 
Adverse Event Classification ................................................................................................... 25 
 
Severity Classification ............................................................................................ 25 
 
Relationship Classification ..................................................................................... 26 
 
Outcome Classification ........................................................................................... 26 
 
Reporting .................................................................................................................................. 27 
 
Reporting of AEs and ADEs ................................................................................... 27 
 
Reporting of SAEs SADEs and USADEs............................................................... 27 
5. 
Statistical Consideration ................................................................................................................. 28 
 
Study Endpoints ....................................................................................................................... 28 
 
Primary Endpoints................................................................................................... 28 
 
Secondary Endpoints............................................................................................... 28 
 
Analysis Sets ............................................................................................................................ 28 
 
Sample Size Considerations ..................................................................................................... 29 
 
Statistical Analysis ................................................................................................................... 29 
 
General Approach/Considerations .......................................................................... 29 
 
Analysis of Key Study Endpoints ........................................................................... 29 
 
Data justification ...................................................................................................................... 29 
 
Missing Data ........................................................................................................... 29 
 
Deviations ............................................................................................................... 30 
6. 
Study Conduct ................................................................................................................................. 30 

 
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Statement of Compliance ......................................................................................................... 30 
 
Source Documents .................................................................................................................... 30 
 
Data Handling and Record Keeping ......................................................................................... 31 
 
Device Accountability............................................................................................. 32 
 
Investigator Responsibilities .................................................................................................... 32 
 
Delegation of Responsibility ................................................................................... 34 
 
Protocol Deviations ................................................................................................. 34 
 
Sponsor Responsibilities .......................................................................................................... 34 
 
Confidentiality ........................................................................................................ 34 
 
Monitoring .............................................................................................................. 35 
 
Insurance ................................................................................................................. 35 
 
Amendments to the CIP .......................................................................................... 35 
7. 
Publications ..................................................................................................................................... 35 
8. 
General Information ........................................................................................................................ 36 
 
Study Contact Information ....................................................................................................... 36 
 
Retention of Records ................................................................................................................ 36 
 
Study Completion/Termination or Suspension of the Study .................................................... 36 
 
Reporting Timelines ................................................................................................ 37 
 
Subject Follow up ................................................................................................... 37 
 
Blinding ................................................................................................................... 37 
9. 
Reference ........................................................................................................................................ 38 
 
 
 

 
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Study Synopsis 
STUDY TITLE 
PROOF: Evaluating the Performance of the KODEX-EPD 
CRyOballoon Occlusion Feature in patients with atrial fibrillation 
STUDY PHASE 
Post-market 
INVESTIGATIONAL 
PRODUCT 
KODEX-EPD System, KODEX-EPD data collection accessories 
INDICATION 
Patients with Atrial Fibrillation 
OBJECTIVE 
Performance of KODEX-EPD PV occlusion feature as compared to 
conventional venographic method of fluoroscopy with contrast dye 
in cryoballoon procedures that is used to guide the procedure. 
Performance will be calculated in terms of accuracy, sensitivity, 
specificity and positive and negative predictive values. In the 
blinded arm of the study, the operator will be blinded for the PV 
occlusion data on the KODEX-EPD system and this data will not be 
used for clinical guidance.  
STUDY DESIGN 
Prospective, multi-center, non-randomized, open label, double arm 
study 
# OF SUBJECTS 
The study will include a maximum of 20 patients per center at 2 
centers in the blinded to KODEX arm of the study. An additional 25 
patients will be included at UZ Brussel in the KODEX guided arm 
of the study. 
 
STUDY DURATION 
18 months 
STUDY POPULATION 
Arrhythmia patients scheduled to undergo a cryo balloon ablation 
procedure for their atrial fibrillation. Both male and female subjects 
who meet all eligibility criteria and give written informed consent 
will be enrolled in the study.  
Inclusion criteria: 
1. Subject must be aged >18 years. 
2. Subject must have signed a written Informed Consent form to 
participate in the study, prior to any study related procedures. 

 
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3. Subject must be willing to comply with the protocol 
requirements. 
4. Subject receives a de novo ablation procedure for treatment 
of atrial fibrillation. 
Exclusion criteria; 
Pregnant women. 
STUDY VISIT SCHEDULE 
AND PROCEDURES 
This is an acute study with no follow-up. 
Before the procedure (Baseline): 
1. Eligibility according to inclusion and exclusion criteria 
2. Obtaining signed Informed Consent Form (ICF) 
3. Demographics 
4. Medical history 
5. Physical examinations 
6. Concomitant medications 
7. Presence/history of atrial fibrillation 
8. Previous and current treatments of atrial fibrillation 
During procedure: 
1. Delivery of standard therapy. The study device will be used 
in the cryoballoon ablation procedure according to the 
instructions for use. PV occlusion will be assessed with the 
KODEX-EPD PV occlusion feature.  
‐ 
Blinded Arm; The physician will be blinded for the 
KODEX-EPD occlusion data and use conventional 
venographic method of fluoroscopy with contrast dye to 
guide the procedure. 
‐ 
KODEX guided Arm; the physician will use the KODEX-
EPD occlusion data to guide the procedure 
2. Confirmation of therapy. Confirm PV isolation using standard 
practice. 
3. Adverse events Reporting. 
PRIMARY ENDPOINTS 
1. The  accuracy, sensitivity, specificity and positive and 
negative predictive values of the KODEX-EPD PV 
occlusion feature as compared to conventional venographic 
method of fluoroscopy with contrast dye that will be used to 
guide the procedure. 
2. The success of the freeze when freeze is initiated based on 
the assessment of the KODEX-EPD PV occlusion feature as 
compared to the success of the freeze when freeze is 

 
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initiated based on the assessment with fluoroscopy and 
contrast dye. 
SECONDARY/ 
EXPLORATORY 
ENDPOINTS 
Procedure data collection: 
 KODEX-EPD data collection 
 Fluoroscopy system data collection 
 Fluoroscopy time 
 Fluoroscopy dose 
 Number of contrast dye injections 
 Contrast dye volume 
 Information on durability of the PV isolation. 
 Time to isolation (TTI)/Success of Isolation 
 Number of ablations per vein 
 Procedure time (skin to skin) 
 
SPONSOR 
EPD Solutions is the sole study sponsor.  This study will be 
conducted according to US 21 CFR 11, 50, 54, 56, 812, ISO 14155: 
2020, the ICH Guidelines for GCP, the Declaration of Helsinki 
(2013) and all other applicable local and national regulations.  The 
study will be registered on www.clinicaltrials.gov.    
 

 
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Acronyms and Definitions 
AE 
Adverse Event 
CRF 
Case Report Form 
EMR 
electronic medical record 
EP 
electrophysiology 
ESI 
Event of Special Interest 
HU 
Healthcare Utilization  
ICF 
Informed Consent Form 
SAE 
Serious Adverse Event 
USADE 
Unanticipated Serious Adverse Device Effect 
 
 
 

 
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1. BACKGROUND AND RATIONALE 
 Overview of Disease 
 Arrhythmias 
Cardiac arrhythmias are common and produce considerable morbidity and mortality and are 
challenging to treati. Symptoms such as dizziness, palpitations, and syncope are frequent complaints 
encountered by family physicians, internists, and cardiologists. In contrast to these ubiquitous 
complaints, which are generally benign, sudden cardiac death remains an important public health 
concern. Statistics from the Centers for Disease Control and Prevention (CDC) have estimated sudden 
cardiac death rates at more than 600,000 per year. Up to 50% of patients have sudden death as the first 
manifestation of cardiac diseaseii.  
Arrhythmias are one of the most complexes, insufficiently studied, and therefore one of the most urgent 
problems of modern cardiology. With a wide introduction in the practice of ECG monitoring by Holter 
as well as the use of individual recorders of electrocardiogram data appeared indicating a much higher 
frequency of cardiac arrhythmiasiii. 
Enormous advances in arrhythmia management have occurred over the 60 years, but important 
challenges remain. Challenges in diagnosis, detection, and risk-stratification include difficulties in 
separating benign from high-risk syncope and pinpointing the underlying causes and inadequate 
identification of sudden-death risk. 
As of 2012, approximately 4.3 million Americans experienced some form of cardiac arrhythmia. 
Annually, 5,750,440 individuals experienced cardiac arrhythmia in the US. Total direct annual 
healthcare cost of cardiac arrhythmia summed up to $US67.4 billion.  Cardiac arrhythmias represent a 
substantial economic burden in the US, especially for the older adult populationiv. 
 Current Treatment Options 
Pharmacologic therapy for arrhythmia is widely used however catheter ablation offers encouraging 
results in the treatment of most cardiac arrhythmias and is considered as a first line therapy by 
international guidelines.v,vi Furthermore in the treatment of Atrial Fibrillation (AF) catheter ablation is 
considered superior regarding freedom of arrhythmia recurrence compared to anti-arrhythmic drug 
therapy.vii,viii,ix 
Current catheter-based therapy utilizes cardiac 3D mapping and navigation systems that were 
introduced more than 20 years ago and allow location of the ablation device within a reconstruction of 
the heart anatomyx,xi,xii,xiii. However, technical limitations specific to each available 3D mapping 
system, such as variability in catheter tip location sensing, alternating location reliability throughout the 
procedure, and the use of costly specialized catheters and additional hardware (e.g. magnets placed 
under the operating table, pose limitations of these systems. Furthermore, all available systems provide 
only an estimate of each individual anatomy, as they do not provide high-quality, real-time 

 
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visualization of anatomical structures, but merely a low-resolution reconstruction. In order to obtain 
more information and a precisely detailed anatomy, time consuming and often costly additional 
imaging such as fluoroscopy, angiography, echocardiography and even pre-procedural computer 
tomography (CT) and magnetic resonance imaging (MRI) is required in many casesxiv.  
In conclusion the current procedures are relatively long, considered highly complex and require 
substantial expertise. In addition specialized catheters and additional hardware is required. The Sponsor 
has identified these challenges and has developed the KODEX - EPD system to address them 
successfully. 
 Cryoballoon Ablation Therapy and Technology 
Pulmonary vein isolation (PVI), by catheter ablation, represents the current treatment for drug-resistant 
AFxv. Due to its ease of use, fast procedures and durability of lesions in a high percentage of PVs 
leading to excellent clinical outcome, Cryoballoon Ablation is a recognized ablation method in patients 
with atrial fibrillationxvi. However, cryoballoon ablation requires extensive fluoroscopic guidance to 
position the balloon catheter at the pulmonary veins often leading to prolonged radiation exposure and 
possible contract induced kidney injury. 
 KODEX-EPD System 
 Description of the KODEX-EPD System 
The KODEX - EPD system is an open platform that uses any validated EP catheter to create real-time 
3D images of the human heart. The KODEX-EPD system takes advantage of the unique dielectric 
properties of biological tissue by inducing anisotropic electrical fields within the patients´ body and 
measuring the resultant subtle electrical field differences on the catheter electrodes as they move in the 
hearts´ chambers. The anisotropic fields are induced by one or multiple sources such as external 
sensors on the body surface and the diagnostic and/or an ablation catheter. The system receives and 
analyzes the electrical field transmission and reflection from all catheter electrodes as they are 
manipulated in the cardiac chambers. Structures such as the endocardial atrial surface, cardiac veins, 
and heart valves cause marked gradients in the electrical field. This “bending of the electrical field” is 
sensed by the system and used to calculate the geometric characteristics of the three-dimensional (3D) 
image. With this technique, the KODEX-EPD System collects anatomic information, without 
immediate physical surface contact, a few millimeters ahead of the catheter electrodes, resulting in a 
certain degree of “far-field imaging”. The catheter serves as an internal distance ruler for scaling of the 
geometry by comparing the known inter electrode spacing versus the voltage difference between the 2 
electrodes. The system records a specific set of electrical field descriptors for each specific position of 
the catheter within the cardiac anatomy and can thereby determine relative positions and distances 
between locations within the chamber. At each location, the electrical field descriptors that the 
KODEX-EPD System acquires are used to reconstruct the chamber geometry.xvii  

 
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 Study device 
The KODEX-EPD system is manufactured by; 
 
Philips Medical Systems Nederland B.V. 
Veenpluis 6 
5684 PC Best 
The Netherlands 
 
The study device hardware consists of a; 
 Processing Unit (version 1.2) 
 Workstation 
 Body Surface pin box 
 Diagnostic Catheter pin box (2x) 
 Recording system pin box (2x) 
 Foot Pedal 
 
 
 
 
 
The most recent commercialized version of the software will be used for the purpose of this study. 
Currently this is software version 1.4.8 
 
The KODEX-EPD system is designed to be used with validated commercially available diagnostic and 
therapeutic catheters. The KODEX-EPD System is supported with dedicated KODEX-EPD sensors and 
catheters activation keys for RF and Cryo ablation interventions. 
 
 
 
Figure 2: Procedural Disposables 
The KODEX - EPD system interfaces with the following commercially available components and 
devices: 
1. Display: shows in real-time, and throughout the procedure, the cardiac chamber’s geometry and all 
indwelling catheters. 
Figure 1: System Overview 

 
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2. RF generator: commercially available RF generators can be connected to the KODEX - EPD 
system PU, which is then connected to the ablation catheter. The following commercially available 
RF generators have been tested with the KODEX - EPD system PU: 
‐ 
KODEX - EPD RF Ablation System 
‐ 
Stockert 70 (Biosense Webster) RF Generator 
‐ 
SmartAblate (Biosense Webster) RF Generator 
‐ 
Maestro 4000 (Boston Scientific) RF Generator 
3. Standard EP diagnostic and ablation catheters: for a full list of commercially available 
compatible catheters, refer to KODEX - EPD system List of Compatible Catheters. 
4. Recording system (includes pacer connection): commercially available recording systems, such 
as Prucka CardioLab EP Recording System (General Electric) or LABSYSTEM PRO (Boston 
Scientific). 
 KODEX-EPD system updates. 
The Instructions for use (IFU) will be provided containing the information on the most current software 
and hardware versions that will be used. Please note that the CIP will not be updated if the 
hardware/software version is updated unless the update results in; 
- 
an updated clinical workflow described in this CIP; 
- 
an updated benefit-risk analysis; 
- 
an update to the study design; 
- 
an update to the data to be collected; 
- 
any other update that would affect the execution of this clinical investigation. 
 
 Intended Use 
The KODEX-EPD system has received FDA approval and CE mark for creating real-time 3D images 
of the human heart using validated commercially available diagnostic and therapeutic catheters. 
For the purpose of this study we will be using the KODEX-EPD system in its intended use as described 
in the User Manual 
 Training and Experience 
Trained sponsor personnel will be responsible for the set-up of the KODEX-EPD system and will 
operate the system during the procedure. Physicians completing the EP procedures will have received 
training on the KODEX-EPD system prior to including the first subject in the study. This training is 
outside the scope of the study. 
 Limitations for use 
There are no special clinical situations that could potentially affect or limit the system performance and 
accuracy.  
  Exposure to Study Device  
The KODEX-EPD System is used to assist the physician during cardiac ablation procedures in patients 
with a cardiac arrhythmia. The patient will be connected to the KODEX-EPD system via the KODEX-

 
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EPD sensors shown in Figure 2. The duration of exposure to the Study device for both the operator and 
patient will be the length of the cardiac ablation procedure. 
 Study design justification 
 (Pre)Clinical Studies with the KODEX-EPD System 
The system’s measurement and localization capabilities have been validated and the location accuracy 
and distance score measurements demonstrated that the system is highly accurate, whereas the 
DURABLE-I clinical study demonstrated safety and efficacy of the KODEX-EPD system. Another 
study demonstrated that the 3D image quality generated by the KODEX-EPD system is noninferior to 
CARTO 3 (Biosense Webster) and accurately detects catheter locationxviii. Clinical data to date has not 
demonstrated any adverse device effects. 
 Cryo Occlusion feature: 
The performance of the Cryo Occlusion feature was validated by means of retrospective analysis of a 
database of KODEX files from routine cases for which the occlusion status on venography was 
available as ground truth. For each occlusion event from the database the occlusion status on KODEX 
was determined with the final version of the KODEX occlusion algorithm and compared against the 
corresponding occlusion status on venography as ground truth. The accuracy of the Cryo Occlusion 
feature for the baseline workflow was 92.1%, and for the injection workflow 90.4%, both of which 
exceed the pre-defined acceptance criteria of ≥ 90%. The clinical acceptability of the workflow of the 
Cryo Occlusion feature was evaluated by replay of a subset of the KODEX files (n=10) from the 
database with a final version of KODEX software. During replay of these cases, five clinical specialists 
filled in a questionnaire in which they each answered questions related to four user requirements of the 
Cryo Occlusion workflow and provided a score using a 5-point Likert scale. The average scores were 
4.0, 4.4, 3.6, and 3.6, and thereby the test was passed because the pre-defined acceptance criteria was 
≥3. 
 Relevant Literature on the KODEX-EPD System Cryoballoon Occlusion feature  
Several manuscripts on the occlusion feature have been published to date, xix,xx,xxi,xxii. reporting that the 
KODEX-EPD Occlusion feature is safe, feasible, and effective in assessing the degree of PV occlusion 
during AF cryoablation.  
 Study Justification 
Current clinical studies on the KODEX-EPD occlusion feature have reported on the safe and effective 
use of the system in standard practice. However, the performance of the KODEX-EPD occlusion 
feature has not been evaluated using a standardized workflow in a blinded setting in a homogenous 
patient group. Furthermore, in an effort to minimize therapy, a direct comparison between the success 
of the freeze when initiating therapy based on the occlusion feature vs the assessment of occlusion by 
fluoroscopy has not been evaluated.  The study design indicates a post-market interventional clinical 

 
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ICF 
Screening 
Pulmonary Vein 
Occlusion with a partial leak on the venogram 
resulting in ablation. 
Occlusion; no visible leak on the venogram 
Large (common) PV ostium > 28mm 
identified with venography and KODEX-EPD 
Exceeding threshold for DTS, DTM or DTO 
on KODEX-EPD
Achieve movement during injection, double 
injection, incorrect timing of injection on 
KODEX-EPD 
Figure 3; Study Schematic 
investigation to evaluate the endpoints of the study. No follow-up is foreseen ensuring a minimal 
burden to the subjects participating in the study.  
2. EXPERIMENTAL PLAN 
 Study Objectives 
The study objective is to evaluate the performance of the KODEX-EPD PV occlusion feature as 
compared to conventional venographic method of fluoroscopy with contrast dye in cryoballoon 
procedures that is used to guide the procedure. Performance will be calculated in terms of accuracy, 
sensitivity, specificity and positive and negative predictive values. In the blinded arm of this 2-armed 
study, the operator will be blinded for the PV occlusion data on the KODEX-EPD system, and this data 
will not be used for clinical guidance. In the KODEX guided arm the operator will use the KODEX-
EPD system occlusion data to guide the procedure. 
 
 Study Design 
 Study Schematic 
 
 
 
 
 
 
 
 
 
 
 
The Cryoballoon procedure consists of the isolation and ablation of the pulmonary veins (PVs). The 
number of PVs and occlusion tests per PV depends on several factors including patient anatomy. 
Therefore, data from the KODEX-EPD PV Occlusion feature will be evaluated as a separate set of data 
for each occlusion test and for each pulmonary vein. Data from a PVI where the diameter of the 
(common) PV ostium > 28mm, or when the threshold for Distance to Shadow (DTS), Distance to Mesh 
(DTM) or Distance to Ostium (DTO) is exceeded, or when the Achieve catheter is moving during the 
Cryoballoon procedure 

 
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injection, there is a double injection or an incorrect timing of the injection, will not be included in the 
primary endpoint analysis. 
 Primary Endpoints 
1. The accuracy, sensitivity, specificity and positive and negative predictive values of the 
KODEX-EPD PV occlusion feature as compared to conventional angiographic method of 
fluoroscopy with contrast dye that will be used to guide the procedure. 
2. The success of the freeze when freeze is initiated based on the assessment of the KODEX-EPD 
PV occlusion feature as compared to the success of the freeze when freeze is initiated based on 
the assessment with fluoroscopy and contrast dye. 
 Secondary and Exploratory Endpoints 
Procedure data collection: 
 KODEX-EPD data collection 
 Fluoroscopy system data collection 
 Fluoroscopy time 
 Fluoroscopy dose 
 Number of contrast dye injections 
 Contrast dye volume 
 Time to isolation (TTI)/Success of Isolation 
 Number of ablations per vein 
 Procedure time (skin to skin) 
 Study Duration 
The study enrolment is expected to take 1.5 years. The study has no F/Up therefore the total duration is 
expected to be 1.5 years. 
 Study Centers 
In total Two (2) centers; Johns Hopkins University in Baltimore, USA and UZ Brussel in Brussel, 
Belgium will participate in the study 
 Number of patients 
A maximum of 20 patients per center will be included in the blinded to KODEX arm of the study. An 
additional 25 patients will be included at UZ Brussel in the KODEX guided arm of the study. 
 Subject Selection and Enrollment 
 Study Population and Eligibility 
Subjects will undergo baseline evaluation to determine eligibility for the study.  

 
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After being informed of the nature of the study, the subject will sign a written informed consent form 
(ICF) that has been approved by the IRB/EC of the clinical site and by the Sponsor. Subjects will be 
considered for the study if they meet the specific inclusion/exclusion criteria. The criteria for 
enrollment must be followed explicitly.  
 Inclusion Criteria 
1. Subject must be aged >18 years. 
2. Subject must have signed a written Informed Consent form to participate in the study, prior to any 
study related procedures. 
3. Subject must be willing to comply with the protocol requirements. 
4. Subject receives a de novo ablation procedure for treatment of atrial fibrillation. 
 
 Exclusion Criteria 
1. Pregnant women. 
 
 Withdrawal  
Every effort should be made to retain subject enrolment for the duration of the study. During the 
informed consent process subjects should be fully informed of the data collection requirements and 
duration and should only be enrolled if willing to fully participate in it. All subjects enrolled in the 
clinical study must be accounted for and documented. Reasons for withdrawal may include; 
 Physician discretion 
 Subject choice to retire consent, loss to Follow up, or death. 
In the event that the subject withdraws from the study every effort should be made to obtain full 
information on any on-going adverse events.  
The reason for withdrawal must be recorded in the End of Study (EoS) CRF and in the patient file. All 
open adverse events should be closed or documented as ongoing. Data collected up to the point of 
subject withdrawal may be used, unless any local regulations prohibits the use of the data. 
 Study Procedures 
 Screening and Informed Consent 
Patients who may be eligible for enrollment will go through the informed consent process. At the 
screening visit, subjects will be approached to obtain written informed consent prior to any study 
specific procedures being performed. The purpose of the study and the benefits and risks of the 
procedures will be explained to the subject and the consent process must be documented accordingly 
in the medical record. Subjects who agree to study participation must sign an approved ICF. Subjects 
will be informed that their participation in this study is voluntary and they may refuse to participate or 
discontinue from the study at any time. Subjects will be given the opportunity to ask questions so that 

 
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they are adequately informed about the research. A copy of the signed informed consent must be 
provided to the subject and the informed consent process will be documented in source documents. 
Subjects are considered enrolled once their informed consent has been correctly documented. 
If new information becomes available that may affect a subject’s decision to continue to take part in 
the study, this information will be discussed with the subject. 
Subjects who are unable or unwilling to provide written informed consent should not be included in 
the investigation.  
The following assessments/procedures will be performed during the screening, following the 
institutions’ standard protocols: 
 Demographics 
 Medical history 
 Physical examinations 
 Concomitant medications 
 Presence/history of atrial fibrillation 
 Previous and current treatments of atrial fibrillation 
 Intervention 
Patient management and treatment decisions are at the discretion of the care team per routine clinical 
practice. The KODEX-EPD system is an open-platform system however all catheters/leads used during 
the intervention need to be calibrated prior to the intervention.  
 Clinical Workflow 
1) Advance the Achieve spiral mapping catheter (Achieve) to the Left Atrium (LA). 
2) Image the LA with the Achieve by maneuvering the catheter around the LA under different 
angles. 
3) Inflate the Cryoballoon (CB) and advance CB to occlude the ostium, make sure the location of 
the Achieve is maximal 15 mm distal to the CB. Hold this location for 5 seconds. 
 KODEX-EPD System will obtain a “shadow” of the Achieve at the current location this 
will take approximately 2 seconds. 
 
Please note that there are 2 types of notifications on the KODEX-EPD system that can be 
shown when obtaining the ‘shadow’; 
‐ 
DTM; When the distance between the Achieve and the Mesh is > 10mm  
‐ 
DTO; When the distance between the Achieve and the Ostium is > 35mm  
It is recommended to reposition the catheter and acquire a new shadow 
 
4) Verify occlusion on fluoroscopy (in the blinded arm) or KODEX(in the KODEX guided arm) 
by selective contrast injection while simultaneously stepping on the KODEX-EPD System’s 
foot pedal/or the injection button in the KODEX-EPD system is pressed to start the occlusion 

 
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assessment with the KODEX-EPD System. The occlusion assessment will take approximately 
12 seconds. After which the physician should decide to; 
 Proceed with CB ablation and move to next PV 
 Reposition CB and repeat step 4. 
 
Please note that for a successful occlusion assessment on the KODEX-EPD system it is 
important that; 
‐ 
The there is no DTM, DTO or DTS ( When the distance between the Achieve and the 
Shadow is > 10mm) notification on the KODEX-EPD system 
‐ 
The injection on the KODEX-EPD system is synced with the actual injection 
‐ 
The Injection is done with one shot. 
If occlusion is not indicated when assessing occlusion in the KODEX guided arm it is recommended to 
reposition the CB and re-assess the occlusion with KODEX. In total 3 consecutive attempts should be 
made to obtain occlusion on KODEX. 
 
 
It is recommended to use an auto-injector where 6cc is injected at 2.5ml/sec and the 
dye/saline ratio is between 50/50 to 100/0. 
 If a manual syringe is used the injection should be swiftly and the dye/saline ratio needs to 
be between 70/30 to 100/0. The amount of injection is at the physician’s discretion. 
 
Considerations for the use of contrast in this workflow are the following; 
‐ 
The contrast injection induces a significant local dielectric change and impacts some/all 
readings off the Achieve electrodes. 
‐ 
The contrast needs to reach and embed the Achieve electrodes. 
‐ 
Monitor no movement during injection. 
‐ 
The Achieve’s proximity to the CB will impact the results. 
 
 Data Collection 
The following data will be collected during the intervention: 
 KODEX-EPD data collection 
 Fluoroscopy system data collection 
 Fluoroscopy time 
 Fluoroscopy dose 
 Number of contrast dye injections 
 Contrast dye volume 
 Information on durability of the PV isolation. 

 
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 Time to isolation (TTI) – if possible 
 Number of ablations per vein 
 Procedure time (skin to skin) 
 cineloops of procedural images 
 Cryoconsole freeze data 
 Safety Events 
 
 Follow up  
This is an acute study and there is no follow-up foreseen. 
 Discharge & End of Study 
The End of Study (EoS) is defined as after patient’s discharge. The following data will be collected 
during the Discharge/EoS visit; 
 Vital signs 
 Concomitant medication 
 Safety Events 
 After End of Study 
After the study participation has ended the subjects will be followed up at the discretion of the 
investigator in accordance with the standard of care. No additional follow up is intended after Subjects’ 
participation in the study has ended.  
Subject data may be collected after the subjects’ end of study. Following the FDA guidance; all AEs 
and non-study related SAEs should be followed up until they have resolved or stabilized or until 30 
days after participants’ EoS. All other SAEs should be followed until resolution or until the condition 
has stabilized with no further change expected. 
Data collected for the purpose of this study may be used for future clinical research in the area of 
cardiac ablations.  
 Schedule of Assessments 
Table 1; Schedule of Assessments 
 
Screening 
Intervention 
Discharge/EoS 
Visit window ≤ - 1 month 
- 
- 
Informed consent 
x 
 
 
Medical History 
x 
 
 
Physical Examinations 
x 
 
 
Vital Signs 
x 
x 
x 
Demographics 
x 
 
 
Incl./Excl. Criteria 
x 
 
 

 
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TEE 
x1 
x2 
 
12-Lead ECG 
x1 
x2 
 
Fluoroscopy time and dose 
 
x3 
 
Contrast dye # of injections and volume 
 
x3 
 
TTI 
 
x 
 
# of Ablations per PV 
 
x 
 
Procedure time 
 
x 
 
cineloops of procedural images 
 
x 
 
Cryoconsole freeze data 
 
x 
 
Concomitant Medications 
x 
x 
x 
(S)AE reporting 
x 
x 
x 
 
1 Only collect data when assessment is done per standard of care within 1 months of screening. Assessment doesn’t require 
to be done for the purpose of the study.   
2  Only collect data when assessment is done per standard of care. Assessment doesn’t require to be done for the purpose of 
the study.  
3 Data from 2 intervals;  
1. start of procedure – transseptal puncture  
2. successful transseptal puncture – isolation 
 Standardization of Study Procedures  
 Measurements of Vital Signs 
Blood Pressure (BP) and Heart Rate (HR) measurements should be determined after the subject has 
been seated for at least 5 minutes. BP should be measured on both arms and the arm with the highest 
systolic reading at screening should be used for BP determination throughout the study. The subject’s 
pulse should be measured for 30 seconds and the number should be multiplied by 2 to obtain HR.  
 Concomitant Medication 
Targeted concomitant therapy and medications will be recorded on the CRF. The following groups of 
concomitant medications will be recorded; 
 Anticoagulants 
 Cardiovascular medications 
 Antiarrhythmic medications/substances 
 Procedural Images 
Cineloops of procedural images are to be created starting just prior to contrast injection for 
fluoroscopic verification of occlusion for a duration of 5 seconds and should include one respiratory 
cycle. A visual assessment of the occlusion should be made by the physician at that time and 
documented in the procedural notes. The images will be collected and reviewed for an independent 
assessment. 
 

 
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3. RISK/BENEFIT ANALYSIS 
 Potential Risk to the Subject 
The KODEX-EPD system used in this study is cleared for commercial use by the FDA and is CE-
certified; therefore, the use described in this protocol constitutes a standard clinical use. Information 
related to contraindications, adverse effects, warnings and precautions are included in the device 
instructions for use. Patients enrolled do not bear additional clinical risk by participating in this study. 
The sponsor has taken all the necessary precautions and applied the required mitigations, as described 
in the risk analysis document, in order to make even the rarest risk become virtually impossible.  
Nevertheless, potential complications that could be related to the system include, but are not limited, to 
the following anticipated AEs: 
 
Skin allergy due to body external patches 
 
Secondary transient hyper-hydrosis due to local skin irritation  
 
Local superficial burns (return electrode)  
 
Hampering the quality of recorded intra-cardiac electrical signals that are being transferred to the 
recording system through the KODEX-EPD system (noise introduction) 
 
Decreasing the power output of the RF generator; thereby potentially affecting the generated 
ablation lesions  
 
Incorrect reading of the catheter's tip electrode impedance at rest or during ablation as presented 
on the RF generator front panel 
 
Incorrect reading and presentation of the tip electrode temperature as read by the RF generator 
 
Incidental electrocution  
 Potential Benefits to the Subject 
No direct benefits to the patient are expected. 
 
 Benefit-Risk Rationale 
The KODEX-EPD and accessories used for the PROOF Study will be commercially available and are 
considered to be SOC for subjects indicated for cryoballoon PVI Procedures. The risks involved with 
subject participation in this study are essentially the same as those for subjects not participating in the 
study. 
 

 
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4. SAFETY DATA COLLECTION, RECORDING AND REPORTING 
Adverse events and serious adverse events as defined below will be captured once the patient has 
signed the informed consent form. However, the primary endpoint analysis will count only adverse 
events for patients that the KODEX-EPD system has been used during the treatment procedure. 
 Definitions 
 Adverse Events (AE) 
Any untoward medical occurrence, unintended disease or injury, or untoward clinical signs (including 
abnormal laboratory findings) in subjects, users or other persons, whether or not related to the 
KODEX-EPD system or accessories and whether anticipated or unanticipated. This definition includes 
events related to the investigational medical device or the comparator. 
Additionally, this definition includes events related to the procedures involved. 
For users or other persons, this definition is restricted to events related to the use of the KODEX-EPD 
system or accessories or comparators. 
This definition includes events related to the procedures involved.  
 Adverse Device Effect (ADE) 
An adverse event related to the use of KODEX-EPD System or accessories or the comparator. 
This definition includes adverse events resulting from insufficient or inadequate instructions for use, 
deployment, implantation, installation, or operation, or any malfunction of the KODEX-EPD System. 
This definition includes any event resulting from use error or from intentional misuse of the KODEX-
EPD System. 
 Serious Adverse Event (SAE) 
The Investigator must decide whether each event meets the definition of a “serious” adverse event 
(SAE).  SAE is defined as any adverse event that: 
 
Led to death, 
 
Led to a serious deterioration in health of the subject, users or other persons that either: 
‐ Resulted in a life-threatening illness or injury, or 
‐ Resulted in a permanent impairment of a body structure or a body function including chronic 
diseases, or 
‐ Required in-patient hospitalization or prolongation of existing hospitalization, or 
‐ Resulted in medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function. 
 Led to fetal distress, fetal death, a congenital abnormality, or birth defect including physical or 
mental impairment 
NOTE: A planned hospitalization for pre-existing condition, or a procedure required by the Clinical 
Investigation Plan, without a serious deterioration in health, is not considered to be a SAE. 

 
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 Serious Adverse Device Effect (SADE) 
An adverse device effect (section 4.1.1) that has resulted in any of the consequences characteristic of a 
serious adverse event as mentioned in section 4.1.2. 
 Unanticipated Serious Adverse Device Event (USADE) 
An unanticipated serious adverse device event (USADE) is defined as any serious adverse device effect 
which by its nature, incidence, severity or outcome has not been identified in the current version of the 
risk analysis report. 
NOTE: Anticipated: an effect which by its nature, incidence, severity or outcome has been previously 
identified in the risk analysis report. 
 Device Deficiencies 
A device deficiency is an inadequacy of a medical device related to its identity, quality, durability, 
reliability, usability, safety, or performance, such as malfunction, misuse or use error and inadequate 
labeling. This definition includes device deficiencies related to the KODEX-EPD System or 
accessories or the comparator. 
All KODEX-EPD system device deficiencies will be documented in the CRF. Devices that malfunction 
during the procedure will be analyzed by the sponsor, after appropriate decontamination per hospital 
guidelines.  
Device deficiencies are NOT to be reported as AEs. However, if there is an AE that results from a 
device deficiency, that specific event would be recorded on the appropriate CRF. 
 Malfunction 
A malfunction is a failure of the KODEX-EPD System or accessories or the comparator to perform in 
accordance with its intended purpose when used in accordance with the instructions for use or CIP, or 
IB. 
 Use Error 
A use error can be defined as a user action or lack of user action while using the KODEX-EPD System 
or comparator that leads to a different result than that intended by the manufacturer or expected by the 
user. This includes the ability by the user to complete a task. 
 
NOTE: A malfunction of a medical device that causes an unexpected result is not considered a use 
error, nor does an unexpected physiological response of the patient. 
 
 Adverse Event Classification 
 Severity Classification 
Severity will be defined according to the following criteria: 

 
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Mild 
Awareness of event, but easily tolerated 
Moderate 
Discomfort enough to cause some interference with activities of daily living (ADL) 
Severe 
Incapacitating, with an inability to perform ADL 
 Relationship Classification 
The investigator’s assessment of an AE/SAE's relationship to study device is part of the documentation 
process, but it is not a factor in determining what is or is not reported in the study.  If there is any doubt 
as to whether a clinical observation is an AE/SAE, the event should be reported. The relationship or 
association of the study device in causing or contributing to the AE/SAE will be characterized as one of 
the following: 
 Not Related: No relationship between the AE and the administration of study treatment and a known 
relationship to other etiologies such as concomitant medications, or subject’s clinical state. 
 Possibly Related: An AE that follows a reasonable temporal sequence from the use of the study 
device/procedure and follows a known response pattern to the study device/procedure but could have 
been produced by the participant’s clinical state or by other therapies. 
 Probably related: An AE that follows a reasonable temporal sequence from the use of the study 
device/procedure; follows a known response pattern to the study device/procedure; and cannot be 
reasonably explained by the known characteristics of the participant’s clinical state or by other 
therapies. 
 Related: An AE that follows a plausible temporal sequence fromthe use of the study device/procedure; 
follows a known response pattern to the study device/procedure. The reaction cannot be reasonably 
explained by the known characteristics of the subject’s clinical state or other modes of therapy 
administered to the subject. 
 Unknown; Given the information available, sequence and timing of events, it is unknown or 
impossible to determine the relationship between the AE and the study device/procedure. 
 Outcome Classification 
Outcome of the event will be defined according to the following:  
 Resolved: The event has fully resolved at the end of the study. 
 Resolved with sequelae: The event has resolved, but retained pathological conditions resulting 
from the prior disease or injury. 
 Continuing: The event is ongoing at the end of the study. 
 Death: This event is determined to be the cause of death. 

 
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 Reporting 
 Reporting of AEs and ADEs 
Information about all adverse events, whether volunteered by the patient, discovered by investigator 
questioning, or detected through physical examination, laboratory test or other means, will be collected 
and recorded on the Adverse Event e-CRF and followed as appropriate. 
For the purpose of this study we will selectively collect AEs; meaning that only AEs directly or 
indirectly related to the EP intervention and/or any cardiac arrhythmia will be collected. Selective AE 
reporting is in line with the FDA’s approach to a safety assessment that is focused on information that 
is useful and adds to current knowledge. 
As far as possible, each adverse event will also be described by: 
 its duration (start and end dates) 
 the severity 
 its relationship to the study device (unrelated/possible/probable) 
 the action(s) taken 
 Reporting of SAEs SADEs and USADEs 
For the purpose of this study and based on the definitions above and the requirements of the European 
authorities the following events are considered reportable events in accordance with Annex 7, section 
2.3.5 and 93/42/EEC respectively: 
 Any SAE whether or not considered as related to study device 
 Any KODEX-EPD system deficiency that might have led to a SAE if: 
a. Suitable action had not been taken, or 
b. Intervention had not been made, or 
c. If circumstances had been less fortunate 
 New findings /updates in relation to already reported events 
 
All USADEs, SAEs and SADEs, will be reported on specific forms, if applicable, and forwarded to the 
Sponsor within 24 hours of first awareness of the event. The Investigator is also responsible for 
complying with the applicable local requirements related to adverse event reporting. 
The investigator must complete the appropriate event report form in English, assess the relationship to 
study device/procedure and e-mail the completed form to the Sponsor at: 
EPDEventReporting@philips.com.  
Follow-up information about previously reported USADEs, SAEs and SADEs must also be reported to 
the Sponsor within 24-hours of receipt. The Follow up information should be reported on a new event 
report form by referring to the subject and event number. Only new/updated information needs to be 
entered on the event report form. 
 
Original and the duplicate copies of the event report forms must be kept at the study site. The monitor 
will review and collect copies of the completed event report forms and related documentation. 

 
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If the SAE has not been previously documented (new occurrence) and it is thought to be related to 
study device, Sponsor’s Medical Expert may contact the investigator to obtain further information. If 
warranted, an investigator alert may be issued, to inform all investigators involved in any study with 
the same device that this serious adverse event has been reported. 
5. STATISTICAL CONSIDERATION 
 Study Endpoints 
 Primary Endpoints 
1. 
The accuracy, sensitivity, specificity and positive and negative predictive values of the 
KODEX-EPD PV occlusion feature as compared to conventional venographic method of fluoroscopy 
with contrast dye that will be used to guide the procedure. 
2. 
The success of the freeze when freeze is initiated based on the assessment of the KODEX-EPD 
PV occlusion feature as compared to the success of the freeze when freeze is initiated based on the 
assessment with fluoroscopy and contrast dye. 
 Secondary Endpoints 
 KODEX-EPD data collection 
 Fluoroscopy system data collection 
 Fluoroscopy time 
 Fluoroscopy dose 
 Number of contrast dye injections 
 Contrast dye volume 
 Time to isolation (TTI) 
 Number of ablations per vein 
 Procedure time (skin to skin) 
 Analysis Sets 
The Primary Analysis Set (PAS) includes all successful occlusion tests. Successful is defined as a test 
for which; 
‐ 
procedural data e.g.: KOPDEX-EPD system data, venograms, and notes are obtained.  
‐ 
Presence of DTS, DTM or DTO notifications were documented before obtaining the shadow.  
This analysis set will be used for the primary endpoint analysis. 
 
The Secondary Analysis Set (SAS) includes all PVIs and ablations done. This analysis set 
will be used for the analysis of the secondary endpoints. 
The ITT (intend to treat) PVs will be used as a secondary analysis of the secondary endpoints. 
 

 
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 Sample Size Considerations 
The sample size for the 1st primary endpoint was determined at 120 resulting in approximately 30 
subjects to be enrolled in the blinded arm.  
The sample size for the 2nd primary endpoint was estimated using the One-Sided Lower-Limit 
Confidence Intervals for One Proportion approach. Expecting a proportion of 80% with a lower bound 
of the 95% confidence interval of about 70% the sample size is estimated to be 87. 
 
A sample size of 87 would require approximately 22 subjects to be enrolled in the KODEX guided arm. 
 
 Statistical Analysis 
 General Approach/Considerations 
Statistical analyses in this data collection study will be descriptive in nature. No statistical inference is 
planned. Subject disposition, demographics and baseline characteristics will be summarized. Summary 
statistics for continuous variables will include the number of subjects, mean, median, standard 
deviation or standard error, minimum, and maximum. For categorical variables, the frequency and 
percentage will be given.  
Interim and final analyses will be based on data collected from this study. There will be no imputation 
for missing data. 
 Analysis of Key Study Endpoints 
 Primary Endpoint Analyses 
Results will be summarized by occlusion test, by PV and by patient. 
 Secondary Endpoint Analyses 
Results will be summarized by PV and by patient. 
 Exploratory Endpoint Analyses 
Results will be summarized by occlusion test, by PV and by patient. 
 Data justification 
Systemic error/bias will be minimized by having operators select subjects from their general patient 
population. Before enrolling subjects, sites/operators will be trained on the study protocol to ensure 
consistency across sites/operators. Subjects will be equally distributed over the 2 sites in the blinded 
arm of the study. 
 Missing Data 
No imputations for missing data will be made. This is an acute study with no F/Up foreseen. 

 
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 Deviations 
Any changes to the planned statistical analyses made will be documented in a separate Statistical 
Analysis Plan. Changes from the planned statistical methods will be documented in the clinical study 
report along with a reason for the deviation. Post-hoc analyses may be conducted according to the 
existing data collected, if necessary 
6. STUDY CONDUCT 
 Statement of Compliance 
This study will be conducted in accordance with ISO 14155:2020 Clinical Investigation of Medical 
Devices for Human Subjects-Good Clinical Practice, and the relevant parts of the ICH Guidelines for 
Good Clinical Practice, ethical principles that have their origins in the Declaration of Helsinki, and 
pertinent individual country laws and regulations including but not limited to EU-MDR. The study shall 
not begin until the required approval/favorable opinion from the Institutional Review Board (IRB)/Ethics 
Committee (EC) and/or regulatory authority has been obtained, if appropriate.  
The Investigator must submit and, where necessary, obtain approval from the IRB/EC for all subsequent 
protocol amendments and changes to the Informed Consent form.  The Investigator must notify the 
IRB/EC of deviations from the protocol or SAEs and USADEs occurring at the site in accordance with 
local procedures. Any additional requirements imposed by the IRB/EC or regulatory authority shall be 
followed, if appropriate. 
The Investigator is responsible for obtaining annual IRB/EC approval and renewal throughout the 
duration of the study where applicable.  Copies of the Investigator’s reports and the IRB/EC continuance 
of approval must be provided to the sponsor. 
Insurance shall be provided for the subjects participating in this clinical trial according to local law. 
The clinical study will be sponsored by EPD Solutions whereas the financial compensation for the 
investigator/site is defined as an Exhibit to the clinical trial agreement.  
 Source Documents 
Source data is all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial.  Examples of these original 
documents and data records include but are not limited to: medical records, clinic and office charts, x-
rays, laboratory notes, study specific worksheets, memoranda, subjects’ diaries or evaluation checklists, 
recorded data from automated instruments, copies or transcriptions certified after verification as being 
accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, subject 
files, and records kept at the pharmacy and at the laboratories involved in the clinical trial. 

 
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Regulations require that the Investigator maintain information in the subjects’ medical/hospital records 
that corroborate data collected for the study.  In order to comply with these regulatory requirements, at 
a minimum, the following is a list of information that should be maintained:  
 
Medical history/general physical condition of the subject before involvement in the study of a 
sufficient nature to verify the protocol eligibility criteria 
 
Dated and signed study/progress notes on the date of entry into the study documenting the 
following: 
o 
The general health of the subject; 
o 
The discussion of the study risks and benefits with the subject; 
o 
Completion of the informed consent process; 
o 
A statement that the subject has reviewed, signed, and received a copy of the Subject Informed 
Consent Form; 
o 
Adverse Events reported and their continuation or resolution, including supporting documents 
such as discharge summaries, X-ray reports, and other test reports; 
o 
Subject’s general health and medical condition upon completion of, or withdrawal from, the 
study. 
Subject confidentiality will be maintained throughout the clinical study in a manner that assures data 
can be traced back to the source documents.  Additionally, subject information will be managed 
according to the Health Insurance Portability and Accountability Act of 1996 (HIPAA). In addition, all 
personal data will be handled in accordance with the EU directive e95/46/EC and as of 25 May 2018 in 
accordance with the GDPR. All data will be de-identified at each site before being entered into EDC. 
Only the investigator and site coordinator will have access to the de-identified data.  The Informed 
Consent Form must include information letting the subject know: 
 
What protected health information (PHI) will be collected during the study; 
 
Who will have access to that information; 
 
Who will use or disclose that information; 
 
The rights of the research subject to revoke their authorization for use of their PHI. 
In the event that the subject revokes authorization, the investigator retains the ability to use all 
information collected prior to the revocation.  The Investigator should attempt to obtain permission to 
collect at least vital status (i.e. that the subject is alive) at the end of their scheduled study period.   
 Data Handling and Record Keeping 
This study will be performed using an electronic data capture (EDC) system. The e-CRF will be used 
for data review, data cleaning and issuing and resolving queries. This e-CRF is a web-based e-CRF 
which is password protected and is 21 CFR part 11 compliant. The investigator and study site staff will 
receive training and support on the use of the EDC system and will be granted specific user privileges. 
All CRF data are to be completed by the investigator, study coordinator, or other designated site 

 
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personnel.  The investigator will perform a final review and sign-off at designated times (e.g. study 
exit). 
 
Site coordinators will be trained to enter data into a web-based electronic data capture system designed 
for this study and for maintaining its data. Source data verification between the CRF and the subject’s 
medical records will be completed by a monitor during onsite visits. Monitoring of the data will be 
completed during ongoing remote data reviews.  The clinical database will be a closed system, 
allowing for tracking all the data elements and any changes made.   
 
Raw data that is collected from the KODEX-EPD System and other image data collected through 
modalities used for during the standard of care intervention will be de-identified and stored in a secured 
location.  
 
Sponsor will provide the investigational site with supplies for setting up the study files.  Study 
documents must be maintained by the Investigator and Sponsor for the duration of the trial and for a 
period of at least 15 years after the trial has been formally closed. 
 Device Accountability 
Although the study does not foresee the provision of study devices, the site will be responsible to 
ensure that all study supplies and patient records are kept in a secure place. 
No accountability records for the KODEX EPD system and sensors must be maintained when these are 
purchased through regular commercial channels. Device accountability is required to be maintained if 
the system and/or sensors are provided for the sole purpose of the study. If device accountability is 
required the principal investigator shall keep records documenting the receipt, use, return and disposal 
of the study device, including date of receipt, identification of each study device, the expiry date, the 
date of use, subject identification, the date of return of unused, expired or malfunctioning 
investigational devices and date on which the investigational was returned. 
 Investigator Responsibilities 
The Principal Investigator of an investigational center is responsible for ensuring that the study is 
conducted in accordance with the Clinical Study Agreement, the investigational plan/protocol, ISO 
14155, ethical principles that have their origins in the Declaration of Helsinki, any conditions of approval 
imposed by the reviewing IRB/EC, and prevailing local and/or country laws and/or regulations, 
whichever affords the greater protection to the subject. 
The Principal Investigator’s responsibilities include, but are not limited to, the following.  
 Prior to beginning the study, sign the Investigator Agreement and Protocol Signature page 
documenting his/her agreement to conduct the study in accordance with the protocol. 
 Provide his/her qualifications and experience to assume responsibility for the proper conduct of the 
study and that of key members of the center team through up-to-date curriculum vitae or other 

 
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relevant documentation and disclose potential conflicts of interest, including financial, that may 
interfere with the conduct of the clinical study or interpretation of results. 
 Make no changes in or deviate from this protocol, except to protect the life and physical well-being 
of a subject in an emergency; document and explain any deviation from the approved protocol that 
occurred during the course of the clinical investigation. 
 Create and maintain source documents throughout the clinical study and ensure their availability with 
direct access during monitoring visits or audits; ensure that all clinical-investigation-related records 
are retained per requirements. 
 Ensure the accuracy, completeness, legibility, and timeliness of the data reported to the sponsor in 
the CRFs and in all required reports. 
 Record, report, and assess (seriousness and relationship to the device/procedure) every adverse event 
and observed device deficiency. 
 Report to the sponsor, per the protocol requirements, all SAEs and device deficiencies that could 
have led to a USADE. 
 Report to the IRB/EC and regulatory authorities any SAEs and device deficiencies that could have 
led to a USADE, if required by the national regulations or this protocol or by the IRB/EC, and supply 
the sponsor with any additional requested information related to the safety reporting of a particular 
event. 
 Allow the sponsor to perform monitoring and auditing activities, and be accessible to the monitor 
and respond to questions during monitoring visits. 
 Allow and support regulatory authorities and the IRB/EC when performing auditing activities. 
 Ensure that informed consent is obtained in accordance with this protocol and local IRB/EC 
requirements. 
 Provide adequate medical care to a subject during and after a subject’s participation in a clinical study 
in the case of adverse events, as described in the Informed Consent Form (ICF). 
 Inform the subject of the nature and possible cause of any adverse events experienced. 
 Inform the subject of any new significant findings occurring during the clinical investigation, 
including the need for additional medical care that may be required. 
 Provide the subject with well-defined procedures for possible emergency situations related to the 
clinical study, and make the necessary arrangements for emergency treatment, Ensure that clinical 
medical records are clearly marked to indicate that the subject is enrolled in this clinical study. 
 Ensure that, if appropriate, subjects enrolled in the clinical investigation are provided with some 
means of showing their participation in the clinical investigation, together with identification and 
compliance information for concomitant treatment measures (contact address and telephone numbers 
shall be provided). 
 Inform, with the subject’s approval or when required by national regulations, the subject’s personal 
physician about the subject’s participation in the clinical investigation. 

 
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 Make all reasonable efforts to ascertain the reason(s) for a subject’s premature withdrawal from 
clinical investigation while fully respecting the subject’s rights. 
 Ensure that an adequate investigation site team and facilities exist and are maintained and 
documented during the clinical investigation. 
 Ensure that maintenance and calibration of the equipment relevant for the assessment of the clinical 
investigation is appropriately performed and documented, where applicable. 
 Delegation of Responsibility 
When specific tasks are delegated by an investigator, included but not limited to conducting the informed 
consent process, the investigator is responsible for providing appropriate training and adequate 
supervision of those to whom tasks are delegated. The investigator is accountable for regulatory 
violations resulting from failure to adequately supervise the conduct of the clinical study.  
 Protocol Deviations 
An Investigator must not make any changes or deviate from this CIP except to protect the life and 
physical well-being of a subject in an emergency. An investigator shall notify the sponsor and the 
reviewing IRB/EC of any deviation from the investigational plan to protect the life or physical well-
being of a subject in an emergency, and those deviations which affect the scientific integrity of the clinical 
investigation.  
All deviations from the investigational plan, with the reason for the deviation and the date of occurrence, 
must be documented and reported to the sponsor within 14 days using the appropriate CRF. Sites may 
also be required to report deviations to the IRB/EC, per local guidelines and government regulations.  
Deviations will be reviewed and evaluated on an ongoing basis and, as necessary, appropriate corrective 
and preventive actions (including notification, center re-training, or discontinuation) will be put into 
place by the sponsor or its representatives. 
 Sponsor Responsibilities 
 Confidentiality 
All information and data sent to the Sponsor concerning subjects or their participation in this study will 
be considered confidential by the Sponsor. Only authorized Sponsor personnel or a Sponsor 
representative will have access to these confidential records. Authorized regulatory personnel have the 
right to inspect and copy all records pertinent to this study. Study data collected during this study may 
be used by the Sponsor for the purposes of this study, publication, and to support future research and/or 
other business purposes. All data used in the analysis and reporting of this study will be without 
identifiable reference to specific subject name. 
The Sponsor will keep subjects’ health information confidential in accordance with all applicable laws 
and regulations.  The Sponsor may use subjects’ health information to conduct this study, as well as for 
additional purposes, such as overseeing and improving the performance of its device, new medical 

 
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research and proposals for developing new medical products or procedures, and other business 
purposes. Information received during the study will not be used to market to subjects; subject names 
will not be placed on any mailing lists or sold to anyone for marketing purposes.  
 Monitoring 
Monitoring (on-site and remote) will be performed during the study to assess continued compliance with 
the protocol and applicable regulations. In addition, the monitor verifies that study records are adequately 
maintained, that data are reported in a satisfactory manner with respect to timeliness, adequacy, and 
accuracy, and that the Investigator continues to have sufficient staff and facilities to conduct the study 
safely and effectively. The Investigator/institution guarantees direct access to original or electronic 
source documents by Sponsor’s personnel, their designees, and appropriate regulatory authorities. 
The study may also be subject to a quality assurance audit by the Sponsor or its designees, as well as 
inspection by appropriate regulatory authorities. It is important that the Investigator and relevant study 
personnel are available during on-site monitoring visits or audits and that sufficient time is devoted to 
the process. 
 Insurance 
The Sponsor maintains appropriate insurance coverage for clinical trials and will follow applicable 
local compensation laws. Patients will be treated and/or compensated for any study related 
illness/injury in accordance with the information provided in the Insurance section of the Informed 
Consent document. 
 Amendments to the CIP 
Non-significant changes of the CIP may be included (minor logistical or administrative changes not 
effecting the rights, safety and well-being of human subjects or not related to the clinical investigation 
objectives or endpoints), without prior approval. Significant changes (such as device modifications, 
study procedures) shall be discussed with the coordinating investigators and principal investigator prior 
approval. All changes will be documented with a justification and described in the CIP. Changes shall 
be authorized by the IRB/EC and if applicable the Competent Authority before implementation. 
Exempt from this requirement are measures which have to be taken immediately in order to protect the 
participants. 
7. PUBLICATIONS 
It is Sponsor’s policy to publish the results of its Clinical Studies. 
This study will be registered on clinicaltrial.gov before first enrollment. 
The publication of the common database will be under the direction of EPD. Publication of the 
complete data set will not be allowed unless approved by the sponsor. 

 
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Individual investigators may publish their own data sets upon sponsor approval, if it contains data that 
is unique to that center. Otherwise, this will not be allowed before the common data sets have been 
published. 
All publications will be reviewed by the Sponsor in order to assure that no confidential information is 
disclosed. Such confidential information will be published only after the Sponsor’s Intellectual 
Property has been protected. 
8. GENERAL INFORMATION 
 Study Contact Information 
Questions regarding this study should be directed to the clinical study manager. 
Marieke van Bussel 
Veenpluis 6  Building QP 
5684 PC Best, The Netherlands 
Tel +31 (0)6 39267909 
Marieke.van.Bussel@philips.com 
 Retention of Records 
All source documents and CRFs will be kept for a period of 2 years after the later of the following 
dates: the date at which the study is terminated or completed or; the date that the records are no longer 
required for supporting marketing applications. 
 Study Completion/Termination or Suspension of the Study 
There are no provisions or interim analyses planned that can result in an early termination of the study. 
The principal investigator, IRB/EC, or regulatory authority may suspend or prematurely terminate 
participation in the clinical study at the investigation sites for which they are responsible.  
Any signs of unknown or increased risks for the subjects will be discussed by the sponsor and 
investigator to assess the impact on the subjects and clinical investigation. If suspicion of an 
unacceptable risk to subjects arises during the clinical investigation, or when so instructed by the 
IRB/EC or regulatory authorities, the sponsor shall suspend the clinical investigation while the risk is 
assessed. 
The sponsor shall terminate the clinical investigation if an unacceptable risk is confirmed. If suspension 
or premature termination occurs, the terminating party shall justify its decision in writing and promptly 
inform the other parties with whom they are in direct communication. The principal investigator and 
sponsor shall keep each other informed of any communication received from either the IRB/EC or the 
regulatory authority.  

 
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 Reporting Timelines  
A final report shall be provided to all reviewing IRBs/ECs, and the participating Investigators within 6 
months after termination/completion. 
 Subject Follow up 
Following an early termination, suspension or study completion, patients who are already treated and 
not discharged will be followed up for adverse events till discharge from hospital. Patients who are 
already discharged from the hospital will be followed up as per standard of care in the hospital, outside 
the study. 
In addition, all AEs and non-study related SAEs should be followed up until they have resolved or 
stabilized or until 30 days after participants’ EoS. All other SAEs should be followed until resolution or 
until the condition has stabilized with no further change expected.  
 Blinding  
The blind of this investigation will not be broken as the blinding in this study is not of influence on the 
treatment, the risks of the study device or the benefit risk ratio to the patient. 
 
 

 
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9. REFERENCES 
 
i Stanley Nattel, j. a. (december 2014). New directions in cardiac arrhythmia management: present 
challenges and future solutions. 30(12), s420–s430. 
 
ii http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/cardiology/cardiac-
arrhythmias/ retrieved from clevelandclinicmeded.  
 
iii Zatonskaya e.v., m. g. (2017). The prevalence and clinical significance of cardiac arrhythmias. . 
rational pharmacotherapy in cardiology., 13(3), 403-408 
 
iv Tang dh, g. a. (2014 , feb). Economic burden and disparities in healthcare resource use among adult 
patients with cardiac arrhythmia. appl health econ health policy. , 12(1), 59-71. 
 
v Priori SG, Blomstrom-Lundqvist C, Mazzanti A, Blom N, Borggrefe M, Camm J, et al. 2015 ESC 
Guidelines for the Management of Patients With Ventricular Arrhythmias and the Prevention of 
Sudden Cardiac Death. Rev Esp Cardiol (Engl Ed). 2016;69(2):176. 
 
vi Page RL, Joglar JA, Caldwell MA, Calkins H, Conti JB, Deal BJ, et al. 2015 ACC/AHA/HRS 
guideline for the management of adult patients with supraventricular tachycardia: A Report of the 
American College of Cardiology/American Heart Association Task Force on Clinical Practice 
Guidelines and the Heart Rhythm Society. Heart rhythm : the official journal of the Heart Rhythm 
Society. 2016;13(4):e136-221. 
 
vii Calkins H, Reynolds MR, Spector P, Sondhi M, Xu Y, Martin A, et al. Treatment of atrial fibrillation 
with antiarrhythmic drugs or radiofrequency ablation: two systematic literature reviews and meta-
analyses. Circulation Arrhythmia and electrophysiology. 2009;2(4):349-61. 
 
viii Wilber DJ, Pappone C, Neuzil P, De Paola A, Marchlinski F, Natale A, et al. Comparison of 
antiarrhythmic drug therapy and radiofrequency catheter ablation in patients with paroxysmal atrial 
fibrillation: a randomized controlled trial. Jama. 2010;303(4):333-40. 
 
ix January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC, Jr., et al. 2014 
AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the 
American College of Cardiology/American Heart Association Task Force on Practice Guidelines and 
the Heart Rhythm Society. Journal of the American College of Cardiology. 2014;64(21):e1-76. 
 
x Kuck KH, Ernst S, Cappato R, Braun E, Lang M, Ben-Haim SA, et al. Nonfluoroscopic endocardial 
catheter mapping of atrial fibrillation. Journal of cardiovascular electrophysiology. 1998;9(8 
Suppl):S57-62.  
 
xi Ben-Haim SA, Osadchy D, Schuster I, Gepstein L, Hayam G, Josephson ME. Nonfluoroscopic, in 
vivo navigation and mapping technology. Nat Med. 1996;2(12):1393-5. 
 

 
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xii Stevenson WG, Delacretaz E, Friedman PL, Ellison KE. Identification and ablation of 
macroreentrant ventricular tachycardia with the CARTO electroanatomical mapping system. Pacing 
and clinical electrophysiology : PACE. 1998;21(7):1448-56. 
 
xiii Gepstein L, Hayam G, Ben-Haim SA. A novel method for nonfluoroscopic catheter-based 
electroanatomical mapping of the heart. In vitro and in vivo accuracy results. Circulation. 
1997;95(6):1611-22. 
 
xiv Maurer T, Kuck KH, First clinical experience in high resolution imaging of cardiac anatomy using 
the novel wide band magneto-electric mapping system KODEX.  
 
xv Haïssaguerre M, Jaïs P, Shah DC, et al. Spontaneous initiation of atrial fibrillation by ectopic beats 
originating in the pulmonary veins. N. Engl. J. Med. [Internet]. 1998;339:659–666. 
 
xvi Osório et. al. Recent advances in cryoballoon ablation for atrial fibrillation. Expert Rev. of Med. 
Devices 2019;16;9:799-808. DOI: 10.1080/17434440.2019.1653181 
 
xvii Maurer T, et. Al. High-Resolution Imaging of LA Anatomy Using a Novel Wide-Band Dielectric 
Mapping System. JACC Clin. EP. DOI: 10.1016/j.jacep.2019.06.020 
 
xviii Romanov et. al.  High-resolution, real-time, and nonfluoroscopic 3-dimensional cardiac imaging 
and catheter navigation in humans using a novel dielectric-based system. Heart Rhythm 2019;16;12 
1890-1891. 
xix Cauti, F. M., Rossi, P., Iaia, L., Polselli, M., Pecere, A., & Bianchi, S. (2021). Accuracy comparison 
of the new and previous Kodex occlusion tool software versions to assess pulmonary vein occlusion in 
atrial fibrillation cryoablation. European Heart Journal, 42(Supplement_1). 
https://doi.org/10.1093/eurheartj/ehab724.0386 
 
xx Cauti, F. M., Solimene, F., Stabile, G., Polselli, M., Schillaci, V., Arestia, A., Shopova, G., Iaia, L., 
Giannitti, C. M., Rossi, P., & Bianchi, S. (2021). Occlusion tool software for pulmonary vein occlusion 
verification in atrial fibrillation cryoballoon ablation. Pacing and Clinical Electrophysiology: PACE, 
44(1), 63–70. https://doi.org/10.1111/pace.14130 
 
xxi Rillig, A., Rottner, L., Nodorp, M., Lin, T., Weimann, J., Münkler, P., Dinshaw, L., Schleberger, R., 
Lemoine, M. D., Nies, M., Risius, T., Blankenberg, S., Kirchhof, P., Meyer, C., Reissmann, B., & 
Metzner, A. (2020). Novel Wide-Band Dielectric Imaging System and Occlusion Tool to Guide 
Cryoballoon-Based Pulmonary Vein Isolation: Feasibility and First Insights. Circulation. Arrhythmia 
and Electrophysiology, 13(12), e009219. https://doi.org/10.1161/CIRCEP.120.009219 
 
xxii Rottner, L., Sinning, C., Reissmann, B., Schleberger, R., Dinshaw, L., Münkler, P., Meyer, C., 
Blankenberg, S., Rillig, A., & Metzner, A. (2020). Wide-Band Dielectric Imaging and the Novel 
Cryoballoon-Occlusion Tool to Guide Cryoballoon-Based Pulmonary Vein Isolation. Circulation. 
Arrhythmia and Electrophysiology, 13(8), e008507. https://doi.org/10.1161/CIRCEP.120.008507 
 
 

 
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Philips’ proprietary information. Unauthorized use is prohibited.