Automated Assessment of Pulmonary Vein Isolation (PVI) Using a Novel EP Recording System (CathVision Cube® System)
Phase: NA
Conditions: Paroxysmal Atrial Fibrillation, Persistent Atrial Fibrillation
Sponsor: CathVision ApS

 
 
CIP – CPVI-002 Rev F  
 
CathVision ApS 
 
 
Page 1 of 39 
 
 
 
 
AUTOMATED ASSESSMENT OF PULMONARY VEIN ISOLATION USING A 
NOVEL EP RECORDING SYSTEM (PVISION) 
 
CLINICAL INVESTIGATION PLAN 
CPVI-002 
 
20 December 2021 
 
SPONSOR 
CathVision ApS 
Titangade 11 
DK-2200 
Copenhagen, DENMARK 
 
DISCLOSURE STATEMENT 
This document contains information that is confidential and proprietary to CathVision ApS. This 
information is being provided to you solely for the purpose of evaluating or conducting a study for 
CathVision ApS.  You may disclose the contents of this document only to study personnel under your 
supervision who need to know the contents for this purpose and to the Ethics Committee (EC) and the 
Competent Authority, otherwise the contents of this document may not be disclosed without the prior 
authorization from CathVision ApS.  The foregoing shall not apply to disclosure required by 
governmental regulations or laws.  Any supplemental information that may be added to this document 
also is confidential and proprietary to CathVision ApS and must be kept in confidence in the same 
manner as the contents of this document. 
 
Document History Clinical Investigation Plan CPVI-002 

 
 
CIP – CPVI-002 Rev F  
 
CathVision ApS 
 
 
Page 3 of 39 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
   
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
e 
 
 
 
 

 
 
CIP – CPVI-002 Rev F  
 
CathVision ApS 
 
 
Page 4 of 39 
 
 
 
PROTOCOL SYNOPSIS 
 
Title 
Automated assessment of pulmonary vein isolation (PVI) using a novel 
EP recording system (CathVision Cube® System). 
Investigational 
Device 
CathVision Cube® System 
Objectives 
The primary objective is to validate the PVI Analyzer software with a 
novel EP recording system (CathVision Cube® System) for assisting 
assessment of isolation status following PVI ablation.  
The secondary objective is to determine the feasibility of "real-time" 
assessment of PVI analysis and rhythm dependent performance using the 
PVI Analyzer and CathVision Cube® System. 
Study Design 
A prospective, multi-center study with the CathVision Cube® system 
and the PVI Analyzer software in radiofrequency (RF), cryo balloon and 
pulse field ablation (PFA) procedures. 
Subjects with paroxysmal or persistent atrial fibrillation (AF) who are 
indicated to undergo first PVI procedure and meet all eligibility criteria 
will be enrolled in the Study. Intracardiac signals will be passively 
recorded using the investigational CathVision Cube® System in parallel 
with the commercial (CE marked) LabSystem Pro, Boston Scientific EP 
recording system. The investigational device will not be used for direct 
clinical care decisions or therapy. 
The validation of the automated algorithm for PVI will be performed 
offline. 
Sample size 
Up to 90 subjects shall be enrolled across participating sites to reach a 
sample size of 210 EGMs required for the primary endpoint of the study. 
 
 
Up to 30 additional subjects may be enrolled for the PFA procedure
 
 Thus, the 
total sample size will be 120 subjects.
 
 
Investigational 
Sites 
Four (4) investigational sites in Europe: 
 
 
Study 
Duration / 
Follow-up 
Period 
 
 
Subjects will have clinical follow-ups until discharged from the hospital. 

 
 
CIP – CPVI-002 Rev F  
 
CathVision ApS 
 
 
Page 5 of 39 
 
 
 
Primary 
Performance 
Endpoint 
 
Assessment of performance of automated PVI Analyzer classification of 
PV isolation in sinus rhythm (SR) during pulmonary vein isolation 
(PVI) treatment. 
 
Secondary 
performance 
Endpoints 
The secondary performance endpoints are: 
• Accuracy of automated PVI Analyzer classification of PV 
isolation in SR during PVI Cryo-balloon ablation 
• Accuracy of automated PVI Analyzer classification of PV 
isolation in SR during RF ablation 
• Assessment of automated PVI Analyzer classification of PV 
isolation in SR after PFA  
• Feasibility of continuous "real-time" assessment of isolation 
• Feasibility of assessment of isolation during AF rhythm 
• Feasibility of assessment of isolation at time of expert-defined 
isolation before the end of the ablation procedure 
• Comparison of device performance on same data recorded by 
CathVision Cube and Boston Scientific LSPro 
 
Safety 
Endpoint 
Evaluation of adverse events and/or device malfunctions reported with 
the use of the CathVision Cube® System during the procedure until 
discharge. 
Enrollment 
Criteria 
Inclusion Criteria 
Eligible subjects will meet all of the following inclusion criteria:  
 
1. Subjects undergoing first time pulmonary vein isolation indicated 
by investigator for the treatment of atrial fibrillation.  
2. Male or non-pregnant female aged ≥21 years.  
3. Able and willing to provide written informed consent prior to any 
clinical investigation related procedure  
Exclusion Criteria 
Eligible subjects will not meet any of the following exclusion criteria: 
 
1. Pregnant or nursing subjects. 
2. Current participation in another investigational drug or device 
study that interferes with this Study. 
3. Subjects who, in the opinion of the investigator, are not candidates 
for this Study. 
4. Patients who have had a prior ablation procedure 
5. Presence of other anatomic or comorbid conditions, or other 
medical, social, or psychological conditions that, in the 
investigator's opinion, could limit the subject's ability to 

 
 
CIP – CPVI-002 Rev F  
 
CathVision ApS 
 
 
Page 6 of 39 
 
 
 
participate in the clinical investigation or to comply with follow-
up requirements, or impact the scientific soundness of the 
clinical investigation results. 
6. Life expectancy less than 12 month, in the opinion of the 
investigator 
7. Subjects who, in the opinion of the investigator, are considered 
part of any vulnerable population. 

 
 
CIP – CPVI-002 Rev F  
 
CathVision ApS 
 
 
Page 7 of 39 
 
 
 
TABLE OF CONTENTS 
1 
INTRODUCTION ................................................................................................................ 10 
1.1 
Cardiac electrophysiology ............................................................................... 10 
1.2 
Intracardiac electrophysiology signals during cardiac electrophysiology 
procedures ....................................................................................................................... 10 
1.3 
Rationale for this Clinical Investigation .......................................................... 10 
2 
DEVICE DESCRIPTION ...................................................................................................... 11 
2.1 
Name of the Device(s) Under Investigation .................................................... 11 
2.2 
 
2.3 
 
 
2.4 
Device Labelling and Handling ....................................................................... 12 
3 
RISK-BENEFIT ANALYSIS ................................................................................................. 13 
4 
CLINICAL INVESTIGATION PLAN (CIP) ............................................................................ 13 
4.1 
Study Objectives .............................................................................................. 13 
4.2 
Study Design .................................................................................................... 14 
4.3 
Study Duration ................................................................................................. 14 
4.4 
Site Selection ................................................................................................... 14 
4.5 
Subject Population and Eligibility Criteria ...................................................... 15 
Inclusion Criteria 15 
Exclusion Criteria ........................................................................................................... 15 
5 
STUDY ENDPOINTS .......................................................................................................... 16 
5.1 
Primary Performance Endpoint........................................................................ 16 
Safety Endpoint 16 
5.2 
Secondary Performance Endpoints .................................................................. 16 
5.3 
Study Procedures ............................................................................................. 17 
Informed Consent............................................................................................................ 17 
Subject Identification ...................................................................................................... 17 
5.4 
Visits ................................................................................................................ 18 
Schedule of assessments and Visits ................................................................................ 18 
Visit 1: screening visit .................................................................................................... 18 
Screen Failures 19 
Visit 2: index procedure .................................................................................................. 19 
Visit 3: discharge 19 
5.5 
Study Completion ............................................................................................ 19 
Upon Study termination, if applicable, the Competent Authorities and ECs will be 
notified. 19 
Completed Cases 19 
Withdrawn Subjects ........................................................................................................ 19 
Premature Study Termination ......................................................................................... 20 
5.6 
Investigational Device Accountability ............................................................. 21 
6 
EXAMINATIONS AND EVALUATIONS ................................................................................ 21 
6.1 
Demographics .................................................................................................. 21 
6.2 
Cardiac and Arrythmia Medical History.......................................................... 21 
6.3 
Cardiac Medications ........................................................................................ 21 

 
 
CIP – CPVI-002 Rev F  
 
CathVision ApS 
 
 
Page 8 of 39 
 
 
 
6.4 
12-Lead ECG ................................................................................................... 22 
6.5 
Pregnancy Test (women of childbearing potential only) ................................. 22 
7. 
SAFETY REPORTING AND DEVICE DEFICIENCIES.............................................................. 22 
7.1 
Adverse Events Definitions ............................................................................. 22 
7.3 
Assessment of Adverse Events ........................................................................ 24 
7.4 
Reporting/Recording of AEs............................................................................ 25 
7.5 
Adverse Events Requiring Expedited Reporting ............................................. 25 
7.5.1 
Investigator Responsibilities ............................................................................. 25 
7.5.2 
Sponsor Responsibilities ................................................................................... 25 
7.6 
Anticipated Adverse Events Related to the CathVision Cube® System ......... 26 
7.7 
Anticipated EP-Procedure Adverse Events ..................................................... 26 
7.8 
Device Deficiencies ......................................................................................... 27 
8 
STATISTICAL METHODS ................................................................................................... 29 
8.1 
 
8.2 
Sample Size Calculation .................................................................................. 29 
8.3 
Descriptive Analyses ....................................................................................... 31 
9 
COMPLIANCE .............................................................................................................. 31 
9.1 
Ethics Committee (EC) .................................................................................... 31 
9.2 
Competent Authority (CA) .............................................................................. 31 
9.3 
Good Clinical Practice Statement .................................................................... 32 
9.4 
Investigator responsibilities ............................................................................. 32 
9.5 
Sponsor Responsibilities .................................................................................. 33 
9.6 
Clinical Investigation Plan Amendments......................................................... 33 
10 
STUDY CONDUCT ............................................................................................................. 33 
10.1 
Informed Consent Process ............................................................................... 33 
10.2 
Study Training ................................................................................................. 34 
10.3 
Study Monitoring and Source Document Verification .................................... 34 
10.4 
 
10.5 
Protocol Deviations .......................................................................................... 35 
10.6 
Insurance .......................................................................................................... 36 
10.7 
 
10.8 
Confidentiality ................................................................................................. 37 
10.9 
Record Keeping and Retention ........................................................................ 37 
10.10 
 
10.11 
Publication Policy ............................................................................................ 38 
 
 
 

 
 
CIP – CPVI-002 Rev F  
 
CathVision ApS 
 
 
Page 9 of 39 
 
 
 
 
ABBREVIATIONS 
 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
AF 
Atrial Fibrillation 
ASD 
Atrial Septal Defect 
β-HCG 
Beta Human Chorionic Gonadotropin 
CA 
Competent Authority 
CIP 
Clinical Investigatn Plan 
CPK 
Creatinine Phosphokinase 
CS 
Clinically Significant 
CVA 
Cerebrovascular Accident 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EGM 
Electrogram 
EP 
Electrophysiology Procedure 
GCP 
Good Clinical Practices 
GDPR 
General Data Protection Regulation 
LV 
Left Ventricular  
NCS 
Not Clinically Significant 
NSR 
Non-Sinus Rhythm, i.e. AF 
PFA 
Pulse Field Ablation 
PFO 
Patent Foramen Ovale 
PI 
Principal Investigator 
PV  
Pulmonary Vein 
PVI 
Pulmonary Vein Isolation 
RF 
Radiofrequency 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SR 
Sinus Rhythm 
SW 
Software 
TIA 
Transient Ischemic Attack 
TEE 
Transesophageal Echocardiogram 
TTM 
Trans telephonic Monitoring 
UADE 
Unanticipated Adverse Device Effect 
 
 
 
 
 
 
 
 
 
 

 
 
CIP – CPVI-002 Rev F  
 
CathVision ApS 
 
 
Page 10 of 39 
 
 
 
 
 
1 Introduction 
 
1.1 Cardiac electrophysiology 
Of the total worldwide population, 1% and 2% of rural and urban areas suffer from cardiac 
arrhythmia, respectively. Approximately 15% of patients do not respond to drug treatment and 
need a device-based interventional treatment. As a result, there is a great need of cardiac 
arrhythmia ablation1,2,3. Today, however, the exact identification of the mechanism of the 
arrhythmia and subsequent successful ablation treatment are challenging for physicians. The 
three most prevalent arrhythmias ("complex arrhythmias") for catheter ablation are atrial 
fibrillation, atrial tachycardia and ventricular tachycardia.  
 
1.2 Intracardiac electrophysiology signals during cardiac electrophysiology 
procedures 
Cardiac electrograms are generated by the potential (voltage) differences recorded at two 
recording electrodes during the cardiac cycle. All clinical electrogram recordings are 
differential recordings from one source that is connected to the anodal (positive) input of the 
recording amplifier and a second source that is connected to the cathodal (negative) input. 
Unipolar recordings are obtained by positioning the exploring electrode in the heart and the 
second electrode (referred to as an indifferent electrode) distant (theoretically an infinite 
distance) from the heart such that it has little or no cardiac signal. Bipolar recordings are 
obtained by connecting two electrodes that are exploring the area of interest to the recording 
amplifier. At each point in time, the potential generated is the sum of the potential from the 
positive input and the potential at the negative input. The potential at the negative input is 
inverted and thus subtracted from that at the positive input. Because the far-field signal is 
similar at each instant in time, it is largely subtracted out, leaving the local signal. In a 
homogeneous sheet of tissue, the initial peak of the bipolar signal coincides with depolarization 
beneath the recording electrode1,2.  
 
1.3 Rationale for this Clinical Investigation 
Electrograms and their interpretation are a key tool for electrophysiologists to target ablation 
sites, and are acquired from electrodes on intracardiac diagnostic catheters and from surface 
electrocardiogram (ECG). Electrograms (EGMs) are usually sampled at 1 to 2kHz, and 
bandpass filtered at 30 to 500Hz for bipolar and 0.5 to 300Hz for unipolar recordings. 64 to 
160 channels are the typical capacity of recording systems today. 
In the operating room, other devices and technologies are present: 3D mapping (triangulation 
of catheter tip position with impedance- and magnetic technology, <0.2 gauss), fluoroscopy/X-
ray, radiofrequency (RF) generator, cryo gas station, stimulator, saline coolant pump for 
ablation catheter RF-tip irrigation, hemodynamics, magnetic catheter steering (0.08T). 
Frequenly the patient is defibrillated to cardiovert them from an arrhythmia. It is common that 
patients have implanted defibrillators (ICDs). 

 
 
CIP – CPVI-002 Rev F  
 
CathVision ApS 
 
 
Page 11 of 39 
 
 
 
It is CathVision's goal to test a PVI Analyzer software intended for assiting assessment of 
pulmonary vein isolation, using a novel electrophysiology recording system with improved 
signal quality. 
An early version of the PVI Analyzer software has been tested and validated previously on 
signals recorded by a conventional EP recording system (Lab-System Pro, Boston 
Scientific)”4,5. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulsed Field Ablation (PFA) is a new ablation modality for the treatment of paroxysmal atrial 
fibrillation through the isolation of pulmonary veins. Instead of using high temperatures to 
destroy cells, as in the case of radio frequency ablation, or extremely low temperatures with 
cryo ablation, PFA uses a technique known as irreversible electroporation where short burst of 
high energy are applied to specific areas which destroy cells and prevent further conduction6. 
This technique has been shown to be fast, effective and safe in studies and this approach is now 
CE approved and commercially available. 
 
2 Device Description 
 
2.1 Name of the Device(s) Under Investigation 
The CathVision Cube® system is under investigation in this Study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
CIP – CPVI-002 Rev F  
 
CathVision ApS 
 
 
Page 13 of 39 
 
 
 
 
Each manufactured device is assigned a unique serial or lot number that is printed on the device 
labeling, providing a means of traceability. 
 
 
 
 
3 Risk-Benefit Analysis 
The clinical investigation has been designed to involve as little pain, discomfort, fear, and any 
other foreseeable risk as possible for subjects. 
 
  
 
 
Potential subject risks include adverse events and potential product failures similar to 
commercially available EP recording systems, with a similar likelihood of occurrence.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
4 Clinical Investigation Plan (CIP) 
4.1 Study Objectives 
The primary objective is to validate the PVI Analyzer software with a novel EP recording 
system (CathVision Cube® System) for assessment of isolation status following PVI ablation.  

 
 
CIP – CPVI-002 Rev F  
 
CathVision ApS 
 
 
Page 14 of 39 
 
 
 
The secondary objective is to determine the feasibility of "real-time" assessment of PVI 
analysis and rhythm dependent performance using the Investigational Device and CathVision 
Cube® System. 
 
4.2 Study Design 
A prospective, multi-center study to evaluate the performance of automated PVI Analyzer 
software with the CathVision Cube® system in RF and Cryo-balloon procedures 
Subjects with paroxysmal or persistent atrial fibrillation (AF) who are indicated to undergo 
first PVIEP procedure and  meet all eligibility criteria will be enrolled in the Study and undergo 
the EP procedure. Intracardiac signals will be passively recorded using the investigational 
CathVision Cube® System in parallel with the commercial (CE marked) Lab-System Pro, 
Boston Scientific EP recording system. 
 
 The EP procedure will be guided by the study site standards 
of care (CLOSE protocol for RF, and routine cryoballoon or PFA procedures according to 
operators preference). 
 
 
 
 
 
 
 
 
 
 
 
4.3 Study Duration 
 
 
 
Subjects will have clinical follow-up until discharged from hospital, regardless of the duration 
of hospitalization. After the EP procedure, the estimated number of days of hospitalization is 
1-2. 
 
4.4 Site Selection 
The Study will be conducted in 4 centers 
 All sites are high-
volume centers experienced in RF ablation procedures 
  
 
 
 
 
 
  
 

 
 
CIP – CPVI-002 Rev F  
 
CathVision ApS 
 
 
Page 15 of 39 
 
 
 
4.5 Subject Population and Eligibility Criteria 
Up to 90 subjects shall be enrolled in the Study, distributed in two different procedures (RF 
and cryo-balloon) according to medical decision and standard of care at the study sites. The 
subjects are distributed among the participating sites with a maximum of 50 subjects per site, 
and a maximum of 25 subjects per procedure type per site. Once enrollment of 90 patients is 
completed, a further 30 subjects with a maximum of 15 per site may be enrolled for treatment 
with PFA, to a maximum of 120 subjects in total. 
Assessment for general eligibility criteria is based on medical records of the site and interview 
with a candidate patient. If some of the clinical and laboratory tests are not included in site 
standard tests, they must be done but after written informed consent is obtained. Patients must 
meet ALL of the inclusion criteria to be considered for the clinical investigation. If ANY of 
the exclusion criteria are met, the patient is excluded from the clinical investigation and cannot 
be enrolled. 
 
Inclusion Criteria 
Eligible subjects will meet all of the following inclusion criteria:  
 
1. Subjects undergoing first-time pulmonary vein isolation indicated by investigator for 
the treatment of atrial fibrillation 
2. Male or non-pregnant female aged ≥21 years.  
3. Able and willing to provide written informed consent prior to any clinical investigation 
related procedure 
Exclusion Criteria 
Eligible subjects will not meet any of the following exclusion criteria: 
 
1. Pregnant or nursing subjects. 
2. Current participation in another investigational drug or device study that interferes 
with this Study. 
3. Subjects who, in the opinion of the investigator, are not candidates for this Study. 
4. Patients who have had a prior ablation procedure 
5. Presence of other anatomic or comorbid conditions, or other medical, social, or 
psychological conditions that, in the investigator's opinion, could limit the subject's 
ability to participate in the clinical investigation or to comply with follow-up 
requirements, or impact the scientific soundness of the clinical investigation results. 
6. Life expectancy less than 12 month 
7. Subjects who, in the opinion of the investigator, are considered part of any vulnerable 
population. 
 
Subject Enrollment 
 
A patient is considered enrolled in the clinical investigation from the moment the patient 
provides written informed consent, has been confirmed to meet all inclusion criteria and none 
of the exclusion criteria, and has undergone initiation of the treatment procedure. 
 

 
 
CIP – CPVI-002 Rev F  
 
CathVision ApS 
 
 
Page 16 of 39 
 
 
 
 
 
 
 
 
 
 
Subjects are enrolled until the maximum of 90 subjects across sites has been reached, 
 
 
 
. Once RF and cryoballoon enrolment is complete, 30 additional PFA subjects will be 
enrolled at three sites. This additional data will be analyzed separately, as specified in the 
Stastistical Analysis Plan (SAP). 
 
 
5 Study Endpoints 
5.1 Primary Performance Endpoint 
The primary performance endpoint is to validate the PVI Analyzer analysis software with a 
novel EP recording system (CathVision Cube® System) for assessment of isolation status 
following PVI ablation. The overall performance of PV isolation classification shall be 
superior to a specified level of performance. 
 
1. Automated PVI Analyzer classification of PV isolation in SR during PVI ablation 
treatment with a specificity and sensitivity both superior to 80%. 
 
 
Safety Endpoint 
The safety endpoint of the Study will evaluate the adverse events and/or device malfunctions 
reported with the use of the CathVision Cube® System.
 
 it is expected that AEs 
related to the device and device malfunctions will be minimal or absent. 
 
5.2 Secondary Performance Endpoints 
The secondary performance endpoints shall determine the feasibility of "real-time" assessment 
of PVI analysis and rhythm dependent performance using the PVI Analyzer software with the 
CathVision Cube® System: 
 
1. Accuracy of automated PVI Analyzer classification of PV isolation in SR during PVI 
Cryo-balloon ablation with a specificity and sensitivity superior to 80%. 
2. Accuracy of automated PVI Analyzer classification of PV isolation in SR during RF 
ablation with a specificity and sensitivity superior to 80%. 
3.  Assessment of automated PVI Analyzer classification of PV isolation in SR after 
PFA 
 
4. Feasibility of PVI Analyzer analysis of PV isolation in NSR during PVI ablation 
treatment. 

 
 
CIP – CPVI-002 Rev F  
 
CathVision ApS 
 
 
Page 17 of 39 
 
 
 
5. Feasibility of continuous “real-time” PVI Analyzer analysis during PVI ablation 
treatment. 
6. Performance assessment of PVI Analyzer classification accuracy at the time of 
expert-defined isolation before the end of the PVI ablation procedure. 
7. Comparison of algorithm performance on same data recorded by CathVision Cube 
and Boston Scientific LSPro systems 
 
 
5.3 Study Procedures 
Informed Consent 
The Patient Informed Consent form must receive approval from the Sponsor and Ethics 
Committee (EC) prior to beginning clinical investigation enrollment.  
 
The Investigator or authorized designee (if applicable) will conduct the Informed Consent 
process, as required by applicable regulations and the EC. 
 
 
 
 
 
 
Withdrawal from the clinical investigation will not jeopardize their future medical care or 
relationship with the investigator.  
 
The subject shall be provided with the Informed Consent form written in a language that is 
understandable to the subject and has been approved by the EC. The subject shall have adequate 
time to review, ask questions, and consider participation. 
 
 
 If the subject agrees to participate, the Informed Consent form must be signed and 
dated by the subject and thereafter by the Investigator (or designee) obtaining the consent prior 
to performing any clinical investigation-specific tests of procedures. 
 
 
 
  
 
 
 
 
 
If, during the clinical investigation, new information becomes available that can significantly 
affect a subject's future health and medical care, the Principal Investigator or authorized 
designee (if applicable) will provide this information to the subject. If relevant, the subject will 
be asked to confirm their continuing informed consent in writing. 
 
Subject Identification 
To maintain confidentiality, the subject's name will not be recorded on any study document 
other than the informed consent form. Each enrolled subject will be pseudonymized 
 
 

 
 
CIP – CPVI-002 Rev F  
 
CathVision ApS 
 
 
Page 20 of 39 
 
 
 
remaining in the Study compromises the subject's health or the subject is not sufficiently 
cooperative.  In either event, reason(s) for withdrawal should be recorded when provided or 
available. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Premature Study Termination 
The Sponsor, Ethics Committee, or Competent Authority have the right to suspend or terminate 
the Study prematurely for any safety, ethical or administrative reason at any time. In addition, 
Investigators can terminate the Study at their sites if considered necessary. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 

 
 
CIP – CPVI-002 Rev F  
 
CathVision ApS 
 
 
Page 21 of 39 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
5.6 Investigational Device Accountability 
 
 
 Investigational devices are to be used only in accordance with this CIP and under 
supervision of the PI or a duly designated person.  It is the PI's responsibility to ensure that all 
study devices are kept in a secure location, with access limited to individuals authorized by the 
investigator.  
 
 
 
 
 
 
6 Examinations and Evaluations 
6.1 Demographics 
 
 
6.2 Cardiac and Arrythmia Medical History 
 
 
 
  
 
 
 
 
6.3 Cardiac Medications 
 
 
 
 
 
 
 
 
 
 
 

 
 
CIP – CPVI-002 Rev F  
 
CathVision ApS 
 
 
Page 23 of 39 
 
 
 
 
 
 
Note: Unchanged, chronic, non-worsening or pre-existing conditions are not AEs and should 
not be reported. 
 
7.2 Serious Adverse Event Definition 
 
If the AE meets any of the criteria below, it is regarded as a serious adverse event (SAE).  
 
a) Led to a death, 
b) Led to a serious deterioration in health of the subject, that either resulted in  
1. a life-threatening illness or injury, or 
2. a permanent impairment of a body structure or a body function, or 
3. in-patient hospitalization or prolongation of existing hospitalization, or 
4. medical or surgical intervention to prevent life threatening illness or injury or 
permanent impairment to a body structure or a body function. 
5. chronic disease  
c) Led to fetal distress, fetal death or a congenital abnormality or birth defect. 
 
Note: A planned hospitalization for pre-existing condition, or a procedure required by the 
CIP, without a serious deterioration in health, is not considered to be an SAE. 
 
Additionally, important medical events that may not result in death, be life-threatening or 
require hospitalization may be considered SAEs when they jeopardize the subject or require 
medical or surgical intervention to prevent one of the serious outcomes listed above.  
 
Adverse device effect (ADE) is an AE related to the use of an investigational medical device.  
Note, this definition includes AEs resulting from insufficient or inadequate instructions for use, 
operation, or any malfunction of the investigational medical device.  In addition, this definition 
includes any event resulting from use error or from intentional misuse of the investigational 
medical device. 
 
Serious adverse device effect (SADE) is an ADE that that has resulted in any of the consequences 
characteristic of a SAE. 
 
An unanticipated adverse device effect (UADE) is defined as any serious adverse effect on 
health or safety or any life-threatening problem or death caused by, or associated with, a device, 
if that effect, problem, or death was not previously identified in nature, severity, or degree of 
incidence in predicate devices, or any other unanticipated serious problem associated with a 
device that relates to the rights, safety, or welfare of subjects. 
 
 

 
 
CIP – CPVI-002 Rev F  
 
CathVision ApS 
 
 
Page 25 of 39 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.4 Reporting/Recording of AEs 
Throughout the course of the Study, all efforts will be made by the investigator to remain alert 
to possible AEs.  The first concern will be the safety of the subject, and for providing 
appropriate medical intervention.  
 
  Any AE should be recorded on the appropriate study CRF. 
 
7.5 Adverse Events Requiring Expedited Reporting 
7.5.1 Investigator Responsibilities 
The Investigator is responsible for reporting all SAEs, SADEs, device deficiencies that could 
have led to a SADE, and any new finding in relation to any event previously mentioned. The 
Invertigator should report them to the EC according to national regulations and EC 
requirements.  
 
  
 
The Investigator will document all SAEs and SADEs, including device deficiencies in the study 
subject's file and report it to the Sponsor and to the Sponsor's (Designee) within 24 hours of 
knowledge of event.  
 
 
 
 
 
In the event of a subject's death, the Investigator will make reasonable effort to obtain a copy 
of the autopsy report and/or death summary.  The Investigator will determine the cause of death 
and its relationship to the investigational device; 
 
 
  
7.5.2 Sponsor Responsibilities 
Upon notification of SAEs, the Sponsor will initiate and complete a review and evaluation of 
the event within time frames that will maintain reporting compliance with applicable regulatory 

 
 
CIP – CPVI-002 Rev F  
 
CathVision ApS 
 
 
Page 26 of 39 
 
 
 
agencies.  
 
 
  
 
 
   
 
 
 
 
 
 
 
7.6 Anticipated Adverse Events Related to the CathVision Cube® System 
 
 
 
 
7.7 Anticipated EP-Procedure Adverse Events 
Anticipated complications/AEs are defined as complications/events that can be reasonably 
associated with the EP catheter ablation procedures. The mitigations and treatments for these 
AEs will follow published guidance for the same AEs occurring with other commercially 
available devices [1].     
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
CIP – CPVI-002 Rev F  
 
CathVision ApS 
 
 
Page 27 of 39 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.8 Device Deficiencies 
Device deficiency is defined as an inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, safety or performance, such as malfunction, misuse or use error 
and inadequate information supplied by the manufacturer. This includes the failure of the 
device to meet its performance specifications or otherwise perform as intended.  
 
 

 
 
CIP – CPVI-002 Rev F  
 
CathVision ApS 
 
 
Page 28 of 39 
 
 
 
 
Device malfunction is the failure of an device to perform in accordance with its intended 
purpose when used in accordance with the instructions for use or CIP. 
 
User error: is the act or omission of an act that results in a different medical device response 
than intended by the manufacturer or expected by the user. 
 
The Device Deficiency CRF is specific for reporting all device deficiencies, or malfunctions 
that occur during the course of the Study, whether or not they were associated with an adverse 
event.  Device Deficiency CRFs should be submitted to the Sponsor within 24 hours of the 
occurrence defining the device deficiency. 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
CIP – CPVI-002 Rev F  
 
CathVision ApS 
 
 
Page 29 of 39 
 
 
 
 
 
 
 
 
  
 
 
 
 
8 Statistical Methods 
 
A detailed description of the protocol for the statistical analysis of each specified endpoint is 
given in the Statistical Analysis Plan (SAP). This includes the plan for interim and final 
analyses.  
 
8.1 Study Population 
 
 
 
 
 
 
 
 
8.2 Sample Size Calculation 
This Study is intended to demonstrate that the performance of the PVI Analyzer software is 
superior to clinically relevant performance level, as established by prior publications. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
CIP – CPVI-002 Rev F  
 
CathVision ApS 
 
 
Page 30 of 39 
 
 
 
 
 
 
 
 
 
a clinically relevant lower limit of performance has been established and 
defined as 80% specificity and 80% sensitivity. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. In total, 90 
subjects are expected to be required to reach the sample size requirement for both specificity 
and sensitivity. 
 
In conclusion, a maximum of 90 subjects will be required. 
 
 
 
 
 
A Chow S, Shao J, Wang H. 2008. Sample Size Calculations in Clinical Research. 2nd Ed. Chapman & 
Hall/CRC Biostatistics Series. 

 
 
CIP – CPVI-002 Rev F  
 
CathVision ApS 
 
 
Page 31 of 39 
 
 
 
each site shall enroll a maximum 25 subjects for RF and Cryo, respectively (50 subjects 
maximum per site). 
 
A cohort of 30 subjects undergoing PFA will be added to the study, 
 
 
 
 
8.3 Descriptive Analyses 
Continuous variables will be summarized using standard quantitative statistics: number of non-
missing observations, mean, standard deviation, median, quartiles and range (minimum and 
maximum observed values). The number of missing observations, if any, will also be 
summarized. 
 
Categorical variables will be summarized using classical frequency statistics: number of non-
missing observations and percentages by categories.  Number and percent of missing data, if 
any, will also be summarized. 
 
 
 
 
 
 
 
9 COMPLIANCE 
 
9.1 Ethics Committee (EC)  
Prior to the initiation of the Study, the CIP, and the informed consent form will be submitted 
to the EC for approval.  By signing the Clinical Study Agreement, the investigator is assuring 
that an EC will be responsible for the initial and continuing review of the proposed Study.  A 
copy of the EC approval letter for the CIP, the informed consent, and the CIP signature page 
must be submitted to the Sponsor or its Designee prior to release of investigational supplies to 
the study site.  The approval letter must refer to the specific CIP and the informed consent 
form.  Any Investigator who is also a member of the EC is not to participate in the study 
approval decision.  This non-participation must be noted in the approval letter.  
 
 
   
 
 
 
 
9.2 Competent Authority (CA) 
The Study will be reviewed by the relevant Competent Authority as well.  The Sponsor or its 
Designee is responsible for obtaining regulatory approval for the Study from the relevant 
Competent Authority.  No subjects may be enrolled in the Study until written notification of 
such approval has been given by the Sponsor.  The Sponsor or its Designee is responsible for 
reporting SAE and Device Deficiencies that might have led to a SADE as appropriate to the 

 
 
CIP – CPVI-002 Rev F  
 
CathVision ApS 
 
 
Page 32 of 39 
 
 
 
relevant Competent Authority.  
 
 
 
 
The Study will not start without the written approval of the EC and the Competent Authority. 
Upon Study termination, if applicable, the Competent Authorities and ECs will be notified. 
 
9.3 Good Clinical Practice Statement  
This Study will be conducted in compliance with the CIP, the signed Clinical Study Agreement 
and with the ethical principles stated in the latest version of the Declaration of Helsinki (2013), 
the applicable guidelines for good clinical practices, EU MDR 2017/745, EN ISO 14155:2020 
(Clinical Investigation of Medical Devices for Human Subjects – Good Clinical Practice), and 
the applicable local and international regulations, in order to provide the greatest protection of 
the individual.  Any deviations from the CIP that may affect the safety and welfare of study 
participants will be immediately reported to the Sponsor and to the Ethics Committee (EC) 
 
 
 
9.4 Investigator responsibilities 
The Principal Investigator of an investigational site is responsible for ensuring that the Study 
is conducted in accordance with the Clinical Study Agreements, the CIP, ISO 14155:2020, 
ethical principles that have their origins in the Declaration of Helsinki, any conditions of 
approval imposed by the reviewing EC, and prevailing local and/or country laws and/or 
regulations, whichever affords the greater protection to the subject.  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  

 
 
CIP – CPVI-002 Rev F  
 
CathVision ApS 
 
 
Page 33 of 39 
 
 
 
• 
 
 
 
  
 
  
 
9.5 Sponsor Responsibilities 
All information and data sent to the Sponsor concerning subjects or their participation in this 
Study will be considered confidential. Only authorized Sponsor or Sponsor's Designee will 
have access to these confidential records. Authorized regulatory personnel have the right to 
inspect and copy all records pertinent to this Study.
 
 
 All data used in the analysis and reporting of this 
Study will be without identifiable reference to specific subject name and will be 
pseudonymized.
 
 
 
 
 
 
 
 
 
 
 
9.6 Clinical Investigation Plan Amendments 
 
  All CIP modifications must be approved by the CA/EC before 
implementation.   
 
 
10 Study Conduct 
 
10.1 Informed Consent Process 
It is the responsibility of the Investigator to inform each subject prior to the screening 
evaluation, of the purpose of this Study, including possible risks and benefits and document 
the informed consent process in the subject's chart.  Any changes made to the informed consent 
must be approved by the Sponsor or its Designee, prior to submission to an EC.  After approval 
by the Sponsor or its Designee, the informed consent must be submitted to and approved by 
the applicable EC.   
The process of obtaining informed consent at a minimum shall include the following steps: 
• Ensure that the principal investigator or its authorized Designee conducts the informed 
consent process 
• Include all aspects of the clinical investigation that are relevant to the subject's decision 
to participate throughout the clinical investigation 
• Avoid any coercion or undue improper influence on, or inducement of, the subject to 
participate 

 
 
CIP – CPVI-002 Rev F  
 
CathVision ApS 
 
 
Page 34 of 39 
 
 
 
• Not waive or appear to waive the subject's legal rights 
• Use native non-technical language that is understandable to the subject 
• Provide ample time for the subject to read and understand the informed consent form 
and to consider participation in the clinical investigation 
• Include personally dated signatures of the subject and the principal investigator or an 
authorized Designee responsible for conducting the informed consent process 
• Provide the subject with a copy of the signed and dated informed consent form and any 
other written information 
Ensure important new information is provided to new and existing subjects throughout 
the clinical investigation  
One original informed consent form is to be retained by the study site and a copy is to be given 
to the subject.  
 
 
 
The informed consent must be written in a language in which the subject is fluent.  If a foreign 
language translation is required, a statement of certification of the translation must be issued.  
Regulations require that foreign language informed consent forms be submitted to the EC for 
approval.  The investigator must forward a copy of the consent form, the certified foreign 
language translation and an EC approval letter to the Sponsor or its Designee. 
 
10.2 Study Training 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Documentation of training will be maintained up to date and periodically reviewed by 
the CRO 
 
 
 
 
10.3 Study Monitoring and Source Document Verification 
 
 
   

 
 
CIP – CPVI-002 Rev F  
 
CathVision ApS 
 
 
Page 35 of 39 
 
 
 
 
During the Study, the CRA will visit the study facilities regularly and utilize telephone and 
written communications on an ongoing basis to ensure adherence to the Protocol, ICH-GCP, 
SOPs and applicable regulatory requirements, maintenance of trial-related source records, 
completeness, accuracy, and verifiability of CRF entries compared to source data..  
 
 
 
  
 
  
 
 
 
 
 
 
Subject safety will be ensured by noting that the consent was properly documented, the CIP 
was followed, and that AEs were reported and followed-up as appropriate. 
 
 
 
 
  
 
10.4 Study Close-out 
 
 
 
 
   
 
10.5 Protocol Deviations 
A protocol deviation is any noncompliance with the CIP, GCP, or IFU requirements. The 
noncompliance may be either on the part of the subject, the investigator, or the trial staff. 
 
   
 
 
 
 
Protocol Deviations must be documented on the appropriate Protocol Deviation CRF within 
30 days of awareness of the deviation. 
 
 
 
 
 

 
 
CIP – CPVI-002 Rev F  
 
CathVision ApS 
 
 
Page 36 of 39 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
10.6 Insurance 
In order to cover possible damage to health, in relation to participation in this Study, the 
Sponsor, has, as required by law, obtained appropriate insurance coverage. 
 
10.7 Data Handling 
 
  
 
 
 
 
   
 
 
    
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
CIP – CPVI-002 Rev F  
 
CathVision ApS 
 
 
Page 37 of 39 
 
 
 
 
 
 
 
 
 
10.8 Confidentiality 
In accordance with GCP and with the national data protection laws, all information concerning 
the subjects in the Study must be treated as strictly confidential by all persons involved in the 
Study.   Health data will be recorded and forwarded to the Sponsor or its Designee, participating 
EC and Competent Authorities, for evaluation as required. Data processing will be performed 
in compliance with the EU General Data Protection Regulation (GDPR) 2016/679, and all 
applicable national laws. 
 
Any information that is obtained in connection with this Study that can be identified with the 
subjects will remain confidential.  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
At the end of the trial, all records will continue to be kept in a secure location for as long 
a period as dictated by the reviewing EC, Institutional policies, or sponsor requirements. 
 
10.9 Record Keeping and Retention 
Data generated for the Study should be stored in a limited-access file area and be accessible 
only to Designees of the study site, the Sponsor and its Designees and relevant health 
authorities/regulatory agencies.  All reports and communications relating to study subjects will 
identify subjects only by subject identification number and will be pseudonymized.  Complete 
subject identification will be kept by the investigator.  This information will be treated with 
strict adherence to professional standards of confidentiality. The Investigator is ultimately 
responsible for maintaining all essential trial documentation and source documentation. 
 
 
 

 
 
CIP – CPVI-002 Rev F  
 
CathVision ApS 
 
 
Page 39 of 39 
 
 
 
11. REFERENCES