BIO monitorinG in Patients With Preserved Left ventricUlar Function AfteR Diagnosed Myocardial Infarction
Phase: NA
Conditions: Myocardial Infarction, Myocardial Infarction, Acute, Myocardial Infarction Old
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. 
 
 
Center for Clinical Research 
Version 7.0; April 06, 2021 
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FOR-137-014-A / SOP-137-020.020 / CRQ-13-00841 
 
 
 
 
 
 
Clinical Investigation Plan 
BIO|GUARD-MI Study 
 
BIO monitorinG in patients with preserved 
left ventricUlar function AfteR Diagnosed 
Myocardial Infarction 
 
 
 
 
Reference Number HS058 
Version 7.0 
April 06, 2021 
 
 
 

BIOTRONIK SE & Co KG 
BIO|GUARD-MI 
 
 
 
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4/101 
 
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Signature of the Principal Investigator 
 
 
 
Name: 
_________________________________________________________ 
 
 
Institution: 
_________________________________________________________ 
 
 
 
_________________________________________________________ 
 
 
Street: 
_________________________________________________________ 
 
 
ZIP code/ City: _________________________________________________________ 
 
 
Country: 
_________________________________________________________ 
 
 
 
 
 
 
➢ I carefully read and fully understood the clinical investigation plan (CIP). I agree to 
conduct the study according to the clinical investigation plan, the Declaration of 
Helsinki, ISO 14155 and all other applicable legal requirements. 
➢ I understand that changes to the clinical investigation plan may only be performed 
after consultation of the coordinating clinical investigator, the clinical project 
management and after amendment submission and approval by the ethics 
committee and regulatory authorities (if applicable). 
➢ I agree to inform all involved personnel on the requirements of the clinical 
investigation plan and ensure that the study will be conducted according to the CIP. 
➢ I agree to report every occurring Adverse Event and Device Deficiency according to 
the timelines and regulations indicated in the CIP. 
 
 
 
_________________________ 
____________________________________________ 
City, date 
Signature of Principal Investigator 
 

BIOTRONIK SE & Co KG 
BIO|GUARD-MI 
 
 
 
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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................. 5 
1 
LIST OF ABBREVIATIONS ................................................................................. 10 
2 
SYNOPSIS ......................................................................................................... 13 
3 
INTRODUCTION ................................................................................................ 18 
4 
INVESTIGATIONAL DEVICE............................................................................... 21 
4.1 
Summary description of the investigational device and its intended purpose ............. 21 
4.2 
Manufacturer .................................................................................................... 21 
4.3 
Model name including software version and accessories .......................................... 21 
4.4 
Description of traceability ................................................................................... 21 
4.5 
Intended purpose and patient population of the device in the study ......................... 22 
4.6 
Description of the investigational device ............................................................... 22 
4.6.1 
BIOTRONIK Home Monitoring® with daily sECGs ................................................ 22 
4.7 
Summary of training and experience needs ........................................................... 22 
4.7.1 
Description of medical and surgical procedures .................................................. 23 
5 
JUSTIFICATION FOR THE DESIGN OF THE CLINICAL INVESTIGATION .............. 24 
5.1 
Pre-clinical data ................................................................................................. 24 
5.2 
Clinical data ...................................................................................................... 24 
5.2.1 
Clinical data to support the safety and efficacy of the BioMonitor ......................... 24 
5.2.1.1 
The BM01 acute study ................................................................................ 24 
5.2.1.2 
BioMonitor Master Study ............................................................................. 24 
5.2.1.3 
BIO|MASTER.BioMonitor 2 Study ................................................................. 25 
5.2.1.4 
BioInsight Study ........................................................................................ 25 
5.2.2 
Clinical data to support the design of the BIO|GUARD-MI study ........................... 26 
5.3 
Justification of the design ................................................................................... 27 
6 
RISKS AND BENEFITS OF THE DEVICE AND CLINICAL  INVESTIGATION ........... 28 
6.1 
Anticipated clinical benefits ................................................................................. 28 
6.1.1 
Benefits for patients randomized to the BioMonitor group ................................... 28 
6.1.2 
Benefits for patients randomized to the control (non-BioMonitor) group ................ 28 
6.1.3 
Benefits for future patients ............................................................................. 28 
6.2 
Anticipated risks ................................................................................................ 28 
6.2.1 
Anticipated adverse device effects ................................................................... 28 
6.2.2 
Residual risks associated with the device .......................................................... 29 
6.2.3 
Risk associated with participation in the study ................................................... 29 
6.2.4 
Possible interactions with concomitant medical treatments .................................. 30 
6.3 
Steps to control or mitigate the risks .................................................................... 30 
6.4 
Risk-to-benefit rationale ..................................................................................... 30 
7 
OBJECTIVES AND HYPOTHESES ........................................................................ 31 
7.1 
Objectives ........................................................................................................ 31 
7.1.1 
Primary objectives ......................................................................................... 31 
7.1.2 
Secondary objective: Arrhythmia detection ....................................................... 31 
7.1.3 
Other secondary objectives ............................................................................. 31 
7.1.3.1 
All-cause mortality ..................................................................................... 31 
7.1.3.2 
Cardiovascular death .................................................................................. 31 
7.1.3.3 
Worsening of the patient status due to heart failure ....................................... 31 
7.1.3.4 
Hospitalization resulting from arrhythmia ...................................................... 31 
7.1.3.5 
Hospitalization resulting from acute coronary syndrome ................................. 31 
7.1.3.6 
Hospitalization or death resulting from stroke ................................................ 31 
7.1.3.7 
Major bleeding requiring hospitalization ........................................................ 32 
7.1.3.8 
Systemic embolism requiring hospitalization ................................................. 32 
7.1.3.9 
Arrhythmias .............................................................................................. 32 

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7.1.3.10 
Type of initiated therapies........................................................................... 32 
7.1.3.11 
Therapies.................................................................................................. 32 
7.1.3.12 
Quality of Life (QoL) ................................................................................... 32 
7.2 
Primary hypotheses ........................................................................................... 32 
7.3 
Secondary hypotheses ....................................................................................... 33 
7.4 
Safety assessments ........................................................................................... 33 
8 
DESIGN OF THE CLINICAL INVESTIGATION ...................................................... 34 
8.1 
General considerations ....................................................................................... 34 
8.2 
Measures taken to minimize or avoid bias ............................................................. 35 
8.2.1 
Randomization .............................................................................................. 35 
8.2.2 
Blinding ........................................................................................................ 35 
8.2.3 
Other ........................................................................................................... 35 
8.2.4 
Final Study Termination Visit ........................................................................... 36 
8.3 
Endpoints ......................................................................................................... 36 
8.3.1 
Primary endpoint ........................................................................................... 36 
8.3.1.1 
Endpoint assessment definitions .................................................................. 38 
8.3.2 
Secondary endpoint: Time to first arrhythmia detection ...................................... 38 
8.3.3 
Other secondary endpoints ............................................................................. 38 
8.3.3.1 
Time to death from any cause or heart transplantation ................................... 39 
8.3.3.2 
Time to cardiovascular death or heart transplantation .................................... 39 
8.3.3.3 
Time to first worsening of the patient status due to heart failure requiring 
hospitalization or urgent visit ...................................................................... 39 
8.3.3.4 
Time to first hospitalization resulting from an arrhythmia................................ 39 
8.3.3.5 
Time to first hospitalization resulting from acute coronary syndrome ................ 39 
8.3.3.6 
Time to first hospitalization resulting from stroke ........................................... 40 
8.3.3.7 
Time to first hospitalization resulting from major bleeding .............................. 40 
8.3.3.8 
Time to first hospitalization resulting from systemic embolism ......................... 40 
8.3.3.9 
Time to first arrhythmia .............................................................................. 40 
8.3.3.10 
Type of initiated therapies........................................................................... 40 
8.3.3.11 
Time to first therapy .................................................................................. 40 
8.3.3.12 
Quality of Life (QoL) ................................................................................... 40 
8.4 
Further data of interest ...................................................................................... 40 
8.4.1 
CRF and Forms .............................................................................................. 41 
8.4.1.1 
Enrollment Form ........................................................................................ 42 
8.4.1.2 
Baseline Form ........................................................................................... 43 
8.4.1.3 
Implantation Form ..................................................................................... 43 
8.4.1.4 
Discharge Form ......................................................................................... 43 
8.4.1.5 
Adverse events .......................................................................................... 44 
8.4.1.6 
Device deficiency ....................................................................................... 44 
8.4.1.7 
ERI form ................................................................................................... 44 
8.4.1.8 
Study termination Forms ............................................................................ 44 
8.4.1.9 
Further eCRFs and forms ............................................................................ 44 
8.5 
Device replacement or explantation ..................................................................... 45 
8.5.1 
Device replacement ....................................................................................... 45 
8.5.2 
Device explantation ....................................................................................... 45 
8.6 
Equipment to be used for the assessment of variables ............................................ 45 
8.7 
Replacement of subjects ..................................................................................... 45 
8.8 
Used devices and comparators ............................................................................ 45 
8.9 
Subjects ........................................................................................................... 45 
8.9.1 
Description of patient collective ....................................................................... 46 
8.9.2 
Inclusion criteria ............................................................................................ 46 
8.9.2.1 
Definition of CHA2DS2-VASc-Score ............................................................... 46 
8.9.3 
Exclusion criteria ........................................................................................... 47 
8.9.4 
Drop-out criteria ............................................................................................ 47 
8.9.4.1 
General .................................................................................................... 47 
8.9.4.2 
Patient death ............................................................................................ 48 

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8.9.4.3 
Withdrawal of patient consent ..................................................................... 48 
8.9.4.4 
Loss to follow-up ....................................................................................... 48 
8.9.4.5 
Early discovery of a violation of inclusion or exclusion criteria .......................... 49 
8.9.4.6 
Investigator initiated drop-out ..................................................................... 49 
8.9.5 
Point of enrollment and study termination ......................................................... 49 
8.9.6 
Timelines ...................................................................................................... 50 
9 
STUDY PROCEDURES ........................................................................................ 51 
9.1 
Overview .......................................................................................................... 51 
9.2 
Enrollment, Baseline and Randomization .............................................................. 51 
9.3 
Implantation ..................................................................................................... 52 
9.4 
Discharge ......................................................................................................... 52 
9.5 
Home Monitoring Analysis ................................................................................... 52 
9.6 
Telephone follow-up ........................................................................................... 53 
9.7 
Study Termination ............................................................................................. 54 
9.8 
Description of those activities performed by sponsor representative ......................... 55 
9.8.1 
Responsibilities of the Endpoint and Adverse Event Board (EAEC) ........................ 55 
9.8.2 
Responsibilities of the Data Safety Monitoring Board (DSMB) .............................. 55 
9.8.3 
Responsibilities of the Steering Committee ........................................................ 55 
9.8.4 
Responsibilities of the Publication Steering Committee (PSC) .............................. 56 
9.8.5 
Responsibilities of the Central Electrocardiogram Monitoring Board (CEMB) ........... 56 
9.8.6 
Responsibilities of the Contract Research Organisation (CRO) .............................. 56 
9.9 
Responsibilities of the investigator ....................................................................... 56 
9.9.1 
Responsibilities of the Principal Investigator ...................................................... 56 
9.9.2 
Responsibilities of the coordinating investigator (CI) and in Germany “Leiter 
klinische Prüfung” (LKP) ................................................................................. 58 
10 
MONITORING PLAN .......................................................................................... 59 
11 
STATISTICAL CONSIDERATIONS ...................................................................... 61 
11.1 
Statistical design, method and analytical procedures .............................................. 61 
11.1.1 
Statistical design ........................................................................................... 61 
11.1.2 
Full Analysis set based on the ITT principle ....................................................... 61 
11.1.3 
Per-Protocol Analysis Set ................................................................................ 61 
11.1.4 
Statistical methods ........................................................................................ 62 
11.2 
Sample size ...................................................................................................... 62 
11.3 
Level of significance and the power of the study .................................................... 63 
11.4 
Expected drop-out rate ....................................................................................... 63 
11.5 
Pass/fail criteria ................................................................................................. 63 
11.6 
Provision for an interim analysis .......................................................................... 63 
11.7 
Termination criteria............................................................................................ 63 
11.8 
Procedures for reporting of deviations to the statistical plan .................................... 63 
11.9 
Specification of subgroups .................................................................................. 64 
11.10 Procedure for accounting of all data for analysis .................................................... 64 
11.11 Handling of missing, unused and spurious data ..................................................... 64 
11.12 Exclusion of data from confirmatory data analysis .................................................. 65 
11.13 Minimum and maximum number of patients per site .............................................. 65 
12 
DATA MANAGEMENT ......................................................................................... 66 
12.1 
Data protection ................................................................................................. 66 
12.2 
Data collection .................................................................................................. 66 
12.3 
Procedures used for data review, CDMS cleaning, and issuing and resolving data 
queries ............................................................................................................. 67 
12.4 
Procedures for verification, validation and securing of electronic data systems .......... 67 
12.5 
Data retention and archiving ............................................................................... 68 
13 
AMENDMENT PROCEDURES ............................................................................... 69 
14 
DEVIATIONS FROM CLINICAL INVESTIGATION PLAN ....................................... 70 
14.1 
CIP compliance and exceptions ............................................................................ 70 

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14.2 
Recording, reporting and analysing deviations ....................................................... 70 
14.2.1 
Site specific deviations ................................................................................... 70 
14.2.2 
Other deviations ............................................................................................ 71 
14.2.3 
Reporting...................................................................................................... 71 
14.3 
Notification requirements and timelines ................................................................ 71 
14.4 
Corrective and preventive actions and disqualification criteria ................................. 71 
15 
DEVICE ACCOUNTABILITY ................................................................................ 72 
16 
STATEMENT OF COMPLIANCE ............................................................................ 73 
16.1 
Applicable ethical standards ................................................................................ 73 
16.2 
Applicable international and national standards ..................................................... 73 
16.3 
Ethics committee and competent authority ........................................................... 73 
16.4 
Statement of adherence to additional requirements ............................................... 73 
16.5 
Statement on subject insurance .......................................................................... 73 
17 
INFORMED CONSENT PROCESS ......................................................................... 75 
17.1 
General considerations ....................................................................................... 75 
17.1.1 
Informing the patient ..................................................................................... 75 
17.1.2 
Allowing the patient ample time to decide ......................................................... 75 
17.1.3 
Documentation of the process ......................................................................... 76 
17.2 
Special circumstances for informed consent .......................................................... 76 
18 
ADVERSE EVENTS AND DEVICE DEFICIENCIES ................................................. 77 
18.1 
Definition of adverse events ................................................................................ 77 
18.2 
Definition of adverse device effects ...................................................................... 77 
18.2.1 
Causality assessment ..................................................................................... 78 
18.3 
Definition of Device Deficiency ............................................................................ 79 
18.4 
Definition of serious adverse events ..................................................................... 79 
18.5 
Definition of serious adverse device effect ............................................................ 80 
18.6 
Definition of unanticipated serious adverse device effects ....................................... 80 
18.7 
Anticipated adverse events ................................................................................. 80 
18.8 
Reporting responsibilities .................................................................................... 80 
18.8.1 
Reporting responsibilities of the investigator to sponsor ...................................... 80 
18.8.2 
Reporting responsibilities of the investigator to other parties ............................... 81 
18.8.3 
Reporting responsibilities of the sponsor ........................................................... 82 
18.9 
Reporting timelines ............................................................................................ 82 
18.10 Emergency contact ............................................................................................ 82 
19 
VULNERABLE POPULATION ............................................................................... 83 
20 
SUSPENSION .................................................................................................... 84 
20.1 
Criteria and procedures ...................................................................................... 84 
20.1.1 
Replacement strategy .................................................................................... 85 
20.2 
Un-blinding procedures ...................................................................................... 85 
20.3 
Requirements for subject follow-up ...................................................................... 85 
21 
PUBLICATION POLICY ...................................................................................... 86 
21.1 
Publication Steering Committee ........................................................................... 86 
21.2 
Authorship guidelines ......................................................................................... 86 
21.2.1 
Purpose ........................................................................................................ 86 
21.2.2 
Validity ......................................................................................................... 86 
21.2.3 
Authorship criteria ......................................................................................... 86 
21.2.4 
Justification and rules for the assessment of “acquisition of data”: ....................... 87 
21.2.5 
Calculation of the total score ........................................................................... 87 
21.2.6 
Authors’ tasks and responsibilities ................................................................... 88 
21.2.7 
Authorship of ancillary publications .................................................................. 88 
21.2.8 
Contributorship and acknowledgement ............................................................. 88 
21.2.9 
Timelines ...................................................................................................... 88 
21.2.10 Compliance ................................................................................................... 89 
21.2.11 Reimbursement ............................................................................................. 89 

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22 
BIBLIOGRAPHY ................................................................................................. 90 
23 
APPENDICES ..................................................................................................... 94 
23.1 
Appendix A: Comparison BIO|GUARD-MI CIP with U.S.-specific CIP amendments ...... 94 
 

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1 LIST OF ABBREVIATIONS 
ACS 
Acute coronary syndrome 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
AF 
Atrial Fibrillation 
AMI 
Acute Myocardial Infarction 
ASADE 
Anticipated serious adverse device effect 
ANF 
Arrhythmia Notification Form 
AV 
Atrioventricular 
BMI 
Body Mass Index 
bpm 
Beats per minute 
CA 
Competent authority 
CAG 
Coronary angiogram 
CI 
Coordinating Investigator 
CDMS 
Clinical Data Management System 
CDW 
Clinical Data Warehouse 
CE 
CE mark, a stylized "CE" (Conformité Européenne) placed on 
products to signify conformance with European Union regulations 
CEMB 
Central Electrocardiogram Monitoring Board 
CFR 
Code of Federal Regulations 
CHADS 
congestive heart failure, hypertension, age, diabetes, stroke 
CI 
Confidence Interval 
CIED 
Cardiac Implantable Electronic Device (ICD, PM, CRT (D) + ICM) 
CIP 
Clinical Investigation Plan 
CIR 
Clinical Investigation Report 
CRA 
Contract Research Associate 
CRF 
Case Report Form 
CRO 
Clinical Research Organization 
CRT-D 
Cardiac Resynchronization Therapy Defibrillator 
CV 
Curriculum Vitae 
DD 
Device Deficiency 
DSMB 
Data Safety Monitoring Board 
e.g. 
exempli gratia 
EAEC 
Endpoint and Adverse Event Committee 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
Electronic Data Capture 
EF 
Ejection Fraction 
EHRA 
European Heart Rhythm Association 
ENF 
Event Notification Form 
ESC 
European Society of Cardiology 
FDA 
US Food and Drug Administration (http://www.fda.gov/) 
FPI 
First Patient In 
FU 
Follow-up 
GCP 
Good Clinical Practice 
GNF 
General Notification Form 
h 
Hour 
H0 
Null Hypothesis 
HA 
Alternative Hypothesis 
HIPAA 
Health Insurance Portability and Accountability Act 
HM 
Home Monitoring 

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HMSC 
Home Monitoring Service Center 
HVR 
High ventricular rate 
HR 
Hazard ratio 
i.e. 
Id est 
IB 
Investigator’s Brochure 
ICD 
Implantable Cardioverter Defibrillator 
ICE 
Intracardiac Echocardiography 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use 
(www.ich.org) 
ICM 
Implantable Cardiac Monitor  
ICS 
Implant Control System (e.g. BIOTRONIK's ICS 3000) 
ID 
Identification Number 
IHF 
Provider of telephone follow-up services 
(IHF GmbH Institut für Herzinfarktforschung) 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization (www.iso.org) 
LA 
Left Atrium 
LKP 
Leiter der klinischen Prüfung 
LPO 
Last Patient Out 
LVEF 
Left Ventricular Ejection Fraction 
MACE 
Major Adverse Cardiac Event 
MedNet 
Supplier of Clinical Trial Software (MedNet Solutions, Inc. 
www.mednetstudy.com) 
MI 
Myocardial Infarction 
NSTEMI 
non-ST Segment Elevation Myocardial Infarction 
NYHA 
New York Heart Association 
OoS 
Out of Service 
p.a. 
per anno 
PCI 
Percutaneous Coronary Intervention 
PID 
Product ID 
PDF 
Portable Document Format (www.adobe.com) 
PI 
Principal Investigator 
PM 
Pacemaker 
PMCF 
Post Market Clincal Follow Up 
PPV 
Positive Predictive Value 
PSC 
Publication Steering Committee 
QoL 
Quality of Life 
QRS 
Electrical complex on an ECG related to the depolarization of the 
ventricles 
s 
Second 
Saas 
Software as a Service 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
SAS 
Statistics and Analysis Software produced by SAS Institute Inc. 
(www.sas.com) 
SAP 
Statistical Analysis Plan 
SDV 
Source Data Verification 
sECG 
subcutaneous Electrocardiogram 
StdDev 
Standard Deviation 
STEMI 
ST Segment Elevation Myocardial Infarction 
TIA 
Transient Ischemic Attack 
USADE 
Unanticipated Serious Adverse Device Effect 
USB 
Universal Serial Bus 

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V 
Volt 
VF 
Ventricular Fibrillation 
VT 
Ventricular Tachycardia  
WHO 
World Health Organization 

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2 SYNOPSIS 
 
Title: 
BIO monitorinG in patients with preserved left 
ventricUlar 
function 
AfteR 
Diagnosed 
Myocardial 
Infarction 
Study acronym: BIO|GUARD-MI study 
Patient collective: 
Patients with a history of myocardial infarction, 
CHA2DS2-VASc-Score ≥ 4 in men / ≥ 5 in women and 
left ventricular ejection fraction > 35 % 
Design: 
Prospective, controlled, randomized (1:1), parallel-
group, open, multi-center, international (including 
USA) 
Investigational device(s) 
Accessory components to 
Investigational device(s) 
BioMonitor or successors  
BIOTRONIK Home Monitoring®: CardioMessenger II, 
IIs or successors; 
Programmer: Renamic, ICS 3000 or successors with 
current software version  
Accessory device: Remote Assistant if applicable 
Primary Objective: 
The primary objective of the BIO|GUARD-MI study is to 
investigate whether the early diagnosis of cardiac 
arrhythmias, provided by the BioMonitor in connection 
with remote monitoring, and the consequent treatment 
of the patient will decrease the risk to experience a 
MACE in patients with a history of MI, CHA2DS2-VASc-
Score ≥ 4 in men / ≥ 5 in women  and LVEF > 35 %. 
Primary endpoint:  
Time to first MACE 
Secondary Objectives: 
All-cause mortality and all individual components of the 
composite primary endpoint will also be evaluated 
separately. 
In addition, the occurrence of arrhythmias and related 
therapies will be evaluated. 
The life quality will be evaluated using the WHO (Five) 
Well-Being Index. 
 
 
 

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Secondary endpoints: 
To assess the time to  
• Death from any cause 
• Cardiovascular death 
First acute unscheduled hospitalization or urgent visit 
for worsening of the patient status due to heart failure 
or first acute unscheduled hospitalization due to 
adverse events of the following list: 
• Arrhythmia 
• Acute coronary syndrome 
• Stroke  
• Major bleeding 
• Systemic embolism 
To assess the time to first 
• Atrial fibrillation 
• Atrial flutter 
• Non-sustained VT 
• Sustained VT 
• Sinus arrest 
• Sinus bradycardia 
• 2,3rd degree AV block or advanced AV block 
To assess the quality of life 
• WHO (Five) Well-Being Index 
Further data of interest 
To assess in a descriptive manner, the types and 
number of therapeutic interventions administered after 
arrhythmias detected by remote monitoring. 
Utility values for an economic evaluation will be 
estimated by using the EQ-5D-5L questionnaire.  
Inclusion criteria 
• Patient has a history of MI according to guidelines 
• CHA2DS2-VASc-Score ≥ 4 in men / ≥ 5 in women  
• LVEF > 35 % as estimated within 6 months before 
enrollment but after conclusion of AMI treatment 
• Patient accepts activation of Home Monitoring 
• Patient is able to understand the nature of the 
clinical study and has provided written informed 
consent 
 
 

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Exclusion criteria 
• Patients with hemorrhagic diathesis 
• Permanent oral anticoagulation treatment for atrial 
fibrillation 
• Indication for chronic renal dialysis 
• Pacemaker or ICD implanted or indication for 
implantation 
• Parkinson’s disease 
• Life expectancy < 1 year 
• Participation in another interventional clinical 
investigation during the course of the study, i.e. the 
participation in a non-interventional1 clinical 
investigation is allowed 
• Age < 18 years 
• Woman who are pregnant or breast feeding  
Study duration: 
Patients are randomized (device yes/no) 1:1. The 
follow-up period of the individual subject is dependent 
on the time of entry into the study. All study subjects 
will be followed until they complete their final study 
termination visit or the sponsor  determines a 
premature study termination after consultation with 
the DSMB and Steering Committee. 
Estimation of total study duration: 74 months 
First Patient In actual: August 2015 
Last Patient Out targeted: ~October 2021 
 
 
 
 
1 Following the definition of the European clinical trial directive 2001/20/EC, we define non-interventional clinical 
investigations as a study where the product(s) under investigation is (are) prescribed in the usual manner in 
accordance with the terms of the marketing authorisation. The assignment of the patient to a particular therapeutic 
strategy is not decided in advance by a trial protocol but falls within current practice and the prescription of the 
product under investigation is clearly separated from the decision to include the patient in the study. No additional 
diagnostic or monitoring procedures shall be applied to the patients andepidemiological methods shall be used for 
the analysis of collected data. 

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Follow-up scheme: 
Enrollment/Baseline  
• Verification of inclusion/exclusion criteria 
• Patient information and provision of written 
informed consent 
• Randomization (device yes/no) 
• Demographics and medical history/medical 
conditions 
• Specification of MI 
• NYHA classification 
• Echocardiographic data  
• Adverse events 
• Scheduling implantation of the Implantable Cardiac 
Monitor and/or discharge 
BioMonitor implantation, if applicable 
(time of implantation: as soon as possible but at latest 
8 weeks after enrollment) 
• Implantation of the BioMonitor 
• Programming of the BioMonitor  
• Adverse events  
• Final patient instruction on investigational device 
Discharge  
(visit window not specified) 
• Final patient instruction on study course 
• Cardiovascular medication and non-cardiovascular 
medication 
• Lab parameters 
• Adverse events 
Follow-up  
• No pre-planned in-hospital follow-up visits  
Unplanned visits (patient- or investigator initiated) 
possible; reason for visit and treatment will be 
documented 
• Initial telephone call at 4 weeks post-enrollment  
• Telephone 
contact 
every 
6 
months 
using 
a 
questionnaire with focus on endpoint-related data  
as well as questionnaires covering quality of life 
aspects (WHO-5 Well-being Index and EQ-5D-5L 
questionnaire)  

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Final Study Termination Visit 
• Final subject contact at the site 
• Document whether the study termination was 
regular or premature and if applicable the reason 
for a premature termination 
• Adverse events 
 
Coordinating Clinical Investigator 
 
Dr. Christian Jons 
Boards and Committees  
• Central Electrocardiogram Monitoring Board  
• Data Safety Monitoring Board  
• Endpoint and Adverse Event Committee  
• Steering Committee  
• Publication Steering Committee  
Sponsor 
BIOTRONIK SE & Co. KG 
Woermannkehre 1 
12359 Berlin 
Germany 
Local Sponsor U.S.  
BIOTRONIK, Inc. 
Clinical Studies Department 
6024 Jean Road 
Lake Oswego, Oregon 97035 
USA 
 
 

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3 INTRODUCTION 
Myocardial Infarction (MI) is the closure of a coronary vessel. It leads to the irreversible 
necrosis of heart muscle secondary to prolonged ischemia. According to the appearance in 
the electrocardiogram (ECG) MI can be classified as non-ST segment elevation myocardial 
infarction (NSTEMI) and ST segment elevation myocardial infarction (STEMI) which 
generally reflects an acute total coronary occlusion. 
Although the treatment of MI has improved over the past decades mainly due to 
introduction of early reperfusion therapy (lytic or percutaneous coronary intervention), 
every sixth man and every seventh woman in Europe will die from MI 1;2. Patients with 
STEMI have a higher acute risk, however, long-term follow-up showed that death rates 
were higher among patients with NSTEMI with a two-fold difference at 4 years 1. An 
explanation for this may be that NSTEMI patients more frequently present with concomitant 
cardiovascular risk factors such as hypertension, obesity, diabetes and higher age 3-6 .  
After MI, the heart adapts to the permanent damage. A generalized autonomic dysfunction 
results in enhanced automaticity of the myocardium and conduction system and can lead to 
complications that include cardiac arrhythmias. The necrosed area acts as a substrate for 
re-entrant circuits and the ongoing coronary artery disease can cause electrolyte imbalances 
and hypoxia which further contribute to the development of cardiac arrhythmias. Cardiac 
arrhythmias 
may 
result 
in 
orthostatic 
hypotension, 
increase 
myocardial 
oxygen 
requirements, and predispose the patient to develop additional malignant ventricular 
arrhythmias. Since arrhythmias are expected to be frequent in MI survivors and contribute 
to the poor prognosis, it may be reasonable to monitor and treat them aggressively. 
Survivors of MI who have a severely impaired left ventricular ejection fraction (LVEF) are at 
high risk of dying suddenly due to cardiac arrhythmias 7-10. CARISMA was the first study to 
use implantable cardiac monitors (ICMs) for continuous ECG monitoring of cardiac 
arrhythmias in the post-MI setting including patients with LVEF ≤ 40 % and still represents 
the only experience in this area 11. This study documented unexpectedly high incidences of 
new-onset atrial fibrillation (AF), high degree atrioventricular (AV) block, sinus bradycardia, 
ventricular 
tachycardia 
(VT) 
and 
ventricular 
fibrillation 
(VF) 
12. 
In 
summary,  
46 % of all patients presented with at least one of the pre-specified cardiac arrhythmias of 
which 85 % were asymptomatic. With a mean follow-up duration of two years, 20 % of 
patients experienced a major adverse cardiac event (MACE) including death or 
hospitalization due to heart failure, re-infarction and stroke. More than 80 % of them were 
diagnosed with an arrhythmia before the event. Hence, a cardiac arrhythmia was the most 
powerful predictor of a MACE. The study, however, left it open whether preventive 
treatment based on ICM detections will decrease the incidence of cardiovascular events in 
high-risk patients.  
The assessed high incidences and prognostic significance of cardiac arrhythmias underline 
the importance of continuous rhythm monitoring in high risk patients after MI. ICMs provide 
a much more detailed picture of the incidence of brady- and tachyarrhythmias than 
conventional follow-up. In addition, newer ICMs (e.g. BioMonitor) include improved 
algorithms that allow distinguishing different arrhythmias, and also the diagnosis of normo-
frequent AF, compared to earlier devices such as those used in the CARISMA study. A 

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unique feature of the BioMonitor is the implemented BIOTRONIK Home Monitoring® function 
which allows remote access to the subcutaneous electrocardiogram (sECG) recordings. It 
has been suggested that remote monitoring significantly increases the efficacy of the ICM 
13. 
The CARISMA study included patients within severly depressed LVEFs ≤ 40 % 11;14. 
However, 80-90 % of patients surviving MI have a relatively preserved LVEF and are 
therefore assumed to be at lower risk for MACE and arrhythmias 4;15. While this group as a 
whole may have a relatively benign prognosis, this may not be justified in subgroups with 
additional cardiovascular risk factors, particularly increasing age, hypertension and 
diabetes. Moreover, reduced LVEF is less frequent after introduction of percutaneous 
coronary intervention (PCI) and addition of multiple antithrombotic agents after 
revascularization. In a recent study including 1500 unselected consecutive patients with AMI 
most of the premature deaths due to cardiovascular cause occurred in the group of patients 
with relatively preserved LVEF but with other risk factors 14. 
Thus, there is a clinical need to identify patients at high risk for MACE and arrhythmias with 
preserved or only mildly reduced cardiac function but other cardiovascular risk factors in 
place. The BIO|GUARD-MI study has been planned to address this need. It was therefore 
crucial to implement a tool for risk stratification beyond LVEF to correctly identify patients at 
high risk after MI.  
Although the CHADS2-score has been designed to estimate the stroke risk in patients with 
AF, evidence has been provided that the score is highly prognostic as a risk stratification 
tool for both MACE and arrhythmias in patients with LVEF ≤ 40 % after MI 16. In this 
population the risk of experiencing a MACE was 8 times higher, and the risk of any 
arrhythmia was 3.7 times increased in patients with CHADS2-score ≥ 3 compared to 
CHADS2-score = 0. Also in other populations, the CHADS2-score is connected to the risk of 
AF 17-19 and bradyarrhythmias 12;20-22. Moreover, the individual components of the CHADS2- 
score (congestive heart failure, hypertension, age, diabetes, stroke) have also been found 
to be independently associated with increased risk of VT/VF 7;23-26 and are all known to be 
independent risk factors for worse outcome in patients after MI 27.  
In recent years, the CHA2DS2-VASc-Score has superseded the CHADS2-score for its original 
purpose of stroke risk estimation in AF patients due to a better performance especially in 
patients with a low risk. Both scores are based on the same items, with the CHA2DS2-VASc-
Score adding points for age above 75 years, female gender and vascular disease. Although 
more data are available on the general cardiovascular risk prediction of the older CHADS2-
Score, it is justified to assume that the CHA2DS2-VASc-Score will perform similarly well for 
the purpose of this study.  Because the CHADS2-score is perceived as outdated and inferior 
by many cardiologists, the CHA2DS2-VASc-Score will be used as main entry criterion of this 
study. 
Compatible with the conclusions drawn from CARISMA, large randomized controlled trials 
have firmly established that post-MI patients with LVEF ≤ 35% benefit from the 
implantation of an ICD, which is reflected in current guidelines 28. However, also patients 
with a preserved or mildly reduced LVEF (≥ 35%) but with additional cardiovascular risk 
factors, such as those expressed within the CHA2DS2-VASc-Score, may be considered at 
high risk for experiencing both cardiac arrhythmias and consequent MACE. Nevertheless, 
scientific studies in this population remain sparse.  

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The BIO|GUARD-MI study therefore aims to investigate whether continuous arrhythmia 
monitoring and detection, using an ICM (BioMonitor) in patients after MI with LVEF > 35 % 
but other cardiovascular risk factors, decreases the risk of MACE if patients are 
appropriately examined and treated for the observed arrhythmias. 
 

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4 INVESTIGATIONAL DEVICE 
4.1 
Summary description of the investigational device and its 
intended purpose 
Investigational device: BioMonitor or CE-approved successor. 
The BioMonitor is an ICM used to automatically detect and record episodes of arrhythmia in 
patients at risk for bradycardia, tachycardia, asystole and AF. The ICM is not intended to 
deliver any therapy. 
The device reports the recorded episodes and the related statistical data via a physician’s 
programmer and telemetrically via BIOTRONIK Home Monitoring®. 
4.2 
Manufacturer 
The manufacturer of the BioMonitor 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 
Devices undergoing clinical investigation:  
• BioMonitor or CE-approved successor 
Participating sites located outside the CE area use the devices after market or study 
approval by the respective regulatory institution according to national regulations. 
The device under investigation is to be used with the following components: 
• BIOTRONIK Renamic or ICS 3000 programmer or CE-approved successor with the 
most recent software and later corresponding software updates 
Patients implanted with a BioMonitor will be monitored with BIOTRONIK’s Home Monitoring® 
system and are therefore provided with the external patient device: 
• BIOTRONIK CardioMessenger II, II-S or CE-approved successor 
Patients who are receiving the investigational device may be provided with a CE approved 
accessory device (Remote Assistant) at the investigator’s discretion. The Remote Assistant 
allows manual triggering of an ECG recording by the patient and thereby supporting the 
treating physician in making an accurate diagnosis.  
4.4 
Description of traceability 
Each BioMonitor, CardioMessenger or Remote Assistant has an unique serial number. The 
traceability is assured by recording the serial number. The information is documented on 

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the corresponding electronic case report form (eCRF) and recorded in the clinical study data 
base. 
4.5 
Intended purpose and patient population of the device in 
the study 
The BioMonitor will be used according to its intended and regulatory approved use as 
outlined in the technical manual. In short, the primary purpose of the BioMonitor is to 
provide early detection and diagnostics of symptoms of cardiac arrhythmias, which can be 
manifested clinically. The BioMonitor is indicated in patients with an increased risk for 
cardiac arrhythmias.  
The population selected for this clinical investigation is expected to have an increased risk of 
cardiac arrhythmias. Consequently, the BioMonitor will be used to facilitate an early 
diagnosis and treatment of cardiac arrhythmias and to prevent a potentially fatal disease 
progression. 
4.6 
Description of the investigational device 
The BioMonitor is a subcutaneous ICM that continuously monitors the heart rhythm. 
Implantation and follow-up are performed with a portable BIOTRONIK programmer. 
Additionally, the Home Monitoring feature enables physicians to perform remote diagnosis 
management over the lifetime of the device. The average service time of the BioMonitor is 4 
years according to the technical manual. 
The BioMonitor records automatically the occurrence of certain cardiac arrhythmias; these 
arrhythmias are classified as AF, high ventricular rate (HVR), asystole, or bradycardia.   
4.6.1 BIOTRONIK Home Monitoring® with daily sECGs 
The BioMonitor has the ability to transmit data over a distance of several meters using bi-
directional long-range telemetry, i.e. without the need of a wand. The data are transmitted 
to a patient device (CardioMessenger) that is placed a few meters away from the patient. In 
case automatically detected arrhythmias occurred, the BioMonitor is able to transfer sECGs 
with a priority ranking which arrhythmia will be sent in accordance with the technical 
manual. Via mobile phone technology, the CardioMessenger forwards the data to the Home 
Monitoring Service Center (HMSC). The data received by the Service Center are arranged in 
graphs and tables in the form of a CardioReport and can be viewed by the physician on a 
secure internet platform. In this study a Central Electrocardiogram Monitoring Board (CEMB 
9.8.5) will be installed to ensure a centralized arrhythmia adjudication process and 
consequent forwarding to the study sites in case of relevant arrhythmia episodes. 
4.7 
Summary of training and experience needs 
The BioMonitor is a medical implant intended for physicians who are familiar with the 
implantation of an ICM. The physician must be familiar with the associated risks and 

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complications. The interrogation and programming of the ICM shall only be done by 
appropriately trained personnel using the BIOTRONIK programmer.  
4.7.1 Description of medical and surgical procedures 
The BioMonitor has to be implanted by a physician in accordance with the standard 
implantation procedure. Specific information pertaining to procedures is provided in the 
technical manual of the BioMonitor.  
In accordance with the technical manual of the BioMonitor the term ‘insertion procedure’ 
could be used synonymously to the term ‘implantation procedure’. 

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5 JUSTIFICATION FOR THE DESIGN OF THE CLINICAL 
INVESTIGATION 
5.1 
Pre-clinical data 
To study the feasibility and several features of the BioMonitor, acute and chronic animal 
studies in Yucatan pigs have already been performed. There were good results without any 
conspicuousness. 
5.2 
Clinical data 
5.2.1 Clinical data to support the safety and efficacy of the BioMonitor  
5.2.1.1 
The BM01 acute study 
The BM01 acute study was an investigational study of the characteristics of the human 
sECG signals as recorded by the BioMonitor. The purpose of the study was to build a library 
of sECG signals from members of the targeted patient population and to evaluate algorithm 
feasibility. The ECG recordings were performed exclusively during the implant procedure of 
a pacemaker or ICD. After preparation of the tissue pocket, the BM01 device was placed in 
this pocket. A wand with a sterile cover was positioned on the BM01 device to interrogate 
ECG signals. The ECG recordings were performed at rest and with patient movements in 
different device orientations.  
The subject pool spanned the range of expected patient ages (41 to 88 years) and body 
builds (BMI 21 to 42) and included patients who had an ongoing cardiac arrhythmia. The 
QRS amplitude signal-to-noise ratios were sufficient for QRS detection. The BM01 signal 
library was used to establish the feasibility of the QRS detection algorithm and the AF 
detection algorithm. 
5.2.1.2 
BioMonitor Master Study  
The objective of the Master Study of the BioMonitor was to confirm the safety and efficacy 
of the ICM to collect post market clinical follow up (PMCF) data. The data of 153 patients, 
enrolled in 17 clinical sites in 6 countries including Germany and Denmark, were included in 
the interim report 29 that was submitted to the respective competent authorities (CA). The 
final report did confirm the results of the interim report 2.  
The patient population was selected according to defined criteria, i.e. patients with 
suspected cardiac arrhythmia, previous AF diagnosis or AF diagnosis before or after ablation 
procedure or stroke of unknown origin. The safety of the ICM (primary endpoint 1) was 
evaluated by the evaluation of the Serious Adverse Device Effect (SADE)-free rate until the 
3-month follow-up visit. The efficacy of the ICM (primary endpoint 2) was evaluated by the 
evaluation of the rate of appropriate QRS detection. 
 
2 Master Study of the Implantable Cardiac Monitor BioMonitor, Clinical Investigation Report. June 2, 2015 

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No BioMonitor related SADE up to the 3 month follow-up has been reported. Regarding the 
efficacy of the BioMonitor, 77 assessments of the QRS-detection performance of the 
BioMonitor were performed. In 72 cases, the QRS-detection was appropriate which yields in 
a rate of 93.5%. Only 5 patients provided a QRS-detection positive predicted value (PPV) 
smaller than 90% (Min 85.5%).  
Hence, as presented in the interim report, the ICM BioMonitor is considered to be safe and 
efficacious 29. 
5.2.1.3 
BIO|MASTER.BioMonitor 2 Study 
The objective of the BIO|MASTER.BioMonitor 2 study was to confirm the safety and efficacy 
of BIOTRONIK’s second generation of ICM, the BioMonitor 2, and its respective insertion tool 
set FIT1 and FIT2. The primary endpoint of the study was to evaluate the device and 
insertion tool related SADE-free rate through the 3-month follow-up is above 90%. R-wave 
amplitude at 1-week post implant of the BioMonitor 2 was also compared to the first 
generation BioMonitor. 
A total of 92 patients were enrolled in 13 clinical sites across 4 countries and 90 subjects 
received a BioMonitor 2 device. A total of 2 SADEs related to the BioMonitor 2 or insertion 
tools were reported resulting in an SADE-free rate of 97.8% (95% CI, 93.3% to 99.7%), 
significantly above 90%. The mean R-wave amplitude for the BioMonitor 2 was 0.75 mV at 
the 1-week follow-up visit. This was significantly higher (p < 0.001) than 0.3 mV, the 
comparison value for the predecessor BioMonitor. 
5.2.1.4 
BioInsight Study   
The BioInsight study was designed to evaluate the safety and feasibility of performing the 
BioMonitor 2 insertion procedure in an office setting. All subjects enrolled in the study had 
an approved indication for continuous arrhythmia monitoring with an ICM and were 
implanted with a US market released BIOTRONIK BioMonitor 2. The primary objective was 
to characterize all insertion procedure-related adverse events though the 90-day follow-up 
visit that require additional invasive intervention to resolve. Secondary objectives included 
characterization of all insertion procedure-related adverse events not included in the 
primary objective, characterization of the insertion procedure, and characterization of 
device functionality post-insertion.  
Of 82 subjects enrolled at 6 study sites in the U.S., 77 patients underwent an insertion 
procedure. All insertion procedure attempts were successful. The most common device 
orientation was position B (parallel to the sternum over the fourth intercostal space), with 
the device antenna pointing down (toward the feet). Incision size ranged from 8 to 21 mm 
with a mean of 14.9 mm and the duration of the procedure averaged 8.4 minutes with a 
range of 3.5 minutes to 30 minutes. 
There were no reported adverse events that met the criteria for primary objective 1; 
therefore, the rate of all insertion procedure-related adverse events that required additional 
invasive intervention to resolve is 0%, 95% CI: (0.0%, 5.0%). Only two adverse events 
were reported and both were classified as insertion procedure-related that did not require 
additional invasive intervention to resolve. The overall event rate for all reported adverse 
events was 2.7%, 95% CI: (0.3%, 9.5%) and is similar to in-office ICM insertion rates 

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reported in literature. The average R-wave amplitude was 0.77 ± 0.5 mV at insertion and 
0.67 ± 0.3 mV at 90 days. The average noise burden was 2.5 ± 4.64 % at wound check 
and 2.7 ± 5.79% at 90 days. Daily BIOTRONIK Home Monitoring® transmissions for 76 
subjects show stable R-wave amplitudes and noise burden through the 90-days post-
insertion with an overall average of 0.68 mV and 2.7% respectively. 
5.2.2 Clinical data to support the design of the BIO|GUARD-MI study  
The BIO|GUARD-MI study aims to investigate whether the risk to experience a MACE in a 
population with history of MI, with LVEF > 35 % and additional cardiovascular risk factors 
can be decreased by an early detection of cardiac arrhythmias provided by continuous ECG 
monitoring using an ICM and the consequent treatment of the patient.  
The first and only study to use ICMs for continuous ECG monitoring of cardiac arrhythmias 
in the post-AMI setting included patients after AMI with LVEF ≤ 40 % 11.  
The primary objective of the study was to describe the incidence of pre-defined cardiac 
arrhythmias. Unexpectedly high incidences of new-onset AF, high degree AV block, sinus 
bradycardia, VT and VF were diagnosed on the ICM during the study 11;12;16. Moreover, with 
a mean follow-up duration of two years, 20 % of patients experienced a MACE and more 
than 80 % of them were diagnosed with an arrhythmia before the event.  
The authors conclude 11: 
- 
that cardiac arrhythmias were the most powerful predictor of a MACE, and many of 
them would have remained unnoticed without an ICM 
- 
to initiate comprehensive diagnosis and appropriate therapies after detection of 
arrhythmias 
The clinical relevance of the study is limited today because it has been shown that post-MI 
patients with EF < 35 % - and thus the majority of the CARISMA patients - are indicated for 
an ICD 28;30. With a LVEF > 35 %, the BIO|GUARD-MI population is not indicated for an 
implantable device and still only little is known about this population which is generally 
considered at moderate risk compared to patients with lower LVEF. However, compared to 
healthy subjects, the MACE rate of post-MI patients with preserved or only moderately 
reduced LVEF is substantial, especially when considering cardiovascular risk factors 
(CHADS2-score) in addition 31-34. 
 
 
 
 
 
 
 
 
 

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5.3 
Justification of the design 
Pre-clinical as well as clinical data did confirm the ICM BioMonitor to be safe and efficacious. 
Although the patient population of this study has not been studied directly, clinical data 
indicate that considerable rates of arrhythmias and MACE must be expected. The population 
of subjects meeting the enrollment criteria is large and the study aim to prevent MACE is 
relevant both for the individual subject and the society. 
The benefit of continuous ICM monitoring in patients at high risk for arrhythmias has been 
shown previously 11. The value of preventive treatment initiated by detected arrhythmias 
has not been shown yet but seems plausible and crucial to investigate. 
To provide continuous monitoring post-MI, patients will be enrolled, randomized (50 % of 
the patients will be implanted with the BioMonitor; see section 8.2.1) and implanted as soon 
as possible, if applicable.  
Other than the implantation of the investigational device, which is not part of the clinical 
routine for the investigated patient population, the chronological order and the scope of this 
study do not interfere with the medical standards at the sites with regards to patient 
treatment or follow-up care. It is solely up to the treating physician how to guide the 
patients. No requirements are placed on the therapy and no pre-planned in-hospital visits 
other than the study termination visit are part of the study. However, treatment 
recommendations compatible with current treatment guidelines will be provided to the 
investigators within a separate document.  
Although the study does not enforce any therapies, certain Home Monitoring messages may 
lead to patient calls, bringing about additional follow-up visits with intensified diagnostic 
procedures, and consequently in the initiation of therapy. 
To ensure complete reporting of MACE endpoints, all patients will be contacted directly via 
telephone at regular intervals.  
 

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6 RISKS AND BENEFITS OF THE DEVICE AND CLINICAL  
INVESTIGATION 
6.1 
Anticipated clinical benefits 
6.1.1 Benefits for patients randomized to the BioMonitor group 
As a result of ICM implantation, the heart rhythm of study patients is closely monitored. 
Participation in the study may lead to the diagnosis of heart rhythm problems and to a 
consecutive benefit from prompt treatment of the detected arrhythmias, or the underlying 
condition of the patient that has caused the arrhythmia. 
6.1.2 Benefits for patients randomized to the control (non-BioMonitor) group 
No obvious benefits are expected for patients randomized to the control group.  
6.1.3 Benefits for future patients 
If the study will be successful, it may show that patients matching the inclusion criteria 
benefit from ICM monitoring by reducing the risk for MACE. It may thereby contribute to a 
better treatment of post-infarct patients. If the study will fail to confirm the primary 
hypothesis, it may still provide information on subgroups with a benefit that will allow for 
the planning of confirmatory studies. 
6.2 
Anticipated risks 
6.2.1 Anticipated adverse device effects 
ICMs are implanted in a subcutaneous position and thus require an invasive implantation 
procedure. Please see Table 1 with a cumulative listing of the associated risks. On 
explantation or replacement, which may be required when the battery is depleted or for 
other reasons, the same risks may apply as for the initial implantation. No data have been 
identified if the incidence of the listed complications is different for explantation or 
replacement, when compared to the initial implantation. 
 
 
 
 
 
 
 
 

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Table 1: Surgical Risks  
 
Frequency 
Percentage (%) 
Risk 
Frequent 
1 to 10 patients 
out of 100 
Up to 335-38 
local infection at insertion site 
Up to 336 
superficial infection at insertion site 
Up to 1,938 
irritation or inflammation at insertions site 
Up to 1,235 
local erosion at insertion site 
Up to 1,536 
erythema at insertion site 
Up to 1,535-38 
persistent pain at inframammary implant site 
Up to 337 
difficulties at device interrogation 
Up to 537 
device migration 
Up to 2,335;37 
device repositioning 
Up to 2,435-38 
device explantation (unplanned) 
Not known 
Frequency not 
assessable on the 
basis of the 
available data 
heating, swelling of 
the skin, impairment 
of wound healing, 
bleeding, hematoma 
 
 
However, it is important to state that ICMs do not require vascular access or direct contact 
with the endocardium. Consequently, ICMs do not carry the same risk of endocardial 
complications known from pacemakers or ICDs 39;40. 
The safety of ICMs has been investigated in many studies with regards to syncope and AF 
management 41. It has been demonstrated successfully that the strategy of prolonged 
monitoring in patients with Cardiac Implantable Electronic Devices (CIED) is safe 42.  
Moreover, the safety of the BioMonitor and BioMonitor 2 was the objective of several 
completed studies. These studies found a very low device-related event rate ranging from 
0% to 2.2%. The procedure-related event rate, including events such as pocket infections, 
pain around the pocket, and swelling of pocket due to hemorrhage, were compatible with 
the event rates presented in Table 1. 
Automatic ICM recording and wireless transmissions are feasible for remote ECG monitoring 
but can be accompanied by a remarkable rate of false detections. This may lead to memory 
saturation and loss of information about true episodes. However, with the remote 
monitoring feature it is possible to identify these patients and take corrective actions during 
an in-hospital visit, i.e. re-programming of the device settings. 
6.2.2 Residual risks associated with the device 
Despite all measures to control the risk (see section 6.3), a residual risk remains. 
6.2.3 Risk associated with participation in the study 
Apart from the anticipated adverse device effects discussed in section 6.2.1, no additional 
risks are associated with participating in this study. Investigators will decide upon therapies 

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based not on ICM diagnosis, but upon thorough examination of the patient after the ICM 
has detected relevant arrhythmias. These therapies will be based on evidence-based 
guideline recommendation. Thus, it is not to be expected that the study will lead to 
unneeded or harmful therapeutic intervention.  
6.2.4 Possible interactions with concomitant medical treatments 
No interactions with concomitant medication or medical treatment are expected.  
6.3 
Steps to control or mitigate the risks 
Risks associated with the BioMonitor (see section 6.2) have been reduced by special risk 
reduction measures listed in the technical manual.  
Among others, the risk is minimized through the utilization of strict aseptic technique, close 
monitoring of the patient’s physiologic status during the implantation procedure and 
compliance with the technical manual. Moreover, with regards to risk control it will be 
crucial to follow this CIP in all aspects and to promptly supply BIOTRONIK with all pertinent 
information required by this CIP. 
There are no known contraindications. However, the particular patient’s state of health 
determines whether a subcutaneous device will be tolerated long term. 
6.4 
Risk-to-benefit rationale 
The investigational device is approved in Europe for standard medical care (CE mark). In 
countries located outside the CE area, devices will only be implanted after market or study 
approval of the responsible regulatory institution. Being expected at increased risk for 
cardiac arrhythmias, the patient population to be enrolled in this clinical study has an 
indication for implantation of the investigational device according to the technical manual. 
Nevertheless, in most cases this will not be clinical routine at the study sites. 
It is not anticipated that the patients participating in this study are exposed to any risks 
beyond those stated in section 6.2.1. Moreover, most risks associated with the implantation 
of the BioMonitor can be solved with non-invasive measures, and even if not, can typically 
be resolved without sequelae. 
The BIO|GUARD-MI study is expected to provide additional insights regarding the reduction 
of the risk for MACE. These insights may be applied to future patients after MI. Therefore, 
the anticipated risks seem to be justified when compared to the potential benefit of the 
study. 

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7 OBJECTIVES AND HYPOTHESES 
7.1 
Objectives 
7.1.1 Primary objectives 
The primary objective of the BIO|GUARD-MI study is to investigate whether the early 
diagnosis of cardiac arrhythmias, provided by the BioMonitor in connection with remote 
monitoring, and the consequent treatment of the patient will decrease the risk to experience 
a MACE in patients with a history of MI, CHA2DS2-VASc-Score ≥ 4 in men / ≥ 5 in women 
and  LVEF > 35 %. 
See section 8.3.1 for the definition of MACE. 
7.1.2 Secondary objective: Arrhythmia detection 
It will be investigated if the implantation of the ICM leads to a faster detection of an 
arrhythmia that requires a guideline-recommended therapy than a strategy of conventional 
follow-up.  
7.1.3 Other secondary objectives  
In parallel to the primary objective and the definition of MACE, all individual MACE 
components will be evaluated separately and compared between the study groups.  
7.1.3.1 
All-cause mortality 
The occurrence of death for any cause will be recorded and analyzed.  
7.1.3.2 
Cardiovascular death 
The occurrence of cardiovascular death will be recorded and analyzed. 
7.1.3.3 
Worsening of the patient status due to heart failure  
The occurrence of worsening of the patient status due to heart failure requiring 
hospitalization or urgent visit will be recorded and analyzed. 
7.1.3.4 
Hospitalization resulting from arrhythmia 
The occurrence of hospitalization resulting from arrhythmia will be recorded and analyzed. 
7.1.3.5 
Hospitalization resulting from acute coronary syndrome 
The occurrence of hospitalization resulting from acute coronary syndrome will be recorded 
and analyzed. 
7.1.3.6 
Hospitalization or death resulting from stroke  
The occurrence of hospitalization or death resulting from stroke will be recorded and 
analyzed. 

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7.1.3.7 
Major bleeding requiring hospitalization 
The occurrence of major bleeding requiring hospitalization will be recorded and analyzed. 
7.1.3.8 
Systemic embolism requiring hospitalization 
The occurrence of systemic embolism requiring hospitalization will be recorded and 
analyzed. 
7.1.3.9 
Arrhythmias 
The occurrence of arrhythmias will be recorded and analyzed independently of whether a 
consequent therapy is indicated.  
7.1.3.10 
Type of initiated therapies 
It will be evaluated which diagnoses will be made and which therapies will be initiated, 
based on ICM-detected arrhythmias. 
7.1.3.11 
Therapies 
It will be investigated if the implantation of the ICM leads to a faster detection of an 
arrhythmia that requires a guideline-recommended therapy than a strategy of conventional 
follow-up. 
7.1.3.12 
Quality of Life (QoL) 
The investigation of the patients’ quality of life is not intended to show a benefit by the 
implantation of the ICM, but to exclude that the implantation or the monitoring of patients 
has a negative impact on their well-being.  
7.2 
Primary hypotheses 
For assessing the primary endpoints, Kaplan-Meier curves will be constructed for the time to 
first MACE for both study groups according to the intention-to-treat principle. The hazard 
ratio is defined as the rate of the BioMonitor group divided by the rate of the control group. 
The following set of hypotheses (null hypothesis H0 and alternative hypothesis HA) will be 
tested. More detailed information about the endpoints is provided in section 8.3: 
 
H0: Null hypothesis: H0 : HR  1 
which means that monitoring patients of the BioMonitor group will not lead to a longer 
time-to-first-event of MACE compared to the control group. 
HA: Alternative hypothesis: HA : HR  1 
 
which means that monitoring patients of the BioMonitor group will lead to a longer time-
to-first-event of MACE compared to the control group. 
 
It is expected that there is a HR < 1 in favour of the BioMonitor group. A rejection of the 
null hypothesis indicates that the BioMonitor group has a statistically significant longer time 
to first MACE event compared to the control group.  

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7.3 
Secondary hypotheses 
The objective to show that arrhythmias requiring guideline-recommended therapy will be 
detected earlier in the BioMonitor group will be formally tested similarly to the primary 
hypothesis. The HR is defined as the rate of the BioMonitor group divided by the rate of the 
control group.  
 
H0: Null hypothesis: H0 : HR  1 
which means that monitoring patients of the BioMonitor group will not lead to a shorter 
time to first arrhythmia that requires guideline-recommended therapy, in the BioMonitor 
group compared to the control group. 
HA: Alternative hypothesis: HA : HR  1 
which means that monitoring patients of the BioMonitor group will lead to a shorter time to 
first arrhythmia that requires guideline-recommended therapy compared to the control 
group. 
 
It is expected that there is a HR > 1 for the BioMonitor group. A rejection of the null 
hypothesis indicates that arrhythmias are detected earlier in the BioMonitor group.  
No hypotheses have been pre-defined for the other secondary objectives. Details will be 
specified in a separate Statistical Analysis Plan (SAP). 
7.4 
Safety assessments 
The safety assessments are already covered by the primary and secondary objectives. The 
occurrence of all AEs during study participation is documented and assessed (see section 
18) and will be evaluated with regards to the primary and secondary objectives. 
 

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8 DESIGN OF THE CLINICAL INVESTIGATION 
8.1 
General considerations 
The BIO|GUARD-MI study is a multicenter, prospective, randomized (1:1), controlled, 
parallel-group, open, international study (including USA) with an event-driven design. The 
study is operatively divided into 2 phases. In the first phase 640 patients will be enrolled 
within approximately 2 years after FPI. After 600 patient years of cumulative follow-up have 
been collected, a blinded analysis will be performed to assess the primary endpoint rate. 
Based on the assessed rate (see section 11.7), the study will enter the second phase or be 
discontinued prematurely. This is necessary because it is impossible to obtain solid 
estimates of the endpoint rates for the included population from the literature. In case of a 
too low endpoint rate, the study could be expected to fail in its primary objective, even if 
the BioMonitor group had a much reduced endpoint rate. 
In the second phase enrollment will continue in the same way, but in more investigational 
sites than the first phase, and without interception until up to 2900 patients entered the 
study. The duration of the second study phase is estimated to last 4 years but ultimately is 
dependent on when the number of needed endpoints for the final analysis is reached. In the 
second phase US patients will contribute to the study. 
As a result of the specific national requirements in the U.S., a U.S.-specific amended 
protocol is valid for U.S. sites. Differences compared to this Clinical Investigation Plan are 
displayed in section 23.1. 
The study includes an enrollment-assessment and randomization procedure. The 
randomization is 1:1, either in the BioMonitor group (patients are implanted with the 
BioMonitor) or in the control group (patients do not receive a device). The qualifying 
measurement of the  LVEF should be from the time after conclusion of the acute treatment 
of the most recent MI but not older than 6 months. For patients randomized to the 
BioMonitor group, the implantation shall be performed as soon as possible but at latest 8 
weeks after enrollment. Most study procedures will typically take place during the index 
hospitalization3 (enrollment, implantation if applicable and discharge).  
Following discharge, patients will be treated according to clinical routine/guidelines. Hence, 
no study specific pre-planned procedures will be performed. The patients will be encouraged 
to contact their general practitioner or cardiologist regularly, as it is clinical practice in the 
investigational site, or in case of symptoms or malaise. The primary or secondary care 
provider will be suggested to transfer the patient to the investigational site only if tertiary 
level care will be required. 
To assess the primary endpoint, all patients will receive telephone calls every 6 months and 
will be interviewed by means of a questionnaire. These phone calls will be conducted in a 
way as not to interfere in the normal health care, i.e. the patient will receive no medical 
advice of any kind but will only be asked about events of the preceding period (see section 
9.6).  
 
3 The term index hospitalization refers to the time of enrollment of the patient at the investigational site. 

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Additionally, patients who are randomized to the BioMonitor group may be contacted and 
scheduled for a visit when an arrhythmia was detected by the BioMonitor, if the investigator 
considers this clinically indicated.  
The follow-up period of the individual patient is dependent on the time of entry into the 
study. All patients will be followed until  a final study termination visit has been completed 
or the sponsor determines a premature study termination after consultation with the DSMB 
and Steering Committee. 
 
The study is designed to test the primary hypothesis defined in section 7.2 based on the 
composite endpoint defined in section 8.3. 
8.2 
Measures taken to minimize or avoid bias  
8.2.1 Randomization 
A block randomization stratified for center effects and STEMI/NSTEMI is used to minimize 
any potential bias due to center specific effects and STEMI/NSTEMI.  
All patients included are assumed to be at increased risk for MACE. However, currently it is 
unknown which patients benefit particularly from the study treatment. Thus, no other strata 
are implemented in the randomization procedure.  
Due to the large sample size, other unbalanced confounding factors are expected to be of 
low relevance.  
For patients of the BioMonitor group and Control group, the randomization date is defined 
as the discharge from the index hospitalization.  
8.2.2 Blinding 
The investigator can’t be blinded because diagnostic information from the ICM has to be 
used. The blinding of the patient is not possible due to the invasive procedure depending on 
the randomization result. All measures will be taken to assure the blinding of the EAEC. 
These measures will be explicitly documented in a separate manual. 
8.2.3 Other 
Several methods to reduce bias are implemented in this study, including, but not limited to: 
• Patient selection according to pre-defined inclusion and exclusion criteria. 
• It is the intention of the study design that all patients will be followed-up and treated 
in accordance with clinical routine/guidelines. Nevertheless, to gather endpoint 
information all patients will be contacted via telephone on a 6 monthly basis (see 
section 9.6). 
• In case of Home Monitoring findings, patients in the BioMonitor group may have more 
contacts to the study site, and thus a potentially more complete reporting of 
endpoints. Nevertheless, the frequency of telephone follow-up calls in both cohorts 
should remain equal and independent of Home Monitoring findings. Thus, the contract 
research organization (CRO) in charge of performing the telephone follow-up (see 

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section 9.6) will remain blinded to information received from other contacts. As a 
quantitative measure for over-reporting, a separate analysis will be conducted 
involving only primary endpoints reported by patients during the telephone follow-up 
calls. 
• Standardized procedures/processes for (see section 9): 
• 
Standardized telephone procedures outlined in a separate telephone manual 
• 
Standardized methods for data collection, including the documentation of potential 
confounding factors, such as patient demographics, medical history and 
procedural parameters  
• 
Standardized procedures for BioMonitor implantation in accordance with the 
technical manual 
• Formation of a Publication Steering Committee (see section 21). 
• Formation of an Endpoint and Adverse Event Committee (EAEC) that will assess all 
cardiovascular SAEs and all cases of patient death in a blinded and standardized 
manner regarding the primary endpoint (see section 9.8.1). 
• A CEMB will be formed to ensure a standardized interpretation of the Home Monitoring 
findings and consequent forwarding to the study sites (see section 9.8.5). 
8.2.4 Final Study Termination Visit 
All active patients will be asked to visit the study site for a final study termination visit. 
After a complete medical record review for adverse events, the investigator will interview 
the patient about any adverse events that occurred during study participation. Additional 
information about adverse events may be obtained from family members, primary care 
providers or other hospitals where care was provided.     
8.3 
Endpoints 
8.3.1 Primary endpoint 
The primary endpoint is the time from randomization (definition see section 8.2.1) to the 
first MACE during the clinical investigation. Patients without MACE are censored, i.e. the 
time from randomization until the earliest date of drop-out, study termination, or date of 
freezing the Clinical Data Management System database (in case of interim analyses) is 
considered. Patients who reach the primary endpoint will continue to be followed up until 
the formal termination of the study is announced (see section 8.1). 
A major adverse cardiac event (MACE) comprises the following events:  
• Cardiovascular death 
• Worsening of the patient status due to heart failure, requiring acute unscheduled 
hospitalization or urgent visit4 
or acute unscheduled hospitalization due to adverse events (AE) of the following list: 
 
4 Like for other endpoints, scientifically accepted definitions will be used also for this endpoint and will be included 
in the EAEC board charter [see Hicks et al, JACC (2015);66:403-69]. 

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• Arrhythmia 
• Acute coronary syndrome 
• Stroke  
• Major bleeding  
• Systemic embolism  
 
 

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8.3.1.1 
Endpoint assessment definitions 
A further specification of the endpoint adjudication process will be given by the experts of 
the EAEC (see section 9.8.1) within a separate charter. 
Rationale:  
The patient population enrolled in the BIO|GUARD-MI study is expected to be at higher risk 
for clinical events and cardiac arrhythmias compared to the general population. Arrhythmias 
are connected to clinical events. All components of this composite primary endpoint are 
relevant clinical events and can occur in the context of arrhythmias.  
BIO|GUARD-MI aims to investigate if cardiac monitoring of arrhythmias by the BioMonitor, 
and the consecutive treatment, is beneficial with respect to a reduction of clinical events 
(MACE). 
Measurement: 
Information about the primary endpoint will be obtained from the Adverse Event reporting 
of the study. Adverse events will be actively addressed by contacting all patients directly via 
telephone every 6 months and completion of a standardized questionnaire. The telephone 
follow-up will be performed by an experienced CRO similarly in charge of tracking the 
respective source data (see section 9.6). All resulting AEs will be brought immediately to 
the attention of the responsible investigator for evaluation and to assure that the reporting 
timelines are met. In addition, all cardiovascular SAEs and cases of patient death will be 
evaluated by a blinded central Endpoint and Adverse Event Committee (EAEC, see section 
9.8.1) and assessed with respect to the definition of the primary endpoint. 
8.3.2 Secondary endpoint: Time to first arrhythmia detection 
This secondary endpoint comprises the time from randomization to the detection of an 
arrhythmia that requires guideline-recommended therapy. Patients without arrhythmia 
detection are censored, i.e. the time from randomization until the earliest date of drop-out, 
study termination, or date of freezing the Clinical Data Management System database (in 
case of interim analyses) is considered. 
Rationale:  
BIO|GUARD-MI aims to investigate if cardiac monitoring of arrhythmias by the BioMonitor is 
effective.  
Measurement: 
Information about the secondary endpoint will be obtained from the Adverse Event 
reporting of the study as described for the primary endpoint. Furthermore arrhythmias and 
related therapies resulting from BioMonitor information will be recorded on the respective 
eCRFs. 
8.3.3 Other secondary endpoints 
All-cause mortality will be analyzed as a secondary endpoint. 
Further, in parallel to the primary endpoint and the definition of MACE, all individual MACE 
components will be evaluated separately and compared between the study groups. It is well 
recognized that, due to the lower numbers of these events, the study is not powered for 
confirmatory hypotheses testing. Thus, no secondary hypotheses have been put forward. 

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Rationale: 
Since the primary endpoint is a composite comprising several clinical events of different 
relevance, it is of interest to analyze the data of each event separately.  
Furthermore, information will be obtained regarding relevant cardiac arrhythmias.  
The combination of information about arrhythmias and clinical events will allow drawing 
conclusions regarding the interrelation of arrhythmias and clinical endpoints. It may be of 
relevance for the risk prediction in these patients and may allow developing treatment 
options. 
Measurement: 
All relevant arrhythmias will be documented by the BioMonitor and consequently 
transmitted via BIOTRONIK Home Monitoring® to the responsible investigator for 
assessment. 
8.3.3.1 
Time to death from any cause or heart transplantation 
Assessment of the time from randomization to death for any reason or heart transplantation 
during the clinical investigation. 
8.3.3.2 
 Time to cardiovascular death or heart transplantation 
Assessment of the time from randomization to cardiovascular death or heart transplantation 
during the clinical investigation. A specified endpoint definition will be given by the 
members of the EAEC (see section 9.8.1) and documented in a separate charter agreement.  
8.3.3.3 
Time to first worsening of the patient status due to heart failure requiring 
hospitalization or urgent visit 
Assessment of the time from randomization to first hospitalization or urgent visit for 
worsening of the patient status due to heart failure, or death due to heart failure. A 
specified endpoint definition will be given by the members of the EAEC and documented in 
the charter agreement.  
8.3.3.4 
Time to first hospitalization resulting from an arrhythmia 
Assessment of the time from randomization to the first hospitalization resulting from an 
arrhythmia or death resulting from arrhythmia. A specified endpoint definition will be given 
by the members of the EAEC and documented in the charter agreement.  
8.3.3.5 
Time to first hospitalization resulting from acute coronary syndrome 
Assessment of the time from randomization to the first hospitalization resulting from acute 
coronary syndrome or death resulting from acute coronary syndrome. A specified endpoint 
definition will be given by the members of the EAEC and documented in the charter 
agreement.  

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8.3.3.6 
Time to first hospitalization resulting from stroke  
Assessment of the time from randomization to the first hospitalization resulting from stroke 
or death resulting from stroke. A specified endpoint definition will be given by the members 
of the EAEC and documented in the charter agreement.  
8.3.3.7 
Time to first hospitalization resulting from major bleeding 
Assessment of the time from randomization to the first hospitalization resulting from major 
bleeding or death resulting from major bleeding. A specified endpoint definition will be given 
by the members of the EAEC and documented in the charter agreement.  
8.3.3.8 
Time to first hospitalization resulting from systemic embolism 
Assessment of the time from randomization to the first hospitalization resulting from 
systemic embolism or death resulting from systemic embolism. A specified endpoint 
definition will be given by the members of the EAEC and documented in the charter 
agreement.  
8.3.3.9 
Time to first arrhythmia 
Assessment of the time from randomization to first arrhythmia. 
8.3.3.10 
Type of initiated therapies 
Evaluation of the diagnoses and consequent type of therapies based on ICM-detected 
arrhythmias. 
8.3.3.11 
Time to first therapy 
Assessment of the time from randomization to first therapy. In this context therapy is the 
attempted remediation of the patient’s regular heartbeat. To ensure a standardized 
proceeding, guideline-based therapy recommendations will be provided to the participating 
investigators within a separate manual. 
8.3.3.12 
Quality of Life (QoL) 
A further secondary endpoint is the assessment of the patient’s quality of life. The patient’s 
quality of life will be recorded during the regular telephone contacts using the WHO-5 Well-
being Index.  
8.4 
Further data of interest 
Home Monitoring data of BioMonitor patients provide statistically processed information 
about further diagnostic or technical data. These data will be analyzed in an explorative 
manner by the sponsor to get hints and information about possible trends.  
In addition, the EQ-5D-5L questionnaire will be administered during the telephone contacts 
to estimate utility values at different time points for an economic evaluation.  
 
 

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8.4.1 CRF and Forms 
All parameters and measurements that are recorded within the study are described in this 
section and are documented on the following eCRFs and forms. Table 2 provides an 
overview of eCRFs and procedures.  
Data collected during study initiation and termination 
• Enrollment CRF 
• Baseline CRF 
• Implantation CRF 
• Discharge CRF 
• Termination visit CRF 
• Study termination CRF 
• Elective Replacement Indicator (ERI) form 
• Remote Assistant form  
• Protocol deviation / Protocol non-compliance CRF 
Data collected due to adverse events (AE) 
• Adverse event CRF 
• Concomitant medication log eCRF, required only if AE is suspected to be due to a 
medication 
• Device deficiency (DD) CRF 
Data collected by the CRO performing the telephone follow-up 
• Telephone follow-up questionnaire (see section 9.6) 
• Quality of life questionnaires (see section 9.6) 
Data resulting from Home Monitoring messages and other medical events requiring tertiary 
level care 
• 
Arrhythmia notification form (see section 9.5) 
• 
General notification form (see section 9.5) 
• 
IHF event notification form  (see section 9.5) 

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Table 2: Overview CRFs and Investigations 
Investigation 
Enrollment 
Baseline 
Implantation 
Discharge 
Telephone 
contacts (every 6 
months) 
Arrhythmia 
notification form  
General 
notification form 
IHF notification 
form 
Termination  
Patient informed consent 
x 
 
 
 
 
 
 
 
 
Verification of in- and  
exclusion criteria 
x 
 
 
 
 
 
 
 
 
Patient demographics 
 
x 
 
 
 
 
 
 
 
NYHA class 
 
x 
 
 
 
 
 
 
x 
Echo parameters 
 
x 
 
 
 
 
 
 
 
Specification of MI 
x 
 
 
 
 
 
 
 
 
Medical history/Co-
morbidities 
 
x 
 
 
 
 
 
 
 
Cardiovascular medication 
 
 
 
x 
 
 
 
 
x 
Lab parameters 
 
 
 
x 
 
 
 
 
 
Randomization result 
 
x 
 
 
 
 
 
 
 
BioMonitor implantation 
 
 
x 
 
 
 
 
 
 
BioMonitor interrogation  
 
 
x 
 
 
 
 
 
 
BioMonitor programming 
 
 
x 
 
 
 
 
 
 
Adverse events 
 
x 
x 
x 
x 
x 
x 
x 
x 
Arrhythmia classification 
 
 
 
 
 
x 
 
 
 
Evaluation of necessity to 
contact patient  
 
 
 
 
 
x 
x 
x 
 
Patient interview 
 
 
 
 
 
x 
x 
x 
x 
Evaluation of necessity of 
diagnostic procedure 
 
 
 
 
 
x 
x 
x 
 
Telephone follow-up 
questionnaire  
 
 
 
 
x 
 
 
 
 
Quality of life questionnaires 
 
 
 
 
x 
 
 
 
 
Documentation of: 
- reason for visit 
- performed examinations, 
therapies, modifications 
 
 
 
 
 
 
x 
 
x 
 
x 
 
Documentation of: 
- regular or premature 
termination 
- reason for premature 
termination 
 
 
 
 
 
 
 
 
x 
 
8.4.1.1 
Enrollment Form 
The following information will be documented in the Enrollment Form:  
- 
Confirmation that patient has provided written informed consent 
- 
Verification of inclusion and exclusion criteria 
- 
Specification of MI  

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8.4.1.2 
Baseline Form 
The following information will be documented separately in the Baseline Form due to a 
possible timely delay to the actual enrollment of the patient: 
- 
Result of the randomization 
- 
Demographic information 
- 
Echocardiographical data  
- 
NYHA class (collection of the most current NYHA class post-MI but within 6 months 
before enrollment, if subject has a history of chronic heart failure) 
- 
Medical history, medical conditions 
- 
Occurrence of AEs after written informed consent has been provided 
- 
Scheduling implantation of the Implantable Cardiac Monitor and/or discharge 
8.4.1.3 
Implantation Form 
The implantation of the BioMonitor is performed according to standard procedures as 
described in the technical manual. The following information will be documented in the 
Implantation Form: 
- 
Serial number and product ID (PID) of the BioMonitor  
- 
Initial implantation or exchange 
- 
Interrogation and programming details 
- 
Home Monitoring (verification that CardioMessenger was handed out to the patient; 
documentation of serial number, general patient instruction on the use of the 
CardioMessenger) 
- 
Occurrence of AEs since baseline 
8.4.1.4 
Discharge Form 
Any actions taken or initiated since the implantation are documented on the Discharge 
Form. The patient will be reminded about general study aspects and will be educated when 
and how to seek medical attention. The latest status with regards to the patient’s 
cardiovascular medication and general lab parameters will be documented. The following 
information will be documented in the Discharge Form: 
- 
Actions taken or initiated at discharge  
- 
General patient instructions on the study course (telephone follow-up, etc)  
- 
Documentation of cardiovascular and non-cardiovascular medication 
- 
Documentation of general lab parameters (no study specific examination) 
o 
The Troponin value collected should be the highest recorded value related to 
the most recent MI, if available 
o 
For other lab parameters the most currently estimated value should be 
collected (not older than 2 months before data of discharge) 
- 
Occurrence of AEs / DDs since baseline / implantation 

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8.4.1.5 
Adverse events  
Adverse event reporting starts with the patient signing the Patient Informed Consent Form. 
The responsible investigator has to evaluate and report any AE that is brought to his 
attention during the course of the study. All AEs must be documented on the corresponding 
eCRF. Investigators have to adhere to notification timelines as outlined in section 18.8. 
8.4.1.6 
Device deficiency 
Device deficiencies (DD) of the BioMonitor will be reported and documented. DDs are 
defined by the ISO 14155. Investigators have to adhere to notification timelines as outlined 
in section 18.8. 
8.4.1.7 
ERI form 
Devices will be explanted according to physician judgment, at the end of battery life or for 
medical reasons. The ERI form will only be completed when the battery of the 
investigational device has reached end of life. In case of explantations due to medical 
reasons, e.g. patient death or implantation of a pacemaker, the reason for explantation will 
be documented on the respective Adverse Event form. 
In case of death the BioMonitor should be interrogated prior to the explantation procedure, 
if possible. If not possible, it is important that the BioMonitor is explanted, and sent to the 
implanting center for interrogation. During explantation and shipping, the device should be 
carefully handled in order to avoid recording false events and allow proper death 
classification (arrhythmic versus non-arrhythmic death). 
8.4.1.8 
Study termination Forms 
Investigator documents the study termination for each patient at the study termination 
visit. Information whether the study termination was regular or premature will be obtained 
with the study termination form. Moreover, the reason for a premature termination will be 
documented. Additionally, all status information about ongoing AEs should be documented.  
In case of regular study termination, information on planning, completion, and outcome of 
the required actions (as outlined in section 8.2.4) to ensure accurate AE reporting is 
documented in the additional termination visit form. 
8.4.1.9 
Further eCRFs and forms 
Further eCRFs and forms referring to the data collected by the CRO performing the 
telephone follow-up and data resulting from Home Monitoring messages and other medical 
events requiring tertiary level care will be considered in section 9 of this protocol. 
 
 
 
 
 
 
 

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8.5 
Device replacement or explantation 
8.5.1 Device replacement 
If the BioMonitor must be replaced due to battery depletion during the study, a replacement 
of the device is recommended because it is assumed that patient’s risk for arrhythmias and 
endpoints is not decreasing compared to the time of enrollment. The final decision on this 
topic is left with the discretion of the investigator. The patient shall remain in the study, 
independent of the decision to replace the device or not.  
8.5.2 Device explantation 
An official point of explantation of the BioMonitor is not mandated by this study protocol and 
is therefore solely left with the discretion of the investigator. Hence, in agreement with the 
patient the investigator is free to monitor the patient even after her or his official 
termination from the study. 
 
8.6 
Equipment to be used for the assessment of variables 
No other equipment will be specifically required for the conduct of this study next to the 
devices listed in section 4.3. 
8.7 
Replacement of subjects 
The sample size was calculated under consideration of a certain number of drop-outs. 
Therefore, it is not planned to replace subjects.  
8.8 
Used devices and comparators 
Half of the randomized patients will be implanted with the BioMonitor. No comparator 
system or specific study related medication will be used during this investigation. 
8.9 
Subjects 
The investigator is responsible for screening all potential patients and selecting those who 
are appropriate for study inclusion. Every investigator can enroll as many patients as 
desired until the sample size for the entire study has been reached. End of patient 
enrollment is announced by the clinical project manager. 

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8.9.1 Description of patient collective 
Patients meeting the inclusion criteria and none of the exclusion criteria will be enrolled in 
the study. According to the sample size calculation (see section 11.2), up to 2900 patients 
will be enrolled into the study including 5 % drop-outs per year. The patient number is 
based on an expected endpoint-rate (see section 11.2) required to reach the study goal of 
372 patients with one or more endpoint events. However, patient number will automatically 
be adapted in case the actual endpoint rate deviates from the expected rate. Thereby the 
limited number of patients to be excluded from the analysis set (see section 11.1.2) is not 
considered. 
The enrolled subjects will be randomized in a 1:1 relation to the following study groups: 
- 
BioMonitor group (best medical care and implanted with BioMonitor) 
- 
Control group (best medical care)  
By defining a termination visit (see section 8.2.4), the study protocol deviates from the 
initial planning with a defined number of primary endpoints. 
8.9.2 Inclusion criteria 
The following inclusion criteria must be met to enroll a patient in this study: 
1. 
Patient has a history of MI according to guidelines 
2. 
CHA2DS2-VASc-Score ≥ 4 in men / ≥ 5 in women (see section 8.9.2.1) 
3. 
LVEF > 35 % as estimated within 6 months before enrollment but after conclusion 
of AMI treatment 
4. 
Patient accepts activation of Home Monitoring 
5. 
Patient is able to understand the nature of the clinical study and has provided 
written informed consent 
8.9.2.1 
Definition of CHA2DS2-VASc-Score 
CHA2DS2-VASc acronym5 
Score 
Congestive heart failure 
• 
Signs/symptoms of heart failure or objective 
evidence of reduced left-ventricular ejection 
fraction 
+1 
Hypertension 
• 
Resting blood pressure >140/90 mmHg on at 
least two occasions or current 
antihypertensive treatment 
+1 
Age 75 years or older 
+2 
Diabetes mellitus 
+1 
 
5 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS, (European 
Heart Journal, doi:10.1093/eurheartj/ehw210)) 
 

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• 
Fasting glucose >125 mg/dL (7 mmol/L) or 
treatment with oral hypoglycaemic agent 
and/or insulin 
Previous stroke, transient ischaemic attack, or 
thromboembolism 
+2 
Vascular disease 
• 
Previous myocardial infarction, peripheral 
artery disease, or aortic plaque 
+1 
Age 65–74 years 
+1 
Sex category (female) 
+1 
8.9.3 Exclusion criteria 
The following exclusion criteria must not be met to enroll a patient in this study: 
1. 
Patients with hemorrhagic diathesis  
2. 
Permanent oral anticoagulation treatment for atrial fibrillation 
3. 
Indication for chronic renal dialysis  
4. 
Pacemaker or ICD implanted or indication for implantation 
5. 
Parkinson’s disease 
6. 
Life expectancy < 1 year 
7. 
Participation in another interventional clinical investigation during the course of the 
study, i.e. the participation in a non-interventional6 clinical investigation is allowed. 
8. 
Age < 18 years 
9. 
Woman who are pregnant or breast feeding  
8.9.4 Drop-out criteria 
8.9.4.1 
General 
A drop-out is defined as any premature termination of a patient’s participation in the study 
before the study termination is formally announced.  
Once a subject is enrolled and successfully implanted in case randomized to the BioMonitor 
group, every effort should be made to continue to follow the subject in the clinical 
investigation. However, it is inevitable that some subjects will decline to participate further, 
change geographic location or become non-compliant with the studies requirements. 
Drop-out from the study will be considered for the following reasons: 
• 
Patient death (see section 8.9.4.2) 
 
6 Following the definition of the European clinical trial directive 2001/20/EC, we define non-interventional clinical 
investigations as a study where the product(s) under investigation is (are) prescribed in the usual manner in 
accordance with the terms of the marketing authorisation. The assignment of the patient to a particular therapeutic 
strategy is not decided in advance by a trial protocol but falls within current practice and the prescription of the 
product under investigation is clearly separated from the decision to include the patient in the study. No additional 
diagnostic or monitoring procedures shall be applied to the patients andepidemiological methods shall be used for 
the analysis of collected data. 

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• 
Withdrawal of patient consent (see section 8.9.4.3) 
• 
Loss to follow-up (see section 8.9.4.4) 
• 
Early discovery of a violation of inclusion or exclusion criteria (see section 8.9.4.5) 
• 
Investigator initiated drop-out (see section 8.9.4.6) 
Applying the intention-to-treat (ITT) principle, patients considered to be drop-outs are not 
excluded from the analysis set, except if the conditions described in section 11.1.2 are 
fulfilled.  
8.9.4.2 
Patient death 
In the event of subject death during study participation, personnel at the investigational site 
are requested to notify BIOTRONIK immediately by completing an adverse event eCRF and 
a study termination eCRF. 
The following information will be required for any subject death in addition to the AE eCRF: 
• 
Death certificate or death report, signed by the investigator, that includes: 
o 
Date of death 
o 
Primary cause of death 
o 
Any other circumstances surrounding the death 
o 
Whether death was device or procedure related if applicable 
Whenever possible, devices that are explanted must be returned to BIOTRONIK for analysis. 
All cases of patient death will be adjudicated by the EAEC. 
In the event of a cardiac transplantation (HTX), the patient’s participation in the study will 
be terminated. If the patient did not yet have a primary endpoint, the admission for the HTX 
procedure will be evaluated as the death of the patient and thus fulfils the criteria for a 
primary endpoint. HTX will also be contribute to the endpoints of all-cause mortality and 
cardiovascular mortality. Secondary endpoints such as the time to first arrhythmia can be 
assumed to differ significantly between post-HTX and post-MI patients and should thus not 
be pooled for analysis.  
8.9.4.3 
Withdrawal of patient consent 
A patient who has consented to participate in the study may withdraw his/her consent for 
study participation at any time without stating the reason(s) and without any unfavorable 
consequences. All data collected from this patient until the date of withdrawal will be used 
in pseudonymized form as long as their further processing or retention is necessary, e.g. to 
fulfil a legal obligation. This also applies if the patient has requested data erasure. 
Depending on the patient's will the collected data will be anonymized once further 
processing or retention is no longer required. A withdrawal sheet and a study termination 
CRF have to be completed by the investigator. 
8.9.4.4 
Loss to follow-up 
Patients lost to follow-up are those for whom contact is lost despite the investigator’s best 
efforts to locate the subject. Study sites should attempt to contact these subjects and all 
contact attempts should be documented. All efforts must be documented in the patient 

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record by copies of correspondence. Patient’s compliance should be pursued until a 
definitive reason for failure to participate is determined (e.g. patient moved with no 
forwarding address). The investigator should also contact the CRO responsible for collecting 
AEs, which will support him in the attempts to locate the patient. 
8.9.4.5 
Early discovery of a violation of inclusion or exclusion criteria 
If a patient of the BioMonitor group or Control group will be identified to violate any in- or 
exclusion criteria before discharge from the index hospitalization, this shall be considered as 
premature study termination, which has to be documented on the Termination Form.  
8.9.4.6 
Investigator initiated drop-out 
The investigator may initiate a premature study termination for legal reasons (e.g. in case 
of pregnancy during the course of the study) or if the study participation endangers the 
patient’s well-being or safety. However, a member of the Steering Committee or CI must be 
consulted before implementation, except in cases of emergency. Since the CIP does not 
enforce or prohibit any treatments, it appears highly unlikely that such a case can occur.  
In contrast, changes of the patient’s treatment, even if related to monitoring or treatment 
of arrhythmias, do not justify a drop-out, since the patient’s further clinical course can be 
recorded. Two examples are the impossibility to use HM in a new environment of the patient 
(e.g. moving to a place without mobile phone coverage or admission to permanent care 
facility or hospice) or the implantation of a pacemaker or implantable cardioverter-
defibrillator. These events are no reason to exclude the patient, because the exclusion of 
such patients might introduce a bias in favour of the ICM arm. 
8.9.5 Point of enrollment and study termination 
The point of enrollment is the time at which a patient signs and dates the informed consent 
form. The informed consent process is described in section 17. Study related procedures, 
documentation and collection/following of adverse events will start from this day on. 
Regular point of termination for the individual patient is the respective date of the final 
study termination visit. 
For all non-regular study terminations, the following rules apply: 
• 
In case of patient death, the date of study termination is the date of death. 
• 
In case of HTX, the discharge date from the HTX procedure’s hospitalization is the 
date of study termination. 
• 
In case of withdrawal of consent, the date of study termination is the date of 
withdrawal of consent. 
• 
If patient is lost to follow-up, the date of termination is the date of last contact of the 
investigator or of the CRO that collects AEs. Data from the HMSC will not be used to 
ascertain the vital status of patients for any primary analysis because this might 
introduce a bias in favor of the BM arm. 
• 
If patient is defined as drop-out patient for any other reason, the date of study 
termination is the date on which the reason for the drop-out became effective, i.e. 

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the date on which a violation of inclusion criteria was discovered, or on which the 
investigator excluded the patient for safety reasons.  
8.9.6 Timelines 
First Patient In (FPI):  
Aug 2015 (actual date of FPI) 
Last Patient Out (LPO):  
~ Oct 2021Total study duration:  ~ 74 months 
 

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9 STUDY PROCEDURES 
9.1 
Overview 
Table 3: Study Flowchart 
 
 
 
9.2 
Enrollment, Baseline and Randomization 
Prior to enrollment into the clinical investigation, all patients will be evaluated by their 
physician with regards to the inclusion and exclusion criteria. If these criteria are fulfilled, 
written informed consent must be obtained from the patient prior to enrollment.  
All successfully enrolled patients will be randomized in a 1:1 fashion to the BioMonitor group 
or the Control group in accordance with the randomization procedure as outlined in section 
8.2.1. The randomisation code will be generated by the electronic data capture (EDC) 
system. 

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9.3 
Implantation 
In patients randomized to the BioMonitor group, the BioMonitor will be implanted after 
enrollment according to standard procedures as described in the technical manual. See 
section 4.7 for the summary of training and experience needs. 
Mandatory arrhythmia detection programming 
The investigator is obligated to switch ON all arrhythmias. Hence, the BioMonitor is 
activated to automatically record the occurrence of AF, HVR, asystole, and bradycardia.  
Specified programming recommendations will be provided to the participating investigators 
within a separate document. However, ultimately the adjustment of the specific arrhythmia 
detection settings is left with the discretion of the investigator. 
Mandatory Home Monitoring programming 
The investigator is obligated to active the Home Monitoring feature. Hence, it is assured 
that Home Monitoring is set for all detection types. 
Patients randomized to the BioMonitor group are educated about how to use the Cardio 
Messenger. The recommended settings for the HMSC will be specified within the CEMB 
charter.  
9.4 
Discharge  
Upon discharge from the index hospitalization 
7, the patient will receive guideline 
recommended prescriptions and education about life-style recommendations. In addition, 
general study aspects such as the telephone follow-up concept will be repeatedly explained 
to the patient and it will be suggested how to seek medical attention. The recommendation 
will be to visit a general practitioner or cardiologist in case of a worsening of symptoms or 
the general well-being. The patient will be further advised to contact the investigational site 
provided that the general practitioner or cardiologist finds a condition for which it appears 
that the attention of a tertiary care facility is required. Hence, the patients will be 
discouraged from contacting the investigational site on his or her own decision but should 
only visit the investigational site after being advised to do so. 
The patients will be given an information card with a notice indicating that he/she is taking 
part in a study and that the investigator should be contacted by medical professional 
personnel in case of any significant medical event. In addition, patients will be suggested to 
remember date and place of any hospitalization, possibly in a diary. This applies to patients 
of both study arms. 
9.5 
Home Monitoring Analysis 
No pre-planned, study specific in-hospital visits will be performed in this study. 
Nevertheless, event triggered, unplanned in-hospital visits are expected as a result of 
arrhythmia detections by the BioMonitor.  The following process will be installed to ensure a 
coherent documentation.  
 
7 The term index hospitalization refers to the time of enrollment of the patient at the investigational site. 

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Home Monitoring data shall be analyzed on all working days by the CEMB (see section 
9.8.5). If an arrhythmia was detected, the CEMB shall contact the investigator immediately. 
Parallel to informing the physician, the detected event shall be entered by the CEMB in the 
CDMS using the ‘Arrhythmia notification form (ANF)’. For a detailed description of the 
CEMB-responsibilities and the respective process, a charter will be developed in 
collaboration with the involved stakeholders. 
After evaluating the event in the HMSC, the investigator shall enter the assumed rhythm in 
the CDMS using the same form (ANF) that was initially applied by the CEMB. Moreover, the 
timely assessment of the arrhythmia by the investigator will be tracked. Based on the 
evaluation of the detected event, the investigator decides whether to contact the patient or 
not. Specifics about the contact and possibly resulting in-hospital visit shall be recorded in 
the ANF and in the adverse event form if applicable. Therefore, event triggered in-hospital 
visits and consequently performed examinations/therapies can be attributed to the 
originating arrhythmia detected by the BioMonitor. To assure an optimal intervention in case 
of detected arrhythmias, guideline-based recommendations will be provided to the 
participating investigators within a separate document. 
In addition to event triggered in-hospital visits, the patient may have been sent in by a 
primary or secondary care provider or the patient appears at the site on his own decision. 
For these cases, the ‘General notification form’ captures the reason for the visit as well as 
the types of examinations and therapies performed. If during in-hospital visits, the 
investigator is notified about adverse events, the information is entered into an AE CRF. To 
avoid a bias in favour of the control group, which might be introduced as a result of a more 
complete AE reporting in the BioMonitor group due to possible more frequent contacts, AEs 
recorded by the investigator during such visits will not be visible to the CRO that performs 
the regular patient interviews (see section 9.8.6). Thus, it will be possible to estimate a 
possible underreporting of primary endpoints by looking separately at the information 
received during the telephone contacts. 
9.6 
Telephone follow-up 
A telephone follow-up regimen will be implemented and replace in-hospital follow-up visits. 
To obtain endpoint related information, all patients will receive telephone calls once 4 weeks 
after enrollment and then every 6 months where they will be asked to answer a study 
specific questionnaire. In addition, the patient’s quality of life will be assessed using the 
WHO-5 Well-being Index.   
The Index was chosen for its: 
- Focus on the emotional well being of the patient 
- Applicability during a telephone contact 
In addition, the EQ-5D-5L questionnaire will be administered during the telephone contacts 
to gather outcome data for an economic evaluation.  
About the EQ-5D-5L: 
- 
The EQ-5D-5L instrument consists of two distinct elements: the EQ-5D descriptive 
classification system and the EQ visual analogue scale (EQ VAS). 

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- 
The descriptive classification system comprises five dimensions: mobility, self-care, 
usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 
levels: no problems, slight problems, moderate problems, severe problems and 
extreme problems. 
- 
 The patient is asked to indicate his/her general health state by indicating the most 
appropriate statement for each of the five dimensions, with each decision resulting in 
a 1-digit number that expresses the level selected for that dimension. The digits for 
the five dimensions can then be combined into a 5-digit number that describes the 
patient’s health state. Valuation sets are available for various countries which can 
then be used to estimate quality-adjusted life-years (QALYs).   
- 
The EQ VAS records the patient’s self-rated health on a vertical visual analogue 
scale, where the endpoints are labelled ‘The best health you can imagine’ and ‘The 
worst health you can imagine’. The VAS can be used as a quantitative measure of 
health outcome that reflects the patient’s own judgement on the day of 
measurement.  
 
Telephonic follow-up activities and consequent source data tracking will be performed by an 
external CRO contracted by the sponsor (see section 9.8.6). Detailed telephone follow-up 
guidelines will be provided in a separate document, the ‘telephone follow-up manual’. 
Since all primary endpoints constitute adverse events, the respective information received 
via telephone contact must be forwarded by the CRO to the respective study site and will 
ultimately be recorded in adverse event forms. The description of every SAE must be 
sufficiently documented and confirmed by source data to allow the adjudication by the 
EAEC.   
9.7 
Study Termination 
The end of study participation of the individual patient will be documented in the Study 
Termination Form, independent of the reason for termination (see also section 8.9.5). 
Reasons for exclusion from the study should be documented as far as possible. All 
applicable eCRFs shall be completed as far as possible. 
All active patients will be asked to visit the study site for a final study termination visit. 
After a complete patient medical record review for adverse events, the study personnel will 
interview the patient about any adverse events that occurred during study participation. 
Additional information about adverse events may be obtained from other sources, in 
accordance with local regulations,  e.g. from family members, primary care providers or 
other hospitals where care was provided. 

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9.8 
After the termination the patient’s ongoing medical 
treatment is to the physician’s discretion or should follow 
the clinical routine.Description of those activities performed 
by sponsor representative 
Monitoring activities will be performed by sponsor representatives as outlined in the 
monitoring plan. In the US, the sponsor is assisted by US based staff, led by the Director of 
Clinical Studies U.S., who is responsible for all U.S.-specific issues during the course of the 
clinical investigation.  
The sponsor might offer, if needed, technical support and training to the investigator e.g. 
for the implantation, interrogation or programming of the BioMonitor.  
External boards, committees and vendors contracted by the sponsor will be responsible for:  
• 
Assessment of the primary endpoint (see section 9.8.1) 
• 
Safety monitoring (see section 9.8.2) 
• 
Overall guidance of the clinical investigation (see section 9.8.3) 
• 
Coordination of the publication process (see section 9.8.4) 
• 
Home Monitoring analysis (see section 9.8.5) 
• 
Telephone follow-up activities (see section 9.8.6) 
9.8.1 
Responsibilities of the Endpoint and Adverse Event Board (EAEC) 
The EAEC will define the criteria for primary endpoint evaluation and will analyze all 
cardiovascular adverse events and all cases of patient death with respect to the specified 
endpoint criteria. Additionally, the EAEC will periodically review a listing of all AEs which 
occurred during the course of the study with regards to their potential contribution to the 
primary endpoint. Details with regards to the specific process will be determined in the 
EAEC charter.  
9.8.2 
Responsibilities of the Data Safety Monitoring Board (DSMB) 
The DSMB will review accumulating study data to address patient safety and ethical issues 
of the study. If applicable, the DSMB will initialize and supervise the two interim analyses 
and the final analysis of the primary endpoint. Based on the interim data, the DSMB will 
give the request to stop the clinical investigation for superiority or give a recommendation 
to the steering committee and the sponsor whether to continue the clinical investigation as 
planned, to adapt the sample size, or to stop the clinical investigation for futility. Details 
with regards to the specific process will be determined in the DSMB charter.  
9.8.3 
Responsibilities of the Steering Committee 
The steering committee will provide overall guidance of the clinical investigation. Therefore, 
it is responsible for the scientific validity of the CIP and the assessment of quality in course 
of the study. The steering committee will identify and approve members of the DSMB and 
EAEC and will monitor their activities during study conduct. Details with regards to the 
specified tasks and responsibilities will be determined in the steering committee charter.  

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9.8.4 Responsibilities of the Publication Steering Committee (PSC) 
Please refer to section 21.1. 
9.8.5 Responsibilities of the Central Electrocardiogram Monitoring Board (CEMB) 
Home Monitoring analysis will be performed by a CEMB. 
All incoming Home Monitoring data are evaluated centrally by the CEMB in accordance with 
the criteria defined in the CEMB charter. Accordingly, the CEMB will inform the respective 
study site in a timely manner about relevant arrhythmia detections (see section 9.5). 
Details with regards to the specific process will be determined in the CEMB charter.  
9.8.6 
Responsibilities of the Contract Research Organisation (CRO) 
An external service provider has been appointed to perform the telephone follow up 
interviews of all patients 4 weeks following enrollment and then every six months until 
study termination (see section 9.6). Furthermore, they will inform the respective site about 
potential AEs and will organize and support the collection of relevant source data. Details 
with regards to the specified tasks and responsibilities will be determined in the ‘telephone 
follow-up manual’. The appointed service provider is:  
IHF GmbH 
Institut für Herzinfarktforschung 
Bremserstraße 79 
67063 Ludwigshafen 
In the course of the study additional service providers might be contracted depending on 
the countries which will be further included. 
9.9 
 Responsibilities of the investigator 
9.9.1 
Responsibilities of the Principal Investigator 
The following extract of responsibilities resides with the Principal Investigators (PI): 
• Demonstration of suitability of the investigational site with respect to a sufficient number 
of patients to be recruited for the study, availability of qualified investigators, support 
staff and adequate facilities, required to execute the study at the investigation site. 
• Communication with the ethics committee (EC). As far as appropriate and according to 
local regulations, the PI will maintain communication with the appropriate EC. This 
includes: 
o 
Communication to obtain a favourable opinion of the ethical committee to 
conduct the study. 
o 
Reporting of safety information and deviations from the study plan affecting 
the rights, safety or well-being of the patients or the scientific integrity of the 
study. 
o 
The PI shall provide the sponsor with copies of any communications between 
the PI and the EC pertaining to this study. 

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• Informed consent process as described in section 17 of this CIP and notification of that 
process and date in the patient record. 
• Ensure that the study is conducted at the investigation site in full compliance with this 
CIP. This includes: 
o 
Confirmation to comply with the study protocol. 
o 
Creation and maintenance of source documents. 
o 
Follow the procedures with respect to study deviations as described in this 
CIP (see section 14). 
o 
Ensure the availability of an adequate investigation team and facilities. 
o 
Ensure accurate, complete and timely reporting of collected data to the 
sponsor. 
o 
Allow the sponsor to perform study monitoring and auditing and be accessible 
for the sponsor with regard to these activities. 
o 
Allow and support auditing activities from regulatory authorities and the 
ethical committee. 
o 
Data retention in compliance with this CIP and local regulations. 
o 
Safeguarding the rights of the physical and mental integrity as well as the 
privacy and the protection of the data of the study patients. 
 
• Medical care of patients participating in this study, specifically including: 
o 
Medical care to patients during and after the patient’s participation in the 
study in case of an adverse event and informing the patient about the nature 
and possible cause of the event. 
o 
Inform patients of any new significant findings occurring during the study. 
o 
Provide patients with well-defined procedures for possible study-related 
emergency situations and make appropriate arrangements for emergency 
treatment. 
o 
Ensure that clinical records are clearly marked to indicate that the patient is 
enrolled in this study. 
o 
Make appropriate efforts to ascertain the reason(s) for a patient to 
prematurely withdraw from the study, while fully respecting the patient’s 
rights. 
o 
Ensure that patients of vulnerable population are not enrolled (see section 
19). 
• Safety reporting (see section 18), including: 
o 
Documentation of every adverse event and observed device deficiency, 
including an assessment. 
o 
Report adverse events and device deficiencies to the sponsor, ethical 
committee and regulatory authorities according to the reporting timelines 
defined in this CIP and in compliance with local regulations. 
o 
Upon the sponsor’s request, provide additional safety-related information to 
the sponsor regarding a particular event. 

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• The PI has to ensure that all participating investigators (including the PI) of the 
corresponding site are adequately qualified. Qualification will be verified by the Sponsor. 
Note, depending on the local regulations it may be necessary to submit evidence of the 
qualification to the responsible EC or the CA. 
• The principle investigator shall provide the necessary documents to the sponsor in 
particular: 
o 
PI’s CV (current, signed and dated) 
o 
CV of key members of the investigation team (current, signed and dated) and 
others who materially contribute to the study 
o 
GCP and/or ISO certificates of the investigation team, depending on the local 
requirements 
o 
Site responsibility log and training log 
o 
Ethics committee notification, correspondence and approval 
o 
Signed contract between the principle investigator and the sponsor 
o 
Investigator statement (signed and dated) 
o 
User and Training Log EDC System 
o 
Signed CIP 
o 
Notification to / approval from CA if applicable 
9.9.2 
Responsibilities of the coordinating investigator (CI) and in Germany 
“Leiter klinische Prüfung” (LKP) 
Responsibilities of the coordinating investigator are among others: 
• Give input and advice for the protocol creation and possible amendments, medical review 
• Consulting and support in case of clinical or organizational issues arising during the 
conduction of the study 
• Advising all investigators in medical questions connected to the study 
• Support of reporting to CA, if applicable 
• Signature of Clinical Investigation Plan (CIP) and Clinical Investigation Report (CIR) 

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10  MONITORING PLAN 
The responsibility of BIOTRONIK SE & Co.KG as sponsor and BIOTRONIK Inc. as local 
sponsor in the U.S. is to ensure protocol and regulatory compliance through proper 
monitoring of the study.  
BIOTRONIK is required to ensure that the BioMonitor 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. 21 CFR, parts 50, 54, 56, and 812, 
ISO 14155, Declaration of Helsinki) and any conditions of approval imposed by the 
reviewing IRB/EC.  
A monitor (authorized BIOTRONIK personnel, Clinical Research Associates (CRAs)/Monitor, 
or by authorized BIOTRONIK designees) 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 data quality. A detailed monitoring plan 
developed by BIOTRONIK will be followed. 
The entries in the electronic eCRF will be reviewed and source data verified at the 
investigational site by monitors as specified in the monitoring plan to ensure that the 
investigator and the clinical investigation team conducts the clinical investigation in 
accordance with the CIP, Declaration of Helsinki, ISO 14155 or ICH-GCP (U.S. sites), 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. 
Periodic monitoring visits will assure, amongst others, that the facilities are still performing 
well; 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. 
During the periodic monitoring visits, assessments of the study site will include but will not 
be limited to the following: 
1. Completion and submission of the required eCRFs including source data verification 
(SDV) and data plausibility checks 
2. Completion and submission of other applicable study documentation 
3. Continued acceptability of the facilities, including storage and maintenance of 
investigational inventory 
4. Adherence to reporting timelines for adverse events 
5. Adherence to the CIP 
6. Adherence to ISO 14155 or ICH-GCP (for U.S. sites) 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. 

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BIOTRONIK will evaluate the non-compliance and issue corrective actions, discontinue 
enrollment or as a last measure close the clinical investigation site (see section 14.4) 
The investigators are obliged to provide adequate access to the original patient records and 
other relevant source data related to the clinical study. Adequate manned and spatial 
resources have to be provided for all monitoring activities. The investigational sites are 
asked to collaborate closely with the clinical monitor. The investigational sites are obliged to 
keep the source data (e.g. patient records) and CRF-entries up-to-date to ensure efficient 
and time-saving monitoring.  
Agreement to monitoring activities was obtained from the patient in the ICF. Detailed 
monitoring activities and monitor responsibilities are listed in the monitoring plan. 
 

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11  STATISTICAL CONSIDERATIONS 
11.1 
Statistical design, method and analytical procedures 
The study was statistically designed to allow for early discontinuation in case of superiority 
and to adapt the sample size in case of positive results but insufficient power to meet the 
statistical significance with the initially planned sample size.  
11.1.1 Statistical design  
According to the original statistical planning, the study was designed as a three-stage 
adaptive group sequential test procedure according to O’Brian Fleming with survival 
endpoint, where the inverse normal method is used to combine the separate stage 
information 43. This strategy is replaced with a single final analysis of all data after study 
termination. 
The first interim analysis has been performed. The planned second interim analysis will not 
be done. Due to the O’Brien Fleming design with a very low alpha_1 = 0.00025 for the first 
interim analysis, an adjusted significance level for the final analysis alpha_final = 0.02476 
will maintain the global 1-sided significance level alpha = 0.025. 
 
11.1.2  Full Analysis set based on the ITT principle 
The analysis of the primary hypothesis is performed on the full analysis set based on the 
intention-to treat (ITT) principle; i.e. the set of data from all randomized patients by 
minimal and justified elimination of subjects. This set is used to estimate the effect of the 
experimental intervention with greatest external validity. Subjects allocated to a 
randomization group are analysed as members of that group irrespective of their 
compliance to the planned course of treatment, e.g. cross-over to the other group. 
The ICH-E9 guideline states that “there are a limited number of circumstances that might 
lead to excluding randomized subjects from the full analysis set including … the failure to 
take at least one dose of trial medication and the lack of any data post randomization.”  
In accordance to this guideline, the following patients will be excluded from the analysis set 
• Patients of the BioMonitor group and control group in case of a drop-out before 
discharge from the index hospitalization 
• Patients without signed informed consent form  
11.1.3  Per-Protocol Analysis Set 
A supportive analysis of the primary hypothesis is performed on the per-protocol set 
(efficacy sample), which is a subset of the patients from the above full analysis set who 
complied sufficiently with the protocol. This set is used to ensure that the data would be 
likely to exhibit the effects of treatment according to the underlying scientific model.  
The Per-Protocol Analysis Set is the subgroup of the Full Analysis set after exclusion of 

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• 
Patients with violation of in- or exclusion criteria at enrollment 
• 
Patients with major deviations from the CIP in accordance with the definition given in 
section 14.1  
• 
Patients of the BioMonitor group without implanted device or drop-out less than 1 
month after implantation  
• 
Patients of the control group in case of a drop-out less than 1 month after index 
hospitalization 
Time-to-first-event data are censored after occurrence of 
• 
Cross-overs from the BioMonitor group to the control group or vice versa 
• 
Major protocol violations as defined in section 14.1 
Primary endpoints are not taken into account in the BioMonitor group and in the control 
group until 1 month after discharge from the index hospitalization. 
11.1.4 Statistical methods 
Descriptive analyses: The data are presented using descriptive statistical methods. For 
metric data sets, the mean values, standard deviation, median, maximum and minimum are 
stated, if appropriate. Ordinal data are described by the median and interquartile range. For 
nominal data, absolute numbers and relative frequencies are determined.  
Inferential analysis of the primary hypothesis: A one-sided log rank test is performed in the 
context of a confirmatory analysis of the primary hypothesis at the interim and the final 
analysis.  
Explorative multivariable analyses are performed (after the termination of the study, i.e. not 
after interim analysis) based on the Cox regression model. 
Inferential analysis: For the inferential analysis of metric, normal–distributed data, a t-test 
for interindividual of independent groups or a paired t-test for the intraindividual 
comparison of paired data is performed. In case the normality assumption of the data is 
either a priori not justified as specified in the SAP or overtly violated (i.e. by a significant 
Kolmogorov-Smirnov-Lilliefors or Shapiro-Wilk test result) a non-parametric Wilcoxon-
Mann-Whitney rank-sum test or a Wilcoxon-signed-rank test is performed, respectively. For 
the analysis of relative frequencies, Fisher’s exact test is used. 
11.2 
Sample size 
The original planning assumed that 372 primary events would be required to accept the 
primary alternative hypothesis with 80% statistical power given an assumed hazard ratio in 
the population of 0.7452, and the study was to be terminated after this number of 
endpoints had been collected.  
Instead, it was decided to enter the termination phase without any avoidable further delay. 
Therefore, the intended number of endpoints may not be reached.  

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11.3 
Level of significance and the power of the study 
The global significance level of the 1-sided hypothesis is 2.5%.  
A statistical power of the final analysis of 80% was used for sample size calculation.    
11.4 
Expected drop-out rate 
A drop-out of 5% of the patients per year is expected. Thereby the limited number of 
patients to be excluded from the analysis set (see section 11.1.2) is not considered. 
11.5 
Pass/fail criteria  
The pass criteria are to accept the primary alternative hypothesis based on the full analysis 
set. 
11.6 
Provision for an interim analysis 
After the first phase, a blinded analysis of the total endpoint rate is planned. Because the 
blinding is not broken, this is not considered as an interim analysis. One interim analysis 
has been done, but no further interim analysis will be conducted. 
 
11.7 
Termination criteria 
There is a blinded evaluation of the MACE rates after the event-check, which is no interim 
analysis because no therapy effect is investigated.  
If the total number of patients with at least one MACE in both groups is less than 20 
patients per 600 patient-years at the end of the event-check phase, the study will be 
terminated. 
Furthermore, the sponsor may decide to discontinue the study due to organizational reasons 
based on the observed event rates and the general feasibility of the study. Based on the 
recommendations of the DSMB after the first interim analysis, the study will be stopped for 
futility when there is a low chance for rejection of the Alternative hypothesis at the final 
analysis or the need for an increase of the sample size, which is refused by the sponsor. 
Stopping for superiority is achieved in case the 1-sided p-value at the interim analyses is 
below the O’Brien Fleming significance value interim1 = 0.00025.. 
11.8 
Procedures for reporting of deviations to the statistical plan 
Deviation(s) from the statistical plan described here are reported via amendments to the 
CIP and / or via a separate SAP. 
An SAP version 1.0 was written as a separate document before 1st patient-in including a 
more technical and detailed elaboration of the statistical considerations as described here. 

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The SAP is reviewed and possibly updated based on a blind review of the data before 
breaking the blind for the interim analysis or the final analysis. 
11.9 
Specification of subgroups 
Subgroups are predefined for exploratory analyses with respect to  
• 
the occurrence of the predefined arrhythmias, and to  
• 
the primary endpoint and other predefined outcomes.  
The following subgroups are predefined according to their presentation at enrollment: 
• 
All individual components of the CHADS2-score except the age-variable 
• 
Age < median vs. ≥ median 
• 
“Early enrollment” within 40 days of most recent MI vs. “late enrollment” after more 
than 40 days 
• 
Men vs. women 
• 
CHA2DS2-VASc-score ≤ 4 in men / ≤ 5 in women vs.  5 in men /  6 in women  
• 
LVEF < median vs. ≥ median 
• 
BMI: < 30 vs. BMI ≥ 30 
• 
History of AF yes vs. no  
• 
NSTEMI vs. STEMI 
• 
History or presence of kidney failure yes vs. no 
11.10 
Procedure for accounting of all data for analysis 
Data to be analysed by descriptive and inferential statistical methods are entered in a 
Clinical Data Management System by the investigators via the EDC system “iMedNet” 
(MedNet Solutions, Inc. USA). 
Data exports from the Clinical Data Management System and the BIOTRONIK Clinical Data 
Warehouse with Home Monitoring data will be analysed with common statistical software 
packages, e.g. SAS Version 9.4 . 
11.11 
Handling of missing, unused and spurious data 
Missing data: With respect to the primary hypothesis, drop-outs are considered as censored 
data and must not be imputed.  
Unused data: Data not needed for pre-specified inferential analyses are minimized and 
limited to baseline information which can be obtained without any additional burden for the 
patient. Such data could be used for descriptive and exploratory analyses. 
Spurious data are clarified via the query management, i.e. corrected after approval of an 
investigator. Outliers are identified during the blind review of the data. In case of a clear 
evidence of a measurement error, the SAP will be updated before breaking the blind in 
order to avoid any bias. 

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11.12 
Exclusion of data from confirmatory data analysis 
Details with regards to the exclusion of data from confirmatory data analysis are provided in 
section 11.1.2. 
11.13 
Minimum and maximum number of patients per site 
Investigation sites are selected with the potential to enroll a minimum number of 40 
patients per year. 
Every investigator is free to enroll as many patients as desired until the sample size for the 
entire study has been reached and the patient recruitment is ended. Due to the large 
sample size of the clinical investigation, no bias is expected. 
 

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12  DATA MANAGEMENT 
12.1 
 Data protection 
According corresponding national laws, the patient (or his or her legal representative) must 
declare in the ICF that he or she agrees to the recording of his or her medical data and their 
transfer to the sponsor, the supporting CRO IHF and, if necessary, to responsible EC and 
CA. The patient agrees that authorized personnel of the sponsor and the involved EC or CA 
(if applicable) may gain insight in the patient record to ensure that the patient was 
adequately informed about the clinical trial and that the CIP was followed properly. 
All patient-related data and information received from the clinical study will be handled 
confidentially. The collected data will be pseudonymized, without using patient initials, date 
of birth or other privacy data, to ensure traceability of data, but preventing unauthorized 
identification of individual patients. The data will be transmitted to the sponsor and if 
necessary, to the supporting CRO IHF for electronic data handling, safety reporting and 
analysis in compliance with the data protection law. Insight will be given to responsible EC 
and CA upon request. 
All involved parties are bound to data secrecy according to the national data protection law. 
All patients will be informed on all relevant regulations concerning data secrecy and data 
protection which are applicable for BIO|GUARD-MI in the ICF. Specifically, patients will be 
educated about their rights concerning data access, data correction, and data deletion 
according to applicable legislation. 
The patient identification log sheet, in which the patient ID code, name, date of birth, serial 
number of the BioMonitor and date of informed consent is entered, will remain at the 
investigational sites.  
The Patient Contact Form containing patient ID code, contact data, name and date of birth 
will be sent to the telephone follow-up provider (IHF) and archived there. 
No copies of the patient identification log sheet or Patient Contact Form will be provided to 
the sponsor. The patients will be informed on the fact that exact identification of the patient 
is only possible for the investigator and the telephone follow-up provider (IHF).  
12.2 
Data collection  
All study-relevant patient data will be documented pseudonymously in eCRF. 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 21 CFR Part 11, HIPAA, EU 
Commission Decision C(2010)593 Standard Contractual Clauses (processors) and EU-US 
Privacy Shield Framework).  
Use of the EDC system will allow 24 hours 7 days a week access to the module. Site staff 
with user access will be directed to a page where they will enter their assigned user ID and 

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password in order to access the system. Once these have been validated, there will be 
options for entering a new patient or new patient data into the system.  
For the majority of the CRF entries source data needs to be maintained at the site and will 
be collected in adequate files (e.g. patient files). The data have to be stored and shall be 
made available upon request in order to allow SDV. Exceptions for which the CRF entry can 
be regarded as source data are indicated in the monitoring plan. 
12.3 
Procedures used for data review, CDMS cleaning, and 
issuing and resolving data queries 
After data entry into the CDMS, the clinical data is automatically checked with programmed 
quality checks. Additionally, the eCRF will be checked against source data by clinical 
monitors during periodic monitoring visits as described in the monitoring plan. Errors, 
discrepancies, missing data, and entries out of range are resolved automatically (CDMS) 
and manually (clinical monitor, clinical data manager) generated data queries.  
The investigational site is obliged to answer all incoming data queries in due time to clarify 
the open issues. Corrections to the eCRF can only be done by the designated site personnel 
and have to be signed by an authorized investigator approving thereby the completeness 
and correctness of the data. The CDMS supports detailed tracking of the query process since 
all changes are automatically recorded in the system’s audit-trail.  
Clarification of all open queries is a precondition for site closure in case of premature or 
regular study termination. 
12.4 
Procedures for verification, validation and securing of 
electronic data systems 
The CDMS is hosted on a dedicated database server at the vendor MedNet Solutions, Inc. 
Only authorized users with fixed roles have access to the CDMS. The access is controlled 
and maintained by the Clinical Data Management of BIOTRONIK. Every access is 
automatically logged and changes of the clinical data are stored in independent audit trails. 
The CDMS is verified and validated accordingly. The user interface and the internal business 
logic is validated accordingly and verified during the study related development and before 
release for data entry. 
An authenticated user account is created and maintained by BIOTRONIK for each authorized 
user once the user has completed appropriate training. Users are obligated to keep their 
password confidential. 
Depending on their role within the investigational study, users are limited to “read only” or 
may be given permits to enter or update data, provide resolutions to queries and apply 
electronic signatures. Only investigators are allowed to sign the entries. 

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12.5 
Data retention and archiving 
All study related electronic documents are stored in the archive of BIOTRONIK which 
provides storage conditions free from risk of fire, flood, theft and vermin. The access to the 
files is controlled. 
After CDMS closure, all eCRF data, the audit trail and other relevant CDMS content are 
exported and stored electronically for at least 15 years on the archive server. At the end of 
this period, requirements from laws and other regulations will be reconsidered in order to 
decide whether the retention period must be extended or data must be deleted. 
All relevant study related documents have to be stored in the Investigator’s File. Documents 
containing patient’s data, raw data and other study related documents have to be archived 
in the investigational site. In case of electronic source data (e.g. electronic patient records) 
adequate actions have to be taken to ensure data availability during the whole archiving 
period. All documents have to be archived by CCR and supporting CRO IHF for at least 15 
years or even longer if indicated by the national legal requirements.  
 
 

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13  AMENDMENT PROCEDURES 
If throughout the course of the study changes to the 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 and the Steering Committee. 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 EC and – if applicable – by the CA. Non substantial amendments are submitted for 
notification only. 
The investigator should not implement any deviation from or changes to the CIP without 
agreement of the sponsor and prior review and documented approval from the EC (and CA 
if required). The only exception is the necessity to eliminate an immediate hazard to the 
subjects, or when the change involves only logistical or administrative aspects of the study. 

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14  DEVIATIONS FROM CLINICAL INVESTIGATION PLAN 
14.1 
CIP compliance and exceptions 
All sponsor personnel, all investigational site personnel as well as other third parties, who 
are involved in tasks covered by this CIP, are generally obliged to comply with this CIP. A 
U.S.-specific amendment is available for investigational sites in the U.S. to better address 
U.S. regulation. The U.S.-specific CIP amendment is valid for U.S. sites, even if differing 
from 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 (in the U.S. the term “violation” will be used). 
Otherwise they are minor deviations (in the U.S. simply referred to as “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. 
Intentional, anticipated deviations from the CIP are only allowed if the deviation is required 
to protect the subject’s rights, safety and well-being or the scientific integrity of the study. 
In such a case, the investigator will contact the sponsor and obtain prior approval for the 
deviation. If the deviation occurs in an emergency situation or any other unforeseen 
situation and is required to protect the patient’s life or wellbeing, no prior sponsor approval 
is required. In case of a study deviation, either anticipated or unanticipated, both the 
investigator as well as the sponsor may request drop-out/premature study termination of 
the patient, based on the nature and/or consequences of the deviation.  
14.2 
Recording, reporting and analysing deviations 
14.2.1  Site specific deviations 
Investigational sites inform the sponsor 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 should be recorded in the monitoring visit 
reports. The deviations will be discussed with the PI or authorized designee. A re-training to 
the respective CIP specification will be performed to prevent further deviations. The 
retraining will be documented accordingly. Other additional suitable actions may be initiated 
after consultation of the clinical project management. All information from site deviation 
logs is consolidated by the sponsor in one overall study deviation log. 

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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 final clinical investigation report.  
14.3 
Notification requirements and timelines 
The investigator shall notify the sponsor immediately after any major deviation from the CIP 
which has been proceeded to protect the life or physical well-being of a subject in an 
emergency situation. All deviations will be documented by the responsible CRA. 
The sponsor records specific notification requirements of the involved ECs and CAs and 
assures that the required timelines are respected. 
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 exclusion would jeopardize the rights, safety or welfare of the patients. 

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15  DEVICE ACCOUNTABILITY 
All medical devices used in this clinical study carry a CE mark and will be used within their 
intended use. For sites not located in the CE area market approval of the devices is 
available according to national regulations. Therefore, this investigation does not require a 
dedicated device accountability procedure. 
For sites not located in the CE area the respective national regulations concerning device 
accountability will be followed as applicable.  
 

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16  STATEMENT OF COMPLIANCE 
16.1 
Applicable ethical standards 
The study will be conducted in compliance with the principles that have their origin in the 
Declaration of Helsinki (current version).  
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 
“Clinical investigation of medical devices for human subjects – Good clinical practice”. For 
U.S. sites, the clinical investigation will be conducted in compliance with ICH-GCP standards 
and all applicable FDA regulations and local laws; however, adverse event definitions follow 
the ISO convention. 
For sites located in the CE area in deviation to ISO 14155, no dedicated Investigator’s 
Brochure (IB) is provided. The investigational device is CE marked and used within the 
intended use, therefore the instruction for use is considered sufficient and substitutes the 
IB. 
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 favourable opinion of the responsible 
EC has been obtained for that site and approval of the CA (if applicable) has been granted 
for the conduct of the study in the respective country.  
A copy of the EC/IRB/CA votes will be provided to all principle investigators identifying the 
documents and amendments on which the opinion was based prior to initiation of the 
respective investigational site. 
16.4 
Statement of adherence to additional requirements 
If any additional requirements will be imposed by an EC or a CA, 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. In case of any injuries possible related to the patient’s 
participation in the study, the patient should inform the investigator. 

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The insurance of the sponsor does not relieve the investigator and the collaborators of any 
obligation to maintain their own liability policy. 
 

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17  INFORMED CONSENT PROCESS 
17.1 
General considerations 
The informed consent procedure is performed by the PI or any investigator designated for 
this task as recorded in the site responsibility 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. Any form of coercion, improper influence or inducement of the patient 
to participate must be avoided. Vulnerable persons (by the investigator’s judgment) will be 
excluded from participation.  
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. 
The Informed Consent Form (ICF) consists of two parts, the Patient Information and the 
Informed Consent Signature Form. Both parts must be reviewed and approved by the 
EC/IRB and CA, if applicable, prior to its use. Any modifications to the Patient Information or 
Informed Consent Signature Form require prior approval from the EC/IRB/CA and the study 
sponsor. Samples of the most recently approved versions of these documents will be filed in 
the Investigator Site File and the Central File at the sponsor. 
The patient informed consent process consists of three steps, outlined below. 
17.1.1  Informing the patient 
The information provided to the patient will include, but is not limited to: 
• The risks and benefits associated with participation in this study. 
• Treatments alternative to those investigated in this study. 
• Privacy provisions and disclosure of personal health information to third parties. 
• The voluntary nature of the patient’s participation and the right to refuse participation or 
withdraw from the study at any time without consequences for further treatment. 
The study sponsor will prepare an ICF including this information. It is the responsibility of 
the investigator to ensure that the patient is appropriately informed and that any questions 
from the patient with respect to his/her participation in this study are adequately answered. 
17.1.2  Allowing the patient ample time to decide 
After providing the information, the patient should be allowed enough time to consider 
participation in this study. Any additional questions or concerns that may arise after 
providing the initial information should be addressed and answered adequately before the 
patient makes the decision regarding his/her participation. 

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17.1.3  Documentation of the process 
If a patient decides to participate in this study, he/she should sign the Informed Consent 
Signature Form. This form will be dated and signed by the patient and the investigator. The 
signed and dated ICF will be filed in the Investigator Site File at the investigational site. 
Except for monitoring purposes this form will not be disclosed to the study sponsor. Copies 
of the signed and dated ICF will be provided to the patient and IHF. The conduction of the 
informed consent process and patient’s participation in the BIO|GUARD-MI study should be 
documented in the hospital’s medical records of the patient. 
Signing of the ICF is the formal moment of enrollment. No study related procedure or data 
collection will be performed prior to signature of the ICF by patient and by investigator. Pre-
screening of the patient record in respect to the inclusion and exclusion criteria is not a 
study specific procedure. 
17.2 
Special circumstances for informed consent 
Inclusion of subjects unable to read or write: 
Informed consent will be obtained through a supervised oral process if a subject is unable to 
read or write. An independent witness will be present throughout the process. The written 
ICF and any other information will be read aloud and explained to the prospective subject 
and, whenever possible, either will sign and personally date the ICF. The witness also signs 
and personally dates the ICF attesting that the information was accurately explained and 
that informed consent was freely given. 

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18  ADVERSE EVENTS AND DEVICE DEFICIENCIES 
In the course of the clinical investigation, undesired medical events can occur in 
participating patients, which are called AEs in the following. Furthermore, 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. For the U.S. sites adverse event reporting is required according to 
21 CFR 812. However, due to the requirements of the sponsor located in Europe, U.S sites 
will also have to follow reporting according to ISO 14155 standards. Detailed reporting 
requirements for U.S. sites within the U.S are defined in the U.S.-specific amendment of the 
BIO|GUARD-MI study. 
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 (see Table 4: Reporting responsibilities of the investigator).  
According to ISO 14155 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.  
The following conditions will not be considered as an Adverse Event in terms of this study: 
• Pre-existing conditions unless the health status of the subjects worsens during the course 
of the study  
• Explantation of the BioMonitor due to battery depletion when in accordance with 
expected longevity 
Arrhythmias that occur for the first time in a patient during the course of the study will be 
reported once at initial detection. For repeated episodes of the same arrhythmia no further 
AE reports will be necessary unless the condition deteriorates into a serious adverse event. 
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.  

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Adverse events, which result from the required medical procedures involved, when 
implanting, using or testing the respective investigational device, even if not directly related 
to the device (e.g. anaesthetic complications, wound healing disturbances etc) are 
considered as procedure related ADEs. 
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/treatment, the natural history of the underlying disease, other concurrent illness 
or risk factors. Each AE will be classified according to five different levels of causality. As 
defined in the Meddev 2.7/3 rev 3, the investigator will use the following definitions to 
assess the relationship of the adverse event to the investigational medical device or 
procedures and the sponsor will review the investigator’s categorization: 
 
Not related: the relationship to the device or procedures can be excluded. 
Unlikely: the relationship with the use of the device seems not relevant and/or the event 
can be reasonably explained by another cause, but additional information may be obtained. 
Possible: the relationship with the use of the investigational device is weak but cannot be 
ruled out completely. Alternative causes are also possible (e.g. an underlying or concurrent 
illness/ clinical condition or/and an effect of another device, drug or treatment). Cases were 
relatedness cannot be assessed or no information has been obtained should also be 
classified as possible. 
Probable: the relationship with the use of the investigational device seems relevant and/or 
the event cannot be 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 
adverse 
events.  
Note:  
• 
In case of a replacement of the investigational device in response to an adverse 
event (the BioMonitor is replaced), the replacement will be considered like an initial 
application of a new investigational device and shall be assessed accordingly. 
• 
Replacement of the BioMonitor due to a regular battery depletion is not considered 
an adverse event. 
• 
An adverse event can be related both to procedures and the investigational device. 
Complications of procedures are considered not related if the said procedures would 

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have been applied to the patients also in the absence of investigational device use or 
application. 
18.3 
Definition of 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 labelling.  
DDs of the investigational device shall be documented throughout the study. DDs which 
caused an AE 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 a DD with SADE potential.  
18.4 
Definition of serious adverse events 
AEs are classified as serious if one or more of the following consequences are fulfilled: 
• led to death 
• led to serious deterioration in the health of the subject, that either resulted in 
o 
a life-threatening illness or injury, or 
o 
a permanent impairment of a body structure or a body function, or 
o 
in-patient or prolonged hospitalization, or 
o 
medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function. 
• led to foetal distress, fatal death or a congenital abnormality or birth defect. 
Note: Hospitalizations planned before enrollment for a pre-existing condition, or a procedure 
required by the CIP, without serious deterioration in health, is not considered as serious 
adverse event. 
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.  
According to national and international requirements some of the involved CA and EC have 
to be informed on the occurrence of SAEs during the course of the study. In general, this 
duty will be fulfilled by the sponsor if not requested otherwise by the EC or CA. The 
investigator is obliged to provide all relevant information on the SAE in a timely manner and 
to follow all SAEs until the date of their resolution.  

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Note: In order to comply with the German national legislation, the German sites shall report 
to the sponsor all events which resulted or could have resulted in the consequences of a 
serious adverse event as serious adverse event (see also section 18.8).  
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. 
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.  
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. 
18.8 
Reporting responsibilities 
In addition to reporting responsibilities defined below, for sites located in the U.S. also U.S. 
specific reporting requirements need to be fulfilled. Details on these national requirements 
are documented in the U.S. specific amendment to the BIO|GUARD-MI CIP. 
18.8.1 Reporting responsibilities of the investigator to sponsor 
The investigator shall document all events on the respective eCRF pages provided within the 
EDC system. The indicated timelines for reporting of initial cases and possible update 
reports shall be strictly followed.  
All adverse events (AE) and adverse device effects (ADEs) shall be reported together with 
an assessment by completing the AE-CRF in accordance with ISO 14155. Note: For German 
sites, the (S)A(D)E definition according to the German national regulation MPSV8 §2 (5)9 
should be applied. 
 
8 Medizinprodukte-Sicherheitsplanverordnung vom 24.Juni 2002 (BGBl. I S.2131) zuletzt geändert durch Artikel 3 
der Verordnung über klinische Prüfungen von Medizinprodukten und zur Änderung medizinprodukterechtlicher 
Vorschriften vom 10.Mai 2010 (BGBl. I. S. 560) 
9 Im Sinne der MPSV ist ein schwerwiegendes unerwünschtes Ereignis jedes in einer genehmigungspflichtigen 
klinischen Prüfung oder einer genehmigungspflichtigen Leistungsbewertungsprüfung auftretende ungewollte 
Ereignis, das unmittelbar oder mittelbar zum Tod oder zu einer schwerwiegenden Verschlechterung des 
Gesundheitszustands eines Probanden, eines Anwenders oder einer anderen Person geführt hat, geführt haben 
 

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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.  
 
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 
According to national and international regulations some of the involved CAs and ECs 
request reporting of SAEs and DDs with SADE potential during the course of the study. 
Investigators have to ensure, that they fulfil the reporting obligations of their local CAs and 
EC/IRBs. 
Table 4: Reporting responsibilities of the investigator  
Event 
Report to 
Timeline 
Adverse Event (AE) / 
Adverse Device Effect 
(ADE) 
CCR BIOTRONIK SE & Co. KG:  
• Documentation in (S)A(D)E-CRF in 
iMedNet 
Within 2 weeks 
 
Serious Adverse Event 
(SAE) /  
Serious Adverse 
Device Effect (SADE) 
CCR BIOTRONIK SE & Co. KG:  
• Documentation in (S)A(D)E -CRF in 
iMedNet 
1) Immediately, latest 
24h after detection 
 
 
Unanticipated Serious 
Adverse Device Effect 
(USADE) 
CCR BIOTRONIK SE & Co. KG:  
• Documentation in (S)A(D)E -CRF in 
iMedNet 
1) Immediately, latest 
24h after detection 
 
Device Deficiencies 
CCR BIOTRONIK SE & Co. KG:  
• Documentation in the DD-CRF in 
iMedNet 
Within 14 days 
 
Device Deficiency with 
SADE potential 
CCR BIOTRONIK SE & Co. KG:  
• Documentation in DD-CRF in iMedNet 
1) Within 24 hours 
 
 
 
könnte oder führen könnte ohne zu berücksichtigen, ob das Ereignis vom Medizinprodukt verursacht wurde; das 
Vorgesagte gilt entsprechend für schwerwiegende unerwünschte Ereignisse, die in einer klinischen Prüfung oder 
Leistungsbewertungsprüfung, für die eine Befreiung von der Genehmigungspflicht nach § 20 Absatz 1 Satz 2 des 
Medizinproduktegesetzes erteilt wurde, aufgetreten sind. 

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18.8.3  Reporting responsibilities of the sponsor 
BIOTRONIK SE & Co. KG will report all SAEs/SADE and all Device Deficiencies with SADE 
potential to the CAs and ECs depending on the local regulatory requirements. 
For the CAs and ECs or IRBs located in the U.S., the local sponsor will report all concerned 
events  according to the national requirements. Details on these national requirements are 
documented in the U.S. specific amendment to the BIO|GUARD-MI CIP. 
Furthermore, BIOTRONIK SE & Co. KG ensures that summarized Safety Reports are 
forwarded to the investigational sites and the ethic committees depending on the local 
requirements.   
For the investigational sites and ethics committees or IRBs located in the U.S., the local 
sponsor will forward all concerned reports  according to the national requirements. Details 
on these national requirements are documented in the U.S. specific amendment to the 
BIO|GUARD-MI CIP. 
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. Event listings will be provided regularly and 
unanticipated serious adverse device effects (USADEs) will be reported immediately. 
For investigators located in the U.S., the local sponsor will report all concerned events and 
listings according to the national requirements. Details on these national requirements are 
documented in the U.S. specific amendment to the BIO|GUARD-MI CIP. 
18.9 
Reporting timelines 
Reporting timelines for investigators are stated in the corresponding Table 4 in section 18.8.  
18.10 
Emergency contact 
A contact address for patients in case of emergency will be provided in the individual ICFs. 
In case technical support is needed the service hotline of BIOTRONIK is available 24 hours a 
day. Phone: +49 (0) 30 68905-1133. For technical support for other devices used in the 
study, please consult the respective manual or support team. 
 

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19  VULNERABLE POPULATION 
Enrollment of patients from a vulnerable population is not anticipated for this study. The PI 
has to take decision about the vulnerability of patients and where appropriate ensure that 
these patients are not enrolled. Examples for vulnerability are an age below 18 years, 
limited contractual capability, and dependence from sponsor or site. 

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20  SUSPENSION 
20.1 
Criteria and procedures 
The study may be suspended or terminated prematurely in all sites or in a single 
investigational site based on a decision by the sponsor, the investigator or the EC/IRB/CA. 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 groups, 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 (see section 20.1.1 with regard to the exclusion of single investigational sites) 
• 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. persistent 
incompliance with the CIP or regulatory requirements) 
 
In case the study sponsor decides to suspend or prematurely terminate the study, the 
sponsor is required to promptly notify the investigator(s) to whom the decision applies. The 
investigator will inform the EC/IRB/CA of this decision. The investigator will also promptly 
inform all patients enrolled at the investigational site and are still actively participating. 
Patients that already left the study shall be informed if they might be affected by safety 
aspects. 
In case of any reasonable ethical concern of the investigator regarding a further study 
conduct in the respective investigational site, the sponsor shall be informed immediately. If 
the investigator decides to suspend or prematurely terminate the study at his/her site 
he/she will promptly inform the study sponsor, the EC/IRB/CA and all enrolled patients of 
this decision. 
If the EC/IRB/CA 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. 

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20.1.1  Replacement strategy 
Each participating study site is obligated to meet the estimated enrollment rate as 
determined during the qualification visit. However, every investigator can enroll as many 
patients as desired until the sample size has been reached and announced.  
The enrollment rate of each site will be evaluated by the study team on a monthly basis. 
The site will be informed immediately in case it is foreseeable that the enrollment 
expectations are not met. In parallel the study team and respective field CRA will offer to 
provide additional support to prevent a possible replacement. However, if despite all efforts 
taken no patient could be enrolled after 3 months the respective site will be closed and 
replaced. 
20.2 
Un-blinding procedures 
Un-blinding procedures are not applicable since the study design is open. 
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 EC/IRB/CA decision, additional requirements from the EC/IRB/CA 
with respect to follow-up and data collection may apply. 
Ongoing SADEs will be followed in a time period of up to 6 weeks after pre-mature 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. 
Patients will be informed on this procedure in written form in the ICF. 

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21  PUBLICATION POLICY 
21.1 
Publication Steering Committee  
A Publication Steering Committee (PSC) is constituted when the protocol is finalized. It may 
include the Coordinating Investigator (CI), members of the Steering Committee, 
investigators and other individuals who have expertise in the area and employees of 
BIOTRONIK. All study stakeholders (e.g. participating investigators, Steering Committee 
members, BIOTRONIK employees) may submit publication ideas through the PSC. Based on 
a charter, the PSC would develop a publication strategy and oversee the development of 
publications and abstracts/presentations according to the publication strategy. All 
manuscripts and abstracts will be reviewed and approved by the PSC, all authors and 
BIOTRONIK. The PSC makes decisions about the authorship and writer(s). Members of the 
PSC may become authors but membership does not automatically result in authorship. The 
PSC will meet approximately every year to refine the publication strategy.  
21.2 
Authorship guidelines  
21.2.1  Purpose 
Purpose of this guideline is to settle criteria to determine which of the contributors to an 
article in a peer reviewed journal or an abstract for a scientific congress based on data from 
the BIO|GUARD-MI study should be identified as authors. 
Criteria of journals or congresses may differ from these guidelines. In this case, 
requirements of journals or congresses are to be respected. 
21.2.2  Validity 
This authorship guideline is valid for all contributors to an article or abstract, including 
investigators taking part in the study, sponsor employees, and individuals contracted by the 
sponsor. All authors listed on an article or abstract must fulfil authorship criteria listed below 
and should sign this agreement. On the other hand, all persons fulfilling the authorship 
criteria listed below shall be considered for authorship. 
21.2.3  Authorship criteria 
Authorship of all publications will be decided by the Publication Steering Committee (PSC). 
Authorship will be determined prior to the development of a publication or presentation. 
Authorship credit should be based on all of the following conditions with regard to the 
International Committee of Medical Journal Editors (ICMJE):  
• 
substantial contributions to conception and design, acquisition of data, or analysis 
and interpretation of data,  
• 
drafting the article or revising it critically for important intellectual content, and  

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• 
final approval of the version to be published.  
The PSC will assure that the assessment of the contribution of all potential authors will be 
fair. Especially, the PSC will weight the importance of a potential author’s contribution to the 
study data, his or her membership on committees and boards, and his or her contribution to 
the publication idea or the discussion of the publication’s content. 
21.2.4  Justification and rules for the assessment of “acquisition of data”:  
Study specific criteria for acquisition of data have been defined. A scoring system will 
consider four components:  
➔ Enrollment of patients,  
➔ prompt classification of arrhythmias detected by the ICM,  
➔ unhesitating contact to the patient and 
➔ conducting an in-office termination visit. 
Justification:  
The importance of enrollments for the study’s success is evident. Without prompt 
classification of arrhythmias and the consecutive contact of patients, the study concept 
cannot be effective. The conduction of in-office termination visits is important for a 
complete adverse event reporting.   
All four elements can be objectively calculated from the study database and together, they 
provide an objective quantification of the contribution of a study site. 
21.2.5  Calculation of the total score 
For each of the four elements, 1000 points are granted. 
➔ For each randomized patient, the number of granted points to the investigational site 
is 1000 divided by the number of randomized patients.  
➔ Further 1000 points are distributed evenly over all classified arrhythmias, which have 
been completed within 5 working days after onset of the arrhythmia. 
➔ Equally, further 1000 points are distributed evenly over all documented contacts to 
patients after arrhythmias, which were done within 7 working days of the 
arrhythmia. 
➔ For each patient seen in-office for the final study termination visit, the number of 
points is 1000 divided by the total number of patients seen in-office for the final 
study termination visit. 
The sites will then be ranked by the total sum of points from the four categories. 
For all publications after the primary publication, investigators who have not been authors 
of accepted publications will be considered preferentially. The number of authors of a study 
site on all publications (weighted by the journals’ latest impact factors) shall be proportional 
to the data contribution measured by the score, which is described here.  

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21.2.6  Authors’ tasks and responsibilities 
This will include but may not necessarily be limited to the following: 
First author 
a) Guarantor for the integrity of the study BIO|GUARD-MI and its report 
b) Lead for writing and managing the manuscript/abstract  
c) Submit the manuscript/abstract to allocated reviewers (co-author, BIOTRONIK etc.) 
according to the publication plan 
d) Preparation and submission of the manuscript/abstract according to timelines, 
defined in the publication plan 
e) Adaptation of the manuscript, based on Journal reviewer feedback 
f) Disclose potential conflicts of interest 
Co-authors 
a) Assist the first author in planning and writing the publication, if needed 
b) Review of the manuscript/abstract and give feedback within the determined time 
window 
c) Agree on the order in which they appear in the manuscript/abstract 
d) Agree on any changes in authorship 
e) Disclose potential conflicts of interest 
21.2.7  Authorship of ancillary publications 
Ancillary publications are publications, which are not part of the publication strategy. The 
PSC must approve ancillary requests and will need to ensure, that these publications do not 
present conflicts with other planned publications or earlier submitted requests. Requests for 
ancillary publications will be evaluated for scientific validity and the ability of BIOTRONIK to 
provide resources. All manuscripts and abstracts will be reviewed and approved by the PSC, 
all authors and BIOTRONIK. The PSC may decide on a different scoring system which 
should, in this case, favour investigators who have contributed more data to the specific 
subject of the publication. 
21.2.8  Contributorship and acknowledgement  
Individuals, including BIOTRONIK employees, who have substantially contributed to a study, 
but who do not meet the authorship criteria, should be listed in the acknowledgement 
section. Any support provided by non-BIOTRONIK-personnel, e.g. a professional medical 
writer must also be disclosed in the acknowledgement section.  
21.2.9  Timelines 
The publication plan gives a detailed overview of timelines for preparation and submission 
of publications. If the first author will not provide a manuscript within appropriate time after 
following reminder, a co-author will be invited to become first author. 

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21.2.10 
Compliance 
The Publication Steering Committee will ensure that authorship guidelines are met and 
authorship is attributed appropriately. The Publication Committee will also track timeline 
adherence.  
21.2.11 
Reimbursement 
No honoraria will be paid for authorship of publications. 
 

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22  BIBLIOGRAPHY 
 
 
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management of syncope and palpitations. Europace 2011;13:431-437. 
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risk score for patients after ST-segment elevation acute myocardial infarction treated 
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myocardial infarction by use of multiple-risk-factor assessment equations: GISSI-
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in post myocardial infarction arrhythmias - a Cardiac Arrhythmias and RIsk 
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 (17)  Chao TF, Liu CJ, Chen SJ et al. CHADS2 score and risk of new-onset atrial fibrillation: 
a nationwide cohort study in Taiwan. Int J Cardiol 2013;168:1360-1363. 
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fibrillation. Am J Cardiol 2013;111:1602-1607. 
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bradycardia requiring pacemaker implantation in patients with atrial fibrillation. Am J 
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 (21)  Gang UJ, Jons C, Jorgensen RM et al. Clinical significance of late high-degree 
atrioventricular block in patients with left ventricular dysfunction after an acute 
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Myocardial Infarction (CARISMA) substudy. Am Heart J 2011;162:542-547. 
 (22)  Vardas PE, Auricchio A, Blanc JJ et al. Guidelines for cardiac pacing and cardiac 
resynchronization therapy: The Task Force for Cardiac Pacing and Cardiac 
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 (23)  Ahmed I, Nelson WB, House CM, Zhu DW. Predictors of appropriate therapy in 
patients with implantable cardioverter-defibrillator for primary prevention of sudden 
cardiac death. Heart Int 2010;5:e4. 
 (24)  Al-Khatib SM, Granger CB, Huang Y et al. Sustained ventricular arrhythmias among 
patients with acute coronary syndromes with no ST-segment elevation: incidence, 
predictors, and outcomes. Circulation 2002;106:309-312. 
 (25)  Desai H, Aronow WS, Tsai FS et al. Statins reduce appropriate cardioverter-
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incidence, time course, and predictors--a systematic, prospective analysis. Stroke 
2012;43:2892-2897. 
 (27)  Montalescot G, Sechtem U, Achenbach S et al. 2013 ESC guidelines on the 
management of stable coronary artery disease: the Task Force on the management 
of stable coronary artery disease of the European Society of Cardiology. Eur Heart J 
2013;34:2949-3003. 
 (28)  Zipes DP, Camm AJ, Borggrefe M et al. ACC/AHA/ESC 2006 guidelines for 
management of patients with ventricular arrhythmias and the prevention of sudden 
cardiac death: a report of the American College of Cardiology/American Heart 
Association Task Force and the European Society of Cardiology Committee for 
Practice Guidelines (Writing Committee to Develop guidelines for management of 
patients with ventricular arrhythmias and the prevention of sudden cardiac death) 
developed in collaboration with the European Heart Rhythm Association and the 
Heart Rhythm Society. Europace 2006;8:746-837. 
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Report. 
 
12-5-2014.  
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patients with myocardial infarction and reduced ejection fraction. N Engl J Med 
2002;346:877-883. 
 (31)  Braunwald E, Domanski MJ, Fowler SE et al. Angiotensin-converting-enzyme 
inhibition in stable coronary artery disease. N Engl J Med 2004;351:2058-2068. 
 (32)  Fox KM. Efficacy of perindopril in reduction of cardiovascular events among patients 
with stable coronary artery disease: randomised, double-blind, placebo-controlled, 
multicentre trial (the EUROPA study). Lancet 2003;362:782-788. 
 (33)  Kruk M, Buller CE, Tcheng JE et al. Impact of left ventricular ejection fraction on 
clinical outcomes over five years after infarct-related coronary artery recanalization 
(from the Occluded Artery Trial [OAT]). Am J Cardiol 2010;105:10-16. 
 (34)  Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-
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 (35)  Krahn AD, Klein GJ, Yee R, Takle-Newhouse T, Norris C. Use of an extended 
monitoring strategy in patients with problematic syncope. Reveal Investigators. 
Circulation 1999;99:406-410. 
 (36)  Pachulski R, Cockrell J, Solomon H, Yang F, Rogers J. Implant evaluation of an 
insertable cardiac monitor outside the electrophysiology lab setting. PLoS One 
2013;8:e71544. 
 (37)  Seidl K, Rameken M, Breunung S et al. Diagnostic assessment of recurrent 
unexplained syncope with a new subcutaneously implantable loop recorder. Reveal-
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 (38)  Sanna T, Diener HC, Passman RS et al. Cryptogenic stroke and underlying atrial 
fibrillation. N Engl J Med 2014;370:2478-2486. 

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 (39)  Smit J, Korup E, Schonheyder HC. Infections associated with permanent pacemakers 
and implanted cardioverter-defibrillator devices. A 10-year regional study in 
Denmark. Scand J Infect Dis 2010;42:658-664. 
 (40)  Tarakji KG, Chan EJ, Cantillon DJ et al. Cardiac implantable electronic device 
infections: presentation, management, and patient outcomes. Heart Rhythm 
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 (41)  Brignole M, Vardas P, Hoffman E et al. Indications for the use of diagnostic 
implantable and external ECG loop recorders. Europace 2009;11:671-687. 
 (42)  Varma N, Epstein AE, Irimpen A, Schweikert R, Love C. Efficacy and safety of 
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 (43)  Wassmer G. Planning and Analyzing Adaptive Group Sequential Survival Trials. 
Biometrical Journal 2006; 48: 714–29 statt Lehmacher W, Wassmer G. Adaptive 
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 (44)  Schoenfeld DA. Sample-size formula for the proportional-hazards regression model. 
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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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23  APPENDICES 
23.1 
Appendix A: Comparison BIO|GUARD-MI CIP with U.S.-
specific CIP amendments 
 
To meet the regulatory requirements for U.S. investigational sites when conducting an IDE 
study, the CIP V7.0 of the BIO|GUARD-MI study is transferred into an amendment, dated 
April 06, 2021 to the U.S.-specific protocol version June 12, 2019. This appendix list 
compares the U.S. specific protocol to the current CIP version 7.0 valid for all out-of-U.S. 
investigational sites. All critical aspects of the study including design and objectives, 
primary 
endpoints, 
secondary 
endpoints, 
additional 
data 
of 
interest, 
enrollment/implant/follow-up procedures, inclusion criteria, exclusion criteria, adverse event 
reporting and Board processes, are identical. The similarity in the clinical study design 
justifies the planned pooling of data from subjects enrolled under both protocols (U.S. and 
non-U.S.) to meet the sample size requirements for the analysis of the primary endpoints.  
An obvious difference between the two protocol versions is the order of sections and 
formatting. However, the content is only changed according to the documentation below. 
The table below outlines the similarities and differences between the protocols. 
Title 
BIOGUARD MI, version 7.0 
BIOGUARD MI, U.S. version 
June 12, 2019 amended April 
06, 2021 
Justification 
General Aspects 
Clinical Trials 
Registration 
NCT02341534 
Single posting 
Region 
Outside U.S. 
U.S. 
All data will be collected 
with the same EDC 
system. Therefore, all 
data collection is 
identical 
Clinical sites 
~ 60 sites outside U.S. 
~ 20 U.S. sites 
Up to 80 sites total 
Number of 
subjects 
Up to 2900 worldwide 
Up to 360 in the United States 
(total worldwide 2900) 
FDA submission 
requires a total number 
of subjects from US 
sites. Overall, the study 
will include up to 2900 
subjects, which includes 
the 360 from the United 
States 
Sample size 
The original planning assumed that 372 primary events would be 
required to accept the primary alternative hypothesis with 80% 
statistical power given an assumed hazard ratio in the population of 
0.7452, and the study was to be terminated after this number of 
endpoints had been collected.  
Instead, it was decided to enter the termination phase without any 
avoidable further delay. Therefore, the intended number of 
endpoints may not be reached. 
Identical sample size 
calculation 

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Title 
BIOGUARD MI, version 7.0 
BIOGUARD MI, U.S. version 
June 12, 2019 amended April 
06, 2021 
Justification 
Coordinating 
Clinical 
Investigator  
Dr. Christian Jons 
 
Identical Coordinating 
Clinical Investigator 
Sponsor 
BIOTRONIK SE & Co. KG 
Woermannkehre 1 
12359 Berlin 
Germany 
BIOTRONIK, Inc. 
6024 Jean Road 
Lake Oswego, OR 97035 
USA 
BIOTRONIK SE & Co. 
KG recognized as the 
global sponsor, while 
BIOTRONIK, Inc. is the 
local sponsor for all 
U.S. sites 
Boards and 
Committees 
Central Electrocardiogram Monitoring Board (CEMB) 
Data Safety Monitoring Board (DSMB) 
Endpoint and Adverse Event Committee (EAEC) 
Steering Committee (SC) 
Publication Steering Committee (PSC) 
Identical boards and 
committees 
Contract 
Research 
Organization 
IHF GmbH 
Institut für Herzinfarktforschung 
Bremserstraße 79 
67063 LudwigshafenGermany 
 
In the course of the 
study, additional service 
providers might be 
contracted depending 
on the countries which 
will be further included. 
Applicable 
regulation 
ISO 14155 and national 
country-specific regulations 
ICH/GCP according to FDA 
requirements (21 CFR Part 812) 
Study procedures in the 
U.S. follow FDA 
requirements. However, 
additional requirements 
of ISO14155 may be 
applicable in specific 
tasks (e.g. AE 
reporting) 
Clinical Report 
Requirements 
Clinical reports will follow 
reporting requirements per 
ISO14155 
Clinical reports will follow FDA 
reporting requirements for IDE 
studies. This includes an annual 
progress report and a current 
list of investigators every 6 
months, in addition to the final 
report. 
Clinical reports will 
follow the requirements 
in the associated 
region. 
Noncompliance 
with study 
protocol 
Noncompliance classification: 
Major Deviation: Deviation that 
are likely to seriously affect or 
that actually have seriously 
affected the rights or safety of 
wellbeing of subjects or the 
scientific integrity of the clinical 
investigation. 
Minor deviation:  Other 
deviation from the protocol that 
do not meet the definition for 
Major Deviation. 
 
All protocol noncompliances are 
recorded by each site on a 
paper deviation log 
Noncompliance classification: 
Protocol Violation: Major 
deviation where the protocol 
requirements and/or regulatory 
guidelines are not followed, and 
are generally more serious in 
nature. They are considered to 
potentially affect the scientific 
soundness of the study and/or 
rights, safety or welfare of 
subjects.  
Protocol Deviation: Other 
deviation from protocol that 
does not meet the definition of 
violation and are generally less 
serious in nature and may not 
require IRB notification as long 
as they do not affect the rights, 
safety, or welfare of the study 
subject. 
 
All protocol noncompliances are 
recorded on a Protocol Non-
compliance eCRF within the EDC 
system. 
Noncompliance 
classifications in the 
regions are similar in 
definition, but each 
protocol follows the 
applicable regulatory 
requirements. The 
statements vary in 
sentence structure and 
word choice. 
 
The U.S. records 
noncompliances 
electronically as part of 
their standard 
processes. All 
noncompliances from 
both regions will be 
merged for reporting 
purposes. 

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Title 
BIOGUARD MI, version 7.0 
BIOGUARD MI, U.S. version 
June 12, 2019 amended April 
06, 2021 
Justification 
SAE/S(U)ADE/DD 
Per ISO14155 
The investigator reports: 
• 
Adverse events  
• 
Serious adverse events 
• 
Serious adverse device 
effect 
• 
Unanticipated serious 
adverse device effect 
• 
Device deficiency 
 
Per ISO 14155 and FDA 21 CFR 
Part 812 
The investigator reports: 
• 
Adverse events  
• 
Serious adverse events 
• 
Unanticipated adverse 
device effects 
• 
Serious adverse device 
effect 
• 
Unanticipated serious 
adverse device effect 
• 
Device deficiency 
• 
Device complaint 
To ensure proper 
reporting, all sites will 
follow ISO14155 and 
U.S. sites will follow 
FDA 21 CFR Part 812, in 
addition to ISO 14155 
Termination 
Criteria 
The sponsor may decide to discontinue the study due to 
organizational reasons based on the observed event rates and the 
general feasibility of the study. Based on the recommendations of 
the DSMB for the study after the first analysis, the study will be 
stopped for futility when there is a low chance for rejection of the 
Alternative hypothesis at the final analysis or the need for an 
increase of the sample size, which is refused by the sponsor. 
Identical termination 
criteria 
Study Design Aspects 
Design 
Prospective, controlled, randomized (1:1), parallel-group, open, 
multi-center, international study with an event-driven design 
Identical study design 
Study phases 
Study designed in two 
enrollment phases, 1 and 2 with 
longer study duration 
Due to the timing of the study, 
the U.S. will only join Phase 2 
Information on different 
phases is reduced in the 
U.S. protocol, as it is 
not applicable in this 
country 
Primary objective 
Investigate whether the early diagnosis of cardiac arrhythmias, 
provided by the BioMonitor in connection with remote monitoring, 
and the consequent treatment of the subject will decrease the risk 
to experience a MACE in patients with MI, CHA2DS2-VASc Score ≥ 4 
in men/ ≥ 5 in women and LVEF > 35% 
Identical primary 
objective 
Secondary 
objective 
All individual components of the composite primary endpoint will 
also be evaluated separately. In addition, the occurrence of 
arrhythmias and related therapies will be evaluated. The life quality 
will be evaluated using the WHO (Five) Well-Being Index. 
Identical secondary 
objective 
Primary 
endpoints 
Time to first MACE 
 
A major adverse cardiac event (MACE) comprises the following 
events:  
• 
Cardiovascular death 
• 
Worsening of the patient status due to heart failure, 
requiring acute unscheduled hospitalization or urgent visit 
or acute unscheduled hospitalization due to adverse 
events (AE) of the following list: 
• 
Arrhythmia 
• 
Acute coronary syndrome 
• 
Stroke  
• 
Major bleeding  
• 
Systemic embolism  
 
Identical primary 
endpoint 

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Title 
BIOGUARD MI, version 7.0 
BIOGUARD MI, U.S. version 
June 12, 2019 amended April 
06, 2021 
Justification 
Secondary 
endpoints 
1. 
To assess the time to 
• 
Cardiovascular death 
• 
First acute unscheduled hospitalization or urgent visit for 
worsening of the patient status due to heart failure or first 
acute unscheduled hospitalization due to adverse events 
of the following list: 
• 
Arrhythmia 
• 
Acute coronary syndrome 
• 
Stroke 
• 
Major bleeding 
• 
Systemic embolism 
2. 
To assess the time to first 
• 
Atrial fibrillation 
• 
Atrial flutter 
• 
Non-sustained VT 
• 
Sustained VT 
• 
Sinus arrest 
• 
Sinus bradycardia 
• 
2nd or 3rd degree AV block or advanced AV block 
3. 
To assess the quality of life WHO (Five) Well-Being Index 
Identical secondary 
endpoints 
Additional data of 
interest 
To assess in a descriptive manner, the types and number of 
therapeutic interventions administered after arrhythmias detected 
by remote monitoring 
Identical additional data 
of interest 
Inclusion criteria 
• 
Patient has a history of MI according to guidelines 
• 
CHA2DS2-VASc Score ≥ 4 in men / ≥ 5 in women 
• 
LVEF > 35% as estimated within 6 months before enrollment 
but after conclusion of AMI treatment 
• 
Patient accepts activation of Home Monitoring 
• 
Patient is able to understand the nature of the clinical study and 
has provided written informed consent 
Identical inclusion 
criteria 
Exclusion criteria 
• 
Platelet count < 90.000 per mm3 or patients with hemorrhagic 
diathesis 
• 
Permanent oral anticoagulation treatment for atrial fibrillation 
• 
Indication for chronic renal dialysis  
• 
Pacemaker or ICD implanted or indication for implantation 
• 
Parkinson’s disease 
• 
Life expectancy < 1 year 
• 
Participation in another interventional clinical investigation 
during the course of the study, i.e. the participation in a non-
interventional clinical investigation is allowed. 
• 
Age < 18 years 
• 
Woman who are pregnant or breast feeding 
Identical exclusion 
criteria 

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Title 
BIOGUARD MI, version 7.0 
BIOGUARD MI, U.S. version 
June 12, 2019 amended April 
06, 2021 
Justification 
Exclusion criteria 
clarification of 
“non-
interventional 
clinical 
investigation” 
Following the definition of the 
European clinical trial directive 
2001/20/EC, 
we 
define  
non-interventional 
clinical 
investigations 
as 
a 
study  
where the product(s) under 
investigation is (are) prescribed 
in 
the 
usual 
manner 
in 
accordance with the terms of 
the 
marketing 
authorisation. 
The assignment of the patient 
to 
a 
particular 
therapeutic 
strategy 
is 
not 
decided 
in 
advance by a trial protocol but 
falls within current practice and 
the prescription of the product 
under investigation is clearly 
separated from the decision to 
include the patient in the study. 
No 
additional 
diagnostic 
or 
monitoring procedures shall be 
applied to the patients and 
epidemiological methods shall 
be used for the analysis of 
collected data. 
We 
define 
non-
interventional 
clinical 
investigations as a study where 
the 
product(s) 
under 
investigation is (are) prescribed 
in 
the 
usual 
manner 
in 
accordance with the terms of the 
marketing 
authorisation. 
The 
assignment of the patient to a 
particular therapeutic strategy is 
not decided in advance by a trial 
protocol but falls within current 
practice and the prescription of 
the product under investigation 
is clearly separated from the 
decision to include the patient in 
the 
study. 
No 
additional 
diagnostic 
or 
monitoring 
procedures shall be applied to 
the patients and epidemiological 
methods shall be used for the 
analysis of collected data. 
Similar statement, but 
the U.S. sites are not 
bound by the European 
clinical trial directive 
2001/20/EC 
Follow-up 
procedures 
Patient Enrollment 
Inclusion and exclusion criteria met 
Informed consent obtained 
Enrollment data collected 
 
Baseline 
 
Randomization 
Randomization selection included in Baseline eCRF 
1:1 randomization to receive BioMonitor Device or standard of care 
(no BioMonitor device) 
 
Implantation 
Only for subjects randomized to receive a BioMonitor device 
No later than 8 weeks following Enrollment 
 
Discharge 
Discharge refers to when subjects leave the investigational site 
where enrollment occurred 
 
Follow up phone contact (every 6 months) 
WHO Quality of Life Questionnaire 
AE collection 
 
Termination 
End of subject participation 
Official point of explantation of BioMonitor not mandated by study 
protocol 
Identical study 
procedures with one 
exception: the U.S. 
protocol amendment 
describes that study 
personnel will conduct 
the interview on 
adverse events at the 
final study termination 
visit while CIP version 
7.0 specifically 
identifies the 
investigator as 
performing the 
interview. 

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Title 
BIOGUARD MI, version 7.0 
BIOGUARD MI, U.S. version 
June 12, 2019 amended April 
06, 2021 
Justification 
Discharge 
The patient will be further 
advised to contact the 
investigational site provided 
that the general practitioner or 
cardiologist finds a condition for 
which it appears that the 
attention of a tertiary care 
facility is required. Hence, the 
patients will be discouraged 
from contacting the 
investigational site on his or her 
own decision, but should only 
visit the investigational site 
after being advised to do so.  
In addition, general study 
aspects such as the telephone 
follow-up concept should be 
repeatedly explained to the 
subject and how to seek medical 
attention per standard of care. 
Each protocol includes 
discharge instructions 
that are amenable to 
regional medical 
practices 
Telephone 
contact 
An external Clinical Research Organization (CRO) will contact all 
study subjects via phone every 6 months. These calls include 
questions about subject’s health and adverse event assessment, 
along with the administration of the WHO Quality of Life 
questionnaire 
Identical telephone 
contact procedures with 
study subjects 
Medical record 
collection 
resulting from 
AEs reported 
during telephone 
contact 
Telephone follow-up activities 
and consequent source data 
collection will be performed by 
an external CRO contracted by 
the main sponsor. 
 
If the event is an SAE, source 
data is provided by the CRO. 
Telephone follow-up activities 
and consequent source data 
tracking will be performed by an 
external CRO contracted by the 
main sponsor. 
 
The site should try to obtain as 
much information regarding the 
adverse event as possible, 
including all applicable medical 
records of the event.  
 
Each protocol includes 
instructions on medical 
record collection 
methods that are 
amenable to regional 
medical practices 
Investigational Medical Devices 
Investigational 
Medical Devices 
BioMonitor  or  approved successor 
Identical medical 
devices currently, but 
future successors may 
not be utilized at same 
time due to varying 
CE/FDA approval dates  
Accessory 
components to 
investigational 
medical devices 
BIOTRONIK 
Home 
Monitoring®: 
CardioMessenger 
II, 
IIs 
or 
successors, programmer: Renamic, ICS 3000 or successors with 
current software version, accessory device Remote Assistant if 
applicable 
 
Identical accessory 
components currently, 
but future successors 
may not be utilized at 
the same time due to 
varying CE/FDA 
approval dates 

BIOTRONIK SE & Co KG 
BIO|GUARD-MI 
 
 
 
Center for Clinical Research 
Version 7.0; April 06, 2021 
100/101 
 
FOR-137-014-A / SOP-137-020.020 / CRQ-13-00841 
Title 
BIOGUARD MI, version 7.0 
BIOGUARD MI, U.S. version 
June 12, 2019 amended April 
06, 2021 
Justification 
Indications for 
use 
The BioMonitor is an ICM used 
to 
automatically 
detect 
and 
record episodes of arrhythmia in 
patients at risk for bradycardia, 
tachycardia, asystole and AF. 
The ICM is not intended to 
deliver any therapy. 
The device reports the recorded 
episodes 
and 
the 
related 
statistical data via a physician’s 
programmer and telemetrically 
via 
BIOTRONIK 
Home 
Monitoring®. 
 
The BioMonitor 2 is indicated to 
detect the following cardiac 
arrhythmias: 
• 
Atrial fibrillation 
• 
Bradycardia 
• 
Sudden rate drop 
• 
High ventricular rate 
(HVR) 
• 
Asytole 
The BioMonitor 2 is indicated for 
use in: 
• 
Patients with clinical 
syndromes or situations 
at increased risk for 
cardiac arrhythmias 
• 
Patients who 
experience transient 
symptoms that may 
suggest a cardiac 
arrhythmia 
• 
The device has not 
been tested for and is 
not intended for 
pediatric use 
Intended use is similar. 
The U.S. protocol 
includes the indications 
for use verbatim from 
the FDA clearance of 
the BioMonitor 2 (Form 
3881). 
Contraindications 
There are no known contraindications 
Contraindications, or 
current lack thereof, 
are identical 
Miscellaneous 
Responsibilities of 
investigator 
Within protocol 
Removed from protocol 
The U.S. uses 
Investigator 
agreements (PI 
agreements and sub-
investigator 
agreements). These 
ancillary documents 
include all investigator 
responsibilities. 
Monitoring  
Within protocol 
Brief review of monitoring 
methods, monitors and 
monitoring visits included. Noted 
that more detail is included 
within the Monitoring Plan, 
separate from the protocol  
The U.S. protocol 
references the 
Monitoring Plan, as this 
is a detailed document 
that is best suited for 
the IDE application 
requirement of 
providing monitoring 
procedures 
Informed Consent 
process 
Detailed explanation of 
informed consent process in the 
protocol according to ISO14155 
European data protection 
regulation. 
The Informed consent form will 
comply with FDA regulations 
(21CFR, Part 50). In addition the 
subject will be informed on 
necessary data protection 
regulation according to 
European data protection 
regulation for subject data 
transferred to the main sponsor 
located in Europe.  
Informed Consent 
processes are largely 
similar in definition, but 
each protocol follows 
the applicable 
regulatory 
requirements. 

BIOTRONIK SE & Co KG 
BIO|GUARD-MI 
 
 
 
Center for Clinical Research 
Version 7.0; April 06, 2021 
101/101 
 
FOR-137-014-A / SOP-137-020.020 / CRQ-13-00841 
Title 
BIOGUARD MI, version 7.0 
BIOGUARD MI, U.S. version 
June 12, 2019 amended April 
06, 2021 
Justification 
Data retention 
and archiving 
All study related electronic 
documents are stored in the 
archive of BIOTRONIK which 
provides storage conditions free 
from risk of fire, flood, theft and 
vermin. The access to the 
files is controlled. After CDMS 
closure, all eCRF data, the audit 
trail and other relevant CDMS 
content are exported and stored 
electronically for at least 15 
years on the archive server. 
At end of the study, all study 
related electronic documents are 
stored in the archive of 
BIOTRONIK SE & Co. KG which 
provides storage conditions free 
from risk of fire, flood, theft and 
vermin. The access to the files is 
controlled. BIOTRONIK, Inc. will 
be provided access to the 
archived data. Furthermore 
BIOTRONIK Inc will provide 
copies of the data for U.S. 
subjects to BIOTRONIK SE & Co. 
KG. After EDC database closure, 
all eCRF data, the audit trail and 
other relevant EDC content are 
exported and stored 
electronically for at least 15 
years on an access protected 
archive server. 
 
Implementation of 
logistical aspects in the 
U.S. protocol assure 
adequate archiving of 
data. 
Record storage 
requirement for 
investigational 
sites 
The sites have to ensure data 
availability during the whole 
archiving period, i.e. for 15 
years. 
Record storage requirements will 
be consistent with local 
regulatory regulations. 
 
U.S. sites follow 21 CFR 
812.140 
Confidentiality of 
Subject Data 
All involved parties are bound to data secrecy according to the 
European Data Protection Regulation (GDPR). All subjects will be 
informed on all relevant regulations concerning data secrecy and 
data protection which are applicable for BIO|GUARD-MI in the ICF. 
Identical responsibilities 
of confidentiality of 
subject data, as both 
regions are following 
GDPR.