BIO-Precision Study
Conditions: Atrial Fibrillation
Sponsor: Biotronik, Inc.

 
 
Clinical Protocol 
for the 
BIO-Precision Study 
 
 
 
Assessment of the utility of BIOMONITOR to identify atrial 
fibrillation (AF) in ablation candidates using precise AF 
detection  
 
NCT04076917 
 
 
 
June 5, 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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Clinical Protocol Version: 05 June 2019 
TABLE OF CONTENTS 
1. INTRODUCTION ............................................................................................................................... 5 
1.1 Study Overview ........................................................................................................................... 5 
1.2 Background .................................................................................................................................. 5 
1.2.1 BioMonitor Single-center AF Detect Study ......................................................................... 6 
1.3 System Description .................................................................................................................... 7 
1.3.1 BIOTRONIK Home Monitoring® with daily sECGs .............................................................. 7 
2. STUDY DESIGN ................................................................................................................................. 8 
2.1 Study Objectives ....................................................................................................................... 12 
2.1.1 Primary Objective .............................................................................................................. 12 
2.1.2 Additional Data of Interest ................................................................................................. 12 
2.2 Subject Status Definitions ...................................................................................................... 14 
2.3 Study Size and Duration ......................................................................................................... 14 
2.4 Sample-Size Analysis ............................................................................................................... 14 
2.5 Data Analyses ............................................................................................................................ 15 
2.5.1 Objective Analysis ............................................................................................................. 15 
2.5.2 Analysis for Data of Interest .............................................................................................. 16 
2.5.3 Analysis Population ........................................................................................................... 16 
2.5.4 Interim Analysis ................................................................................................................. 16 
3. PROTOCOL REQUIREMENTS ...................................................................................................... 17 
3.1 Patient Population ..................................................................................................................... 17 
3.1.1 Indications ......................................................................................................................... 17 
3.1.2 Contraindications .............................................................................................................. 17 
3.1.3 Inclusion Criteria ............................................................................................................... 17 
3.1.4 Exclusion Criteria .............................................................................................................. 18 
3.2 Study Procedures ...................................................................................................................... 18 
3.2.1 Pre-Screening ................................................................................................................... 21 
3.2.2 Consent and Eligibility ....................................................................................................... 21 
3.2.3 Insertion ............................................................................................................................ 22 
3.2.4 Baseline Medical History ................................................................................................... 23 
3.2.5 Pre-Holter Observation Period .......................................................................................... 23 
3.2.6 48 hr Holter Monitoring Initiation Visit ............................................................................... 23 
3.2.7 48 hr Holter Monitoring Completion Visit .......................................................................... 24 
3.2.8 System Revisions .............................................................................................................. 25 
3.3 Study Exits ................................................................................................................................. 25 
3.3.1 Screen Failures ................................................................................................................. 26 
3.3.2 Withdrawal of Consent ...................................................................................................... 26 
3.3.3 Subject Death .................................................................................................................... 26 
3.3.4 BIOMONITOR Removal .................................................................................................... 26 
3.3.5 Lost to Follow-up ............................................................................................................... 27 
3.3.6 Investigator Initiated Withdrawal ....................................................................................... 27 
3.3.7 Pre-Holter Observation Period Withdrawal ....................................................................... 27 
3.3.8 Study Participation Complete ............................................................................................ 27 
4. DATA COLLECTION ........................................................................................................................ 27 
4.1 IRB Approval .............................................................................................................................. 27 
4.2 Other Institutions and Physicians.......................................................................................... 28 
4.3 Informed Consent ..................................................................................................................... 28 
4.4 Data Collection .......................................................................................................................... 28 
4.4.1 Electronic Data Capture (EDC) ......................................................................................... 28 
4.4.2 Electronic Case Report Forms (eCRFs) ........................................................................... 28 

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4.4.3 BIOTRONIK Home Monitoring® Data ............................................................................... 29 
4.5 Data Quality Control ................................................................................................................. 29 
4.6 Subject Data Confidentiality ................................................................................................... 29 
4.7 Protocol Non-compliance ......................................................................................................... 30 
4.7.1 Protocol Violations ............................................................................................................ 30 
4.7.2 Protocol Deviations ........................................................................................................... 30 
4.7.3 IRB Reporting of Non-Compliance .................................................................................... 31 
5. RISKS AND RISK MINIMALIZATION ..................................................................................... 31 
6. STUDY ORGANIZATION .............................................................................................................. 32 
6.1 Sponsor ....................................................................................................................................... 32 
6.2 Holter Core Laboratory ............................................................................................................ 32 
7. MONITORING .................................................................................................................................. 32 
7.1 Summary .................................................................................................................................... 32 
7.2 Monitors ...................................................................................................................................... 34 
8. STUDY COMPLETION .................................................................................................................... 34 
9. ADVERSE EVENTS .......................................................................................................................... 34 
9.1 Reportable Adverse Events ..................................................................................................... 35 
9.1.1 Insertion Procedure-Related Adverse Events ................................................................... 35 
9.1.2 Device-Related Adverse Events ....................................................................................... 35 
9.1.3 Non-Procedure Non-System Related Adverse Events ..................................................... 35 
9.1.4 Study Procedure Related .................................................................................................. 36 
9.2 Adverse Event Reporting ......................................................................................................... 36 
10. RECORDS AND REPORTS ............................................................................................................ 36 
10.3 Investigator Records ............................................................................................................. 36 
10.4 Investigator Reporting Responsibilities ............................................................................. 37 
10.5 Sponsor Records .................................................................................................................... 38 
10.6 Sponsor Reporting Requirements ....................................................................................... 38 
11. REFERENCES .................................................................................................................................... 40 
12. APPENDIX A: DEFINITION OF TERMS ................................................................................... 41 
 

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Clinical Protocol Version: 05 June 2019 
BIO-Precision Clinical Study 
 
 
PROTOCOL SIGNATURE PAGE 
 
The signature below constitutes the receipt and review of the BIO-Precision Clinical 
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 U.S. federal regulations, ICH, and GCP guidelines. 
 
 
STUDY SITE PRINCIPAL INVESTIGATOR: 
 
 
Signed: 
 
 
 
 
Name (please print) 
 
 
 
 
 
Signature 
 
Date 
 

BIOTRONIK, Inc.  
 
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Clinical Protocol Version: 05 June 2019 
SUMMARY 
Title 
BIO-Precision Study  
Descriptor 
Assessment of the utility of BIOMONITOR to identify AF in 
ablation candidates using precise AF detection 
Design 
Prospective, multicenter, observational study  
Purpose 
The purpose of this study is to evaluate the diagnostic utility 
of BIOTRONIK’s subcutaneous cardiac rhythm monitor 
(SCRM) for the detection of AF prior to an ablation 
procedure. 
Subject Population 
Study population includes patients diagnosed with 
paroxysmal AF being evaluated for an AF ablation.  
Sample Size 
This study will enroll up to 100 subjects, to obtain 60 usable 
Holter recordings.  
Clinical Sites 
Up to 5 U.S. sites. 
Follow-up Period 
All subjects will be followed for three months post  
48 hr Holter monitoring.  
Primary Objective 
The primary objective of this study is to determine the 
diagnostic utility of the BIOMONITOR to detect AF within 
study subjects who are being evaluated for an ablation. 
Specifically, the diagnostic sensitivity of the BIOMONITOR 
will be determined by comparing AF events detected by the 
BIOMONITOR and 48 hr Holter monitor for each subject. 
Using the 48 hr Holter monitor as the gold standard, 
subjects with AF events detected by the BIOMONITOR will 
be categorized as true positive or false positive.  
Study Risk 
Determination 
Standard of care study including market released devices 
implanted according to FDA approved indications for use.  
Sponsor 
BIOTRONIK, Inc. 
Clinical Studies Department 
6024 SW Jean Road 
Lake Oswego, Oregon 97035 
 

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1. INTRODUCTION 
1.1 Study Overview 
BIO-Precision is a post-market study investigating the utility of atrial fibrillation 
(AF) detection using BIOTRONIK’s subcutaneous cardiac rhythm monitor (SCRM). 
The purpose of this study is to evaluate the diagnostic utility of BIOTRONIK’s SCRM 
for the detection and confirmation of AF prior to an ablation procedure. Study 
population includes patients with paroxysmal AF being evaluated for an AF ablation. 
This study will enroll up to 100 subjects, to obtain 60 usable Holter recordings, at 5 
study sites within the United States (U.S.). Study subjects will be followed for three 
months after the completion of a 48 hr Holter monitor.   
1.2 Background 
SCRMs are devices capable of long-term cardiac rhythm monitoring. These devices 
are commonly used to assist in the diagnosis of unexplained palpitations and 
syncope. SCRMs provide more reliable and accurate monitoring than a routine 
surface ECG and can provide continuous long term monitoring compared to Holter 
monitoring. A growing use of SCRMs is for the detection and management of AF, in 
particular in patients with high thromboembolic risk. SCRMs were originally 
designed after pacemaker technology, however, current SCRMs have significantly 
decreased profiles, allowing for less-invasive insertion procedures1 and low 
complication rates,2,3 making them a safe and efficient option for arrhythmia 
diagnosis.  
Atrial fibrillation is the most common diagnosed arrhythmia, and it is estimated to 
effect 6-12 million people in the U.S. by 2050.4,5 AF has many causes and can be 
both symptomatic and asymptomatic, and is associated with an increase in 
hospitalizations, stroke, and heart failure.6 Recent studies have suggested that the 
adverse effects of AF may be correlated with AF episode duration;7 therefore it is 
important to appropriately capture AF episodes and their durations to adequately 
treat patients and reduce their AF burden.8 AF can be diagnosed through medical 
history, exam, and a surface ECG; however, for non-sustained or paroxysmal AF, a 
surface ECG may not be sufficient to accurately detect the patient’s true AF burden. 
Therefore, the use of a SCRM may result in precise and accurate AF detection over 
a longer period of time as compared to traditional surface (e.g. Holter) monitors.  
Recent guidelines recommend AF ablation in patients with symptomatic AF, 
refractory or intolerant to at least one Class 1 or 3 antiarrhythmic medication. 
Asymptomatic patients may choose to pursue an AF ablation as an alternative to 
continuous, long-term anticoagulation therapy.9 ECG monitoring is recommended 
pre- and post AF ablation procedure. Prior to undergoing an ablation, it is important 
for the physician to confirm the presence of AF as well as the current AF burden. 
Available methods for ECG monitoring, as discussed above, range from in office 
ECG, Holter (24 hours to 7 days), or SCRMs (up to 4 years of continuous 
arrhythmia monitoring). Not only are SCRMs valuable for detecting AF and AF 
burden prior to ablation, they may also provide important data post-ablation in 

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assisting the physician in determining the success rate of the ablation procedure. 
The focus of this study is to determine the utility of SCRMs for AF detection in 
patients who are being evaluated for an ablation.    
1.2.1 BioMonitor Single-center AF Detect Study 
BIOTRONIK conducted an AF Detection clinical study in order to assess the 
performance of the BioMonitor AF feature in clinical practice. This study used 
BIOTRONIK’s first generation SCRM, which received FDA approval on June 2, 2014 
(510(k) number: K132960). The ability of BioMonitor to detect episodes of AF was 
quantified in comparison with the gold-standard, expert-annotated, external Holter 
ECG recorder. Sixty six (66) participants with suspected paroxysmal or persistent 
atrial fibrillation who had been implanted with a BioMonitor were additionally 
equipped with an external Holter ECG recorder.  
The main aim of the AF Detect study was to record surface electrocardiograms 
(ECG) to reference it with the subcutaneous ECG of the BioMonitor. For this reason 
a Holter ECG device was applied, and the patient was asked to come back after 2 
days. All episodes were interrogated and a memory dump was conducted. The site 
was equipped with the long-term three channel Holter ECG system “LifeCard” from 
the company “Spacelabs Healthcare” (www.spacelabshealthcare.com). This is a CE-
approved compact Holter Ambulatory ECG Recorder that is capable of storing a 
continuous, 48-hour recording of up to 3 leads onto a Compact Flash (CF) card. 
Lifecard ECG was used to establish an independent assessment of AF, and 
represents the gold standard for AF detection. The LifeCard ECGs were manually 
annotated for AF episode onset and termination, and the annotations were verified 
by an independent ECG reviewer. 
The surface ECG of the Holter ECG and the subcutaneous ECG of the BioMonitor 
were synchronized by time and date and manually assessed to determine the AF 
detection performance. Furthermore, automatically detected arrhythmias were 
assessed and documented. BioMonitor and LifeCard AF episodes were directly 
compared to one another on an episode-by-episode basis, by which each episode 
longer than 2 minutes in duration (default BioMonitor confirmation window) was 
classified as true positive (TP), false positive (FP), or false negative (FN).  
Of the 66 participants in AF Detect, 39 showed at least one true AF episode during 
the 48-hour Holter period, with a maximum of 30 distinct, true AF episodes 
experienced by one subject. A total of 146 AF episodes were annotated from 2878 
hours of Holter ECG data. During the execution of the AF Detection study, three 
subjects had missing Holter data, and hence were excluded from the analysis. The 
primary endpoint analysis determined  an AF detection sensitivity of 95.4% ± 
13.3% and a positive predictive value of 76.3% ± 38.7%.10 

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1.3 System Description  
This study utilizes BIOTRONIK’s subcutaneous cardiac rhythm monitor (SCRM).  
The BIOMONITOR is a SCRM that continuously monitors the heart rhythm. 
BIOMONITOR programming and data collection during insertion 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 BIOMONITOR records automatically the occurrence of certain cardiac 
arrhythmias.  
The BIOMONITOR is indicated to detect the following cardiac arrhythmias: 
· 
Atrial fibrillation 
· 
Bradycardia 
· 
Sudden rate drop 
· 
High ventricular rate (HVR) 
· 
Asystole 
Devices included in the clinical study:  
· BioMonitor 2 (FDA clearance April 11, 2016; K152995 number) or FDA cleared 
successor (hereafter, referred to as BIOMONITOR) 
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 inserted with a BIOMONITOR will be remotely monitored with 
BIOTRONIK’s Home Monitoring® system and will be provided a BIOTRONIK 
CardioMessenger II, II-S or FDA-cleared successor. The BIOTRONIK Remote 
Assistant may also be provided and allows manual triggering of an ECG recording 
by the patient.  
1.3.1 BIOTRONIK Home Monitoring® with daily sECGs 
The BIOTRONIK Home Monitoring® system provides early detection of arrhythmic 
events such as high ventricular rates and of silent, asymptomatic events like atrial 
fibrillation (Figure 1), through the transmission of detection and termination 
snapshots of the indicated event. Transmissions include both periodic and triggered 
subcutaneous electrocardiogram (sECG) recordings.  

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Figure 1: Atrial Fibrillation sECG Transmission Example 
 
 
 
 
 
The BIOMONITOR has the capability to transmit messages including sECG signals to 
the BIOTRONIK Home Monitoring® Service Center daily so that the monitoring 
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 and can process them 
into graphical and tabular format.  
 
2. STUDY DESIGN 
The BIO-Precision study is a post-market, multicenter, prospective, observational 
study designed to evaluate AF detection performance of BIOTRONIK’s SCRM, 
BIOMONITOR. Up to 100 subjects will be enrolled to collect a total of 60 usable 
Holter recordings. The subject population includes patients that are diagnosed with 
paroxysmal AF and are being evaluated for an AF ablation procedure. Study 
subjects will be enrolled at up to 5 participating U.S. sites. Subjects will be followed 
for three months after the completion of 48 hr Holter monitoring.  
Potential subjects will be identified by the investigator from their general patient 
population and must have an approved indication for continuous arrhythmia 
monitoring with an SCRM according to local regulations. Subjects will be consented 
no more than 14 days prior to the insertion procedure (Figure 2) and screened to 
ensure they meet all of the inclusion and none of the exclusion criteria. Subjects 
may also be screened and consented up to 30 days following the insertion of a 
BIOMONITOR (Figure 2). All subjects will be considered ‘provisionally enrolled’ until 
they initiate the 48 hr Holter monitoring, at which time they are considered fully 
enrolled.  

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For subjects with an existing BIOMONITOR, a pre-Holter observation period will be 
initiated at enrollment (Figure 2). This observation period should be 12-16 days in 
duration and will allow for characterization of the BIOMONITOR performance prior 
to Holter monitoring. Following this observation period, Holter monitoring should be 
initiated within 7 days. For subjects consented before BIOMONITOR insertion, the 
insertion procedure should be completed within 14 days, followed by the pre-Holter 
observation period (Figure 2). Holter monitoring should be initiated within 7 days 
after the completion of the observation period.  
Figure 2: Enrollment Pre- and Post-BIOMONITOR insertion 
 

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The primary analysis will focus on the utility of the BIOMONITOR for the detection 
of AF within patients who are being evaluated for an ablation. Data will be collected 
from in-person visits at study enrollment, BIOMONITOR insertion, and initiation and 
completion of 48 hr Holter monitoring. In addition, BIOMONITOR performance data 
will be collected throughout the study duration using BIOTRONIK Home 
Monitoring®, including a required Home Monitoring data check at the end of the 
pre-Holter observation period. Holter monitor recordings will be evaluated by a 
Holter Core Laboratory. In addition, BIOMONITOR detections may be adjudicated by 
an event adjudication committee, if applicable. 
Figure 3 provides an overview of the clinical study design. Details of subject 
eligibility requirements are noted in Section 3.2.2 and details of other study specific 
procedures and data collection are noted in Section 3.2 and Section 4.  
Figure 3: BIO-Precision Study Design Flowchart 

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2.1 Study Objectives  
This study includes the assessment of one primary objective related to the 
diagnostic utility of the BIOMONITOR to detect AF prior to an ablation procedure. 
Additional data of interest will be collected and assessed.  
2.1.1 Primary Objective  
The primary objective of this study is to determine the diagnostic utility of the 
BIOMONITOR to detect AF within study subjects who are being evaluated for an 
ablation. Specifically, the diagnostic sensitivity of the BIOMONITOR will be 
determined by comparing AF events detected by the BIOMONITOR and 48 hr Holter 
monitor for each subject. Using the 48 hr Holter monitor as the gold standard, 
subjects with AF events detected by the BIOMONITOR will be categorized as true 
positive or false positive.  
It is expected that sensitivity will be greater than 90% in detecting AF within study 
subjects that are being evaluated for ablations.  
Diagnostic Sensitivity:  
Ho: The Sensitivity (Se) for detecting at least one true positive AF episode per 
subject will be less than or equal to 90%.  (Se ≤ 90%) 
Ha: The Sensitivity for detecting at least one true positive AF episode per subject 
will be greater than 90% (Se > 90%) 
A rejection of the null hypothesis would demonstrate that there is evidence that 
Sensitivity is greater than 90%.  
2.1.2 Additional Data of Interest 
Additional information will be collected to characterize the study population, 
BIOMONITOR usage, and progress of the study. Specifically, data of interest will 
include: 
· 
Baseline demographics, including age, gender, height, weight, race and ethnicity 
(optional) 
· 
Medical history 
· 
Cardiovascular medication  
· 
Insertion procedure information, including success/failure of insertion, procedure 
times, location and orientation of the BIOMONITOR, and reason for insertion. 
Data may be collected retrospectively if insertion occurred prior to enrollment. 
· 
Inserted device information, including model, serial number, and insertion date   
· 
Ablation procedure information, including date of ablation and the utility of the 
BIOMONITOR in determining ablation candidates  

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· 
Compliance to protocol requirements and study visit schedule 
· 
Success of Home Monitoring transmissions 
· 
BIOMONITOR performance during the study including, but not limited to, 
R-wave amplitude and arrhythmia detections as reported using BIOTRONIK 
Home Monitoring® 
· 
AF episodes as detected by the Holter monitor and BIOMONITOR, as well as 
additional arrhythmic episodes. AF detections will be used to support patient, 
episode, and duration metrics including sensitivity, specificity, positive predictive 
value, and negative predictive value of the BIOMONITOR.  
· 
Visibility of P-waves from recorded BIOMONITOR episodes 
· 
AF episodes within the pre-Holter observation period  

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2.2 Subject Status Definitions  
The subject status definitions utilized in this study are provided in Table 1.  
Table 1: Subject Status Definitions 
Subject Status 
Definition 
Provisionally Enrolled 
Subject has provided written informed consent but has not 
initiated 48 hr Holter monitoring.  
Provisionally enrolled subjects that initiate 48 hr Holter 
monitoring will be considered fully enrolled.   
Provisionally enrolled subjects that do not initiate 48 hr 
Holter monitoring will be exited. These subjects will be 
included in the additional data of interest analysis 
population. 
Screen Failure 
Subject has signed consent, but at the time of consent it was 
identified the subject does not meet all inclusion/exclusion 
criteria 
OR 
Subject consented prior to insertion, but exited prior to 
insertion or does not receive a BIOMONITOR. 
Subject will be exited and will not be included in the analysis 
population. 
Enrolled 
 
Subject has met all inclusion and exclusion criteria, provided 
written informed consent, successfully inserted with a 
BIOMONITOR, and initiates 48 hr Holter monitoring.  
Subject will be included in the analysis population. 
2.3 Study Size and Duration 
During this study, data will be gathered, analyzed, and reported to evaluate the 
diagnostic utility of the BIOMONITOR. It is anticipated that up to 100 subjects will 
be enrolled to have 60 subjects who will complete 48 hr Holter monitoring and will 
be followed for three months post 48 hr Holter monitoring at up to 5 U.S. sites.   
2.4 Sample-Size Analysis 
The study is designed to limit the number of subjects involved while still exposing 
the device to a sufficiently large subject population to evaluate the utility of 
BIOMONITOR in subjects that are being evaluated for AF ablation. A sample size of 
60 subjects with evaluable data sets is required to evaluate the diagnostic 
sensitivity with the following assumptions: 

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· 
Prevalence of AF during Holter test: 50% 
· 
Confidence interval: 95% 
· 
Precision level: 6.35% 
· 
Expected patient-based sensitivity: 97% 
· 
Drop-out rate after 48 hr Holter monitoring is initiated: 8% 
To account for expected attrition due to subject withdrawal following consent but 
prior to completion of the study testing period: 
· 
Up to 100 subjects will be provisionally enrolled 
· 
Assumed 40% drop out rate between consent and the initiation of 48 hr 
Holter monitoring (e.g. R-wave amplitude <0.25 mV, no AF detection during 
pre-Holter observation period, withdrawn consent, etc.) 
· 
Sixty subjects will undergo 48 hr Holter monitoring (fully enrolled) 
2.5 Data Analyses 
Descriptive statistics will be used to present and summarize the data collected in 
the clinical study. Frequency distributions and cross tabulations will be presented 
for discrete variables. Means, standard errors, and ranges will be presented for 
continuous variables. 
2.5.1 Objective Analysis 
The primary objective analysis will calculate the diagnostic sensitivity of the 
BIOMONITOR. Diagnostic sensitivity is the ability of the BIOMONITOR to correctly 
identify subjects who have AF as determined by the Holter monitor.  
Specifically, diagnostic sensitivity is determined as: 
Diagnostic sensitivity = 
Number of TP patients 
Number of TP + Number of FP patients 
 
 
Where TP is true positive and FP is false positive. 
To test the primary hypotheses, sensitivity will be calculated and a one-tailed 
binomial test will be implemented to determine if there is evidence to support the 
rejection of the null hypothesis. 

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2.5.2 Analysis for Data of Interest 
Additional data of interest, which includes the characterization of the insertion 
procedure and device functionality, will be analyzed quantitatively and statistically 
where appropriate. All available results will be categorized and summarized.  
Data from the 48 hr Holter recording will support metrics including sensitivity, 
specificity, positive predictive value, and negative predictive value. Holter 
monitoring will be used as the gold standard for AF detection. Sensitivity is defined 
as the proportion of true positives that are correctly identified as positive. 
Specificity is defined as the proportion of true negatives that are correctly identified 
as negative. The positive predictive value is defined as the proportion of positive 
detected episodes that are true positive. The negative predictive value is defined as 
the proportion of negative detected episodes that are true negative. Evaluation may 
be performed on an episode, subject, or duration basis. Additional, non-AF episodes 
recorded on the BIOMONITOR may be compared to Holter data to confirm the onset 
of different arrhythmias.  
2.5.3 Analysis Population 
The analysis population for the primary objective includes all subjects that are 
enrolled in the study and have evaluable 48 hr Holter data and BIOMONITOR data. 
If an evaluable 48 hr Holter contains segments which are marked as not 
interpretable by the Holter Core Laboratory, these segments will be excluded from 
analysis. Subjects may be allowed to repeat 48 hr Holter monitoring if the Holter 
Core Laboratory determines a significant portion of the recording is uninterpretable.  
Evaluable BIOMONITOR data is defined as successful collection of the complete 
BIOMONITOR data set from the 48 hr Holter period. In the event that some 
BIOMONITOR detections are not available due to the number of detected events 
exceeding the device storage capacity, the segments with missing BIOMONITOR 
information will be excluded from the analysis.  
Data of interest elements that require comparison to the 48 hr Holter monitor data 
will use the same analysis population. Analysis for additional data of interest will be 
completed with both provisionally enrolled and fully enrolled study populations. 
2.5.4 Interim Analysis  
In the BIO-Precision study, one interim analysis is planned and will occur once all 
eligible fully enrolled subjects have completed their 48 hr Holter monitoring visits. 
This analysis will assess the outcomes of the primary objective.  At this interim 
analysis, the study objectives and additional data of interest may be evaluated to 
characterize initial results of the BIO-Precision Study. 

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3. PROTOCOL REQUIREMENTS 
3.1 Patient Population 
The investigator is responsible for screening all potential subjects and selecting 
those who are appropriate for study inclusion. Potential subjects will be evaluated 
to determine if they meet the inclusion and exclusion criteria described below in 
Sections 3.1.3 and 3.1.4. The subjects selected for participation should be from the 
investigator's general patient population according to the inclusion and exclusion 
criteria. Patients who require a legally authorized representative will not be allowed 
in the study. 
3.1.1 Indications 
The BIOMONITOR is a SCRM 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.  
3.1.2 Contraindications 
There are no known contraindications for the insertion of the BIOMONITOR. 
However, the patient’s particular medical condition may dictate whether or not a 
subcutaneous, chronically inserted device can be tolerated. 
3.1.3 Inclusion Criteria 
To support the objectives of this investigation, the inclusion criteria at the time of 
patient enrollment for this study include the following requirements: 
· 
Meet the indications for SCRM insertion according to local regulations  
· 
Patient is able to understand the nature of the study and provide written 
informed consent 
· 
Inserted within the prior 30 days, or scheduled for insertion within 14 days, with 
BIOTRONIK’s most current SCRM 
· 
Diagnosed with paroxysmal9 atrial fibrillation and being evaluated for an AF 
ablation  
· 
Agree to wearing a 48 hr Holter monitor  
· 
Able and willing to complete all study visits at the study site for the study 
duration  

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· 
Able and willing to use a CardioMessenger® and accepts Home Monitoring 
concept 
· 
Age greater than or equal to 18 years 
3.1.4 Exclusion Criteria 
To support the objectives of this investigation, the exclusion criteria at the time of 
patient enrollment include the following requirements: 
· 
Patient meets none of the indications for a BIOMONITOR 
· 
Patient is planned to have an ablation prior to BIOMONITOR insertion or 48 hr 
Holter monitoring visit   
· 
Patient is currently diagnosed with long-standing persistent9 or permanent AF  
· 
Patient is enrolled in another study that may change or alter the cardiac rhythm 
that occurs prior to the completion of the Holter  
· 
Currently indicated for or implanted with a pacemaker, ICD device, or 
hemodynamic monitoring system 
· 
Life expectancy less than 6 months 
· 
Patients reporting pregnancy at the time of enrollment 
For patients enrolled after BIOMONITOR insertion: 
· 
R-wave sensing <0.25 mV according to the most recent Home Monitoring 
CardioReport or device interrogation available prior to enrollment  
After the pre-Holter observation period but prior to 48 hr Holter monitoring 
initiation, confirm the absence of the following exclusion criteria based on the 
CardioReport collected at the end of the observation period:  
· 
No AF episodes observed or transmitted during pre-Holter observation period 
· 
R-wave sensing <0.25 mV during pre-Holter observation period as reported by 
the 24 hr mean or mean value since last follow-up 
3.2 Study Procedures 
Subjects with a previously inserted BIOMONITOR will be provisionally enrolled once 
consent is given and will be considered fully enrolled once 48 hr Holter monitoring 
has been initiated. Subjects consented prior to insertion will be considered 
provisionally enrolled until the successful insertion of a BIOMONITOR and the 
initiation of 48 hr Holter monitoring.  
BIOTRONIK Home Monitoring® should be activated in all subjects. Data will be 
collected at all visits starting at insertion (e.g. enrollment, Home Monitoring data 
check following the pre-Holter observation period, 48 hr Holter monitoring initiation 
and completion visit, and study exit). Enrollment data will include informed 
consent, subject demographics, and relevant medical history.  

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Insertion data will include procedure time, insertion location and orientation, and 
device serial numbers. Following insertion or at the time of enrollment, for subjects 
previously inserted with a BIOMONITOR, the BIOMONITOR must be programmed to 
the required programming settings to initiate the pre-Holter observation period.  
Following the 12 to 16 day pre-Holter observation period, the presence of AF 
episodes and R-wave sensing performance will be evaluated. Subjects with no AF 
episodes during this time will not complete the Holter visit and will be exited from 
the study. Subjects with R-wave sensing <0.25 mV, as reported by the 24 hour 
mean or the mean value since last follow-up on the Home Monitoring CardioReport 
collected at the end of the pre-Holter observation period, will not complete 48 hr 
Holter monitoring and will be exited form the study.  
For subjects presenting with at least one AF episode during the pre-Holter 
observation period, patient specific BIOMONITOR programming settings may be 
provided by BIOTRONIK prior to starting 48 hr Holter monitoring. Data will be 
collected at the 48 hr Holter monitoring initiation visit and will include Holter start 
time and selected programming. Data will also be collected at the completion of 48 
hr Holter monitoring including the Holter recordings and all sECGs from the 
BIOMONITOR. The Holter data will be sent to the Holter Core Laboratory for 
evaluation.  
BIOMONITOR performance data will be collected throughout the course of this 
study by BIOTRONIK Home Monitoring®. Subjects will be followed for three months 
after the completion of their 48 hr Holter visit. At study exit, data will be collected 
on adverse events and reason for study exit. Additionally, date of ablation, if 
performed, and physician feedback on the diagnostic utility of the BIOMONITOR to 
determine the need of the ablation will be collected at the time of study exit.  
Study Procedure Visits: 
· 
Enrollment (subjects are considered provisionally enrolled until undergoing 
successful insertion and initiation of 48 hr Holter monitoring) 
· 
Insertion (if subject does not have an existing BIOMONITOR) 
· 
Home Monitoring data check (after completion of the pre-Holter observation 
period) 
· 
48 hr Holter Monitoring Initiation 
· 
48 hr Holter Monitoring Completion 
Table 2 summarizes the study procedures. Table 3 summarizes the visit schedule.  

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Table 2: Study Procedures  
 
Enrollment 
Insertion1 
Home 
Monitoring 
data check 
48 hr 
Holter 
Monitoring 
Initiation 
Visit2 
48 hr 
Holter 
Monitoring 
Completion 
Visit 
Study 
Exit 
Informed 
Consent 
(enrollment) 
X 
 
 
 
 
 
Demographics 
and Medical 
History 
X 
 
 
 
 
 
Insertion 
Information  
 
X 
 
 
 
 
Device 
Programming 
X3 
X4 
 
X 
 
 
Device 
Evaluation 
and Data 
Collection 
 
 
X 
X 
X 
 
Holter Data 
Collection 
 
 
 
 
X 
 
Adverse Event 
Assessment 
 
X 
 
X 
X 
X5 
Ablation 
Procedure 
Information 
 
 
 
 
 
X 
Complete 
eCRF 
X 
X 
X 
X 
X 
X 
 
 
1Insertion should be completed within 14 days of provisional enrollment/informed consent. If subject has 
a prior insertion, retrospective data collection of insertion procedure information will be required. 
248 hr Holter Monitoring Initiation Visit should occur within 7 days following the pre-Holter observation 
period. 
3Device programming is required at enrollment for subjects enrolled after BIOMONITOR insertion. 
4Device programming is required at insertion for subject enrolled prior to BIOMONITOR insertion. 
5Adverse event assessment at study exit will involve medical record review for reportable events and to 
identify updates to previously reported events. 
 
 
 

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Table 3: Study Visit Schedule 
 
Visit Window 
Enrollment 
30 days post 
BIOMONITOR insertion 
-OR- 
14 days prior to 
BIOMONITOR insertion 
Insertion 
30 days prior to 
enrollment 
-OR- 
14 days post 
enrollment 
Home Monitoring 
data check 
At the completion of the 12-16 day Pre-Holter 
Observation Period 
48 hr Holter 
Monitoring 
Initiation Visit 
Within 7 days of the Home Monitoring data check 
48 hr Holter 
Monitoring 
Completion Visit 
48 hours after the Holter Monitoring Initiation Visit 
Study Exit 
Three months (-0/+30 days) after the 48 hr Holter 
Monitoring Completion Visit 
 
3.2.1 Pre-Screening 
Prior to consent, the patient’s medical history must be reviewed in order to ensure 
that the patient is an appropriate candidate for the study. This review should 
include verification of any available historical inclusion and exclusion criteria. This 
includes having a BIOMONITOR inserted no more than 30 days prior to date of 
consent or having plans to insert a BIOMONITOR no more than 14 days after 
consent. Written informed consent must be obtained from the patient prior to 
collecting any study specific data.  
3.2.2 Consent and Eligibility 
If the potential subject meets all inclusion and exclusion criteria (see sections 3.1.3 
and 3.1.4), the potential subject is informed about the study and asked to read and 
sign an Informed Consent Form. The potential subject should be provided with 
sufficient time to consider participation in the study. The consent process, including 
discussion of the study, should be documented within the subject’s medical record. 
Consented subjects must be entered in the subject identification log and will be 
reflected on the electronic enrollment log once entered in the electronic data 
capture system. 
 

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The following data collection and reporting procedures are performed at the consent 
visit: 
1. 
Verification that subject meets all of the inclusion criteria and none of the 
exclusion criteria 
2. 
Obtain informed consent and upload the unredacted signed informed consent 
form to the Informed Consent eCRF* 
3. 
Complete all required eCRFs 
If the subject is consented after BIOMONITOR insertion, the BIOMONITOR should 
be programmed to the required programming settings and the pre-Holter 
observation period should be initiated at time of enrollment.  
3.2.3 Insertion 
BIOMONITOR insertion should occur no more than 14 days after informed consent 
(consented prior to insertion) or no more than 30 days prior to informed consent 
(consented after insertion). Insertion details and device information will be collected 
retrospectively if insertion occurred prior to consent. 
The following insertion data and procedures will be collected for enrolled subjects: 
1. 
Collect insertion information 
· Date of insertion procedure 
· Insertion location  
· Device orientation 
· Primary indication for insertion  
2. 
Collect inserted system information model and serial number 
3. 
Review for any reportable adverse events (See section 9.1)  
a. Only adverse events occurring in enrolled subjects on or after the date of 
insertion through the duration of the study will be collected. 
b. All insertion procedure-related, device-related and non-procedure non-
system related AEs will be reported as outlined in Section 9.1. 
4. 
Complete all required eCRFs and upload source documentation 
 
* Sites that are unable to upload unredacted signed informed consents will be asked to provide a copy of the IRB 
and/or institutional policy stating they are not allowed to upload unredacted source documentation.  

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If the subject is consented prior to BIOMONITOR insertion, the BIOMONITOR should 
be programmed to the required programming settings at the time of insertion and 
the pre-Holter observation period should be initiated following insertion and 
programming.  
3.2.4 Baseline Medical History 
Baseline medical history information will be entered into the Enrollment eCRF, if 
available. Baseline information includes, but is not limited to demographics, 
arrhythmias, comorbidities and cardiovascular medication. Reported data should be 
from the medical record and obtained from records no more than 90 days prior to 
consent. If subject is a screen failure, baseline medical history will not be collected 
for the study. 
3.2.5 Pre-Holter Observation Period 
Subjects will undergo a 12 to 16 day pre-Holter observation period following 
enrollment, for subjects inserted with a BIOMONITOR prior to consent, or following 
insertion, for subjects consented prior to BIOMONITOR insertion. The BIOMONITOR 
must be programmed to the required programming settings either at enrollment or 
insertion, respectively. Subjects with a new BIOMONITOR device should be 
educated on the set up and use of the CardioMessenger to ensure Home Monitoring 
data is transmitted during the 12 to 16 day observation period. For subjects 
implanted before consent, Home Monitoring transmission status should be verified 
and any transmission issues resolved. 
Following this pre-Holter observation period, a Home Monitoring data check will be 
performed and CardioReport obtained, containing a listing of all episode recordings. 
Information on AF episodes within the observation period will be collected. 48 hr 
Holter monitoring will not be performed for subjects with no AF episodes recorded 
or transmitted during the observation period or in subjects with R-wave sensing < 
0.25 mV, as reported on the CardioReport collected at the completion of the 
observation period, and these subjects will exit the study. For subjects with AF 
episodes, BIOTRONIK may provide additional programming settings prior to 
initiation of 48 hr Holter monitoring.  
3.2.6 48 hr Holter Monitoring Initiation Visit   
Subjects should undergo 48 hr Holter monitoring within 7 days of the completion of 
the pre-Holter observation period. The following study procedures are performed at 
the 48 hr Holter Monitoring Initiation visit: 
1. 
Ensure Holter monitor and BIOMONITOR date and time are accurate and 
synchronized. 
a. Ensure correct time and date on the programmer, which will set the time 
on the BIOMONITOR upon interrogation. 
b. Adjust Holter time and date to match the BIOMONITOR.  

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2. 
Interrogate the BIOMONITOR and clear previous stored episodes and reset 
device counters.  
a. Navigate to the ‘Recordings’ page of the BIOMONITOR from the main 
follow up screen.  
b. From the ‘Recordings’ page, select ‘Restart’  
c. Navigate to the ‘Diagnostics’ page of the BIOMONITOR from the main 
follow up screen.  
d. From the ‘Diagnostics’ page, select ‘Start statistics’  
3. 
Reprogram the BIOMONITOR to updated programming settings based on the 
data collected from the pre-Holter observation period, if applicable. Updated 
programming will be provided by BIOTRONIK prior to the 48 hr Holter initiation 
visit. 
4. 
Provide the subject with the Holter Monitor and program the Holter Monitor for 
48 hours of monitoring.  
a. Educate the subject on proper Holter use for the next 48 hours.  
b. Schedule the subject to return following 48 hours of Holter monitoring. 
5.   Review for any new reportable adverse events and updates to previously 
reported adverse events. 
6.   Review and complete the appropriate eCRFs, including upload of BIOMONITOR 
interrogation, including current programming,  and documentation of 48 hr 
Holter Monitoring Initiation visit to EDC. 
3.2.7 48 hr Holter Monitoring Completion Visit   
Subjects should undergo the Holter Monitoring Completion visit 48 hours after the 
Holter Monitoring Initiation visit. The following study procedures are performed at 
the Holter Monitoring Completion visit: 
1. 
Verify Holter monitor and BIOMONITOR date and time are accurate and 
synchronized. 
a. Record standard time, Holter monitor time, and BIOMONITOR time to 
document any differences in the dates/times.  
2. 
At the end of the 48 hours, collect Holter device and obtain the Holter data.  
3. 
Interrogate the BIOMONITOR and download all recorded episodes and the 
episode list.   
a. Navigate to the ‘Recordings’ page of the BIOMONITOR from the main 
follow up screen.  
b. From the ‘Recordings’ page, view all recordings.  
c. Ensure data, including the recording list, is saved on a USB for upload to 
EDC.  

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4. 
Program BIOMONITOR parameters to best suit the needs of the subject, per 
physician discretion. 
5. 
Review for any new reportable adverse events and updates to previously 
reported adverse events. 
6. 
Send Holter data to the Holter Core Laboratory with required Holter Core 
Laboratory documentation. 
7. 
Review and complete the appropriate eCRFs, including upload of BIOMONITOR 
data and documentation of 48 hr Holter Monitoring Completion visit in EDC. 
If the Holter Core Laboratory determines a significant amount of the Holter 
recording is uninterpretable, the site will be notified and the subject may be asked 
to complete a second 48 hr Holter monitoring session if they are willing and able, 
and ablation has not been completed or is not scheduled to be complete prior to 
completion of the repeat Holter. If a repeat Holter is completed, the 3 month 
follow-up after Holter completion will be based off of the date of completion of the 
first 48 hr Holter monitoring session.  
3.2.8 System Revisions 
Subjects who have a revision of the BIOMONITOR after successful insertion of the 
device will be exited. The reason and date of exit will be obtained and a Study Exit 
eCRF will be completed.   
3.3 Study Exits 
Regular study exit will occur 3 months (-0/+30 days) after 48 hr Holter monitor 
completion. Occurrence of ablation procedure will be documented in the Study Exit 
eCRF. 
Once a subject is enrolled and successfully undergoes insertion, every effort should 
be made to continue to follow the subject in the study. However, it is inevitable that 
some subjects will decline to participate further, change geographic location, or 
become non-compliant with the visit schedule. Appropriate source documentation 
must be uploaded to the Study Exit eCRF. For all subjects that have a Holter 
recording initiated and are fully enrolled, data collected through the date of exit 
may be used for analysis. If the BIOMONITOR is explanted, the subject will be 
withdrawn.  
The following study procedures are performed at Study Exit: 
1. 
Review the subject’s medical records to ensure that all protocol defined 
adverse events have been documented in the EDC system. This includes any 
new reportable adverse events and updates to previously reported adverse 
events.  
a. All previously unreported, protocol defined adverse events should be 
documented on Adverse Event eCRFs. 
2. 
Determine the reason for study exit.  

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3. 
Review and complete the appropriate eCRFs.  
4. 
Appropriate source documentation must be uploaded to the Study Exit eCRF.  
For fully enrolled subjects, the following study procedures are also performed at 
Study Exit: 
1. 
Collect date of ablation procedure, if performed, and information on 
BIOMONITOR utility to make treatment decisions regarding whether or not to 
perform an ablation. 
3.3.1 Screen Failures 
Screen failures, as defined in Section 2.2, will be exited in the EDC system. 
Subjects with unsuccessful insertion procedures are considered screen failures. The 
reason and date of withdrawal will be obtained and a Study Exit eCRF will be 
completed. 
3.3.2 Withdrawal of Consent  
If consent is withdrawn, the reason and date of withdrawal will be obtained and a 
Study Exit eCRF will be completed. 
3.3.3 Subject Death  
In the event of subject death during study participation, personnel at the study site 
are asked to notify BIOTRONIK as soon as possible by completing a Study Exit 
eCRF. If subject death was associated with an adverse event, an Adverse Event 
eCRF will also be required.  
The following information should be provided for any subject death: 
· 
Subject records such as a death certificate, death report source documentation 
worksheet signed by the investigator, or other relevant medical records that 
include the following details: 
· 
Date of death 
· 
Place death occurred 
· 
Immediate cause of death 
Whenever possible, devices that are removed should be returned to BIOTRONIK for 
analysis. 
3.3.4 BIOMONITOR Removal 
Any subject who has the BIOMONITOR removed during the follow-up period will be 
withdrawn from the study. Study Exit eCRF should only be completed after 
documentation of the device removal or replacement procedure is available (see 
Section 3.2.8).  

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Whenever possible, devices that are removed should be returned to BIOTRONIK for 
analysis. 
3.3.5  Lost to Follow-up 
Subjects lost to follow-up are those for whom contact is lost despite the 
investigator’s best efforts to locate the subject. Study sites should attempt to 
contact these subjects in order to maintain study visit compliance and all contact 
attempts should be documented. At a minimum, the site should make and 
document two attempts to contact the subject by phone and one attempt by 
certified mail. 
In the event the subject cannot be contacted using the above methods, the subject 
should be exited from the study by completing a Study Exit eCRF. BIOTRONIK 
Home Monitoring® device data may be utilized to support analysis of additional data 
of interest in the event that the subject is lost to follow-up. 
3.3.6 Investigator Initiated Withdrawal 
In addition to subject initiated withdrawal of consent, a study site investigator may 
determine that a subject should be withdrawn for other reasons such as following 
with a different physician, changes to insurance, non-compliance, etc. Details 
related to investigator initiated withdrawal such as reason for withdrawal and 
attempts made to retain subject should be collected. The investigator determined 
end date of subject participation should be reported as the date of exit. 
3.3.7 Pre-Holter Observation Period Withdrawal 
Subjects will be withdrawn from the study if there are no recorded or transmitted 
AF episodes during the pre-Holter observation period. Additionally, if R-wave 
sensing is <0.25 mV as reported by the 24 hr mean or mean value since last 
follow-up on the CardioReport obtained at the end of the observation period. The 
reason and date of withdrawal will be obtained and a Study Exit eCRF will be 
completed. 
3.3.8 Study Participation Complete 
All subjects who undergo successful insertion procedures are expected to be 
followed for three months post 48 hr Holter monitoring. After a subject completes 
three months of Home Monitoring post 48 hr Holter, their study participation is 
complete and the subject will be exited from the study by completing a Study Exit 
eCRF. 
4. DATA COLLECTION 
4.1 IRB Approval  
Institutional Review Board (IRB) approval is required from each institution prior to 
participation in this clinical study. Subject enrollment may not begin until both the 

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IRB and BIOTRONIK have granted approval for the study site. IRB approval is also 
required throughout the duration of this clinical study. If IRB approval is withdrawn, 
BIOTRONIK must be notified within 5 working days.  
4.2 Other Institutions and Physicians 
This clinical study is not transferable to other institutions attended by the study site 
investigators unless prior approval is obtained from both BIOTRONIK and the 
appropriate IRB. Only approved investigators are authorized to participate in the 
study. If a site enrolls subjects after insertion, the inserting physician does not need 
to be an approved investigator. 
There are certain situations where a study site investigator might not be 
immediately available to provide the necessary medical care for a subject enrolled 
in the clinical study (such as a subject emergency room visit for medical 
treatment). In these instances a protocol non-compliance will not be issued and all 
available data will be utilized. In any such situations, the IRB and the investigator 
must continue to provide oversight for that patient’s medical care and rights as a 
research subject.  
4.3 
Informed Consent  
All subjects must sign and date an IRB approved Informed Consent Form (ICF) 
prior to collecting any study specific data. Informed consent should be obtained in 
accordance with the FDA regulations (21 CFR Part 50) and any other national or 
local requirements. The study site is required to inform BIOTRONIK and the 
reviewing IRB within 5 days if any subject was not appropriately consented to 
participate in the study.  
4.4 
 Data Collection 
4.4.1 Electronic Data Capture (EDC) 
MedNet Solutions Incorporated is a privately held company that specializes in web-
based clinical data management technology. MedNet will host the EDC system and 
provide a secure environment that is accessible to authorized individuals through 
the internet. BIOTRONIK will implement a study specific configuration using this 
software to meet the data collection requirements of the protocol. The EDC system 
is 21 CFR Part 11 compliant and is the platform for electronic case report form 
(eCRF) data entry; clinical data discrepancy resolution; and provides access to 
reports for BIOTRONIK, specified study sites, and any other parties authorized by 
BIOTRONIK. 
4.4.2 Electronic Case Report Forms (eCRFs) 
Original data will be collected from each study site and recorded into the EDC 
system via completion of eCRFs, which are audited and monitored by BIOTRONIK. 

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The study site investigators will be required to use an electronic signature to 
approve the content of the data reported in the eCRFs. 
4.4.3 BIOTRONIK Home Monitoring® Data 
Home Monitoring Service Center data from enrolled study subjects will be 
accessible to the sponsor from insertion through the date of subject withdrawal of 
consent, subject death, or completion of the study. For subjects that are exited for 
other reasons (including physician withdrawal, subject moving, and lost to follow-
up) BIOTRONIK Home Monitoring® data may be collected for the proposed study 
duration (i.e., up to 3 months post-ablation). BIOTRONIK Home Monitoring® data 
might be used for evaluation and publication if desired by the sponsor. 
All data are transferred to the sponsor in a pseudonymized form. Data includes all 
information transmitted from the device (e.g. sECGs, statistics). 
4.5 
Data Quality Control 
BIOTRONIK will review study data reported in the EDC system. At any time, reports 
may be generated on data completion and missing data for each study site. The 
EDC system will be used to track received and expected follow-up data and eCRFs 
for each participant. This system provides the capability to monitor the status, 
volume, and disposition of data. In addition, study data will undergo automatic edit 
and plausibility checks, which provides information to the study sites to help 
improve and maintain data quality control procedures designed to detect 
inaccuracies and inconsistencies.  
To ensure protocol compliance at all participating investigational sites, BIOTRONIK 
monitors will conduct centralized monitoring and/or monitoring visits throughout 
the course of the study (see section 9 for more information).  
To ensure compliance with federal regulations, internal policies and procedures, and 
the study protocol, Holter Core Laboratories and EDC vendor will also be monitored 
and/or audited by BIOTRONIK or a BIOTRONIK representative during the course of 
the study. 
4.6 
Subject Data Confidentiality 
All information and data collected for BIO-Precision concerning subjects or their 
participation in this investigation will be considered confidential by BIOTRONIK, 
BIOTRONIK’s parent company, subsidiaries, and affiliates, as well as contracted 
designees, Holter Core Laboratory, EDC vendors, and any other authorized third 
parties.  
Applicable national and local laws pertaining to subject data protection will be 
applied to the study. As such, all data used in the analysis and reporting of this 
investigation will not include an identifiable reference to specific subject name, or 

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other protected confidential subject, nor will it contain other confidential subject 
identifiers. 
In order to verify the study data and ensure study integrity, monitors and 
representatives from BIOTRONIK, the U.S. FDA, other national regulatory and/or 
public health authorities and the reviewing Investigational Review Board may 
review and/or copy the study records. Source documents used to support Holter 
Core Laboratory activities will have confidential subject identifiers and other 
protected health information redacted prior to transmission.  
4.7 
Protocol Non-compliance 
Study site investigators are required to conduct this study in accordance with the 
signed investigator agreement and clinical protocol. The investigator shall notify 
BIOTRONIK and the reviewing IRB in writing no later than 5 working days after any 
significant deviation from the clinical protocol to protect the life or physical well-
being of a subject in an emergency. Except in such emergency, prior approval by 
BIOTRONIK is required for significant deviations from the clinical protocol.  
The site is responsible for reporting non-compliance via Protocol Non-compliance 
eCRFs. BIOTRONIK categorizes protocol non-compliance instances as either 
violations or deviations.  
4.7.1 Protocol Violations 
Protocol violations are defined as instances 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 plan and/or the rights, safety, or welfare of subjects. 
Protocol violations include, but are not limited to: 
· 
Failure to obtain consent or other instances in which the subject did not 
provide consent 
· 
Subject enrolled, but did not meet all inclusion/exclusion criteria 
4.7.2  Protocol Deviations 
Protocol deviations are defined as instances where protocol requirements and/or 
regulatory guidelines were not followed, and are generally less serious in nature 
than violations. Protocol deviations generally do not affect the subject's rights, 
safety, or well-being and/or the completeness, accuracy, and reliability of data 
supporting the primary objective. Instances of non-compliance should be 
considered a deviation if it does not meet the criteria for being considered a 
violation. 
 

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Protocol deviations include, but are not limited to: 
· 
Informed Consent documentation issues such as incomplete ICF, missing 
dates for signature(s), missing initials or illegible information, subject 
signature date completed by someone other than subject, utilization of an 
outdated or non-IRB approved ICF, or incomplete associated forms required 
at time of consent, etc. (this is not an exclusive list) 
· 
Visit not performed within the visit window 
· 
Device information or other required data not obtained at follow-up visit 
4.7.3 IRB Reporting of Non-Compliance 
The study site must notify the reviewing IRB of all non-compliance issues per the 
IRB and protocol reporting requirements. At a minimum, all violations and non-
compliance issues related to informed consent and informed consent documentation 
should be reported to the IRB.  
In some instances, such as failure to obtain consent, the study site should also seek 
guidance from the IRB to ensure the subject received appropriate information to 
consider her or his participation in the study. 
The site should provide a copy of the IRB protocol non-compliance notification (as 
applicable) to BIOTRONIK.  
5. RISKS AND RISK MINIMALIZATION 
All devices, device programmers, and Home Monitoring® systems included in the 
BIO-Precision Study are legally marketed and being prescribed by physicians 
according to FDA approved indications for use. Additionally, all visits, outside of the 
48 hr Holter monitoring visit, in this post-market observational study are standard 
of care. There are no new known risks associated with participation in this study. 
Please refer to the product manuals for risks associated with the BIOMONITOR.  
According to the American Heart Association, wearing a Holter monitor poses no 
risks other than the possibility of mild skin irritation due to the tape or adhesives 
associated with the electrodes.  
The only research related risk is the potential loss of confidentiality that is 
minimized as outlined in Section 4.6.  

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6. STUDY ORGANIZATION 
6.1 Sponsor 
BIOTRONIK is the "sponsor" of the clinical investigation.  A "sponsor" is defined as 
an entity that initiates but does not conduct an investigation.  BIOTRONIK’S 
responsibility as the clinical study sponsor is to ensure protocol and regulatory 
compliance through proper monitoring of the investigation.     
6.2 Holter Core Laboratory  
The Holter Core Laboratory will be responsible for manually annotating arrhythmia 
episode onset and termination from the Holter monitor, classification of these 
episodes, and reporting in the EDC system. The Core Lab will create a study specific 
charter defining the Holter monitor data review and annotation process, specifically 
detailing review guidelines along with appropriate response timelines. 
7. MONITORING 
7.1 Summary 
The responsibility of BIOTRONIK as sponsor is to ensure protocol and regulatory 
compliance through proper monitoring of the clinical study at sites. As a study site 
investigator, the physician is responsible for conducting the clinical study 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 study site principal investigator must also accept 
responsibility for all aspects of the clinical study including the actions of any sub-
investigators participating in the clinical study at the investigational site. 
BIOTRONIK utilizes a risk-based monitoring strategy consistent with FDA’s 
Guidance for Industry:  Oversight of Clinical Investigations – A Risk-Based 
Approach to Monitoring, August 201311. Risk-based monitoring starts with 
performing a study risk assessment of the identified critical data and processes. The 
resulting monitoring plan focuses on targeted source data verification and trend 
analyses to improve oversight and data quality, while integrating predefined 
triggers for additional on-site monitoring. The detailed study risk-based monitoring 
plan developed by BIOTRONIK focuses on a combination of centralized and on-site 
monitoring. Monitors may periodically conduct on-site or remote monitoring visits 
periodically during the clinical study in accordance with the monitoring plan. On-site 
monitoring visits are an in-person evaluation carried out at the study site. Remote 
monitoring visits are a remote evaluation of a study site for those sites providing 
remote sponsor access to the electronic medical record system. Sites are required 
to support these monitoring visits and the study monitoring effort, including either 
direct monitor or site-assisted access to the applicable medical record systems. The 
study site principal investigator is encouraged to be available during monitoring 

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visits. Monitoring visits will also provide an assessment of the continued 
acceptability of the facilities to continue participation in the study.  
Centralized monitoring is conducted via electronic case report forms (eCRFs) 
through the source data verification of source documents uploaded to the eCRF. 
Some examples of data that may be monitored remotely include: unredacted 
informed consent forms, eligibility, baseline data, insertion, study exit, device data, 
and adverse events reported in the EDC system. Sites are required to support 
centralized monitoring by providing signed, dated, final source documents to 
BIOTRONIK in order to source data verify data reported in the EDC system and 
resolving queries in a timely manner.  
The E6(R2) Good Clinical Practice: Integrated Addendum to International Council 
for Harmonisation (ICH) E6 (R1) Guidance for Industry dated March 2018 outlines 
the ALCOA-C guidelines for source documentation. All source documentation and 
study records should meet these ALCOA-C guidelines of attributable, legible, 
contemporaneous, original, accurate and complete. This guidance ensures the 
confidentiality, credibility, accuracy and validation of research records. All pages of 
source documents should be labelled with the subject ID. It is critical that the fully 
executed and unredacted informed consent form and all necessary source 
documentation are uploaded to the EDC in a timely manner. 
The entries in the eCRF will be reviewed and source data verified by monitors 
(authorized BIOTRONIK personnel, or by authorized BIOTRONIK designees) to 
ensure that the study site investigators and the study team conducts the study in 
accordance with the 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 may require the 
presence of personnel from BIOTRONIK at the insertion and/or follow-up visits 
outlined in this protocol in order to assist the study site investigators and other site 
personnel. 
Through monitoring, BIOTRONIK will assess the site’s performance in the following 
areas: 
· Verification that informed consent was obtained and documented properly 
· Adherence to protocol eligibility criteria and requirements 
· Conduct and documentation of procedures and assessments related to: 
o Study objectives 
o Protocol required data collection and procedures 
o Evaluating, documenting, and reporting adverse events, and 
withdrawals, especially when a withdrawal may be related to an 
adverse event  
o Investigator oversight and delegation of authority to site personnel 
o Verification of study-specific required documentation 

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o Conduct and documentation of procedures essential to trial 
integrity 
o Adherence to applicable requirements regarding the obligations of 
the investigator and maintenance of records. 
If a monitor becomes aware that an investigator is not complying 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 
monitor is obliged to notify BIOTRONIK study management. BIOTRONIK will 
evaluate the noncompliance and issue corrective actions, as necessary, which may 
include but are not limited to, re-training, discontinuing enrollment at the study 
site, or closing the study site. 
7.2 Monitors 
Monitors are trained, qualified, and designated by BIOTRONIK management to 
oversee the progress of an investigation at the clinical site. Additional monitors may 
be appointed as necessary.  
8. STUDY COMPLETION 
BIOTRONIK will notify the study site upon completion or termination of the clinical 
study or of the study site investigator’s participation in the study. Whenever 
possible, BIOTRONIK will provide a final report and a copy of the site’s eCRFs to 
each study site. BIOTRONIK will determine if sites will have a close out visit and 
provide details on closure activities to all study site investigators to ensure the 
investigators understand any applicable regulatory requirements, including those 
related to record retention. All participating study site investigators are requested 
to promptly notify BIOTRONIK if their financial disclosure information has any 
relevant changes during the course of the investigation and for 1 year following 
completion of the study. 
9. ADVERSE EVENTS 
An AE is defined as any unfavorable and unintended event that occurs during the 
course of the study. The investigator will be required to assess and classify the type 
of each reported adverse event as insertion procedure-related, device-related, non-
procedure non-system related, or study procedure related. For all consented 
subjects, only adverse events occurring on or after the date of insertion through the 
duration of the study will be collected. The study site should report each adverse 
event via an Adverse Event eCRF and provide a copy of the IRB adverse event 
notification to BIOTRONIK.  

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9.1 Reportable Adverse Events 
All insertion procedure-related, device-related, non-procedure non-system related, 
and study procedure related AEs will be reported. The following AEs categories, 
sorted by type, will be reported. The types listed below are general classifications 
for site reporting purposes.  
9.1.1 Insertion Procedure-Related Adverse Events 
The AE type will be classified as procedure-related if any one of the following occurs 
as a result of the insertion procedure: 
· 
Device damage 
· 
Excessive bleeding 
· 
Fluid accumulation within the device pocket 
· 
Hematoma 
· 
Inability to insert BIOMONITOR 
· 
Non-healing pocket dehiscence requiring intervention  
· 
Pocket pain 
· 
Primary infection 
· 
Superficial infection 
· 
Surrounding tissue damage 
9.1.2 Device-Related Adverse Events 
The AE type will be classified as device-related if any one of the following occurs: 
· 
Device failure 
· 
Device migration 
· 
Device protrusion 
· 
Device rejection phenomena  
· 
Skin erosion 
9.1.3 Non-Procedure Non-System Related Adverse Events 
The AE type will be classified as non-procedure non-system related if any of the 
following occur and require device removal: 
· 
Secondary infection 
· 
Other non-elective intervention 

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9.1.4 Study Procedure Related 
The AE type will be classified as study procedure related if any of the following 
occur as a result of Holter monitoring: 
· 
Skin irritation at the site of electrode placement 
· 
Other events that the investigator classifies as related to Holter monitoring 
9.2 Adverse Event Reporting 
BIOTRONIK requires that the investigator reports protocol-defined AEs (as defined 
in section 9.1) that occur during the BIO-Precision Study to BIOTRONIK. The AEs 
that an IRB considers reportable are dependent on the particular IRB. Investigators 
should follow their IRB requirements regarding AE reporting. 
The study site will report the AE on the Adverse Event eCRF. Additionally, study 
sites may report AEs through MedWatch, FDA’s adverse event reporting tool for 
market-released devices. As defined in BIOTRONIK’s internal procedures, AEs may 
be reported by BIOTRONIK through manufacturer’s MedWatch reports. 
10. RECORDS AND REPORTS 
10.3 Investigator Records 
Study site investigators are required to maintain on file the following accurate, 
complete and current records relating to this investigation: 
· 
All correspondence relating to the study with another investigator, an IRB, 
BIOTRONIK, a monitor, or the FDA (e.g., a letter sent from the investigator 
to the IRB) 
· 
A copy of the clinical study protocol 
· 
Signed investigator or research agreement 
· 
Signed Financial Disclosure Form 
· 
A copy of the IRB approval for the research study 
· 
A copy of the IRB approved subject Informed Consent Form 
· 
All clinical forms and documentation, including: 
o A copy of all signed Informed Consent Forms 
o All supporting documentation for data entered into the EDC system 
o Records of any adverse events, including supporting documentation 
o Records pertaining to subject deaths during the study 

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o Documentation and rationale for any deviations from the clinical protocol 
o Documentation of training 
o Any other records required by BIOTRONIK 
Study site investigators must retain records related to the study for a minimum 
period of 2 years after the investigation is completed consistent with FDA 
regulations, IRB requirements, and institutional policies. During the required 2 year 
period, investigators are responsible for notifying BIOTRONIK of the following: 
transfer of study records, investigator site address changes, or changes in study 
site principal investigator status. 
10.4 Investigator Reporting Responsibilities 
Study site investigators are required to prepare and submit to BIOTRONIK the 
following complete, accurate, and timely reports on this investigation as identified 
in the table below which outlines the responsibilities, including time constraints, for 
submitted required reports. Additionally, investigators are required to provide any 
other information upon request from an IRB, FDA, or BIOTRONIK. 
Table 4: Investigator Reporting Responsibilities 
Type of Report 
Prepared by Investigator 
for: 
Time Constraints of 
Notification 
Subject death during study 
participation 
BIOTRONIK, IRB 
Documentation via EDC eCRF 
BIOTRONIK as soon as 
possible and as required by 
reviewing IRB 
Withdrawal of IRB approval 
BIOTRONIK 
Within 5 working days of 
receipt of notice of 
withdrawal of approval 
Significant deviations from 
protocol 
BIOTRONIK, IRB 
Within 5 working days after 
emergency to protect life or 
physical well-being of 
subject, otherwise prior 
approval by BIOTRONIK is 
required 
Informed consent not 
obtained 
BIOTRONIK, IRB 
Within 5 working days of 
occurrence 
Progress Report(s) 
BIOTRONIK, IRB 
Submitted no less than 
yearly  

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Final report 
BIOTRONIK, IRB 
Within 3 months after 
termination or completion of 
the study or investigator’s 
part of the study 
10.5 Sponsor Records 
BIOTRONIK will maintain the following records: 
· 
All correspondence with the investigator(s), IRB, and FDA that pertains to the 
study  
· 
Investigator agreements, financial disclosures, and current curriculum vitae 
· 
Name and address of each study site investigator and each IRB that is 
involved with the investigation 
· 
Adverse events  
· 
Adverse device effects  
· 
Electronic Case Report Form data 
· 
Confirmation of completed subject Informed Consent Forms 
· 
Clinical study protocol  
· 
Screening visit reports 
· 
Monitoring visit reports 
· 
Clinical progress reports 
10.6 Sponsor Reporting Requirements 
BIOTRONIK is responsible for preparing the following reports, when necessary: 
Table 5: Sponsor Reporting Requirements 
Type of Report 
Prepared by 
BIOTRONIK for: 
 
Time Constraints 
of Notification 
Withdrawal of IRB 
approval 
All reviewing IRBs and 
participating investigators 
Within 5 working days after receipt 
of notice of withdrawal of approval 
Progress report 
All reviewing IRBs 
Submitted at least annually 
Recall and device 
disposition 
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 

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Final report 
All reviewing IRBs and 
participating investigators 
A final report will be submitted 
within 6 months after completion 
or termination of the study. 
 
  

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11. REFERENCES 
1. 
Purerfellner, H. et al. Miniaturized Reveal LINQ insertable cardiac monitoring 
system: First-in-human experience. Hear. Rhythm 12, 1113–1119 (2015). 
2. 
Mittal, S. et al. Safety Profile of a Miniaturized Insertable Cardiac Monitor: 
Results from Two Prospective Trials. Pacing Clin. Electrophysiol. 38, 1464–
1469 (2015). 
3. 
Pachulski, R., Cockrell, J., Solomon, H., Yang, F. & Rogers, J. Implant 
evaluation of an insertable cardiac monitor outside the electrophysiology lab 
setting. PLoS One 8, e71544–e71544 (2013). 
4. 
Morillo, C. A., Banerjee, A., Perel, P., Wood, D. & Jouven, X. Atrial fibrillation: 
the current epidemic. J. Geriatr. Cardiol. 14, 195–203 (2017). 
5. 
Chugh, S. S. et al. Worldwide epidemiology of atrial fibrillation: a Global 
Burden of Disease 2010 Study. Circulation 129, 837–847 (2014). 
6. 
Stewart, S., Hart, C. L., Hole, D. J. & McMurray, J. J. V. A population-based 
study of the long-term risks associated with atrial fibrillation: 20-year follow-
up of the Renfrew/Paisley study. Am. J. Med. 113, 359–364 (2002). 
7. 
Ogawa, H. et al. Progression From Paroxysmal to Sustained Atrial Fibrillation 
Is Associated With Increased Adverse Events. Stroke 49, 2301–2308 (2018). 
8. 
Botto, G. L. et al. Presence and duration of atrial fibrillation detected by 
continuous monitoring: crucial implications for the risk of thromboembolic 
events. J. Cardiovasc. Electrophysiol. 20, 241–248 (2009). 
9. 
Calkins, H. et al. 2012 HRS/EHRA/ECAS expert consensus statement on 
catheter and surgical ablation of atrial fibrillation: recommendations for 
patient selection, procedural techniques, patient management and follow-up, 
definitions, endpoints, and research trial design. J. Interv. Card. 
Electrophysiol. 33, 171–257 (2012). 
10. 
Ciconte, G. et al. Atrial fibrillation detection using a novel three-vector cardiac 
implantable monitor: the atrial fibrillation detect study. Eur.  Eur. pacing, 
arrhythmias, Card. Electrophysiol.  J.  Work. groups Card. pacing, 
arrhythmias, Card. Cell. Electrophysiol. Eur. Soc. Cardiol. 19, 1101–1108 
(2017). 
11. 
Oversight of Clinical Investigations – A Risk-Based Approach to Monitoring, 
Guidance for Industry. (2013). 
 

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12. APPENDIX A: DEFINITION OF TERMS 
CFR  – Code of Federal Regulations 
Device Damage – Visible damage to the antenna or device body or mechanical 
malfunction that leads to the inability of the device to correctly sense the heart 
signals. 
Device Failure – Inability of the device to correctly sense the heart signals, not 
attributable to a mechanical malfunction that remains unresolved despite 
reprogramming and/or repositioning. 
Device Migration – Visual, radiographic, electrical or electrocardiographic 
evidence of device displacement from the original implant site or electrode 
displacement that adversely affects device performance or subject health. 
Device Protrusion – Device or antenna perforation through the skin that is not a 
result of skin erosion.  
Device Rejection Phenomena – Reaction to device materials; includes local 
tissue reaction and metal sensitivity. 
Excessive Bleeding – Bleeding during the insertion procedure that cannot be 
stopped by applying pressure alone. 
Fluid Accumulation within the Device Pocket - Fluid swelling within the 
insertion site that is not related to infection or considered to be a hematoma, which 
requires surgical intervention to resolve. 
Hematoma – An accumulation or persistent swelling of blood that requires 
evacuation, drainage, post-insertion hospitalization, or blood transfusion. 
Holter Monitor – A battery-operated portable device that measures and records 
your heart’s activity (ECG) continuously for 24 to 48 hours 
Inability to insert BIOMONITOR – BIOMONITOR insertion was attempted but not 
successfully placed.  
Long-standing Persistent AF – Long-standing persistent AF is defined as 
continuous AF of greater than 12 months’ duration. 
Non-healing Pocket Dehiscence – Separation of wound edges around the 
insertion site of the device that has not healed; excludes hematoma, seroma, 
infection, and erosion. 
Paroxysmal AF – Paroxysmal AF is defined as AF that terminates spontaneously or 
with intervention within 7 days of onset. 

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Permanent AF – Permanent AF is defined as the presence of AF that is accepted 
by the patient and physician, and for which no further attempts to restore or 
maintain sinus rhythm will be undertaken. The term permanent AF represents a 
therapeutic attitude on the part of the patient and physician rather than an inherent 
pathophysiological attribute of AF.  
Pocket Pain – Pain greater than 1 week post-insertion requiring intervention with 
a narcotic (if narcotics are not already prescribed) or requiring pocket revision. 
Primary Infection – Infection requiring intervention such as IV antibiotics, device 
removal, or hospitalization. Excludes superficial infection that is resolved with 
outpatient antibiotics. 
Secondary Infection – Infection that is determined not to be a result of the 
insertion procedure, but may be due to previous course of therapy or pre-existing 
infection. 
Skin Erosion – Deterioration of tissue over the implant site or the movement of 
the device or antenna through the skin. 
Superficial Infection – Infection that only involves the skin and surrounding 
subcutaneous tissue around the incision site of the insertion procedure that is 
treated on an outpatient basis or a stitch abscess that requires outpatient 
antibiotics.  
Surrounding Tissue Damage – Significant physical damage to the pocket or 
surrounding subcutaneous tissues as a result of insertion procedure.