BIO|CONCEPT.Renamic Neo
Conditions: Medical Devices
Sponsor: Biotronik Australia Pty Ltd.

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Document Title: 
Clinical Investigation Plan for the BIO|CONCEPT.Renamic 
Neo Study 
Document Version and Date: 
Version 1-0, 05-Dec-2019 
ClinicalTrials.gov Identifier: 
NCT04350008 
 

 
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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Clinical Investigation Plan 
for the 
BIO|CONCEPT.Renamic Neo Study 
 
 
 
 
Reference Number:  
 
BA112 
Version  
 
 
1-0 
Date of CIP: 
 
 
05-Dec-2019 
Investigational devices:  
Renamic Neo programmer, programmer 
software NEO 2001.A and PK-222-L ECG cable 
 
 

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Director Clinical Project 
Management 
 
 
 
 
 
BIOTRONIK SE & Co. KG 
Center for Clinical Research  
Woermannkehre 112359 Berlin 
Germany 
 
Date 
 
Signature 
 
 
 
 
 
 
Clinical Project Manager 
 
 
 
 
 
BIOTRONIK SE & Co. KG 
Center for Clinical Research  
Woermannkehre 1 
12359 Berlin 
Germany 
 
Date 
 
Signature 
 
 
 
 
 
 
Director Clinical and 
Regulatory Affairs 
 
 
 
 
 
BIOTRONIK Australia Pty. Ltd. 
Level 4, Building 2, 20 Bridge St 
Pymble NSW 2073 
Australia 
 
Date 
 
Signature 
 
 
 
 
 
Sponsor 
BIOTRONIK Australia Pty. Ltd. 
Level 4, Building 2, 20 Bridge St 
Pymble NSW 2073 
Australia 
 
 
 
 
 
 
 
 
 
 
 
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 ................................................................................... 9 
2 
SYNOPSIS ......................................................................................................... 12 
3 
INTRODUCTION ................................................................................................ 14 
4 
INVESTIGATIONAL DEVICE............................................................................... 15 
4.1 
Summary description of the device and its intended purpose ................................... 15 
4.2 
Manufacturer ..................................................................................................... 15 
4.3 
Model name including software version and accessories ........................................... 16 
4.4 
Description of traceability .................................................................................... 16 
4.5 
Intended purpose of the device in the study ........................................................... 17 
4.6 
Intended patient population and indications ........................................................... 18 
4.7 
Description of the investigational device ................................................................ 18 
4.7.1 
Renamic Neo hardware and software................................................................ 18 
4.7.1.1 
Renamic Neo hardware ............................................................................... 19 
4.7.1.2 
Graphical User Interface (GUI) .................................................................... 19 
4.7.1.3 
The Pacing System Analyzer........................................................................ 20 
4.7.1.4 
Interrogation of implanted devices ............................................................... 20 
4.7.2 
PK-222-L ECG cable ....................................................................................... 21 
4.8 
Summary of training and experience needs ............................................................ 22 
4.8.1 
Description of medical and surgical procedures .................................................. 22 
5 
JUSTIFICATION FOR THE DESIGN OF THE CLINICAL INVESTIGATION .............. 23 
5.1 
Pre-clinical data .................................................................................................. 23 
5.2 
Clinical data ....................................................................................................... 23 
5.3 
Justification........................................................................................................ 23 
6 
RISKS AND BENEFITS OF THE DEVICE AND CLINICAL INVESTIGATION ............ 25 
6.1 
Anticipated clinical benefits .................................................................................. 25 
6.2 
Anticipated risks ................................................................................................. 25 
6.2.1 
Anticipated adverse device effects ................................................................... 25 
6.2.2 
Residual risks associated with the device .......................................................... 25 
6.2.3 
Risk associated with participation in the study ................................................... 25 
6.2.4 
Possible interactions with concomitant medical treatments .................................. 26 
6.3 
Steps to control or mitigate the risks ..................................................................... 26 
6.4 
Risk-to-benefit rationale ...................................................................................... 26 
7 
OBJECTIVES AND HYPOTHESES ........................................................................ 27 
7.1 
Objectives ......................................................................................................... 27 
7.2 
Endpoints and hypotheses ................................................................................... 27 

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7.2.1 
Primary endpoint and hypotheses .................................................................... 27 
7.2.2 
Endpoints ..................................................................................................... 27 
 
 
7.4 
Safety assessments ............................................................................................ 27 
7.5 
Further data of interest ....................................................................................... 27 
8 
DESIGN OF THE CLINICAL INVESTIGATION ...................................................... 29 
8.1 
General considerations ........................................................................................ 29 
8.1.1 
Type of clinical investigation............................................................................ 29 
8.1.2 
Measures taken to minimize or avoid bias ......................................................... 29 
8.1.3 
Selection of measurements for endpoints .......................................................... 29 
8.1.4 
Methods ....................................................................................................... 29 
8.1.4.1 
Source Data Verification ............................................................................. 30 
8.1.4.2 
Device Log ................................................................................................ 30 
8.1.5 
Equipment to be used for the assessment of variables ........................................ 30 
8.1.6 
Replacement of subjects ................................................................................. 31 
8.2 
Used devices and comparators ............................................................................. 31 
8.2.1 
Description of exposure to the investigational device and/or comparator .............. 31 
8.2.2 
Justification of the choice of comparators .......................................................... 31 
8.2.3 
List of any other medical device and/or medication to be used during the 
investigation ................................................................................................. 31 
8.2.4 
Number of investigational devices to be used and a justification .......................... 31 
8.3 
Subjects ............................................................................................................ 31 
8.3.1 
Description of patient population ..................................................................... 31 
8.3.2 
Inclusion criteria ............................................................................................ 31 
8.3.3 
Exclusion criteria ........................................................................................... 32 
8.3.4 
Screening failure ........................................................................................... 32 
8.3.5 
Drop-out criteria ............................................................................................ 32 
8.3.5.1 
Withdrawal of patient consent ..................................................................... 32 
8.3.5.2 
Patient is lost to follow-up ........................................................................... 32 
8.3.5.3 
Drop-out according to protocol .................................................................... 32 
8.3.5.4 
Patient death ............................................................................................ 32 
8.3.6 
Point of enrollment and study termination ......................................................... 33 
 
 
9 
STUDY PROCEDURES ........................................................................................ 34 
9.1 
Overview ........................................................................................................... 34 
9.2 
Enrollment / Baseline visit (all patients) ................................................................ 35 

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9.3 
Implantation (only patients enrolled for implantation and PHD cases, excluding 
ICMs) ................................................................................................................ 35 
9.3.1 
Documentation and procedures during implantation ........................................... 35 
9.4 
Pre-hospital discharge (only patients enrolled for implantation and PHD cases) .......... 36 
9.4.1 
Documentation and procedures at pre-hospital discharge ................................... 36 
9.5 
Follow-up (only patients enrolled for follow-up case) ............................................... 37 
9.5.1 
Documentation and procedures at follow-up ...................................................... 37 
9.6 
Termination and post treatment ........................................................................... 37 
9.7 
Description of those activities performed by sponsor representative .......................... 37 
9.8 
Responsibilities ................................................................................................... 38 
9.8.1 
Responsibilities of the sponsor ......................................................................... 38 
9.8.1.1 
Project management .................................................................................. 39 
9.8.1.2 
Data Management...................................................................................... 39 
9.8.1.3 
Biostatistician ............................................................................................ 39 
9.8.1.4 
Monitor ..................................................................................................... 39 
9.8.2 
Responsibilities of the investigators .................................................................. 39 
9.8.2.1 
Investigator .............................................................................................. 39 
9.9 
Possible influencing factors on outcome or interpretation of results ........................... 40 
10 
MONITORING PLAN .......................................................................................... 41 
11 
STATISTICAL CONSIDERATIONS ...................................................................... 42 
11.1 
Statistical design, method and analytical procedures ............................................... 42 
11.2 
Sample size ....................................................................................................... 42 
11.2.1 
Implantation ................................................................................................. 42 
11.2.2 
Pre-hospital discharge and follow-up ................................................................ 42 
11.3 
Level of significance and the power of the study ..................................................... 42 
11.4 
Expected drop-out rate ........................................................................................ 42 
11.5 
Pass/fail criteria .................................................................................................. 43 
11.6 
Provision for an interim analysis ........................................................................... 43 
11.7 
Termination criteria............................................................................................. 43 
11.8 
Procedures for reporting of deviations to the statistical plan ..................................... 43 
11.9 
Specification of subgroups ................................................................................... 43 
11.10 Procedure for accounting of all data for analysis ..................................................... 43 
11.11 Handling of missing, unused and spurious data ...................................................... 43 
11.12 Exclusion of data from confirmatory data analysis ................................................... 43 
11.13 Minimum and maximum number of patients per site ............................................... 43 
12 
DATA MANAGEMENT ......................................................................................... 44 
12.1 
Data protection .................................................................................................. 44 
12.2 
Data collection ................................................................................................... 44 

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12.3 
Procedures used for data review, CDMS cleaning, and issuing and resolving data 
queries .............................................................................................................. 44 
12.4 
Procedures for verification, validation and securing of electronic data systems ........... 45 
12.5 
Data retention and archiving ................................................................................ 45 
13 
AMENDMENT PROCEDURES ............................................................................... 46 
14 
DEVIATIONS FROM CLINICAL INVESTIGATION PLAN ....................................... 47 
14.1 
CIP compliance and exceptions ............................................................................. 47 
14.2 
Recording, reporting and analyzing deviations ........................................................ 47 
14.2.1 
Site specific deviations ................................................................................... 47 
14.2.2 
Other deviations ............................................................................................ 47 
14.2.3 
Reporting...................................................................................................... 47 
14.3 
Notification requirements and timelines ................................................................. 47 
14.4 
Actions .............................................................................................................. 48 
15 
DEVICE ACCOUNTABILITY ................................................................................ 49 
16 
STATEMENT OF COMPLIANCE ............................................................................ 50 
16.1 
Applicable ethical standards ................................................................................. 50 
16.2 
Applicable international and national standards ...................................................... 50 
16.3 
Ethics committee and competent authority ............................................................ 50 
16.4 
Statement of adherence to additional requirements ................................................ 50 
16.5 
Statement on subject insurance ........................................................................... 50 
17 
INFORMED CONSENT PROCESS ......................................................................... 51 
17.1 
General considerations ........................................................................................ 51 
17.2 
Special circumstances for informed consent ........................................................... 51 
18 
ADVERSE EVENTS AND DEVICE DEFICIENCIES ................................................. 52 
18.1 
Definition of adverse events ................................................................................. 52 
18.2 
Definition of adverse device effects ....................................................................... 52 
18.2.1 
Causality Assessment ..................................................................................... 52 
18.3 
Definition of device deficiency .............................................................................. 53 
18.4 
Definition of serious adverse events ...................................................................... 53 
18.4.1 
Patient death ................................................................................................ 54 
18.5 
Definition of serious adverse device effect ............................................................. 54 
18.6 
Definition of unanticipated serious adverse device effects ........................................ 54 
18.7 
Anticipated adverse events .................................................................................. 54 
18.8 
Reporting responsibilities ..................................................................................... 56 
18.8.1 
Reporting responsibilities of the investigator to sponsor ...................................... 56 
18.8.2 
Reporting responsibilities of the investigator to other parties ............................... 57 
18.8.3 
Reporting responsibilities of the sponsor ........................................................... 57 

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18.9 
Reporting timelines ............................................................................................. 57 
18.10 Emergency contact ............................................................................................. 58 
18.11 Data (safety) monitoring committee ...................................................................... 58 
19 
VULNERABLE POPULATION ............................................................................... 59 
20 
SUSPENSION .................................................................................................... 60 
20.1 
Criteria and procedures ....................................................................................... 60 
20.2 
Un-blinding procedures ....................................................................................... 60 
20.3 
Requirements for subject follow-up ....................................................................... 60 
21 
PUBLICATION POLICY ...................................................................................... 62 
21.1 
Decision for publication ....................................................................................... 62 
21.2 
Authorship guidelines .......................................................................................... 62 
21.3 
Contributorship and acknowledgement .................................................................. 62 
21.4 
Ancillary publications........................................................................................... 63 
22 
BIBLIOGRAPHY ................................................................................................. 64 
 

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1 
LIST OF ABBREVIATIONS 
 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
ASADE 
Anticipated Serious Adverse Device Effect 
ATP 
Antitachycardia Pacing 
AV 
Atrio-Ventricular 
BP 
Bipolar 
CA 
Competent Authority 
CCR 
Center for Clinical Research; BIOTRONIK SE & CO. KG study department  
CDMS 
Clinical Datamanagement System 
CE 
CE mark, a stylized ‘CE’ (Conformité Européenne) placed on products to 
signify conformance with European Union regulations 
CFR 
Code of Federal Regulations der USA (www.gpoaccess.gov/cfr) 
CI 
Coordinating Investigator 
CIP 
Clinical Investigation Plan 
CIR 
Clinical Investigation Report 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CRM 
Cardiac Rhythm Management 
CRT 
Cardiac Resynchronization Therapy 
CRT-D 
Cardiac Resynchronization Therapy Defibrillator 
CRT-P 
Cardiac Resynchronization Therapy Pacemaker  
DAL 
Device Accountability Log 
DD 
Device Deficiency 
DDD 
Dual chamber with atrial and ventricular pacing, atrial and ventricular 
sensing, tracking and inhibition capability 
DDI 
Dual chamber with atrial and ventricular pacing, atrial and ventricular sensing 
and inhibition capability 
DVI 
Dual chamber with atrial and ventricular pacing, ventricular sensing and 
inhibition capability 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
EU 
European Union 
FDA 
US Food and Drug Administration (www.fda.gov) 
FPI 
First Patient In 
FSR 
Funktionale Systemrisikoanalyse  
FU 
Follow-up visit 
GCP 
Good Clinical Practice 

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GUI 
Graphical User Interface: 
ICD 
Implantable Cardioverter Defibrillator 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (www.ich.org) 
ICM 
Implantable cardiac monitor 
ICMJE 
International Committee of Medical Journal Editors 
IPG 
Implantable Pulse Generator / Pacemaker 
ID 
Identification Number 
IEGM 
Intracardiac Electrocardiogram 
IFU 
Instructions For Use (user manual) 
iMedNet 
Web-based electronic data entry (EDC) system for clinical trials provided by 
MedNet Solutions Inc. 
ISO14155 
International Organization for Standardization, norm no. 14155 
ITT 
Intention to Treat Analysis 
LAN 
Local Area Network 
LPI 
Last Patient In 
LPO 
Last Patient Out 
LTE 
Long Term Evolution 
MAUDE 
Manufacturer and User Facility Device Experience Database 
MDR 
Medical Device Reporting (FDA) 
NHMRC 
National Health and Medical Research Council 
PGH 
Programmer Head 
PHD 
Pre-hospital Discharge 
PI 
Principal Investigator 
PNS 
Peripheral Nerve Stimulation 
PSA 
Pacing Sensing Analyzer 
QM 
Quality Management 
QP 
Quadripolar 
RF 
Radio Frequency  
SA 
SinoAtrial 
SaaS 
Software as a Service 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
Serious Adverse Reaction 
SAS 
Statistics and Analysis Software produced by SAS Institute Inc. 
(www.sas.com) 
SDS 
Source Data Sheet 

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SOP 
Standard Operating Procedure 
TGA 
Therapeutic Goods Administration 
UMTS 
Universal Mobile Telecommunications System 
USADE 
Unanticipated Serious Adverse Device Effect 
USB 
Universal Serial Bus 
VDD 
Pacemaker Mode (ventricular pacing / atrial and ventricular sensing / atrial 
and ventricular triggering and inhibiting) 
VVI 
Pacemaker Mode (ventricular pacing / ventricular sensing / and inhibiting) 
WLAN 
Wireless LAN 
 
 

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2 
SYNOPSIS 
 
Title 
BIO|CONCEPT.Renamic Neo 
 
Patient population 
Patients that are planned to receive or are already 
implanted with a programmable BIOTRONIK 
cardiac rhythm management (CRM) device. 
  
Design 
Observational, prospective, open, un-controlled, 
non-randomized, multicenter 
 
Investigational devices 
 Renamic Neo programmer  
 Programmer software NEO 2001.A and 
successor 
 PK-222-L ECG cable 
 
Objectives 
Collection of clinical data on the safety, 
performance and usability of the Renamic Neo 
programmer system to support regulatory approval
 
Endpoints 
Adverse device effects and device deficiencies 
 
Data of interest: 
The following functionalities will be assessed 
 Pacing System Analyzer (PSA) 
 Sensing, pacing threshold and impedance tests 
with implanted device  
 Interrogation and programming of implanted 
devices 
 Data export and printing 
 General performance, safety and usability of 
Renamic Neo system 
 Performance of used accessories 
 
Inclusion criteria 
 Patient is planned for de novo implantation or 
already has a BIOTRONIK active, implantable 
device.  
 Patient is able to understand the nature of the 
study and provides written informed consent. 
 
Exclusion criteria 
 Patient is implanted with a Stratos pacemaker. 
 Patient is planned for implant exchange or 
upgrade. 

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 Patient is pregnant or breast feeding. 
 Patient is less than 18 years old. 
 
Study duration 
April 2020 – July 2020 (approx. 3 months) 
 
Sample size 
Approximately 120 patients will be enrolled in 
order to collect data from 50 implantations and 
100 pre-hospital discharge or follow-up cases 
performed with 20-30 programmer devices. 
 
Investigational sites 
Approximately 10  
 
Follow-up scheme 
For patients who are scheduled for a BIOTRONIK 
device implantation (except ICMs):  
 Enrollment 
 Implantation  
 PHD 
 Termination 
For patients who are already implanted with a 
BIOTRONIK active device:  
 Enrollment 
 Follow-up visit 
 Termination 
 
Sponsor 
BIOTRONIK Australia Pty. Ltd. 
Level 4, Building 2, 20 Bridge St 
Pymble NSW 2073 
Australia 

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3 
INTRODUCTION 
A programming device is an essential user interface for active cardiac implants and as such it 
is an external component of the implant system.  
The Renamic Neo programmer is BIOTRONIK’s latest generation of programming devices.  The 
Renamic Neo programmer system includes the programming device Renamic Neo, the 
programmer software NEO 2001.A and the new electrocardiogram (ECG) cable PK-222-L. 
The Renamic Neo system provides communication with BIOTRONIK implantable implantable 
pulse generator (IPG), implantable cardioverter defibrillators (ICDs), cardiac resynchronization 
therapy (CRT) devices and implantable cardiac monitors (ICM) thereby constitutes a 
substantial external component of the implant system. The clinical functions exist within the 
implant, and the programmer simply provides bidirectional communication with the implant, 
displays implant data and parameters, and allows the programming of implant parameters 
during implantations and follow-ups according to the state-of-the-art concept for programming 
devices 1–3. 
Furthermore, during implantations the integrated Pacing System Analyzer (PSA) enables the 
user to perform intraoperative measurements like sensing, pacing and impedance tests of the 
leads by connecting the leads directly to the programmer.  
The overall use concept for Renamic Neo is inherited from previous BIOTRONIK programmers, 
particularly from the direct predecessor Renamic which gained CE-mark in September 2010 
and regulatory approval in Australia in June 2011. The programmer must enable different use 
scenarios depending on which active implant is to be interrogated, whether the interrogation 
relates to implantation or to clinical follow-up, and the clinical context and patient specific 
requirements in which the active implant is to be used. The purpose of the development of 
Renamic Neo has been to provide a programmer based on up to date hardware components 
and to optimize the integration into the clinical workflow.  
This study is designed as a pre-market study to provide clinical data and supporting evidence 
of the safety, performance and usability of the Renamic Neo programmer system.   
 

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4 
INVESTIGATIONAL DEVICE 
4.1 
Summary description of the device and its intended purpose 
The investigational devices used in this clinical investigation are the programmer device 
Renamic Neo, the programmer software NEO 2001.A and the PK-222-L ECG cable. In the 
following text the term ‘Renamic Neo system’ refers to the Renamic Neo hardware, software 
and the PK-222-L cable, unless otherwise stated. 
Renamic Neo is a portable programmer and monitoring device that must enable the intended 
use of the compatible active implants. It is operated via a touch sensitive display and 
interrogation of the implant is achieved through a programming head (PGH) or via wandless RF 
telemetry. This is state-of-the art for cardiac rhythm management (CRM) programmers. 
Renamic Neo has an integrated PSA, which is used during implantation of BIOTRONIK 
implantable devices to perform intraoperative tests at the leads. In daily operation, the 
Renamic Neo can be operated with a power supply brick or, alternatively, with a battery. It can 
be custom-equipped with a mobile internet stick authorized by BIOTRONIK. 
Notable enhancements to Renamic Neo with respect to the predecessor programmer Renamic 
include: 
 Connectivity to fast mobile networks, WLAN, LAN 
 Capacitive touchscreen 
 High resolution display  
 Smaller and lighter hardware compared to the predecessor Renamic 
 Operation for a minimum of 1.5 hours through an optional internal battery 
 Integration of the Pacing System Analyzer  
Unlike Renamic, Renamic Neo does not have an internal printer and instead printing is possible 
through connection via LAN, USB or wirelessly to an external printer. Apart from the internal 
printer, all fundamental functionalities of Renamic are also realized in Renamic Neo. 
The programmer software NEO 2001.A is highly similar in functioning to the programmer 
software of the predecessor Renamic. Some software features have been optimized to deliver 
the same overall PSA functionality and clinical performance, but with improved adaptation of 
usability to the preferences of the clinical user.  
The PK-222-L ECG cable patient cable is used with a surface ECG to connect the ECG 
electrodes to a programmer from BIOTRONIK. As part of implantations and follow-ups of IPGs, 
ICDs, CRTs and ICMs from BIOTRONIK, the signals are transmitted via the patient cable for 
representation of the surface ECG on the screen. The ECG cable PK-222-L differs from the 
approved PK-222-EU cable in its length and the permanently mounted patient cable electrode 
clips.  
4.2 
Manufacturer 
The manufacturer of the Renamic Neo system is: 
BIOTRONIK SE & Co. KG 
Woermannkehre 1 
12359 Berlin 
Germany 
www.biotronik.com 

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4.3 
Model name including software version and accessories 
The devices undergoing clinical investigation are BIOTRONIKs Renamic Neo programmer, the 
programmer software NEO 2001.A and the ECG cable PK-222-L. These investigational devices 
have not been approved for the market release yet by a regulatory authority or notified body. 
Clinical data on these devices are collected to support regulatory approval.  
Table 1: Investigational Devices 
Model Name 
Model Number 
Renamic Neo  
including rechargeable battery 
424722 
445510 
Programmer software NEO 2001.A and successor 
449859 
PK-222-L ECG cable 
429747 
In addition, data on the following BIOTRONIK available accessories (additional devices) may be 
collected, as required to support regulatory requirements (Table 2). Except for the accessory 
bag the listed accessories used in the scope of this clinical study are certified by the Australian 
Therapeutic Goods Administration (TGA). 
 
Table 2: Available Accessories 
Model Name 
Model Number 
Accessory bag 
445749 
PK-222 EU / 2.8 m ECG cable 
335284 
PK Electrode Clip 
340293 
Patient cable PK-141 
353181 
Patient cable PK-67-S 
128085 
Patient cable PK-67-L 
123672 
Patient cable PK-155 
337358 
Patient adapter PA-1-B 
123751 
Patient adapter PA-1-C 
349723 
Patient adapter PA-2 
123157 
4.4 
Description of traceability 
Every Renamic Neo programmer can be identified by its unique 8 digit serial number.  Each 
ECG cable PK-222-L will be allocated a unique number for the use during the study. The 
programmer software NEO 2001.A is identifiable by its version number. The traceability is 
assured by recording the serial numbers or unique numbers in the device accountability log 
(DAL, section 15) of the clinical data management system (CDMS). This documents the 
shipment, receipt, transfer and/or return to the sponsor of used, unused or malfunctioned 
investigational devices. Device information as model name, serial/unique number, date of 
shipment or return and shipment destination is entered in the DAL.  
Moreover, identifying numbers of investigational devices and patient ID are recorded during 
each use of the programmer at implantation and/or follow-up. This information is documented 
in the corresponding electronic case report form (CRF) in the CDMS.  

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Investigational devices have to be clearly visible labeled as investigational devices. Only 
trained BIOTRONIK personnel or trained site personal is authorized to have access and to 
handle investigational devices.  
Malfunctioning investigational devices shall be sent back to the manufacturer. The investigator 
shall contact the respective sales representative in order to organize shipment.  
After study termination all investigational devices have to be returned to the sponsor.  
4.5 
Intended purpose of the device in the study 
The Renamic Neo programmer, programmer software NEO 2001.A and PK-222-L ECG cable will 
be used according to their intended use outlined in the respective instructions for use.  
The Renamic Neo programmer system provides communication with BIOTRONIK implantable 
IPGs, ICDs, ICMs or CRT devices during the implantation or a follow-up. It is intended to 
enable normal use of the implantable products by providing a user interface for the functions 
of the device.  
The programmer is used for the following applications: 
 For verification and optimization of the therapy which is delivered by the active implant 
 For support of the diagnosis of the patient status through data that is sent by the device 
This is achieved by providing product properties that enable the execution of the following 
tasks: 
 Identify supported implantable devices and retrieve, display, and print current parameter 
settings 
 Retrieve, display, and print the recorded statistical data and episodes from the memory of 
the device 
 Retrieve real-time IEGM data from the device 
 Retrieve real-time ECG data from the ECG leads affixed to the patient 
 Select the appropriate settings for the supported implantable devices by the user 
 Program the supported devices with the selected parameter values 
 Execute test functions (e.g. sensing, pacing threshold, and impedance test) in order to 
determine the internal status of the device, the connected leads, and the patient 
 Initiate special programs and shocks for therapeutic purposes 
 Support the implantation of leads through intraoperative measurements of the 
electrophysiological parameters, such as the detection of intrinsic cardiac signals, pacing 
threshold, lead impedance, and timing features (timing cycles) as well as to provide 
temporary functions of an external pacemaker 
 Export data (including recordings of real-time data) of the implanted device for analysis and 
reporting purposes, as an automatic and user-initiated function, to a data storage unit or to 
a data processing system 

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4.6 
Intended patient population and indications 
The intended patient population comprises all patients that are implanted with or are intended 
for de novo implantation with a BIOTRONIK IPG, ICD, CRT-D (CRT-defibrillator), CRT-P (CRT-
pacemaker) or ICM that can be adequately programmed and interrogated by the Renamic Neo 
programmer system.  
Contraindications: 
There are no contraindications for the Renamic Neo device itself. The following applications are 
contraindicated for use of the integrated pacing system analyzer (PSA): 
 With AV conduction disorders: 
 Atrial single-chamber pacing 
 With competing intrinsic rhythms: 
 Modes that have no sensing and inhibition function in the corresponding chamber 
 With chronic atrial tachycardia as well as chronic atrial fibrillation or flutter: 
 Atrial-controlled modes (DDD, VDD) 
 With poor tolerance of high ventricular rates (e.g., angina pectoris): 
 High upper rate 
 Under certain conditions: atrial-controlled modes 
 With retrograde conduction after ventricular pacing: 
 Programming a short AV delay 
 Under certain conditions: DDI, DVI, or VVI mode 
 Use as an external pacemaker outside of the implantation procedure 
4.7 
Description of the investigational device 
4.7.1 Renamic Neo hardware and software  
The Renamic Neo programmer system comprises the Renamic Neo hardware, software and the 
ECG cable PK-222-L. The functional design is highly similar to the predecessor Renamic. Some 
software features related to PSA functionalities and the graphical user interface (GUI) have 
been optimized and are described below. 
The hardware consists of the Renamic Neo, the programmer head (PGH), the battery and the 
pacing system analyzer (PSA). Several accessories can be used with the programmer to record 
ECG or to conduct lead positioning checks during implantations. These include ECG cables, 
patient cables, electrode clips and patient adapters.  

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4.7.1.1 
Renamic Neo hardware 
 
 
Figure 1: Description of the Renamic Neo hardware. 
1. Pacing system analyzer (PSA), 2. Cable feedthrough for ECG cable, 3. Closed screen (touch screen), 4. 
Ventilation slots, 5. Carrying handle, 6. Screen release key, 7. Open screen (touch screen), 8. Programming 
head (PGH) and ECG cable compartment, 9. Stylus in pen holder, 10. Release key for the PGH/ECG power 
cord compartment, 11./12. USB port for connecting a printer or for exporting data to a USB flash memory 
stick, 13. Mini display port, 14. Ethernet port, 15. Power supply port, 16. Ventilation slots 
The Renamic Neo is folded for transportation and storage (Figure 1). The monitor can be 
unlocked and tilted upwards to its operating position. There is a compartment under the 
monitor for the programming head (PGH) and the ECG cable. The ECG cable connector is 
located in this compartment. The PGH is permanently connected to Renamic Neo. In addition, 
there are two small compartments at the back of the device, to provide covered USB 
communication interfaces for the LTE/ UMTS-stick. The monitor provides all functions for 
patient-monitoring and for interrogation and programming of the implant. Additionally, buttons 
for activation of the emergency program of the implant are located on the upper front of the 
programmer: the emergency shock button (ICD only) and the safe program.   
4.7.1.2 
Graphical User Interface (GUI) 
The programmer provides an interface for the user to the implant, and allows the user to 
carry-out implant interrogation, programming and implant dependent tests during implantation 
and during follow-up.  
All available functions are displayed on the screen and can be activated by touching the screen 
via the supplied stylus or the user’s finger (with exception of the 2 emergency program buttons 
discussed above). The screen is designed in such a way that certain information is displayed 
permanently, including the heart rate, the surface ECG and important navigation elements.  
In contrast to the predecessor device the following information is displayed on the left side bar 
of the screen (see Figure 2):  
(1) Patient, device and telemetry information 
(2) Connectivity information 
(3) Programmer battery indicator (% / time) 
(4) Date and time always visible 

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Figure 2: Screen-shot showing an example of the GUI layout.  
The precise GUI layout depends on the functionality used and on the nature of the clinical use-
case. In this case a ‘Follow-up’ screenshot is shown. 
4.7.1.3 
The Pacing System Analyzer  
The Pacing System Analyzer (PSA) is a built-in medical diagnostic functionality to perform 
intraoperative measurements and tests during implantation of IPGs, ICDs and CRT-devices.  
For this purpose, the PSA is directly connected to the implanted leads via patient cables with 
alligator clamps and adaptors.  
The intra-cardiac signals from each lead are continuously acquired and displayed on the 
display of the Renamic Neo to allow monitoring of the patient’s heart activity during the tests.  
There are several changes to the predecessor device:  
 The PSA hardware was fully  integrated in the Renamic Neo programmer 
 Polarity selection parameter was raised to the first level in the test screen. In addition, the 
range of selectable polarities was extended, according to the needs of quadripolar (QP) 
leads. 
 Polarity 
selection 
allows 
documentation 
of 
the 
polarities 
including 
quadripolar 
measurements. Polarities are tested by the positioning of the alligator clips on the lead-
connector.  
 Phrenic nerve stimulation (PNS) including threshold value can be documented. 
 The amplitude selection GUI has been unified with the GUI of latest implantable devices. 
4.7.1.4 
Interrogation of implanted devices 
For programming an implanted device the interrogation of the implantable device is 
automatically started when the PGH is placed above the implanted device. Thus, the follow-up 

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session starts and all relevant parameters of the implant are transmitted to the programmer 
and displayed on the screen (Figure 2). The clinical user can activate various functions on 
request – the range of functions available depends upon the range of functions of the 
respective implant.  
Functions may include:  
 Interrogation, display, modification and storage of the parameters of the implant 
 Analysis of the real-time IEGM or marker channel 
 Performing tests (e.g. threshold and impedance tests) 
 Display of episodes and statistics 
 Display and change of patient data 
 Print documentation of the follow-up care 
The follow-up procedures are archived automatically in Renamic Neo, and as such follow-up 
data is saved on the programming device and can be displayed, printed (externally), saved on 
a storage media or sent to other systems at any time. This data includes: 
 Program parameters at the beginning and end of follow-up  
 Results of the tests performed during follow-up 
 Patient data 
IEGM-episodes that were recorded by the implant are not automatically transferred to Renamic 
Neo due to their size.  
4.7.2 PK-222-L ECG cable 
The PK-222-L ECG cable is used to transmit signals from the ECG electrode to the BIOTRONIK 
programmer in order to display surface ECGs on the programmer screen. 
The PK-222-L ECG cable is longer (4 m) than its predecessor and has four color-coded and 
permanently mounted patient cable electrode clips on the patient side for extremity derivations 
according to Einthoven. They are compatible with adhesive and clamp electrodes with snap 
connectors.  
 
Figure 3: ECG cable PK-222-L 
The assignment of the four color-coded patient cable electrode clips for extremity derivations 
according to Einthoven is as follows: 
 
Extremity  
PK-222-L ECG cable  
Right arm  
R / red  
Left arm  
L / yellow  
Left leg  
F / green  
Right leg  
N / black  
 

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4.8 
Summary of training and experience needs 
The Renamic Neo system is an external medical device intended for clinical staff members who 
are familiar with the use of programmers during implantations and follow-ups of cardiac 
implants. The user must be familiar with the Renamic Neo system including the new features. 
Therefore, study team members will be trained by a qualified representative of the sponsor on 
the Renamic Neo system. 
The physician must be familiar with the associated risks and complications. The handling and 
use instructions are described in the respective Technical Manuals (instructions for use) for the 
Renamic Neo programmer, the software NEO 2001.A and the PK-222-L ECG cable4–6.  
The interrogation and programming of BIOTRONIK implantable devices by the Renamic Neo 
system shall only be done by an appropriately trained investigator. All study team members 
must be adequately trained on the study procedures. 
The analysis of interrogated data, conducted tests and the assessment of the implant 
programming has to be performed by qualified clinical staff.  
4.8.1 Description of medical and surgical procedures 
The Renamic Neo system will be used during implantations, pre-hospital discharges (PHDs) 
and follow-ups according to clinical routine and current instructions for use. This includes the 
recording of surface ECGs and the use of the PSA to test for correct lead positioning during 
implantations by connecting the programmer to the implanted leads.  
 

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5 
JUSTIFICATION FOR THE DESIGN OF THE CLINICAL 
INVESTIGATION 
5.1 
Pre-clinical data 
No pre-clinical data are available for the Renamic Neo programmer, software or PK-222-L 
cable. Animal tests were not performed for the Renamic Neo programmer as it is an external 
device. The most relevant verification and validation tests for the Renamic Neo system are 
described in the Investigator’s Brochure7. Investigational devices will not be provided to study 
sites until all tests are successfully completed.  
5.2 
Clinical data 
For the Renamic Neo system, no clinical data are available yet.  
The preceding programmer Renamic has been used in many BIOTRONIK sponsored clinical 
studies, e.g. 
 QP ExCELs (NCT03155724)8 
 Eluna Family Sentus BP Master Study (NCT02059629)9 
 Matrix (NCT01774357)10 
 BIO|MASTER.Ilivia / Plexa Family (NCT02774616)11 
 BIO|MASTER.BioMonitor 2 (NCT02565238)12 
Renamic was granted CE approval in Sep 2010 and was predominantly used in any BIOTRONIK 
study starting from January 2015 onwards that supported regulatory approval. Renamic was 
not explicitly investigated in these studies, but the positive results of these studies imply a 
correct and safe functioning of this programmer generation. As the functioning of the Renamic 
Neo is highly similar to that of the Renamic it is expected that the complication rate will be 
very low. 
5.3 
Justification 
The main objective of this study is to provide evidence for the clinical safety, performance and 
usability of the Renamic Neo programming device including software and PK-222-L ECG cable.  
The study is designed in a use case centric approach, i.e. it follows the usage of Renamic Neo 
programmer system and not the individual patients, so that a sufficient number of use cases is 
collected that allows for the detection of possible adverse device effects and device deficiencies 
caused by the programmer.  
Patients will stay in the study only for implantation and PHD or follow-up and are terminated 
directly afterwards as ADEs and DDs related to the programmer are expected to occur only 
during the use of the programmer.  
As the Renamic Neo system will be used for the first time in clinical routine, a significant 
number of use cases from implantation – given that the PSA module might be used – and 
follow-ups shall be included in this study. Please refer to section 11 for the justification of the 
sample size calculation.  
Approximately 10 clinics with 2-3 Renamic Neo systems each are planned to participate. The 
multi-centric design will ensure that different environments in which the programmer is placed 
and used as well as potential hospital specific differences in programmer handling and usage 
are covered. While just several sites would be sufficient for that purpose, approximately 10 
sites will be involved in order to realize a fast study completion. Depending on the special 
requirements of the sites to use the programmer at different locations at the same time, sites 
will receive 2-3 Renamic Neo device systems respectively. This results in an approximate 
number of 20-30 investigational devices.  
To cover a broad range of programmer functionalities the device will be used during 
implantations including PSA usage, if applicable, and follow-up visits. Furthermore, the 

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enrollment of patients will not be restricted to any subgroup or indication in order to cover use 
cases for the different CRM devices.  
The endpoints adverse device effects and device deficiencies are selected to analyze the safety 
of the Renamic Neo system and to identify possible residual risks of the programmer. Based on 
rare observations of events caused by the programming device in the past, only a small 
number of events are expected. Therefore, no power calculation and no hypothesis for the 
event-free rate can be provided.  
Additional data from implantation and follow-up visits will be collected to confirm the 
performance and usability of the Renamic Neo system. 
 
 

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6 
RISKS AND BENEFITS OF THE DEVICE AND CLINICAL 
INVESTIGATION 
6.1 
Anticipated clinical benefits 
The Renamic Neo device is a state of the art programming device that is designed to integrate 
into the clinical workflow in order to make the clinical routine more efficient. Apart from this 
potentially better workflow there will be no benefit for patients that participate in this clinical 
study.  
6.2 
Anticipated risks 
6.2.1 Anticipated adverse device effects 
Adverse device effects anticipated for the use of the Renamic Neo system are described in 
section 18.7. Since no additional procedures outside the clinical routine are required in this 
study, no further study-specific adverse device effects (ADEs) are anticipated.  
6.2.2 Residual risks associated with the device 
In principle, technical failures in the programmer due to transmission errors, random 
component failures, software malfunction, or other events that could lead to harm, cannot be 
ruled out completely. These are expected but unlikely events. 
Instructions for use to support correct use and to avoid use error are provided, but user errors 
cannot be prevented completely. Potential harm related to technical failure of the programmer 
or use errors have been evaluated 13 and are listed below:  
 Nausea / sickness / slight dizziness  
 Cardiac arrest and tachycardia  
 Prolonged undesired medical condition, anesthesia or psychological stress 
 Acute and serious heart failure  
 Thermal tissue load  
 Misdiagnosis and repeated invasive intervention 
 Infection 
 Asystole 
There may be other risks associated with the devices that are currently unforeseeable.  
6.2.3 Risk associated with participation in the study 
Unauthorized access to the patient data or inadequate data protection (e.g. submission of non-
pseudonymized data to the sponsor representatives) are possible risks associated with the 
participation. BIOTRONIK undertakes technical and organizational measures to protect 
patient’s data privacy and adheres to applicable European data protection laws.  
There are no study-related procedures outside the clinical routine care planned. PSA 
measurement procedures do not differ from the procedure with the predecessor Renamic PSA 
module. Therefore, no additional risks or burdens are expected to derive from participating in 
the study. 

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6.2.4 Possible interactions with concomitant medical treatments 
The use of the Renamic Neo is not expected to interfere with concomitant medication or other 
medical treatment.  
The individual cardiovascular medication may have to be adapted to the patient’s needs 
independent of the Renamic Neo device. 
6.3 
Steps to control or mitigate the risks 
Risks related to the design, the technical characteristics, and the handling of the Renamic Neo 
programmer as mentioned above and in section 18.7 have been reduced by appropriate risk 
control measures defined in the respective BIOTRONIK Function System Risk Analysis (FSR) 13.    
They are minimized through the compliance with the technical manual and special training of 
the clinical site staff on the Renamic Neo by BIOTRONIK staff, compliance with this clinical 
investigation plan and technical procedures, close monitoring of the patient’s physiologic status 
during the use of the Renamic Neo, and by promptly supplying BIOTRONIK with all pertinent 
information required by this clinical investigation plan. 
National data protections laws and the European Regulation (EU) 2016/679 must be followed. 
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. Access  to investigational devices is restriced (see section 15) Nevertheless, a 
residual risk remains (see section 6.2.2). 
6.4 
Risk-to-benefit rationale 
Patients participating in the BIO|CONCEPT.Renamic Neo study are scheduled for an 
implantation of an IPG, ICD, CRT device or ICM from BIOTRONIK or already have such a 
BIOTRONIK device implanted. Programming devices are essential to adapt the implants to the 
patient’s needs and to obtain data about device function and physiologic data. By participating 
in this study patients have no direct benefits, but they contribute to the medical progress 
which may benefit other patients in the future. The advanced features and properties (e.g. 
internal battery, less weight) of the Renamic Neo system may improve the clinical workflow. 
The use of programmers to interrogate, and program IPGs, ICDs, CRT-devices and ICMs is 
state-of-the-art. Programmer-related complications are rare. The risks of the use of Renamic 
Neo system do not exceed the levels expected and acknowledged for programmers, and are 
clearly outweighed by the possible benefits. 
The Renamic Neo system therefore has a favorable benefit-risk profile - the benefit-risk profile 
according to current knowledge and the state-of-the-art in the affected medical areas and 
according to available medical alternatives is positive. 

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7 
OBJECTIVES AND HYPOTHESES 
7.1 
Objectives 
This study is designed as a pre-market clinical study to provide evidence on the safety, 
performance and usability of the Renamic Neo programmer hardware, software and ECG cable 
PK-222-L to support regulatory approval, with a focus on requirements of the European 
Medical Device Regulation (MDR). The study is also intended to identify and evaluate residual 
risks associated with the use of the Renamic Neo programmer system that remained 
unrevealed even after risk analysis, risk mitigation and completed validation of the device. The 
results will be used to update the clinical evaluation of the devices. 
7.2 
Endpoints and hypotheses 
7.2.1 Primary endpoint and hypotheses 
There is no pre-specified statistical hypothesis and thus no primary endpoint. All analyses are 
explorative only.    
7.2.2 Endpoints 
In this study the number of adverse device effects and device deficiencies (DD) that occur in 
patients, users or other persons will be evaluated. Definitions are given in section 18. The 
investigator is asked to report any ADEs or DD that occurred during implantations and follow-
ups.  
 Number of adverse device Effects / device deficiencies per number of implantations 
 Number of adverse device Effects / device deficiencies and per number of follow-up cases 
ADEs will be adjudicated by an internal adjudication board, whereby the seriousness and 
device relatedness will be re-examined. If any amply documented external physical influence 
(e.g. accident, general power blackout) or medical AE caused the ADE, it does not contribute 
to this endpoint. 
 
 
 
7.4 
Safety assessments 
Adverse events, adverse device effects and device deficiencies will be assessed in this clinical 
study as described in section 18 and according to the SOPs of the Sponsor. Steps to mitigate 
and control risks and anticipated adverse device effects as described in section 6.2 are 
addressed in section 6.3. 
7.5 
Further data of interest 
General information 
 Patient demographics and medical history  
 Implant type and model, all other implanted devices 
 Lead model and programmer software version 
During implantation and follow-ups additional data on safety, performance and usability of the 
Renamic Neo system and accessories will be collected.  
 Use and assessment of PSA functionality (sensing, pacing and impedance tests) 
 Success of adequate programming of the implant  

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 Evaluation of interrogation of the implant including RF telemetry 
 Overall assessment of device hardware or software performance including battery use 
 Data export evaluation (used connectivity, destination, printing) 
 Export of programmer data export files that document the performed use case for 
evaluation at the sponsor 
 Information on additionally used accessories or other implanted cardiac devices 
 

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8 
DESIGN OF THE CLINICAL INVESTIGATION 
8.1 
General considerations 
8.1.1 Type of clinical investigation 
The study is designed as an observational, prospective, open, non-randomized, non-controlled, 
multicenter study that is planned to be conducted in Australia and New Zealand. 
8.1.2 Measures taken to minimize or avoid bias 
The study will be conducted according to BIOTRONIK’s internal Standard Operating Procedures 
to minimize and avoid potential bias. 
The study does not require randomization or blinding as it does not require a control group.  
It will be conducted at up to 10 sites to avoid a hospital-specific bias caused by the specific 
hospital environment or the programmer user. A maximum number of 30 programmer use 
cases (implantations and FUs) per site is defined to avoid site specific bias in case of high 
enrollment rates of single sites. Exemptions will be communicated in written form in case 
enrollment is too slow. 
Furthermore, the number of implantations and follow-ups for a specific implant type is defined 
for the whole study to avoid an unbalanced usage of specific, implant related programmer 
functions. The 50 implantation and 100 follow-up (including PHD) cases should be distributed 
as follows: 
 IPG,  ICD:  ~15 implantations and ~20 follow-up cases for each 
 ICM:  
~20 follow-up cases  
 CRT-D /-P:  ~20 implantations and ~40 follow-up cases for both combined 
As no PSA measurements will be performed for ICMs no implantation cases or PHDs shall be 
performed for ICMs, but only follow-up cases. 
A survey for implantation and follow-up numbers for each implant type is implemented in the 
iMedNet system. The sponsor will immediately inform all sites whenever the required number 
of a certain implant type has been reached.  
8.1.3 Selection of measurements for endpoints 
For the defined endpoints the number of adverse device effects and device deficiencies will be 
determined for implantation cases and for follow-up cases separately as different programmer 
features are used for both use case types. The Renamic Neo system shall be used according to 
clinical routine, therefore no study specific measurements are planned. The measurements for 
Renamic Neo performance will be focused but not restricted to new features compared to its 
predecessor Renamic as for the Renamic sufficient experience in clinical use is available. 
8.1.4 Methods  
All clinical procedures in this study will be performed according to clinical routine. Detailed 
information on the use of the Renamic Neo system can be found in the Technical Manuals and 
other study documents. The time schedule and all parameter and measurements that are 
recorded during the study are described in section 9.1. The corresponding data will be 
documented in the respective CRFs at the following points in time: 
 

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For patients who are scheduled for a 
BIOTRONIK active device implantation 
For patients who are already implanted 
with a BIOTRONIK active device: 
 Enrollment/ baseline  
 Implantation 
 Pre-hospital discharge 
 Termination 
 Enrollment/ baseline 
 Follow-up 
 Termination 
 
 
The following events shall be documented at any time 
 Adverse events (including device related adverse events in users and other persons) 
 Device deficiencies 
8.1.4.1 
Source Data Verification 
Source data, e.g. medical records, for data entered in the CRFs have to be available for source 
data verification by the sponsor’s clinical monitor. Patients have to consent to the use of their 
medical data prior to enrollment by signing the informed consent form.  
Source data sheets (SDS) shall be completed and signed by authorized clinical study team 
members if the data entered in the CRFs is not documented elsewhere as source data. This 
includes the assessments of the Renamic Neo system during implantation and follow-ups. 
8.1.4.2 
Device Log 
Information on implanted devices (type and model), leads and used accessories shall be 
entered in the device log  
 at baseline, if patient is enrolled for follow-up 
 at implantation, if patient is enrolled for device implantation  
8.1.5 Equipment to be used for the assessment of variables  
The following equipment is used during the study to collect data in combination with the 
Renamic Neo or as optional accessories: 
Cables and adapters: 
 PK-222 EU / 2.8 m ECG cable 
 PK Electrode Clip 
 Patient cable PK-141 
 Patient cable PK-67-S 
 Patient cable PK-67-L 
 Patient cable PK-155 
 Patient adapter PA-1-B 
 Patient adapter PA-1-C 
 Patient adapter PA-2 
All devices are used within their intended purpose. 

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8.1.6 Replacement of subjects 
Patients are enrolled in the study only for the time of study related measurements during 
implantation and PHD or follow-up. Patients that drop out before any study related use of the 
Renamic Neo system will be replaced. No drop-out rate was defined (see section 11.4).  
8.2 
Used devices and comparators 
8.2.1 Description of exposure to the investigational device and/or comparator 
The Renamic Neo system is an external device. During implant interrogation the programmer 
head (PGH) might have contact to the intact skin when the PGH is placed above the implant 
site. For PSA measurements during implantation the leads are connected to the Renamic Neo 
via patient cables and alligator clamps but there will be no direct exposure to the Renamic Neo 
device. For surface ECGs the ECG cable PK-222-L will connect the ECG electrodes to the 
programmer and might have contact with the intact skin of the patient. 
No comparator is used in this study. 
8.2.2 Justification of the choice of comparators 
Not applicable. 
8.2.3 List of any other medical device and/or medication to be used during the investigation 
See section 8.1.5 for medical device accessories that are used during this clinical study. No 
medication is required by this study protocol. 
8.2.4 Number of investigational devices to be used and a justification 
In this study 20-30 Renamic Neo programmers including software NEO 2001.A will be used at 
different investigational sites. The sample size calculation (see section 11.2) is based on the 
number of use cases at implantation and at PHDs plus follow-ups and not on the number of 
devices as unforeseen safety issues are expected to be rather related to software problems 
than to the Renamic Neo hardware.   
8.3 
Subjects 
8.3.1 Description of patient population 
The patient population comprises all patients with BIOTRONIK CRM devices that can 
communicate with the Renamic Neo programmer. These are patients with an indication for a 
IPG, ICD, CRT or ICM device according to current clinical practice who are implanted with or 
are intended to be implanted with a respective BIOTRONIK device according to the 
investigator’s decision. Therefore the patient population in the study represents a diverse 
patient population and use cases that are expected for the Renamic Neo system. Patients with 
a Stratos pacemaker are excluded as this device model is no longer supported by the Renamic 
Neo system. Patients who are planned for a device exchange or device upgrade are excluded 
from this study as polarity measurements of the newer quadripolar leads are planned in the 
study and these are most likely not implanted in patients with older implants. 
8.3.2 Inclusion criteria 
To be eligible for the participation in the BIO|CONCEPT.Renamic Neo study, patients must 
fulfill the following inclusion criteria at the time of enrollment: 

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 Patient is planned for de novo implantation or already has a BIOTRONIK active, implantable 
device 
 Patient is able to understand the nature of the study and provides written informed consent. 
8.3.3 Exclusion criteria 
The following exclusion criteria must not be fulfilled at enrollment: 
 Patient is implanted with a Stratos pacemaker. 
 Patient is planned for implant exchange or upgrade. 
 Patient is pregnant or breast feeding. 
 Patient is less than 18 years old. 
Note: The inclusion and exclusion criteria apply at enrollment. 
8.3.4 Screening failure 
No screening procedure is planned for this study. 
8.3.5 Drop-out criteria 
8.3.5.1 
Withdrawal of patient consent 
Patients may withdraw their consent for study 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 filled in by the investigator.  
8.3.5.2 
Patient is lost to follow-up 
The patient should be terminated if he or she is lost to follow-up. In such a case the 
investigators shall use all justified means to try and contact the patient before premature 
termination. 
8.3.5.3 
Drop-out according to protocol  
The investigator shall exclude a patient due to the following reason and after all adverse 
events have been reported and the corresponding CRFs have been thoroughly completed: 
Violation of inclusion or exclusion criteria is detected before any measurements with the 
Renamic Neo system were performed, for example, if the patient does not receive an implant 
device. This shall be considered as premature termination and has to be documented in the 
termination form. 
8.3.5.4 
Patient death 
The investigator shall terminate the patient’s study participation after their deaths and report 
the death as an adverse event on the corresponding CRF.  

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8.3.6 Point of enrollment and study termination 
Point of enrollment is the date of signature of the informed consent form by the patient. 
Date of regular termination for each patient is the date of discharge from the index 
hospitalization for implantation cases or the date of follow-up after follow-up completion for 
follow-up cases.  
In case of premature termination the following rules apply: 
 In case of withdrawal of a patient’s consent, the date of study termination shall be the date 
of withdrawal of consent. 
 If patient is lost to follow-up, the date of study termination shall be the day of the last 
contact of the site study team (e.g. investigator or study nurse) with the patient 
 If the implantation is not performed succesfully due to any reasons the date of study 
termination shall be the date of the unsuccessful implantation attempt if another attempt is 
not planned within the following 2 weeks.  
 In case of patient death, the date of study termination shall be the date of death.  
 In case the patient is terminated prior to study specific procedures because a violation of an 
inclusion/exclusion criterion was discovered the date when the violation was discovered 
shall be the date of termination. 
Study related procedures and documentation shall end at the day of study termination for the 
respective patient. However, all adverse device effects will be followed for up to 2 weeks after 
study termination of the respective patient. 
 
 
 
  
 
 
 
 
 
 
 
 
 
 

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9 
STUDY PROCEDURES 
9.1 
Overview 
Patients will be enrolled either for implantation including subsequent pre-hospital discharge or 
for a follow-up visit only. ICM patients will be included for follow-ups only. As the total study 
duration is planned for only 3 months different patients will be included for implantation and 
for follow-up. Patients that have been enrolled in the study and were terminated shall not be 
included a second time in the study.  
All study related procedures performed (Table 3) have to be documented in the CRFs.  
Table 3: Overview of study procedures 
Investigations 
Enrollment / 
Baseline 
 
For patients enrolled 
before implantation 
For patients 
enrolled after 
implantation 
Implantation 
Pre-hospital 
discharge 
Follow-up 
Patient informed consent 
x 
 
 
 
Verification of in- and exclusion criteria 
x 
 
 
 
Demographics and medical history  
x 
 
 
 
Information on implanted IPG, ICD, 
CRT or ICM, leads (device log) 
x* 
x 
 
 
PSA measurements and evaluation 
 
x 
 
 
Device based measurements and 
evaluation, if applicable 
 
x 
x 
x 
Evaluation of implant interrogation and 
programming functionality 
 
x 
x 
x 
General assessment of Renamic Neo 
hardware and software 
 
x 
x 
x 
Evaluation of usability of Renamic Neo 
system 
 
x 
x 
x 
Data export (connectivity, printing) 
 
x 
x 
x 
Data export of use case data for 
evaluation at sponsor 
 
x 
x 
x 
Used accessories (including entry in 
device log) 
 
x 
x 
x 
Battery usage 
 
x 
x 
x 
Adverse event and device deficiency 
reporting 
x 
x 
x 
x 
Concomitant medication  
x1 
x1 
x1 
x1 
Regular termination 
 
 
x 
x 
x  point in time of study procedure depends if patient is enrolled for implantation use case (includes PHD) or for follow-up 
use case. 
x* point in time for follow-up cases 
x1 only if related to an AE  
 
All Renamic Neo programmer systems at a given site should be used roughly for the same 
number of use cases. Further measures to avoid bias are described in section 8.1.2. This 

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includes the distribution of implantation and follow-up cases between implant types. The use of 
the ECG cable PK-222-L is optional but use and evaluation have to be documented in the 
respective CRFs.  
 
9.2 
Enrollment / Baseline visit (all patients) 
Prior to enrollment into the clinical investigation the investigator has to verify the eligibility of 
the patient based on all inclusion and exclusion criteria (see section 8.3.2 and section 8.3.3.). 
The informed consent has to be signed and dated by the patient and the investigator. The date 
of patient enrollment is defined as the date of patient signature.  
The informed consent process has to be documented in the subject’s medical records and the 
subject 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 the sponsor’s monitor. 
In the enrollment CRF the following data has to be recorded: 
 Version number of the ICF 
 Confirmation that patient met all inclusion and none of the exclusion criteria 
 Confirmation that the patient dated and signed the patient ICF personally or an independent 
witness dated and signed the ICF since the patient is unable to write 
 Date of patient signature on the informed consent form 
 Date of investigator signature on the informed consent form 
After a subject has been enrolled, the following data needs to be collected and entered in the 
baseline evaluation or device log CRF. 
 Date of baseline assessment 
 Demographic characteristics  
 Medical history  
 Enrollment for implantation case or follow-up case 
 Only for follow-up patients at baseline: implant type and model and implanted leads in the 
device log  
 Any adverse event or device deficiency that occurs after enrollment. Adhere to the reporting 
timelines listed in section 18.9.  
9.3 
Implantation (only patients enrolled for implantation and PHD cases, 
excluding ICMs) 
The device implantation has to be completed within 2 weeks after enrollment. Otherwise the 
patient’s study participation will be terminated. Patients with ICMs shall not be enrolled for 
implantation cases and PHDs. 
The device will be implanted according to clinical routine and as described in the respective 
IFU. The PSA functionality of the Renamic Neo shall be used for lead measurements.  
9.3.1 Documentation and procedures during implantation 
 Document serial number of investigational devices used (programmer, and ECG cable PK-
222-L if applicable) and version of Renamic Neo software. 
 Document implant type and model, as well as leads and used accessories in the device log. 
 Complete implantation SDS and enter data in the iMedNet EDC database in the implantation 
CRF 

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 Document any adverse event or device deficiency that occurs during the procedure in the 
respective CRFs. Adhere to the reporting timelines listed in section 18.9.  
 The following procedures shall be performed in the study. Perform intraoperative 
measurements at leads with the PSA of the Renamic Neo system according to clinical 
routine. The used functionalities shall be assessed and documented. These include if 
applicable for the device type:  
 Sensing, pacing threshold and impedance tests 
­ Documentation on device mode used for PSA measurements (1, 2 or 3 chambers) 
­ Quadripolar measurement (only for QP lead) 
­ Documentation of tested polarities, if applicable   
 Phrenic Nerve Stimulation (PNS) test and threshold documentation, if applicable 
 Documentation of RF surgical equipment if used during PSA measurements 
 Documentation of burst, if applicable   
 Evaluation of accuracy of PSA measurements compared to results of implant 
measurements (see below)  
 Perform according to clinical routine, document and assess functionalities used with the 
implanted device. These include for all CRM devices if applicable for the device type: 
 Sensing, pacing threshold and impedance tests  
 LV VectorOpt (only for QP leads) 
 Documentation of PNS test if performed 
 Evaluate if device interrogation (including RF telemetry) and adequate programming was 
successful  
 Assess programmable parameters (e.g. programmer preferences and PSA)  
 Export programmer data files for evaluation at sponsor 
 Transmit clinical documentation with the programmer for own usage and assess (data 
export and / or printing) 
 Mobile usage of programmer with battery  
9.4 
Pre-hospital discharge (only patients enrolled for implantation and PHD cases) 
Patients enrolled for implantation cases will have a pre-hospital discharge (PHD) in most cases 
which will count as follow-up case.  
Device interrogation and programming during the PHD has to be performed according to 
clinical routine.  
9.4.1 Documentation and procedures at pre-hospital discharge 
 Document serial number of investigational devices used (programmer, and ECG cable PK-
222-L if applicable) and version of Renamic Neo software. 
 Document any adverse event or device deficiency that occurred in the respective CRFs. 
Adhere to the reporting timelines listed in section 18.9. 
 Complete the PHD/FU source data sheet and enter data in the iMedNet EDC data base in the 
respective CRF. 
The same procedures as for implantation (section 9.3.1) shall be documented and evaluated if 
performed except for procedures related to PSA functionalities. 

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9.5 
Follow-up (only patients enrolled for follow-up case) 
Patients enrolled for a follow-up case require the same enrollment and baseline documentation 
as described in section 9.2.  
Patients can be included for any IPG, ICD, CRT or ICM follow-up. It should be assured that 
patients have sufficient time for the informed consent process. If applicable, patients should be 
informed about the study upfront by mail. 
9.5.1 Documentation and procedures at follow-up 
 Document serial number of investigational devices used (programmer, and ECG cable PK-
222-L if applicable) and version of Renamic Neo software. 
 Document any adverse event or device deficiency that occurred during follow-up in the 
respective CRFs. Adhere to the reporting timelines listed in section 18.9. 
 Complete the PHD/FU source data sheet and enter data in the iMedNet EDC data base in the 
respective CRF. 
 The following procedures shall be performed in the study. Perform according to clinical 
routine, document and assess functionalities used with the implanted device. These include 
for all CRM devices if applicable for the device type: 
 Sensing, pacing threshold and impedance tests 
 LV VectorOpt (only for QP leads) 
 Documentation of PNS test if performed 
 Evaluate if device interrogation (including RF telemetry) and adequate programming was 
successful  
 Assess programmable parameters (e.g. programmer preferences and PSA)  
 Export programmer data files for evaluation at sponsor 
 Transmit clinical documentation with the programmer for own usage and assess (data 
export and / or printing) 
 Mobile usage of programmer with battery  
9.6 
Termination and post treatment 
The study termination CRF must be completed to determine the date and reason for study 
termination of the individual patient. The regular termination of the patient is defined as the 
date of the pre-hospital discharge after device implantation for those patients who were 
included for implantation use cases. Patients who were enrolled for follow-up use cases will be 
terminated directly after the completion of the follow-up.  
Follow-up of subjects which have withdrawn consent is covered in section 8.3.5.1. 
9.7 
Description of those activities performed by sponsor representative 
Qualified sponsor representatives might support the investigator during implantation or follow-
up procedures as part of their general technical assistance service if this is part of the clinical 
routine. The interrogation and programming of the implant lies within the responsibilities of the 
investigator or authorized study team members who shall decide on programming parameter 
settings and shall conduct the assessment of safety, usability and performance of the 
investigational devices. 

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9.8 
Responsibilities  
9.8.1 Responsibilities of the sponsor 
The sponsor of the BIO|CONCEPT.Renamic Neo is: 
BIOTRONIK Australia Pty. Ltd. 
Level 4, Building 2 
20 Bridge St 
Pymble NSW 2073 
Australia  
Comprehensive responsibilities regarding study conduct and management are delegated to: 
BIOTRONIK SE & Co. KG 
Center for Clinical Research (CCR) 
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. Additionally, a summary presented in terms that are 
easily understandable will be made available to the intended user. According to current 
standard operative procedures, the CIR is written by scientist of the team Scientific Affairs 
based on the Clinical Investigation Plan including all amendments, the latest version of the 
Statistical Analysis Plan and the Statistical Analysis Report provided by the biostatistician. 
The CIR undergoes an internal review by the project manager, the biostatistician, and other 
relevant functions using a pre-specified checklist. The CIR is signed-off by the CIR writer, 
the project manager, the biostatistician, the Director Clinical Project Management and the 
representative of the local sponsor. 

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9.8.1.1 
Project management 
The clinical project manager is responsible for the following (selected items): 
 Development of the clinical investigation plan and possible amendments. 
 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). 
9.8.1.2 
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. 
9.8.1.3 
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. 
9.8.1.4 
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. 
9.8.2 Responsibilities of the investigators  
9.8.2.1 
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. 

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 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. 
 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. 
 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. 
9.9 
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. BIOTRONIK is required to ensure that the Renamic 
Neo programmer, software NEO 2001.A and ECG cable PK-222-L are used under the 
immediate direction of an investigator. As the investigator, the physician is responsible for 
conducting the study in accordance with the signed clinical trial agreement, clinical 
investigation plan, applicable laws, 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, 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, including storage and maintenance of 
investigational inventory 
3. Adherence to the clinical investigation plan 
4. Adherence to current version of ISO 14155 and applicable 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 
For continuous variables descriptive statistics (mean, standard deviation, median, quartiles, 
minimum, and maximum) will be calculated. For nominal and ordinal variables absolute and 
relative frequencies will be calculated based on non-missing data. Ordinal variables are 
described similar as continuous data (minimum, median, quartiles, and maximum) or by 
absolute and relative frequencies based on non-missing data of each category. Further details 
will be provided in the separate Statistical Analysis Plan (SAP). 
11.2 Sample size 
No hypotheses can be pre-specified for this clinical investigation, which is completely 
exploratory.  
This clinical investigation should be able to identify unforeseen safety problems.  While it is 
unlikely that the number of ADEs or DDs will be sufficient for inferential statistical conclusions, 
a discussion of the types of events and of the circumstances of their appearance might reveal 
indicators for hidden risks and trigger further dedicated investigations or statistical tests to 
substantiate such findings. 
Unforeseen safety problems are more likely related to software problems between Renamic 
Neo and implanted devices but less likely to hardware problems of the Renamic Neo. Thus, the 
sample size is related to use cases per implantation, pre-hospital discharge, and follow-up but 
not to the total number of Renamic Neo devices.  
11.2.1 Implantation 
With reference to a statistical approach for such situations recommended by Viechtbauer et al. 
[Viechtbauer W et al. J Clin Epidemiol. 2015; 68:1375-9], a sample size of 50 documented 
implantations using a Renamic Neo would allow identifying at least one/two/three ADEs or DDs 
with 92 % / 72 % / 46 % confidence if any problem related to the Renamic Neo exists with 5 % 
probability in the population. 
11.2.2 Pre-hospital discharge and follow-up 
Because of the short study duration, no patient is expected to provide data from implantation 
or pre-hospital discharge on the one hand and follow-up on the other hand. Thus, all data are 
from other patients, i.e. independent samples when there is no effect of a specific Renamic 
Neo device effect as discussed before. 
Unforeseen problems that require implant programming adjustments will be more relevant 
during follow-up visits. Thus 100 such use cases will be investigated. Thereby, at least 
one/two/three ADEs or DDs would be identified with 99%/96%/88% confidence if any problem 
related to the Renamic Neo exists with 5% probability in the population. 
11.3 Level of significance and the power of the study 
Because there are no pre-specified hypotheses, all analyses will be exploratory. For inferential 
analyses, a two-sided p-value less than 5% will be considered statistically significant. In 
accordance to the exploratory approach there will be no adjustment for multiplicity. 
11.4 Expected drop-out rate 
Patients that drop-out prior to any use of the Renamic Neo system investigation, e.g. 
withdrawal just after enrollment, will be replaced. Based on this definition, no drop-outs are 
expected.   

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11.5 Pass/fail criteria  
There are no pass/fail criteria. Any potential ADEs or DDs will be analyzed and discussed. 
11.6 Provision for an interim analysis 
There is one planned interim analyses for internal purposes. Except for safety reasons no 
investigator is informed about the results and, thus, no bias is expected. There will be no 
adjustment for multiplicity. 
11.7 Termination criteria 
There is no termination of the clinical investigation on statistical grounds. 
11.8 Procedures for reporting of deviations to the statistical plan 
A separate SAP will be finalized after go-life of the Clinical Data Management System (CDMS) and 
can be updated before CDMS freeze or closure. Any deviation from the valid version of the SAP will 
be indicated in the Statistical Analysis Report (SAR) and clinical investigation report (CIR). 
11.9 Specification of subgroups 
Potential critical events will be analyzed whether there is any connection to the subgroups IPG, 
ICD, CRT, or ICM. 
11.10 Procedure for accounting of all data for analysis 
All data are entered in a CDMS by the investigators via an electronic data capture system 
(iMedNet, MedNet Solutions). Exports from the database will be analyzed with common 
validated statistical software packages (e.g. SAS 9.4 or updates, SAS Institute GmbH). 
11.11 Handling of missing, unused and spurious data 
For the endpoints, missing data will not be imputed. Free text will be used to clarify other data. 
Spurious data will be clarified via the query management system, i.e. corrected after approval 
of an investigator. Remaining outliers will be identified during the review of the data before 
CDMS closure. In case of a clear evidence of a measurement error, the Statistical Analysis Plan 
will be updated in order to avoid any bias. Spurious data, which were not clarified by the query 
process before CDMS freeze or closure, will be indicated. If appropriate, analyses will be 
performed both with/without such data. 
11.12 Exclusion of data from confirmatory data analysis 
No data are documented or analyzed from patients without documented informed consent. 
11.13 Minimum and maximum number of patients per site 
In order to preserve the multicentric character of the study, the number of implantations and 
FUs per investigational site should not exceed 30 use cases.  

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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.Renamic Neo 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 (FDA 21 CFR 
Part 11, HIPAA and EU GDPR).  
Use of the clinical data management system (CDMS) will allow 24 hours 7 days a week access 
to the module. The PI as well as those co-investigators to whom the PI delegates data entry 
and authorization of CRFs need 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 

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against source data by clinical monitors during periodic monitoring visits as described in the 
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. Archiving 
of the clinical study data and the source data need to be according to the national law. 

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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.  
All principal investigators have to acknowledge the receipt of an amendment either by 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 and – if applicable – by the competent authority. 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. 
In order to comply with guidance from the Australian government agency, the National Health 
and Medical Research Council (NHMRC), it needs to be ensured that serious breaches of GCP 
are reported within 7 calendar days to the respective EC.  
A serious breach is a deviation from the CIP which is likely to affect to a significant degree  
 the safety or rights of a trial participant, or  
 the reliability and robustness of the data generated in the clinical investigation. 

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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 
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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15 
DEVICE ACCOUNTABILITY 
The investigational devices in this clinical study are not approved for an overall market release 
(Renamic Neo, programmer software NEO 2001.A and ECG cable PK-222-L) and are labeled 
‘exclusively for clinical investigation’ (Renamic Neo and ECG cable PK-222-L). They have to be 
stored under special conditions.  
The sponsor keeps records to document the physical location of all investigational devices 
including the shipment of investigational devices to the investigational sites or to the local 
units, storage, usage and return. An electronic device accountability log is used for the 
documentation of the whole process. See also information on device traceability in section 4.4. 
Access to investigational devices is controlled and the devices are used in the clinical 
investigation only and according to the CIP. The Renamic Neo will be protected by a password 
known only to study team members to avoid usage outside the clinical study. 
The principal investigator or an authorized designee shall keep records documenting the 
receipt, location and return of the investigational devices. The electronic device accountability 
log is used for this site specific documentation. Usage will be documented in the respective 
CRF. 
The responsible field CRA checks the storage, usage and documentation and verifies the 
completeness of the device accountability log in the CDMS regularly during his/her visits.  
After the closure of the study, the summary of this log will be used for the final report.  

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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’.  
In deviation to ISO 14155 no coordinating investigator has been nominated for this multicenter 
study, as only documentation of safety, performance and usability of routine programmer 
usage occurs during the patient’s study participation which does not require additional 
coordination between the PIs.  
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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17 
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. 
Patients, especially those included only for follow-up, should have sufficient time to be 
informed and decide about study participation. If applicable, patients should receive the 
patient information about the study upfront by mail. 
17.2 Special circumstances for informed consent 
Not applicable. 

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18 
ADVERSE EVENTS AND DEVICE DEFICIENCIES 
In the course of the clinical investigation, undesired medical events can occur in participating 
patients, users and other persons, which are called adverse events (AEs) in the following. 
Furthermore, device deficiencies (DD) may also be observed. All AEs and DDs of the 
investigational device 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 investigational device 
 Events related to the procedures involved  
 For users or other persons, this definition is restricted to events related to the 
investigational devices.  
*see ISO 14155 3.2 
18.2 Definition of adverse device effects 
An adverse device effect (ADE)* is an AE that is related to the use of an investigational device. 
This includes any AE resulting from insufficient or inadequate instructions for use or the 
deployment, implantation, installation, 
or 
operation, or 
any 
malfunctioning of the 
investigational device and any event resulting from use error or from unintentional misuse of 
the investigational device.  
*see ISO 14155 3.1 
18.2.1 Causality Assessment 
The relationship between the use of the investigational device (including the medical-surgical 
procedure) and the occurrence of each adverse event shall be assessed and categorized, 
considering the presence of confounding factors, such as concomitant medication and 
treatment, the natural history of the underlying disease, other concurrent illness or risk 
factors.  
Each AE will be classified according to five different levels of causality. As defined in the 
Meddev 2.7/3 rev 3, the investigator will use the following definitions to assess the relationship 
of the adverse event to the investigational device or procedures and the sponsor will review 
the investigators categorization: 
Not related: the relationship to the device or procedures can be excluded 
Unlikely: the relationship with the use of the device seems not relevant and/or the event can 
be reasonably explained by another cause, but additional information may be obtained. 
Possible: the relationship with the use of the investigational device is weak but cannot be 
ruled out completely. Alternative causes are also possible (e.g. an underlying or concurrent 
illness / clinical condition or/and an effect of another device, drug or treatment). Cases were 
relatedness cannot be assessed or no information has been obtained should also be classified 
as possible. 

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Probable: the relationship with the use of the investigational device seems relevant and/or 
the event cannot reasonably explained by another cause, but additional information may be 
obtained. 
Causal relationship: Causal relationship: the serious event is associated with the 
investigational device or with procedures beyond reasonable doubt.  
The investigators will distinguish between the adverse events related to the investigational 
device and those related to the device procedures (any procedure specific to the 
investigational device). Procedure related events refers to the procedure related to the 
application of the investigational device only and therefore not to any other procedure for 
other devices and not to any other procedures or treatments applied later throughout the 
clinical investigation, for instance to treat (serious) adverse events. In case of a replacement 
of the investigational device in response to an adverse event (e.g. programmer replacement 
after failed implant interrogation), the replacement will be considered like an initial application 
of a new investigational device and shall be assessed accordingly. 
AEs that occur during implantation are not considered as ADEs related to the investigational 
device procedure unless the implementation/use of the investigational device, in this case the 
programmer, caused the AE. For example, the RF telemetry failed and the implant device could 
not be programmed appropriately which caused an AE.    
An adverse event can be related both to the procedure and the investigational device. 
Complications of procedures are considered not related if the said procedures would have been 
applied to the patients also in the absence of investigational device use or application. 
18.3 Definition of device deficiency 
Device deficiency (DD)* is defined as inadequacy of a device with respect to its identity, 
quality, durability, reliability, safety, or performance, including malfunctions, use errors and 
inadequate labeling.  
*see ISO 14155 3.15 
DDs of the investigational device shall be documented throughout the study. DDs which 
caused an adverse event are reported on the respective adverse event form. In case the DD 
did not cause an adverse event the provided DD form shall be used to document this ‘non-
medical’ event.  
If a DD could have led to a SADE,  
 if either suitable action had not been taken, 
 if intervention had not been made, or 
 if circumstances had been less fortunate, 
the DD is classified as an DD with an SADE potential.  
18.4 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. 

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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 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.  
18.4.1 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 shall be sent to 
BIOTRONIK promptly. 
On the AE-CRF, the following information needs to be provided, if available: 
 Cause of death 
 Date and time of death 
 Place death occurred 
 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. 
18.5 Definition of serious adverse device effect 
An ADE* that resulted in any of the consequences characteristic of a serious adverse event is 
considered serious. 
*see ISO 14155 3.36 
18.6 Definition of unanticipated serious adverse device effects 
SADEs* are defined as unanticipated if by their nature, incidence, severity or outcome they 
have not been identified in the current version of the risk analysis report.  
*see ISO 14155 3.42 
These events must be reported to the sponsor immediately.  
A root-cause analysis will be performed and the possibility of reoccurrence will be evaluated 
immediately. 
Note: Anticipated serious adverse device effect (ASADE) is an effect which by its nature, 
incidence, severity or outcome has been identified in the risk analysis report. 
18.7 Anticipated adverse events 
As the Renamic Neo systems is not yet approved, only clinical data of it is predecessors 
including Renamic or programmers in general are available. 
The available data does not allow a precise calculation of complication rates (e.g. per 
application or per patient-year). Nevertheless, considering the number of sold devices (e.g. 
more than 20,000 Renamic programmers worldwide) and their frequent use, the data suggest 
that clinical complications associated with the devices are rather rare. However, due to the 
nature of their application and the associated risk, adverse events, including serious adverse 
events, cannot be ruled out. 

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A summary of the clinical complications reported in the MAUDE database and in BIOTRONIK 
sources is provided. The following sources were searched for relevant information on adverse 
events and adverse device effects related to the investigational devices: 
 Systematic literature search using programmer related terms  
 Manufacturer and User Facility Device Experience Database (MAUDE) 
 BIOTRONIK vigilance database 
A systematic literature search using programmer related search terms was performed. The 
search did not retrieve any relevant hits (Table 4). This low yield is in line with previous 
systematic searches for programmer devices. 
Table 4: Literature search results for CRM device programmers. 
Search term 
Initial results 
After title 
screening 
After 
abstract 
screening 
After full text 
screening  
(Selected 
publications) 
(programmer OR "pacing system analyzer" OR 
"pacing system analyser" OR PSA)  
AND  
(pacemaker OR defibril* OR IPG OR ICD OR 
bradycardia OR tachycardia OR loop recorder 
OR ICM OR ILP) 
AND 
("complication"[Title/Abstract] OR 
"complications"[Title/Abstract] OR "adverse 
event"[Title/Abstract] OR "adverse 
events"[Title/Abstract] OR 
safety[Title/Abstract]) 
AND 
("2009/01/01"[PDAT] : "2019/12/31"[PDAT]) 
AND 
"humans"[MeSH Terms] 
18 
12 
0 
0 
Source: PubMed 
Therefore, a comprehensive overview of clinical complications for this device group cannot be 
generated based on scientific literature. 
The FDA Manufacturer and User Facility Device Experience Database (MAUDE) was examined 
to understand the number and types of adverse events for currently approved CRM 
programming devices.  
MAUDE data represents reports of adverse events involving medical devices. MAUDE data is 
not intended to be used either to evaluate rates of adverse events or to compare adverse 
event occurrence rates across devices. Submission of the report does not mean the device 
caused the adverse event. In most cases, further investigation is necessary to understand the 
cause of the adverse event. 

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Table 5: Overview of adverse events reported in the MAUDE database 
Adverse event term 
Programmer 
  
BIOTRONIK 
Medtronic 
Boston Scientific 
Abbott 
MicroPort 
Vitatron 
Death 
0 
2 
0 
1 
0 
0 
Asystole 
1 
0 
0 
5 
0 
0 
Syncope 
0 
0 
0 
2 
0 
0 
Inappropriate shock 
0 
0 
0 
1 
0 
0 
Electrical shock 
2 
0 
0 
24 
0 
0 
Pain 
0 
1 
0 
0 
0 
0 
The three death cases described in Table 5 occurred during programmer use but according to 
the case descriptions it is unlikely that they are related to the programmer.  
More than 300.000 implantations of IPGs or ICDs are performed in the US per year and  
several million patients are interrogated during follow-ups with a programming device 14–18.  
Considering these high numbers of applications of the programmer the number of reports of 
adverse events in the MAUDE data base is low. 
Data from the vigilance database of BIOTRONIK’s Center for Clinical Research (CCR) were 
analyzed to identify adverse events or device deficiencies that are possibly related to the 
following programming devices and their accessories19: 
 Renamic 
 Renamic PSA 
 ICS 3000 
 PSW (software) 
 PK-222   
 other accessories (e.g. PGH, pen, USB) 
The analysis covered data from ~8,800 study patients collected from 2014 to 2019. The data 
origins from studies with ICMs, IPGs, ICDs, and CRT-devices.  
Fourteen AEs were identified, in which the case description contained one or more of the 
search terms in one or more of the four text fields. None of the events was related to a 
BIOTRONIK product 19,20 
Depending on the patient's condition and depending on the scope and type of pacing program, 
the following possible complications associated with the use of pacing system analyzers are 
reported in medical references: life-threatening atrial and ventricular arrhythmia, bradycardia, 
tachycardia, and asystole. 
18.8 Reporting responsibilities 
18.8.1 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 adverse events (AE) and adverse device effects (ADEs) shall be reported together with an 
assessment by completing the AE-CRF in accordance with ISO 14155:2011.  
For device deficiencies of the investigational device, a DD-CRF shall be completed.  

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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)A(D)Es 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. Ongoing SADEs related to the investigational device 
will be followed for a maximum time period of either 2 weeks after pre-mature or regular study 
termination of the individual patient. 
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. 
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. 
18.8.2 Reporting responsibilities of the investigator to other parties 
According to national and international regulations some of the involved competent authority 
(CA) and ethics committees define specific safety reporting requirements. Investigators have 
to ensure, that they fulfil these local reporting obligations given by their competent authority 
and ECs, in case they are more restrictive than the general requirements stated in the section 
reporting timelines below. 
18.8.3 Reporting responsibilities of the sponsor 
BIOTRONIK SE & Co. KG will report all serious adverse events (SAEs)/serious adverse device 
effects (SADE) and all device deficiencies with a SADE potential to the competent authority 
depending on the local regulatory requirements.  
Furthermore, BIOTRONIK SE & Co. KG ensures that Safety Reports are forwarded to the 
investigational sites and the ethics committees depending on the local requirements.   
BIOTRONIK SE & Co. KG will inform the investigators about all reported SAEs and DDs that 
could have led to a SADE on a regular basis. As a proposal, regular listings may be provided 
quarterly and unanticipated serious adverse device effects (USADEs) shall be reported 
immediately. 
18.9 Reporting timelines 
The reporting timelines for the investigator are displayed in Table 6. 
Table 6: Reporting timelines 
Event 
Report to 
Timeline 
Adverse Event (AE) / 
Adverse Device Effect 
(ADE) 
CCR BIOTRONIK SE & Co. KG: 
Documentation in the AE CRF  
Preferably within 14 
days 
 
Serious Adverse Event 
(SAE) / Serious 
Adverse Device Effect 
(SADE) 
CCR BIOTRONIK SE & Co. KG: 
Documentation in AE-CRF 
 
Immediately, latest 
24h after detection 
 

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Unanticipated Serious 
Adverse Device Effect 
(USADE) 
CCR BIOTRONIK SE & Co. KG: 
Documentation in AE-CRF 
 
Immediately, latest 
24h after detection 
 
Device Deficiencies 
CCR BIOTRONIK SE & Co. KG: 
Documentation in the DD-CRF 
Preferably within 14 
days 
 
Device Deficiency with 
SADE potential 
CCR BIOTRONIK SE & Co. KG: 
Documentation in DD-CRF 
Within 24 hours 
 
 
The obligation to assess and report SA(D)Es and Serious Device Deficiencies 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. 
18.10 Emergency contact 
A contact address for patients in case of emergency will be provided in the individual patient 
informed consent forms. 
In case technical support is needed the service hotline of BIOTRONIK is available 24 hours a 
day. 
  
18.11 Data (safety) monitoring committee 
Not applicable. 
 
 

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19 
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. 
 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 ‘Study 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 Un-blinding procedures 
Not applicable. 
20.3 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 per CIP. If the 

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suspension is due to an EC decision, additional requirements from the EC with respect to 
follow-up and data collection may apply. 
If an (S)A(D)E 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’. 
Ongoing SADEs related to the investigational device will be followed for a maximum time 
period of either 2 weeks after pre-mature or regular study termination of the individual 
patient. 
Patients have to be informed on this procedure in written form in the patient informed consent 
form. 

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21 
PUBLICATION POLICY 
21.1 Decision for publication  
The study will be registered in a publicly accessible database (e.g. clinicaltrials.gov). 
In accordance with the good publication practice guidelines, it is generally planned to publish 
the study results also in case of negative findings. It is currently planned to submit an abstract 
to a congress within one year after finalization of the clinical investigational report. Moreover, 
the results of the study will be published in the publicly accessible database (see above). Due 
to the limited amount of clinical data collected within this study, a manuscript publication 
seems not feasible. 
The abstracts will be reviewed and approved by all authors and BIOTRONIK.  
21.2 Authorship guidelines 
Purpose of this authorship guideline is to settle criteria which of the contributors to this study 
should be identified as authors. It is valid for all contributors to the study, including 
investigators, sponsor employees, and other individuals contracted by the sponsor.  
Following the International Committee of Medical Journal Editors (ICMJE), authorship credit 
should generally be based on all of the following conditions:  
1) 
Substantial contributions to conception and design, acquisition of data, or analysis and 
interpretation of data,  
2) 
drafting the article or revising it critically for important intellectual content, and  
3) 
final approval of the version to be published.  
For the planned congress contribution, acquisition of data will be weighted based on the 
number of reported use cases. First authorship will be offered to the principal investigator that 
included the highest number of use cases.  
The first author takes the responsibility for the following actions: 
 Guarantee the integrity of the publication 
 Support members of BIOTRONIK in preparation of abstract, poster, presentation – 
especially regarding the medical perspective 
 Presentation at the congress or delegation of a substitute 
 Disclose potential conflicts of interest 
All co-authors have the following tasks and responsibilities: 
 Review of abstract, poster, presentation and give feedback within the determined time 
window 
 Agree on the order in which they appear in the publication 
 Agree on any changes in authorship 
 Disclose potential conflicts of interest 
No honoraria will be paid for authorship of publications. 
21.3 Contributorship and acknowledgement  
Individuals, including BIOTRONIK employees, who have substantially contributed to a study, 
but who do not meet the authorship criteria, should be listed in the acknowledgement section. 
Any support provided by a professional medical writer must also be disclosed in the 
acknowledgement section.  

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21.4 Ancillary publications  
There are no ancillary manuscript publications planned.  

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22 
BIBLIOGRAPHY 
 
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Springer Berlin; Springer, 2019. 
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