Collection of ECG Signals From Various Patient Groups for the Development of Algorithms for Sensing and Detection of Rhythm Anomalies
Phase: NA
Conditions: Heart Diseases, Rhythm; Abnormal
Sponsor: Biotronik SE & Co. KG

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Document Title: 
Clinical Investigation Plan for the BIO|CONCEPT.ECG-
Library Study 
Document Version and Date: 
Version 1-0, 28-NOV-2019 
ClinicalTrials.gov Identifier: 
NCT04243070 
 

This document contains confidential information and should be maintained in a 
secure location and should not be copied or made available for review by any 
unauthorized personnel. 
 
 
 
 
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FOR-137-014-F / SOP-137-020.020 / CRQ170002722 
 
 
 
 
Clinical Investigation Plan 
for the 
BIO|CONCEPT.ECG-Library 
 
Collection of ECG signals from various patient groups for the development of 
algorithms for sensing and detection of rhythm anomalies 
 
 
 
Reference Number:   
RD023 
Version  
 
 
1.0 
Date of CIP:  
 
28-NOV-2019 
 
 
 

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Director Clinical Project 
Management 
 
 
 
 
 
BIOTRONIK SE & Co. KG 
Center for Clinical Research  
Woermannkehre 1 
D-12359 Berlin 
 
Date 
 
Signature 
 
 
 
 
 
Project Manager 
 
 
 
 
 
BIOTRONIK SE & Co. KG 
Center for Clinical Research  
Woermannkehre 1 
D-12359 Berlin 
 
Date 
 
Signature 
 
 
 
 
 
 
 
 
 
 
 
 
Sponsor 
BIOTRONIK SE & Co. KG 
Woermannkehre 1 
D-12359 Berlin 
 
 
 
 
 
 
List of principal investigators, investigation(al) sites, and institutions 
A current list of the principal investigators at each investigational site, the address details for 
each investigational site, the emergency contact details for the principal investigator at each 
site and a detailed list of sponsor contacts are filed in the Central File.  

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Signature of the Principal Investigator 
 
 
Name: 
_____________________________________________________________ 
 
Institution: 
_____________________________________________________________ 
 
 
 
_____________________________________________________________ 
 
 
Street: 
_____________________________________________________________ 
 
 
ZIP code/ City: _____________________________________________________________ 
 
 
Country: 
___________________________________________________________________________ 
 
 
 
 
I have read this Clinical Investigation Plan (CIP) and agree to adhere to the requirements 
described in this study protocol. 
I will provide copies of this study protocol and all necessary information about this study to the 
staff under my supervision. 
I will discuss this material with them and ensure they are fully informed about the devices 
under investigation as well as all aspects concerning the conduct of this study. 
 
 
 
_________________________ 
_____________________________________________ 
City, date 
Signature of Principal Investigator 
 

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TABLE OF CONTENTS 
 
TABLE OF CONTENTS .................................................................................................. 4 
1 
LIST OF ABBREVIATIONS ................................................................................... 8 
2 
SYNOPSIS ........................................................................................................... 9 
3 
INTRODUCTION ................................................................................................ 11 
4 
INVESTIGATIONAL DEVICE............................................................................... 12 
4.1 
Summary description of the device and its intended purpose .................................. 12 
4.2 
Intended patient population and indications .......................................................... 12 
4.3 
Summary of training and experience needs ........................................................... 12 
5 
JUSTIFICATION FOR THE DESIGN OF THE CLINICAL INVESTIGATION .............. 13 
5.1 
Pre-clinical data and Clinical data ......................................................................... 13 
5.2 
Justification....................................................................................................... 13 
6 
RISKS AND BENEFITS OF THE DEVICE AND CLINICAL INVESTIGATION ............ 14 
6.1 
Anticipated clinical benefits ................................................................................. 14 
6.2 
Anticipated risks ................................................................................................ 14 
6.2.1 
Anticipated adverse device effects ................................................................... 14 
6.2.2 
Residual risks associated with the device .......................................................... 14 
6.2.3 
Risk associated with participation in the study ................................................... 14 
6.3 
Steps to control or mitigate the risks .................................................................... 14 
6.4 
Risk-to-benefit rationale ..................................................................................... 15 
7 
OBJECTIVES AND HYPOTHESES ........................................................................ 16 
7.1 
Objectives ........................................................................................................ 16 
7.2 
Endpoints and hypotheses .................................................................................. 16 
7.3 
Further data of interest ...................................................................................... 16 
8 
DESIGN OF THE CLINICAL INVESTIGATION ...................................................... 17 
8.1 
General considerations ....................................................................................... 17 
8.1.1 
Type of clinical investigation............................................................................ 17 
8.1.2 
Measures taken to minimize or avoid bias ......................................................... 17 
8.1.3 
Methods ....................................................................................................... 17 
8.1.3.1 
CRFs ........................................................................................................ 17 
8.1.3.2 
Source Data verification.............................................................................. 17 
8.1.3.3 
Allocation of patients to a subgroup by the sponsor ........................................ 18 
8.1.4 
Replacement of subjects ................................................................................. 18 
8.2 
Used devices ..................................................................................................... 18 
8.2.1 
List of any other medical device to be used during the investigation ..................... 18 

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8.2.2 
Number of investigational devices to be used and a justification .......................... 18 
8.3 
Subjects ........................................................................................................... 18 
8.3.1 
Description of patient population ..................................................................... 18 
8.3.2 
Inclusion criteria ............................................................................................ 18 
8.3.3 
Exclusion criteria ........................................................................................... 19 
8.3.4 
Drop-out criteria ............................................................................................ 20 
8.3.4.1 
Drop-out criteria according to protocol ......................................................... 20 
8.3.4.2 
Withdrawal of patient consent ..................................................................... 20 
8.3.5 
Point of enrollment and study termination ......................................................... 20 
8.3.6 
Timelines ...................................................................................................... 20 
9 
STUDY PROCEDURES ........................................................................................ 21 
9.1 
Overview .......................................................................................................... 21 
9.2 
Enrollment/Baseline visit .................................................................................... 21 
9.3 
Holter ECG applications ...................................................................................... 22 
9.3.1 
Holter ECG with 3-patch electrode interface for EPS candidates ........................... 23 
9.3.2 
Holter ECG with 10-patch electrode interface for non-EPS candidates ................... 24 
9.3.3 
Holter ECG setup tasks performed by the study staff .......................................... 25 
9.3.4 
Body Motion Test (BMT) ................................................................................. 26 
9.3.5 
24-hour Daily Living Observation (DLO) ............................................................ 27 
9.3.6 
Holter ECG completion and data retrieval .......................................................... 28 
9.4 
Patient reimbursement ....................................................................................... 28 
9.5 
Termination ...................................................................................................... 28 
9.6 
Description of those activities performed by sponsor representative ......................... 29 
9.7 
Responsibilities .................................................................................................. 29 
9.7.1 
Responsibilities of the sponsor ......................................................................... 29 
9.7.1.1 
Project management .................................................................................. 29 
9.7.1.2 
Data Management...................................................................................... 30 
9.7.1.3 
Biostatistician ............................................................................................ 30 
9.7.1.4 
Monitor ..................................................................................................... 30 
9.7.2 
Responsibilities of the investigators .................................................................. 30 
9.7.2.1 
Investigator .............................................................................................. 30 
9.8 
Possible influencing factors on outcome or interpretation of results .......................... 31 
10 
MONITORING PLAN .......................................................................................... 32 
11 
STATISTICAL CONSIDERATIONS ...................................................................... 33 
11.1 
Statistical design, method and analytical procedures .............................................. 33 
11.2 
Sample size ...................................................................................................... 33 
11.3 
Expected drop-out rate ....................................................................................... 33 

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11.4 
Pass/fail criteria ................................................................................................. 33 
11.5 
Provision for an interim analysis .......................................................................... 33 
11.6 
Termination criteria............................................................................................ 33 
11.7 
Procedures for reporting of deviations to the statistical plan .................................... 33 
11.8 
Specification of subgroups .................................................................................. 33 
11.9 
Procedure for accounting of all data for analysis .................................................... 33 
11.10 Handling of missing, unused and spurious data ..................................................... 33 
11.11 Exclusion of data from confirmatory data analysis .................................................. 34 
11.12 Minimum and maximum number of patients per site .............................................. 34 
12 
DATA MANAGEMENT ......................................................................................... 35 
12.1 
Data protection ................................................................................................. 35 
12.2 
Data collection .................................................................................................. 35 
12.3 
Procedures used for data review, CDMS cleaning, and issuing and resolving data queries
 ....................................................................................................................... 35 
12.4 
Procedures for verification, validation and securing of electronic data systems .......... 36 
12.5 
Data retention and archiving ............................................................................... 36 
13 
AMENDMENT PROCEDURES ............................................................................... 37 
14 
DEVIATIONS FROM CLINICAL INVESTIGATION PLAN ....................................... 38 
14.1 
CIP compliance and exceptions ............................................................................ 38 
14.2 
Recording, reporting and analyzing deviations ....................................................... 38 
14.2.1 
Site specific deviations ................................................................................... 38 
14.2.2 
Other deviations ............................................................................................ 38 
14.2.3 
Reporting...................................................................................................... 38 
14.3 
Notification requirements and timelines ................................................................ 38 
14.4 
Actions ............................................................................................................. 38 
15 
DEVICE ACCOUNTABILITY ................................................................................ 40 
16 
STATEMENT OF COMPLIANCE ............................................................................ 41 
16.1 
Applicable ethical standards ................................................................................ 41 
16.2 
Applicable international and national standards ..................................................... 41 
16.3 
Ethics committee and competent authority ........................................................... 41 
16.4 
Statement of adherence to additional requirements ............................................... 41 
16.5 
Statement on subject insurance .......................................................................... 41 
17 
INFORMED CONSENT PROCESS ......................................................................... 42 
17.1 
General considerations ....................................................................................... 42 
17.2 
Special circumstances for informed consent .......................................................... 42 
18 
ADVERSE EVENTS ............................................................................................. 43 
18.1 
Definition of adverse events ................................................................................ 43 
18.2 
Definition of serious adverse events ..................................................................... 43 

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18.2.1 
Patient death ................................................................................................ 43 
18.3 
Anticipated adverse events ................................................................................. 44 
18.4 
Reporting responsibilities .................................................................................... 44 
18.4.1 
Reporting responsibilities of the investigator to sponsor ...................................... 44 
18.4.2 
Reporting responsibilities of the investigator to other parties ............................... 44 
18.4.3 
Reporting responsibilities of the sponsor ........................................................... 45 
18.5 
Reporting timelines ............................................................................................ 45 
18.6 
Emergency contact ............................................................................................ 45 
19 
VULNERABLE POPULATION ............................................................................... 46 
20 
SUSPENSION .................................................................................................... 47 
20.1 
Criteria and procedures ...................................................................................... 47 
20.2 
Requirements for subject follow-up ...................................................................... 47 
21 
PUBLICATION POLICY ...................................................................................... 49 
22 
BIBLIOGRAPHY ................................................................................................. 50 
 

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1 
LIST OF ABBREVIATIONS 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
AF 
Atrial Fibrillation 
AVNRT 
Atrioventricular Nodal Reentrant Tachycardia 
AVRT 
Atrioventricular Reentrant Tachycardia 
BMT 
Body Motion Test 
CA 
Competent Authority 
CDMS 
Clinical Data Management System 
CF 
Compact Flash 
CIP 
Clinical Investigation Plan 
CRA 
Clinical Research Associate 
DLO 
Daily Living Observation 
EC 
Ethic Committee 
ECG 
Electrocardiogram 
CRF 
electronic Case Report Forms 
EPS 
Electrophysiology Study 
FDA 
US Food and Drug Administration 
FPI 
First Patient In 
ICD 
Implantable Cardioverter Defibrillator 
ICF 
Informed Consent Form 
ID 
Identification Number 
ILR 
Implantable Loop Recorder 
ISO14155 
International Organization for Standardization, norm no. 14155 
LBBB 
Left Bundle Branch Block 
LPI 
Last Patient In 
LPO 
Last Patient Out 
NYHA 
New York Heart Association 
PI 
Principal Investigator 
RBBB 
Right Bundle Branch Block 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
VES  
Ventricular Extrasystole 
VT 
Ventricular Tachycardia 
WPW 
Wolff-Parkinson-White 
 

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2 
SYNOPSIS 
 
Title 
Collection of ECG signals from various patient groups for 
the development of algorithms for sensing and detection of 
rhythm anomalies 
Patient population 
Patients from the investigator’s general collective and with 
different forms of diagnosed arrhythmias and/or specific 
ECG characteristics from heart diseases as listed in the 
inclusion criteria.  
Design 
Prospective, multicenter, non-randomized, interventional 
Objectives 
Collect data from surface ECGs by using Holter ECG 
recordings from patients with different forms of diagnosed 
arrhythmias and/or specific ECG characteristics from heart 
diseases to support the development of new sensing and 
detection algorithms for implants.  
Endpoints 
Number of successful ECG recordings per condition  
Additional Data of Interest 
• 
Demographic data, medical history, ECG diagnosis 
• 
Adverse Events related to the study procedure  
• 
Optional: chest x-ray, only if available and part of a 
procedure prior to enrollment   
Inclusion criteria 
• 
Patient is able to understand the nature of the study 
and willing to provide written informed consent 
• 
Patient is willing and able to attend Holter ECG 
procedure following a visit 
• 
History of at least one of the following conditions 
(established via ECG prior to enrollment):  
(A) Patient with pacemaker/ICD and 
1. Ventricular stimulation > 30 % or 
(B) Patient either without pacemaker/ICD, or with 
pacemaker/ICD but without significant atrial and 
ventricular stimulation, and at least one of the 
following:   
2. Frequent 
Ventricular 
Extrasystoles 
(VES) 
(incl. 
Bigeminus) or 
3. Atrioventricular 
Reentrant 
Tachycardia 
(AVRT)/ 
Wolff-Parkinson-White (WPW) syndrome or 
4. Atrioventricular 
Nodal 
Reentrant 
Tachycardia 
(AVNRT) or 
5. Sinus Tachycardia at rest or 
6. Atrial Flutter or 
7. Any form of Ventricular Tachycardia (VT) or 
8.  Silent/paroxysmal/persistent/permanent AF or 
9. Brugada syndrome or 
10. Long QT syndrome or 
11. Right Bundle Branch Block (RBBB) or 

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12. Left Bundle Branch Block (LBBB) or 
13. Myocardial Ischemia/Acute Myocardial Infarction or 
14. Other abnormal QRS(T) complex, ST segment or T-
wave morphology, i.e. any other 
o 
QRS anomaly 
o 
ST segment elevation 
o 
ST segment depression 
o 
T wave changes  
Exclusion criteria 
• 
Any condition which precludes the patient’s ability to 
comply with the study requirements  
• 
Known allergy to patch electrodes  
• 
Pregnant or breast feeding  
• 
Less than 18 years old  
• 
Participation 
in 
another 
interventional 
clinical 
investigation 
Study duration 
Approx. 
January 
2020 
– 
November 
2020 
(approx. 11 months) 
Sample size 
100 patients 
Investigational sites 
Approx. 5 
Number of follow-ups per 
patient 
• 
One investigational procedure scheduled, in general in 
conjunction to a routine follow-up. 
• 
In case of participation in the Daily Living Observation: 
One visit for the return of the Holter ECG device. 
Follow-up scheme 
Scheduling of patient enrollment and data collection, 
including Holter ECG recording, is left to the investigator’s 
discretion. It is expected that in most cases this will happen 
in conjunction to a routine follow-up. 
Study procedures: 
• 
Enrollment 
• 
Holter 
ECG 
Recording 
(procedure 
depending 
on 
inclusion criteria): 
- 
3-Patch Holter ECG Recording: Holter Recording 
during Electrophysiological Studies (EPS) followed 
by 24-hour Holter ECG Recording with Daily Living 
Observation (optional) 
- 
10-Patch 
Holter 
ECG 
Recording: 
Holter 
ECG 
recording during Body Motion Test followed  by 24-
hour Holter ECG Recording with Daily Living 
Observation 
• 
Termination 
Sponsor 
BIOTRONIK SE & Co. KG 
Woermannkehre 1 
D-12359 Berlin 

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3 
INTRODUCTION 
In cardiology, a variety of biomedical implants uses Electrocardiograms (ECGs) from various 
types of electrodes for different diagnostic and therapeutic purposes. For subcutaneous ECG 
recorders and subcutaneous implantable cardioverter defibrillators (ICDs), placement of their 
subcutaneous electrodes poses a special technical challenge, since an unreliable signal 
detection limits the performance of these implants [1][2].   
For all such devices, signal quality is highly dependent on the positioning and type of 
electrode. It is assumed that ECGs obtained from surface patch electrodes are similar to those 
from subcutaneous electrodes [3]. 
In this study, data gathered from various patient groups with heart rhythm disorders and ECG 
anomalies will be collected and used to improve ECG evaluation and specific algorithms for 
medical devices and implants, such as subcutaneous ICDs or implantable loop recorders.  

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4 
INVESTIGATIONAL DEVICE 
4.1 
Summary description of the device and its intended purpose 
This study will not investigate a medical device or medicinal product. This exploratory 
investigation aims to collect clinical real-life data of different heart conditions which can be 
observed via Holter ECG recordings.  
Therefore no investigational device is defined.  
4.2 
Intended patient population and indications 
According to the exploratory character of the study, the patient population will be chosen from 
the investigator’s general collective and with different forms of diagnosed arrhythmias and/or 
specific ECG characteristics from heart diseases as listed in the inclusion criteria (section 
8.3.2). This can include, but is not limited to: 
• Patients undergoing an electrophysiological study (EPS)  
• Patients attending a routine follow-up for their cardiac disease 
• Patients attending a device follow-up 
• Patients indicated for a pacemaker/ICD implant or exchange 
• Patients indicated for the implantation of an implantable loop recorder (ILR) 
4.3 
Summary of training and experience needs 
All (co-)investigators must have a record of adequate research training and experience. 
Training on ISO 14155 and/or several years of experience in conducting clinical trials are 
generally required. All participating site staff will be trained by the sponsor or its 
representative on the requirements of this Clinical Investigation Plan (CIP). 
The investigator or his designated representative must be familiar with the use of the Holter 
ECG equipment and in conducting Holter ECG recordings. For the placement of the ECG patch 
electrodes, the set-up, and the conduct of the Holter ECG recording, instructions will be given 
in section 9 as well as supporting documents will be provided by the sponsor.  
 
 

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5 
JUSTIFICATION 
FOR 
THE 
DESIGN 
OF 
THE 
CLINICAL 
INVESTIGATION 
5.1 
Pre-clinical data and Clinical data 
Since the aim of this study is to obtain real-life information on ECGs from a variety of different 
arrhythmias and heart conditions via surface ECG, this study set-up is not experimental and 
does not require clinical testing.  
5.2 
Justification 
Subcutaneous ECG recorders and electrodes are implanted for diagnostic monitoring purposes 
and - in case of electrodes - for treatment of occurring arrhythmias. However, unreliable signal 
detection limits the success of such implants. For the development of appropriate detection 
and sensing algorithms in such devices, a prospective and non-randomized design was chosen 
to acquire ECG examples from patient groups with different cardiac indications. In addition, a 
multi-centric approach was chosen to avoid investigator- or site-related bias. 
In previous studies, investigations were mainly conducted to collect ECGs to evaluate the 
placement of electrode specific for implantable loop recorders; however, for the development 
of additional detection and sensing algorithms for electrodes, ECGs from additional electrode 
placements are required.  
Since ECGs vary in the different forms of cardiac diseases, patients exhibiting different forms 
of arrhythmias and/or heart diseases need to be enrolled. Patients will be screened prior to 
enrollment by the study staff for their assignment to one of these groups. If a patient can be 
assigned to more than one subgroup, the resulting ECG will be evaluated internally by the 
sponsor and allocated to one or more subgroups.   

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6 
RISKS 
AND 
BENEFITS 
OF 
THE 
DEVICE 
AND 
CLINICAL 
INVESTIGATION 
6.1 
Anticipated clinical benefits 
The study is designed to gain real life clinical data from various patient groups who suffer from 
different arrhythmias and/or heart diseases. Data gathered in this investigation will be used to 
further the development and improvement of algorithms required for the sensing and detection 
of such arrhythmias. Future patient populations might benefit from the diagnostics and 
therapeutic devices developed by the use of the study data.  
The subject participating in the study may benefit from its study participation in that the 
study-specific ECG recording might reveal a so far unknown medical condition.   
6.2 
Anticipated risks 
6.2.1 Anticipated adverse device effects 
Since no investigational device will be used in the study, no adverse device effects are 
anticipated during the study.  
6.2.2 Residual risks associated with the device 
Since the study does not evaluate an investigational device, no such residual risk can be 
implied. 
6.2.3 Risk associated with participation in the study 
There is a potential risk for the subject to develop skin reactions in response to the application 
of multiple surface ECG electrodes, such as irritation or inflammation. In addition, the subject 
may experience a discomfort caused by wearing the ECG patches, the Holter ECG device, or 
the cabling of the device. Discomfort or dizziness may also occur during the study specific 
Body Motion Test (BMT) during the recordings.  
Unauthorized access to the patient data or inadequate data protection (e.g. submission of non-
pseudonymized data to the sponsor representatives) is a possible risk associated with the 
participation. BIOTRONIK undertakes technical and organizational measures to protect 
patient’s data privacy and adheres to applicable European data protection laws. 
No other risks are anticipated with the participation in the study. 
6.3 
Steps to control or mitigate the risks 
Risks associated with a Holter ECG recording which are mentioned above, as well as in section 
18.3, are minimized through the utilization of hypo-allergenic patch electrodes, compliance 
with the user manual, compliance with this clinical investigation plan and technical procedures, 
adhering to the guidelines for selection of patients, close monitoring of the patient’s 
physiologic status during the procedures, and by promptly supplying BIOTRONIK with all 
pertinent information required by this clinical investigation plan.  
Data protection laws, in particular the Regulation (EU) 2016/679 of the European Parliament 
and of the Council and its Corrigendum dated May 23, 2018 as well its respective national 
versions must be followed where applicable. Thus, patient names may not be used as patient 
IDs. Non-pseudonymized data inadvertently sent to the sponsor will be handled upon 
discovery according to BIOTRONIK’s internal processes to ensure that only pseudonymized 
documents are available at and used by the sponsor. Access to the clinical data management 
system (CDMS) is restricted by secured internet platforms using user IDs and passwords. 
Further details on the risk mitigation regarding the CDMS are outlined in the data management 
plan of the study. Nevertheless, a residual risk remains. 

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6.4 
Risk-to-benefit rationale 
The patient may directly benefit from possible findings or observations, which could prevent 
potential unobserved risks. Possible risks associated with the Holter ECG procedure and the 
Body Motion Test are temporary in nature and in general not considered serious. 
The main long term clinical benefit will derive from substantial improvements of sensing and 
detection algorithms, thus ultimately affecting patient safety by developing new leads and 
devices. 
Therefore it can be concluded that the overall benefits outweigh the risks. 
 

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7 
OBJECTIVES AND HYPOTHESES 
7.1 
Objectives 
The objective is to build a library of surface ECG signals from patient groups with different 
forms of diagnosed arrhythmias and/or specific ECG characteristics from heart diseases. The 
signals will be used to support the development and improvement of algorithms for the 
accurate detection and sensing of rhythm anomalies.  
7.2 
Endpoints and hypotheses 
As described in section 11.2, the number of successful ECGs per condition stated in the 
inclusion criteria (section 8.3.2) was chosen as an endpoint, whereat each condition shall be 
included at least six times and at most ten times; with the exception of ‘Any form of 
Ventricular Tachycardia (VT)’ being included at least twelve times or more.  
There are no predefined hypotheses. 
7.3 
Further data of interest 
• 
Demographic data, medical history, ECG diagnosis 
• 
Adverse Events related to the study procedure 
• 
Optional: chest x-ray, only if already available and part of a procedure (e.g. implantation) 
that occurred prior to enrollment 

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8 
DESIGN OF THE CLINICAL INVESTIGATION 
8.1 
General considerations 
8.1.1 Type of clinical investigation 
The clinical investigation is a prospective, multicenter, non-randomized, interventional data 
collection with no additional follow-up procedures. 
8.1.2 Measures taken to minimize or avoid bias 
A multicenter approach was chosen to reduce bias that might arise from site or investigator 
specific methods and customs. 
8.1.3 Methods  
8.1.3.1 
CRFs 
All procedures that are recorded within the study are described in section 9 and are 
documented on the corresponding electronic case report forms (CRFs). The investigator is 
required to use an electronic signature to approve the content of the data reported in the 
CRFs. BIOTRONIK will monitor the content of the CRFs as described in section 10. Data from 
the following procedures will be collected: 
• Enrollment/Baseline  
• Holter ECG recording, including participation in the Body Motion Test (BMT) and Daily Living 
Observation (DLO) 
• Termination 
The following events can be documented at any time: 
• Adverse Event (AE) 
Source data, e.g. medical records, have to be available for all data entered in the CRFs, unless 
specified differently by this CIP. CRFs will be verified by the sponsor’s clinical monitors. 
If necessary, the sponsor will request pseudonymized electronic source documents (e.g. 
medical records about AEs for the assessment of seriousness and relatedness). 
Patients have to consent to the use of their medical data in the patient file by signing the 
informed consent form.  
8.1.3.2 
Source Data verification  
For the following inclusion/exclusion criteria, the CRF is accepted as source: 
• 
Patient is able to understand the nature of study and willing to provide written informed 
consent 
• 
Patient is willing and able to attend the Holter ECG recording  
• 
Any condition which precludes the patient’s ability to comply with the study             
requirements 
• 
Known allergy to patch electrodes 
• 
Pregnant or breast feeding 
• 
Participation in another interventional clinical investigation according to the definition given 
below. 
The following Source data sheet (SDS) is recommended to be used: 

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• 
Holter ECG recording  
8.1.3.3 
Allocation of patients to a subgroup by the sponsor 
As stated in section 7.2, at least 6 but no more than 10 patients shall be included for each 
subgroup which defined in the inclusion criteria (section 8.3.2), the exception being  ‘Any form 
of Ventricular Tachycardia (VT)’ which shall be included at least 10 times or more.  
A first allocation of the patient to one or more subgroups will be done by the investigator by 
completing the enrollment CRF.  
A subsequent allocation to a single subgroup will be done internally after the evaluation of the 
ECG recording by the sponsor’s research and development department. After reaching the 
desired number in one of the subgroups, the sponsor will announce its closure to the 
participating investigators and data entry will be restricted for patients who are allocated only 
to this single subgroup. 
8.1.4 Replacement of subjects 
During the course of the study, patients who drop out prior to or during the Holter ECG 
recording can be replaced as long as the enrollment phase has not been closed by the sponsor. 
Patients can also be replaced if they prematurely terminate the Holter ECG recording without 
documentation of the intended ECG pattern or if the recording cannot be evaluated due to 
quality issues. Patients in whom the expected ECG-pattern could not be recorded during the 
course of their regular study participation (e.g. patients with paroxysmal AF) will not be 
replaced.   
Due to replacements, the total number of enrolled patients might exceed the planned sample 
size. 
8.2 
Used devices  
8.2.1 List of any other medical device to be used during the investigation 
The following equipment is used during the study to collect data: 
• 
Holter ECG: 
Lifecard CF Holter device with 3-patch interface (Spacelabs Healthcare) 
Lifecard CF Holter device with 10-patch interface (Spacelabs Healthcare) 
Compact Flash Card, 256 MB (Spacelabs Healthcare) 
• 
Software: 
Pathfinder®, Sentinel® (Spacelabs Healthcare) 
8.2.2 Number of investigational devices to be used and a justification 
Not applicable. 
8.3 
Subjects 
8.3.1 Description of patient population 
Data will be collected from patients with cardiac arrhythmias.  
8.3.2 Inclusion criteria 
• 
Patient is able to understand the nature of the study and willing to provide written informed 
consent. 
• 
Patient is willing and able to attend Holter ECG procedure following a visit 
• 
History of at least one of the following conditions (established via ECG prior to enrollment): 
(A) Patient with pacemaker/ICD and 

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1. 
Ventricular stimulation > 30 % or 
(B) Patient either without pacemaker/ICD or with pacemaker/ICD, but without significant 
atrial and ventricular stimulation and at least one of the following:  
2. 
Frequent Ventricular Extrasystoles (VES) (incl. Bigeminus) or 
3. 
Atrioventricular Reentrant Tachycardia (AVRT)/Wolff-Parkinson-White (WPW) 
syndrome or 
4. 
Atrioventricular Nodal Reentrant Tachycardia (AVNRT) or 
5. 
Sinus Tachycardia at rest or 
6. 
Atrial Flutter or 
7. 
Any form of Ventricular Tachycardia (VT) or 
8. 
Silent/Paroxysmal/persistent/permanent AF or 
9. 
Brugada syndrome or 
10. 
Long QT syndrome or 
11. 
Right Bundle Branch Block (RBBB) or 
12. 
Left Bundle Branch Block (LBBB) or 
13. 
Myocardial Ischemia/Acute Myocardial Infarction or 
14. 
 Other abnormal QRS(T) complex, ST segment or T-wave morphology, i.e. any 
other 
o 
QRS anomaly 
o 
ST segment elevation 
o 
ST segment depression 
o 
T wave changes  
 
8.3.3 Exclusion criteria 
• 
Any condition which precludes the patient’s ability to comply with the study             
requirements. 
• 
Known allergy to patch electrodes. 
• 
Pregnant or breast feeding. 
• 
Less than 18 years old. 
• 
Participation in another interventional clinical investigation according to the definition given 
below.1,2 
1Based on the EU Clinical Trials Regulation a study is considered as interventional which fulfils any of the following 
conditions: (a) the assignment of the subject to a particular therapeutic strategy is decided in advance and does not 
fall within normal clinical practice of the Member State concerned; (b) the decision to prescribe the investigational 
medicinal products is taken together with the decision to include the subject in the clinical study; or (c) diagnostic or 
monitoring procedures in addition to normal clinical practice are applied to the subjects. 
2Patients shall not be enrolled in two interventional clinical investigations at the same time. Enrollment of patients who 
are already enrolled into an interventional clinical investigation is prohibited by an exclusion criterion. If the patient 
wants to consent for another study, and the investigator knows this beforehand, the investigator shall ask for an 
agreement from the sponsor, and if not granted, shall ask the patient not to participate in the second study. If the 
investigator finds out that the patient has been enrolled into another study, the investigator shall inform the sponsor 
(see section 9.10.2 ‘Responsibilities of the investigator’). The sponsor may decide to exclude the patient from the 
study only if further CIP required procedures offer a risk of a reciprocal effect with the treatment of the other study. 
Decisions and deviations have to be discussed upfront (if applicable, during the advisory stakeholder meeting) and 
documented respectively (e.g. via Note to File and reported as CIP deviation or supporting document ‘Internal Steering 
Committee’).  

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8.3.4 Drop-out criteria 
8.3.4.1 
Drop-out criteria according to protocol 
The investigator shall prematurely terminate a patient’s study participation due to the following 
reasons: 
• 
Patient is unable or unwilling to proceed with the Holter ECG recording due to 
discomfort when wearing the electrodes.  
• 
Patient is unable or unwilling to proceed with the Holter ECG recording due to 
discomfort or dizziness during the Body Motion Test.  
• 
Holter ECG recording does not take place for any reasons within 14 days after 
enrollment.  
8.3.4.2 
Withdrawal of patient consent 
Patients may withdraw their consent for participation at any time without stating the reason 
and without any unfavorable consequences. All data which are collected until the date of 
withdrawal will be used in pseudonymized form as long as their further processing or retention 
is necessary, e.g. to fulfil a legal obligation. This also applies if the patient has requested data 
erasure. Depending on the patient's will, the collected data will be anonymized once further 
processing or retention is no longer required. A withdrawal sheet and a study termination CRF 
have to be completed by the investigator. 
8.3.5 Point of enrollment and study termination 
The point of enrollment is defined as the time of signature of the informed consent form by the 
patient. Study related procedures, documentation and collection/following of adverse events 
will start from this time on. 
The patient’s study participation ends regularly at the moment when the last study procedure 
according to protocol has been completed. 
The point of non-regular study termination can be the following: 
• 
Date of withdrawal of consent 
• 
Date of patient death  
• 
If patient is a drop-out, the date of last patient related patient contact. 
Study related procedures and data collection must end at the day of study termination.  
8.3.6 Timelines 
First patient in (FPI): 
 
~ Jan 2019 
Last patient in (LPI):  
 
~ Oct 2020 
Enrollment period: 
 
 
~ 10 months 
Last patient out (LPO): 
 
~ Nov 2020 
Duration of study participation: 
up to 30 days, with up to 2 days active study participation 
Finalization of study report  
~ Mar 2021 
All timelines are subject to change without requiring protocol amendments. 
 

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9 
STUDY PROCEDURES 
 
9.1 
Overview 
The following study related procedures (Table 9-1) apply and have to be documented in the 
respective electronic case report form (CRF) for each patient enrolled.  
Table 9-1: Overview of study procedures.  
Investigations 
Enrollment/ 
Baseline  
ECG  
Recording 
(0 to 14 days) 
Termination 
3-Patch 
(EPS) 
10-Patch 
(non-EPS) 
Patient informed consent 
x 
 
 
 
Demographic data 
x 
 
 
 
NYHA class  
x 
 
 
 
ECG history prior to 
enrollment 
x 
 
 
 
Medical history 
x 
 
 
 
ECG during EPS 
 
x 
 
 
Body Motion Test 
 
 
x 
 
Daily Living Observation 
(24-hour ECG) 
 
(x) 
x 
 
Patient diary 
 
(x)1 
x 
 
Return of Holter ECG 
device 
 
 
 
x 
Adverse event reporting 
x 
x 
x 
x 
CRF completion 
x 
x 
x 
x 
EPS = electrophysiological study 
(x) = optional, (x)1 = optional, only during 24 h ECG, x = if applicable 
9.2 
Enrollment/Baseline visit 
Prior to enrollment into the clinical investigation, the investigator has to check whether all 
inclusion criteria are met and confirm the absence of all exclusion criteria. For the enrollment 
to be valid, the informed consent form has to be signed and dated both by the patient and the 
investigator. The date of enrollment is defined as the date the patient signed the informed 
consent. The informed consent process has to be documented in the patient record. After 
obtaining informed consent, the patient has to be registered in the iMedNet System. After 
registration, the patient will be assigned an ID code to be used in the study and the patient 
has to be entered in the patient identification log. The signed informed consent will be verified 
by sponsor appointed monitoring personnel. 
After a subject has been enrolled, the following data have to be collected and entered in the 
respective CRF: 
• 
Date of baseline assessment 
• 
Demographic data  

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• 
Medical history (for NYHA class and ECG diagnostics: within three months prior to 
enrollment) 
Note: Medication shall be documented in the context of adverse events. 
During the baseline visit, the study staff may discuss with the patient their options for 
scheduling the different Holter ECG applications:  
For patients undergoing an EPS procedure, the Holter ECG will be done in conjunction to the 
EPS; however the patient has the option either to deny the Daily Living Observation, to 
continue directly after the EPS procedure (either at home or during his/her hospitalization), or 
to participate at a later point in time (up to 14 days after the EPS procedure). 
For patients participating in the Body Motion Test (‘non EPS candidates’), the Holter ECG can 
be done in conjunction with a routine follow-up or scheduled for a later point in time (up to 14 
days after enrollment). After completion of the Body Motion Test, the patient shall be asked 
whether he/she wants to continue with the Daily Living Observation right after the Body Motion 
Test or at a later point in time (up to 14 days after the Body Motion Test). 
 
9.3 
Holter ECG applications 
EPS candidates get a Holter ECG with a 3-patch electrode interface (section 9.3.1). Typical EPS 
candidates may be patients from the following inclusion groups (compared with inclusion 
criteria, section 8.3.2):  
• 
(2) Frequent Ventricular Extrasystoles (VES) (incl. Bigeminus) 
• 
(3) Atrioventricular Reentrant Tachycardia (AVRT)/Wolff-Parkinson-White (WPW) 
syndrome 
• 
(4) Atrioventricular Nodal Reentrant Tachycardia (AVNRT) 
• 
(6) Atrial Flutter 
• 
(7) Any form of Ventricular Tachycardia (VT) 
• 
(9) Silent/paroxysmal/persistent permanent AF 
• 
(14) Other abnormal QRS(T) complex, ST segment or T-wave morphology 
Non-EPS candidates get a Holter ECG with a 10-patch electrode interface (section 9.3.2). 
Typical non-EPS candidates may be patients attending a routine follow-up for their cardiac 
disease, patients attending a device follow-up or being indicated for implantation or exchange 
of an ICD or pacemaker. They may be from the following inclusion groups (compared with 
inclusion criteria, section 8.3.2): 
• 
(1) Patient with pacemaker/ICD and ventricular stimulation > 30 % 
• 
 (5) Patient with frequent Sinus Tachycardia at rest 
• 
(9) Patient with Brugada syndrome 
• 
(10) Patient with Long QT syndrome  
• 
(11) Patient with Right Bundle Branch Block (RBBB) 
• 
(12) Patient with Left Bundle Branch Block (LBBB) 
• 
(13) Myocardial Ischemia/Acute Myocardial Infarction 
• 
(15) Other abnormal QRS(T) complex, ST segment or T-wave morphology 
However, the decision on whether a patient is included as an EPS candidate or non-EPS 
candidate is at the physician’s discretion. 

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9.3.1 Holter ECG with 3-patch electrode interface for EPS candidates 
If the patient undergoes an EPS procedure, the Holter ECG recording will be done using a 3-
patch electrode interface. The ECG patch electrodes will be placed as shown in Figure 9-1. The 
placement and exact location of each electrode are described detailed in Table 9-2. It is 
assumed that a standard 12-lead ECG measurement (as indicated in Figure 9-1) is additionally 
applied. 
In this scenario, no extra EPS protocol is planned for the patient, but an ECG is recorded for 
the whole duration of the EPS after initializing the Holter ECG recording. 
At the physician’s discretion, additionally, a 24-hour Daily Living Observation (DLO) as 
described in section 9.3.5 can be done. This test might be performed using the same Holter 
ECG device with the already applied 3-patch electrode interface. The recording might be in 
addition to a standard 12-lead ECG measurement for out-of-study purposes within the scope of 
the routine EPS.  
Holter ECG setup tasks must be performed by the study staff according to section 9.3.3. After 
initialization of the Holter device, the recording shall run continuously throughout the whole 
EPS procedure unless there are compelling medical reasons for interruption. 
There is no extra study-related EPS protocol for the patient and thus there are no supervised 
activities during EPS. 
After execution of the protocol(s), i.e. after EPS procedures or after the 24-hour ECG recording 
(DLO), respectively, the patient gets the Holter recording stopped (by removing the CF card 
from the Holter device) and the equipment removed. 
Additional documentation will be provided including more details on Holter ECG application. 
Figure 9-1: Position of the three ECG electrodes 
 
 
 

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Table 9-2: Description of electrode placement for the 3-patch Holter ECG during an EPS. 
9.3.2 Holter ECG with 10-patch electrode interface for non-EPS candidates 
For patients without EPS procedure, there is a protocol called Body Motion Test (BMT) (section 
9.3.4) where various body positions and activities shall be performed by the patient after 
initialization of the Holter ECG recording.  
For those patients, the Holter ECG recording will be done using a 10-patch electrode interface. 
The ECG patch electrodes will be placed as shown in Figure 9-2. The placement and exact 
location of each electrode are described detailed in Table 9-3. 
In addition, a 24-hour Daily Living Observation (DLO) shall be performed using the same 
Holter ECG device with the already applied 10-patch electrode interface.  
After execution of the protocols, i.e. after the 24-hour ECG recording (DLO), the patient gets 
the Holter recording stopped (by removing the CF card from the Holter device) and the 
equipment removed. 
Additional documentation will be provided including more details on Holter ECG application. 
Figure 9-2: Position of the ten ECG electrodes 

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Table 9-3: Description of electrode placement for the 10-patch Holter ECG during Body Motion 
Test (BMT) and/or during a 24-hour Daily Living Observation (DLO). 
9.3.3 Holter ECG setup tasks performed by the study staff 
Before starting the ECG Holter recording, the following setup tasks have to be performed by 
the study staff. 
 
Open the ECG Holter device. 
 
Insert a new battery (Alkali-AAA, LR0) as provided (take a new one for every patient). 
 
Label CF card with patient ID 
 
Insert CF card. 
 
In case of a patient being an non-EPS candidate: 
o 
Attach the 10-patch interface (Varios yoke) as rear lid to the ECG Holter device. 
 
 

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 
In case of a patient being a EPS candidate: 
o 
Attach the 3-patch interface (standard) as rear lid to the ECG Holter device. 
 
Safely close the ECG Holter device. 
 
Synchronize the ECG Holter clock to an appropriate clock, e.g. the clock of your mobile 
phone using correct local date and time, accurate to the minute (use Holter device 
menu ‘Set up’  Time; navigate with yellow button and enter with green button). 
 
In case of a patient being an EPS candidate: 
o 
Prepare and attach three single ECG patch electrodes to the patient as depicted 
in Figure 9-1 and described in Table 9-2. 
o 
Connect the ECG Holter device (with the 3-patch interface) to the patch 
electrodes following the color codes as depicted in Figure 9-1 to ensure a correct 
step-by-step connection of one cable and one electrode. 
 
In case of a patient being a non-EPS candidate: 
o 
Prepare and attach ten single ECG patch electrodes to the patient as depicted in 
Figure 9-2 and described in Table 9-3. 
o 
Connect the ECG Holter device (with the 10-patch interface) to the patch 
electrodes following the color codes as depicted in Figure 9-2 to ensure a correct 
step-by-step connection of one cable to one electrode. 
• Confirm ECG signal quality on the ECG Holter. At least two electrodes should have clear 
QRS complexes. Check the electrodes and cables where appropriate and reposition 
electrodes in case of ECG instability/poor quality. 
 
Use adequate tape (e.g. Ambu SkinFix) to attach the electrode cables and the thicker 
10-patch interface (Varios yoke), respectively, to the patient’s torso. 
 
Use strain reliefs (e.g. loop between electrode and adhesive tape) to compensate for 
patient movements such as stretching of the arms to avoid any accidental 
disconnection. 
 
Confirm ECG signal quality again. At least two electrodes should have clear QRS 
complexes. Check the electrodes and cables where appropriate and reposition 
electrodes in case of ECG instability/poor quality. 
 
Start the Holter ECG recording using on-screen menus (with green button). 
 
ECG signal can be displayed by simultaneous pressing of the green and yellow button.  
 
Secure the ECG Holter unit comfortably to the patient. At best, attach to a belt, or place 
in a pocket/pouch. 
 
Additional documentation will be provided including more details on the setup tasks. 
9.3.4 Body Motion Test (BMT) 
For patients without EPS procedure, the BMT shall be performed. It comprises ECG recordings 
with various body positions, and activities to be performed after initialization of the Holter ECG 
recording. The Holter ECG with 10-patch electrode interface must be applied according to 
section 9.3.2. 
Holter ECG setup tasks must be performed by the study staff according to section 9.3.3. After 
initialization of the Holter device, the recording shall run continuously throughout the whole 
BMT procedure unless there are compelling medical reasons for interruption. 
The following activities must be supervised by the study staff during BMT. 
 
Instruct the patient that he or she will be performing a series of activities. 

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 
Note the starting time of the supervised activities. 
 
Guide the patient through the following activities, press the green button on the Holter 
ECG and note the stopwatch time at which each activity is started. Each activity shall be 
performed for approx. 30 to 40 seconds and is followed by 20 to 30 seconds of rest 
before proceeding to the next activity: 
 
Body position: Supine. 
 
Body position: Right lateral. 
 
Body position: Left lateral. 
 
Body position: Prone (if applicable). 
 
Body position: Seated. 
 
Body position: Standing. 
 
Body position: Standing with arms stretched out frontward. 
 
Body position: Standing with arms extended out to sides. 
 
Body position: Standing with arms stretched above the head. 
 
Body position: Standing with alternating arm movements (one arm positioned 
next to the body and the other stretched above the head). 
 
Tension movements: Seated with rubber band under feet, picking the ends of 
the rubber band with both hands, and alternating flexing/stretching the arms by 
leading hands to shoulders and back. 
 
Tension movements: Seated/Standing with rubber band between hands, and 
alternating flexing/stretching the arms by leading hands out to sides and back. 
 
Tension movements: Seated/Standing with rubber band between hands, arms 
above head, and alternating flexing/stretching the arms by leading hands out to 
sides and back. 
 
Tension movements: Seated/Standing, pressing hands together in front of chest. 
 
Activity: Slow walking. 
 
Activity: Slow climbing stairs (up/downstairs) (if acceptable). 
 
Activity: Faster walking. 
 
Resting for 1 minute. 
 
Additional documentation will be provided including more detailed instructions for the BMT. 
9.3.5 
24-hour Daily Living Observation (DLO) 
A 24-hour Holter ECG is to be recorded from a non-EPS patient. The Holter ECG with 10-patch 
electrode interface must be applied according to section 9.3.2, and setup tasks must be 
performed by the study staff according to section 9.3.3. If the patient has just undergone ECG 
recording during BMT, the Holter device and setting as well as the already applied electrodes 
can be left as they are. In this case, the recording is already running and must not be 
restarted. Alternatively, the 24-hour Daily Living Observation can be done up to 14 days after 
enrollment.  
Optionally, a 24-hour Holter ECG might be recorded from an EPS patient right after the EPS 
procedure or up to 14 days after enrollment. The Holter ECG with 3-patch electrode interface 
must be applied according to section 9.3.1, and setup tasks must be performed by the study 
staff according to section 9.3.3. If the patient has just undergone ECG recording during EPS, 
the Holter device and setting as well as the already applied electrodes can be left as they are. 
In this case, the recording is already running and must not be restarted. 

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Before the patient leaves to perform the unsupervised DLO, the patient shall be informed by 
the study staff on how to handle the 24-hour Holter device, especially 
• 
that she/he should wear the Holter ECG device now for 24 hours while going about 
normal daily routine including all activities, but 
• 
that she/he should avoid activities that might lead to the monitor getting wet, like 
taking a bath or shower; 
• 
that magnetic and electrical fields may interfere with the function of the Holter monitor; 
• 
that she/he or any relative may reattach a cable and/or patch electrode in case of a 
noticed dislodgement. 
 
Furthermore, the patient must be informed by the study staff on how to keep the patient diary, 
especially 
• 
Note the time of DLO start (time of leaving). 
• 
Explain some examples to the patient. 
• 
Remind the patient to bring back the diary at the scheduled visit. 
• 
Note the time of DLO end (time of re-visit). 
 
If the patient cannot return in person after completing the 24 hour DLO, he/she may be 
instructed on how to detach all electrodes himself/herself. An appointment shall be made to 
return the Holter ECG and the patient diary to the study staff.  
 
9.3.6 Holter ECG completion and data retrieval 
The following tasks have to be done after completion of a Holter ECG recording: 
• 
Remove the Holter ECG device 
o 
Press the green button to set final marker. 
o 
Detach all electrodes from the patient and remove the ECG Holter device.  
o 
Open the ECG Holter device. 
o 
Remove both battery and CF card from the device. 
o 
Ensure labeling of CF card with correct patient ID. 
o 
Safely close the ECG Holter device. 
• 
Ask for the patient diary form (in case a 24-hour ECG recording was performed) 
• 
Provide data to the sponsor by sending CF Card and patient diary (pseudonymized with 
the patient ID) to sponsor. 
9.4 
Patient reimbursement 
After completion of the Holter ECG recording, the patient will receive a compensation for 
his/her expenses and time. Reimbursements will be done by the sites according to the 
procedures as defined in the clinical trial agreement.  
9.5 
Termination  
The patient’s study participation ends regularly at the moment when the last study procedure 
according to protocol has been completed. The CRF ‘Termination’ has to be completed. 

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In case of any premature study termination, the CRF ‘Termination’ has to be completed with 
the reason for study termination. If the Holter ECG could not be completed successfully, the 
reason must be provided.  
Follow-up of patients who have withdrawn consent is covered in section 8.3.4.2. 
9.6 
Description of those activities performed by sponsor representative 
Sponsor representatives are not planned to take over specific activities. Yet, it might happen 
that sponsor representatives will support the investigator or his/her dedicated study team 
during the conduct of the Holter ECG recording, handling of the Holter ECG device or 
shipment/delivery of study equipment. Nevertheless, the investigator and the trained study 
team are responsible to adhere to the clinical investigation plan. 
Monitoring will be performed by a sponsor representative according to the monitoring plan and 
as described in section 10. 
9.7 
Responsibilities  
9.7.1 Responsibilities of the sponsor 
The sponsor of the BIO|CONCEPT.ECG-Library study is: 
BIOTRONIK SE & Co. KG 
Woermannkehre 1 
12359 Berlin 
Germany 
The sponsor ensures that all documents, information and necessary human resources are 
made available for initiation, conduct and termination of the study. 
In addition, the sponsor is obliged to fulfill the following tasks (selection of items): 
• Maintaining insurance cover or indemnification of subjects in case of injury in accordance 
with applicable laws. 
• Contracting of investigational sites and investigators, specifically determining the agreement 
between sponsor and the research site with respect to such as but not limited to the 
following: conducting the contract research, obligations of the sponsor/the investigational 
site/the investigator, fee payments of the sponsor, intellectual property and publication of 
research results, confidentiality, insurance coverage and compliance with applicable 
laws/regulations and ethical standards. Selection of suitable investigational sites, 
investigators and clinical monitors. 
• Obtaining of a favorable ethics vote(s) for conduct of the clinical study. 
• Obtaining approval of the involved competent authorities (if applicable). 
• Responsibility for all payments and financial coverage of the study. 
• Supervision of study conduct according to the legal regulatory requirements and the 
requirements of the CIP. 
• Fulfill reporting duties of the sponsor to the ethic committees and regulatory authorities. 
• Data analysis and data management. 
• Performance of on-site audits as planned routine audits, on demand in case of detected 
non-compliances, or as preparation for an announced inspection by a Competent Authority. 
• 
Provision of the final clinical investigation report (CIR) in accordance with applicable legal 
requirements and ethical principles.  
9.7.1.1 
Project management 
The clinical project manager is responsible for the following (selected items): 
• Development of the clinical investigation plan and possible amendments. 

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• Coordination of all study-related activities dedicated to the sponsor. 
• Support of investigational sites during the study (obtaining ethic committee votes, etc.). 
• Continuous information of investigational sites and clinical monitors on study progress. 
• The clinical project manager is supported by other staff members of the sponsor (e.g. in-
house clinical research associates, data assistants, data base managers). 
9.7.1.2 
Data Management 
The data manager is responsible for the following items (selection of items): 
• 
Development and maintenance of the clinical data management system (CDMS; iMedNet of 
the company MedNet Solutions Inc, Minnetonka, MN 55305 USA). 
• 
Development of the data management plan. 
• 
Development of the CRF user guide. 
• 
Data management. 
• 
User Management 
9.7.1.3 
Biostatistician  
The statistician is responsible for the following items (selection of items): 
• 
All statistical aspects within the clinical investigation plan. 
• 
Statistical analysis for clinical investigation report. 
The statistician will be supported by other staff members of the sponsor. 
9.7.1.4 
Monitor 
The sponsor names clinical monitors for each participating investigational site prior to initiation 
of the respective site. Names and contact data will be provided to the investigational sites in 
due time. In case of changes, the investigational site will be informed by the sponsor. An 
adequate monitoring will be ensured by the sponsor. Monitoring will be conducted according to 
the SOPs of the sponsor. Responsibilities of the clinical monitors are described in section 10 of 
this document. 
9.7.2 Responsibilities of the investigators  
9.7.2.1 
Investigator  
The study shall be conducted by qualified investigators.  
Rights and duties of the investigators are specified in the clinical investigation plan and are 
further regulated in the contract for study conduct. The principal investigator named in the 
study contract may share the rights and duties with investigators and other staff at the 
investigational sites. Nevertheless, the principal investigator retains the main responsibility for 
proper study conduct with respect to the following duties: 
• Registration of the study to the bodies responsible for the investigational site (e.g. hospital 
administrative department). 
• Notification to competent authority (if applicable) responsible for the investigational site. 
• If required, obtaining of a positive vote of the ethics committee responsible for the 
investigational site. 
• Adverse Event reporting according to the clinical investigation plan. 
• Recruitment of suitable patients in an adequate time frame. 
• Patient information and obtaining of written informed consent of the patient according to 
the requirements of the CIP. 
• Safe and efficient use of devices. 

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• Inform the sponsor about new study team members before authorizing them for study 
related activities. 
• Provide the sponsor with required documentation for assessing the qualification of study 
team members. 
• Authorize co-investigators only after documented adequate study specific training. 
• Discourage patients to consent for other interventional clinical investigations, in case the 
investigator is aware of such intentions beforehand. Inform the sponsor and follow the 
sponsor´s guidance, in case a patient has already been enrolled into another interventional 
clinical investigation. Obtain the sponsors permission before enrolling the patient into 
another interventional clinical investigation. 
• Conduct of the study according to the CIP. 
• Data collection and data entry in accordance with the requirements of the CIP. 
• Providing supporting material, if necessary. 
• Submission of safety reports and protocol deviations to ethics committee and competent 
authorities (if applicable). 
• Support of monitoring and auditing activities. 
• Confidential treatment of all study-related documents and information. 
 
In case the principal investigator (or authorized staff) does not fulfill the requirements defined, 
the sponsor is entitled to exclude the respective investigational site or principal investigator 
from further study participation. 
 
9.8 
Possible influencing factors on outcome or interpretation of results 
No factors that could influence the outcome or interpretation of the results are known at this 
time. 
 

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10 
MONITORING PLAN 
The responsibility of BIOTRONIK as sponsor is to ensure protocol and regulatory compliance 
through proper monitoring of the study. As the investigator, the physician is responsible for 
conducting the study in accordance with the signed clinical trial agreement the clinical 
investigation plan, applicable laws, and/or local regulations and any conditions of approval 
imposed by the reviewing EC.  
The entries in the CRF will be reviewed and source data verified at the investigational site by 
monitors (authorized BIOTRONIK personnel, Clinical Research Associates (CRAs), or by 
authorized BIOTRONIK designees) to ensure that the investigator and the clinical investigation 
team conducts the clinical investigation in accordance with the CIP, The Declaration of Helsinki, 
ISO 14155 (as applicable), and applicable laws and regulations to ensure adequate protection 
of the rights, safety and wellbeing of subjects and the quality and integrity of the resulting 
data. 
A monitor will visit the study site periodically during the study. All actively enrolling sites will 
have at least an initiation visit, one early monitoring visit after the first patients have been 
enrolled in order to detect and prevent systematic errors in study conduct or documentation, 
and a close-out visit. Additional monitoring visits will be conducted based on risk related 
criteria such as e.g. recruitment rate and documentation quality. Details on criteria for 
initiating monitoring visits as well as strategy and extent of source data verification are subject 
to a detailed monitoring plan developed by BIOTRONIK as an internal document.  
Monitoring visits will assure, amongst others, that the facilities are still acceptable, that the CIP 
is being followed, that the EC/CA has been informed about approved CIP changes as required, 
that records on study conduct and data collection are complete and present, that appropriate 
and timely reports have been made to the sponsor and the authorities, and that the 
investigator is carrying out all agreed activities. 
Assessments of the study site will include but will not be limited to the following: 
1. Completion and submission of the required electronic case report forms (CRFs) and 
other applicable study documentation 
2. Continued acceptability of the facilities 
3. Adherence to the clinical investigation plan 
4. Adherence to current version of ISO 14155 (as applicable) and local regulations and 
laws 
If a monitor becomes aware that an investigator is not complying with the requirements 
mentioned above, the monitor is obliged to notify BIOTRONIK study management. BIOTRONIK 
will evaluate the non-compliance and issue corrective actions, discontinue enrollment or as a 
last measure close the clinical investigational site (see section 14 and 20) 

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11 
STATISTICAL CONSIDERATIONS 
11.1 Statistical design, method and analytical procedures 
Exploratory data analysis will be used to describe the patient population.  
11.2 Sample size 
For this study, no statistical hypotheses can be formulated; therefore a sample size calculation 
is not applicable. However, at least six patients for each condition (see section 4.2) should be 
enrolled for the following reasons: 
A minimum sample size of six would be needed to draw a conclusion with inferential statistics 
from binary data; e.g. to successfully apply a new algorithm in all 6 samples, a random effect 
can be excluded based on a 5 % significance level with an exact 95 % confidence interval 
larger than 50 %. Since ventricular tachycardia is most important in the development of 
certain detection algorithms, a minimum of ten patients is foreseen. Thus, in case of a 
successful application of a new algorithm in 10 of 12 samples, a random effect can be excluded 
based on a 5 % significance level. Consequently, 13 x 6 + 12 = 90 patients should be at least 
enrolled. Due to an assumed rate of 10 % non-evaluable ECG recordings, at least 100 patients 
should be enrolled in the study. However, due to the conditions defined for replacements of 
patients (section 8.1.4) and a potential time delay in ECG analysis by the sponsor (section 
8.1.3.3), the total number of enrolled patients might exceed the planned sample size.  
11.3 Expected drop-out rate 
It is expected that at least 10 % of the enrolled patients can only be partly included or not at 
all in the analysis of data, e.g. due to withdrawal of consent, refusal to participate in the Holter 
ECG or premature termination without documentation of the intended ECG pattern.  
11.4 Pass/fail criteria  
Not applicable. 
11.5 Provision for an interim analysis 
As there is no hypothesis to test, no comprehensive interim analysis is planned at a certain 
point in time. The acquired data will be continuously forwarded to the technical department for 
analysis.  
11.6  Termination criteria 
Not applicable 
11.7  Procedures for reporting of deviations to the statistical plan 
If deviations to the statistical plan become necessary for the clinical report, the changes and 
the reason(s) for the changes will be reported in the clinical report. 
11.8 Specification of subgroups 
There are no pre-defined sub-groups. 
11.9 Procedure for accounting of all data for analysis 
Due to the use of the electronic data capture and the required strict adherence to the 
monitoring plan, an adequate data acquisition of all data is ensured. 
11.10 Handling of missing, unused and spurious data 
Missing or spurious data will not be imputed. 

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11.11 Exclusion of data from confirmatory data analysis 
In the following cases, data is to be excluded from analysis or prevented from inclusion into 
analysis: 
• No data is allowed to be collected and included in the absence of a documented consent  
Details are provided in the Statistical Analysis Plan. 
11.12 Minimum and maximum number of patients per site 
There is no maximum or minimum number of patients per site.  
 

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12 
DATA MANAGEMENT 
12.1 Data protection 
According to corresponding national laws, the patient (or his or her legal representative) must 
declare in the Informed Consent Form (ICF) that he or she agrees to the recording of his or 
her medical data and their pseudonymized transfer to the sponsor, and, if necessary, to 
responsible Ethic Committee (EC) and Competent Authority (CA). The patient agrees that 
authorized personnel or designees of the sponsor and the involved EC or CA (if applicable) may 
gain insight in the patient file to ensure that the patient was adequately informed about the 
clinical investigation and that the clinical investigation plan was followed properly. 
All patient-related data and information received from the clinical study will be handled 
confidentially. The collected data will be transmitted to the sponsor for electronic data 
processing, safety reporting and analysis in compliance with the data protection law. The data 
will be pseudonymized at the sites before transmission, without using patient initials, to ensure 
traceability of data, but preventing unauthorized identification of individual patients. All clinical 
data will be stored in a validated system environment with adequate protection against 
unauthorized access. Insight will be given to responsible EC and CA upon request. 
All involved parties, including subcontractors, are bound to data privacy according to the 
applicable data protection law. All patients will be informed on all relevant regulations 
concerning data secrecy and data protection which are applicable for the BIO|CONCEPT.ECG-
Library study in the patient informed consent form. Specifically, all patients will be educated 
about their rights concerning data access, data correction, and data deletion according to 
applicable legislation. 
The patient identification log sheet, in which the patient ID code, name, date of birth and date 
of informed consent is entered, will remain at the investigational sites. No copies of the patient 
identification log sheet will be provided for the sponsor. The patients will be informed on the 
fact that exact identification of the patient is only possible for the investigator. 
12.2 Data collection 
All study-relevant patient data will be documented pseudonymously in electronic case report 
forms (CRF). The established Clinical Data Management System (CDMS) is ‘iMedNet’ of the 
vendor MedNet Solutions, Inc. As a pure internet-based application that is used with the 
current versions of current internet browsers, there is no specific local software to support 
(cloud based ‘Software as a Service’ SaaS). iMedNet supports industry standards (Regulation 
(EU) 2016/679 (incl. Corrigendum dated 23 May 2018), FDA 21 CFR Part 11 and HIPAA).  
Use of the clinical data management system (CDMS) will allow 24 hours 7 days a week access 
to the module. The Principal Investigator (PI) as well as those co-investigators to whom the PI 
delegates data entry and authorization of CRFs needs to be trained on iMedNet. After 
appropriate documentation of the training, user access is granted. Site staff with user access 
will be directed to a page where they will enter their assigned user ID and password in order to 
access the system. Once these have been validated, there will be options for entering a new 
patient or new patient data into the system.  
For the majority of the CRF entries, source data needs to be maintained at the site and will be 
collected in adequate files (e.g. patient files). The data have to be stored and shall be made 
available upon request in order to allow source data verification. Exceptions for which the CRF 
entry can be regarded as source data are indicated in the Monitoring plan or in the respective 
section of the CIP. 
12.3 Procedures used for data review, CDMS cleaning, and issuing and resolving 
data queries 
After data entry into the Clinical Data Management System (CDMS), the clinical data is 
automatically checked with programmed quality checks. Additionally, the CRF will be checked 
against source data by clinical monitors during periodic monitoring visits as described in the 

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Monitoring Plan. Errors, discrepancies, missing data, and entries out of range are resolved by 
automatically (CDMS) and manually (clinical monitor, clinical data manager) generated data 
queries and deviation forms.  
The investigational site is obliged to answer all incoming data queries and deviation forms in 
due time to clarify the open issues. Corrections to the CRF can only be done by the designated 
site personnel and have to be signed by an authorized investigator approving thereby the 
completeness and correctness of the data. The CDMS supports detailed tracking of the query 
process since all changes are automatically recorded in the system’s audit-trail.  
Clarification of all open queries is a precondition for site closure in case of premature or regular 
study termination. 
Prior to the final data analysis, all endpoint relevant data are checked for consistency and 
plausibility in a blinded way by the biostatistician.  
12.4 Procedures for verification, validation and securing of electronic data systems 
The Clinical Data Management System (CDMS) is hosted on a dedicated database server at the 
vendor MedNet Solutions, Inc. Only authorized users with fixed roles have access to the 
Clinical Data Management System (CDMS). The access is controlled and maintained by the 
Clinical Data Management. Every access is automatically logged and changes of the clinical 
data are stored in independent audit trails. The CDMS is verified and validated accordingly. The 
user interface and the internal business logic is validated accordingly and verified during the 
study related development and before release for data entry. 
An authenticated user account is created and maintained by BIOTRONIK for each authorized 
user once the user has completed appropriate training. Users are obligated to keep their 
password confidential. 
Depending on their role within the investigational study, users are limited to ‘read only# or 
may be given permits to enter or update data, provide resolutions to queries and apply 
electronic signatures.  Only investigators are allowed to sign the entries. 
12.5 Data retention and archiving 
All study related electronic documents are stored in the archive of BIOTRONIK which provides 
storage conditions free from risk of fire, flood, theft and vermin. The access to the files is 
controlled. 
After CDMS closure, all CRF data and the audit trail and other relevant CDMS content are 
exported and stored electronically for at least 15 years on the archive server. 
At the end of this period, requirements from laws and other regulations will be reconsidered in 
order to decide whether the retention period must be extended or data must be deleted.  
All relevant study related documents have to be stored in the Investigator Site File. Documents 
containing patient’s data, raw data and other study related documents have to be archived in 
the investigational site. In case of electronic source data (e.g. electronic patient files) adequate 
actions have to be taken to ensure data availability during the whole archiving period. 

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13 
AMENDMENT PROCEDURES 
If throughout the course of the study changes to the Clinical Investigation Plan (CIP) are 
deemed to be necessary, a change justification has to be prepared which includes the rationale 
and content of the adjustment. The modification of the CIP can either be summarized in a 
separate document as an attachment to the current applicable version of the CIP or result in a 
new version of the CIP.  
If the changes have impact on study related procedures or data analysis they are substantial 
by definition.  
New versions of the CIP or substantial amendments have to be reviewed and confirmed by the 
Coordinating Investigator. All principal investigators have to acknowledge the receipt of an 
amendment by either signing the CIP acknowledgement page which is part of the CIP, or by 
signing the amendment agreement form if no new CIP version was created. 
Before implementation of any changes, substantial amendments have to be approved by the 
Ethics Committee (EC) and – if applicable – by the Competent Authority (CA). Non-substantial 
amendments are submitted for notification only. 
The investigator should not implement any deviation from or changes to the CIP without 
agreement of the sponsor and prior review and documented approval from the EC (and CA if 
required). The only exception is the necessity to eliminate an immediate hazard to the 
subjects, or when the change involves only logistical or administrative aspects of the study. 

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14 
DEVIATIONS FROM CLINICAL INVESTIGATION PLAN 
14.1 CIP compliance and exceptions 
All sponsor personnel, all investigational site personnel as well as other third parties, who are 
involved in tasks covered by this CIP, are generally obliged to comply with this CIP. 
A deviation is any failure to follow, intentionally or unintentionally, the requirements of the 
CIP, including laws, guidelines and other regulation as far as required by the CIP and 
applicable laws, as well as applicable amendments. Deviations that are likely to seriously affect 
or that actually have seriously affected the rights or safety or wellbeing of subjects or the 
scientific integrity of the clinical investigation are major deviations. Otherwise they are minor 
deviations. 
Erroneous, spurious or missing data in a CRF is not a deviation in itself and is handled 
according to the query processes described in the data management section of this CIP. 
However, the underlying reason might be a deviation. 
Under emergency circumstances, deviations from the CIP to protect the rights, safety and 
well-being of human subjects may proceed without prior approval of the sponsor and the 
ethics committee.  
No waivers from the CIP are allowed.   
14.2 Recording, reporting and analyzing deviations 
All deviations are recorded and reported electronically in the CDMS system iMedNet. If the CRF 
logic has detected a CIP deviation based on the data entry, deviation forms are triggered 
automatically by iMedNet. Additionally, deviation forms can be created manually via iMedNet 
by the site or by the sponsor personnel. 
14.2.1 Site specific deviations 
Investigational sites are obliged to record any deviation immediately as they become aware of 
it. In addition, compliance to the CIP is verified by the sponsor through monitoring visits. Each 
site specific deviation is assessed for the need of corrective or preventive actions.  
14.2.2 Other deviations 
Deviations by sponsor personnel or third parties shall be reported immediately to the sponsor 
by anyone who becomes aware of it. They are recorded in the deviation log BIOTRONIK 
personnel/Third Parties, and assessed for the need of corrective or preventive actions. 
14.2.3 Reporting 
Deviations are reported in the interim and final clinical investigation reports.  
14.3 Notification requirements and timelines 
The sponsor records specific notification requirements of the involved ethics committees and 
competent authorities and assures that the required timelines are respected. 
14.4 Actions 
Actions are taken in order to repair or to avoid any negative consequences caused by a 
deviation. Furthermore, actions are taken to avoid that the same sort of deviation reappears. 
Every individual deviation is assessed by the sponsor for the need of appropriate action. In 
addition, the sponsor regularly evaluates the overall study deviation report to identify the need 
of general preventive actions. 
All persons involved in a deviation have to co-operate with the sponsor in identifying and 
implementing the appropriate actions. Performance and implementation of these actions are 

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documented in iMedNet or in the corresponding deviation log BIOTRONIK personnel/Third 
Parties, and later filed in the central file and, in the case of site specific deviations, in the 
respective investigator site file. 
Disqualification of study personnel or investigational sites is the ultimate escalation step of 
preventive actions. This means that in case of major deviations that seriously affect the safety 
and well-being of subjects or that bear a high risk of refusal of the clinical data and mistrust to 
the results of the study and that are likely to reappear despite other actions, the responsible 
person or investigational site is excluded from further conduct of the study, unless this action 
would jeopardize the rights, safety or welfare of the patients. 

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DEVICE ACCOUNTABILITY 
Not applicable. 

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16 
STATEMENT OF COMPLIANCE 
16.1 Applicable ethical standards 
The study will be conducted in compliance with the principles that have their origin in the 
Declaration of Helsinki (current version). Each step in the clinical investigation, from the initial 
consideration of the need and justification for the study to the publication of the results, if any, 
will be carried out in accordance with recognized ethical principles. 
The study will be registered at the publicly accessible database ClinicalTrials.gov. 
16.2 Applicable international and national standards 
The study will be conducted in compliance with the international standard ISO 14155:2011 
‘Clinical investigation of devices for human subjects – Good clinical practice’. With regard to 
the exploratory character of this study and since no investigational device will be used in the 
study, the following deviations to ISO 14155:2011 occur:  
• 
No investigational device will be used in the study, therefore no dedicated Investigator’s 
Brochure or Instructions for Use are provided. 
• 
No coordinating investigator has been nominated for this multicenter study, as only 
documentation of Holter ECGs occur during the patient’s study participation which does not 
require additional coordination between the PIs, nor medical advice. 
• 
No investigational device will be used, therefore no device deficiencies and (S)ADEs will be 
reported 
• 
No investigational device will be used, therefore no investigational device accountability is 
necessary 
The study will also be conducted according to the applicable national legal requirements of the 
participating investigational sites. 
16.3 Ethics committee and competent authority 
The study will not begin at an investigational site until favorable opinion of the responsible 
ethics committee has been obtained for that site and approval of the competent authority (if 
applicable) has been granted for the conduct of the study in the respective country.  
16.4 Statement of adherence to additional requirements 
If any additional requirements will be imposed by an ethics committee or a competent 
authority, these requirements will be followed, if appropriate. 
16.5 Statement on subject insurance 
All participants of this clinical study are insured against study related injury according to 
applicable provisions of law. 
The insurance of the sponsor does not relieve the investigator and the collaborators of any 
obligation to maintain their own liability policy. 

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INFORMED CONSENT PROCESS 
A patient information form including the informed consent form has been prepared by the 
Project Manager. The content of this document needs to be reviewed and approved by the 
ethics committee, and suggested changes need to be implemented. 
17.1 General considerations 
The informed consent procedure is performed by the Principal Investigator or any investigator 
designated for this task as recorded in the delegation of duties log. The investigator has to 
fully inform the patient of all pertinent aspects of the clinical investigation in language and 
terms she/he is able to understand. Special attention has to be paid to the individual 
information needs of the patient, and the appropriate methods used for the interview. The 
investigator has to verify that the patient has understood all information. The patient is given 
adequate time to consider his or her decision to participate in the clinical investigation. 
When the patient agrees in the study participation, the patient personally writes the date and 
signs on the informed consent form. Afterwards, the investigator who performed the informed 
consent discussion writes the date and signs on the informed consent form. Both parties 
should sign on the same day. By signing the informed consent form, the patient is included in 
the study. Pre-screening of the patient chart in respect to the inclusion and exclusion criteria is 
not a study specific procedure.  
Date of the informed consent discussion as well as date of patient's signature of the informed 
consent form should be documented in patient's medical record. A copy of the signed and 
dated written informed consent form is provided to the patient. Both signatures need to be 
obtained before any study related procedure. The investigator ensures that no subjects are 
included in this clinical study who are unable to give informed consent by selecting patients 
with age ≥ 18 years, who understand the nature of the procedure.  
If the patient is unable to write, consent may be given and recorded through appropriate 
alternative means in the presence of at least one impartial witness, who then signs and dates 
the informed consent form.  
If during the course of the clinical investigation new information emerges, the investigator 
informs the patient accordingly. If this information concerns safety aspects or other aspects 
that could influence the decision of the patient to continue participating in the study, the 
patient shall be informed immediately. 
Each informed consent form contains the emergency contact details for the respective principal 
investigator. 
17.2 Special circumstances for informed consent 
Not applicable. 

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ADVERSE EVENTS  
In the course of the clinical investigation, undesired medical events can occur in participating 
patients, which are called adverse events (AEs) in the following. All AEs shall be assessed by 
the investigator and shall be documented and reported throughout the clinical investigation 
within the timelines defined below.  
The investigator shall document all events on the respective CRF pages provided within the 
clinical data management system (CDMS) iMedNet. The indicated timelines for reporting of 
initial cases and possible update reports shall be strictly followed.  
According to ISO 14155:2011 events will be classified on the basis of the definitions below. 
18.1 Definition of adverse events 
An AE is defined* as 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 investigational device. This includes events related to 
the procedures involved.  
Since no investigational devices are used in this study, the references to ‘investigational 
devices’ are not applicable.   
*see ISO 14155:2011 3.2 
18.2 Definition of serious adverse events 
AEs are classified as serious* if one or more of the following consequences are fulfilled: 
• led to death. 
• led to serious deterioration in the health of the subject, that either resulted in 
− a life-threatening illness or injury, or 
− a permanent impairment of a body structure or a body function, or 
− in-patient or prolonged hospitalization, or 
− 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 or a congenital abnormality or birth defect. 
Note: Planned hospitalization for a pre-existing condition, or a procedure required by the CIP, 
without serious deterioration in health, is not considered a serious adverse event. 
*see ISO 14155:2011 3.37 
In-patient hospitalization is defined as at least one overnight stay (change of date) in a 
hospital. In case a patient is only for some hours in the hospital (without change of date), this 
event will not be documented as serious, unless one or more of the other seriousness criteria 
are fulfilled.  
18.2.1 Patient death 
If the death of a patient emerges during the study, this SAE might be subject to special 
reporting requirements in some countries. Therefore, as much information as possible should 
be provided to enable BIOTRONIK to explain the circumstances leading to the death. At least a 
pseudonymized copy of the death records, an autopsy report (if performed) and a doctor´s 
letter detailing the medical history and the circumstances of the death should be sent to 
BIOTRONIK promptly. 
On the AE-CRF, the following information should be provided, if available: 
• Cause of death 
• Date and time of death 

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• Place death occurred 
• Device status at the time of death 
• Statement whether the event was device or study procedure related 
In addition to the adverse event CRF, a study termination form has to be completed. 
Whenever possible, devices that are explanted must be returned to BIOTRONIK SE & Co. KG 
for analysis. 
18.3 Anticipated adverse events 
Risks of Holter Monitoring are rare, but may include skin irritation at the application site of the 
adhesive electrode patches. In addition, the patient may experience a discomfort caused by 
wearing the ECG patches, the Holter ECG device, or the cabling of the device. Discomfort or 
dizziness may also occur during the study specific activity tests and/or position of the subject 
during the recordings.  
In addition, the procedure may reveal previously undetected medical conditions or device 
issues. These conditions will be treated according to the physician’s discretion.  
18.4 Reporting responsibilities 
18.4.1 Reporting responsibilities of the investigator to sponsor 
The investigator shall document all events on the respective CRF pages provided within the 
CDMS. The indicated timelines for reporting of initial cases and possible update reports shall be 
strictly followed. 
All Serious Adverse Events (SAE) shall be reported together with an assessment by completing 
the AE-CRF in accordance with ISO 14155:2011.  
The reports shall be done with all information available, even if this results in an incomplete 
report. The investigator has to follow-up ongoing (S)AEs either as long as the patient 
participates in the study, the clinical investigation is terminated prematurely or until the event 
has been resolved, whatever comes first. 
Multiple events may occur simultaneously in one subject. For each medically independent 
event an individual report must be provided. 
In addition, the action taken/ treatment should also be provided with any supportive 
documentation available.  
The investigator has to ensure that all relevant information is available. This also includes 
information from other parties (family, other hospitals etc.).  
If a patient dies during the study this might be subject to special reporting requirements in 
some countries. Therefore as much information as possible should be provided to enable 
BIOTRONIK to explain the circumstances leading to the death. At least a pseudonymized copy 
of the death records and an autopsy report (if performed) should be sent to BIOTRONIK 
promptly. All actions taken, which were initiated to gain further information must be 
documented in writing and provided to BIOTRONIK. 
18.4.2 Reporting responsibilities of the investigator to other parties 
According to national and international regulations some of the involved competent authorities 
(CAs) and ethics committees define specific safety reporting requirements. Investigators have 
to ensure, that they fulfil these local reporting obligations given by their competent authorities 
and ECs, in case they are more restrictive than the general requirements stated in the section 
reporting timelines below. 

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18.4.3 Reporting responsibilities of the sponsor 
BIOTRONIK SE & Co. KG will report all serious Adverse Events (SAEs) to the competent 
authorities depending on the local regulatory requirements.  
Furthermore, BIOTRONIK SE & Co. KG ensures that Safety Reports are forwarded to the 
investigational sites and the Ethic committees depending on the local requirements.   
BIOTRONIK SE & Co. KG will inform the investigators about all reported SAEs on a regular 
basis. 
18.5 Reporting timelines 
The reporting timelines for the investigator are displayed in Table 18-1. 
 
Table 18-1: Reporting timelines. 
Event 
Report to 
Timeline 
Adverse Event (AE) 
CCR BIOTRONIK SE & Co. KG: 
Documentation in the AE CRF  
Preferably within 2 
weeks 
 
Serious Adverse Event 
(SAE) 
CCR BIOTRONIK SE & Co. KG: 
Documentation in AE-CRF 
 
 
Immediately, latest 
24-hour after 
detection 
 
 
The obligation to assess and report SAEs to the sponsor without unjustified delay is an 
important part of the Principal Investigator’s responsibilities as defined by ISO 14155:2011. 
This obligation is not restricted to scheduled patient follow ups according to the CIP, but it is a 
continuous responsibility for the duration of the study, making sure that any unexpected risks 
originating from the study procedures or the investigational product are identified as soon as 
possible and patients are adequately protected. The Principal Investigator is responsible to set 
up appropriate workflows at his/her site, making sure that: 
• 
the site study team is continuously informed on any relevant interactions or interventions 
concerning study patients at the site, regardless if members of the study team are directly 
involved or not; 
• 
if the site is part of a larger organizational structure - e.g. a multi-faculty-hospital - a 
notification system is in place, making sure that other departments clinics are aware of the 
patient’s study participation and that relevant events, such as hospitalizations, are notified 
to the site study team without delay; 
• 
if information on relevant events from external sources reaches the site (e.g. medical 
reports from other facilities), these are made available to the study team without delay. 
Please note that in this context the site is defined as the organizational unit (e.g. a hospital or 
a department/clinic within a multi-faculty-hospital), which serves as BIOTRONIK’s contract 
partner for the study. Information that is part of the medical records hosted by the site is 
considered as known to the study team and subject to reporting. 
 
18.6 Emergency contact 
A contact address for patients in case of emergency will be provided in the individual patient 
informed consent forms. 
 

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VULNERABLE POPULATION 
There are no health needs or clinical priorities for vulnerable populations which would justify 
the participation of these populations. Only legally competent patients shall be enrolled in this 
clinical investigation. Patients aged less than 18 years, pregnant or breast-feeding women and 
patients which are not able to understand the nature of the clinical investigation are excluded 
(see 8.3.2 and 8.3.3). Therefore no provisions for vulnerable patients have to be arranged. 
 
 

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20 
SUSPENSION 
20.1 Criteria and procedures 
Suspension or premature study termination may occur due to several reasons: 
• On behalf of the sponsor 
• On behalf of the investigator 
• On behalf of the EC 
The sponsor is authorized to terminate the clinical study prematurely due to relevant medical/ 
organizational reasons.  
A consultation of all parties involved prior to study termination is preferable. Reasons for 
premature study termination should be documented in an adequate way. 
The sponsor has the right for premature study termination of the whole study, of single study 
phases or arms, or to exclude single investigational sites from further study participation.  
Reasons for termination may be: 
• Occurrence of severe Adverse Events that result in a non-acceptable risk for further study 
participation. 
• The number of premature study terminations exceeds the tolerable percentage of drop-outs 
so that proper completion of the study cannot be expected anymore. 
• Insufficient enrollment rates so that proper completion of the study cannot be expected 
anymore. 
• No enrollment in one of the subgroups mentioned in section 8.3.2 for at least 30 days  
• Results from other clinical investigation indicate a non-tolerable risk for further conduction 
of this study. 
• Attempted fraud or fraud that may be evidenced. 
• Poor data quality 
• Missing compliance of the respective investigator or study site (e.g. protocol violations). 
In case the study sponsor decides to suspend or prematurely terminate the study, the sponsor 
is required to promptly notify the investigator(s) to whom the decision applies. The 
investigator will inform the EC of this decision. The investigator will also promptly inform all 
patients enrolled at the investigational site and are still actively participating. Patients that 
already left the study shall be informed if they might be affected by safety aspects. 
In case of any reasonable ethical concern of the investigator regarding a further study conduct 
in the respective investigational site, the sponsor shall be informed immediately. 
If the investigator decides to suspend or prematurely terminate the study at his/her site 
he/she will promptly inform the study sponsor, the EC and all enrolled patients of this decision. 
If the EC decides to suspend or prematurely terminate the study, the investigator will promptly 
inform the study sponsor (or vice versa as applicable) and all enrolled patients of this decision. 
The CRF for ‘Termination’ has to be completed in all of the above cases.  
All open CRFs have to be completed as far as possible by the investigational site. 
20.2 Requirements for subject follow-up 
In case of a study suspension, no new patients will be enrolled until the suspension has been 
lifted. During the suspension, follow-up and data collection will continue as required per CIP. If 
the suspension is due to an EC decision, additional requirements from the EC with respect to 
follow-up and data collection may apply. 

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If an (S)AE is ongoing at time of the last study related visit or study termination, whatever 
comes first, the outcome of the event has to be updated to ‘Ongoing at study termination’.  
Patients have to be informed on this procedure in written form in the patient informed consent 
form. 

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21 
PUBLICATION POLICY 
The study will be registered in a publicly accessible database (e.g. clinicaltrials.gov). 
Due to the nature of the study, no publication of the results is planned.  
 
 

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22 
BIBLIOGRAPHY 
[1] Aziz S, Leon AR, El-Chami MF. The subcutaneous defibrillator: a review of the literature. J 
Am Coll Cardiol 2014; 63(15): 1473-1479. 
[2] Adduci C, Palano F, Francia P. Safety, Efficacy and Evidence Base for Use of the 
Subcutaneous Implantable Cardioverter Defibrillator. J Clin Med 2018;7(3). 
[3] Baez-Escuadero J, Hamilton A, Walcott G, Killingsworth CR, Burke MC. Are cutaneously 
derived electrocardiography signals reliable surrogates for subcutaneous sensing algorithm 
testing? J Electrocardiol 2010; 43(6):645.