BIO|Sync-HUTT: Head-up Tilt Test in Patients With Reflex Syncope and Asystolic Response Who Received a Dual-chamber Pacemaker With the Closed Loop Stimulation (CLS) and Participated in the BIOSync Trial
Conditions: Syncope, Syncope, Vasovagal
Sponsor: Biotronik SE & Co. KG

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. 
 
 
BA117_CIP_2-0| Version 2-0 | 20-Apr-2022 | Page 1/61 
FOR-137-014-H / SOP-137-020.020 / CRQ200005199 
 
 
 
Clinical Investigation Plan 
for the 
BIO|Sync-HUTT 
Head-up Tilt Test in patients with reflex syncope and asystolic response who 
received a dual-chamber pacemaker with the Closed Loop Stimulation (CLS) 
and participated in the BIOSync trial  
 
 
Reference number:  
BA117 
Version:  
2-0 
Date of CIP: 
April 20, 2022 
Investigational device:  
Dual-chamber pacemaker with CLS feature 
 
 
 
Revision History:  
Title 
Scope 
Key words 
Date 
CIP 2-0 
Amendment 1 
ALL sites 
Change of the exclusion criterion 
No. 2 (substantial) 
20-Apr-2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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

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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................. 4 
1 
LIST OF ABBREVIATIONS ................................................................................... 8 
2 
SYNOPSIS ........................................................................................................... 9 
3 
INTRODUCTION ................................................................................................ 12 
4 
DEVICE(S) USED IN THE STUDY ....................................................................... 13 
4.1 
Model name including software version and accessories.......................................... 13 
4.2 
Description of traceability ................................................................................... 13 
4.3 
Intended purpose of the device(s) in the study ...................................................... 13 
4.4 
Intended patient population and indications .......................................................... 13 
4.5 
Description of the CLS algorithm ......................................................................... 13 
4.6 
Summary of training and experience needed ......................................................... 14 
5 
JUSTIFICATION FOR THE DESIGN OF THE CLINICAL INVESTIGATION.............. 15 
6 
BENEFITS AND RISKS OF THE DEVICE, CLINICAL PROCEDURE, AND CLINICAL 
INVESTIGATION ............................................................................................... 16 
6.1 
Anticipated clinical benefits ................................................................................. 16 
6.2 
Anticipated adverse device effects ....................................................................... 16 
6.3 
Risk associated with participation in the clinical investigation .................................. 16 
6.4 
Possible interactions with concomitant medical treatments...................................... 16 
6.5 
Steps to control or migrate the risk ...................................................................... 16 
6.6 
Rationale for benefit-risk ratio ............................................................................. 16 
7 
OBJECTIVES AND HYPOTHESES ........................................................................ 17 
7.1 
Purpose of the clinical investigation ...................................................................... 17 
7.2 
Objectives (Endpoints) ....................................................................................... 17 
7.3 
Hypotheses ....................................................................................................... 17 
7.4 
Risks and anticipated adverse device effects ......................................................... 17 
8 
DESIGN OF THE CLINICAL INVESTIGATION ...................................................... 18 
8.1 
General considerations ....................................................................................... 18 
8.1.1 
Design type of clinical investigation .................................................................. 18 
8.1.2 
Measures taken to minimize or avoid bias ......................................................... 18 
8.1.3 
Data of interest ........................................................................................... 18 
8.1.4 
Methods ...................................................................................................... 19 
8.1.4.1 
CRFs ........................................................................................................ 19 
8.1.4.2 
Source Data Sheets ................................................................................... 19 
8.1.5 
Equipment to be used for the assessment of variables ........................................ 19 
8.1.6 
Replacement of patients ................................................................................. 19 
8.1.7 
Investigation sites ......................................................................................... 19 

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8.1.8 
Completion of the clinical investigation ............................................................. 20 
8.2 
Patients ............................................................................................................ 20 
8.2.1 
Inclusion criteria ............................................................................................ 20 
8.2.2 
Exclusion criteria ........................................................................................... 20 
8.2.3 
Criteria and procedures for subject withdrawal .................................................. 20 
8.2.3.1 
Withdrawal of patient consent ..................................................................... 20 
8.2.3.2 
Impossibility of device programming at enrolment visit .................................. 21 
8.2.4 
Point of enrollment ........................................................................................ 21 
8.2.5 
Total expected duration of the clinical investigation ............................................ 21 
8.2.6 
([SHFWHGGXUDWLRQRIHDFKVXEMHFW¶VSDUWLFLSDWLRQ ............................................... 21 
8.2.7 
Number of subjects required to be included ...................................................... 21 
8.2.8 
Estimated time needed to select patients .......................................................... 21 
9 
STUDY PROCEDURES ........................................................................................ 22 
9.1 
Overview .......................................................................................................... 22 
9.2 
Enrollment/study visit ........................................................................................ 23 
9.2.1 
Baseline assessment ...................................................................................... 23 
9.2.2 
Study procedures after baseline assessment ..................................................... 23 
9.2.3 
Head-up tilt test ............................................................................................ 24 
9.2.3.1 
Timing of tilt down ..................................................................................... 25 
9.3 
Termination and post treatment .......................................................................... 25 
9.4 
Description of those activities performed by sponsor representative ......................... 25 
9.5 
Possible influencing factors on outcome or interpretation of results .......................... 25 
10 
RESPONSIBILITIES .......................................................................................... 26 
10.1 
Responsibilities of the sponsor............................................................................. 26 
10.1.1 
Project management ...................................................................................... 26 
10.1.2 
Data management ......................................................................................... 26 
10.1.3 
Biostatistician ................................................................................................ 27 
10.1.4 
Monitor......................................................................................................... 27 
10.2 
Responsibilities of the investigators ...................................................................... 27 
10.2.1 
Coordinating investigator ................................................................................ 27 
10.2.2 
Investigator .................................................................................................. 28 
11 
MONITORING PLAN .......................................................................................... 30 
12 
STATISTICAL DESIGN AND ANALYSIS .............................................................. 31 
12.1 
Analysis population ............................................................................................ 31 
12.2 
Descriptive statistics .......................................................................................... 31 
12.3 
Analytical procedures ......................................................................................... 31 

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12.4 
Significance level, statistical power, and statistical testing ...................................... 31 
12.5 
Sample size ...................................................................................................... 31 
12.6 
Interim analyses ................................................................................................ 31 
12.7 
Bias ................................................................................................................. 31 
12.8 
Subgroups ........................................................................................................ 31 
12.9 
Missing, unused, and spurious data ...................................................................... 31 
12.10 Deviations from the original statistical plan ........................................................... 32 
13 
DATA MANAGEMENT ......................................................................................... 33 
13.1 
Methods for data entry and collection ................................................................... 33 
13.2 
Procedures used for data review, database cleaning, and issuing and resolving data 
queries ............................................................................................................. 33 
13.3 
Procedures for verification, validation, and securing of electronic clinical data systems 33 
13.4 
Procedures to maintain and protect subject privacy ............................................... 34 
13.5 
Methods for database locking at the start of the analysis and storage upon completion 
of the clinical investigation .................................................................................. 34 
13.6 
Procedures for data retention .............................................................................. 35 
13.7 
Specified retention period ................................................................................... 35 
14 
AMENDMENT PROCEDURES ............................................................................... 36 
15 
DEVIATIONS FROM CLINICAL INVESTIGATION PLAN ....................................... 37 
15.1 
CIP compliance and exceptions ............................................................................ 37 
15.2 
Recording, reporting and analyzing deviations ....................................................... 37 
15.2.1 
Site specific deviations ................................................................................... 37 
15.2.2 
Other deviations ............................................................................................ 37 
15.2.3 
Reporting ..................................................................................................... 37 
15.3 
Notification requirements and timelines ................................................................ 37 
15.4 
Actions ............................................................................................................. 38 
16 
DEVICE ACCOUNTABILITY ................................................................................ 39 
17 
STATEMENT OF COMPLIANCE............................................................................ 40 
17.1 
Applicable ethical standards ................................................................................ 40 
17.2 
Applicable international and national standards ..................................................... 40 
17.3 
Ethics committee and competent authority ........................................................... 40 
17.4 
Adherence to additional requirements .................................................................. 40 
17.5 
Patient insurance ............................................................................................... 40 
17.6 
Financing .......................................................................................................... 40 
18 
INFORMED CONSENT PROCESS ......................................................................... 41 
18.1 
General considerations ....................................................................................... 41 
19 
ADVERSE EVENTS AND DEVICE DEFICIENCIES ................................................. 42 
19.1 
Definition of adverse events ................................................................................ 42 

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19.2 
Definition of adverse device effects ...................................................................... 42 
19.2.1 
Causality Assessment ..................................................................................... 42 
19.3 
Definition of device deficiency ............................................................................. 43 
19.4 
Definition of serious adverse events ..................................................................... 43 
19.4.1 
Patient death ................................................................................................ 44 
19.5 
Definition of serious adverse device effect ............................................................ 44 
19.6 
Definition of unanticipated serious adverse device effects ....................................... 44 
19.7 
Definition of serious public health threat ............................................................... 45 
19.8 
Anticipated adverse events ................................................................................. 45 
19.9 
Reporting responsibilities .................................................................................... 54 
19.9.1 
Reporting responsibilities of the investigator to sponsor ...................................... 54 
19.9.2 
Reporting responsibilities of the investigator to other parties ............................... 54 
19.9.3 
Reporting responsibilities of the sponsor ........................................................... 54 
19.10 Reporting timelines ............................................................................................ 55 
19.11 Emergency contact ............................................................................................ 55 
20 
VULNERABLE POPULATION ............................................................................... 57 
21 
SUSPENSION .................................................................................................... 58 
21.1 
Criteria and procedures ...................................................................................... 58 
21.2 
Requirements for patient follow-up and continued care .......................................... 58 
22 
PUBLICATION POLICY ...................................................................................... 60 
22.1 
Decision for publication ...................................................................................... 60 
22.2 
Authorship guidelines ......................................................................................... 60 
22.3 
Contributorship and acknowledgement ................................................................. 60 
22.4 
Ancillary publications ......................................................................................... 60 
23 
BIBLIOGRAPHY................................................................................................. 61 
 

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1 
LIST OF ABBREVIATIONS 
 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
ASADE 
Anticipated Adverse Device Effect 
BP 
Blood Pressure 
CA 
Competent Authority 
CDMS 
Clinical Data Management System 
CE 
CE mark, a stylized "CE" (Conformité Européenne) placed on products to 
signify conformance with European Union regulations 
CI 
Coordinating Investigator 
CIP 
Clinical Investigation Plan 
CIR 
Clinical Investigation Report 
CLS 
Closed Loop Stimulation 
CRF 
Case Report Form 
DD 
Device Deficiency 
eTMF 
electronic Trial Master File 
EC 
Ethics Committee 
FU 
Follow-up visit 
HR 
Heart rate 
HUTT 
Head-Up Tilt Test 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (www.ich.org) 
IEGM 
Intracardiac Electrocardiogram 
IRB 
Institutional Review Board 
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 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistics and Analysis Software produced by SAS Institute Inc. www.sas.com) 
SDS 
Source Data Sheet 
SV 
Stroke Volume 
TPR 
Total Peripheral Resistance 

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2 
SYNOPSIS 
 
Title 
BIO|Sync-HUTT 
Patient population 
The study will select patients with reflex 
syncope and positive cardioinhibitory response 
to Head-Up Tilt Test (HUTT) who had already 
participated in the BIOSync study.  
Design 
Prospective, 
non-randomized, 
multi-center, 
observational, acute study. 
Investigational device(s) 
The closed-loop stimulation (CLS) algorithm 
implemented 
in 
current 
dual-chamber 
pacemakers manufactured by BIOTRONIK. 
Objectives 
To provide standardized, complete and quality 
controlled data sets with parameters that 
describe hemodynamic changes and their 
timing with respect to CLS pacing activation 
during reflex syncope induced by HUTT. 
Data of interest  
a) Heart rate, blood pressure, stroke volume, 
and peripheral resistance at the following 
time-points during HUTT: 
x 
Time of maximum spontaneous heart 
rate (end of phase 1/beginning phase 2 
of the reflex); 
x 
Time of pacing onset; 
x 
Time 
of 
recovery 
of 
spontaneous 
rhythm after pacing (end of recovery 
period); 
x 
time 
of 
syncope 
(i.e. 
loss 
of 
consciousness) 
during 
HUTT 
(also 
assessed by video recording if available 
at investigational site); 
x 
time 
of 
tilt-down 
(supine 
patient 
position just after tilt-down); 
b) Above-mentioned 
times 
of 
interest 
expressed as intervals (MM:SS) from the 
start of the HUTT 
c) Duration of the recovery phase (interval 
from maximum pacing rate to basic rate or 
spontaneous rhythm expressed in MM:SS 
from the start of the HUTT) 
d) Slopes in heart rate (bpm per sec) and 
systolic blood pressure (mmHg per sec) 
during the recovery phase  

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Title 
BIO|Sync-HUTT 
Inclusion criteria 
x Ability to understand the nature of the 
study.  
x Willingness to provide written informed 
consent. 
x Patients undergoing HUTT for monitoring of 
syncope, therapy adjustment, training or 
other medical reasons during ordinary 
follow-up, 
irrespective 
of 
study 
participation. 
x Patients who participated in the BIOSync 
study*. 
x Patients with a dual-chamber pacing system 
equipped with the CLS algorithm. 
 
* If needed, inclusion of other patients who 
did not participate in the BIOSync study will 
be considered to complete study cohort, 
provided that they have already a CLS 
pacemaker 
system 
and 
fulfill 
the 
same 
inclusion/exclusion criteria of the BIOSync 
study. 
Exclusion criteria 
x 
Pregnant or breast feeding women. 
x 
Age less than 40 years. 
x 
Patients who after the BIOSync study 
participation have developed the following: 
- 
Any indication to pacemaker different 
from reflex syncope with positive HUTT 
response; or 
- 
Any classified indication to implantable 
defibrillator, cardiac resynchronization 
therapy 
according 
to 
current 
guidelines; or 
- 
Any cardiac dysfunctions likely leading 
to loss of consciousness 
Study duration 
~ Q1 2022 ± Q3 2023 (~ 19 months) 
Sample size 
A total of 20 patients will be included in the 
study. 
Number of investigational sites 
The study will be conducted in at least 2 sites. 
Number of follow-ups per patient 
This 
is 
an 
acute 
study. 
Investigational 
procedures will be conducted at any HUTT 
performed 
according 
to 
routine 
clinical 
practice. Patients who undergo HUTT during 
ordinary follow-up visits irrespective of study 
participation, are eligible. The study has no 
additional follow-ups after HUTT execution. 
Coordinating investigator 
Prof. Michele Brignole 
Boards (if applicable) 
None 
Prof. Michele Brignole

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Title 
BIO|Sync-HUTT 
Sponsor 
BIOTRONIK SE & Co. KG 
Center for Clinical Research 
Woermannkehre 1 
D-12359 Berlin 
 
In this investigational study the term 'patient' is identical with the term 'subject' as defined in 
ISO 14155, because all study participants are patients treated by physicians at the 
investigational sites. 
 

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3 
INTRODUCTION 
 
The 2021 European Society of Cardiology guidelines recommend cardiac pacing in patients 
aged >40 years with tilt-induced asystolic reflex syncope (class I, level of evidence A). (1) The 
recommendation relies on recent results from the multicentre, randomised, double-blinded, 
parallel-design BIOSync trial. (2) The BIOSync study provided evidence of benefit of dual-
chamber pacing in patients with tilt-induced reflex syncope and confirmed the role of Head-up 
Tilt Table (HUTT) test as a diagnostic method for cardiac pacing in reflex syncope. The study 
randomised patients aged  \HDUV Zith frequent reflex syncope and VASIS 2B cardio-
inhibitory response to HUTT to receive either an active or an inactive dual-chamber pacemaker 
with the CLS pacing mode. The rationale for pacing with CLS in cardioinhibitory reflex syncope 
was recently reviewed by Tomaino et al. (3) CLS is able to measure changes in intracardiac 
impedance during the systolic phase of each cardiac cycle which are strictly correlated to the 
increased heart rate and right ventricular contraction speed which are usually present during 
the pre-syncope phase of the reflex. It was hypothesized that an early onset of CLS pacing 
may be triggered by the compensatory increase in heart rate to counteract vasodilation and 
pressure drop during the pre-syncope phase of the reflex. The BIOSync study showed a 77% 
reduced risk of syncope in the DDD-CLS group as compared to pacing off. The design of the 
BIOSync study did not allow to assess the specific effect that CLS adds to dual-chamber 
pacing. Despite DDD-CLS pacing, 22% of patients had syncopal recurrence in 2 years. Further 
investigations are therefore needed in order to reduce this failure rate. Indeed, it is still 
unclear whether syncopal recurrences should be ascribed to dominant vasodilation or if the 
CLS programming/functioning needs optimization to more adequately sustain cardiac output 
during reflex in these specific cases. (3) The purpose of this study is to explore changes in 
hemodynamic parameters during HUTT and their timing with respect to CLS pacing activation. 
This study may add knowledge to better understand the mechanisms underlying recurrent 
syncopal events and optimal pacing programming. 
 

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4 
DEVICE(S) USED IN THE STUDY 
 
The following devices, tools and accessories will be used during the study: 
x 
the CLS algorithm (as investigational device in this investigation according to, ISO14155) 
implemented in current dual-chamber pacemakers manufactured by: 
BIOTRONIK SE & Co. KG 
 
Woermannkehre 1 
 
12359 Berlin 
 
Germany  
www.biotronik.com 
x 
RENAMIC programmers or later models; 
x 
Any external monitor capable of measuring continuously patient's hemodynamics (e.g. 
Task Force Monitor); 
x 
Standard equipment needed for the HUTT execution. 
Such devices must be available at the investigational sites before study participation and will 
not be provided by the Sponsor. 
4.1 
Model name including software version and accessories 
All models of current dual-chamber pacemakers manufactured by BIOTRONIK implementing 
the CLS algorithm may be included in the study. Devices are used along with any CE-marked 
leads. A detailed description of the pacing systems is reported in their user manual. 
4.2 
Description of traceability 
All medical devices used in the study will be tracked by serial numbers. 
4.3 
Intended purpose of the device(s) in the study 
All above-mentioned medical devices are CE-certified and will be used within their intended 
use and according to their user manual.  
4.4 
Intended patient population and indications 
Pacemakers included in this study are used for all bradycardia arrhythmia indications to 
improve patients' symptoms that can be clinically manifested and compensate bradycardia by 
atrial, ventricular or Atrio-Ventricular sequential pacing. 
The intended study population consists of patients who have indication for the pacemaker 
therapy according to the current European guidelines. (1) BIOTRONIK pacemakers equipped 
with CLS are therefore used within their indication. 
4.5 
Description of the CLS algorithm  
 The CLS algorithm was developed to provide a physiologic pacing rate modulation in response 
to metabolic demand and it is based on an analysis of the right ventricle unipolar impedance 
trend during systole. Impedance trend is obtained by sampling with high frequency 
subthreshold pulse train: an increase of the impedance trend slope, with respect to a (rest) 
reference, is an indication of an increased metabolic demand and it is used to adapt heart rate 
accordingly. In particular, impedance changes depend on the amount of blood and myocardial 
tissue in the volume surrounding the tip of the right ventricular lead. During contraction, blood 
ejection causes tighter electrode contact with myocardial tissue (involving a larger proportion 
of tissue relative to blood volume), leading to a progressive impedance increase towards late 
systole (3). CLS automatically increases pacing rate in response to detected changes in 
myocardial contractility. CLS functioning actively interacts with the autonomic regulation 

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process of cardiac output, occurring under several conditions of everyday life, not limited to 
exercise. (4) 
4.6 
Summary of training and experience needed 
All investigators must dispose of adequate research training and experience. Training on ISO 
14155 and/or several years of experience in conducting clinical trials are generally required. 
In addition to having basic medical knowledge, investigators must be thoroughly familiar with 
cardiac pacing and conduction of HUTT Investigators will be trained on the study procedures. 
 

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5 
JUSTIFICATION FOR THE DESIGN OF THE CLINICAL 
INVESTIGATION 
Although cardiac pacing is recommended in population investigated in this study, there is still a 
number of them who experience syncopal recurrences despite pacing. A better understanding 
of physiology of syncopal reflex and the effect of cardiac pacing is needed. To this purpose, an 
exploratory study design without additional follow-ups after HUTT executed as per standard 
clinical practice was chosen. There are no endpoints in this study due to its exploratory design 
without statistical hypotheses to be tested. The in- and exclusion criteria are defined in a way 
to select patients from the BIOSync study for whom the performance of dual-chamber pacing 
with CLS was already documented allowing to better correlate new insights from this study 
with the benefit of therapy. A rationale for the chosen sample size is given in section 12.5. 
All devices are CE-certified and used according to their indication and user manual. Therefore, 
the use in human subjects is justified. 
 

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6 
BENEFITS AND RISKS OF THE DEVICE, CLINICAL PROCEDURE, AND 
CLINICAL INVESTIGATION 
6.1 
Anticipated clinical benefits 
Participating subjects will benefit from an accurate programming of cardiac pacing and CLS 
function, based on the detailed evaluation of pacing activation during the reflex induced by the 
HUTT. This may help further prevent syncopal relapses. 
6.2 
Anticipated adverse device effects 
No additional risks related to the CLS function or the equipment used for HUTT are expected 
resulting from the participation in the study. Study patients have already received pacemaker 
therapy according to current guidelines. Anticipated Adverse Device Effects (ASADE) 
associated with pacemaker therapy are described in section 19.8. 
Participating patients will undergo HUTT as per standard clinical practice. No serious adverse 
events related to the HUTT are expected in literature except for known adverse effects of 
nitroglycerine. These may include: dizziness, weakness, palpitations, vertigo, headaches, 
nausea, vomiting, diaphoresis, syncope, hypotension, pallor, flushing, exfoliative dermatitis, 
drug rash (5-7). 
6.3 
Risk associated with participation in the clinical investigation 
The investigational procedures performed during routine patient follow-up do not involve 
additional risks for the enrolled subjects. Participating patients will undergo a HUTT 
examination at enrollment visit according to their normal follow-up schedule. HUTT is a safe 
procedure and often considered as part of normal clinical practice in the study population, even 
after pacemaker implant, to predict response to or adjust therapy. There have been reported 
neither deaths nor severe complications during the tests. 
Unauthorized access to 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 
SDWLHQW¶VGDWDDQGDGKHUHVWo applicable European data protection laws. 
6.4 
Possible interactions with concomitant medical treatments  
No interactions are expected with medical treatments. 
6.5 
Steps to control or migrate the risk  
Careful selection of participants and accurate conduction of HUTT according to the procedures 
described in section 9 will allow to minimize potential risks.The following measures shall be 
taken during a HUTT: 
x 
Adherence to relevant medical guidelines 
x 
Use of nitroglycerine during active phase of the HUTT 
x 
Resuscitation equipment available and trained personnel during test procedures 
Study staff will be trained at study start (Initiation Visit) and periodically re-trained if 
necessary. 
6.6 
Rationale for benefit-risk ratio 
As no additional risks are expected in association with study procedures, as described in 
sections 6.2 to 6.5, expected benefits reported in section 6.1 outweigh risks. In addition, the 
knowledge gained from the study will help improve diagnosis and treatment of patients with 
reflex syncope and asystolic HUTT response. 
 

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7 
OBJECTIVES AND HYPOTHESES 
 
7.1 
Purpose of the clinical investigation  
The purpose of this study is to add knowledge to better understand the hemodynamic 
mechanisms underlying recurrent syncopal events and optimal pacing programming. 
 
7.2 
Objectives (Endpoints) 
This study will provide standardized, complete and quality controlled data sets with parameters 
that describe hemodynamic changes and their timing with respect to CLS pacing activation 
during reflex syncope induced by HUTT. 
7.3 
Hypotheses 
Due to the exploratory design of the study there are no statistical hypotheses (null/alternative 
hypotheses) associated with study objectives. 
 
7.4 
Risks and anticipated adverse device effects 
There will be assessments of risks and anticipated adverse device effects throughout the 
clinical investigation as described in section 19. 
Anticipated adverse device effects and risks associated with participation in the clinical 
investigation are described in subchapter 6.2 and 6.3. 

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8 
DESIGN OF THE CLINICAL INVESTIGATION 
8.1 
General considerations 
 
8.1.1 
Design type of clinical investigation 
The study is designed as a prospective, non-randomized, multi-center, observational acute 
study without additional follow-ups after HUTT execution. 
 
8.1.2 
Measures taken to minimize or avoid bias 
Accurate patient selection as described in section 8.2 and precise conduction of HUTT 
according to the procedures described in section 9 will allow to minimize potential confounding 
factors. 
 
8.1.3 
Data of interest 
a) Heart rate, blood pressure, stroke volume, and peripheral resistance will be collected at the 
following time-points during HUTT: 
x 
time of maximum spontaneous heart rate (end of phase 1/beginning phase 2 of the 
reflex); 
x 
time of pacing onset; 
x 
time of recovery of spontaneous rhythm after pacing (end of recovery period); 
x 
time of syncope (i.e. loss of consciousness) during HUTT (also assessed by video 
recording if available at investigational site) 
x 
time of tilt-down (supine patient position just after tilt-down) 
b) Above-mentioned times of interest (expressed in HH:MM:SS from the start of the HUTT) 
c) Duration of the recovery phase (interval from maximum pacing rate to basic rate or 
spontaneous rhythm expressed in MM:SS from the start of the HUTT) 
d) Slopes in heart rate (bpm per sec) and systolic blood pressure (mmHg per sec) during the 
recovery phase  
 
Definitions.  
Phase 1 of reflex during HUTT is defined as the interval from the start of blood pressure 
decrease due to a reduced venous return (and consequent corrective heart rate increase) to 
the beginning of phase 2. 
 
Phase 2 is characterized by decrease of heart rate due to the activation of vagal reflex. Phase 
2 (HR drop) may be partially masked by pacing activation. 
 
Recovery phase is defined as the interval from maximum pacing rate to basic rate or 
spontaneous rhythm, if pacing is not delivered.  
 
 
 

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8.1.4 
Methods  
8.1.4.1 
CRFs 
All parameters and measurements that are recorded within the registry are documented on the 
corresponding electronic case report forms (CRFs) listed below. The investigator is required to 
use an electronic signature to approve the content of the data reported in the CRFs.  
Following CRFs are used: 
 
Enrollment/Baseline Form 
 
Device Interrogation Form 
 
HUTT Form 
 
Adverse Event/Device Deficiency Form 
 
Study Termination Form 
 
The corresponding time schedule is described in Section 9. 
8.1.4.2 
Source Data Sheets 
For HUTT data collection the following Source data sheets (SDS) are recommended to be used: 
 
HUTT examination (preparation phase) SDS 
 
HUTT examination (execution phase) SDS 
 
8.1.5 
Equipment to be used for the assessment of variables  
Implanted device and related equipment are described in Section 4. 
Patients will undergo HUTT exam as per clinical practice during ordinary follow-ups irrespective 
of study participation. This test will require the use of standard CE-marked equipment, such as 
tilt tables and tools to electronically record continuous data on HR, BP, SV, and TPR. Time of 
syncope may be assessed also by video-recording (if available at the investigational site). 
 
8.1.6 
Replacement of patients 
A total of 20 subjects who had been already enrolled in the BIOSync study will be asked to 
participate in the present BIO|Sync-HUTT study. If less than 20 BIOSync patients will accept to 
participate for any reasons, participants may be replaced until fully analysable data set will be 
collected from 15 participants.  
Replacements will consist of patients who already received a dual-chamber pacemaker with the 
CLS function who meet the same subset of inclusion/exclusion criteria of the BIOSync study 
(8).  
 
8.1.7 
Investigation sites 
The study will be conducted in at least 2 investigational sites that already participated in the 
BIOSync trial. 
 

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8.1.8 
Completion of the clinical investigation 
 The study will be completed when the last visit of the last subject will be available and 
documented in the CRFs (as defined in section 8.1.4.1). 
 
8.2 
Patients 
The intended patient population consists of all patients with reflex syncope and positive 
cardioinhibitory response to HUTT who had already participated in the BIOSync study. As 
described in section 8.1.6 replacements are allowed, if needed. 
8.2.1 
Inclusion criteria 
x Ability to understand the nature of the study.  
x Willingness to provide written informed consent. 
x Patients undergoing HUTT for monitoring of syncope, therapy adjustment, training or other 
medical reasons during ordinary follow-up, irrespective of study participation 
x Patients who participated in the BIOSync study*. 
x Patients with a dual-chamber pacing system equipped with the CLS algorithm. 
 
* If needed, inclusion of other patients who did not participate in the BIOSync study will be 
considered to complete study cohort, provided that they have already a CLS pacemaker 
system and fulfill the same inclusion/exclusion criteria of the BIOSync study. 
 
8.2.2 
Exclusion criteria 
x Pregnant or breast feeding women. 
x Age less than 40 years. 
x Patients who after the BIOSync study participation have developed the following: 
 Any indication to pacemaker different from reflex syncope with positive HUTT response; 
or 
 Any classified indication to implantable defibrillator, cardiac resynchronization therapy 
according to current guidelines; or 
 Any cardiac dysfunctions likely leading to loss of consciousness (overt heart failure, 
ejection fraction <40%, myocardial infarction, diagnosis of hypertrophic or dilated 
cardiomyopathy, clinically significant valvular disease, sinus bradycardia <50 bpm or 
sinoatrial block, Mobitz I second degree atrioventricular block, Mobitz II second or third-
degree atrioventricular block, complete bundle-branch block). 
 
8.2.3 
Criteria and procedures for subject withdrawal  
8.2.3.1 
Withdrawal of patient consent 
Patients may withdraw their consent for study participation at any time without stating the 
reason and without any unfavourable consequences. All data that is collected until the date of 
withdrawal will be deleted immediately by effective anonymization, unless their further 
processing is still required as regulated by the legal exceptions to the deletion obligations. This 
also applies if the patient has requested data erasure. Depending on the patient's decision to 
delete the data, it will be deleted by effective anonymization as soon as the conditions for the 

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legal exceptions on further retention and processing cease to apply. A withdrawal sheet and a 
study termination CRF have to be filled in by the investigational site. 
8.2.3.2 
Impossibility of device programming at enrolment visit 
If during the enrolment visit a device programming according to Table 2 (as reported in section 
9.2.2) is not possible for any reason, the patient shall terminate study participation before 
performing the HUTT (dropout). 
 
8.2.4 
Point of enrollment 
A subject is considered enrolled in the BIO|Sync-HUTT Study upon the signature of the 
Informed Consent Form after confirmation of the elegibility criteria by the investigator. 
8.2.5 
Total expected duration of the clinical investigation 
The expected total duration of the study is 19 months after the first enrolment.  
 
8.2.6 
Expected duration of each VXEMHFW¶VSDUWLFLSDWLRQ 
Subjects participate from consent to HUTT execution with not further follow-up. Figure 1 shows 
the flowchart of the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1: Flowchart for the BIO|Sync-HUTT study 
 
8.2.7 
Number of subjects required to be included  
A maximum of 20 subjects will be enrolled (including replacements as described in section 
8.1.6). Please refer to section 12.5 for further details on the planning of the sample size. 
8.2.8 
Estimated time needed to select patients  
The enrolment period is expected to last 9 months. 

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9 
STUDY PROCEDURES 
9.1 
Overview 
 
This section describes all the study-related procedures as listed in Table 1 which will be 
performed during a routine scheduled patient follow-up.  
Prior to obtaining informed consent, the pDWLHQW¶V EDFNJUound and medical history will be 
reviewed in order to ensure he/she is an appropriate candidate for the study. Patient who 
undergo HUTT during ordinary follow-up visits irrespective of study participation, is eligible. 
After the patient has been determined to be eligible for the study, written informed consent 
will be obtained and demographic and medication data will be collected. Syncope and pre-
syncope questionnaires will be self-administered. Prior to the HUTT, pacemaker interrogation 
will be performed in order to check programming settings and to collect device diagnostics. 
The HUTT may be performed and also recorded by a high-definition camera if available. Full 
hemodynamic parameters and ECG traces will be acquired during the HUTT. Any collected data 
and adverse events will be documented in an electronic CRF. 
 
 
Table 1: Investigation Schedule 
Investigations 
Enrollment/study visit 
Verification of in- and exclusion 
criteria 
X 
Patient informed consent 
X 
Demographic data 
X 
Medical history 
X 
Co-morbidities 
X 
Medication therapy 
X 
Patient self-administered syncope and 
pre-syncope questionnaires 
X 
ECG 
X 
Device programming settings and 
diagnostics 
X 
Head-up tilt test (including video 
recording if available) 
X 
Collection of primary and secondary 
endpoint-related measurements 
X 
(S)AE, (S)ADE, DD monitoring 
X 

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9.2 
Enrollment/study visit 
9.2.1 
Baseline assessment  
The baseline data will be collected after consenting procedures are completed. 
For baseline evaluation, the investigator collects the following data on an CRF: 
x 
Demographic data 
x 
Medical history 
x 
Comorbidities 
x 
Cardiomyopathies 
x 
Arrhythmias 
x 
Prior ECG 
x 
Medication therapy 
x 
Syncope and pre-syncope questionnaires 
x 
Previous participation in the BIOSync study 
x 
Date of pacemaker implantation  
x 
Device programming 
 
 
9.2.2 
Study procedures after baseline assessment  
The following procedures shall be conducted after baseline assessment: 
 Interrogate the pacemaker and save the pacemaker diagnostics; 
 Make sure that the DDD-CLS pacing mode has been activated since for at least 10 days. If 
the CLS mode is not active or any pacing mode other than DDD-CLS is active at the time of 
interrogation, reprogram the device as reported in the Table 2 below, and reschedule a new 
visit in at least 10 days to perform the HUTT. If device programming according to Table 2 is 
not possible for any reason, the patient shall terminate study participation before 
performing the HUTT (dropout). 
 Perform standard tests to assess correct pacing and sensing function with current settings; 
 Check that the device programming is set as reported in Table 2. Parameters which 
are not listed have to be intended freely selectable*; 
 Switch off the programmer; 
 Perform the head-up tilt testing as reported in section 9.2.3; 
 
* Note: any device re-programming involving a switch from CLS-OFF to CLS-ON or a 
change in the CLS-mode pacing will require to postpone HUTT execution for at least 
10 days. Any other device re-programming according to table 2 will require patient 
to wait 10 minutes in a sitting position before HUTT execution due to the time period 
needed to fine-tune impedance reference waveforms. Also it shall be ensured that 
the nominal AV-delay (excluding hysteresis) is programmed sufficiently short 
(intrinsic conduction time minus at least 43 ms) in order to avoid fusion beats. 
 

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As per standard of care, PM programming will be optimized if needed, according to 
observations collected during the HUTT. 
 
Table 2 ± Device programming 
Parameter 
Pacing Mode 
 
 
DDD-CLS 
 
Basic rate  
 
 
50 bpm 
 
Maximum CLS rate 
 
 
120 bpm 
 
Upper tracking rate 
 
 
130 bpm 
 
Atrioventricular delay 
 
 
Low; 180±140 ms 
 
Atrioventricular hysteresis mode 
 
 
IRSplus 
 
CLS Resting Rate Control 
 
 
OFF 
 
Atrial pacing polarity 
 
 
Unipolar 
 
Ventricular pacing polarity 
 
Unipolar 
 
 
 
9.2.3 
Head-up tilt test 
The HUTT will be performed according to the Italian protocol (9) and patient's hemodynamics 
will be continuously monitored during the entire test. Specifically, an external monitor will be 
used for continuous measurement and recording of systolic and diastolic BP, HR, SV, and TPR. 
Prior to the start of the HUTT, a trained member of the study team will prepare the patient and 
set up the equipment needed for the test as follows: 
x 
patient shall be supine on the tilt table and secured to it with the BP sensor cuff of the 
external monitor on his/her finger. Hand wearing the pressure sensor shall be placed on 
the chest at about 10 cm from heart and held in this position throughout the test; 
x 
ECG leaGVVKDOOEHSODFHGRQSDWLHQW¶VFKest and a BP cuff on his/her arm; 
x 
If used, a high-definition camera may be placed to contemporarily pick up both patient 
and the external monitor positioned close to the tilt table. 
Note: video recordings of the entire test shall not be provided to the Sponsor 
and will be destroyed immediately after the examination. The investigator will 
assess the time of symptoms onset and will report it in the CRF. 
 
After 10 minutes in supine position, the patients will be tilted to 70° using an electronically 
operating tilt-table with a footboard. 

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9.2.3.1 
Timing of tilt down 
In this study the HUTT will not be performed for diagnostic purposes but rather to verify the 
proper functioning of the implanted pacemaker. Therefore, HUTT is aimed to induce the 
vasovagal reflex, confirmed by the onset of symptoms and by onset of pacing and not to 
induce syncope. Given ethical issues, the table will be tilted down at the time of loss of 
consciousness. In case of negative test, the table will be tilted down at the end of test-time. 
 
The following procedures shall be conducted after HUTT completion: 
x 
Document outcome measurements on the CRF; 
x 
Provide continuous electrocardiogram traces printed at 5 mm/sec from the time of 
maximum spontaneous HR increase during phase 1 until the end of the exam. 
 
9.3 
Termination and post treatment 
The patients terminate the study regularly after the completion of the enrollment visit including 
HUTT and collection of study data. The CRF µ6WXG\ terminatioQ¶KDVWREHILOOHGLQ,Qcase of 
any premature study termination, the CRF Study Termination has to be completed with the 
reason for study termination. The process of consent withdrawal is described in section 
8.2.3.1.  
After study termination the patients will continue to be treated according to standard routine 
care. The device programming is at the investigDWRU¶VGLVFUHWLRQ 
9.4 
Description of those activities performed by sponsor representative 
Sponsor representatives may support the investigator for pacemaker programming and 
interrogation or for the download of data of the programmer as needed. 
Monitoring will be performed by Sponsor representatives according to the monitoring plan. 
 
9.5 
Possible influencing factors on outcome or interpretation of results 
No factors that could influence the outcome or interpretation of the results are known at time 
of protocol drafting. 

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10 RESPONSIBILITIES 
10.1 
Responsibilities of the sponsor 
The sponsor of the BIO|Sync-HUTT study is: 
BIOTRONIK SE & Co. KG 
 
Woermannkehre 1 
 
12359 Berlin  
Germany 
The sponsor ensures that all documents, information and necessary human resources are 
made available for initiation, conduct and termination of the study. 
In addition, the sponsor is obliged to fulfill the following tasks (selection of items): 
x Maintaining insurance cover or indemnification of patients in case of injury in accordance 
with applicable laws. 
x Contracting of investigational sites and investigators.  
x Responsibility for all payments and financial coverage of the study. 
x Selection of suitable investigational sites, investigators and clinical monitors.  
x Creating a Master template for informed consent form and obtain approval of the Master 
template by the leading ethical committee (EC), if required. 
x Obtaining of a favorable ethics vote(s) for conduct of the clinical study. 
x Obtaining approval of the involved competent authorities (if applicable). 
x Supervision of study conduct according to the legal regulatory requirements and the 
requirements of the CIP. 
x Fulfill reporting duties of the sponsor to the ethic committees and regulatory authorities. 
x Data analysis and data management. 
x 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. 
x Provision of the final clinical investigation report (CIR) in accordance with applicable legal 
requirements and ethical principles. 
10.1.1 
Project management 
The clinical project manager is responsible for the following (selected items): 
x Development of the clinical investigation plan and possible amendments. 
x Coordination of all study-related activities dedicated to the sponsor. 
x Support of investigational sites during the study (obtaining ethic committee votes, etc.). 
x Continuous information of investigational sites and clinical monitors on study progress. 
x 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).  
 
10.1.2 
Data management 
The data manager is responsible for the following items (selection of items): 
x Development and maintenance of the clinical data management system (CDMS; iMedNet of 
the company MedNet Solutions Inc, Minnetonka, MN 55305 USA). 
x Development of the data management plan. 

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x Development of the CRF user guide. 
x Data management. 
 
10.1.3 
Biostatistician  
The statistician is responsible for the following items (selection of items): 
x All statistical aspects within the clinical investigation plan. 
x Statistical analysis for clinical investigation report. 
The statistician will be supported by other staff members of the sponsor. 
 
10.1.4 
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 11 of 
this document. 
 
10.2 
Responsibilities of the investigators 
10.2.1 
Coordinating investigator 
This study is coordinated by: 
Prof. Michele Brignole 
IRCCS Istituto Auxologico Italiano  
Faint & Fall programme, Dept. of Cardiovascular, Neural and Metabolic Sciences, Ospedale San 
Luca 
Piazzale Brescia, 20 
20149/Milano (MI), Italy  
 
The responsibilities of the CI are listed in the following: 
x Development and review of the clinical investigation plan. 
x Procurement of the central vote of an ethics committee. 
x Performance and progress control of the study. 
x Continuous assessment of the risk/benefit ratio. 
x If necessary, decision on premature study termination in consultation with the sponsor. 
x Contribution to coordination of publication and presentations of study results. 
x Advising all investigators in medical questions related to the study or study conduction. 
x Evaluation of potential unexpected adverse events. 
x Discussion of possible interim results. 
x Cooperation in writing of the final clinical report. 
Prof. Michele Brignole

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The coordinating investigator is supported by the clinical Project Manager and other members 
of the sponsor.  
In addition, the CI has the same rights and duties as other principal investigators. 
 
10.2.2 
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: 
x Registration of the study to the bodies responsible for the investigational site (e.g. hospital 
administrative department). 
x Notification to competent authority (if applicable) responsible for the investigational site. 
x If required, obtaining of a positive vote of the ethics committee responsible for the 
investigational site. 
x Safeguarding the rights of the physical and mental integrity as well as the privacy and the 
protection of the data of the study patients. 
x Adverse Event reporting according to the clinical investigation plan. 
x Recruitment of suitable patients in an adequate time frame. 
x Patient information and obtaining of written informed consent of the patient according to the 
requirements of the CIP. 
x Safe and efficient use of devices. 
x Inform the sponsor about new study team members before authorizing them for study 
related activities.  
x Provide the sponsor with required documentation for assessing the qualification of study 
team members.  
x Authorize co-investigators only after documented adequate study specific training. 
x Discourage patients to consent for other interventional clinical investigations, in case the 
investigator is aware of such intentions beforehand. Inform the sponsor, in case a patient 
has already been enrolled into another interventional clinical investigation without undue 
delay. Obtain the sponsors permission before enrolling the patient into another 
interventional clinical investigation.  
x Conduct of the study according to the CIP 
x Provide the sponsor with a ISO14155 training documentation 
x Data collection and data entry in accordance with the requirements of the CIP. Patient 
records shall include the relevant medical history and progress of the disease of each 
patient.  
x Providing supporting material, if necessary. 
x Submission of safety reports and protocol deviations to ethics committee and competent 
authorities (if applicable). 
x Support of monitoring and auditing activities. 
x Confidential treatment of all study-related documents and information. 

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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. 
 

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11 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 
investigational device is 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, the clinical investigation plan, applicable laws, and/or local 
regulations and any conditions of approval imposed by the reviewing IRB/EC.  
The entries in the CRF will be reviewed and source data verified at the investigational site by 
monitors (authorized BIOTRONIK personnel, 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 patients and 
the quality and integrity of the resulting data. 
A monitor will visit the study site periodically during the study. All participating sites will be 
monitored during the course of the study with visits occurring as frequently as deemed 
necessary to ascertain adherence to the protocol procedures, as well as maintenance of the 
highest quality data. A detailed monitoring plan developed by BIOTRONIK will be followed.  
Monitoring visits will assure, amongst others, that the facilities are still acceptable, that the CIP 
is being followed, that the EC/IRB/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. 
Periodic monitoring visits and assessments of the study site will include but will not be limited 
to the following: 
1. Completion and submission of the required electronic case report forms (CRFs) and other 
applicable study documentation 
2. Continued acceptability of the facilities 
3. Adherence to the clinical investigation plan 
4. Adherence to current version of ISO 14155 and local regulations and laws 
5. Availability and correctness of the signed patient informed consent 
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. 
 
A monitoring plan will be prepared as additional document. It provides detailed information 
about frequency and extent of monitoring. 

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12 STATISTICAL DESIGN AND ANALYSIS 
12.1 
Analysis population 
All patients with valid patient informed consent are included in the analysis set. 
12.2 
Descriptive statistics 
Standard descriptive statistical methods are used depending on the type of the available data. 
For continuous variables, mean value, standard deviation, median, minimum, maximum and 
quartiles are calculated. For nominal variables, absolute and relative frequencies are calculated 
based on non-missing data. For ordinal variables, median, minimum, maximum and quartiles 
or absolute and relative frequencies are calculated for each category based on non-missing 
data. 
12.3 
Analytical procedures 
Standard inferential statistical methods are used depending on the type of the available data. 
For mean values, confidence intervals are calculated based on a t-distribution. For relative 
frequencies, confidence intervals are calculated based on a binomial distribution. Thereby, the 
significance value specified in the following sub-chapter is considered.  
12.4 
Significance level, statistical power, and statistical testing  
Because there are no pre-specified hypotheses, all analyses are exploratory. However, a result 
of a two-sided statistical test with a p-value less than 5% or a one-sided statistical test with a 
p-value less than 2.5% is considered statistically significant. 
For any inferential analyses, the result of a two-sided statistical test with a p-value less than 
5% or a one-sided statistical test with a p-value less than 2.5% is considered statistically 
significant. 
12.5 
Sample size 
Since the study has an exploratory design without hypotheses to be tested, the sample size 
cannot be based on a specific calculation. The sample size was chosen considering the 
objective of the study to understand hemodynamic mechanisms underlying syncope 
recurrences and CLS activation during HUTT. Based on such objective, a sample size of 20 was 
chosen without need for a lager number of patients. (10-13) 
12.6 
Interim analyses 
There are no pre-planned interim analyses. 
12.7 
Bias 
In case of a clear evidence of bias, which was not considered before, the Statistical Analysis 
Plan (SAP) is updated to avoid any bias. 
See also chapter 8.1.2. 
12.8 
 Subgroups 
There are no pre-specified subgroups. However, some comparisons may be worth performing, 
e.g. between subgroups with and without syncopal relapses during participation in the 
BIOSync study or after pacing activation (with or without CLS). 
12.9 
Missing, unused, and spurious data 
All data needed to be analyzed are pre-documented in a Statistical Analysis Plan (SAP).  

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During a blind review process before any pre-planned analysis, missing and spurious data, 
which are relevant at least for the endpoints, are identified. In case such data FDQ¶WEHFODULILHG
via a query management process, the Statistical Analysis Plan (SAP) is updated to avoid any 
bias. If appropriate, analyses will be performed both with/without spurious data. 
Number of missing data are reported for each descriptive and inferential analysis in the 
Statistical Analysis Report (SAR) and Clinical Investigation Report (CIR), if applicable. Spurious 
data are commented in the Clinical Investigation Report (CIR), if applicable. Drop-outs are 
reported in the Statistical Analysis Report (SAR) and Clinical Investigation Report (CIR), if 
applicable.  
Missing data will not be replaced. 
 
12.10 Deviations from the original statistical plan  
A Statistical Analysis Plan (SAP) is provided after go-life of the Clinical Data Management 
System (CDMS). The SAP can be updated before CDMS-freeze or closure based on a review of 
the data, whereby the new version is containing a change history. Any deviation from the valid 
SAP version with respect to inferential analyses are indicated in the Clinical Investigation 
Report (CIR), if applicable. 

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13 DATA MANAGEMENT 
 
13.1 
Methods for data entry and collection 
All study-relevant medical patient data will be entered and documented pseudonymized in 
electronic case report forms (CRF), designed, validated and released within a Clinical Data 
Management System (CDMS). The established CDMS is µi0HG1HW¶ RI WKH YHQdor MedNet 
Solutions, Inc. As a cloud based SaaS (Software as a Service) application, that is applicable 
with the current versions of current internet browsers, no specific local software installation to 
functionality support necessary. iMedNet supports industry standards (FDA 21CFR11, HIPAA 
and Safe Harbor). 
Use of the CDMS will allow access 24 hours 7 days a week to the study specific community 
(syn. study database). The PI, as well as those co-investigators to whom the PI delegates data 
entry and authorization of CRF, need to be trained on CDMS 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 CDMS. Once these have been validated, there will be options for adding new patients or 
entering new medical patient data into the CDMS. 
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 has 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 at the respective 
section of the CIP. 
 
13.2 
Procedures used for data review, database cleaning, and issuing and resolving 
data queries  
After data entry into the CDMS, the clinical data is automatically checked with programmed 
quality checks within CDMS. The CRFs will be checked against source data by clinical monitors 
as described in the Monitoring Plan. Errors, discrepancies, missing data, and entries out of 
range are resolved both automatically (CDMS) and manually (clinical monitor, clinical data 
manager) via 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 thereby approving 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 audit trail.  
 
13.3 
Procedures for verification, validation, and securing of electronic clinical data 
systems 
The CDMS is hosted on a dedicated database server at the vendor MedNet Solutions, Inc. The 
data connections between the Internet browser of the user and the data servers of the service 
provider MedNet Solutions, Inc., are established with secure and certified connections. The 
user access and assigned roles within the CDMS is controlled and maintained by the 
responsible clinical data manager. Every access is automatically logged and changes of the 
clinical data are recorded in an independent audit trail. The CDMS is verified, validated and 
documented according to guidelines by BIOTRONIK and applicable regulations, e.g. FDA 21 
Part 11. The user interface and the internal business logic is validated accordingly and verified 
during the study specific development and before the release of the CDMS for data entry. 

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An authenticated user account is created and maintained by BIOTRONIK for each authorized 
user once the user has completed the appropriate training. Users are obligated to keep their 
password confidential. 
Depending on their role within thHLQYHVWLJDWLRQDOVWXG\XVHUVDUHOLPLWHGWRµUHDGRQO\¶RUPD\
be given permits to enter or update data, provide resolutions to queries and apply electronic 
signatures. Only investigators are allowed to sign the entries. The user role and rights 
management is documented accordingly. 
 
13.4 
Procedures to maintain and protect subject privacy 
The EU GDPR guideline and related EU contractual clauses are implemented by the service 
provider MedNet Solutions, Inc., for CDMS and BIOTRONIK. 
According to corresponding additional national laws, the patient or legal representative must 
declare in the Informed Consent Form (ICF) that the patient agrees to recording the patient 
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 and pseudonymized. The collected data will be securely transmitted to 
BIOTRONIK and, if necessary, to the external assessment committees (e.g. CEC) 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 patient data, but preventing unauthorized identification of individual 
patients, a pseudonymized patient ID is used that consists of a clinic number and a 
consecutive number for the patient, however no additional patient identification characteristics. 
All clinical data will be stored in the validated electronic system environment with adequate 
and documented protection against unauthorized user access.  
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 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. 
 
13.5 
Methods for database locking at the start of the analysis and storage upon 
completion of the clinical investigation  
Resolution of open queries is a precondition for site closure in case of premature or regular 
study termination. 
For database locking, the CDMS has been prepared and a review for completeness, 
consistency, plausability and integrity according to the CIP and CDMP was performed: 
x all expected data retrieved, 
x all received data cleaned (i.e. all discrepancies have been raised and resolved for all 
expected data), 
x all electronic data received, loaded, reconciled and cleaned, 
x all coding completed and 

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x SAE and AE reconciliation completed. 
x for final data analysis, all endpoint relevant data are checked in a blinded way by the 
biostatistician. 
After ensuring completeness and integrity, the write access to the CDMS is limited to prevent 
any unplanned and non-authorized changes to the patient data. The clinical data together with 
the system audit trail will be securely exported from the CDMS and must be stored on a 
protected file server at BIOTRONIK. The export must be saved in different common and human 
readable file formats. Finally all user rights in the CDMS are revoked. 
 
13.6 
Procedures for data retention 
Archiving of the clinical study data and the source data need to be according to the national 
law. 
After CDMS closure, all CRF data, the audit trail and other relevant CDMS content are securely 
exported in human readable file formats. 
All study related data and 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. 
All relevant study related documents have to be stored in the Investigator Site File at the 
investigational sites 'RFXPHQWV FRQWDLQLQJ SDWLHQW¶V 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 complete archiving period. 
 
13.7 
Specified retention period 
Investigational data are 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. 
 

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

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15 DEVIATIONS FROM CLINICAL INVESTIGATION PLAN 
 
15.1 
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 patients 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 patients may proceed without prior approval of the sponsor and the ethics 
committee. 
No waivers from the CIP are allowed. 
 
15.2 
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. 
 
15.2.1 
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.  
 
15.2.2 
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 CDMS system iMedNet, and 
assessed for the need of corrective or preventive actions. 
 
15.2.3 
Reporting 
Deviations are reported in the interim and final clinical investigation reports.  
 
15.3 
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. 

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15.4 
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 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 patients 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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16 DEVICE ACCOUNTABILITY 
All devices used in this clinical study carry a CE mark and will be used within their intended 
use. Therefore special device accountability procedures are not applicable. However, the 
implanted  pacing systems implementing the CLS function are identifiable by a unique serial 
number. This number will be recorded on the relevant form in the CRF. By need or at least at 
the end of the study, a list with all used devices will be created. 

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17 STATEMENT OF COMPLIANCE 
 
The study will be conducted in compliance with the international standard ISO 14155:2011 
µ&OLQLFDOLQYHVWLJDWLRn of devices for human subjects ± Good clinical practicH¶DQGVXEVHTXHQW
version ISO 14155:2020. 
17.1 
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. 
17.2 
Applicable international and national standards 
The study will be conducted in compliance with the international standard ISO 14155 µClinical 
investigation of devices for human subjects ± Good clinical practice¶.  
The study will also be conducted according to the applicable national legal requirements of the 
participating investigational sites. 
 
17.3 
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.  
 
17.4 
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. 
 
17.5 
Patient 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. 
 
17.6 
Financing 
This clinical investigation is financed by the sponsor BIOTRONIK SE & Co.KG. Contracting of 
investigation sites and investigators is in the responsibility of the sponsor, as mentioned in 
section 10.1 µ5HVSonsibility of the sponsRU¶ 7KH DJUHHPHQW Eetween the sponsor and the 
research site determines inter alia the following aspects: 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. 
 

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18 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. 
 
18.1 
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 shall 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 patients are included in 
this clinical study who are unable to give informed consent by selecting patients with age t 18 
years, who understand the nature of the procedure.  
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. 

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19 ADVERSE EVENTS AND DEVICE DEFICIENCIES 
In the course of the clinical investigation, undesired medical events can occur in participating 
patients, 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 14155:2020 events will be classified on the basis of the definitions below. 
19.1 
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 and whether anticipated or 
unanticipated. This includes: 
x Events related to the investigational device or the comparator 
x Events related to the procedures involved  
x For users or other persons, this definition is restricted to events related to the investigational 
devices.  
*see ISO 14155 3.2 
 
It is worth specifying that syncope, pre-syncope, heart rate and blood pressure drop during the 
HUTT which do not result in any consequence shall not be reported as adverse events in itself, 
as expected events and part of the test itself. If these events will result in any consequence of 
a (S)AE, the (S)AE shall be reported. 
19.2 
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 
 
19.2.1 
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 serious AE will be classified according to four different levels of causality. As defined in 
the Medical Device Coordination Group guidance (MDCG 2020-10/1), 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 
Possible: the relationship with the use of the investigational device, or the relationship with 
procedures, is weak but cannot be ruled out completely. Alternative causes are also possible 

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(e.g. an underlying or concurrent illness / clinical condition or/and an effect of another device, 
drug or treatment). Cases where relatedness cannot be assessed or no information has been 
obtained should also be classified as possible. 
Probable: the relationship with the use of the investigational device, or the relationship with 
procedures, seems relevant and/or the event cannot reasonably explained by another cause. 
Causal relationship: the event is associated with the investigational device or with 
procedures beyond reasonable doubt.  
The sponsor and the investigators will distinguish between the serious adverse events related 
to the investigational device and those related to the procedures (any procedure specific to the 
clinical investigation).  
An adverse event can be related both to procedures and the investigational device. 
Complications caused by concomitant treatments not imposed by the clinical investigation plan 
are considered not related. Similarly, several routine diagnostic or patient management 
procedures are applied to patients regardless of the clinical investigation plan. If routine 
procedures are not imposed by the clinical investigation plan, complications caused by them 
are also considered not related.  
In some particular cases the event may not be adequately assessed because information is 
insufficient or contradictory and/or the data cannot be verified or supplemented. The sponsor 
and the Investigators will make the maximum effort to define and categorize the event and 
avoid these situations. Where an investigator assessment is not available and/or the sponsor 
remains uncertain about classifying the serious adverse event, the sponsor should not exclude 
the relatedness; the event should be clDVVLILHGDV³SRVVLEOH´Dnd the reporting not be delayed.  
Particular attention shall be given to the causality evaluation of unanticipated serious adverse 
events. The occurrence of unanticipated events related could suggest that the clinical 
investigation places subjects at increased risk of harm than was to be expected beforehand. 
19.3 
Definition of device deficiency 
Device deficiency (DD)* is defined as inadequacy of a device with respect to its identity, 
quality, durability, reliability, usability, safety or performance, including malfunctions, use 
errors and inadequate labeling.  
*see ISO 14155 3.19 
 
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 providHG'' IRUPVKDOOEHXVHGWRGRFXPHQWWKLV µnon-medical¶
event.  
If a DD could have led to a SADE,  
x if either suitable action had not been taken, 
x if intervention had not been made, or 
x if circumstances had been less fortunate, 
the DD is classified as an DD with an SADE potential.  
 
19.4 
Definition of serious adverse events 
AEs are classified as serious* if one or more of the following consequences are fulfilled: 
x led to death 
x led to serious deterioration in the health of the subject, users, or other persons as defined 
by one or more of the following:  

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- a life-threatening illness or injury, or 
- a permanent impairment of a body structure or a body function including chronic diseases, 
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. 
x led to fetal distress, fetal death or a congenital abnormality or birth defect including physical 
or mental impairment. 
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 3.45 
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.  
 
19.4.1 
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 should be sent to 
BIOTRONIK promptly. 
On the AE-CRF, the following information should be provided, if available: 
x Cause of death 
x Date and time of death 
x Place death occurred 
x Device status at the time of death 
x Statement whether the event was device or study procedure related 
In addition to the adverse event CRF, a study termination form has to be completed. 
Whenever possible, devices that are explanted must be returned to BIOTRONIK SE & Co. KG 
for analysis. 
 
19.5 
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 
 
19.6 
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 assessment.  
*see ISO 14155 3.51 
These events must be reported to the sponsor immediately.  

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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. 
 
19.7 
Definition of serious public health threat 
A serious public health threat is defined as a signal from any adverse event or device 
deficiency that indicates an imminent risk of death or a serious deterioration in the health in 
subjects, users or other persons, and that requires prompt remedial action for other subjects, 
users or other persons. 
Note: This would include events that are of significant and unexpected nature such that they 
become alarming as a potential serious health hazard or possibility of multiple deaths occurring 
at short intervals. 
Signals from adverse events or device deficiencies that might indicate a serious health threat 
can be detected by either the sponsor or principal investigator but are evaluated by the 
sponsor. 
 
19.8 
Anticipated adverse events 
The following Adverse Events may possibly occur as medical complications of a pacemaker 
implantation. The most common adverse events related to the pacemaker are listed in Table 3 
(list based on Clinical Complication Analysis No. 000-004-711 Rev. A, 07 Sep 2021). All 
references used for this chapter refer to the list at the end of this section. 
 
Table 3. Adverse events and probability ranges associated with pacemaker therapy 
Frequency 
Event Type 
Reference ID 
Frequent 
¾ 
Shoulder pain 
[10] 
Device stimulation issue (LV-lead) 
[5] 
Probable 
¾½ 0%) 
Device lead issue (LV-Lead) 
[6, 32] 
Oversensing (Total) 
[42, 47, 69] 
Device lead issue (Total) 
[4, 24±31] 
Lead dislodgement (LV-Lead) 
[6, 18±21] 
Device capturing issue (LV-Lead) 
[46] 
Implant site reaction (Total) 
[4, 7±10, 12±15, 24, 26±28, 
30±41, 45, 49±65, 70±73] 
Device stimulation issue (Total) 
[3±8] 
Oversensing (RV) 
[42, 69] 
Lead dislodgement (RA-Lead) 
[6±15, 17, 20, 22, 23] 
Frequency 
Frequent 
¾
Probable
¾½ 0%)
ce ID
69] 
]
]
,
12±15, 24, 26±28, 
5, 49±65, 70±73]
, 20, 22, 23]
Event Type
Referenc
Shoulder pain
[10]
Device stimulation issue (LV-lead) 
[5]
Device lead issue (LV-Lead) 
[6, 32]
Oversensing (Total)
[42, 47, 6
Device lead issue (Total) 
[4, 24±31
Lead dislodgement (LV-Lead) 
[6, 18±21
Device capturing issue (LV-Lead) 
[46] 
Implant site reaction (Total) 
[4, 7±10,
30±41, 45
Device stimulation issue (Total)
[3±8] 
Oversensing (RV) 
[42, 69] 
Lead dislodgement (RA-Lead) 
[6±15, 17

BIOTRONIK SE & Co.KG // BIO|Sync-HUTT 
 
BA117_CIP_2-0 | Version 2-0| 20-Apr-2022 | Page 46/61 
FOR-137-014-H / SOP-137-020.020 / CRQ200005199 
Frequency 
Event Type 
Reference ID 
Device dislocation 
[12, 30, 48] 
Implant site haematoma 
[4, 7±10, 13±15, 24, 27, 28, 
30±32, 34±37, 49, 51±53, 56±
63 65 70 73]
Device lead damage (RV-Lead) 
[42] 
Device capturing issue (RV-Lead) 
[12, 42, 43] 
Device lead issue (RA-Lead) 
[23, 32±35] 
Nerve injury 
[10, 49] 
Lead dislodgement (RV-Lead) 
[7, 9±17] 
Haemorrhage (Total) 
[7, 26, 36±41] 
Implant site haemorrhage 
[7, 26, 36±41] 
Complication of device insertion (LV-
Lead) 
[6] 
Device capturing issue (Total) 
[6, 12, 42±44, 46, 47] 
Device lead issue (RV-Lead) 
[23, 32, 33, 35] 
Oversensing (RA) 
[69] 
Implant site erosion 
[7, 8, 10, 12, 30, 45, 54] 
Device pacing issue (RV-lead) 
[14, 42, 43] 
Pain (Total) 
[4, 10, 14, 28] 
Device pacing issue (Total) 
[7, 8, 14, 19, 42±45] 
Incision site impaired healing 
[8, 65] 
Vessel puncture site phlebitis 
[10, 55] 
Device electrical impedance issue (RV-
Lead) 
[42] 
Implant site reaction (Total, during an 
MRI procedure) 
[74] 
Implant site paraesthesia (during an 
MRI procedure) 
[74] 
Occasional 
Implant site infection 
[7, 8, 13, 14, 28, 30, 31, 33, 
36, 45, 49, 50, 52±55, 59, 60, 
Frequency 
Event Type
Reference ID
Device dislocation 
[12, 30, 48]
Implant site haematoma
[4, 7±10, 13±15, 24, 27, 28,
30±32, 34±37, 49, 51±53, 56±
63 65 70 73]
Device lead damage (RV-Lead) 
[42]
Device capturing issue (RV-Lead) 
[12, 42, 43] 
Device lead issue (RA-Lead) 
[23, 32±35]
Nerve injury 
[10, 49]
Lead dislodgement (RV-Lead) 
[7, 9±17]
Haemorrhage (Total) 
[7, 26, 36±41]
Implant site haemorrhage
[7, 26, 36±41]
Pain (Total) 
[4, 10, 14, 28] 
Device pacing issue (Total) 
[7, 8, 14, 19, 42±45]
Incision site impaired healing
[8, 65]
Vessel puncture site phlebitis
[10, 55]
Device electrical impedance issue (RV-
Lead) 
[42]
Implant site reaction (Total, during an
MRI procedure) 
[74]
Implant site paraesthesia (during an
MRI procedure) 
[74]
Occasional 
Implant site infection
[7, 8, 13, 14, 28, 30, 31, 33,
36, 45, 49, 50, 52±55, 59, 60,
Complication of device insertion (LV-
Lead) 
[6]
Device capturing issue (Total) 
[6, 12, 42±44, 46, 47]
Device lead issue (RV-Lead) 
[23, 32, 33, 35]
Oversensing (RA)
[69]
Implant site erosion
[7, 8, 10, 12, 30, 45, 54]
Device pacing issue (RV-lead)
[14, 42, 43]

BIOTRONIK SE & Co.KG // BIO|Sync-HUTT 
 
BA117_CIP_2-0 | Version 2-0| 20-Apr-2022 | Page 47/61 
FOR-137-014-H / SOP-137-020.020 / CRQ200005199 
Frequency 
Event Type 
Reference ID 
¾½  
Infection (Total) 
[4, 7, 8, 10, 12±15, 17, 19, 20, 
24±34, 36, 37, 45, 46, 48±68] 
Medical device site discomfort 
[7, 64] 
Ventricular tachycardia 
[58] 
Pacemaker syndrome 
[8, 33, 59] 
Device pacing issue (RA-lead) 
[14] 
Ventricular arrhythmia 
[30] 
Pneumothorax 
[4, 6±8, 10, 13±15, 20, 22, 24, 
26±28, 30±32, 35, 36, 41, 45, 
49 51 55 56 58 60 65]
Implant site pain 
[4, 10, 28] 
Undersensing (RA) 
[14, 15, 69] 
Thromboembolic event 
[36, 38, 60] 
Undersensing (Total) 
[14, 15, 43, 69] 
Device capturing issue (RA-Lead) 
[46] 
Device pacing issue (LV-lead) 
[19] 
Device related infection 
[12, 15, 17, 19, 20, 24, 27, 34, 
37, 46, 48, 55, 56, 62±64, 66, 
67] 
Device computer issue 
[7] 
Endocarditis 
[3, 7, 24, 25, 28, 30, 31, 33, 
50, 53, 55, 64] 
Cardiac 
perforation/Cardiac 
tamponade/Pericardial effusion (Total) 
[4, 7, 10, 11, 13, 15, 16, 23±
29, 31, 32, 35±37, 41, 44, 49, 
51, 55, 56, 58±61, 63, 64, 71, 
74, 75] 
Device 
electrical 
impedance 
issue 
(Total) 
[7, 42, 47] 
Pericardial effusion 
[7, 23, 36, 44, 49, 55, 60, 63, 
71, 74] 
Cardiac perforation 
[7, 10, 11, 13, 15, 16, 23±25, 
27±29, 31, 32, 35, 41, 51, 58, 
59, 64, 74, 75] 
Allergic reaction 
[61] 
Cardiac tamponade 
[4, 10, 15, 16, 23, 26, 27, 37, 
55, 56, 61] 
Frequency 
Event Type
Reference ID
¾½ 
Infection (Total)
[4, 7, 8, 10, 12±15, 17, 19, 20,
24±34, 36, 37, 45, 46, 48±68]
Medical device site discomfort 
[7, 64]
Ventricular tachycardia 
[58]
Pacemaker syndrome 
[8, 33, 59]
Device pacing issue (RA-lead) 
[14]
Ventricular arrhythmia
[30]
Pneumothorax 
[4, 6±8, 10, 13±15, 20, 22, 24,
26±28, 30±32, 35, 36, 41, 45, 
49 51 55 56 58 60 65]
Implant site pain
[4, 10, 28]
Undersensing (RA)
[14, 15, 69] 
Device computer issue 
[7]
Endocarditis 
[3, 7, 24, 25, 28, 30, 31, 33,
50, 53, 55, 64] 
Cardiac 
perforation/Cardiac
tamponade/Pericardial effusion (Total)
[4, 7, 10, 11, 13, 15, 16, 23±
29, 31, 32, 35±37, 41, 44, 49,
51, 55, 56, 58±61, 63, 64, 71,
74, 75] 
Device 
electrical 
impedance 
issue 
(Total) 
[7, 42, 47]
Pericardial effusion 
[7, 23, 36, 44, 49, 55, 60, 63,
71, 74] 
Cardiac perforation
[7, 10, 11, 13, 15, 16, 23±25, 
27±29, 31, 32, 35, 41, 51, 58,
59, 64, 74, 75]
Allergic reaction
[61]
Cardiac tamponade
[4, 10, 15, 16, 23, 26, 27, 37,
55, 56, 61] 
Thromboembolic event
[36, 38, 60] 
Undersensing (Total)
[14, 15, 43, 69] 
Device capturing issue (RA-Lead)
[46] 
Device pacing issue (LV-lead) 
[19]
Device related infection 
[12, 15, 17, 19, 20, 24, 27, 34,
37, 46, 48, 55, 56, 62±64, 66, 
67]

BIOTRONIK SE & Co.KG // BIO|Sync-HUTT 
 
BA117_CIP_2-0 | Version 2-0| 20-Apr-2022 | Page 48/61 
FOR-137-014-H / SOP-137-020.020 / CRQ200005199 
Frequency 
Event Type 
Reference ID 
Chest pain 
[14] 
Circulatory collapse 
[35, 49, 55] 
Cardiac arrest 
[62] 
Cardiac vein dissection 
[4, 6, 35] 
Subclavian artery perforation 
[59] 
Vascular injury (Total) 
[4, 6, 35, 57, 59] 
Embolism (Total) 
[24, 29, 36, 38, 55, 60] 
Implant site cellulitis 
[10] 
Sepsis 
[55, 64] 
Cerebrovascular accident 
[10, 28, 55] 
Device connection issue 
[4, 6, 7, 15, 17, 28, 32, 42, 51] 
Neurological symptom 
[57] 
Arrhythmia (Total) 
[7, 14, 30, 58, 59, 62] 
Pulmonary embolism 
[55] 
Device deployment issue (Lead) 
[7] 
Device deployment issue (Total) 
[7, 15] 
Device deployment issue (RV-Lead) 
[15] 
Implant site thrombosis 
[4, 14, 26] 
Thrombosis (Total) 
[4, 14, 15, 26, 28, 58, 65] 
Pacemaker generated arrhythmia 
[7, 59] 
Pericarditis 
[23, 55] 
Haemothorax 
[4, 8, 24, 62, 63, 70, 76] 
Device battery issue 
[4, 30] 
Embolism venous 
[24, 29, 55] 
Frequency 
Event Type
Reference ID
Chest pain
[14]
Circulatory collapse
[35, 49, 55] 
Cardiac arrest
[62]
Cardiac vein dissection
[4, 6, 35]
Subclavian artery perforation 
[59]
Vascular injury (Total) 
[4, 6, 35, 57, 59]
Embolism (Total) 
[24, 29, 36, 38, 55, 60]
Implant site cellulitis
[10]
Sepsis
[55, 64]
Device deployment issue (Total)
[7, 15]
Device deployment issue (RV-Lead) 
[15] 
Implant site thrombosis 
[4, 14, 26]
Thrombosis (Total) 
[4, 14, 15, 26, 28, 58, 65] 
Pacemaker generated arrhythmia 
[7, 59]
Pericarditis 
[23, 55]
Haemothorax 
[4, 8, 24, 62, 63, 70, 76]
Device battery issue 
[4, 30]
Embolism venous
[24, 29, 55] 
Cerebrovascular accident
[10, 28, 55] 
Device connection issue
[4, 6, 7, 15, 17, 28, 32, 42, 51]
Neurological symptom 
[57]
Arrhythmia (Total)
[7, 14, 30, 58, 59, 62]
Pulmonary embolism 
[55]
Device deployment issue (Lead) 
[7] 

BIOTRONIK SE & Co.KG // BIO|Sync-HUTT 
 
BA117_CIP_2-0 | Version 2-0| 20-Apr-2022 | Page 49/61 
FOR-137-014-H / SOP-137-020.020 / CRQ200005199 
Frequency 
Event Type 
Reference ID 
Atrial tachycardia 
[14] 
Bacteraemia 
[14] 
Complication of device insertion (RV 
Lead) 
[7] 
Device electrical impedance issue (LV-
Lead) 
[7] 
Device programming error 
[7] 
Myocardial infarction 
[28, 55] 
Ventricular fibrillation 
[62] 
Hot flush (during an MRI procedure) 
[74] 
Implant site pain (during an MRI 
procedure) 
[74] 
Implant site warmth (during an MRI 
procedure) 
[74] 
Arrhythmia 
(Total, 
during 
an 
MRI 
procedure) 
[78] 
Atrial 
arrhythmia 
(during 
an 
MRI 
procedure) 
[78] 
Improbable 
¾½ 10%) 
Twiddler's syndrome 
[17, 28, 68, 77] 
Implant site dehiscence 
[51, 55] 
Not known 
Frequency 
not 
assessable based on 
the available data 
Arteriovenous fistula 
[8] 
Embolism atrial 
[55] 
Undersensing (RV) 
[43, 69] 
Ventricular arrhythmia (during an MRI 
procedure) 
[78] 
 
1 
Schwarzer G. General Package for Meta-Analysis: Brief overview of methods and general hints 
2020. 
2 
Schwarzer G, Carpenter JR, Rücker G. Meta-Analysis with R: Springer International Publishing 
2015. 
3 
Adeoye PO, Okonta KE, Salami MA, et al. Experience with permanent pacemaker insertion at the 
University College Hospital, Ibadan, Nigeria. Nig J Cardiol 2013;10(1):3. 
4 
Barra S, Providência R, Boveda S, et al. Device complications with addition of defibrillation to 
cardiac 
resynchronisation 
therapy 
for 
primary 
prevention. 
Heart 
2018;104(18):1529±35. 
doi:10.1136/heartjnl-2017-312546 [published Online First: 14 March 2018]. 
5 
Biffi M, Exner DV, Crossley GH, et al. Occurrence of phrenic nerve stimulation in cardiac 
resynchronization therapy patients: The role of left ventricular lead type and placement site. 
Europace 2013;15(1):77±82. doi:10.1093/europace/eus237 [published Online First: 29 July 2012]. 
Frequency 
Event Type
Reference ID
Atrial tachycardia
[14]
Bacteraemia 
[14]
Complication of device insertion (RV
Lead) 
[7]
Device electrical impedance issue (LV-
Lead) 
[7]
Device programming error 
[7]
Myocardial infarction
[28, 55]
Ventricular fibrillation
[62]
Hot flush (during an MRI procedure)
[74]
l
(d
[
]
Not known
Frequency 
not
assessable based on
the available data
Embolism atrial 
[55]
Undersensing (RV)
[43, 69]
Ventricular arrhythmia (during an MRI
procedure)
[78]
1 
Schwarzer G. General Package for Meta-Analysis: Brief overview of methods and general hints
2020.
2 
Schwarzer G, Carpenter JR, Rücker G. Meta-Analysis with R: Springer International Publishing
2015.
3 
Adeoye PO, Okonta KE, Salami MA, et al. Experience with permanent pacemaker insertion at the
University College Hospital, Ibadan, Nigeria. Nig J Cardiol 2013;10(1):3.
l
4 
Barra S, Providência R, Boveda S, et al. Device complications with addition of defibrillation to
cardiac 
resynchronisation 
therapy 
for 
primary 
prevention. 
Heart 
2018;104(18):1529
t
±35.
doi:10.1136/heartjnl-2017-312546 [published Online First: 14 March 2018].
5 
Biffi M, Exner DV, Crossley GH, et al. Occurrence of phrenic nerve
stimulation in cardiac
resynchronization therapy patients: The role of left ventricular lead type and placement site.
Europace 2013;15(1):77±82. doi:10.1093/europace/eus237 [published Online First: 29 July 2012]. 
Implant site
pain (during an MRI 
procedure)
[74]
Implant site warmth (during an MRI 
procedure)
[74]
Arrhythmia 
(Total, 
during 
an 
MRI 
procedure)
[78]
Atrial 
arrhythmia 
(during
an 
MRI
procedure)
[78]
Improbable 
¾½ 10%)
Twiddler's syndrome 
[17, 28, 68, 77] 
Implant site dehiscence
[51, 55] 
Arteriovenous fistula
[8]

BIOTRONIK SE & Co.KG // BIO|Sync-HUTT 
 
BA117_CIP_2-0 | Version 2-0| 20-Apr-2022 | Page 50/61 
FOR-137-014-H / SOP-137-020.020 / CRQ200005199 
6 
Ritter P, Delnoy PPHM, Padeletti L, et al. A randomized pilot study of optimization of cardiac 
resynchronization therapy in sinus rhythm patients using a peak endocardial acceleration sensor vs. 
standard methods. Europace 2012;14(9):1324±33. doi:10.1093/europace/eus059 [published 
Online First: 1 May 2012]. 
7 
Udo EO, Zuithoff NPA, van Hemel NM, et al. Incidence and predictors of short- and long-term 
complications in pacemaker therapy: The FOLLOWPACE study. Heart Rhythm 2012;9(5):728±35. 
doi:10.1016/j.hrthm.2011.12.014 [published Online First: 17 December 2011]. 
8 
Dong-ming X, Jia-he X, Yi-hong Y. Analysis of the complications in 296 patients with permanent 
pacemaker implantation. Heart 2012;98(Suppl 2):E220.2-E221. 
9 
Budano C, Garrone P, Castagno D, et al. Same-day CIED implantation and discharge: Is it possible? 
The E-MOTION trial (Early MObilization after pacemaker implantaTION). International Journal of 
Cardiology 2019;288:82±86. doi:10.1016/j.ijcard.2019.04.020 [published Online First: 8 April 
2019]. 
10 
Carrión-Camacho MR, Marín-León I, Molina-Doñoro JM, et al. Safety of Permanent Pacemaker 
Implantation: A Prospective Study. J Clin Med 2019;8(1). doi:10.3390/jcm8010035 [published 
Online First: 1 January 2019]. 
11 
Elmouchi DA, Rosema S, Vanoosterhout SM, et al. Cardiac perforation and lead dislodgement after 
implantation of a MR-conditional pacing lead: A single-center experience. Pacing Clin Electrophysiol 
2014;37(1):4±10. doi:10.1111/pace.12293 [published Online First: 11 November 2013]. 
12 
Falase B, Sanusi M, Johnson A, et al. Analysis of a five year experience of permanent pacemaker 
implantation at a Nigerian Teaching Hospital: Need for a national database. Pan Afr Med J 
2013;16:16. doi:10.11604/pamj.2013.16.16.2644 [published Online First: 15 September 2013]. 
13 
Leong KMW, Pollard C, Cooke CJ. Cardiology registrars and permanent pacemaker complication 
rates in a district general hospital--safety and service implications. Clin Med (Lond) 2014;14(1):34±
37. 
14 
Osman F, Krishnamoorthy S, Nadir A, et al. Safety and cost-effectiveness of same day permanent 
pacemaker implantation. The American Journal of Cardiology 2010;106(3):383±85. 
15 
Pakarinen S, Oikarinen L, Toivonen L. Short-term implantation-related complications of cardiac 
rhythm management device therapy: A retrospective single-centre 1-year survey. Europace 
2010;12(1):103±08. 
16 
Witt CM, Lenz CJ, Shih HH, et al. Right ventricular pacemaker lead position is associated with 
differences in long-term outcomes and complications. Journal of Cardiovascular Electrophysiology 
2017;28(8):924±30. doi:10.1111/jce.13256 [published Online First: 21 June 2017]. 
17 
Wollmann CG, Thudt K, Vock P, et al. Clinical routine implantation of a dual chamber pacemaker 
system designed for safe use with MRI: A single center, retrospective study on lead performance of 
Medtronic 
lead 
5086MRI 
in 
comparison 
to 
Medtronic 
leads 
4592-53 
and 
4092-58. 
Herzschrittmacherther Elektrophysiol 2011;22(4):233-6, 239-42. 
18 
Biffi M, Bertini M, Ziacchi M, et al. Left ventricular lead stabilization to retain cardiac 
resynchronization therapy at long term: When is it advisable? Europace 2014;16(4):533±40. 
doi:10.1093/europace/eut300 [published Online First: 26 September 2013]. 
19 
Leclercq C, Padeletti L, Cihák R, et al. Incidence of paroxysmal atrial tachycardias in patients 
treated with cardiac resynchronization therapy and continuously monitored by device diagnostics. 
Europace 2010;12(1):71±77. 
20 
Thirunavukarasu S, Chadaide S, Balachandran K. 35 Appropriate patient selection for CRT 
pacemaker implantation results in improved left ventricular function beyond nice recommended ICD 
criteria. In: Heart Failure: BMJ Publishing Group Ltd and British Cardiovascular Society 2018:A33.1-
A33. 
21 
Ziacchi M, Giannola G, Lunati M, et al. Bipolar active fixation left ventricular lead or quadripolar 
passive fixation lead? An Italian multicenter experience. J Cardiovasc Med (Hagerstown) 
2019;20(4):192±200. 
22 
Hao Y, Li Y, Liao D, et al. A comparative analysis of the effectiveness of active versus passive atrial 
lead fixation in Chinese patients with cardiac implantable electrical devices: A long term, 
retrospective, observational, single-center study. Curr Med Res Opin 2017;33(3):573±78. 
doi:10.1080/03007995.2016.1275938 [published Online First: 17 January 2017]. 
6 
Ritter P, Delnoy PPHM, Padeletti L, et al. A randomized pilot study of optimization of cardiac
resynchronization therapy in sinus rhythm patients using a peak endocardial acceleration sensor vs.
standard methods.
Europace
2012;14(9):1324±33. doi:10.1093/europace/eus059 [published
Online First: 1 May 2012]. 
7 
Udo EO, Zuithoff NPA, van Hemel NM, et al. Incidence and predictors of sh
f
ort- and long-term
complications in pacemaker therapy: The FOLLOWPACE study. Heart Rhythm 2012;9(5):728±35.
doi:10.1016/j.hrthm.2011.12.014 [published Online First: 17 December 2011].
8 
Dong-ming X, Jia-he X, Yi-hong Y. Analysis of the complications in 296 patients with permanent
pacemaker implantation. Heart 2012;98(Suppl 2):E220.2-E221. 
t
9 
Budano C, Garrone P, Castagno D, et al. Same-day CIED implantation and discharge: Is it possible?
The E-MOTION trial (Early MObilization after pacemaker implantaTION). 
f
Int
I
ernational Journal of
t
Cardiology 2019;288:82
y
±86. doi:10.1016/j.ijcard.2019.04.020 [published Online First: 8 April
2019].
10
Carrión-Camacho MR, Marín-León I, Molina-Doñoro JM, et al. Safety of Permanent Pacemaker
Implantation: A Prospective Study. J Clin Med 2019;8(1). doi:10.3390/jcm8010035 [published
d
Online First: 1 January 2019].
11
Elmouchi DA, Rosema S, Vanoosterhout SM, et al. Cardiac perforation and lead dislodgement after
implantation of a MR-conditional pacing lead: A single-center experience. Pac
P
ing Clin Electrophysiol
r
J
n
±
t
c
e
h
y
r
f
Medtronic 
lead 
5086MRI 
in
comparison 
to 
Medtronic 
leads 
4592-53 
and 
4092-58.
Herzschrittmacherther Elektrophysiol 2011;22(4):233-6, 239-42.
18 
Biffi M, Bertini M, Ziacchi M, et al. Left ventricular lead
stabilization to retain cardiac
resynchronization therapy at long term: When is it advisable? Europace 2014;16(4):533±40.
doi:10.1093/europace/eut300 [published Online First: 26 September 2013].
19 
Leclercq C, Padeletti L, Cihák R, et al. Incidence of paroxysmal atrial tachycardias in patients
treated with cardiac resynchronization therapy and continuously monitored by device diagnostics.
Europace 2010;12(1):71±77.
20 
Thirunavukarasu S, Chadaide S, Balachandran K. 35 Appropriate patient selection for CRT
pacemaker implantation results in improved left ventricular function beyond nice recommended ICD
criteria. In: Heart Failure: BMJ Publishing Group Ltd and British Cardiovascular Society 2018:A33.1-
A33. 
21
Ziacchi M, Giannola G, Lunati M, et al. Bipolar active fixation left ventricular lead or quadripolar
passive fixation lead? An Italian multicenter experience.
J Cardiovasc Med (Hagerstown)
v
2019;20(4):192±200. 
22 
Hao Y, Li Y, Liao D, et al. A comparative analysis of the effectiveness of active versus passive atrial
lead fixation in Chinese patients with cardiac implantable electrical devices: A long term,
retrospective, observational, single-center study. Curr Med Res Opin 2017;33(3):573±78.
doi:10.1080/03007995.2016.1275938 [published Online First: 17 January 2017]. 
2014;37(1):4±10. doi:10.1111/pace.12293 [published Online First: 11 November 2013]. 
12
Falase B, Sanusi M, Johnson A, et al. Analysis of a five year experience of permanent pacemaker
implantation at a Nigerian Teaching Hospital: Need for a national database. Pan Afr Med J
2013;16:16. doi:10.11604/pamj.2013.16.16.2644 [published Online First: 15 September 2013]. 
13
Leong KMW, Pollard C, Cooke CJ. Cardiology registrars and permanent pacemaker complication
rates in a district general hospital--safety and service implications. Clin Med (Lond) 2014;14(1):34±
37.
14
Osman F, Krishnamoorthy S, Nadir A, et al. Safety and cost-effectiveness of same day permanent
pacemaker implantation. The American Journal of Cardiology 2010;106(3):383
y
±85.
15
Pakarinen S, Oikarinen L, Toivonen L. Short-term implantation-related complications of cardiac
rhythm management device therapy: A retrospective single-centre 1-year survey.
Europace
2010;12(1):103±08. 
16
Witt CM, Lenz CJ, Shih HH, et al. Right ventricular pacemaker lead position is associated with
differences in long-term outcomes and complications. Journal of Cardiovascular Electrophysiology
2017;28(8):924±30. doi:10.1111/jce.13256 [published Online First: 21 June 2017]. 
17
Wollmann CG, Thudt K, Vock P, et al. Clinical routine implantation of a dual chamber pacemaker
system designed for safe use with MRI: A single center, retrospective study on lead performance of
Medtronic
lead
5086MRI
in
comparison
to
Medtronic
leads
4592-53
and
4092-58.

BIOTRONIK SE & Co.KG // BIO|Sync-HUTT 
 
BA117_CIP_2-0 | Version 2-0| 20-Apr-2022 | Page 51/61 
FOR-137-014-H / SOP-137-020.020 / CRQ200005199 
23 
Witt CM, Lenz CJ, Shih HH, et al. Right atrial lead fixation type and lead position are associated with 
significant 
variation 
in 
complications. 
J 
Interv 
Card 
Electrophysiol 
2016;47(3):313±19. 
doi:10.1007/s10840-016-0181-y [published Online First: 9 September 2016]. 
24 
Cantillon DJ, Exner DV, Badie N, et al. Complications and Health Care Costs Associated With 
Transvenous Cardiac Pacemakers in a Nationwide Assessment. JACC Clin Electrophysiol 
2017;3(11):1296±305. doi:10.1016/j.jacep.2017.05.007 [published Online First: 30 August 2017]. 
25 
Cantillon DJ, Dukkipati SR, Ip JH, et al. Comparative study of acute and mid-term complications 
with leadless and transvenous cardiac pacemakers. Heart Rhythm 2018;15(7):1023±30. 
26 
Gadler F, Valzania C, Linde C. Current use of implantable electrical devices in Sweden: Data from 
the 
Swedish 
pacemaker 
and 
implantable 
cardioverter-defibrillator 
registry. 
Europace 
2015;17(1):69±77. doi:10.1093/europace/euu233 [published Online First: 21 October 2014]. 
27 
Haug B, Kjelsberg K, Lappegård KT. Pacemaker implantation in small hospitals: Complication rates 
comparable to larger centres. Europace 2011;13(11):1580±86. doi:10.1093/europace/eur162 
[published Online First: 28 June 2011]. 
28 
Kirkfeldt RE, Johansen JB, Nohr EA, et al. Complications after cardiac implantable electronic device 
implantations: An analysis of a complete, nationwide cohort in Denmark. European Heart Journal 
2014;35(18):1186±94. 
29 
Moore K, Ganesan A, Labrosciano C, et al. Sex Differences in Acute Complications of Cardiac 
Implantable 
Electronic 
Devices: 
Implications 
for 
Patient 
Safety. 
J 
Am 
Heart 
Assoc 
2019;8(2):e010869. 
30 
2SLü 3 YDQ .UDQHQEXUJ 0 <ap S-C, et al. Complications of pacemaker therapy in adults with 
congenital 
heart 
disease: 
A 
multicenter 
study. 
International 
Journal 
of 
Cardiology 
2013;168(4):3212±16. doi:10.1016/j.ijcard.2013.04.114 [published Online First: 3 May 2013]. 
31 
Ozcan KS, Osmonov D, Altay S, et al. Pacemaker implantation complication rates in elderly and 
young patients. Clin Interv Aging 2013;8:1051±54. doi:10.2147/CIA.S47121 [published Online 
First: 7 August 2013]. 
32 
Kirkfeldt RE, Johansen JB, Nohr EA, et al. Risk factors for lead complications in cardiac pacing: A 
population-based cohort study of 28,860 Danish patients. Heart Rhythm 2011;8(10):1622±28. 
doi:10.1016/j.hrthm.2011.04.014 [published Online First: 14 April 2011]. 
33 
%LV-*RĞFLĔVNa-BLV.*RáED.6HWDO3HUPDQHQWpacemaker implantation after cardiac surgery: 
Optimization 
of 
the 
decision 
making 
process. 
J 
Thorac 
Cardiovasc 
Surg 
2020. 
doi:10.1016/j.jtcvs.2020.01.082 [published Online First: 19 February 2020]. 
34 
Jama A, Rabinstein A, Hodge D, et al. Cardiac device complications in the cognitively impaired. 
Pacing Clin Electrophysiol 2013;36(9):1061±67. doi:10.1111/pace.12205 [published Online First: 3 
July 2013]. 
35 
Larsen PD, Kerr AJ, Hood M, et al. Pacemaker Use in New Zealand - Data From the New Zealand 
Implanted Cardiac Device Registry (ANZACS-QI 15). Heart Lung Circ 2017;26(3):235±39. 
doi:10.1016/j.hlc.2016.06.1206 [published Online First: 19 July 2016]. 
36 
Airaksinen KEJ, Korkeila P, Lund J, et al. Safety of pacemaker and implantable cardioverter-
defibrillator implantation during uninterrupted warfarin treatment--the FinPAC study. International 
Journal of Cardiology 2013;168(4):3679±82. doi:10.1016/j.ijcard.2013.06.022 [published Online 
First: 9 July 2013]. 
37 
Chen H-C, Chen Y-L, Guo B-F, et al. Thrombocytopenia, dual antiplatelet therapy, and heparin 
bridging strategy increase pocket hematoma complications in patients undergoing cardiac rhythm 
device implantation. Can J Cardiol 2013;29(9):1110±17. doi:10.1016/j.cjca.2012.12.014 [published 
Online First: 6 March 2013]. 
38 
Kosiuk J, Koutalas E, Doering M, et al. Comparison of Dabigatran and Uninterrupted Warfarin in 
Patients With Atrial Fibrillation Undergoing Cardiac Rhythm Device Implantations. Circ J 
2014;78(10):2402±07. 
39 
Nichols CI, Vose JG. Incidence of Bleeding-Related Complications During Primary Implantation and 
Replacement of Cardiac Implantable Electronic Devices. J Am Heart Assoc 2017;6(1). 
doi:10.1161/JAHA.116.004263 [published Online First: 22 January 2017]. 
40 
Said SM, Esperer HD, Hahn J, et al. Influence of oral antiplatelet therapy on hemorrhagic 
complications 
of 
pacemaker 
implantation. 
Clin 
Res 
Cardiol 
2013;102(5):345±49. 
doi:10.1007/s00392-013-0543-8 [published Online First: 6 February 2013]. 
23 
Witt CM, Lenz CJ, Shih HH, et al. Right atrial lead fixation type and lead position are associated with 
significant 
variation 
in 
complications. 
J 
Interv 
Card 
Electrophysiol 
2016;47(3):313
l
±19. 
doi:10.1007/s10840-016-0181-y [published Online First: 9 September 2016]. 
24 
Cantillon DJ, Exner DV, Badie N, et al. Complications and Health Care Costs Associated With 
Transvenous Cardiac Pacemakers in a Nationwide Assessment. JACC Clin Electrophysiol
2017;3(11):1296±305. doi:10.1016/j.jacep.2017.05.007 [published Online First: 30 August 2017].
25
Cantillon DJ, Dukkipati SR, Ip JH, et al. Comparative study of acute and mid-term complications 
with leadless and transvenous cardiac pacemakers. Heart Rhythm 2018;15(7):1023±30. 
26
Gadler F, Valzania C, Linde C. Current use of implantable electrical devices in Sweden: Data from 
the 
Swedish 
pacemaker 
and 
implantable 
cardioverter-defibrillator 
registry. 
Europace
2015;17(1):69±77. doi:10.1093/europace/euu233 [published Online First: 21 October 2014].
27
Haug B, Kjelsberg K, Lappegård KT. Pacemaker implantation in small hospitals: Complication rates
comparable to larger centres. Europace
2011;13(11):1580±86. doi:10.1093/europace/eur162 
[published Online First: 28 June 2011]. 
28
Kirkfeldt RE, Johansen JB, Nohr EA, et al. Complications after cardiac implantable electronic device 
implantations: An analysis of a complete, nationwide cohort in Denmark. European Heart Journal
2014;35(18):1186±94.
29
Moore K, Ganesan A, Labrosciano C, et al. Sex Differences in Acute Complications of Cardiac 
Implantable 
Electronic 
Devices: 
Implications 
for 
Patient 
Safety. 
J 
Am 
Heart 
Assoc
Implanted Cardiac Device Registry (ANZACS-QI 15). Heart Lung Circ 2017;26(3):235
c
±39.
doi:10.1016/j.hlc.2016.06.1206 [published Online First: 19 July 2016]. 
36 
Airaksinen KEJ, Korkeila P, Lund J, et al. Safety of pacemaker and implantable cardioverter-
defibrillator implantation during uninterrupted warfarin treatment--the FinPAC study. International 
Journal of Cardiology 2013;168(4):3679
y
±82. doi:10.1016/j.ijcard.2013.06.022 [published Online 
First: 9 July 2013].
37
Chen H-C, Chen Y-L, Guo B-F, et al. Thrombocytopenia, dual antiplatelet therapy, and heparin
bridging strategy increase pocket hematoma complications in patients undergoing cardiac rhythm
device implantation. Can J Cardiol 2013;29(9):1110
l
±17. doi:10.1016/j.cjca.2012.12.014 [published
Online First: 6 March 2013].
38
Kosiuk J, Koutalas E, Doering M, et al. Comparison of Dabigatran and Uninterrupted Warfarin in 
Patients With Atrial Fibrillation Undergoing Cardiac Rhythm Device Implantations. Cir
C c J
r
2014;78(10):2402±07.
39
Nichols CI, Vose JG. Incidence of Bleeding-Related Complications During Primary Implantation and 
Replacement of Cardiac Implantable Electronic Devices. J Am Heart Assoc
2017;6(1).
doi:10.1161/JAHA.116.004263 [published Online First: 22 January 2017]. 
40
Said SM, Esperer HD, Hahn J, et al. Influence of oral antiplatelet therapy on hemorrhagic 
complications 
of 
pacemaker 
implantation.
Clin 
Res 
Cardiol 
2013;102(5):345
l
±49.
doi:10.1007/s00392-013-0543-8 [published Online First: 6 February 2013]. 
2019;8(2):e010869.
30
2SLü 3 YDQ .UDQHQEXUJ 0 <ap S-C, et al. Complications of pacemaker therapy in adults with 
congenital 
heart 
disease: 
A 
multicenter 
study.
International 
Journal 
of 
Cardiology
2013;168(4):3212±16. doi:10.1016/j.ijcard.2013.04.114 [published Online First: 3 May 2013].
31 
Ozcan KS, Osmonov D, Altay S, et al. Pacemaker implantation complication rates in elderly and 
young patients. Clin Interv Aging 2013;8:1051±54. doi:10.2147/CIA.S47121 [published Online 
First: 7 August 2013].
32 
Kirkfeldt RE, Johansen JB, Nohr EA, et al. Risk factors for lead complications in cardiac pacing: A 
population-based cohort study of 28,860 Danish patients. Heart Rhythm 2011;8(10):1622±28.
doi:10.1016/j.hrthm.2011.04.014 [published Online First: 14 April 2011]. 
33
%LV-*RĞFLĔVNa-BLV.*RáED.6HWDO3HUPDQHQWpacemaker implantation after cardiac surgery:
Optimization 
of 
the 
decision 
making
process.
J 
Thorac 
Cardiovasc 
Surg
2020. 
doi:10.1016/j.jtcvs.2020.01.082 [published Online First: 19 February 2020]. 
34 
Jama A, Rabinstein A, Hodge D, et al. Cardiac device complications in the cognitively impaired. 
Pacing Clin Electrophysiol 2013;36(9):1061±67. doi:10.1111/pace.12205 [published Online First: 3 
July 2013]. 
35
Larsen PD, Kerr AJ, Hood M, et al. Pacemaker Use in New Zealand - Data From the New Zealand 

BIOTRONIK SE & Co.KG // BIO|Sync-HUTT 
 
BA117_CIP_2-0 | Version 2-0| 20-Apr-2022 | Page 52/61 
FOR-137-014-H / SOP-137-020.020 / CRQ200005199 
41 
Soleimani Rahbar A, Hsu JC, Han FT, et al. Trainee inexperience is associated with longer procedure 
times but no increase in complications for cardiac device implantation. Heart Rhythm 
2013;10(12):1755±58. doi:10.1016/j.hrthm.2013.09.003 [published Online First: 6 September 
2013]. 
42 
Reinhart Dorman HG, van Opstal JM, Stevenhagen J, et al. High failure rate of the 5 French Sorin 
Hepta 4B pacemaker lead. Europace 2014;16(1):88±91. doi:10.1093/europace/eut245 [published 
Online First: 2 August 2013]. 
43 
JastrzĊbski M, Moskal P, Bednarek A, et al. His-bundle pacing as a standard approach in patients 
with permanent atrial fibrillation and bradycardia. Pacing Clin Electrophysiol 2018;41(11):1508±12. 
doi:10.1111/pace.13490 [published Online First: 19 September 2018]. 
44 
Wilkoff BL, Bello D, Taborsky M, et al. Magnetic resonance imaging in patients with a pacemaker 
system designed for the magnetic resonance environment. Heart Rhythm 2011;8(1):65±73. 
doi:10.1016/j.hrthm.2010.10.002 [published Online First: 7 October 2010]. 
45 
Lone NA, Naiku BA, u Din KM. Decade of permanent cardiac pacing in a tertiary care hospital of 
Northern India. Int. J. Med. Med. Sci. 2016;8(12):140±44. 
46 
Schuchert A, Muto C, Maounis T, et al. Lead complications, device infections, and clinical outcomes 
in the first year after implantation of cardiac resynchronization therapy-defibrillator and cardiac 
resynchronization therapy-pacemaker. EP Europace 2013;15(1):71±76. 
47 
Zhu DWX, Chu MM, Zager AJ, et al. Inappropriate noise detection in Tendril family pacing leads. 
Journal 
of 
Cardiovascular 
Electrophysiology 
2019;30(11):2484±91. 
doi:10.1111/jce.14194 
[published Online First: 25 September 2019]. 
48 
Patel AM, Verma D, Jiang S-F, et al. Permanent Pacemaker Implantation Early After Cardiac 
Surgery: A Descriptive Study of Pacemaker Utility After One Year of Follow-Up. J Card Surg 
2016;31(3):132±38. doi:10.1111/jocs.12680 [published Online First: 12 January 2016]. 
49 
Squara F, Tomi J, Scarlatti D, et al. Self-taught axillary vein access without venography for 
pacemaker implantation: Prospective randomized comparison with the cephalic vein access. 
Europace 2017;19(12):2001±06. 
50 
Ann HW, Ahn JY, Jeon YD, et al. Incidence of and risk factors for infectious complications in patients 
with cardiac device implantation. International Journal of Infectious Diseases 2015;36:9±14. 
51 
Choi JH, Kim J, Jo U, et al. Abstract 17155: Complications with Cardiac Perforation and Lead 
Dislodgement of the 5086 MRI Pacing Lead. Circulation 2014;130(suppl_2):A17155-A17155. 
https://doi.org/10.1161/circ.130.suppl_2.17155. 
52 
Chow V, Ranasinghe I, Lau J, et al. Peri-procedural anticoagulation and the incidence of haematoma 
formation 
after 
permanent 
pacemaker 
implantation 
in 
the 
elderly. 
Heart 
Lung 
Circ 
2010;19(12):706±12. doi:10.1016/j.hlc.2010.08.011 [published Online First: 18 September 2010]. 
53 
Datta G. Effect of pacemaker pocket toileting by antibiotic solution on pocket infection rate. 
Pakistan Heart Journal 2019;52(04):333±37. 
54 
Fanourgiakis J, Simantirakis E, Maniadakis N, et al. Complications Related to Cardiac Rhythm 
Management Device Therapy and Their Financial Implication: A Prospective Single-Center TwoYear 
Survey. Hellenic J Cardiol 2016;57(1):33±38. 
55 
Gillam MH, Pratt NL, Inacio MCS, et al. Rehospitalizations for complications and mortality following 
pacemaker implantation: A retrospective cohort study in an older population. Clin Cardiol 
2018;41(11):1480±86. doi:10.1002/clc.23091 [published Online First: 19 October 2018]. 
56 
Hayward RM, Dewland TA, Moyers B, et al. Device complications in adult congenital heart disease. 
Heart Rhythm 2015;12(2):338±44. doi:10.1016/j.hrthm.2014.10.038 [published Online First: 31 
October 2014]. 
57 
Hosseini SM, Moazzami K, Rozen G, et al. Utilization and in-hospital complications of cardiac 
resynchronization therapy: Trends in the United States from 2003 to 2013. European Heart Journal 
2017;38(27):2122±28. 
58 
Khanal J, Poudyal RR, Devkota S, et al. Clinical Profile and Early Complications after Single and Dual 
Chamber Permanent Pacemaker Implantation at Manmohan Cardiothoracic Vascular and Transplant 
Centre, Kathmandu, Nepal. J Nepal Health Res Counc 2015;13(30):138±43. 
59 
Liu X, Wei Q, Li Y, et al. Analysis of clinical efficacy and factors affecting complications of permanent 
pacemaker 
implantation. 
International 
Journal 
of 
Clinical 
and 
Experimental 
Medicine 
2019;12(2):1972±78. 
41 
Soleimani Rahbar A, Hsu JC, Han FT, et al. Trainee inexperience is associated with longer procedure 
times but no increase in complications for cardiac device implantation.
Heart Rhythm
2013;10(12):1755±58. doi:10.1016/j.hrthm.2013.09.003 [published Online First: 6 September 
2013].
42 
Reinhart Dorman HG, van Opstal JM, Stevenhagen J, et al. High failure rate of the 5 French Sorin 
Hepta 4B pacemaker lead. Europace 2014;16(1):88±91. doi:10.1093/europace/eut245 [published
Online First: 2 August 2013]. 
43 
JastrzĊbski M, Moskal P, Bednarek A, et al. His-bundle pacing as a standard approach in patients
with permanent atrial fibrillation and bradycardia. Pacing Clin Electrophysiol 2018;41(11):1508±12.
doi:10.1111/pace.13490 [published Online First: 19 September 2018].
44
Wilkoff BL, Bello D, Taborsky M, et al. Magnetic resonance imaging in patients with a pacemaker 
system designed for the magnetic resonance environment. Heart Rhythm
2011;8(1):65±73.
doi:10.1016/j.hrthm.2010.10.002 [published Online First: 7 October 2010].
45
Lone NA, Naiku BA, u Din KM. Decade of permanent cardiac pacing in a tertiary care hospital of 
Northern India. Int. J. Med. Med. Sci. 2016;8(12):140±44.
46
Schuchert A, Muto C, Maounis T, et al. Lead complications, device infections, and clinical outcomes
in the first year after implantation of cardiac resynchronization therapy-defibrillator and cardiac 
resynchronization therapy-pacemaker. EP Europace 2013;15(1):71±76.
47
Zhu DWX
Chu MM
Zager AJ
et al
Inappropriate noise detection in Tendril family pacing leads
Pakistan Heart Journal 2019;52(04):333
l
±37.
54
Fanourgiakis J, Simantirakis E, Maniadakis N, et al. Complications Related to Cardiac Rhythm 
Management Device Therapy and Their Financial Implication: A Prospective Single-Center TwoYear 
Survey. Hellenic J Cardiol 2016;57(1):33
l
±38.
55
Gillam MH, Pratt NL, Inacio MCS, et al. Rehospitalizations for complications and mortality following 
pacemaker implantation: A retrospective cohort study in an older population.
Clin Cardiol
2018;41(11):1480±86. doi:10.1002/clc.23091 [published Online First: 19 October 2018]. 
56
Hayward RM, Dewland TA, Moyers B, et al. Device complications in adult congenital heart disease.
Heart Rhythm 2015;12(2):338±44. doi:10.1016/j.hrthm.2014.10.038 [published Online First: 31
October 2014]. 
57
Hosseini SM, Moazzami K, Rozen G, et al. Utilization and in-hospital complications of cardiac
resynchronization therapy: Trends in the United States from 2003 to 2013. European Heart Journal
2017;38(27):2122±28.
58
Khanal J, Poudyal RR, Devkota S, et al. Clinical Profile and Early Complications after Single and Dual 
Chamber Permanent Pacemaker Implantation at Manmohan Cardiothoracic Vascular and Transplant 
Centre, Kathmandu, Nepal. J Nepal Health Res Counc 2015;13(30):138
c
±43.
59
Liu X, Wei Q, Li Y, et al. Analysis of clinical efficacy and factors affecting complications of permanent
pacemaker 
implantation.
International 
Journal 
of 
Clinical 
and 
Experimental 
Medicine
2019;12(2):1972±78.
47
Zhu DWX, Chu MM, Zager AJ, et al. Inappropriate noise detection in Tendril family pacing leads. 
Journal 
of 
Cardiovascular 
Electrophysiology
2019;30(11):2484
y
±91. 
doi:10.1111/jce.14194
[published Online First: 25 September 2019]. 
48 
Patel AM, Verma D, Jiang S-F, et al. Permanent Pacemaker Implantation Early After Cardiac
Surgery: A Descriptive Study of Pacemaker Utility After One Year of Follow-Up. J Card Surg
2016;31(3):132±38. doi:10.1111/jocs.12680 [published Online First: 12 January 2016].
49 
Squara F, Tomi J, Scarlatti D, et al. Self-taught axillary vein access without venography for 
pacemaker implantation: Prospective randomized comparison with the cephalic vein access.
Europace 2017;19(12):2001±06.
50
Ann HW, Ahn JY, Jeon YD, et al. Incidence of and risk factors for infectious complications in patients
with cardiac device implantation. International Journal of Infectious Diseases 2015;36:9±14.
51 
Choi JH, Kim J, Jo U, et al. Abstract 17155: Complications with Cardiac Perforation and Lead 
Dislodgement of the 5086 MRI Pacing Lead. Circulation
2014;130(suppl_2):A17155-A17155.
https://doi.org/10.1161/circ.130.suppl_2.17155.
52
Chow V, Ranasinghe I, Lau J, et al. Peri-procedural anticoagulation and the incidence of haematoma 
formation 
after 
permanent 
pacemaker 
implantation 
in 
the 
elderly.
Heart 
Lung 
Circ
2010;19(12):706±12. doi:10.1016/j.hlc.2010.08.011 [published Online First: 18 September 2010]. 
53
Datta G. Effect of pacemaker pocket toileting by antibiotic solution on pocket infection rate.

BIOTRONIK SE & Co.KG // BIO|Sync-HUTT 
 
BA117_CIP_2-0 | Version 2-0| 20-Apr-2022 | Page 53/61 
FOR-137-014-H / SOP-137-020.020 / CRQ200005199 
60 
Malagù M, Trevisan ) 6FDORQH $ HW DO )UHTXHQF\ RI ³3RFNHW´ +HPDWRPD LQ 3DWLHQWV 5HFHLYLQJ
Vitamin K Antagonist and Antiplatelet Therapy at the Time of Pacemaker or Cardioverter 
Defibrillator Implantation (from the POCKET Study). The American Journal of Cardiology 
2017;119(7):1036±40. 
61 
Matsuda Y, Masuda M, Asai M, et al. Comparison of prognosis and safety of pacemaker implantation 
in patients aged less than or 85 years and older. J Interv Card Electrophysiol 2020. 
doi:10.1007/s10840-020-00797-9 [published Online First: 12 June 2020]. 
62 
Nowak B, Misselwitz B, Erdogan A, et al. Do gender differences exist in pacemaker implantation?--
results of an obligatory external quality control program. Europace 2010;12(2):210±15. 
doi:10.1093/europace/eup312 [published Online First: 28 October 2009]. 
63 
Nowak B, Tasche K, Barnewold L, et al. Association between hospital procedure volume and early 
complications after pacemaker implantation: Results from a large, unselected, contemporary cohort 
of the German nationwide obligatory external 
quality assurance programme. Europace 
2015;17(5):787±93. doi:10.1093/europace/euv003 [published Online First: 1 March 2015]. 
64 
Shakya S, Matsui H, Fushimi K, et al. In-hospital complications after implantation of cardiac 
implantable electronic devices: Analysis of a national inpatient database in Japan. J Cardiol 
2017;70(5):405±10. doi:10.1016/j.jjcc.2017.02.013 [published Online First: 20 April 2017]. 
65 
Vanegas-Cadavid DI, Ibatá-Bernal L, Franco-Garrido PA, et al. Complications related to cardiac 
implantable electronic devices. Revista Colombiana de Cardiología 2020;27(5):420±27. 
66 
Barra S, Duehmke R, Providencia R, et al. Patients upgraded to cardiac resynchronization therapy 
due to pacing-induced cardiomyopathy are at low risk of life-threatening ventricular arrhythmias: A 
long-term cause-of-death analysis. Europace 2018;20(1):89±96. 
67 
Lin Y-S, Hung S-P, Chen P-R, et al. Risk factors influencing complications of cardiac implantable 
electronic device implantation: Infection, pneumothorax and heart perforation: a nationwide 
population-based cohort study. Medicine 2014;93(27):e213. 
68 
Nakajima H, Nishii N. Infection and migration incidence of cardiac implantable electrical devices in 
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Alings M, Vireca E, Bastian D, et al. Clinical use of automatic pacemaker algorithms: Results of the 
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70 
Dai Y, Chen K-P, Hua W, et al. Dual antiplatelet therapy increases pocket hematoma complications 
in Chinese patients with pacemaker implantation. J Geriatr Cardiol 2015;12(4):383±87. 
71 
Kosiuk J, Koutalas E, Doering M, et al. Treatment with novel oral anticoagulants in a real-world 
cohort of patients undergoing cardiac rhythm device implantations. Europace 2014;16(7):1028±32. 
doi:10.1093/europace/eut423 [published Online First: 31 January 2014]. 
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g]FDQ .6 2VPRQRY ' <ÕOGÕUÕP ( HW DO +HPDWRPD FRPSOLFDWLQJ SHUPDQHQW SDFHPDNHU
implantation: The role of periprocedural antiplatelet or anticoagulant therapy. J Cardiol 
2013;62(2):127±30. doi:10.1016/j.jjcc.2013.03.002 [published Online First: 21 April 2013]. 
73 
Sridhar ARM, Yarlagadda V, Yeruva MR, et al. Impact of haematoma after pacemaker and CRT 
device implantation on hospitalization costs, length of stay, and mortality: A population-based 
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April 2015]. 
74 
Gimbel JR, Bello D, Schmitt M, et al. Randomized trial of pacemaker and lead system for safe 
scanning at 1.5 Tesla. Heart Rhythm 2013;10(5):685±91. doi:10.1016/j.hrthm.2013.01.022 
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75 
Piekarz J, Lelakowski J, Rydlewska A, et al. Heart perforation in patients with permanent cardiac 
pacing ± pilot personal observations. aoms 2012;1:70±74. 
76 
Sutton R, Ungar A, Sgobino P, et al. Cardiac pacing in patients with neurally mediated syncope and 
documented asystole: Effectiveness analysis from the Third International Study on Syncope of 
Uncertain 
Etiology 
(ISSUE-3) 
Registry. 
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77 
Osoro M, Lorson W, Hirsh JB, et al. Use of an antimicrobial pouch/envelope in the treatment of 
Twiddler's syndrome. Pacing Clin Electrophysiol 2018;41(2):136±42. doi:10.1111/pace.13259 
[published Online First: 16 January 2018]. 
60 
Malagù M, Trevisan ) 6FDORQH $ HW DO )UHTXHQF\ RI ³3RFNHW´ +HPDWRPD LQ 3DWLHQWV 5HFHLYLQJ
Vitamin K Antagonist and Antiplatelet Therapy at the Time of Pacemaker or Cardioverter 
Defibrillator Implantation (from the POCKET Study). The American Journal of Cardiology
2017;119(7):1036±40.
61
Matsuda Y, Masuda M, Asai M, et al. Comparison of prognosis and safety of pacemaker implantation
in patients aged less than or 85 years and older.
J Interv Card Electrophysiol
2020. 
doi:10.1007/s10840-020-00797-9 [published Online First: 12 June 2020].
62
Nowak B, Misselwitz B, Erdogan A, et al. Do gender differences exist in pacemaker implantation?--
results of an obligatory external quality control program. Europace 2010;12(2):210±15. 
doi:10.1093/europace/eup312 [published Online First: 28 October 2009].
63 
Nowak B, Tasche K, Barnewold L, et al. Association between hospital procedure volume and early
complications after pacemaker implantation: Results from a large, unselected, contemporary cohort
of the German nationwide obligatory external 
quality assurance programme.
Europace
2015;17(5):787±93. doi:10.1093/europace/euv003 [published Online First: 1 March 2015].
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Shakya S, Matsui H, Fushimi K, et al. In-hospital complications after implantation of cardiac
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implantable electronic devices: Analysis of a national inpatient database in Japan. J Cardiol
2017;70(5):405±10. doi:10.1016/j.jjcc.2017.02.013 [published Online First: 20 April 2017].
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Vanegas-Cadavid DI, Ibatá-Bernal L, Franco-Garrido PA, et al. Complications related to cardiac 
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l
t bl
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t
i
d
i
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i t
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d
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di l
í
2020 27(5) 420 27
72
g]FDQ .6 2VPRQRY ' <ÕOGÕUÕP ( HW DO +HPDWRPD FRPSOLFDWLQJ SHUPDQHQW SDFHPDNHU
implantation: The role of periprocedural antiplatelet or anticoagulant therapy. J Cardiol
2013;62(2):127±30. doi:10.1016/j.jjcc.2013.03.002 [published Online First: 21 April 2013].
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Sridhar ARM, Yarlagadda V, Yeruva MR, et al. Impact of haematoma after pacemaker and CRT 
device implantation on hospitalization costs, length of stay, and mortality: A population-based 
study. Europace 2015;17(10):1548±54. doi:10.1093/europace/euv075 [published Online First: 7 
April 2015]. 
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Gimbel JR, Bello D, Schmitt M, et al. Randomized trial of pacemaker and lead system for safe
scanning at 1.5 Tesla.
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2013;10(5):685±91. doi:10.1016/j.hrthm.2013.01.022
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Piekarz J, Lelakowski J, Rydlewska A, et al. Heart perforation in patients with permanent cardiac 
pacing ± pilot personal observations. aoms 2012;1:70±74.
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Sutton R, Ungar A, Sgobino P, et al. Cardiac pacing in patients with neurally mediated syncope and
documented asystole: Effectiveness analysis from the Third International Study on Syncope of 
Uncertain 
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(ISSUE-3) 
Registry. 
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2014;16(4):595±99. 
doi:10.1093/europace/eut323 [published Online First: 9 January 2014].
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Osoro M, Lorson W, Hirsh JB, et al. Use of an antimicrobial pouch/envelope in the treatment of 
Twiddler's syndrome. Pacing Clin Electrophysiol 2018;41(2):136±42. doi:10.1111/pace.13259 
[published Online First: 16 January 2018].
implantable electronic devices. Revista Colombiana de Cardiología 2020;27(5):420±27.
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Barra S, Duehmke R, Providencia R, et al. Patients upgraded to cardiac resynchronization therapy 
due to pacing-induced cardiomyopathy are at low risk of life-threatening ventricular arrhythmias: A 
long-term cause-of-death analysis. Europace 2018;20(1):89±96.
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Lin Y-S, Hung S-P, Chen P-R, et al. Risk factors influencing complications of cardiac implantable
electronic device implantation: Infection, pneumothorax and heart
perforation: a nationwide 
population-based cohort study. Medicine 2014;93(27):e213.
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Nakajima H, Nishii N. Infection and migration incidence of cardiac implantable electrical devices in 
Japan: 
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2020;36(4):780±83.
doi:10.1002/joa3.12345 [published Online First: 21 April 2020]. 
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Alings M, Vireca E, Bastian D, et al. Clinical use of automatic pacemaker algorithms: Results of the 
AUTOMATICITY registry. Europace 2011;13(7):976±83. doi:10.1093/europace/eur052 [published 
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Dai Y, Chen K-P, Hua W, et al. Dual antiplatelet therapy increases pocket hematoma complications 
in Chinese patients with pacemaker implantation. J Geriatr Cardiol 2015;12(4):383
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71 
Kosiuk J, Koutalas E, Doering M, et al. Treatment with novel oral anticoagulants in a real-world 
cohort of patients undergoing cardiac rhythm device implantations. Europace 2014;16(7):1028±32. 
doi:10.1093/europace/eut423 [published Online First: 31 January 2014].
72
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78 
Russo RJ, Costa HS, Silva PD, et al. Assessing the Risks Associated with MRI in Patients with a 
Pacemaker or Defibrillator. N Engl J Med 2017;376(8):755±64. 
 
19.9 
Reporting responsibilities 
19.9.1 
Reporting responsibilities of the investigator to sponsor 
The investigator shall document all events on the respective CRF pages provided within the 
CDMS (iMedNet). The indicated timelines for reporting of initial cases and possible update 
reports shall be strictly followed. 
All Serious Adverse Events (SAE) and Serious Adverse Device Effects (SADEs) shall be 
reported together with an assessment by completing the AE-CRF in accordance with ISO 
14155:2020.  
For device deficiencies of the investigational device, a DD-CRF shall be completed. 
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 or until the event has been 
resolved, whatever comes first.  
The investigator must characterize each event by a single primary diagnose. The primary 
diagnose may describe an event consisting of several clinically recognizable features, 
symptoms or secondary diagnoses. Note: The observed symptoms and secondary diagnoses 
must be properly documented in the respective CRF. 
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, the investigator shall document the cause of death, 
circumstances and place of death.. All actions taken, which were initiated to gain further 
information must be documented in writing and provided to BIOTRONIK. 
 
19.9.2 
Reporting responsibilities of the investigator to other parties 
According to national and international regulations some of the involved competent authorities 
(CAs) and ethics committees request reporting of SAEs and DDs with SADE potential during 
the course of the study. Investigators have to ensure, that they fulfil these local reporting 
obligations given by their competent authorities and EC/IRBs. 
 
19.9.3 
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 authorities 
depending on the local regulatory requirements.  
Furthermore, BIOTRONIK SE & Co. KG ensures that safety reports are forwarded to the 
investigational sites and the ethic committees depending on the local requirements.  
BIOTRONIK SE & Co. KG will inform the investigators about all reported SAEs and DDs that 
could have led to a SADE on a regular basis. As a proposal, regular listings may be provided 
78 
Russo RJ, Costa HS, Silva PD, et al. Assessing the Risks Associated with MRI in Patients with a
Pacemaker or Defibrillator. N Engl J Med 2017;376(8):755
d
±64.

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quarterly and unanticipated serious adverse device effects (USADEs) shall be reported 
immediately. 
 
19.10 Reporting timelines 
The reporting timelines for the investigator are displayed in Table 4. 
 
Table 4: 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 within 
3 days after detection1 
Unanticipated serious adverse device 
effect (USADE) 
CCR BIOTRONIK SE & Co. KG: 
Documentation in AE-CRF 
Immediately, latest 24 
hours 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 eficiencies to the sponsor 
without unjustified delay is an important part of the principal investigator¶VUHVSRnsibilities as 
defined by ISO 14155:2020. 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: 
x 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; 
x 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 
SDWLHQW¶VVWXG\Sarticipation and that relevant events, such as hospitalizations, are notified 
to the site study team without delay; 
x 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 DV %,27521,.¶V FRQWUact 
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. 
 
19.11 Emergency contact 
A contact address for patients in case of emergency will be provided in the individual patient 
informed consent forms. 
 
1 If national legislation requires faster reporting the national requiremet shall be observed. 

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In case technical support is needed the service hotline of BIOTRONIK is available 24 hours a 
day. Phone: +49 (0) 30 68905-1133.  
 

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20 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. 
Therefore no provisions for vulnerable patients have to be arranged. 

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21 SUSPENSION 
 
21.1 
Criteria and procedures 
Suspension or premature study termination may occur due to several reasons: 
x On behalf of the sponsor 
x On behalf of the investigator 
x On behalf of the EC/IRB 
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: 
x Occurrence of severe adverse events that result in a non-acceptable risk for further study 
participation. 
x The number of premature study terminations exceeds the tolerable percentage of drop-outs 
so that proper completion of the study cannot be expected anymore. 
x Insufficient enrollment rates so that proper completion of the study cannot be expected 
anymore. 
x Results from other clinical investigation indicate a non-tolerable risk for further conduction of 
this study. 
x Attempted fraud or fraud that may be evidenced. 
x Poor data quality 
x 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/IRB of this decision. The investigator will also promptly inform 
all patients enrolled at the investigational(al) 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(al) 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/IRB and all enrolled patients of this 
decision. 
If the EC/IRB 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 IRUµStudy 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. 
 
21.2 
Requirements for patient follow-up and continued care 
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/IRB decision, additional requirements from the EC/IRB with respect 
to follow-up and data collection may apply. 
 
Ongoing SADEs and SAEs of the patient will be followed in a time period of 6 weeks after 
premature or regular study termination of the individual patient in order to follow the outcome, 
clarify open questions or for collection of missing information concerning the respective SADE 
or SAE. Ongoing SADEs related to the investigational device will be followed over a maximum 
period of 6 months after study termination of the respective patient if not resolved before. 
 
Patients have to be informed on this procedure in written form in the patient informed consent 
form. 

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22 PUBLICATION POLICY 
 
22.1 
Decision for publication  
The study will be registered in a publicly accessible database (e.g. clinicaltrials.gov) and the 
results will be made publicly available after completion of related publication activities. 
All furthers decisions on publications will be made by the Publication Team, consisting of the 
coordinating investigator and member(s) of BIOTRONIK. 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 at least an abstract to a congress OR a 
manuscript within about 18 months after analysis with sponsor approval. 
In case of realizing publications, the rights in regard to publication of the main results of the 
study, i.e., regarding the outcomes, belong to the coordinating investigator. The manuscripts 
and abstracts will be reviewed and approved by the coordinating investigator, all authors and 
BIOTRONIK.  
 
22.2 
Authorship guidelines 
The first author of the publication of study results will be established according to the number 
of enrollments. The last author of the publication will be the Prof Brignole. BIOTRONIK 
employees who meet the authorship criteria may be included in the author list. 
 
22.3 
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.  
 
22.4 
Ancillary publications  
Ancillary publications are publications in addition to the primary publication. All study 
stakeholders (e.g. participating investigators, BIOTRONIK employees) may submit publication 
ideas through the coordinating investigator.  
Requests for ancillary publications will be evaluated for scientific validity and the ability of 
BIOTRONIK to provide resources. All manuscripts and abstracts will be reviewed and approved 
by the coordinating investigator, all authors and BIOTRONIK. 
Prof Brignole.

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23 BIBLIOGRAPHY 
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Boriani G, Braunschweig F, Brignole M, Burri H, Coats AJS, Deharo JC, Delgado V, Diller GP, 
Israel CW, Keren A, Knops RE, Kotecha D, Leclercq C, Merkely B, Starck C, Thylén I, 
Tolosana JM; ESC Scientific Document Group. 2021 ESC Guidelines on cardiac pacing and 
cardiac resynchronization therapy. Eur Heart J. 2021 Sep 14;42(35):3427-3520. doi: 
10.1093/eurheartj/ehab364. PMID: 34455430. 
(2) Brignole M, Russo V, Arabia F, Oliveira M, Pedrote A, Aerts A, Rapacciuolo A, Boveda S, 
Deharo JC, Maglia G, Nigro G, Giacopelli D, Gargaro A, Tomaino M, BioSync CSL trial 
Investigators. Cardiac pacing in severe recurrent reflex syncope and tilt-induced asystole. 
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