Benefit of Dual-chamber Pacing With Closed Loop Stimulation (CLS) in Tilt-induced Cardioinhibitory Reflex Syncope. A Randomized Double-blind Parallel Trial.
Phase: NA
Conditions: Syncope
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. 
 
 
BIO-ITA Local Clinical Unit  
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Clinical Investigation Plan 
 
 
Benefit of dual-chamber pacing with Closed 
Loop Stimulation (CLS) in tilt-induced cardio-
inhibitory reflex syncope.  
A randomized double-blind parallel trial 
 
BIOSync CLS trial 
 
 
Reference Number BA103 
Version 7-0 
Date, 20-JUN-2016 
 

BIOTRONIK SE & Co KG 
BIOSync CLS 
 
BIO-ITA Local Clinical Unit 
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Coordinating Clinical 
Investigator 
 
 
 
 
Dr. M. Brignole 
Ospedali del Tigullio 
Arrhythmologic Centre, 
Department of Cardiology 
Via Don Bobbio, 25 
16033 Lavagna (GE) - Italy 
 
Date 
 
Signature 
 
 
 
 
 
Coordinating Clinical 
Investigator 
 
 
 
 
Dr. Marco Tomaino 
Ospedale Centrale di Bolzano 
Department of Cardiologia e Prove 
Funzionali 
Via Lorenz Böhler, 5 
39100 Bolzano - Italy 
 
Date 
 
Signature 
 
 
 
 
 
Director, Clinical Project 
Management 
 
 
 
 
Dr. Evelyn Diessel on behalf of 
Mathias Freudigmann 
BIOTRONIK SE & Co. KG 
Center for Clinical Research  
Woermannkehre 1 
D-12359 Berlin 
 
Date 
 
Signature 
 
 
 
 
 
Regional Clinical Interface 
 
 
 
 
Angel Madrid 
BIOTRONIK SE & Co. KG 
Center for Clinical Research  
Woermannkehre 1 
D-12359 Berlin 
 
Date 
 
Signature 
 
 
 
 
 
Project Manager 
 
 
 
 
Alessio Gargaro 
BIOTRONIK SE & Co. KG 
Center for Clinical Research  
Woermannkehre 1 
D-12359 Berlin 
 
Date 
 
Signature 
 
 
 
 
 
Sponsor 
BIOTRONIK SE & Co. KG 
Woermannkehre 1 
D-12359 Berlin 
 
 
 
 
 
 
List of principal investigators, investigation sites, and institutions 
A current list of participating investigators, investigational sites, and institutions and a detailed 
list of sponsor contacts are filed in the Trial Master File. 

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

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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................. 4 
1 
LIST OF ABBREVIATIONS ................................................................................... 7 
2 
SYNOPSIS ........................................................................................................... 8 
3 
INTRODUCTION ................................................................................................ 10 
3.1 
Rationale for a large randomized trial ................................................................... 10 
3.2 
Possible benefits from the Closed-Loop Stimulation (CLS) ....................................... 10 
4 
INVESTIGATIONAL DEVICE............................................................................... 12 
4.1 
Summary description of the device and its intended purpose .................................. 12 
4.2 
Manufacturer .................................................................................................... 12 
4.3 
Model name including software version and accessories .......................................... 12 
4.4 
Description of traceability ................................................................................... 12 
4.5 
Intended purpose of the device in the study .......................................................... 12 
4.5.1 
Description of the ODO function ....................................................................... 13 
4.6 
Intended patient population and indications .......................................................... 13 
4.7 
Summary of training and experience needs ........................................................... 13 
4.7.1 
Description of medical and surgical procedures .................................................. 13 
5 
JUSTIFICATION FOR THE DESIGN OF THE CLINICAL INVESTIGATION .............. 14 
6 
RISKS AND BENEFITS OF THE DEVICE AND CLINICAL INVESTIGATION ............ 15 
6.1 
Anticipated clinical benefits ................................................................................. 15 
6.2 
Anticipated risks ................................................................................................ 15 
6.2.1 
Anticipated adverse device effects ................................................................... 15 
6.2.1.1 
Protective measures ................................................................................... 16 
6.2.2 
Residual risks associated with the device .......................................................... 16 
6.2.3 
Risk associated with participation in the study ................................................... 16 
6.2.4 
Possible interactions with concomitant medical treatments .................................. 17 
6.3 
Steps to control or mitigate the risks .................................................................... 17 
6.4 
Risk-to-benefit rationale ..................................................................................... 17 
7 
OBJECTIVES AND HYPOTHESES ........................................................................ 19 
7.1 
Objectives ........................................................................................................ 19 
7.1.1 
Primary objectives ......................................................................................... 19 
7.1.2 
Secondary objectives: clinical outcome ............................................................. 19 
7.2 
Primary hypotheses ........................................................................................... 19 
7.2.1 
Comparison of syncope survival rate during 2-year follow-up .............................. 19 
7.3 
Secondary hypotheses ....................................................................................... 20 
7.3.1 
Comparison of pre-syncope or syncope survival rate during 2-year follow-up ........ 20 
7.4 
Safety assessments ........................................................................................... 20 
8 
DESIGN OF THE CLINICAL INVESTIGATION ...................................................... 21 
8.1 
General considerations ....................................................................................... 21 
8.2 
Endpoints ......................................................................................................... 21 
8.2.1 
Primary endpoint ........................................................................................... 21 
8.2.2 
Secondary endpoints ...................................................................................... 21 
8.3 
Measures taken to minimize or avoid bias ............................................................. 21 
8.3.1 
Randomization .............................................................................................. 21 
8.3.2 
Blinding ........................................................................................................ 21 
8.3.3 
Primary and clinical secondary endpoint assessment .......................................... 22 
8.4 
Methods ........................................................................................................... 22 
8.4.1 
eCRF ............................................................................................................ 22 
8.5 
Equipment to be used for the assessment of variables ............................................ 22 
8.6 
Replacement of subjects ..................................................................................... 23 
8.7 
Used devices and comparators ............................................................................ 23 
8.7.1 
Description of exposure to the investigational device and/or comparator .............. 23 

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8.7.2 
Justification of the choice of comparators .......................................................... 23 
8.7.3 
List of any other medical device and/or medication to be used during the 
investigation ................................................................................................. 23 
8.7.4 
Number of investigational devices to be used and a justification .......................... 23 
8.8 
Subjects ........................................................................................................... 24 
8.8.1 
Description of patient population ..................................................................... 24 
8.8.2 
Inclusion criteria ............................................................................................ 24 
8.8.3 
Exclusion criteria ........................................................................................... 24 
8.8.4 
Screening failure ........................................................................................... 25 
8.8.5 
Drop-out criteria ............................................................................................ 25 
8.8.5.1 
Withdrawal of patient consent ..................................................................... 25 
8.8.6 
Point of enrolment and study termination ......................................................... 25 
8.8.7 
Timelines ...................................................................................................... 25 
9 
STUDY PROCEDURES ........................................................................................ 26 
9.1 
Overview .......................................................................................................... 26 
9.1.1 
Remote monitoring ........................................................................................ 26 
9.2 
Enrolment ......................................................................................................... 28 
9.3 
Implantation ..................................................................................................... 28 
9.4 
Pre-hospital discharge ........................................................................................ 28 
9.4.1 
ODO mode programming ................................................................................ 29 
9.4.2 
AV Delay programming ................................................................................... 30 
9.4.3 
Patient's Questionnaire ................................................................................... 30 
9.5 
In-hospital follow-up visits .................................................................................. 30 
9.5.1 
1-month in-hospital visit (optional) .................................................................. 30 
9.5.2 
Tilt Test procedure at 1-month in-hospital follow-up (optional) ............................ 31 
9.5.3 
In hospital follow-ups at 12 and 24 months ....................................................... 31 
9.5.4 
Interim follow-up ........................................................................................... 32 
9.5.5 
Study termination .......................................................................................... 32 
9.5.5.1 
ODO mode disabling .................................................................................. 32 
9.6 
Primary endpoint collection ................................................................................. 32 
9.7 
Description of the activities performed by sponsor representative ............................ 33 
9.8 
Responsibilities of the coordinating clinical investigator and the Steering Committee .. 33 
9.9 
Primary and clinical secondary endpoint Adjudication Board .................................... 34 
9.10 
Possible influencing factors on outcome or interpretation of results .......................... 34 
10 
MONITORING PLAN .......................................................................................... 35 
11 
STATISTICAL CONSIDERATIONS ...................................................................... 36 
11.1 
Statistical design, method and analytical procedures .............................................. 36 
11.2 
Sample size calculation ...................................................................................... 36 
11.2.1 
Required number of primary endpoint events .................................................... 36 
11.3 
Level of significance and the power of the study .................................................... 37 
11.4 
Expected drop-out rate ....................................................................................... 37 
11.5 
Pass/fail criteria ................................................................................................. 37 
11.6 
Provision for interim analyses .............................................................................. 37 
11.7 
Termination criteria............................................................................................ 38 
11.7.1 
Stopping Rules .............................................................................................. 38 
11.8 
Procedures for reporting of deviations to the statistical plan .................................... 39 
11.9 
Specification of subgroups .................................................................................. 39 
11.10 Procedure for accounting of all data for analysis .................................................... 39 
11.11 Handling of missing, unused and spurious data ..................................................... 39 
11.12 Exclusion of data from confirmatory data analysis .................................................. 39 
11.13 Minimum and maximum number of patients per site .............................................. 39 
12 
DATA MANAGEMENT ......................................................................................... 41 
12.1 
Procedures used for data review, database cleaning, and issuing and resolving data 
queries ............................................................................................................. 41 
12.2 
Procedures for verification, validation and securing of electronic data systems .......... 41 
12.3 
Procedures for data retention .............................................................................. 41 
12.4 
Specified retention period ................................................................................... 41 

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AMENDMENT PROCEDURES ............................................................................... 42 
14 
DEVIATIONS FROM CLINICAL INVESTIGATION PLAN ....................................... 43 
14.1 
13.1 CIP compliance and exceptions .................................................................... 43 
14.2 
Recording, reporting and analyzing deviations ....................................................... 43 
14.2.1 
Site specific deviations ................................................................................... 43 
14.2.2 
Other deviations ............................................................................................ 43 
14.2.3 
Reporting...................................................................................................... 43 
14.3 
Notification requirements and timelines ................................................................ 43 
14.4 
Corrective and preventive actions and disqualification criteria ................................. 44 
15 
DEVICE ACCOUNTABILITY ................................................................................ 45 
16 
STATEMENT OF COMPLIANCE ............................................................................ 46 
16.1 
Applicable ethical standards ................................................................................ 46 
16.2 
Applicable international and national standards ..................................................... 46 
16.3 
Ethics committee and competent authority ........................................................... 46 
16.4 
Statement of adherence to additional requirements ............................................... 46 
16.5 
Statement on subject insurance .......................................................................... 46 
17 
INFORMED CONSENT PROCESS ......................................................................... 47 
17.1 
General considerations ....................................................................................... 47 
18 
ADVERSE EVENTS AND DEVICE DEFICIENCIES ................................................. 48 
18.1 
Definition of adverse events ................................................................................ 48 
18.2 
Definition of adverse device effects ...................................................................... 48 
18.2.1 
Causality Assessment ..................................................................................... 48 
18.3 
Definition of device deficiency ............................................................................. 49 
18.4 
Definition of serious adverse events ..................................................................... 49 
18.5 
Definition of serious adverse device effect ............................................................ 50 
18.6 
Definition of unanticipated serious adverse device effects ....................................... 50 
18.7 
Anticipated adverse events ................................................................................. 50 
18.8 
Reporting responsibilities .................................................................................... 50 
18.8.1 
Reporting responsibilities of the investigator to sponsor ...................................... 50 
18.8.2 
Reporting responsibilities of the investigator to other parties, if applicable ............ 51 
18.8.3 
Reporting responsibilities of the sponsor, if applicable ........................................ 52 
18.9 
Reporting timelines ............................................................................................ 52 
18.10 Emergency contact ............................................................................................ 52 
18.11 Data safety monitoring committee ....................................................................... 52 
19 
VULNERABLE POPULATION ............................................................................... 53 
20 
SUSPENSION .................................................................................................... 54 
20.1 
Criteria and procedures ...................................................................................... 54 
20.2 
Un-blinding procedures ...................................................................................... 55 
20.3 
Requirements for subject follow-up ...................................................................... 55 
21 
PUBLICATION POLICY ...................................................................................... 56 
22 
BIBLIOGRAPHY ................................................................................................. 57 
 

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1 
LIST OF ABBREVIATIONS 
ADE: Adverse Device Effect 
AE: Adverse Event 
AV: Atrio-Ventricular 
BP: Blood Pressure 
CA: Competent Authority 
CCI: Coordinating Clinical Investigator 
CDMS: Clinical Data Management System 
CIP: Clinical Investigation Plan 
CLS: Closed Loop Stimulation 
CRO: Contract Research Organization 
CRT: Cardiac Resynchronization Therapy 
DD: Device Deficiency 
DSMB: Data Safety Monitoring Board 
EC: Ethics Committee 
ECG: Electrocardiogram 
eCRF: electronic Case Report Form 
EDC: Electronic Data Capture 
ESC: European Society of Cardiology 
IB: Investigator Brochure 
ICD: Implantable Cardioverter Defibrillator 
IEGM: Internal Electrogram 
IPG: Implantable Pulse Generator (pacemaker) 
IRB/EC: Institutional Review Board/Ethics Committee 
ITT: Intention to treat 
LVEF: Left Ventricle Ejection Fraction 
RCT: Randomized Clinical Trial 
SADE: Serious Adverse Device Effect 
SAE: Serious Adverse Event 
SAV: spontaneous atrio-ventricular interval 
SBP: Systolic Blood Pressure 
TT: tilt table test 
 

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2 
SYNOPSIS 
Title: 
BIOSync CLS. Benefit of dual-chamber pacing with Closed Loop 
Stimulation (CLS) in tilt-induced cardio-inhibitory reflex syncope. 
A randomized double-blind parallel trial 
Patient collective: 
The study will select 128 patients with a Class IIb indication for 
cardiac pacing due to tilt-induced cardio-inhibitory response with 
recurrent frequent unpredictable syncope and age ≥40 years, 
after alternative therapy has failed. 
Design: 
Prospective, multi-center, double-blinded, randomized, intention-
to-treat, placebo-controlled study 
Investigational device(s) 
BIOTRONIK Eluna 8, Epyra 8, Etrinsa 8 IPG families. Dual-
chamber IPGs only will be included in this investigation. 
Objectives  
The study has the primary objective of comparing syncopal 
recurrences between an active group treated with the Closed Loop 
Stimulation (CLS) in addition to the DDD pacing and a control 
group of patients with pacemaker programmed in ODO mode 
(sensing only). The study hypothesis is that DDD pacing with CLS 
stimulation is able to prevent syncopal recurrence completely or 
partially by transforming syncope in pre-syncope. 
Definitions of end-points 
Syncope is defined as a transient complete loss of consciousness 
characterized by rapid onset, short duration, and spontaneous 
complete recovery. 
Pre-syncope is defined as any of the various signs and symptoms 
which are recognized by the patients as premonitory of imminent 
syncope but not followed by syncope.  
Primary endpoint:  
The Primary Endpoint will be the time to the first post 
randomization recurrence of syncopal episode 
Secondary endpoint: 
The Secondary endpoint 1 will be the time to the first post 
randomization recurrence of pre-syncope or syncope, whichever 
comes first 
Inclusion criteria 
Patients affected by clinical diagnosis of reflex syncope who meet 
all the following criteria: 
 
age ≥40 years  
 
significant limitation of social and working life due to 
unpredictable frequent syncope recurrences, ≥2 within the 
last year. 
 
type 2B cardio-inhibitory response to TT (according to the 
VASIS classification). 
 
Alternative therapies have failed or were not feasible. 
 
exclusion of other possible competitive causes of syncope. 
Exclusion criteria 
 
Any other indication to IPG, implantable defibrillator (ICD), 
cardiac resynchronization therapy (CRT), according to 
current guidelines 
 
Any cardiac dysfunctions possibly leading to loss of 
consciousness: 
o 
overt heart failure; 
o 
ejection fraction (LVEF) <40% (Echo-assessed within 

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3-month prior to study participation); 
o 
myocardial infarction; 
o 
diagnosis of hypertrophic or dilated cardiomyopathy;  
o 
clinically significant valvular disease; 
o 
sinus bradycardia <50 bpm or sinoatrial block; 
o 
Mobitz I second-degree atrioventricular block; 
o 
Mobitz II second or third-degree atrioventricular 
block; 
o 
bundle-branch block; 
o 
rapid paroxysmal supraventricular tachycardia or 
ventricular tachycardia; 
o 
preexcited QRS complexes; 
o 
prolonged QT interval; 
o 
Brugada syndrome; 
o 
arrhythmogenic right ventricular cardiomyopathy) 
 
Symptomatic 
orthostatic 
hypotension 
diagnosed 
by 
standing BP measurement; 
 
Nonsyncopal 
loss 
of 
consciousness 
(eg, 
epilepsy, 
psychiatric, metabolic, drop-attack, cerebral transient 
ischemic attack, intoxication, cataplexy). 
 
Symptomatic 
cardioinhibitory 
carotid 
sinus 
hypersensitivity. 
Study duration: 
~ Q2 2015 – Q2 2019 Year (~ 48 months) 
Number of follow-ups per 
patient 
A maximum of 3 scheduled in-hospital follow-ups. 
Follow-up scheme: 
In-hospital: 12-, 24-month follow-up 
Anonymous patient questionnaires quarterly collected by and 
independent institution 
Coordinating Clinical 
Investigator 
Dr. M. Brignole 
Dr. M. Tomaino 
Boards (if applicable) 
Steering Committee, Data Safety Monitoring Board, Primary Event 
Adjudication Board 
Sponsor 
BIOTRONIK SE & Co. KG 
Center for Clinical Research  
Woermannkehre 1 
D-12359 Berlin 

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3 
INTRODUCTION 
3.1 
Rationale for a large randomized trial 
The latest update of the European Society of Cardiology (ESC) guidelines for cardiac pacing 
has set a Class IIb (evidence B) indication for permanent cardiac pacing in patients with tilt-
induced cardio-inhibitory response with recurrent, frequent, unpredictable syncope and age 
≥40 years after alternative therapy has failed.(1)  
The reason behind the indication is that randomized clinical trials (RCTs) did not lead to a 
conclusive evidence due to some limitations in study design and controversial results. In 
particular: 
 
The SYDIT(2) and VASIS PM(3) trials selected patients with positive cardio-inhibitory 
(mostly asystolic) response during tilt test. Two-year results were in favor of pacing 
with a significant reduction of syncopal recurrences in the pacemaker (IPG) arm. 
However the SYDIT study was early terminated and both SYDIT and VASIS studies 
were open-label. Particularly, studies on syncope recurrences may be prone to potential 
bias deriving from a lack of blinding. 
 
On the other hand, the VPS II(4) and the SYNPACE(5) studies, which included younger 
patients with both cardio- and non-cardio-inhibitory response to tilt test, failed to 
demonstrate significant superiority of pacing. 
 
A recent small sub-study of the International Study on Syncope of Uncertain Etiology 3 
(ISSUE-3(6)) showed that syncope still recurred after cardiac pacing in 35% (95% CI, 
13–75) of patients at 12 months. 
Consequently, the status quo is that pacing may be considered (Class IIb indication) in 
patients with a cardio-inhibitory response to Tilt-Test (TT), after any cardiac dysfunction likely 
leading to loss of consciousness and other non-syncopal causes (including epilepsy, 
psychiatric, metabolic, drop-attack, etc.) have been excluded. 
On the hand, the 2009 ESC guidelines for diagnosis and management of syncope established 
that cardiac pacing showed higher evidence of benefit and should be considered (Class IIa 
indication) in patients with frequently recurrent reflex syncope, age ≥40 years and 
spontaneous cardio-inhibitory episodes during long-term monitoring.(7) 
Recently, a sub-analysis of the ISSUE-3(6) showed that an asystolic response to TT predicts 
similar clinical forms of asystolic syncopal events during follow-up with an 86% probability, 
thus tracing back to a Class IIa indication for cardiac pacing. This is the main reason why 
pacing is currently preferred in structured Syncope Units and, more generally, in normal 
medical practice. 
In conclusion, the ESC Task Force consider further research is extremely important as it is very 
likely to have an important impact on recommendations.(1) This is the objective of the BIOSync 
CLS study. 
3.2 
Possible benefits from the Closed-Loop Stimulation (CLS) 
In all the cited trials, a dual-chamber pacing mode was used with an automatic feature 
promptly responding to heart rate drops by rapid DDD pacing for a programmed interval. 
However, few small studies have reported that the DDD-CLS mode may be effective as well.(8)-
(12) 
During the CLS mode intracardiac impedance curves are collected during systolic phases by 
injecting subthreshold high frequency current pulses. The waveforms of such rheometric 
signals are influenced by contractility, and this principle is exploited to adjust the pacing rate 
in normal rate responsive operation.(13) 

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It has been hypothesized that the detection of an increase in contractility in the early stage of 
a vasovagal syncope could allow the system to activate atrio-ventricular pacing that may 
anticipate withdrawal of sympathetic tone and counterbalance vagal tone reaction.(8) Therefore 
CLS would react early during a first sympathetic phase of the reflex, while rate-drop response 
functions would intervene after the vagal reaction (bradycardia) has been already triggered for 
a while. Since cardiac output is the result of the product of BP and heart rate, an early heart 
rate increase achieved by CLS detection during the phase preceding syncope could be able to 
sustain cardiac output even when BP start falling thus counteracting, at least in part, the 
vasodepressor reflex and avoiding syncope or at least delaying it. Results appeared amazing so 
far: no syncope recurrence was reported in the CLS arm by a first randomized study testing 
CLS against placebo during one-year follow-up(9); 83% of patients remained free from 
recurrences after a 3-year period(10); the number of recurrences of syncope or presyncope 
were reduced by 87% and 83% respectively, in a within-patient comparison obtained in a 18-
month period crossover-designed study(12); finally, CLS appeared superior even when 
compared with the rate-drop-response pacing functions, with a 90% relative reduction of the 
recurrence rate, as reported by a retrospective analysis.(11) 
However despite these impressive data, all the studies conducted so far suffered from severe 
limitations in study population size, design and conduct methods which made conclusions less 
firmly supported by evidence. Nevertheless these first clues would deserve a rigorous 
assessment by means of a large randomized double-blinded clinical study testing CLS against 
placebo in a parallel design. 
The BIOSync CLS is a RCT designed to reliably assess the benefit of pacing against placebo, by 
using the CLS algorithm on top of DDD mode, in patients with frequent syncope recurrences, 
age ≥40, cardio-inhibitory response to TT, after all competing causes have been excluded. 

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4 
INVESTIGATIONAL DEVICE 
4.1 
Summary description of the device and its intended purpose 
The investigational devices included in the BIOSync study are the BIOTRONIK Eluna 8, Epyra 
8, Etrinsa 8 dual chamber IPG families. 
All the mentioned investigational devices provide a function called CLS, developed to provide a 
physiologic pacing rate modulation. CLS is based on an indirect monitoring of the myocardial 
contractility, which is a function of the neurovegetative tone. Such monitoring is obtained via a 
permanent sampling of the intraventricular impedance signal by a high frequency sub-
threshold pulse train: an increase of the impedance curve slope, with respect to a reference 
rest curve, is an indication of an increased activity and it is used by the algorithm to adapt the 
heart rate. CLS functioning actively interacts with the autonomic regulation process of cardiac 
output, occurring under any condition of daily life, not only exercise-related stresses.(14) 
 
4.2 
Manufacturer 
The manufacturer of the Eluna 8, Epyra 8, Etrinsa 8 IPGs is the sponsor of the study: 
BIOTRONIK SE & Co. KG 
Woermannkehre 1 
D – 12359 Berlin 
Germany 
www.biotronik.com 
4.3 
Model name including software version and accessories 
The following models will be included in the study: 
 
BIOTRONIK Eluna 8 DR(/-T/ProMRI), software PSW 1303.A and later versions 
 
BIOTRONIK Epyra 8 DR-T(/ProMRI), software PSW 1303.A and later versions 
 
BIOTRONIK Etrinsa 8 DR-T(/ProMRI), software PSW 1303.A and later versions 
These devices will be used along with any CE-marked bipolar leads. A detailed description of 
these systems is reported in their product manual and the Investigator Brochure (IB). 
4.4 
Description of traceability 
Device traceability will be obtained by serial numbers. 
4.5 
Intended purpose of the device in the study 
According to IFU, the implantable pacemakers listed in section 4.3 may be implanted for all 
bradycardia arrhythmia indications. The primary objective of the therapy consists of improving 
patients' symptoms that can be clinically manifested. The implantation of the pacemaker is a 
symptomatic therapy with the objective of compensating bradycardia by atrial, ventricular, or 
AV sequential pacing.  

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In order to conduct the BIOSync CLS study, a special function (ODO mode) will be activated in 
patient randomized to the control group. This function inhibits any pacing functions until 
reprogramming, as described in section 4.5.1. The activation of this function is therefore an 
off-label use of the above listed pacemaker models. 
4.5.1 
Description of the ODO function  
Among the programmable pacing modes, the user can activate the ODO mode with the 
programmer device, by selecting "OFF" in the "Modes" window. During the ODO mode the 
pacemaker does not deliver any pacing therapy, while it maintains all the sensing and related 
diagnostic functions to monitor cardiac rhythm. In standard operating conditions, pacing OFF is 
a temporary function: it is active until the programming head is applied or the radiofrequency 
telemetry connection (SafeSync)is enabled. The BIOSync CLS study design requires the 
pacing OFF condition (ODO mode) to be permanently active (without the programming head or 
radiofrequency connection) during the patient's participation in the study (that is until the first 
adjudicated syncope recurrence, follow-up termination or study withdrawal). 
In order to activate the OFF mode permanently, a special code is required by the programmer 
software.  
4.6 
Intended patient population and indications 
The IPG systems used 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 (AV) sequential pacing. 
The patient collective selected for this study have a Class IIb indication for the IPG therapy 
according to the current European guidelines(1). The investigational devices are therefore used 
within their indication. 
4.7 
Summary of training and experience needs 
In addition to having basic medical knowledge, the Investigators must be thoroughly familiar 
with the operation of a device system. Only qualified medical specialists having the special 
knowledge required for the proper use of implanted devices are permitted to use them. 
Investigators will be trained. 
4.7.1 
Description of medical and surgical procedures 
The investigational devices will be implanted and followed up according to standard techniques 
and normal clinical practice. The study protocol does not require any additional procedure 
during implantation beyond those normally performed in normal clinical practice. 

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5 
JUSTIFICATION FOR THE DESIGN OF THE CLINICAL 
INVESTIGATION 
As discussed in the Section 3, there are data suggesting that CLS functioning on top of dual-
chamber pacing may be beneficial in preventing syncopal recurrences in patients affected by 
tilt-induced cardio-inhibitory syncope. However a definitive evidence of benefit from pacing, in 
general, with the addition of the CLS function, in particular, has never been obtained. 
Therefore, evaluating this benefit (if it exists) by means of a double-blinded, placebo-
controlled, randomized trial, is justified. 
 

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6 
RISKS AND BENEFITS OF THE DEVICE AND CLINICAL 
INVESTIGATION 
6.1 
Anticipated clinical benefits 
There are no specific benefits for the individual patient directly deriving from the participation 
to the study. Nevertheless, the patients included in the study will have a thoroughly monitored 
medical supervision. 
6.2 
Anticipated risks 
6.2.1 
Anticipated adverse device effects 
Patients fulfilling the inclusion/exclusion criteria of the BIOSync CLS study have a Class IIb 
indication to pacemaker implant. The risks related to the implantable pacemaker therapy are 
reported below in this section. These risks were excluded from the Risk Analysis as they have 
already been considered for the CE certification of the pacemakers manufactured by 
BIOTRONIK SE & Co. KG and used in the BIOSync CLS investigation.  
Known adverse events associated with pacemaker therapy are listed below along with 
probability ranges. 
 
Table 1. Adverse events and probability ranges associated with pacemaker therapy 
Adverse Event 
Range of probability (%) 
References 
Related to venous access 
 
 
Pneumothorax 
1-10 
20-22 
Hemothorax 
0.1-0.01 
20-22 
Massive air embolism 
1-0.1 
23 
Air embolism 
>10 
24-26 
Endocarditis 
0.06-7 
39 
Related to leads 
 
 
Lead dislodgment 
1-10 
20-22 
Pericardial tamponade 
0.1-0.01 
20-22 
Malposition 
unknown 
21 
Deep vein thrombosis 
0.1-1 
27 
Exit block 
unknown 
 
Insulation failure/conductor fracture 
0.1-1 
27 
Related to pocket 
 
 
Hematoma 
1-10 
27 
Infection 
1-10 
21, 27 
Wound dehiscence 
unknown 
21 
Pain 
unknown 
21 
Skin erosion 
0.1-1 
27 
Device migration 
unknown 
21 
Device function issues 
 
 
Externally mediated damage 
0.1-1 
27 
Oversensing 
0.1-1 
28 
Undersensing 
unknown 
21 
Crosstalk/far-field sensing 
unknown 
21 
Pacemaker syndrome 
unknown 
21 
Pacemaker-mediated-tachycardia 
unknown 
21 

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Device failure (early battery depletion, 
advisory, electronic failure, etc.) 
13 (of explanted devices) 
29 
 
The term "unknown" for the probability range has been used when frequency was not 
assessable on the basis of recent scientific literature. 
Other possible adverse events of unknown frequency are:(21, 30-38) allergic reaction to contrast 
media or dexamethasone acetate, bleeding, brachial plexus injury, diaphragmatic stimulation, 
discomfort, failure to insulate set screw, hemoptysis, injury to vagus nerve, lead insulation 
fracture, lead microdislocation, local tissue reaction, loosing of set screw, muscle stimulation, 
nerve stimulation (general), myocardial lesion, phrenic nerve stimulation, pocket seroma, 
subclavian artery puncture, higher x-ray load due to extended fluoroscopy times, injury due to 
implantation accessories, connector deficiency, chronic nerve damage, fibrotic tissue 
formation, keloid formation, formation of cysts, sensing of myopotentials, pulse generator 
failures, device extrusion, vein occlusion, Twiddler's syndrome. 
Patients assigned to the treatment group will have the pacemaker CLS function activated. No 
major complications associated with this function are expected. However, palpitations have 
been reported in rare cases, eliminated by proper device reprogramming.(8) 
Patients assigned to the control group will have the ODO function activated (see section 4.5). 
This particular operating mode is outside the intended use for pacemaker models included in 
the study. Anticipated hazards have been analyzed in the Risk Analysis and reported in the IB. 
6.2.1.1 
Protective measures 
The above mentioned adverse device effects will be minimized by the following additional 
protective measures: 
 
During pacemaker implant and follow-up, only CE-marked medical devices will be used 
according to their IFU: pacemaker (except for the ODO mode), leads, programmer, 
accessories, surgical equipment and external medical devices; 
 
Only study sites and investigators with proven long-term experience in pacemaker 
implantation will be included in the BIOSync CLS investigation; 
 
Only study sites and investigators for whom the pacemaker therapy is routinely 
practiced in the patient population enrolled in the BIOSync CLS study will be selected 
6.2.2 
Residual risks associated with the device 
The devices used for the treatment group are CE certified and used within the approved 
intended use.  
Patients in the control group will receive the same CE-marked pacemaker model, in which the 
ODO function will be activated. Residual risks of the ODO mode and their acceptance criteria 
were analyzed in the Risk Analysis report and reported in the IB. 
6.2.3 
Risk associated with participation in the study 
The implantation of the investigational device systems and the follow-up procedures do not 
differ from the procedures in routine care with comparable systems. 
Patients will undergo a randomization procedure which will assign each of them either to the 
treatment (pacing ON with CLS) or to the placebo. Placebo will consist of the implantation of 
the investigational device and subsequent programming with only sensing and diagnostic 
functions activated (ODO mode). This mode is outside the intended use of the pacemaker 
models included in the BIOSync CLS study. Risks associated with the ODO mode have been 
analyzed in the Risk Analysis and reported in the IB. 

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Participating patients may optionally undergo a TT examination one month after hospital 
discharge. TT 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 the therapy. There 
have been no reported deaths nor severe complications during the tests. 
6.2.4 
Possible interactions with concomitant medical treatments 
No interactions are expected with medical treatments.  
6.3 
Steps to control or mitigate the risks 
As reported in the Risk Analysis and in the IB the following measures will be adopted to 
mitigate the risks associated with the participation in the study. 
Clinical Investigation Plan and Study Design shall include: 
1) 
An independent DSMB will be monitoring the study conduct reviewing all available 
source document related to any death occurring during the study and recommending early 
study termination, if deemed appropriate. 
2) 
Should a patient in ODO mode study arm die, source document review will be 
performed immediately, without any undue delay as soon as all relevant documents are 
available 
3) The following procedures have been introduced in the study CIP: 
- Subjects terminate study participation at the first adjudicated syncope recurrence 
- Three interim analysis are planned to early terminate the study in case of evidence of 
superiority of the treatment arm 
- independent DSMB to periodically monitor the study status and preliminary results, 
recommending termination in case of unacceptable risk 
- Investigators are allowed to take any medical decision deemed appropriate, including 
pacemaker reprogramming 
- Advice the patient to avoid activity which may pose risks in case of  transient loss of 
consciousness 
4) The password/code is communicate only to hospital staff involved in the study after 
appropriate training 
5) Resuscitation equipment available during pacemaker setup 
6) The following measures must be taken during a TT: 
- a pacemaker programmer available in the room and switched on before the test starts 
- Adherence to current guidelines 
- Use of nitroglycerine 
- Resuscitation equipment available during tests 
7) Initial training and, if necessary, periodic re-training of the hospital study staff 
6.4 
Risk-to-benefit rationale 
According to the Risk Analysis, considering their probability of occurrence and their severity, 
the residual risks associated with the study participation are considered acceptable. 
Patients are provided with one of the latest BIOTRONIK IPG systems. They are monitored 
closely due to regularly scheduled follow-ups. The CLS function may physiologically support 

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the heart rate improving exercise and general quality of life, while presumably reducing the 
risk of a syncopal recurrence. Also, patients in the placebo arm may benefit from the 
diagnostics features of the implanted device, and from pacing after the first occurrence of a 
primary endpoint event. 
The follow-ups are not expected to last longer than a routine follow-up. The general benefit of 
the study is the collection of clinical data including the proof of efficacy of CLS in preventing 
syncopal recurrences. 

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7 
OBJECTIVES AND HYPOTHESES 
The hypothesis of the study is that DDD pacing with CLS stimulation is able to overcome the 
cardioinhibitory reflex with DDD pacing and to counteract, at least in part, the vasodepressor 
component of the reflex - which is usually associated in tilt-positive patients- with CLS 
activation. The study hypothesis is that DDD pacing with CLS stimulation is able to prevent 
syncopal recurrence completely or partially by transforming syncope in pre-syncope. 
7.1 
Objectives 
7.1.1 
Primary objectives 
The study has the primary objective of comparing time to first syncopal recurrence between 
 
active group (CLS): CLS in addition to DDD pacing mode; and  
 
control group (CTL): sensing only, ODO mode. 
 
Definition. According to the 2009 ESC guidelines(7), a syncopal recurrence is defined as a 
transient complete loss of consciousness characterized by rapid onset, short duration, and 
spontaneous complete recovery. 
7.1.2 
Secondary objectives: clinical outcome 
The Secondary endpoint will be the time to the first recurrence of pre-syncope or syncope, 
whichever comes first, compared between the study groups during follow-up 
Definition. Pre-syncope is defined as any of the various signs and symptoms which are 
recognized by the patients as premonitory of imminent syncope but not followed by syncope. 
7.2 
Primary hypotheses 
7.2.1 
Comparison of syncope survival rate during 2-year follow-up 
Null: the 2-year survival rate of syncopal recurrence in the treatment arm (SCLS) is equal to the 
2-year survival rate of the control arm (SCTL), assuming an exponential distribution with 
proportional hazard rates. 
H0: SCLS(t=2 years) = SCTL(t=2 years)  
 
Alternative: the 2-year survival rate of syncopal recurrence in the treatment arm is different 
from the 2-year survival rate of the control arm. 
H1: SCLS(t=2 years) ≠ SCTL(t=2 years)  

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7.3 
Secondary hypotheses 
7.3.1 
Comparison of pre-syncope or syncope survival rate during 2-year follow-up 
Null: the 2-year survival rate to the combined event of pre-syncope or syncope, (t), is equal 
in both study groups 
H0: CLS(t=2 years) = CTL(t=2 years)  
 
Alternative: the 2-year survival rate to the combined event of pre-syncope or syncope is 
different in the two study groups. 
H1: CLS(t=2 years) ≠  CTL(t=2 years)  
7.4 
Safety assessments 
All Adverse Events (AE) and Adverse Device will be reported and documented and risk analysis 
will be constantly updated throughout the study. 
An independent DSMB will be monitoring the study conduct reviewing all available source 
document related to any death occurring during the study and recommending early study 
termination, if deemed appropriate. 
Should a patient in ODO mode study arm die, source document review will be performed 
immediately, without any undue delay as soon as all relevant documents are available 
 

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8 
DESIGN OF THE CLINICAL INVESTIGATION 
8.1 
General considerations 
The study is a prospective, multi-center, double-blinded, randomized, intention-to-treat, 
placebo-controlled study. 
8.2 
Endpoints 
8.2.1 
Primary endpoint 
The Primary Endpoint will be the time to the first post randomization recurrence of a syncopal 
episode as defined in Section 7.1.1. 
8.2.2 
Secondary endpoints 
The Secondary endpoint will be the time to the first post randomization recurrence of a pre-
syncope or syncope episode (as defined in Section 7.1 and 7.1.2.1), whichever comes first. 
8.3 
Measures taken to minimize or avoid bias 
8.3.1 
Randomization 
Patients will be randomized to the active group or to placebo immediately after their enrolment 
and before any subsequent study-related procedure. 
 
Active group: before post-implant hospital discharge, IPG will programmed in a dual-
chamber DDD pacing mode with the CLS function ON, and according to the 
programming recommendations reported in section 9.4. 
 
Control group: before post-implant hospital discharge, pacing will be programmed in 
the ODO mode, according to the programming recommendations reported in section 
9.4. 
Randomization ratio will be 1:1, therefore the randomization procedure will ensure that each 
individual patient will have (approximately) 50% chance to be assigned to the active group or 
to the control. 
A centralized block-randomization procedure will be used. Block size will vary from 2 to 4 and 
investigators will not be aware of randomization block sizes at any time. Randomization will 
not be stratified. 
Randomization will be communicated with an online procedure: investigators will connect to a 
dedicated webpage of the electronic Case Report Form (eCRF). 
8.3.2 
Blinding 
Patients will be blinded to the treatment assignment until the end of the study or the first 
endpoint event. 
Investigators will not be blinded to the randomizations but they will not assess the primary 
endpoint events. 

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The primary endpoint events will be collected by dedicated patients' self-administered 
structured questionnaire. Responses to the questionnaire will determine whether or not the 
event description and the associated symptoms are consistent with a primary endpoint event. 
Questionnaires will be anonymous, identified by the patient ID study code, and provided to 
patients at enrolment. Questionnaires will be prepared upfront in 8 pre-paid envelops 
(additional backup questionnaires may be provided) addressed to an external contract 
research organization (CRO), whose personnel will remain blinded both to patients' identity 
and randomization assignment.  
8.3.3 
Primary and clinical secondary endpoint assessment 
At enrolment, participating subjects will be instructed on how and when to fill in and mail the 
questionnaires to the CRO. 
A questionnaire will be completed by the patient him-/herself at home separately after each 
single experienced syncope or pre-syncope event. Every 3 months starting from enrolment 
date patients will mail the collected questionnaires to the CRO using the pre-paid and pre-
addressed envelops provided at enrolment. If a patient will not experience any syncopal or 
pre-syncopal event during a 3-month period, he/she will complete a single questionnaire 
documenting the absence of any recurrence. 
Patients will be instructed to mail only anonymous questionnaires and envelops. 
CRO personnel will monitor the timing of questionnaire flow. In case of delays, the CRO staff 
will inform the investigator, who will contact the patient to solicit the questionnaire or to fix 
any related problems. The CRO will also inform the investigators about the occurrence of a 
syncope or pre-syncope event. 
Responses to the questionnaire will determine whether or not the event description and the 
associated symptoms are consistent with a primary or secondary endpoint event. 
8.4 
Methods 
8.4.1 
eCRF 
All parameters and measurements that are recorded within the study are described in this 
section and are documented on the appropriate eCRFs. 
The corresponding time schedule is described in Section 9. 
 
Enrollment Form 
 
Baseline Form 
 
Implantation Form 
 
Pre-Hospital Discharge Form 
 
In-hospital Follow-up Form for 1- (optional), 12-, 24-month follow-up visits, as well as 
interim visits. 
 
Patient's self-administered questionnaire 
 
Adverse Event/Device Deficiency Form 
 
Study Termination Form 
8.5 
Equipment to be used for the assessment of variables 
Implanted device and related equipments and accessories are described in Section 4.3. 

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In addition, at investigator's discretion, selected patients may undergo TT exam before and 
during study participation (1-month after discharge). This test will require the use of standard 
CE-marked equipments, such as TT tables and related tools to electronically record continuous 
data on BP and heart rate. 
8.6 
Replacement of subjects 
The sample size is calculated in consideration of an expected dropout rate. Therefore it is not 
planned to replace subjects. 
However a patient undergoing a surgical implant revision (implying skin incision for pocket and 
lead position revision) before the 1-month follow-up, will continue his/her study. 
8.7 
Used devices and comparators 
8.7.1 
Description of exposure to the investigational device and/or comparator 
All patients are exposed to the investigational devices Eluna 8, Epyra 8, Etrinsa 8 IPGs as 
described in Section 4.3. 
8.7.2 
Justification of the choice of comparators 
The comparator is the same investigational device programmed in the ODO mode. Justification 
is given in section 3.1. 
8.7.3 
List of any other medical device and/or medication to be used during the 
investigation 
In addition to the investigational device, the following devices, tools and accessories may be 
used during device implantation and follow-up: 
 
Threshold analyzer; 
 
RENAMIC programmers or later models; 
 
Implant accessory kits 
The remote monitoring system, namely BIOTRONIK Home Monitoring (HM), is recommended 
during the study. The HM enables automatic daily transmissions from the implant to a patient 
unit (CardioMessenger) which forwards diagnostic, therapy and device data to Service Center 
(SC). Data resident in the SC are available to the attending physician by connecting to a 
secure web page. 
As per clinical practice, selected patients will undergo TT exam before and, optionally, at 1-
month follow-up during study participation. This test will require the use of standard CE-
marked equipments: TT tables and CE-marked devices to electronically record continuous data 
on blood pressure (BP) and heart rate. 
Such devices must be available at the investigational sites before study participation and will 
not be provided by the Sponsor. 
8.7.4 
Number of investigational devices to be used and a justification 
Within the study, 128 Eluna 8 DR(/-T/ProMRI), Epyra DR-T(/ProMRI), Etrinsa DR-T(/ProMRI) 
IPGs willl be used. 
Justification is given in Section 11. 

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8.8 
Subjects 
8.8.1 
Description of patient population 
Patient selection adheres to the class IIb indication for cardiac pacing of the guidelines of the 
European Society of Cardiology(1). 
8.8.2 
Inclusion criteria 
Patients affected by clinical diagnosis of reflex (neurally-mediated) syncope who meet all the 
following criteria: 
 
age ≥40 years 
 
significant limitation of social and working life due to unpredictable frequent syncope 
recurrences, ≥2 of which within the last year. 
 
type 2B cardio-inhibitory response (VASIS classification) during TT performed according 
to the 'Italian protocol'.(7, 17) 
 
alternative therapies have failed or were not feasible. 
 
exclusion of other possible competitive causes of syncope. 
8.8.3 
Exclusion criteria 
 
Any classified indication to pacemaker different from reflex syncope with positive Tilt Test 
response 
 
Any classified indication implantable defibrillator (ICD), cardiac resynchronization 
therapy (CRT), according to current guidelines 
 
Any cardiac dysfunctions likely leading to loss of consciousness: 
o 
overt heart failure; 
o 
ejection fraction (LVEF) <40% (Echo-assessed within 3-month prior to study 
participation); 
o 
myocardial infarction; 
o 
diagnosis of hypertrophic or dilated cardiomyopathy;  
o 
clinically significant valvular disease; 
o 
sinus bradycardia <50 bpm or sinoatrial block; 
o 
Mobitz I second degree atrioventricular block; 
o 
Mobitz II second or third-degree atrioventricular block; 
o 
bundle-branch block; 
o 
rapid paroxysmal supraventricular tachycardia or ventricular tachycardia; 
o 
pre-excited QRS complexes; 
o 
prolonged QT interval; 
o 
Brugada syndrome; 
o 
arrhythmogenic right ventricular cardiomyopathy; 
 
Symptomatic orthostatic hypotension diagnosed by standing BP measurement; 
 
Nonsyncopal loss of consciousness (eg, epilepsy, psychiatric, metabolic, drop-attack, 
cerebral transient ischemic attack, intoxication, cataplexy). 
 
Symptomatic cardio-inhibitory carotid sinus hypersensitivity.  

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8.8.4 
Screening failure 
Screening will be based on patient's medical history and documented type 2B (cardio-
inhibitory) response of the the VASIS classification(3) during baseline TT, according to the 
Italian protocol. (7) 
Type 2B TT response is defined as asystole occurring for more than 3 sec irrespective of BP 
fall. 
Patients who will not meet these requirements in addition to the inclusion/exclusion criteria 
cannot be enrolled in the study. Screening will be documented in the Screening Log Sheet. 
8.8.5 
Drop-out criteria 
8.8.5.1 
Withdrawal of patient consent 
Informed patient consent is voluntary and required from all patients. The patient can withdraw 
her or his consent at any time. If a patient withdraws her or his consent, the investigator 
should try to ascertain the reasons of withdrawal while fully respecting patient’s rights.  
If the health status of the patient does not allow further participation in the study the 
investigator will decide on early study termination. An early study termination or withdrawal 
will not affect the patient’s future medical care in any way. 
8.8.6 
Point of enrolment and study termination 
A subject is considered enrolled in the BIOSync CLS Study upon the signature of the Informed 
Consent Form. 
Patients will terminate their study participation at the 24-month in-hospital follow-up or at the 
assessment of a primary endpoint event occurrence, whichever comes first. 
8.8.7 
Timelines 
The study is planned to start in the second quarter of 2015 and will be probably completed in 
2019. The enrolment period is expected to last 24 months and the planned duration of 
subject’s participation is 2 years. 
 

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9 
STUDY PROCEDURES 
9.1 
Overview 
This section describes all the study-related procedures. 
At enrolment, patients will receive anonymous syncope and pre-syncope assessment 
questionnaires to be self-administered upon each primary and secondary endpoint event 
experienced and mailed (by ordinary mail) to an external CRO every 3 months after discharge 
by using anonymous pre-paid and pre-addressed envelops. 
Furthermore, subsequent to the IPG implant and hospital discharge, patients will be visited in 
hospital at 12-, and 24-months. More frequent scheduled visits are optional and can be 
performed according to the site clinical practice. However, any scheduled or unscheduled in-
hospital visit must be documented in the appropriate eCRF. Optionally, a 1-month (±14 days) 
in-hospital visit may be performed to repeat the TT. 
The follow-ups should take place within a certain time frame as listed in Table 1. This schedule 
should be followed as closely as possible. If circumstances prevent the presence of the patient 
at the follow-up visit, the reason for the missed follow-up has to be indicated on the eCRF. 
9.1.1 
Remote monitoring 
Home Monitoring is highly recommended for remote control in order to optimize patient 
retention and reduce loss. It may be activated at any time throughout the study. It does not 
replace in-hospital visits for the purpose of this study. 
 
Enrollment
IPG implant
R
IPG implant 
hospitalization
1:1
Optional
In-hospital visit
30 ± 14 days
after discharge
for TT exam
Optional
in-hospital visit
30 ± 14 days
after discharge
for TT exam
Collecting 
questionnaires 
every 3 months
Randomization
In-hospital visits
Patient Questionnaires
Monitoring of primary endpoint event occurrence
Scheduled follow-up
Unscheduled follow-up
DDD+CLS
ODO
Discharge
In-hospital visits
@ 12±1 months
after discharge
In-hospital visits
@ 12±1 months
after discharge
Closeout
In-hospital visits
@ 24±1 months
after discharge
In-hospital visits
@ 24±1 months
after discharge
Collecting 
questionnaires 
every 3 months
 
 
Figure 1. Study flow-chart 
 

This document contains confidential information and should be maintained in a secure location and should not be copied or made available for 
review by any unauthorized personnel. 
 
 
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Table 2. Investigation schedule 
 
 
 
 
 
 
 
 
 
 
 
Investigations 
Enrollment 
Implantation
/Discharge 
Month 0 
Month 1 
± 14 days 
in-hospital 
(optional) 
Month 3 
PSAQ* 
collection 
Month 6 
PSAQ 
collection 
Month 9 
PSAQ 
collection 
Month 12 
PSAQ 
collection; 
±30 days in-
hospital  
Month 15 
PSAQ 
collection 
Month 18 
PSAQ 
collection 
Month 21 
PSAQ 
collection 
Month 24 
PSAQ 
collection; ±30 
days in-hospital  
Patient informed consent 
x 
 
 
 
 
 
 
 
 
 
 
Verification of in- and exclusion 
criteria 
x 
 
 
 
 
 
 
 
 
 
 
Demographic data 
x 
 
 
 
 
 
 
 
 
 
 
ECG 
x 
 
 
 
 
 
 
 
 
 
 
Echo data (not older than 3 months) 
x 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
Co-morbidities  
x 
 
 
 
 
 
 
 
 
 
 
Cardiovascular medication 
x 
 
 
 
 
 
x 
 
 
 
x 
Tilt table test  
x 
 
x  
 
 
 
 
 
 
 
 
IPG implantation 
 
x 
 
 
 
 
 
 
 
 
 
Randomization 
 
x 
 
 
 
 
 
 
 
 
 
Device programming settings and 
diagnostics 
 
x 
x 
 
 
 
x 
 
 
 
x 
Primary endpoint assessment 
(syncope) by independent agency  
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
Pre-syncope assessment by 
independent agency 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
Other secondary endpoint 
assessment 
 
 
x 
 
 
 
 
 
 
 
 
(S)AE, (S)ADE, DD 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
PSAQ= Patient self-administered questionnaire 
 

This document contains confidential information and should be maintained in a secure location 
and should not be copied or made available for review by any unauthorized personnel. 
 
 
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9.2 
Enrolment 
If the patient meets all the inclusion criteria and no exclusion criterion, he/she will be asked to 
read and sign an Informed Consent Form. This will allow a detailed recording of data being 
evaluated during the study. The consenting process is described in detail in Section 17. A 
subject is considered enrolled in the BIOSync CLS Study upon signing the Informed Consent 
Form. The patient will be advised to avoid activities which may pose risks in case of transient 
loss of consciousness. 
The baseline data may be collected the same day the consenting procedures are completed. 
For baseline evaluation, the investigator collects the following data on an eCRF: 
 
Demographic characteristics 
 
Device therapy indication 
 
ECG diagnosis 
 
Number and type of previous ineffective therapies for reflex syncope  
 
Comorbidities 
 
Cardiomyopathies 
 
Arrhythmias 
 
Cardiovascular medication 
 
Baseline TT response which includes time of onset of pre-syncope (first symptoms), BP 
value at the time of onset of pre-syncope, occurrence and time of onset of syncope, 
type and duration of asystole, minimum BP. 
Enrolments take place before IPG implantation. 
9.3 
Implantation 
IPG implantation will be performed according to standard technique and will be conducted so 
as to ensure optimal pacemaker functioning with acceptable pacing, sensing, impedance 
values. 
9.4 
Pre-hospital discharge 
After implant and prior to hospital discharge, the investigator shall query and obtain the 
patient randomization by accessing the dedicated web site. The IPGs will be programmed 
accordingly. 
Programming details are reported in the following Table 3. Parameters which are not listed 
have to be intended freely selectable. 
 
Table 3. Device programming recommendations 
Parameter 
Active group 
Control group 
Mode 
DDD-CLS 
OFF* 
Basic rate Day/Night 
50 bpm/OFF 
--- 

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Maximum CLS rate** 
120 bpm 
--- 
CLS response** 
Medium 
 
CLS Resting rate control** 
OFF 
--- 
Mode switching 
OFF 
--- 
AV Delay 
Low; 150-120ms 
--- 
AV hysteresis mode 
IRSplus 
 
Atrial Overdrive Pacing 
OFF 
--- 
PMT protection 
ON 
--- 
IEGM recordings 
 
 
High atrial rate 
AT 
AT 
High ventricular rate 
ON 
ON 
Patient triggering 
OFF 
OFF 
Rates for statistics 
 
 
HAR limit 
200 bpm 
200 bpm 
HVR limit 
180 bpm 
180 bpm 
HVR counter 
8 events 
8 events 
Home Monitoring** 
ON 
ON 
Time of transmission*** 
01:00 am 
01:00 am 
Periodic IEGM*** 
30 days 
30 days 
High Atrial Rate*** 
AT 
AT 
Ongoing Atrial Episode*** 
12 h 
12 h 
High Ventricular Rate*** 
ON 
ON 
* In the investigational devices, the pacing OFF mode can be normally programmed only 
temporarily for diagnosis purpose. However it can be made permanent in this study by 
releasing a special code in the programming software. 
** Recommended value. The parameter can be modified if necessary. Different settings are 
not considered protocol deviations. 
*** If HM is activated. 
9.4.1 
ODO mode programming 
The ODO mode can be activated by selecting "OFF" in the "Modes" window. In standard 
operating conditions, pacing OFF is a temporary function: it is active until the programming 
head is applied or the radiofrequency telemetry connection (SafeSync®)is enabled. This is 
indicated by a "Conflict" symbol and explained by the text "The OFF mode is only intended for 
diagnostic purposes during follow-up. Therefore it can only be temporarily programmed", 
appearing on the programmer display when clicking on the "Conflict" button, once the OFF 
program is enabled. When the programming head is removed or the SafeSync® telemetry is 
disabled, the OFF program is cancelled and the latest pacing mode is restored. 
In order to activate the OFF mode permanently, a special code will be required by the 
programmer software. To release the code the user must access the "Release" tab under the 
"More" menu of the programming device. The password/code is communicated only to hospital 
staff involved in the study after appropriate training. 

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A "Conflict" symbol will still be displayed on the programmer screen. The OFF program will 
then be permanently active even after the programming head removal or the radiofrequency 
connection interruption. 
 
9.4.2 
AV Delay programming 
The AV Delay programming should favor the intrinsic conduction as much as possible. 
In addition, in patients in the active group (DDD-CLS) the AV Delay should be programmed to 
ensure that both during spontaneous and paced atrial rhythms, the intrinsic AV conduction 
always occurs at least 80 ms earlier that the programmed ventricular pace. 
9.4.3 
Patient's Questionnaire 
At enrolment or at post-implant hospital discharge, enrolled patients will be provided with a 
questionnaire for self-reporting of syncopal recurrences and syncope/pre-syncope-related 
symptoms. 
Patients must be thoroughly instructed on the scope of the diary and when and how it must be 
filled in. 
9.5 
In-hospital follow-up visits 
9.5.1 
1-month in-hospital visit (optional) 
A 1-month follow-up may take place 30 ± 14 days after post-implant hospital discharge, in 
order to repeat a TT and assess the effect of pacing therapy on TT response. This additional 
visit is optional and the decision on whether or not to perform it, is left to Investigator's 
discretion. If preformed, the procedures described below should be followed. 
Before performing the TT, the following procedures should be performed, in order to assess the 
correct functioning of the pacing system: 
 
Interrogate the IPG and document (print or save electronically) all the manually or 
automatically measured results of the P/R-wave amplitude, threshold, impedance tests. 
 
Document and assess any spontaneous high atrial or ventricular rate episode, by 
electronically saving or printing the relative IEGM (whenever available) occurred since 
the last interrogation. 
 
Check the activation of required and recommended parameter settings (see Table 3). In 
case the CLS function is not active in a subject randomized to the Active group, 
immediately activate the CLS and do not perform the TT immediately. Reschedule 
another appointment 24 hours later or as soon as possible thereafter. 
 
Report any adverse event or device deficiency. In case of a serious adverse event, 
please provide the information immediately to BIOTRONIK, and inform the ethical 
committee and competent authority, if required. 
 
Interrogate and store the final programmed parameters. 
 
Perform the TT as reported in next subsection. 
 
Schedule the next in-hospital visit within the allowed time windows. 
 
Complete the appropriate eCRF. Store IPG data of the programmer (Renamic) on USB 
flash drive and send it via email to the project management.  

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9.5.2 
Tilt Test procedure at 1-month in-hospital follow-up (optional) 
The same device programming assigned by the randomization must be maintained throughout 
the TT: patients randomized to the Active arm will perform TT in DDD-CLS mode and patients 
randomized to the Control arm will perform TT in ODO mode.  
A pacemaker programmer must be available in the room and switched on before the test 
starts. TT will be performed according to the Italian protocol(7). Electrocardiogram and systolic 
and diastolic BP will be continuously monitored and recorded using an external device (see 
Section 4.3). After 10 min of supine rest, the patients will be tilted to 70° using an 
electronically operating tilt-table with a footboard. If syncope will not occur after 20 min, 300 
mg of nitroglycerin will be administered sublingually, and the test continued for a further 20 
min or until syncope occurrence. 
TT response includes: time of onset of DDD pacing and its duration, BP value at the time of 
onset of DDD pacing, time of onset of pre-syncope (as defined in the section 7.1.2.1), BP value 
at the time of onset of pre-syncope, occurrence and time of onset of syncope, type and 
duration of asystole, minimum BP. ECG strip of the event must be collected. 
In case of device interrogation, the following procedures should be performed: 
 
During the device interrogation an emergency equipment for resuscitation must be kept 
at hand and properly certified staff must be available. 
 
Continuously monitor the patient's hemodynamics during the entire device interrogation 
using at least one of the following parameters: blood oxygen saturation, blood pressure 
or ECG. 
9.5.3 
In hospital follow-ups at 12 and 24 months 
Routine in-hospital follow-up visits will occur 12 and 24 months after post-implant hospital 
discharge, within a ±30 days interval, in order to check for the correct functioning of the 
pacing system. More frequent visits should be documented. 
The following procedures should be performed: 
 
During the device interrogation an emergency equipment for resuscitation must be kept 
at hand and properly certified staff must be available. 
 
Continuously monitor the patient's hemodynamics during the entire device interrogation 
using at least one of the following parameters: blood oxygen saturation, blood pressure 
or ECG. 
 
Interrogate the IPG and document (print or save electronically) all the manually or 
automatically measured results of the P/R-wave amplitude, threshold, impedance tests.  
 
Document and assess any spontaneous high atrial or ventricular rate episode, by 
electronically saving or printing the relative IEGM (whenever available) occurred since 
the last interrogation. 
 
Check the activation of required and recommended parameter settings (see Table 3). 
 
Report any adverse event or device deficiency. In case of a serious adverse event, 
please provide the information immediately to BIOTRONIK, and inform the ethical 
committee and competent authority, if required. 
 
Interrogate and store the final programmed parameters. 
 
Schedule the next in-hospital visit within the allowed time windows. 
 
Complete the appropriate eCRF. Store IPG data of the programmer (Renamic) on USB 
flash drive and send it via email to the project management. 
 

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9.5.4 
Interim follow-up 
Unscheduled interim follow-up may occur anytime during the course of the study. No specific 
study procedures are required for interim follow-up. 
If any adverse events or device deficiencies occurred, they must be documented on the 
respective eCRFs. 
In case of device interrogation, the following procedures should be performed: 
 
During the device interrogation an emergency equipment for resuscitation must be kept 
at hand and properly certified staff must be available. 
 
Continuously monitor the patient's hemodynamics during the entire device interrogation 
using at least one of the following parameters: blood oxygen saturation, blood pressure 
or ECG. 
9.5.5 
Study termination 
Should the dropout criterion (section 8.8.5) or a termination criterion (section 8.8.6) be met 
for a patient, a follow-up must be performed. This follow-up can coincide with one of the 
scheduled study follow-ups. If the patient's pacemaker was programmed in ODO mode, this 
must be deactivated (see section 9.5.5.1) and a different pacing mode must be programmed. 
The physician is responsible for the correctness and appropriateness of the pacemaker 
programming after this follow-up. The programmer printout of the follow-up must be filed in 
the Investigator Site File for source data verification. 
9.5.5.1 
ODO mode disabling 
As any other pacing mode, the OFF program may be disabled by applying the programming 
head (or enabling the SafeSync telemetry), interrogating the device with the programmer 
and selecting and transmitting a different pacing mode. 
 
9.6 
Primary endpoint collection 
Self-administered anonymous patient questionnaires will be collected every 3 months after 
post-implant hospital discharge (within a ±14 day interval) by independent personnel of a CRO 
as described in section 8.3.3. 
Syncope and pre-syncope assessment will be exclusively based on what patients will refer by 
self-administering the questionnaire, at home, separately for each event. 
Despite patients will be instructed to fill in the study questionnaire, they might react differently 
to a syncope recurrence during the study. The following Table 4 reports the most awaited 
situations and illustrates the subsequent steps accordingly. 
 
Table 4. After a syncopal and pre-syncopal recurrence 
Situation: 
The patient fills in the questionnaire 
The patient shows up for a medical examination  
1 step 
The CRO quarterly collects patient 
questionnaires 
The investigator recommends the patient to mail the 
questionnaire to the CRO in due time and reports 
any AE 
2 step 
If an AE occurred, the CRO informs the 
investigator 
 
 

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Any change of the programmed pacing mode not justified by a primary endpoint (even when 
a-posteriori assessed), will be considered as a crossover, but analyzed according to the 
Intention-To-Treat (ITT) principle, see Section 11) 
9.7 
Description of the activities performed by sponsor representative 
Sponsor representatives may support the investigator by conducting lead and device based 
measurements at IPG implant or in-hospital visits. They might also support the investigator for 
IPG programming. 
During follow-up procedures, sponsor’s representatives might support the interrogation of the 
IPG or memory dump download as needed. Monitoring will be performed by Sponsor 
representatives or delegated CRO personnel according to the monitoring plan. 
9.8 
Responsibilities of the coordinating clinical investigator and the 
Steering Committee 
The BIOSync CLS clinical study is coordinated by: 
Dr. med. Michele Brignole 
Arrhythmologic Centre 
Department of Cardiology 
Ospedali del Tigullio 
Via Don Bobbio, 25 
16033 Lavagna (GE) 
Italy 
Dr. med. Marco Tomaino will co-chair the Steering Committee. 
The Steering Committee will consist of a local study coordinator in participating country with a 
sufficient number of active investigational sites. 
The CCI (M. Brignole) and the co-CCI (M. Tomaino) will be supported in the following activities 
by the Steering Committee. 
The responsibilities of the CCI and the Steering Committee are: 
- Development and review of the clinical investigation plan 
- Procurement of the central vote of an ethics committee (CCI) 
- Performance and progress control of the study 
- Continuous assessment of the risk/benefit ratio 
- If necessary, decision on premature study termination in consultation with the sponsor 
- Contribution to coordination of publication and presentations of study results 
- Advising all investigators in medical questions related to the study or study conduction 
- Evaluation of potential unexpected adverse events 
- Discussion of possible interim results 
- Cooperation in writing of the final clinical report 
The CCI and the Steering Committee are supported by the clinical study manager and other 
members of the sponsor. 
In addition, the CCI and the Steering Committee members have the same rights and duties as 
other investigators which are described in the Investigator Agreement. 

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9.9 
Primary and clinical secondary endpoint Adjudication Board 
All the unclassified syncope or pre-syncope episodes (see section 8.3.3) will be adjudicated by 
an Adjudication Board of at least 3 members. The members will be selected among 
experienced physicians with documented expertise in syncope. The members will not 
participate in the study as Investigators  
The Adjudication Board will review unclassified endpoint events according to a charter provided 
in a separate document. 
The members will remain blinded to the randomization, even if they will have access to the 
electronic CRF. 
The adjudication process will be requested by the study Project Manager after the required 
number of primary endpoint events for the interim analyses has exceeded the predefined 
levels (see section 11.6). 
The interim analyses will be performed only with the events collected at the times of the call 
for the adjudication from the Project Manager. Further events possibly occurring thereafter will 
not be included. 
9.10 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 
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 investigation agreement, the study protocol, applicable laws, and FDA and/or 
local regulations (e.g. CFR 21, parts 50, 54, 56, and 812, ISO 14155, Declaration of Helsinki) 
and any conditions of approval imposed by the reviewing IRB/EC.  
The entries in the eCRF will be reviewed and source data verified at the investigational site by 
monitors (authorized BIOTRONIK personnel, Clinical Research Associates-CRAs, or by 
authorized BIOTRONIK designees) to ensure that the investigator and the clinical investigation 
team conducts the clinical investigation in accordance with the CIP, The Declaration of Helsinki, 
ISO 14155, and applicable FDA and local laws and regulations to ensure adequate protection of 
the rights, safety and wellbeing of subjects and the quality and integrity of the resulting data. 
A monitor will visit the study site periodically during the study. All 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. 
Periodic 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, assessments of the study site will include but will not be limited to 
the following: 
1. Availability and correctness of the signed patient informed consent 
2. Completion and submission of the required case report forms and other applicable 
study documentation 
3. Continued acceptability of the facilities 
4. Adherence to the clinical investigation plan 
5. Adherence to current version of ISO 14155 and applicable FDA and local regulations 
and laws 
If a monitor becomes aware that an investigator is not complying with the requirements 
mentioned above, the monitor is obliged to notify BIOTRONIK study management. BIOTRONIK 
will evaluate the non-compliance and issue corrective actions, discontinue enrollment or as a 
last measure close the clinical investigation site. 
A monitoring plan will be prepared as additional document. It provides detailed information 
about frequency and extent of monitoring. 

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11 
STATISTICAL CONSIDERATIONS 
11.1 Statistical design, method and analytical procedures 
Standard summary statistics will be calculated for all patients and study outcome variables. 
Categorical data will be summarized via distributions of absolute and relative frequencies. For 
all relevant parameters 95% confidence intervals will be calculated. 
For the analysis of the primary endpoint and the secondary endpoint the Kaplan-Meier plots 
will be generated and the estimated survival functions of the study groups tested with the two- 
sided log-rank test. Dependence of survival on major baseline predictors will be studied with 
proportional hazard Cox models. Hazard ratios and relative 95% confidence intervals for each 
predictor will be calculated, respectively. Data will be censored at the date of last patient 
contact. The ITT principle will be applied. 
Statistical calculations will be carried out by using STATA 11.1 ®, SAS 9.3 © or R. 
11.2 Sample size calculation 
The study sample size calculation is based on the minimum relative difference in the 2-year 
incidence of syncopal recurrences as compared with placebo (pacemaker OFF). 
The 2-year incidence of the primary endpoint in the control group will be assumed equal to the 
incidence observed in the control arm of the ISSUE 3 trial:(16) this was reported as high as 
57%. The ISSUE 3 trial was considered as it selected a large population, had very similar 
inclusion/exclusion criteria, was recently published. 
The BIOSync CLS study is designed to detect a 40% relative reduction of the 2-years incidence 
of syncopal recurrences (from 57% to 34%) with a statistical Type I and II errors of 0.05 
(bilateral) and 0.20, respectively. 
Further assumptions: 
 
Exponential distribution of times to first recurrence 
 
Accrual time: 2 years 
 
Total study time: 4 years 
 
Randomization ratio: 1:1 
 
Loss incidence: 10% (both arms) 
With these assumptions a sample size of 62 patients per study arm (124 in total) is required. 
This estimate must be further increased by 2%, due to the slight power loss induced by the 
interim analyses (see section 11.6). 
In summary, 128 subjects (64 per study arm) are necessary to reach the study primary 
objective with the required power. 
11.2.1 
Required number of primary endpoint events 
The required number of primary endpoint events is 62, as calculated with the formula: 

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

)
log(
25
.0
2
2
/
HR
z
z
events




 
where 
2
/
z
 and 
z
 are the standard normal percentiles (=0.05, =0.20), HR is the expected 
hazard ratio. A HR of about 0.49 was calculated assuming an exponential model of the survival 
functions with proportional hazard rates. 
11.3 Level of significance and the power of the study 
Target study power: 80% 
Significance level: 0.05 (bilateral) 
11.4 Expected drop-out rate 
Loss incidence: 10% (both arms) 
11.5 Pass/fail criteria  
The clinical investigation is deemed to be passed if the alternative hypothesis of the primary 
endpoint is reached. 
11.6 Provision for interim analyses 
Interim analyses will be performed at t = 0.4 and 0.7 of the required primary endpoint events 
or, equivalently, after 25 and 43 endpoint events will be collected. 
The final analysis will be performed after the study database has been closed out. 
In order to keep the overall type I error at the level of 0.05, two-sided, symmetric O’Brien–
Fleming boundaries generated with the Lan–DeMets spending function approach to group-
sequential testing will be assumed as early stopping rules for efficacy. 
t 
0.40 
0.70 
1.00 
No. endpoint events 
25 
43 
62 
Zup 
3.3569 
2.4445 
2.0005 
Zlow 
-3.3569 
-2.4445 
-2.0005 
p 
0.0008 
0.015 
0.05 
 

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Figure 2. Sequential boundaries during interim analyses. R Software version 3.1.0 (2014-04-
10). 
11.7 Termination criteria 
With a sequential study design the study will stop when a total of 62 primary endpoint 
events will be collected by the independent agency. The following stopping rules will be used. 
11.7.1 
Stopping Rules 
1. The CCI will be informed monthly by the CRO about the total number of patients who will 
experience a syncope recurrence (primary endpoint event). 
2. When the number of events will reach1 the predefined limits for interim analyses (40% and 
70% of the expected number of events), open queries will be resolved and on site 
monitoring visits for source data verification will be performed. 
3. Unclassified primary endpoint events will be adjudicated (see section 9.9). If available 
primary endpoint events will be less than the predefined limits for interim analyses after 
the adjudication process, endpoint point event collection will continue until the required 
number will be reached. 
4. When data set will be cleaned the clinical project manager of the study will inform the 
appointed independent statistician. 
5. The independent statistician will analyze the data according to the Statistical Analysis Plan 
(SAP). The results will be communicated to the CCI and the sponsor of the study. If the 
                                           
1 The number of events may exceed the programmed limit whenever 2 or more events occur 
at the same time. 

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primary objective is reached the study stops immediately. The stop date of the study is 
the date of insertion in the database of the last syncopal recurrence. If the primary 
objective is not reached the independent statistician will recommend to continue the study 
until 62 events will be collected. Investigators will not be informed of the results of the 
interim analyses. 
6. After study closure investigators shall complete missing data (apart from the primary 
events) and close open queries within the following 2 months. Events occurring after the 
stop date shall not be considered either for primary or for secondary endpoints. 
11.8 Procedures for reporting of deviations to the statistical plan 
Deviations from the statistical plan are documented accordingly. 
11.9 Specification of subgroups 
No subgroups are pre-specified. 
11.10 
Procedure for accounting of all data for analysis 
The required strict adherence to the monitoring plans of the respective reference studies will 
ensure acquisition of all data. 
11.11 
Handling of missing, unused and spurious data 
Missing or spurious data is not substituted; all data – as far as correctly measured – is 
analyzed. 
11.12 
Exclusion of data from confirmatory data analysis 
In some cases, particular clinical data is excluded from analysis. The following reasons 
are possible: 
 
Data is not measured as described in this clinical investigation plan. 
 
Data is evaluated beyond the required follow-up schedule. 
 
Patient has to be excluded because she/he does not fulfill the exclusion/inclusion 
criteria. 
 
Patient requires that all recorded data has to be deleted. 
 
There is no valid patient consent form available. 
11.13 
Minimum and maximum number of patients per site 
It may be expected that every 100 over-40 subjects undergoing a head up tilt test and 
reporting 3 or more syncopal episodes, about 50 of them would be positive, 12 would be 
eligible with a type 2B cardio-inhibitory response(18), 6 would accept to implant a pacemaker 
and about 3 to participate to the study, undergoing the randomization(19). Therefore only 
centers performing a high number of tilt test examinations per year (≥200 per year) may 
participate in the trial to effectively contribute to enrolment in a reasonable time period. Each 

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center should enroll at least 5 patients in the course of the study, in a competitive enrolment 
process. 

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12 
DATA MANAGEMENT 
The established Clinical Data Management System (CDMS) is “iMedNet” of the vendor MedNet 
Solutions, Inc. As a pure internet-based application that is used with the current versions of 
most internet browsers, there is no specific local software to support (cloud based “Software as 
a Service” SaaS). iMedNet supports industry standards (FDA 21CFR11, HIPAA and Safe 
Harbor). 
12.1 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. Errors, discrepancies, missing data, and entries out of range are resolved by 
automatically (CDMS) and manually (clinical monitor, data manager) generating data queries. 
The system supports detailed tracking of the query process. Corrections to eCRF can only be 
done by the designated site personnel and need to be signed by the investigator. All changes 
are automatically recorded in the system’s audit-trail. 
12.2 Procedures for verification, validation and securing of electronic 
data systems 
The Clinical Data Management System (CDMS) is hosted on a dedicated database server at the 
vendor MedNet Solutions, Inc. Only authorized users with fixed roles have access to the clinical 
database. The access is controlled and maintained by the Clinical Data Management. Every 
access is automatically logged and changes of the clinical data are stored in independent audit 
trails. The CDMS is verified and validated accordingly. The user interface and the internal 
business logic of the clinical database is validated accordingly and verified during the study 
related development and before release for data entry. 
An authenticated user account is created and maintained by BIOTRONIK for each authorized 
user once the user has completed appropriate training. Users are obligated to keep their 
password confidential. 
Depending on their role within the investigational study, users are limited to “read only” or 
may be given permits to enter or update data, provide resolutions to queries and apply 
electronic signatures. Only investigators are allowed to sign the entries. 
12.3 Procedures for data retention 
All study related electronic documents are stored in the archive of BIOTRONIK which provides 
storage conditions free from risk of fire, flood, theft and vermin. The access to the files is 
controlled. 
After database closure, all eCRF data and the audit trail and other relevant database content 
are exported and stored electronically on the archive server. 
12.4 Specified retention period 
All electronic documents and exported data from relevant databases are stored for at least 15 
years. 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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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 Clinical Investigator. All investigators have to acknowledge the receipt of an 
amendment by signing an amendment agreement form. 
Before implementation of any changes, substantial amendments have to be approved by the 
Ethics Committee (EC) and – if applicable – by the Competent Authority (CA). Non substantial 
amendments are submitted for notification only. 
The investigator should not implement any deviation from or changes to the CIP without 
agreement of the sponsor and prior review and documented approval from the EC (and CA if 
required). The only exception is the necessity to eliminate an immediate hazard to the 
subjects, or when the change involves only logistical or administrative aspects of the study. 

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DEVIATIONS FROM CLINICAL INVESTIGATION PLAN 
14.1 13.1 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, as well as 
applicable amendments. Deviations that are likely to seriously affect or that actually have 
seriously affected the rights or safety or wellbeing of subjects or the scientific integrity of the 
clinical investigation are major deviations. Otherwise they are minor deviations. 
Erroneous, spurious or missing data in a CRF is not a deviation in itself and is handled 
according to the query processes described in the data management section of this CIP. 
However, the underlying reason might be a deviation. 
Under emergency circumstances, deviations from the CIP to protect the rights, safety and 
well-being of human subjects may proceed without prior approval of the sponsor and the 
ethics committee. 
14.2 Recording, reporting and analyzing deviations 
14.2.1 
Site specific deviations 
Investigational sites inform the monitor immediately about any deviation 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 recorded by monitors in the respective site deviation log 
and assessed for the need of corrective or preventive actions. Additional information on the 
type of deviation, actions taken and outcome may be recorded in the monitoring visit 
reports. All information from site deviation logs is consolidated by the sponsor in one overall 
study deviation log. 
14.2.2 
Other deviations 
Deviations by sponsor personnel or third parties are reported immediately to the sponsor by 
anyone who becomes aware of it. They are recorded in the study deviation log and assessed 
for the need of corrective or preventive actions. 
14.2.3 
Reporting 
Deviations are reported in the interim and final clinical investigation reports.  
14.3 Notification requirements and timelines 
The sponsor records specific notification requirements of the involved ethics committees and 
competent authorities and assures that the required timelines are respected. 

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14.4 Corrective and preventive actions and disqualification criteria 
Corrective actions are taken in order to repair or to avoid any negative consequences caused 
by a deviation. Preventive 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 log 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 by the sponsor and filed in the central file and, in the case of site specific 
deviations, in the respective investigator site file. 
Disqualification of study personnel or investigational sites is the ultimate escalation step of 
preventive actions. This means that in case of major deviations that seriously affect the safety 
and well-being of subjects or that bear a high risk of refusal of the clinical data and mistrust to 
the results of the study and that are likely to reappear despite other actions, the responsible 
person or investigational site is excluded from further conduct of the study, unless this action 
would jeopardize the rights, safety or welfare of the patients. 

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DEVICE ACCOUNTABILITY 
Investigational devices which are not approved for an overall market release are labeled 
“Exclusively for clinical investigations” and have to be stored under special conditions.  
The sponsor keeps records to document the physical location of all investigational devices from 
shipment of investigational devices to the investigation sites until usage, disposal or return. An 
electronic central device accountability log is used for the documentation of the whole process.  
Access to investigational devices is controlled and the devices are used in the clinical 
investigation only and according to the CIP. 
The principal investigator or an authorized designee shall keep records documenting the 
receipt, usage, return and disposal of the investigational devices. A site device accountability 
log is used for the site specific documentation. 
The responsible field CRA checks the storage, usage and documentation and verifies the 
completeness of the site device accountability log with the entries in iMedNet, the source data 
and the electronic central device accountability log regularly during his/her visits.  
The information of the site device accountability log will be incorporated in the central device 
accountability log by the responsible BIOTRONIK personnel. After the closure of the study, the 
summary of this log will be used for the final report. 

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STATEMENT OF COMPLIANCE 
16.1 Applicable ethical standards 
The study will be conducted in compliance with the principles that have their origin in the 
Declaration of Helsinki (current version).  
The study will be registered at the publicly accessible database ClinicalTrials.gov. 
16.2 Applicable international and national standards 
The study will be conducted in compliance with: 
 
the international standard ISO 14155 (current version) “Clinical investigation of medical 
devices for human subjects – Good clinical practice”.  
 
the international standard ISO 14971 (current version) "Application of risk management 
to medical devices“. 
The study will also be conducted according to the applicable national legal requirements of the 
participating investigation sites. 
16.3 Ethics committee and competent authority 
The study will not begin at an investigation site until favorable opinion of the responsible ethics 
committee has been obtained for that site and approval of the competent authority (if 
applicable) has been granted for the conduct of the study in the respective country.  
16.4 Statement of adherence to additional requirements 
If any additional requirements will be imposed by an ethics committee or a competent 
authority, these requirements will be followed, if appropriate. 
16.5 Statement on subject insurance 
All participants of this clinical study are insured against study related injury according to 
applicable provisions of law. 
The insurance of the sponsor does not relieve the investigator and the collaborators of any 
obligation to maintain their own liability policy. 

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INFORMED CONSENT PROCESS 
A patient information form including the informed consent form has been prepared by the 
Project Manager. The content of this document needs to be reviewed and approved by the 
ethics committee, and suggested changes need to be implemented. 
17.1 General considerations 
The informed consent procedure is performed by the Principal Investigator or any investigator 
designated for this task as recorded in the delegation of duties log. The investigator has to 
fully inform the patient of all pertinent aspects of the clinical investigation in language and 
terms she/he is able to understand. When the patient agrees in the study participation the 
written informed consent form shall be personally dated and signed by the patient and by the 
investigator who performed the informed consent discussion. The result of the informed 
consent process is documented in the patients hospital chart by the investigator. A copy of the 
signed and dated written informed consent form is provided to the patient. 
The investigator ensures that no subjects are included in this clinical study who are unable to 
give informed consent by selecting patients with age  18 years, who understand the nature of 
the procedure.  
By signing the informed consent form, the patient is included in the study. Only after that 
procedure any study specific procedure is performed. Pre-screening of the patient chart in 
respect to the inclusion and exclusion criteria is not a study specific 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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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 
EDC system. The indicated timelines for reporting of initial cases and possible update reports 
shall be strictly followed.  
According to ISO 14155:2011 events will be classified on the basis of the definitions below. 
18.1 Definition of adverse events 
An AE is defined* as any untoward medical occurrence, unintended disease or injury, or 
untoward clinical signs (including abnormal laboratory findings) in subjects, users or other 
persons whether or not related to the investigational medical device. This includes: 
 
Events related to the investigational medical device or the comparator 
 
Events related to the procedures involved  
 
For users or other persons, this definition is restricted to events related to the 
investigational medical devices. 
It is worth specifying that syncope, pre-syncope, heart rate and blood pressure drop during the 
1-month TT which do not result in any consequence of a SAE shall not be reported as adverse 
events, as intended events and part of the test itself. If these events will result in any 
consequence of a SAE, then they will be definitively reported. 
 
*see ISO14155 3.2 
18.2 Definition of adverse device effects 
An adverse device effect (ADE)* is an AE that is related to the use of an investigational 
medical 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 ISO14155 3.1 
 
 
18.2.1 
Causality Assessment 
The relationship between the use of the investigational device (including the medical-surgical 
procedure) and the occurrence of each adverse event shall be assessed and categorized, 
considering the presence of confounding factors, such as concomitant medication and 
treatment, the natural history of the underlying disease, other concurrent illness or risk 
factors.  
Each SAE will be classified according to five different levels of causality. As defined in the 
Meddev 2.7/3 rev 3, the investigator will use the following definitions to assess the relationship 
of the serious adverse event to the investigational medical device or procedures: 

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Not related: the relationship to the device or procedures can be excluded 
Unlikely: the relationship with the use of the device seems not relevant and/or the event can 
be reasonably explained by another cause, but additional information may be obtained. 
Possible: the relationship with the use of the investigational device is weak but cannot be 
ruled out completely. Alternative causes are also possible (e.g. an underlying or concurrent 
illness/ clinical condition or/and an effect of another device, drug or treatment). Cases were 
relatedness cannot be assessed or no information has been obtained should also be classified 
as possible. 
Probable: the relationship with the use of the investigational device seems relevant and/or 
the event cannot reasonably explained by another cause, but additional information may be 
obtained. 
Causal relationship: the serious event is associated with the investigational device or with 
procedures beyond reasonable doubt. 
The investigators will distinguish between the serious adverse events related to the 
investigational device and those related to the device procedures (any procedure specific to 
the investigational device). Procedure related events refer to the procedure related to the 
application of the investigational medical device only and therefore not to any other procedure 
for other devices and not to any other procedures or treatments applied later throughout the 
clinical investigation, for instance to treat (serious) adverse events. In case of a replacement 
of the investigational device in response to an adverse event (e.g. pacemaker replacement due 
to battery depletion or malfunction), the replacement will be considered like an initial 
application of a new investigational device and shall be assessed accordingly. 
An adverse event can be related both to the procedure and the investigational device. 
Complications of procedures are considered not related if the said procedures would have been 
applied to the patients also in the absence of investigational device use or application. For 
example, in the active arm of this clinical investigation, a cardiac perforation with the right 
ventricular lead will not be considered as related to the procedure of investigational device use 
since the right ventricular lead is not specific for the use of the investigational pacemaker. 
18.3 Definition of device deficiency 
Device deficiency (DD)* is defined as inadequacy of a medical device with respect to its 
identity, quality, durability, reliability, safety, or performance, including malfunctions, use 
errors and inadequate labeling.  
*see ISO14155 3.15 
DDs of the investigational device shall be documented throughout the study. DDs which 
caused an adverse event are reported on the respective adverse event form. In case the DD 
did not cause an adverse event the provided DD form shall be used to document this “non-
medical” event.  
If a DD could have led to a SADE,  
 
if either suitable action had not been taken, 
 
if intervention had not been made, or 
 
if circumstances had been less fortunate, 
the DD is classified as an DD with an SADE potential.  
18.4 Definition of serious adverse events 
AEs are classified as serious* if one or more of the following consequences are fulfilled: 
 
led to death 

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 
led to serious deterioration in the health of the subject, that either resulted in 
 
a life-threatening illness or injury, or 
 
a permanent impairment of a body structure or a body function, or 
 
in-patient or prolonged hospitalization, or 
 
medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function. 
 
led to fetal distress, fetal death or a congenital abnormality or birth defect. 
Note: Planned hospitalization for a pre-existing condition, or a procedure required by the CIP, 
without serious deterioration in health, is not considered a serious adverse event. 
*see ISO14155 3.37 
In-patient hospitalization is defined as at least one overnight stay (change of date) in a 
hospital. In case, a patient is only for some hours in the hospital (without change of date), this 
event will not be documented as serious, unless one or more of the other seriousness criteria 
are fulfilled.  
18.5 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 ISO14155 3.6 
18.6 Definition of unanticipated serious adverse device effects 
SADEs* are defined as unanticipated if by their nature, incidence, severity or outcome they 
have not been identified in the current version of the risk analysis report.  
*see ISO14155 3.42 
These events must be reported to the sponsor immediately.  
A root-cause analysis will be performed and the possibility of reoccurrence will be evaluated 
immediately. 
Note: Anticipated serious adverse device effect (ASADE) is an effect which by its nature, 
incidence, severity or outcome has been identified in the risk analysis report. 
18.7 Anticipated adverse events 
See Section 6.2.1. 
18.8 Reporting responsibilities 
18.8.1 
Reporting responsibilities of the investigator to sponsor 
The investigator shall document all events on the respective CRF pages provided within the 
EDC system. 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 SAE-CRF in accordance with ISO 
14155:2011.  

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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 with a primary diagnose 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. 
18.8.2 
Reporting responsibilities of the investigator to other parties, if applicable 
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 fulfill the reporting obligations 
of their local competent authorities and EC/IRBs. 
 
 
 
 
 
Table 5. Event reporting line and time line 
Event 
Report to 
Timeline 
Adverse Event (AE) / 
Adverse Device Effect 
(ADE) 
CCR BIOTRONIK SE & Co. KG:  
Documentation in the AE CRF  
Within 2 weeks 
 
Serious Adverse Event 
(SAE) / Serious 
Adverse Device Effect 
(SADE) 
CCR BIOTRONIK SE & Co. KG: 
Documentation in AE-CRF 
 
 
Immediately, latest 
24h after detection 
 
Unanticipated Serious 
Adverse Device Effect 
(USADE) 
CCR BIOTRONIK SE & Co. KG: 
Documentation in AE-CRF 
 
 
Immediately, latest 
24h after detection 
Immediately 
Device Deficiencies 
CCR BIOTRONIK SE & Co. KG: 
Documentation in the DD-CRF 
 
Within 14 days 
 
Device Deficiency with 
SADE potential 
CCR BIOTRONIK SE & Co. KG: 
Documentation in DD-CRF 
 
Within 24 hours 
 
 
 

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18.8.3 
Reporting responsibilities of the sponsor, if applicable 
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 Ethics committees depending on the local requirements.  
BIOTRONIK SE & Co. KG will inform the investigators about all reported SAEs and DDs that 
could have led to a SADE on a regular basis. As a proposal, regular listings may be provided 
quarterly and unanticipated serious adverse device effects (USADEs) shall be reported 
immediately. 
18.9 Reporting timelines 
18.10 
Emergency contact 
A contact address for patients in case of emergency will be provided in the individual patient 
informed consent forms. 
In case technical support is needed the service hotline of BIOTRONIK is available 24 hours a 
day. Phone: +49 (0) 30 68905-1133. 
18.11 
Data safety monitoring committee 
The Data Safety Monitoring board will consist of the same members of the Endpoint 
Adjudication Board (see section 9.9). 

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VULNERABLE POPULATION 
No vulnerable population is expected to be consented for this clinical investigation. 

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SUSPENSION 
20.1 Criteria and procedures 
Suspension or premature study termination may occur due to several reasons: 
 
On behalf of the sponsor 
 
On behalf of the investigator/Steering Committee 
 
On behalf of the IRB/EC 
The sponsor is authorized to terminate the clinical study prematurely due to relevant medical/ 
organizational reasons.  
A consultation of all parties involved prior to study termination is preferable. Reasons for 
premature study termination should be documented in an adequate way. 
The sponsor has the right for premature study termination of the whole study, of single study 
phases, or to exclude single investigational sites from further study participation.  
Reasons for termination may be: 
 
Occurrence of severe Adverse Events that result in a non-acceptable risk for further 
study participation. 
 
The number of premature study terminations exceeds the tolerable percentage of drop-
outs so that proper completion of the study cannot be expected anymore. 
 
Insufficient enrollment rates so that proper completion of the study cannot be expected 
anymore. 
 
Results from other clinical trials indicate a non-tolerable risk for further conduction of this 
study. 
 
Attempted fraud or fraud that may be evidenced. 
 
Poor data quality 
 
Missing compliance of the respective investigator or study site (e.g. protocol violations). 
In case the study sponsor decides to suspend or prematurely terminate the study, the sponsor 
is required to promptly notify the investigator(s) to whom the decision applies. The 
investigator will inform the IRB/EC of this decision. The investigator will also promptly inform 
all patients enrolled at the investigational site and are still actively participating. Patients that 
already left the study shall be informed if they might be affected by safety aspects. 
In case of any reasonable ethical concern of the investigator regarding a further study conduct 
in the respective investigational site, the sponsor shall be informed immediately. 
If the investigator decides to suspend or prematurely terminate the study at his/her site 
he/she will promptly inform the study sponsor, the IRB/EC and all enrolled patients of this 
decision. 
If the IRB/EC decides to suspend or prematurely terminate the study, the investigator will 
promptly inform the study sponsor (or vice versa, as applicable) and all enrolled patients of 
this decision. 
The eCRF for “Study Termination” has to be completed in all of the above cases. 
All open eCRFs have to be completed as far as possible by the investigational site. 
Whatever the reason for early or natural study termination, the final dataset will be available 
to the CCI and the Steering Committee for analysis and publishing. A final study report will be 
generated. 

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20.2 Un-blinding procedures 
The subjects enrolled in this study and the CRO personnel collecting self-administered patients' 
questionnaires will be blinded to the treatment assigned by the randomization procedure 
throughout the study course, until a termination criterion occurs (see section 8.8.6) 
The investigators and study site staff may not be blinded, however they should not disclose 
the assignment both to patients and CRO personnel during study-related procedures, until the 
patient study termination (see Section 8.8.6). As the ITT principle will be used, investigators 
should not disclose the IPG pacing mode programmed even in case of crossover. 
20.3 Requirements for subject follow-up 
In case of a study suspension no new patients will be enrolled until the suspension has been 
lifted. During the suspension, follow-up and data collection will continue as per CIP. If the 
suspension is due to an MEC/IRB decision, additional requirements from the MEC/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 will be informed on this procedure in written form in the patient informed consent 
form. 

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PUBLICATION POLICY 
The first author of the primary publications will be Dr. Brignole, CCI and chairman of the 
Steering Committee of the BIOSync CLS trial. Dr Brignole will be responsible for the 
preparation of the final study report and of the manuscript of the main paper which must be 
approved by the Steering Committee before submission for publication 
The authors of the primary publication will be 10 investigators (or more, depending on the 
journal requirements) with the highest scores. A minimum of 5 members of the Steering 
Committee is warranted. All the members of the Steering Committee will always be cited in 
any publication of study results. 
Each Investigator will receive: 
 
1 point for each enrolled subject 
 
1 point for each enrolled subject with complete and compliant data set (by source data 
verification) 
 
+0.25 points for each compliant and fully reported scheduled in-hospital follow-up 
 
-0.25 points for each unreported or incompliant (e.g., out of window) scheduled follow-
up visit 
 
-1 point for each underreported or delayed reported Serious Adverse Event, and 
(Serious) Adverse Device Effect. 
The study design may be submitted for publication and the authors of this publication will be 
the members of the SC. Case reports cannot be submitted for publication by the investigators 
before the paper on the study design has been published. 
Publication of sub-analysis will be submitted after the first main publication and the proposing 
center will have 2 or more authors. Sub-analysis must be approved by the Steering 
Committee. 

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BIBLIOGRAPHY 
(1) 
Authors/Task Force Members. 2013 ESC Guidelines on cardiac pacing and cardiac 
resynchronization therapy: The Task Force on cardiac pacing and resynchronization therapy of 
the European Society of Cardiology (ESC). Developed in collaboration with the European Heart 
Rhythm Association (EHRA). European Heart Journal (2013) 34, 2281–2329 
(2) 
Ammirati F, Colivicchi F, Santini M. Permanent cardiac pacing versus medical treatment 
for the prevention of recurrent vasovagal syncope: a multicenter, randomized, controlled trial. 
Circulation 2001;104:52–57. 
(3) 
Sutton R, Brignole M, Menozzi C, Raviele A, Alboni P, Giani P, Moya A. Dualchamber 
pacing in the treatment of neurally mediated tilt-positive cardio-inhibitory syncope : 
pacemaker versusno therapy: amulticenter randomized study.The Vasovagal Syncope 
International Study (VASIS) Investigators. Circulation 2000;102: 294–299. 
(4) 
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