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

 
 
 
 
Clinical Protocol 
for the 
BIO|GUARD-MI Study 
 
BIO monitorinG in patients with preserved left 
ventricUlar function AfteR Diagnosed Myocardial 
Infarction 
 
IDE # G180155 
June 12, 2019 
 
 
 
 
 
BIOTRONIK, Inc. 
6024 Jean Road 
Lake Oswego, Oregon 97035 
 
This document contains confidential information for use only by investigators participating in 
the clinical study.  Therefore, this document should be maintained in a secure location and 
should not be copied or made available for review by any unauthorized personnel. 

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TABLE OF CONTENTS 
1. INTRODUCTION............................................................................................... 13 
1.1 Background .................................................................................................. 13 
2. INVESTIGATIONAL DEVICE ............................................................................. 17 
2.1 Name of Investigational Device ....................................................................... 17 
2.2 System Description ....................................................................................... 17 
2.3 Description of traceability............................................................................... 18 
2.4 Description of the investigational device .......................................................... 18 
2.4.1 BIOTRONIK Home Monitoring® with daily sECGs....................................... 18 
2.4.2 Remote Assistant for Patient Triggering................................................... 20 
2.5 Summary of training and experience needs ...................................................... 20 
3. JUSTIFICATION FOR THE DESIGN OF THE CLINICAL INVESTIGATION ............ 21 
3.1 Clinical data to support the safety and efficacy of the BioMonitor ........................ 21 
3.1.1 The BM01 acute study .......................................................................... 21 
3.1.2 BioMonitor Master Study ....................................................................... 21 
3.1.3 BIO|MASTER.BioMonitor 2 Study ............................................................ 22 
3.1.4 BioInsight Study .................................................................................. 22 
3.2 Clinical data to support the design of the BIO|GUARD-MI study .......................... 23 
3.3 Justification of the design ............................................................................... 23 
4. STUDY DESIGN ................................................................................................ 25 
4.1 Objectives .................................................................................................... 26 
4.1.1 Primary objectives ................................................................................ 26 
4.1.2 Secondary objective: Arrhythmia detection.............................................. 26 
4.1.3 Other secondary objectives ................................................................... 26 
4.2 Measures taken to minimize or avoid bias ........................................................ 27 
4.2.1 Randomization ..................................................................................... 27 
4.2.2 Blinding .............................................................................................. 27 
4.2.3 Other .................................................................................................. 27 
5. STUDY ENDPOINTS AND HYPOTHESES ............................................................ 29 

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5.1 Primary hypotheses ....................................................................................... 29 
5.2 Primary endpoint .......................................................................................... 29 
5.2.1 Endpoint assessment definitions ............................................................. 30 
5.3 Secondary hypotheses ................................................................................... 30 
5.4 Secondary Endpoints ..................................................................................... 31 
5.4.1 Secondary endpoint: Time to first arrhythmia detection ............................ 31 
5.4.2 Other secondary endpoints .................................................................... 31 
5.5 Further data of interest .................................................................................. 33 
6. STATISTICAL CONSIDERATIONS ..................................................................... 34 
6.1 Statistical design, method and analytical procedures ......................................... 34 
6.1.1 Group sequential design ........................................................................ 34 
6.1.2 Full Analysis set based on the ITT principle .............................................. 34 
6.1.3 Per-Protocol Analysis Set....................................................................... 34 
6.1.4 Statistical methods ............................................................................... 35 
6.2 Sample size.................................................................................................. 35 
6.3 Level of significance and the power of the study ............................................... 36 
6.4 Expected drop-out rate .................................................................................. 36 
6.5 Replacement of subjects ................................................................................ 36 
6.6 Pass/fail criteria ............................................................................................ 36 
6.7 Provision for an interim analysis ..................................................................... 37 
6.8 Termination criteria ....................................................................................... 37 
6.9 Procedures for reporting of deviations to the statistical plan ............................... 37 
6.10 Specification of subgroups ........................................................................... 37 
6.11 Procedure for accounting of all data for analysis ............................................. 38 
6.12 Handling of missing, unused and spurious data ............................................... 38 
6.13 Exclusion of data from confirmatory data analysis ........................................... 38 
6.14 Minimum and maximum number of subjects per site ....................................... 38 
7. PROTOCOL REQUIREMENTS ............................................................................. 39 
7.1 Subject Population ........................................................................................ 39 

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7.1.1 Indications .......................................................................................... 39 
7.1.2 Contraindications ................................................................................. 39 
7.1.3 Inclusion Criteria .................................................................................. 39 
7.1.4 Exclusion Criteria ................................................................................. 40 
7.2 Electronic CRFs and Forms ............................................................................. 41 
8. STUDY PROCEDURES ....................................................................................... 44 
8.1 Enrollment and Randomization ....................................................................... 44 
8.2 Baseline ....................................................................................................... 45 
8.3 Implantation ................................................................................................ 45 
8.3.1 Mandatory programming ....................................................................... 46 
8.4 Discharge .................................................................................................... 46 
8.5 Home Monitoring Analysis and In-Office Visits .................................................. 47 
8.6 Telephone contact ......................................................................................... 48 
8.7 Device replacement or explantation ................................................................. 49 
8.7.1 Device replacement .............................................................................. 49 
8.8 Study Termination ........................................................................................ 49 
9. STUDY EXITS ................................................................................................... 50 
9.1 Drop Out Criteria .......................................................................................... 50 
9.1.1 Subject death ...................................................................................... 50 
9.1.2 Withdrawal of subject informed consent .................................................. 51 
9.1.3 Lost to follow-up .................................................................................. 51 
9.1.4 Early discovery of a violation of inclusion or exclusion criteria .................... 52 
9.1.5 Investigator initiated drop-out ............................................................... 52 
9.2 Point of enrollment and study termination ........................................................ 52 
10. ADDITIONAL STUDY CONDITIONS .................................................................. 54 
10.1 IRB Approval .............................................................................................. 54 
10.2 Consent Materials ....................................................................................... 54 
10.3 Other Institutions and Physicians .................................................................. 54 
10.4 Electronic Case Report Forms (eCRFs) ........................................................... 54 

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10.5 Handling of Electronic Data .......................................................................... 55 
10.5.1 
Data protection ............................................................................. 55 
10.5.2 
Data collection .............................................................................. 55 
10.5.3 
Procedures used for data review, EDC cleaning, and issuing and resolving 
data queries ................................................................................................. 56 
10.5.4 
Procedures for verification, validation and securing of electronic data 
systems 
56 
10.5.5 
Data retention and archiving ........................................................... 57 
10.6 Confidentiality of Subject Data ..................................................................... 57 
10.7 Data Quality Control .................................................................................... 57 
10.8 Study Completion ....................................................................................... 58 
11. BENEFIT/RISK ANALYSIS ............................................................................... 59 
11.1 Potential Benefits ........................................................................................ 59 
11.1.1 
Benefits for subjects randomized to the BioMonitor group ................... 59 
11.1.2 
Benefits for subjects randomized to the control (non-BioMonitor) group 59 
11.1.3 
Benefits for future subjects ............................................................. 59 
11.2 Potential Risks ............................................................................................ 59 
11.2.1 
Anticipated adverse device effects ................................................... 59 
11.2.2 
Risk associated with participation in the study ................................... 61 
11.3 Steps to control or mitigate the risks ............................................................. 61 
11.4 Risk-to-benefit rationale .............................................................................. 61 
12. STUDY OVERSIGHT .......................................................................................... 62 
12.1 Responsibilities of the Endpoint and Adverse Event Board (EAEC) ..................... 62 
12.2 Responsibilities of the Data Safety Monitoring Board (DSMB)............................ 62 
12.3 Responsibilities of the Steering Committee ..................................................... 62 
12.4 Responsibilities of the Central Electrocardiogram Monitoring Board (CEMB) ........ 63 
12.5 Responsibilities of the Contract Research Organization (CRO) ........................... 63 
12.6 Responsibilities of the coordinating investigator (CCI) ..................................... 63 
13. STUDY MONITORING ....................................................................................... 65 
13.1 Methods .................................................................................................... 65 

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13.2 Monitors .................................................................................................... 65 
14. DEVIATIONS FROM CLINICAL INVESTIGATION PLAN ..................................... 67 
14.1 Recording deviations ................................................................................... 67 
14.2 Reporting Deviations ................................................................................... 67 
14.2.1 
Protocol Violations/Major Deviations ................................................ 68 
14.2.2 
Protocol Deviations ........................................................................ 68 
14.3 Corrective and preventive actions and disqualification criteria ........................... 68 
15. ADVERSE EVENTS ............................................................................................ 69 
15.1 Definitions ................................................................................................. 69 
15.1.1 
Definition of Adverse Event ............................................................. 69 
15.1.2 
Definition of Adverse Device Effect................................................... 69 
15.1.3 
Definition of Unanticipated Adverse Device Effects ............................. 70 
15.1.4 
Definition of Serious Adverse Events ................................................ 70 
15.1.5 
Definition of Serious Adverse Device Effect ....................................... 71 
15.1.6 
Definition of Unanticipated Serious Adverse Device Effects .................. 71 
15.1.7 
Definition of Device Deficiency ........................................................ 71 
15.1.8 
Definition of Device Complaint......................................................... 72 
15.2 Causality Assessment .................................................................................. 72 
15.3 Reporting responsibilities ............................................................................. 73 
15.3.1 
Reporting responsibilities of the investigator to sponsor ..................... 73 
15.3.2 
Reporting responsibilities of the sponsor ........................................... 73 
16. RECORDS AND REPORTS ................................................................................. 75 
16.1 Investigator Records ................................................................................... 75 
16.2 Investigator Reports .................................................................................... 75 
16.3 Sponsor Records ......................................................................................... 78 
16.4 Sponsor Reports ......................................................................................... 79 
17. PUBLICATION POLICY ..................................................................................... 80 
17.1 Publication Steering Committee .................................................................... 80 
17.2 Authorship guidelines .................................................................................. 80 

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17.2.1 
Purpose ........................................................................................ 80 
17.2.2 
Validity......................................................................................... 80 
17.2.3 
Authorship criteria ......................................................................... 80 
17.2.4 
Justification and rules for the assessment of “acquisition of data” ........ 81 
17.2.5 
Calculation of the total score ........................................................... 82 
17.2.6 
Authors’ tasks and responsibilities ................................................... 82 
17.2.7 
Authorship of ancillary publications .................................................. 83 
17.2.8 
Contributorship and acknowledgement ............................................. 83 
17.2.9 
Timelines ...................................................................................... 83 
17.2.10 
Compliance ................................................................................... 83 
17.2.11 
Reimbursement ............................................................................. 83 
18. BIBLIOGRAPHY ............................................................................................... 84 
19. LIST OF ABBREVIATIONS ................................................................................ 88 
 

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 U.S. specific amendment of 
 
BIO|GUARD-MI Study 
BIO monitorinG in patients with preserved left ventricUlar 
function AfteR Diagnosed Myocardial Infarction 
 
PROTOCOL SIGNATURE PAGE 
The signature below constitutes the receipt and review of the BIOGUARD MI Study protocol 
and any attachments, and provides the necessary assurances that this study will be 
conducted according to all stipulations of the protocol, including all statements regarding 
confidentiality, and according to local legal and regulatory requirements and applicable 
guidelines. 
 
 
Principal Investigator: 
 
 
 
 
Name (please print) 
 
 
 
 
Signature 
 
Date 
 
 
 

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Summary 
Title 
BIO monitorinG in patients with preserved left ventricUlar function 
AfteR Diagnosed Myocardial Infarction 
Acronym 
BIO|GUARD-MI study 
Subject collective 
Patients with a 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 study with an event-driven design 
Investigational 
Medical Device(s) 
BioMonitor 2 or successor implantable cardiac monitor 
Accessory 
components to 
Investigational 
Medical Device 
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 subject 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 objective 
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 
· 2nd or 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. 
Sample size 
Up to 360 subjects within the United States, up to 2900 subjects 
worldwide 
Study sites 
Up to 20 sites within the United States, up to 80 sites worldwide 
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-
interventional* clinical investigation is allowed 
· 
Age < 18 years 
· 
Woman who are pregnant or breast feeding  
Study duration 
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 
the number of needed endpoints for the final analysis is reached or 
the DSMB determines a premature study termination.  
 
* 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. 

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Follow-up scheme: 
Enrollment/Baseline  
· 
Verification of inclusion/exclusion criteria 
· 
Subject 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 
(As soon as possible but at latest 8 weeks after enrollment) 
· 
Implantation of the BioMonitor 
· 
Programming of the BioMonitor  
· 
Adverse events  
· 
Final subject instruction on BioMonitor  
Discharge  
· 
Final subject instruction on study course 
· 
Cardiovascular medication and non-cardiovascular medication 
· 
Lab parameters 
· 
Adverse events 
Follow-up  
· 
No pre-planned in-office follow-up visits  
· 
Unplanned visits (subject- 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) 
Termination 
· 
Final subject contact, either via office visit or telephone contact 
· 
Documentation whether the study termination was regular or 
premature and if applicable the reason for a premature 
termination 
· 
Adverse events 

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Sponsors 
BIOTRONIK SE & Co.KG 
Center for Clinical Research             
Woermannkehre 1 
12359 Berlin, Germany 
 
Represented by local sponsor in 
the U.S.:                                       
BIOTRONIK, Inc. 
Clinical Studies Department 
6024 Jean Road 
Lake Oswego, Oregon 97035 
 
Coordinating 
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 
 

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1. 
Introduction 
The BIOGUARD MI study aims to investigate whether continuous arrhythmia monitoring and 
detection, using an ICM (BioMonitor 2 or market released successor, hereafter referred to as 
BioMonitor) in patients after a myocardial infarction (MI) with LVEF > 35% but with other 
cardiovascular risk factors, decreases the risk of MACE if patients are appropriately 
examined and treated for the observed arrhythmias. The population selected for this clinical 
investigation is expected to have an increased risk of cardiac arrhythmias. It is expected 
that the BioMonitor will facilitate early diagnosis of cardiac arrhythmias and result in 
treatment of the arrhythmias or other cardiac conditions that may present, to prevent 
clinical endpoints and disease progression. This study will enroll up to 2900 subjects at up 
to 80 clinical study sites worldwide. Up to 360 subjects at 20 study sites are planned within 
the United States.  
Subjects eligible for the study have had an myocardial infarction with a CHA2DS2-VASc 
Score ≥ 4 in men / ≥ 5 in women and left ventricular ejection fraction > 35%.  Prior to 
enrollment, eligible subjects will be identified and will be asked to provide written informed 
consent. Subjects will be randomized 1:1 to receive a BioMonitor device or standard of care 
(no BioMonitor device). Post enrollment, subjects will complete a pre-hospital discharge 
visit, an initial telephone call at 4 weeks, and then continue with telephone contacts every 6 
months until the end of the study. A final study termination visit may also be performed.  
This clinical study protocol is U.S. specific based on the basic international protocol of the 
BIOGUARD MI study. The international protocol is applicable for all non-U.S. sites and based 
on the international standard ISO 14155. The U.S. protocol is applicable for all U.S. sites 
based on FDA GCP requirements. The U.S. sites are also reporting adverse events in 
accordance with ISO 14155. The local study sponsor for all U.S. sites is BIOTRONIK, Inc., 
Lake Oswego, OR, USA. The main sponsor for the study is BIOTRONIK SE & Co. KG, Berlin, 
Germany.  
All scientific aspects of the study design, including devices used, primary endpoints, 
secondary endpoints, additional data of interest, enrollment/implant/follow-up procedures, 
inclusion criteria, exclusion criteria, and study specific boards/committees are identical. The 
BIOGUARD MI study has a single registration with ClinicalTrials.gov (NCT02341534) that 
covers both U.S. and non-U.S. protocols.  
1.1 
Background 
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) Myocardial Infarction (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. 

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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 arrhythmias7-10. CARISMA was the first study to 
use implantable cardiac monitors (ICMs) for continuous ECG monitoring of cardiac 
arrhythmias in the post-AMI setting including patients with LVEF ≤ 40% and still represents 
the only experience in this area11. 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 AMI. 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 AF, 
compared to earlier devices such as those used in the CARISMA study. A 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. 

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The CARISMA study included patients within severely 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  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, 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 

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experiencing both cardiac arrhythmias and consequent MACE. Nevertheless, scientific 
studies in this population remain sparse.  
 

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2. 
Investigational Device 
2.1 
Name of Investigational Device 
This study utilizes BIOTRONIK’s BioMonitor insertable cardiac monitor. The current model, 
BioMonitor 2, is BIOTRONIK’s second generation and is available in one model within the 
U.S., the BioMonitor 2-AF. The BioMonitor 2 received FDA clearance on April 11, 2016 
(K152995 number).  
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 
Although the BioMonitor 2 is legally marketed in the U. S. for arrhythmia detection, 
BIO|GUARD-MI is an investigational study because the BioMonitor 2 is being evaluated for 
possible benefit in an alternative population of people with increased risk for cardiac 
arrhythmias that have previously not been studied. 
2.2 
System Description 
Devices included in the clinical study:  
· BioMonitor 2 or FDA cleared successor (Figure 1) 
The BioMonitor is to be used with the following components: 
· BIOTRONIK Renamic or ICS 3000 programmer or FDA-cleared successor with the most 
recent software and later corresponding software updates 
Subjects 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 FDA-cleared successor 
Patients who are receiving the investigational device may be provided with a FDA cleared 
accessory device (Remote Assistant) at the investigator’s discretion. The Remote Assistant 

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allows manual triggering of an ECG recording by the patient and thereby supporting the 
treating physician in making an accurate diagnosis.  
Figure 1: BioMonitor 2 
 
 
2.3 
Description of traceability 
Each BioMonitor, CardioMessenger or Remote Assistant has a unique serial number. The 
traceability is assured by recording the serial number. The information is documented on 
the corresponding electronic case report form (eCRF) and recorded in the EDC system. 
2.4 
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, sudden rate drop, or 
bradycardia.   
2.4.1 BIOTRONIK Home Monitoring® with daily sECGs 
The BIOTRONIK Home Monitoring® system provides early detection of arrhythmic events 
like high ventricular rates and of silent, asymptomatic events like atrial fibrillation, through 
the transmission of periodic (Figure 2) and triggered sECG recordings.  

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Figure 2: Periodic sECG Transmission Example 
 
The BioMonitor 2 has the capability to transmit messages including sECG signals to the 
BIOTRONIK Home Monitoring Service Center daily so that the responsible physician will 
have updated data on the technical and physiological parameters of the patient every 24 
hours. BIOTRONIK Home Monitoring® can be used to provide the physician with advance 
reports from the BioMonitor 2 and can process them into graphical and tabular format. This 
information helps the physician optimize the therapy process, as it allows the patient to be 
scheduled for additional clinical appointments between regular follow-up visits if necessary. 
In this study a Central Electrocardiogram Monitoring Board will be installed to ensure a 
centralized arrhythmia event management process, filtering of false positive events, and 
consistent alerting of the study sites in case of confirmed events. 
BIOTRONIK conducted the TRUST study to evaluate the safety and effectiveness of 
BIOTRONIK Home Monitoring®. BIOTRONIK received FDA approval (P050023/S020, 
approved May 12, 2009) of the following labeling claims regarding BIOTRONIK Home 
Monitoring®: 
1. BIOTRONIK Home Monitoring® information may be used as a replacement for device 
interrogation during in office follow up visits. 
2. A strategy of care using BIOTRONIK Home Monitoring® with office visits when needed 
has been shown to extend the time between routine, scheduled in office follow ups of 
BIOTRONIK implantable devices in many patients. BIOTRONIK Home Monitoring® data is 
helpful in determining the need for additional in office follow up. 
3. BIOTRONIK Home Monitoring® patients—who are followed remotely with office visits 
when needed—have been shown to have similar numbers of strokes, invasive procedures 
and deaths as patients followed with conventional in office follow ups. 
4. BIOTRONIK Home Monitoring® provides early detection of arrhythmias. 
5. BIOTRONIK Home Monitoring® provides early detection of silent, asymptomatic 
arrhythmias. 
6. Automatic early detection of arrhythmias and device system anomalies by BIOTRONIK 
Home Monitoring® allows for earlier intervention than conventional in office follow ups. 

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7. BIOTRONIK Home Monitoring® allows for improved access to patient device data 
compared to conventional in office follow ups since device interrogation is automatically 
scheduled at regular intervals. 
2.4.2 Remote Assistant for Patient Triggering 
The Remote Assistant patient device is a hand-held, battery-operated device which uses 
radio-frequency and coil telemetry to communicate with the BioMonitor 2. The Remote 
Assistant is intended for unsupervised patient use away from a hospital or clinic to allow the 
patient to activate storage of cardiac data when a symptomatic event occurs or has 
occurred. The Remote Assistant, shown in Figure 3, activates the data management 
features in the BioMonitor 2 to initiate recording of cardiac event data in the device memory 
by the single, user-operated button located on the middle area of the Remote Assistant 
patient device.  
Figure 3: Remote Assistant Patient Device 
 
2.5 
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 
complications. The interrogation and programming of the ICM shall only be done by 
appropriately trained personnel using the BIOTRONIK programmer.  
The BioMonitor should be implanted by a physician in accordance with the standard 
implantation procedures and techniques. 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’. 
 
 Record 
 Telemetry status light 
Low battery light 

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3. 
Justification for the design of the clinical investigation 
3.1 
Clinical data to support the safety and efficacy of the 
BioMonitor  
3.1.1 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. 
3.1.2 BioMonitor Master Study  
The objective of the Master Study of the BioMonitor was to confirm the safety and efficacy 
of the BioMonitor to collect post market clinical follow up (PMCF) data. The data of 153 
enrolled patients (152 of which received a BioMonitor implant) from 17 clinical sites in 6 
countries, including Germany and Denmark, was included within the final report†.  
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. 
No BioMonitor related SADEs up to the 3 month follow-up were 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 
 
† Master Study of the Implantable Cardiac Monitor BioMonitor, Clinical Investigation Report. June 2, 2015 

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a rate of 93.5%. Only 5 patients provided a QRS-detection positive predicted value (PPV) 
smaller than 90% (Min 85.5%).  
3.1.3 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. 
3.1.4 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 requiring additional invasive 
intervention to resolve though the 90-day follow-up. 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 showed 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. 
3.2 
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 other 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 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;29. 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 30-33. 
3.3 
Justification of the design 
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 

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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, potential subjects will be enrolled, randomized 
(50% of the subjects will be implanted with the BioMonitor) 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 studied 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-office visits are 
part of the study. However, treatment recommendations for detected arrhythmias 
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 subject 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 subjects will be contacted directly via 
telephone at regular intervals every 6 months.  
 

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4. 
Study Design 
The BIO|GUARD-MI study is a multicenter, prospective, randomized (1:1), controlled, 
parallel-group, open, international study with an event-driven design.  
The study was divided into two phases. The U.S. sites will be joining the second phase of 
the study. At the time of submission of the U.S. study protocol the gate to enter the second 
phase (20 endpoints reached) was estimated by the main sponsor after blinded review of all 
cardiovascular SAEs. After the Endpoint and Adverse Event Committee (EAEC) has officially 
adjudicated that 20 subjects have reached an endpoint a statement will be prepared to 
announce the official start of the second phase of the study. 
The second phase is currently planned to last until approximately 2021. As study stop will 
be announced once the required number of endpoints is reached, the individual time for 
subject participation depends on time of enrollment of the subject in the study. As U.S. 
subjects will start in phase 2 of the study, the estimated individual subject study 
participation duration is between 0 and 35 months. The study includes an enrollment-
assessment and randomization procedure. The randomization is 1:1, either in the 
BioMonitor group (subjects are implanted with the BioMonitor) or in the control group 
(subjects 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 subjects randomized to the BioMonitor group, the implant shall be performed 
as soon as possible, but no more than 8 weeks after enrollment. Most study procedures will 
typically take place during the index hospitalization‡ (enrollment, implantation if applicable 
and discharge).  
Following discharge, subjects will be treated according to clinical routine/guidelines. Hence, 
no study specific pre-planned procedures will be performed.  Subjects should contact their 
general practitioner (GP) or cardiologist as in standard post-MI care as needed for their care 
or in the event of any new symptoms. 
To assess the primary endpoint, all subjects 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 subject will receive no medical 
advice of any kind but will only be asked about events of the preceding period (see section 
8.6).  
Additionally, subjects 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 subject is dependent on the time of entry into the 
study. All subjects will be followed until the number of needed endpoints for the final 
 
‡ The term index hospitalization refers to the time of enrollment of the subject at the study site. 

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analysis is reached or the DSMB determines a premature study termination. Thereafter, the 
formal study termination is announced and all subjects will receive a final telephone call to 
inform them about the study end and, if applicable, to schedule the study termination visit.  
4.1 
Objectives 
4.1.1 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 subject will decrease the risk to 
experience a MACE in subjects with a history of MI, CHA2DS2-VASc Score ≥ 4 in men / ≥ 5 
in women    and  LVEF > 35%. 
See Section 5.2 for the definition of MACE. 
4.1.2 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.  
4.1.3 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.  
· 
All-cause mortality: The occurrence of death for any cause will be recorded and 
analysed.  
· 
Cardiovascular death: The occurrence of cardiovascular death will be recorded and 
analyzed. 
· 
Worsening of the subject status due to heart failure: The occurrence of worsening of 
the subject status due to heart failure requiring hospitalization or urgent visit will be 
recorded and analyzed. 
· 
Hospitalization resulting from arrhythmia: The occurrence of hospitalization resulting 
from arrhythmia will be recorded and analyzed. 
· 
Hospitalization resulting from acute coronary syndrome: The occurrence of 
hospitalization resulting from acute coronary syndrome will be recorded and 
analyzed. 
· 
Hospitalization or death resulting from stroke: The occurrence of hospitalization or 
death resulting from stroke will be recorded and analyzed. 

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· 
Major bleeding requiring hospitalization: The occurrence of major bleeding requiring 
hospitalization will be recorded and analyzed. 
· 
Systemic embolism requiring hospitalization: The occurrence of systemic embolism 
requiring hospitalization will be recorded and analyzed. 
· 
Arrhythmias: The occurrence of arrhythmias will be recorded and analyzed 
independently of whether a consequent therapy is indicated.  
· 
Type of initiated therapies: It will be evaluated which diagnoses will be made and 
which therapies will be initiated, based on ICM-detected arrhythmias. 
· 
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. 
· 
Quality of Life (QoL): The investigation of the subjects’ quality of live is not intended 
to show a benefit by the implantation of the ICM, but to exclude that the 
implantation or the monitoring of subjects has a negative impact on their well-being. 
4.2 
Measures taken to minimize or avoid bias  
4.2.1 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 subjects included are assumed to be at increased risk for MACE. However, currently it is 
unknown which subjects 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 subjects of the BioMonitor group and Control group, the randomization date is defined 
as the discharge from the index hospitalization.  
4.2.2 Blinding 
The investigator can’t be blinded because diagnostic information from the ICM has to be 
used. The blinding of the subject 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. 
4.2.3 Other 
Several methods to reduce bias are implemented in this study, including, but not limited to: 

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· 
Potential subject selection according to pre-defined inclusion and exclusion criteria. 
· 
It is the intention of the study design that all subjects will be followed-up and treated 
in accordance with clinical routine/guidelines. Nevertheless, to gather endpoint 
information all subjects will be contacted via telephone every 6 months. 
· 
In case of Home Monitoring findings, subjects 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 contacts 
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 subjects during the telephone calls. 
· 
Standardized procedures/processes for: 
o 
Standardized telephone procedures outlined in a separate telephone manual 
o 
Standardized methods for data collection, including the documentation of 
potential confounding factors, such as subject demographics, medical history 
and procedural parameters  
o 
Standardized procedures for BioMonitor implantation in accordance with the 
technical manual 
· 
Formation of a Publication Steering Committee. 
· 
Formation of an Endpoint and Adverse Event Committee (EAEC) that will assess all 
cardiovascular SAEs and all cases of subject death in a blinded and standardized 
manner regarding the primary endpoint. 
· 
A CEMB will be formed to ensure a standardized interpretation of the Home 
Monitoring findings and consequent forwarding to the study sites. 

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5. 
Study Endpoints and Hypotheses 
5.1 
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.  
H0: 
Null hypothesis: H0 : HR ³ 1 
 
which means that monitoring subjects of the BioMonitor group will not lead to a long
time-to-first-event of MACE compared to the control group. 
HA: 
Alternative hypothesis: HA : HR < 1 
 
which means that monitoring subjects of the BioMonitor group will lead to a long
time-to-first-event of MACE compared to the control group. 
It is expected that there is a HR < 1 in favor 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.  
5.2 
Primary endpoint 
The primary endpoint is the time from randomization to the first MACE during the clinical 
investigation. Subjects 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. Subjects who 
reach the primary endpoint will continue to be followed up until the formal termination of 
the study is announced. 
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  

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· 
Systemic embolism  
5.2.1 Endpoint assessment definitions 
A further specification of the endpoint adjudication process will be given by the experts of 
the Endpoint and Adverse Event Committee (EAEC) 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 subjects 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. 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 subject death will be evaluated by a blinded 
central EAEC and assessed with respect to the definition of the primary endpoint. 
5.3 
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 subjects of the BioMonitor group will not lead to 
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 subjects of the BioMonitor group will lead to a shorte
time to first arrhythmia that requires guideline-recommended therapy compared to
the control group. 

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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). 
5.4 
Secondary Endpoints 
5.4.1 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. Subjects 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. 
5.4.2 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. 
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 

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relevance for the risk prediction in these subjects 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. 
5.4.2.1 
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. 
5.4.2.2 
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 and documented in a separate charter agreement.  
5.4.2.3 
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 subject 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.  
5.4.2.4 
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.  
5.4.2.5 
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.  
5.4.2.6 
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.  

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5.4.2.7 
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.  
5.4.2.8 
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.  
5.4.2.9 
Time to first arrhythmia 
Assessment of the time from randomization to first arrhythmia. 
5.4.2.10 
Type of initiated therapies 
Evaluation of the diagnoses and consequent type of therapies based on ICM-detected 
arrhythmias. 
5.4.2.11 
Time to first therapy 
Assessment of the time from randomization to first therapy. In this context therapy is the 
attempted remediation of the subject’s regular heartbeat. To ensure a standardized 
proceeding, guideline-based therapy recommendations will be provided to the participating 
investigators within a separate manual. 
5.4.2.12 
Quality of Life (QoL) 
A further secondary endpoint is the assessment of the subject’s quality of life. The subject’s 
quality of life will be recorded during the regular telephone contacts using the WHO-5 Well-
being Index. 
5.5 
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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6. 
Statistical considerations 
6.1 
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.  
6.1.1 Group sequential design  
The study is 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 42.  
6.1.2  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 subjects 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 analyzed 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 subjects will be excluded from the analysis set 
· 
Subjects of the BioMonitor group and control group in case of a drop-out before 
discharge from the index hospitalization 
· 
Subjects without signed informed consent form  
6.1.3  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 subjects 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 
· 
Subjects with violation of inclusion or exclusion criteria at enrollment 

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· 
Subjects with major deviations/violations from the protocol in accordance with the 
definition given in section 14.2.1 
· 
Subjects of the BioMonitor group without implanted device or drop-out less than 1 
month after implantation  
· 
Subjects 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 deviations/violations as defined in section 14.2.1 
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. 
6.1.4 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: The inverse normal combination test is used 
to combine the independent increment to a global test statistic. A one-sided logrank test is 
performed in the context of a confirmatory analysis of the primary hypothesis at every 
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. 
6.2 
Sample size 
It is expected that there will be pC1year = 5% subjects with at least one MACE per year in the 
control group and pBioM1year = 3.75% subjects with at least one MACE per year in the 
BioMonitor group, which results in a Hazard Ratio = 0.7452 in favour of the BioMonitor.  

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According to the approximation of Schoenfeld 43 363 events are needed. However, there is a 
slight increase of the sample size due to the group-sequential design of O’Brien Fleming. 
The interim analyses and the final analysis should be conducted with 124, 248, and 372 
subjects with at least one MACE during the clinical investigation, respectively. 
In total, up to 2900 subjects may be enrolled. The subject number of up to 2900 is based 
on an expected endpoint-rate of 5%/3.75% per subject year required to reach the study 
goal of 372 endpoint events. The subject number will be automatically adjusted in the event 
the endpoint rate deviates from the expected rate. All subjects will be followed until the end 
of the clinical investigation. The study duration will be approximately 3 years, but ultimately 
study closure is dependent on when the number of needed endpoints for the final analysis is 
reached. 
This accounts also for loss of information due to drop-outs which remain in the analysis set. 
According to the adaptive group-sequential design, the sample size can also be adjusted 
after the first or second interim analysis based on the recommendations of the DSMB. 
However, the sponsor must confirm any sample size increase and has the right to refuse it. 
There is no adjustment of the significance value for stopping for futility. 
6.3 
Level of significance and the power of the study 
The global significance level is of the 1-sided hypothesis is 2.5%. The significance level of 
the interim analyses and final analysis is given by the O’Brien Fleming  method: ainterim1 = 
0.00025, ainterim2 = 0.007, and afinal = 0.0225 44. 
The statistical power of the final analysis is 80%.   
6.4 
Expected drop-out rate 
A drop-out of 5% of the subjects per year is expected. Thereby the limited number of 
subjects to be excluded from the analysis set is not considered. 
6.5 
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.  
6.6 
Pass/fail criteria  
The pass criteria are to accept the primary alternative hypothesis based on the full analysis 
set. 

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6.7 
Provision for an interim analysis 
There are two interim analyses based on 1/3 and 2/3 of the total number of subjects with at 
least one MACE.  
6.8 
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 and second 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 values ainterim1 = 0.00025 and ainterim2 = 0.007, 
respectively. 
6.9 
Procedures for reporting of deviations to the statistical plan 
Deviation(s) from the statistical plan described here are reported via amendments to the 
protocol and/or via a separate SAP. 
6.10 
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. ³ 5 in men / ³ 6 in women  
· 
LVEF < median vs. ≥ median 
· 
BMI: < 30 vs. BMI ≥ 30 
· 
History of AF yes vs. no  

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· 
NSTEMI vs. STEMI 
· 
History or presence of kidney failure yes vs. no 
6.11 
Procedure for accounting of all data for analysis 
Data to be analyzed 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 analyzed with common statistical software 
packages, e.g. SAS Version 9.3 or IBM SPSS Version 21 for Windows or higher. 
6.12 
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 analyzes are minimized and 
limited to baseline information which can be obtained without any additional burden for the 
subject. 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. 
6.13 
Exclusion of data from confirmatory data analysis 
Details with regards to the exclusion of data from confirmatory data analysis are provided in 
section 6.1.2. 
6.14 
Minimum and maximum number of subjects per site 
Investigation sites are selected with the potential to enroll a minimum number of 40 
subjects per year. 
Every investigator is free to enroll as many subjects as desired until the sample size for the 
entire study has been reached and the subject recruitment is ended. Due to the large 
sample size of the clinical investigation, no bias is expected. 

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7. 
Protocol Requirements 
7.1 
Subject Population 
The investigator is responsible for screening all potential subjects and selecting those who 
are appropriate for study inclusion.  The patients selected for participation should be from 
the investigator's general patient population according to the inclusion and exclusion 
criteria. 
Every investigator can enroll as many subjects as desired until the sample size for the entire 
study has been reached.  
Potential subjects meeting the inclusion criteria and none of the exclusion criteria may be 
enrolled in the study. According to the sample size calculation (see section 6.2), up to 2900 
subjects will be enrolled into the study including 5% drop-outs per year. Thereby the limited 
number of subjects to be excluded from the analysis set (see section 6.1.2) is not 
considered. 
The enrolled subjects will be randomized in a 1:1 relation to the following study groups: 
- 
BioMonitor group (standard of care and implanted with BioMonitor) 
- 
Control group (standard of care) 
Vulnerable persons (by the investigator’s judgment) will be excluded from participation. 
Examples for vulnerability include, but are not limited to: an age below 18 years, limited 
contractual capacity, and inability to understand written informed consent. Patients who 
require a legally authorized representative will not be allowed in the study. 
7.1.1 Indications 
The BioMonitor is an ICM that records subcutaneous ECG (sECG) and is indicated for: 
· 
Patients with clinical syndromes or situations at increased risk of cardiac arrhythmias 
· 
Patients who experience transient symptoms that may suggest a cardiac arrhythmia 
· 
The device has not been tested for and it is not intended for pediatric use  
7.1.2 Contraindications 
There are no known contraindications for the BioMonitor. However, the particular patient’s 
state of health may determine whether a subcutaneous device will be tolerated long term. 
7.1.3 Inclusion Criteria 
To support the objectives of this investigation, the inclusion criteria at the time of subject 
enrollment for this study include the following requirements: 

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· 
Patient has a history of MI according to guidelines 
· 
CHA2DS2-VASc Score ≥ 4 in men / ≥ 5 in women (see section 7.1.3.1) 
· 
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 
7.1.3.1 
Definition of CHA2DS2-VASc Score 
CHA2DS2-VASc acronym§ 
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 
· 
Fasting glucose >125 mg/dL (7 mmol/L) or treatment with oral 
hypoglycaemic agent and/or insulin 
+1 
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 
7.1.4 Exclusion Criteria 
To support the objectives of this investigation, the exclusion criteria at the time of subject 
enrollment include the following requirements: 
 
§ 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS, (European 
Heart Journal, doi:10.1093/eurheartj/ehw210)) 
* Hemorrhagic diathesis is defined as an increased susceptibility to bleeding due to a coagulation defect, which can 
be genetic (e.g., Haemophilia, Glanzmann disease, von Willebrand disease) or acquired (e.g., scurvy, vitamin-K 
deficiency, leukaemia). 

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· 
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  
7.2 
Electronic CRFs 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 1 provides an 
overview of eCRFs and procedures. 
Data collected during subject enrollment, phone contact and termination 
· 
Enrollment eCRF 
· 
Baseline eCRF 
· 
Implantation eCRF 
· 
Discharge eCRF 
· 
Study termination eCRF 
· 
Elective Replacement Indicator (ERI) eCRF 
· 
Remote Assistant eCRF 
Data collected due to adverse events (AE) 
· 
Adverse event eCRF 
· 
Concomitant medication log eCRF, required only if AE is suspected to be due to a 
medication 
 
** 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. 

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· 
Device deficiency (DD) eCRF 
Data collected by the CRO performing the telephone contact 
· 
Telephone follow-up questionnaire 
· 
Quality of life questionnaires  
Data resulting from Home Monitoring messages and other medical events requiring 
additional medical care 
· 
Arrhythmia notification eCRF 
· 
General notification eCRF 
· 
IHF event notification eCRF 
Any deviations or violations from the protocol 
· 
Protocol non-compliance (PNC) eCRF 

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Table 1: Overview eCRFs and Procedures 
Procedures 
Enrollment 
Baseline 
Implantation 
Discharge 
Telephone 
contacts (every 6 
months) 
Arrhythmia 
notification eCRF 
General 
notification eCRF 
IHF notification 
eCRF 
Termination 
Subject informed consent 
x 
 
 
 
 
 
 
 
 
Verification of inclusion- and  
exclusion criteria 
x 
 
 
 
 
 
 
 
 
Subject demographics 
 
x 
 
 
 
 
 
 
 
NYHA class 
 
x 
 
 
 
 
 
 
 
Echo parameters 
 
x 
 
 
 
 
 
 
 
Specification of MI 
x 
 
 
 
 
 
 
 
 
Medical history/Co-morbidities 
 
x 
 
 
 
 
 
 
 
Cardiovascular medication 
 
 
 
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 subject 
 
 
 
 
 
x 
x 
x 
 
Subject interview 
 
 
 
 
 
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 

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8. 
Study procedures  
Subjects who have successfully been enrolled in the study will be evaluated at discharge, 
phone calls every 6 months and a termination visit.  
Table 2 provides an overview of the clinical study design. Details of subject eligibility 
requirements are noted in section 7.1. Details of other specific study procedures and 
collected data are noted in sections 8.1 to 8.8. 
Table 2: Study Flowchart 
 
 
8.1 
 Enrollment and Randomization 
Prior to enrollment into the clinical investigation, all potential subjects 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 potential subject prior to 
enrollment. A subject is considered enrolled upon signing the Informed Consent Form. The 

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consent process should be documented within the subject’s medical record. The Enrollment 
eCRF will document confirmation that subject has provided written informed consent, 
verification that inclusion/exclusion criteria were met, specifics related to the subject’s 
history of MI, and confirmation LVEF was greater than 35% within the 6 months prior to 
enrollment, but after the conclusion of AMI treatment. 
All successfully enrolled subjects 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 
4.2.1. The randomization code will be generated by the electronic data capture (EDC) 
system. 
8.2 
Baseline 
The Baseline information collection may occur the same day as Enrollment or it may be 
delayed from the Enrollment visit, due to the scheduled date of the BioMonitor 2 implant. 
The following information will be documented in the Baseline Form: 
· 
Result of the randomization 
· 
Demographic information (age, gender, weight, height) 
· 
Echocardiographical data, including LVEF measurement, left atrial volume and left 
ventricular volume 
· 
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 and medical conditions, including cardiac history and TIA/Stroke 
history 
· 
Occurrence of AEs after written informed consent has been provided 
8.3 
Implantation 
In subjects randomized to the BioMonitor group, the BioMonitor will be implanted after 
enrollment according to standard procedures as described in the technical manual. See 
section 2.6 for the summary of training and experience needs. 
The implantation of the BioMonitor should be 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 implant or exchange 
· 
Interrogation and programming details 

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· 
Home Monitoring (verification that CardioMessenger was handed out to the subject 
and turned “on”, plus documentation of serial number, general patient instruction on 
the use of the CardioMessenger) 
· 
Occurrence of AEs since baseline (Any AEs will be collected on a separate eCRF) 
8.3.1 Mandatory programming 
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. 
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. 
8.4 
Discharge  
Upon discharge from the index hospitalization††, the subject should receive guideline 
recommended prescriptions and education about life-style recommendations according to 
standard of care. 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. The subjects 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, subjects in both 
study arms should be reminded to report the details of any hospitalizations and other 
adverse events. Discharge also includes the 
documentation of cardiovascular and non-
cardiovascular medication and the documentation of general lab parameters (no study 
specific examination). 
· 
The Troponin value collected should be the highest recorded value related to the 
most recent MI, if available 
 
†† The term index hospitalization refers to the time of enrollment of the patient at the investigational site. 

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· 
For other lab parameters the most currently estimated value should be collected (not 
older than 2 months before data of discharge) 
  
8.5 
Home Monitoring Analysis and In-Office Visits 
No pre-planned, study specific in-office follow-up visits will be performed in this study. 
Nevertheless event triggered, unplanned in-office visits are expected as a result of 
arrhythmia detections by the BioMonitor.  The following process will be installed to ensure 
coherent documentation.  
Home Monitoring data shall be analyzed on all working days by the CEMB (see section 
12.4). If an arrhythmia was detected, the CEMB shall contact the investigator immediately. 
Contact includes an initial email to the investigator followed by email reminders and a 
telephone call, if necessary. Parallel to informing the physician, the detected event shall be 
entered by the CEMB in the EDC system using the ‘Arrhythmia notification eCRF (ANF)’. A 
detailed description of the CEMB-responsibilities and the respective process will be 
documented in a charter. 
After evaluating the event in the Home Monitoring Service Center, the investigator shall 
enter the assumed rhythm in the EDC system using the same ANF eCRF 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 subject or not. Specifics about the contact and possibly 
resulting in-office visit shall be recorded in the ANF eCRF and in the adverse event form if 
applicable. Therefore, event triggered in-office 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-office visits, the subject may be referred by a primary or 
secondary care provider or the subject may appear at the site on his/her own decision. For 
these cases, the ‘General notification eCRF’ captures the reason for the visit as well as the 
types of examinations and therapies performed. If during in-office visits the investigator is 
notified about adverse events, the information is entered into an AE eCRF. To avoid a bias in 
favor 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 
subject interviews (see section 12.5). Thus it will be possible to estimate a possible 
underreporting of primary endpoints by looking separately at the information received 
during the telephone contacts. 

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8.6 
Telephone contact 
A telephone contact regimen will be implemented and replace in-office follow-up visits. To 
obtain endpoint related information, all subjects 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 subject’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 subject 
- 
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). 
- 
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.  
Telephone follow-up activities and consequent source data tracking will be performed by an 
external CRO contracted by the main sponsor (see section 12.5). Detailed telephone follow-
up guidelines will be provided in a separate document, the ‘telephone follow-up manual’. 
The telephone calls made every 6 months are to be made no earlier than 7 before and 6 
weeks after the due date of the telephone contact. 
There will also be an initial telephone follow-up within 4 weeks of enrollment. The purpose 
of this call is for the CRO to introduce themselves to the subject and ascertain the best 

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time/day to follow up with the subject via phone. AEs will not be assessed during this call; 
however if the subject spontaneously reports an AE, the CRO will follow up per their 
guidelines. 
If an AE is reported during the telephone contact, then the CRO must forward this 
information to the respective study site for appropriate follow up and data entry in the EDC 
system of the reported adverse event(s). The site should try to obtain as much information 
regarding the adverse event as possible, including all applicable medical records of the 
event. If the event is an SAE the description of every SAE must be sufficiently documented 
and confirmed by source data to allow the adjudication by the EAEC. Any event reviewed by 
the EAEC must have sufficient source documentation to allow for appropriate adjudication. 
8.7 
Device replacement or explantation 
8.7.1 Device replacement 
Devices will be explanted according to physician judgment, at the end of battery life or for 
medical reasons. 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 subject’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 subject 
shall remain in the study, independent of the decision to replace the device or not.  
The ERI form will only be completed when the battery of the device has reached end of life. 
In case of explantation due to medical reasons, e.g. subject death or implantation of a 
pacemaker, the reason for explantation will be documented on the respective Adverse Event 
form. 
8.8 
Study Termination 
The end of study participation of the individual subject will be documented in the Study 
Termination Form, independent of the reason for termination (see also section 9.2). 
Reasons for exclusion from the study should be documented as far as possible. All 
applicable eCRFs shall be completed as far as possible. 
After the termination the subject’s ongoing medical treatment is to the physician’s discretion 
or should follow the clinical routine. 
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 
subject, the investigator is free to monitor the subject even after her or his official 
termination from the study. 
 

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9. 
Study Exits 
9.1 
Drop Out Criteria 
A drop-out is defined as any premature termination of a subject’s participation in the study 
before the study termination is formally announced.  
Once a subject is enrolled and successfully implanted (if 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: 
· 
Subject death (see section 9.1.1) 
· 
Withdrawal of subject informed consent (see section 9.1.2) 
· 
Loss to follow-up (see section 9.1.3) 
· 
Early discovery of a violation of inclusion or exclusion criteria (see section 9.1.4) 
· 
Investigator initiated drop-out (see section 9.1.5) 
Applying the intention-to-treat (ITT) principle, subjects considered to be drop-outs are not 
excluded from the analysis set, except if the conditions described in section 6.1.2 are 
fulfilled.  
Investigator documents the study termination for each subject. Information whether the 
study termination was regular or premature will be obtained with the study termination 
eCRF. Moreover, the reason for a premature termination will be documented. Additionally, 
all status information about ongoing AEs should be documented. 
9.1.1 Subject death 
In the event of subject death during study participation, personnel at the study site are 
requested to notify BIOTRONIK, Inc. 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 

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Whenever possible, devices should be interrogated prior to the explantation procedure, if 
possible. If not possible, it is important that the BioMonitor is explanted and returned to the 
manufacturer for interrogation and analysis. 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). 
All cases of subject death will be adjudicated by the EAEC. 
In the event of a cardiac transplantation (HTX), the subject’s participation in the study will 
be terminated. If the subjects did not yet have a primary endpoint, the admission for the 
HTX procedure will be evaluated as the death of the subject and thus fulfils the criteria for a 
primary endpoint. HTX will also be contribute to the endpoints of all-cause moratlity and 
cardiovascular mortality. Secondary endpoints such as the time to first arrhythmia can be 
assumed to differ significantly between post-HTX and post-MI subjects and should thus not 
be pooled for analysis.  
9.1.2 Withdrawal of subject informed consent 
A subject who has consented to participate in the study may withdraw his/her consent at 
any time without specifying the reason(s) for withdrawal and without disadvantageous 
consequences for further treatment. Data collected from this subject until the time of 
withdrawal will be included in the data analysis. The study termination eCRF has to be 
completed by the study site. 
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. 
9.1.3 Lost to follow-up 
Subjects lost to follow up are those for whom contact is lost despite best efforts to locate 
the subjects. In the event a subject is lost to follow up after the CRO has contacted the 
subject per the guidelines in the telephone manual, the CRO should then contact the study 
site. Study sites should attempt to contact the subject also and all contact attempts are 
documented. Study sites are requested to continue attempts to contact until a definitive 
reason for failure to participate is determined (e.g. subject moved with no forwarding 
address). In the event the study site is first to determine a subject is lost to follow up, then 
they should contact the CRO responsible for collecting AEs in an attempt to locate the 
subject. 

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In the event the subject cannot be contacted using the above methods, the subject is 
terminated from the clinical investigation by completing a Study Termination eCRF. 
9.1.4 Early discovery of a violation of inclusion or exclusion criteria 
If a subject of the BioMonitor group or Control group will be identified to violate any 
inclusion 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.  
9.1.5 Investigator initiated drop-out 
The investigator may initiate a premature study termination for legal reasons or if the study 
participation endangers the subject’s well-being or safety. However, a member of the 
Steering Committee or CI must be consulted before implementation, except in cases of 
emergency.  
In contrast, changes of the subject’s treatment, even if related to monitoring or treatment 
of arrhythmias, do not justify a drop-out, since the subject’s further clinical course can be 
recorded. Two examples are the impossibility to use HM in a new environment of the 
subject (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 subject, because the exclusion of 
such subjects might introduce a bias in favour of the ICM arm. 
9.2 
Point of enrollment and study termination 
The point of enrollment is the time at which a subject signs and dates the informed consent 
form. Study related procedures, documentation and collection/following of adverse events 
will start from this day on. 
Regular point of termination for all subjects is the date when the formal study termination is 
announced. 
For all non-regular study terminations, the following rules apply: 
· 
In case of subject 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 the subject 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 

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used to ascertain the vital status of subjects for any primary analysis because this 
might introduce a bias in favor of the BM arm. 
· 
If the subject is defined as drop-out subject for any other reason, the date of study 
termination is the date on which the reason for the drop-out became effective, i.e. 
the date on which a violation of inclusion criteria was discovered, or on which the 
investigator excluded the subject for safety reasons.  
Study related procedures and documentation should end at the day of study termination for 
the respective subject. 

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10. Additional Study Conditions 
10.1 
IRB Approval 
Institutional Review Board (IRB) approval is required for each study site and investigator 
prior to participation in this clinical study according to local requirements. Subject 
enrollment may not begin until both the IRB and BIOTRONIK, Inc. have granted approval 
for the study site. If IRB approval is withdrawn at any time during the study, BIOTRONIK, 
Inc. must be notified by the investigator within 5 working days.  
10.2 
Consent Materials 
Prior to the subject's enrollment or participation in the investigation, informed consent is 
required from all subjects. Informed consent should be obtained in accordance with the FDA 
regulations (21CFR, Part 50).  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. The investigator is required to inform BIOTRONIK, Inc. 
and the reviewing IRB within 5 days if any subject was not appropriately consented to 
participate in the study.  BIOTRONIK, Inc. is then required to report any failure to obtain 
informed consent to the FDA within 5 working days of learning of such an event.  In order to 
assist with the consent process, BIOTRONIK, Inc. will provide a template consent form to 
study sites participating in the study. Vulnerable persons (by the investigator’s judgment) 
will be excluded from participation. 
10.3 
Other Institutions and Physicians 
This clinical study is not transferable to other institutions attended by the investigator 
unless prior approval is obtained from both BIOTRONIK, Inc. and the appropriate IRB. Only 
approved investigators are authorized to participate in the clinical investigation. However, 
there are certain situations where an investigator might not be immediately available to 
provide the necessary medical care for a subject enrolled in the clinical investigation (such 
as a subject emergency room visit for medical treatment). 
In case technical support is needed the service hotline of BIOTRONIK, Inc. is available 24 
hours a day. Phone: 1-800-547-0394. 
10.4 
Electronic Case Report Forms (eCRFs) 
Original data will be collected from each study site and recorded into the EDC system via 
completion of eCRFs. The investigator will be required to use an electronic signature to 
approve the content of the data reported in the eCRFs. BIOTRONIK, Inc. will audit and 
monitor the content of the eCRFs for the US sites as described in section 13. 

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Information from electronically delivered source data (e.g. programmers) will be captured 
and stored in a validated environment until the end of the study. 
10.5 
Handling of Electronic Data 
10.5.1 Data protection 
The subject must declare in the ICF that he or she agrees to the recording of his or her 
medical data and their transfer to the main sponsor, the supporting CRO IHF and, if 
necessary, to responsible IRB. The subject agrees that authorized personnel of the local and 
main sponsor and the involved IRB (if applicable) may gain insight in the subject record to 
ensure that the patient was adequately informed about the clinical trial and that the 
protocol was properly followed. 
All subject-related data and information received from the clinical study will be handled 
confidentially. The collected data will be pseudonymized, without using subject initials, date 
of birth or other privacy data, to ensure traceability of data, but preventing unauthorized 
identification of individual subjects. The data will be transmitted to the main sponsor and if 
necessary to the supporting CRO IHF for electronic data handling, safety reporting and 
analysis in compliance with applicable regulations.  
In addition, all subject data transferred to the main sponsor of this clinical study, CRO, IHF 
or the respective boards located in the EU (e.g. iMedNet entries, adverse event source data) 
will be protected in the EU according to the European data protection law (General Data 
Protection Regulation “GDPR”). The Subject Contact Form containing subject ID code, 
contact data, name and date of birth will be sent to the telephone follow-up provider (IHF) 
and archived there. 
Copies of the Subject Enrollment Log and Subject Contact Form will not be provided to the 
sponsor and will remain at study sites. The subjects will be informed their identity and 
contact information will be available to the investigator and the telephone follow-up provider 
(IHF). 
10.5.2 Data collection  
All study-relevant subject data will be documented pseudonymously in eCRF. The 
established Electronic Data Capture system (EDC) 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 and 
EU Commission Decision C (2010)593 Standard Contractual Clauses (processors) and EU-US 
Privacy Shield Framework).  

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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 
password in order to access the system. Once these have been validated, there will be 
options for entering a new subject or new subject data into the system.  
For the majority of the eCRF entries source data needs to be maintained at the site and will 
be collected in adequate files (e.g. subject binder). The data have to be stored and shall be 
made available upon request in order to allow source data verification.  
10.5.3 Procedures used for data review, EDC cleaning, and issuing and 
resolving data queries 
After data entry into the EDC system, 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 (in 
EDC) 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 EDC system 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. 
10.5.4 Procedures for verification, validation and securing of electronic data 
systems 
The EDC system is hosted on a dedicated database server at the vendor MedNet Solutions, 
Inc. Only authorized users with fixed roles have access to the EDC system. The access is 
controlled and maintained by the Center for Clinical Research (CCR) Clinical Data 
Management Department of BIOTRONIK SE & Co. KG in coordination with BIOTRONIK, Inc. 
for US sites. Every access is automatically logged and changes of the clinical data are stored 
in independent audit trails. The EDC system 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 CC CCR Clinical Data 
Management of BIOTRONIK SE & Co. KG in coordination with BIOTRONIK, Inc. for each 
authorized user once the user has completed appropriate training. Users are obligated to 
keep their password confidential. 

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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. 
10.5.5 Data retention and archiving 
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.  
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. 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 can 
be deleted. 
10.6 
Confidentiality of Subject Data 
Information sent to BIOTRONIK, Inc. pertaining to study subjects will be kept confidential at 
BIOTRONIK, Inc. and is subject to audit by IRB and other regulatory authorities. For 
reporting purposes, data collected from U.S. sites will be shared with BIOTRONIK SE & Co. 
KG. Information shared with BIOTRONIK SE & Co. KG will be kept confidential and will be 
handled by BIOTRONIK SE & Co.KG according to the European data protection regulation 
(GDPR). Reports submitted to physicians and data presented in publications of study results 
will not make any reference to subject name. 
In order to verify the study data and ensure study integrity, authorized monitors from 
BIOTRONIK, Inc., authorized personnel from BIOTRONIK SE & Co. KG, regulatory 
authorities, and the reviewing IRB may review and/or copy the study records. BIOTRONIK 
will be informed about access to the clinical data for review and copying for external 
stakeholders.  
10.7 
Data Quality Control 
BIOTRONIK, Inc. will regularly review study data from U.S. subjects. At any time, reports 
can be generated on entered or missing data by BIOTRONIK, Inc. or by approved research 
personnel at each study site. The EDC system will be used to track received and expected 
visit data and eCRFs for each subject. This system also provides the capability to monitor 
the status, volume, and disposition of data. In addition, all study data will undergo 
extensive automatic edit and plausibility checks that provide information to the study sites 
to help improve and maintain data quality control procedures designed to detect 
inaccuracies and inconsistencies.  

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10.8 
Study Completion 
BIOTRONIK, Inc. will notify the study site upon completion or termination of the 
investigation or investigator’s participation in the clinical study.  At BIOTRONIK’s request, an 
investigator will return any devices, equipment, and pertinent information in their 
possession.  BIOTRONIK, Inc. will provide a final report to each study site as required by 
FDA regulations.  Monitors may conduct a study closure visit.  During this visit, BIOTRONIK, 
Inc. will verify study records and ensure that the investigator understands any applicable 
regulatory requirements including those related to record retention. Record storage 
requirements will be consistent with local regulatory regulations. 
 
 
 

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11. Benefit/Risk Analysis 
11.1 
Potential Benefits 
11.1.1 Benefits for subjects randomized to the BioMonitor group 
As a result of ICM implantation, the heart rhythm of study subjects 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 subject that has caused the arrhythmia. 
11.1.2 Benefits for subjects randomized to the control (non-BioMonitor) 
group 
No obvious benefits are expected for subjects randomized to the control group.  
11.1.3 Benefits for future subjects 
If the study will be successful, it may show that subjects 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 subjects. 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. 
11.2 
Potential Risks 
11.2.1 Anticipated adverse device effects 
ICMs are implanted in a subcutaneous position and thus require an invasive implantation 
procedure. Please see Table 3 for 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 3: Surgical Risks 
Frequency 
Percentage (%) 
Risk 
Frequent 
1 to 10 patients 
out of 100 
Up to 334-37 
local infection at insertion site 
Up to 335 
superficial infection at insertion site 
Up to 1,937 
irritation or inflammation at insertions site 
Up to 1,234 
local erosion at insertion site 
Up to 1,535 
erythema at insertion site 
Up to 1,534-37 
persistent pain at inframammary implant site 
Up to 336 
difficulties at device interrogation 
Up to 536 
device migration 
Up to 2,334;36 
device repositioning 
Up to 2,434-37 
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 38;39. 
The safety of ICMs has been investigated in many studies with regards to syncope and AF 
management 40. It has been demonstrated successfully that the strategy of prolonged 
monitoring in patients with Cardiac Implantable Electronic Devices (CIED) is safe 41.  
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 3. 
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 subjects and take corrective actions during 
an in-office visit, i.e. re-programming of the device settings. 

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11.2.2 Risk associated with participation in the study 
Apart from the anticipated adverse device effects discussed in section 11.2.1, no additional 
risks are associated with participating in this study. Investigators will decide upon therapies 
based not on ICM diagnosis, but upon thorough examination of the subject 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.  
11.3 
Steps to control or mitigate the risks 
Risks associated with the BioMonitor (see section 11.2.1) 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 subject’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 protocol in all aspects and to promptly supply the sponsors with all 
pertinent information required by this protocol. 
11.4 
Risk-to-benefit rationale 
The investigational device is approved in Europe for standard medical care (CE mark) and 
within the United States (FDA clearance). It is not anticipated that the subjects participating 
in this study are exposed to any risks beyond those stated in section 11.2.1. 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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12. Study Oversight 
The sponsor will 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 12.1) 
- 
Safety monitoring (see section 12.2) 
- 
Overall guidance of the clinical investigation (see section 12.3) 
- 
Coordination of the publication process (see section 12.3) 
- 
Home Monitoring analysis (see section 12.4) 
- 
Telephone follow-up activities (see section 12.5) 
- 
Coordination of the publication process (see section 17) 
12.1 
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 subject 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.  
12.2 
Responsibilities of the Data Safety Monitoring Board 
(DSMB) 
The DSMB will review accumulating study data to address subject 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.  
12.3 
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 protocol and the assessment of quality in 

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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.  
12.4 
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 8.5). 
Details with regards to the specific process will be determined in the CEMB charter.  
12.5 
Responsibilities of the Contract Research Organization 
(CRO) 
An external service provider has been appointed to perform the telephone follow up 
interviews of all subjects 4 weeks following enrollment and then every six months until 
study termination (see section 8.6). 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 
Germany 
In the course of the study additional service providers might be contracted to serve included 
countries.  
12.6 
Responsibilities of the coordinating investigator (CI)  
Responsibilities of the coordinating investigator are among others: 
- 
Give input and advice for the protocol creation and possible amendments, medical 
review 

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- 
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 

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13. Study Monitoring 
13.1 Methods 
The responsibility of BIOTRONIK, Inc. as local sponsor is to ensure protocol and regulatory 
compliance through proper monitoring of the clinical investigation in U.S. sites. BIOTRONIK, 
Inc. is also required to ensure that the investigational device is used under the immediate 
direction of an investigator. As the investigator, the physician is responsible for conducting 
the clinical investigation in accordance with the signed Investigator Agreement, the study 
protocol, applicable laws, and FDA and/or local regulations and any conditions of approval 
imposed by the reviewing IRB. The primary investigator must also accept responsibility for 
all aspects of the clinical investigation including the actions of any co-investigators 
participating in the clinical investigation at the investigational site. 
The entries in the eCRF will be reviewed and source data verified at the investigational site 
or remotely by monitors (authorized BIOTRONIK, Inc. personnel, Clinical Research 
Associates-CRAs, or by authorized BIOTRONIK, Inc. designees) to ensure that the 
investigator and the clinical investigation team conducts the clinical investigation in 
accordance with the clinical investigation protocol 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. In addition, BIOTRONIK, Inc. may require the 
presence of personnel from BIOTRONIK, Inc. at implant and/or follow-up visits outlined in 
this protocol in order to assist the investigator and other site personnel. 
A detailed monitoring plan developed by BIOTRONIK will be followed. Monitors will visit the 
study site periodically during the clinical investigation in accordance with the monitoring 
plan.  
13.2 Monitors 
Monitors are trained, qualified, and designated by BIOTRONIK, Inc. management to oversee 
the progress of a study at the clinical site. 
Periodic monitoring visits will assure, amongst others, that the facilities are still acceptable; 
that the protocol is being followed, that the IRB has been informed about approved protocol 
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, IRB, and other 
authorities, and that the investigator is carrying out all agreed activities. 
Periodic monitoring visits, assessments of the study site will include but will not be limited 
to the following: 
· 
Completion and submission of the required electronic case report forms (eCRFs) and 
other applicable study documentation 
· 
Continued acceptability of the facilities  

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· 
Adherence to the clinical investigation plan 
· 
Adherence to applicable FDA and/or 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, Inc. study management. 
BIOTRONIK, Inc. will evaluate the non-compliance and issue corrective actions, discontinue 
enrollment or as a last measure close the clinical investigation site. 
 
 

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14. Deviations from Clinical Investigation Plan 
All sponsor personnel, all investigational site personnel as well as other third parties, who 
are involved in tasks covered by this protocol, are generally obliged to comply with this 
protocol. The investigator is required to conduct this study in accordance with the signed 
investigator agreement and clinical protocol. The investigator shall notify BIOTRONIK, Inc. 
and reviewing IRB in writing no later than 5 working days after any significant deviation 
from the clinical protocol that has occurred to protect the life or physical well-being of a 
subject in an emergency. Except in such emergency situations, prior approval by 
BIOTRONIK, Inc. is required for significant deviations from the clinical protocol.   
14.1 
Recording deviations 
Study sites will be requested to inform the sponsor about any deviation as they become 
aware of the deviation. In addition, compliance to the protocol will be verified by the 
sponsor at monitoring visits. Each site specific deviation is recorded within the EDC system 
on a Protocol Non-Compliance (PNC) eCRF. The sponsor will assess 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 should 
be discussed with the PI or authorized designee and re-training may be performed to 
prevent further deviations. Retraining will be documented accordingly when completed. 
Other additional suitable actions may be initiated after consultation of the clinical project 
management. 
Deviations by sponsor personnel or third parties are reported immediately to the sponsor by 
anyone who becomes aware of it. They will be assessed for the need of corrective or 
preventive actions. 
14.2 
 Reporting Deviations 
All deviations will be reported in the interim and final clinical investigation reports.  
Study sites will be requested to inform the sponsor about any deviation as they become 
aware of the deviation. In addition to reporting deviations to BIOTRONIK, Inc., certain types 
of deviations may also require IRB notification. 
BIOTRONIK, Inc. categorizes protocol non-compliance instances as either protocol violations 
or protocol deviations. Both protocol violations and deviations will be reported in the interim 
and final clinical progress reports. 
 

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14.2.1 Protocol Violations/Major Deviations 
Protocol violations are major deviations where the protocol requirements and/or regulatory 
guidelines were not followed, and are generally more serious in nature. Protocol violations 
are considered to potentially affect the scientific soundness of the study and/or the rights, 
safety, or welfare of subjects. Protocol violations include, but are not limited to, failure to 
obtain 
consent, 
unapproved 
investigator 
implanting 
a 
device, 
and 
subject 
inclusion/exclusion violations.  
The investigator must notify the reviewing IRB of all protocol violations per the reporting 
requirements. In some instances, such as failure to obtain consent, the investigator should 
also seek guidance from the IRB to ensure the subject received appropriate information to 
consider their participation in the study.  
14.2.2 Protocol Deviations 
Protocol deviations not meeting the definition of a violation 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. 
14.3 
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 reported deviations 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, if necessary. 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 subjects. 
 

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15. Adverse Events 
In the course of the clinical investigation, undesired medical events can occur in 
participating subjects, which are called adverse events (AEs). Furthermore, device 
deficiencies (DD) or complaints may also be observed. All AEs and device deficiencies and 
complaints of the investigational device shall be assessed by the investigator and shall be 
documented and reported throughout the clinical investigation.  
Adverse event reporting starts with the signing of the Informed Consent Form. The 
responsible investigator has to evaluate and report any AE that is brought to his/her 
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 below and in section 
16.2. 
15.1 
Definitions 
15.1.1 Definition of Adverse Event 
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 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 
medical devices.  
The following conditions will not be considered as an Adverse Event in terms of this study: 
- 
Preexisting 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 subject 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. 
15.1.2 Definition of Adverse Device Effect 
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 

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the investigational device and any event resulting from use error or from unintentional 
misuse of the investigational device.  
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. anesthetic complications, wound healing disturbances, etc.) are 
considered ADEs. 
15.1.3 Definition of Unanticipated Adverse Device Effects 
As defined in 21 CFR Part 812.3, an unanticipated adverse device effect (UADE) is any 
serious adverse effect on health or safety or any life-threatening problem or death caused 
by, or associated with, a device, if that effect, problem or death was not previously 
identified in nature, severity or degree of incidence in the study protocol or application 
(including a supplementary plan or application), or any other unanticipated serious problem 
associated with a device that relates to the rights, safety or welfare of subjects. A root-
cause analysis will be performed and the possibility of reoccurrence will be evaluated 
immediately. 
A listing of previously identified adverse events along with anticipated frequency is provided 
in section 11.2.1. It is important to note that random component failures or problems 
caused by misuse of the product are not considered unanticipated adverse device effects.  
15.1.4 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 fetal distress, fetal death or a congenital abnormality or birth defect. 
Note: Planned hospitalization for a pre-existing condition, or a procedure required by the 
protocol, without serious deterioration in health, is not considered a serious adverse event. 
In-patient hospitalization is defined as at least one overnight stay (change of date) in a 
hospital. Events for which subjects are hospitalized for less than 24 hours without change of 
date will not be documented as serious, unless one or more of the other seriousness criteria 
are fulfilled.  

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According to national and international requirements some of the involved Competent 
Authorities (CA) and Ethics Committees (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 main 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.  
For OUS reporting requirements, SADEs are defined as unanticipated if by their nature, 
incidence, severity or outcome they have not been identified in the current risk analysis. 
These events must be reported to the main sponsor immediately. A root-cause analysis will 
be performed and the possibility of reoccurrence will be evaluated immediately. 
15.1.5 Definition of Serious Adverse Device Effect 
An ADE that resulted in any of the consequences characteristic of a serious adverse event is 
considered serious. 
15.1.6 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 risk analysis.  
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 current risk analysis. 
15.1.7 Definition of Device Deficiency  
Device deficiency (DD) is defined as inadequacy of a medical device with respect to its 
identity, quality, durability, reliability, safety, or performance, including malfunctions, use 
errors and inadequate labelling.   
DDs of the investigational device shall be documented throughout the study. DDs which 
caused an AE are reported on the respective Adverse Event eCRF. In the case the DD did 
not cause an adverse event, the Device Deficiency eCRF shall be used to document this 
“non-medical” event. 
If a “non-medical” 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, 

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the DD or complaint is classified as having SADE potential.  
15.1.8 
Definition of Device Complaint 
A device complaint is any written, electronic or oral communication that alleges deficiencies 
related to the identity, quality, durability, reliability, safety, effectiveness or performance of 
a device after it is released for distribution. If the Device Complaint is caused by an AE, then 
the Device Complaint that caused the AE will be reported on the respective Adverse Event 
eCRF. In the event the Device Complaint did not cause an adverse event, the Device 
Deficiency eCRF shall be used to document this “non-medical” event. 
15.2 Causality Assessment 
The relationship between the use of the investigational device (including the 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. 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 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 device seems relevant and/or the 
event cannot reasonably explained by another cause, but additional information may 
be obtained. 
· 
Causal relationship: the serious event is associated with the device or with 
procedures beyond reasonable doubt. 
The investigators will distinguish between the adverse events related to the investigational 
device and those related to the device procedures (any procedure specific to the 
investigational device). Procedure related events refer to the procedure related to the 
application of the investigational medical device only and therefore not to any other 

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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 device in response to an adverse event (the 
BioMonitor is replaced), the replacement will be considered like an initial application 
of a new device and shall be assessed accordingly. 
· 
Replacement of the BioMonitor due to regular battery depletion is not considered an 
adverse event. 
· 
An adverse event can be related both to procedures and the device. Complications of 
procedures are considered not related if the said procedures would have been 
applied to the patients also in the absence of device use or application. 
15.3  Reporting responsibilities 
15.3.1  Reporting responsibilities of the investigator to sponsor 
The investigator shall document all events on the respective eCRF pages provided within the 
EDC system. The timelines for reporting of initial cases and possible update reports are 
indicated in Table 4. Due to the reporting requirements in the EU, all adverse events shall 
be reported with an assessment in accordance with ISO14155. Reporting requirements per 
FDA requirements will also be observed. 
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 subject 
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 diagnosis 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 subject 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. 
 Reporting responsibilities of the sponsor 
To ensure reporting requirements are met during the study, adverse event information 
reported for all study sites, both those within the U.S. and outside of the U.S., will be 

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reviewed by BIOTRONIK, Inc. and BIOTRONIK SE & Co. KG to ensure region specific 
reporting requirements are met.  
As such, unanticipated adverse device effects identified outside of the U.S. will be reported 
to FDA, all reviewing IRBs, and participating investigators per the standard requirements 
and timelines. 
Conversely, BIOTRONIK SE & Co. KG will report all serious adverse events, serious adverse 
device effects, unanticipated serious device effects and all device deficiencies with serious 
adverse device effect potential that are identified at a U.S. site to the competent authorities 
and investigators as required and depending on the local regulatory requirements.  
 

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16. Records and Reports 
16.1 
Investigator Records 
Investigators are required to maintain the following accurate, complete and current records 
relating to this study: 
· 
All correspondence relating to the study with another investigator, an IRB, 
BIOTRONIK, Inc., a monitor, or any regulatory agency (e.g., a letter sent from the 
investigator to the IRB) 
· 
A copy of the study protocol 
· 
Signed investigator or research agreement 
· 
Signed Financial Disclosure Form 
· 
A copy of the IRB letter approving research study 
· 
A copy of the IRB approved subject Informed Consent Form 
· 
All clinical forms and documentation, including: 
o 
A copy of all signed subject Informed Consent Forms 
o 
All  supporting documentation for data entered into the EDC system 
o 
Records 
of 
any 
adverse 
events, 
adverse 
device 
effect, 
or 
device 
deficiency/complaint, including supporting documentation 
o 
Records pertaining to subject deaths during the study 
o 
Documentation and rationale for any deviations from the clinical protocol 
o 
Any other records required by BIOTRONIK, Inc. 
The investigator must retain records related to the study according to FDA regulations, IRB 
requirements and local regulatory regulations. 
16.2 
Investigator Reports 
Investigators are required to prepare and submit to BIOTRONIK, Inc. the following 
complete, accurate and timely reports on this study, when necessary: 
· 
Notification of a subject death during the study 
· 
Any unanticipated adverse device effects 
· 
Notification of the withdrawal of IRB approval 
· 
Annual progress reports prepared for the IRB  
· 
Notification of any deviations from the clinical protocol 

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· 
Notification that informed consent was not obtained from a subject 
· 
Final summary report prepared for the IRB 
· 
Any other information upon the request of an IRB, FDA, other regulatory authority, 
or BIOTRONIK, Inc. 
Table 4 outlines the responsibilities, including time constraints, for submitting the above 
reports.  

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Table 4: Investigator Reporting Responsibilities 
Type of Report 
Investigator Reporting Responsibilities 
Report 
Prepared 
For 
Reporting Timeframe 
FDA-Defined Reports 
Unanticipated adverse device 
effect 
Sponsor 
 
IRB/EC* 
As soon as possible, upon awareness of the effect. 
Within 10 working days after the investigator first learns of 
the effect 
Unanticipated serious adverse 
device effect 
Sponsor 
 
IRB/EC* 
As soon as possible, upon awareness of the effect. 
Within 24** hours after the investigator first learns of the 
effect. 
Device deficiencies 
Sponsor 
 
IRB/EC* 
Within 14 days after the investigator first learns of the effect. 
Device complaints 
Sponsor 
 
IRB/EC* 
Within 14 days after the investigator first learns of the effect. 
Withdrawal of IRB/EC approval 
or other action on part of the 
IRB/EC that affects the study 
Sponsor 
Within 5 working days of receipt of notice of withdrawal of 
approval  
Subject death 
Sponsor and 
IRB/EC* 
As soon as possible upon awareness of death 
Progress reports 
IRB/EC* 
At regular intervals, but in no event less than yearly. 
Significant 
deviations 
from 
investigational plan 
Sponsor and 
IRB/EC* 
Emergency: ASAP but in no event later than 5 working 
days after emergency occurs to protect the life or physical 
well-being of a subject in an emergency. 
Non-emergency: prior approval by Sponsor and, if 
deviation may affect scientific soundness of the trial or the 
rights, safety or welfare of subject, also by the IRB/EC and 
FDA as an IDE supplement. 
Informed consent not obtained 
Sponsor and 
IRB/EC* 
Within 5 working days of use of the investigational device. 
Final report 
Sponsor and 
IRB/EC* 
Within 3 months after termination or completion of study or 
termination of site’s participation. 

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ASAP: as soon as possible; EC: Ethics Committee; FDA: Food and Drug Administration; IDE: 
investigational device exemption; IRB: Institutional Review Board. 
* Reporting to IRB/EC only where required by local legal requirements. 
** FDA requires 10 working days. 
***Term not defined by FDA.  
16.3 
Sponsor Records 
BIOTRONIK, Inc. will maintain the following records: 
· 
All correspondence with the investigator(s), IRBs, and FDA that pertains to the study 
· 
Investigator agreements, financial disclosures, and current curriculum vitae 
· 
Name and address of each investigator and each IRB that is involved with the 
investigation 
· 
Adverse events and complaints 
· 
Adverse device effects (whether anticipated or unanticipated) 
· 
Electronic Case Report Form data 
· 
Confirmation of completed subject informed consent forms 
· 
Clinical investigation protocol and report of prior investigations 
· 
Screening visit reports 
· 
Monitoring reports 
· 
Clinical progress reports 
· 
Statement of the extent to which the good manufacturing practice regulation in part 
21 CFR 820 will be followed in manufacturing the device 
Other Reports 
Adverse Events (AE)/Adverse Device Effect 
(ADE) 
Sponsor 
and 
IRB/EC* 
Within two weeks of site notification of 
AE/ADE 
Device deficiencies with SADE potential*** 
Sponsor 
 
IRB/EC* 
As soon as possible, upon awareness of 
the deficiency. 
Within 24** hours after the investigator first 
learns of the effect 
Serious 
Adverse 
Event 
(SAE)/Serious 
Adverse Device Effect (SADE)*** 
Sponsor 
 
IRB/EC* 
Immediately upon site notification. At latest, 
24 hours after notification. 

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16.4 
Sponsor Reports 
BIOTRONIK, Inc. is responsible for preparing the following reports, when necessary, as 
listed in Table 5. 
Table 5: Sponsor Reporting Responsibilities 
Type of Report 
Prepared by 
BIOTRONIK, Inc. for 
Time Constraints 
of Notification 
Unanticipated adverse 
device effect 
FDA, all reviewing IRBs, 
participating 
investigators 
Within 10 working days after 
notification of effect 
Withdrawal of IRB 
approval 
FDA, all reviewing IRBs, 
participating 
investigators 
Within 5 working days of receipt of 
notice of withdrawal of approval 
Withdrawal of FDA 
approval 
Reviewing IRBs, 
participating 
investigators 
Within 5 working days 
Current investigator 
list 
FDA 
Names and addresses of participating 
investigators at 6 month intervals 
Progress report 
FDA, all reviewing IRBs 
Submitted at least annually 
Recall and disposition 
FDA, all reviewing IRBs 
Within 30 working days and will 
include reasons for any request that 
an investigator return, repair, or 
otherwise dispose of any devices 
Final report 
FDA, all reviewing IRBs, 
participating 
investigators 
Notification within 30 working days of 
the completion or termination of the 
investigation. A final report will be 
submitted within 6 months after 
completion or termination of the 
study. 
Informed consent not 
obtained 
FDA 
Within 5 working days of notification 
of occurrence 

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17. Publication policy 
17.1 
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.  
17.2 
Authorship guidelines  
17.2.1  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. 
17.2.2  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 fulfill 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. 
17.2.3  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):  

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· 
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  
· 
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 weigh 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. 
17.2.4  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 two components: enrollment of subjects and the complete documentation of the 
reaction to HM containing the classification of an arrhythmia detected by the ICM, the 
resulting subject contact and, if a change in therapy is indicated, also the documentation of 
the therapy changes. 
Enrollment: The importance of subject enrollment for the success of the study is obvious. 
All subjects are counted if they are randomized and included in the analysis population. 
Reaction to HM: The thoroughly conducted diagnostic work-up and consequent treatment, 
if required, after ICM detected arrhythmias is the mechanism by which the study attempts 
to improve the outcome in the treatment arm. Since the study does not enforce therapy, 
documented cases of arrhythmia and subject contact will be acknowledged independent of 
the question whether it resulted in a therapy or not.  
Besides the assumed influence on the primary study outcome, the complete documentation 
of event chains is an important secondary objective of the study. 
To be counted, the following requirements must be fulfilled: 
- 
An arrhythmia reported by the CEMB was classified by the investigator 
- 
The subject was contacted, if applicable 
- 
If a diagnostic work-up was considered necessary, the diagnostic results and therapy 
changes are reported  
- 
The overall delay from CEMB report to classification by the investigator did not 
exceed 7 days 
- 
The information was recorded in the corresponding eCRFs and no open queries 
remain at study termination. 
To calculate the value of reaction to HM cases, the following rules apply: The time from 
CEMB notification to subject contact must not exceed 7 days. Within this period, the 

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investigator must have studied the HM content and classified the subject’s rhythm, and 
must have contacted the subject, if applicable.  
If this timeline is met, the full value is granted for the case.  
17.2.5  Calculation of the total score 
For all randomized subjects together, 1000 points are granted. For each randomized 
subject, the number of granted points to the study site is 1000 divided by the number of 
randomized subjects.  
For all Reaction to HM cases fulfilling the defined conditions together, 1000 points are 
granted. For each case, the value granted to the study site is 1000 divided by the total 
number of cases. These points may be reduced if the delays occurred, as defined above.  
The points are added for all study sites. If, for example 3000 subjects will be enrolled and 
5000 cases of arrhythmia and contact are documented, all sites will receive 0.33 points per 
enrolled subject, and 0.2 points per timely documented event chain. 
The sites will then be ranked by the number of points. 
17.2.6  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 

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17.2.7  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, favor investigators who have contributed more data to the specific 
subject of the publication. 
17.2.8  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.  
17.2.9  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. 
17.2.10 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.  
17.2.11 Reimbursement 
No honoraria will be paid for authorship of publications. 
 

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18.  Bibliography 
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elevation myocardial infarction outcomes in a large registry database: are non-ST 
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fraction after acute myocardial infarction: the Cardiac Arrhythmias and Risk 
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a nationwide cohort study in Taiwan. Int J Cardiol 2013;168:1360-1363. 
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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. 
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patients with acute coronary syndromes with no ST-segment elevation: incidence, 
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 (25)  Desai H, Aronow WS, Tsai FS et al. Statins reduce appropriate cardioverter-
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 (26)  Kallmunzer B, Breuer L, Kahl N et al. Serious cardiac arrhythmias after stroke: 
incidence, time course, and predictors--a systematic, prospective analysis. Stroke 
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 (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 
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Association Task Force and the European Society of Cardiology Committee for 
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 (29)  Moss AJ, Zareba W, Hall WJ et al. Prophylactic implantation of a defibrillator in 
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 (30)  Braunwald E, Domanski MJ, Fowler SE et al. Angiotensin-converting-enzyme 
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The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 
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 (34)  Krahn AD, Klein GJ, Yee R, Takle-Newhouse T, Norris C. Use of an extended 
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 (35)  Pachulski R, Cockrell J, Solomon H, Yang F, Rogers J. Implant evaluation of an 
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 (36)  Seidl K, Rameken M, Breunung S et al. Diagnostic assessment of recurrent 
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 (37)  Sanna T, Diener HC, Passman RS et al. Cryptogenic stroke and underlying atrial 
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 (38)  Smit J, Korup E, Schonheyder HC. Infections associated with permanent pacemakers 
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19. List of Abbreviations 
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 
CA 
Competent authority 
CI 
Coordinating Investigator 
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) 
CRO 
Clinical Research Organization 
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 
ESC 
European Society of Cardiology 

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FDA 
US Food and Drug Administration (www.fda.gov) 
GCP 
Good Clinical Practice 
GDPR 
EU General Data Protection Regulation 
H0 
Null Hypothesis 
HA 
Alternative Hypothesis 
HIPAA 
Health Insurance Portability and Accountability Act 
HM 
Home Monitoring 
HMSC 
Home Monitoring Service Center 
HVR 
High ventricular rate 
HR 
Hazard ratio 
i.e. 
Id est 
ICD 
Implantable Cardioverter Defibrillator 
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) 
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 

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PCI 
Percutaneous Coronary Intervention 
PID 
Product ID 
PI 
Principal Investigator 
PMCF 
Post Market Clinical 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 
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 
sECG 
subcutaneous Electrocardiogram 
STEMI 
ST Segment Elevation Myocardial Infarction 
TIA 
Transient Ischemic Attack 
VF 
Ventricular Fibrillation 
VT 
Ventricular Tachycardia  
WHO 
World Health Organization