Plexa ICD Lead Registry
Conditions: Implantable Defibrillator User
Sponsor: Biotronik, Inc.

Plexa Registry
NCT03103503
Study Protocol and 
Statistical Analysis Plan
March 1, 2017 
This document contains confidential information for use only by investigators and sites 
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.
6024 Jean Road
Lake Oswego, OR 97035

 
 
 
Clinical Protocol 
for the 
Plexa Registry 
 
 
March 1, 2017 
 
 
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 .................................................................................................................................... 5 
1.1 Name of Device .............................................................................................................................. 5 
1.2 Registry Overview .......................................................................................................................... 5 
1.3 Background .................................................................................................................................... 5 
1.3.1 GALAXY Lead Registry: Clinical Experience with Linox ICD Lead .................................... 6 
1.3.2 Protego Lead Registry: Clinical Experience with Protego ICD Lead .................................. 8 
1.4 Device Description........................................................................................................................ 10 
1.4.1 Plexa Lead Description ..................................................................................................... 10 
1.4.2 BIOTRONIK Home Monitoring® ........................................................................................ 10 
2. REGISTRY DESIGN ............................................................................................................................ 14 
2.1 Registry Endpoints ....................................................................................................................... 16 
2.1.1 Primary Endpoint 1............................................................................................................ 16 
2.1.2 Secondary Endpoints ........................................................................................................ 16 
2.1.3 Additional Data of Interest ................................................................................................. 17 
2.2 Registry Size and Duration ........................................................................................................... 17 
2.3 Sample-Size Analysis ................................................................................................................... 17 
2.3.1 Attrition .............................................................................................................................. 18 
2.3.2 Replacement of Subjects .................................................................................................. 18 
2.4 Data Analyses .............................................................................................................................. 18 
2.4.1 Endpoint Analysis .............................................................................................................. 18 
2.4.2 Trend Analyses ................................................................................................................. 19 
2.4.3 Missing Data ..................................................................................................................... 19 
2.4.4 Poolability Analysis ........................................................................................................... 19 
3. PROTOCOL REQUIREMENTS ........................................................................................................... 20 
3.1 Subject Population........................................................................................................................ 20 
3.1.1 Indications ......................................................................................................................... 20 
3.1.2 Contraindications .............................................................................................................. 20 
3.1.3 Inclusion Criteria ............................................................................................................... 20 
3.1.4 Exclusion Criteria .............................................................................................................. 20 
3.2 Registry Procedures ..................................................................................................................... 21 
3.2.1 Registry Pre-Screening ..................................................................................................... 22 
3.2.2 Plexa Lead Implant ........................................................................................................... 22 
3.2.3 Enrollment Visit ................................................................................................................. 22 
3.2.4 Routine Follow-ups ........................................................................................................... 23 
3.2.5 Interim Follow-ups ............................................................................................................. 24 
3.2.6 System Revisions .............................................................................................................. 24 
4. DATA COLLECTION ........................................................................................................................... 25 
4.1 Electronic Data Capture (EDC) .................................................................................................... 25 
4.2 Electronic Case Report Forms (eCRFs)....................................................................................... 25 
4.3 Data Quality Control ..................................................................................................................... 25 
4.4 Subject Retention ......................................................................................................................... 26 
4.5 Subject Data Confidentiality ......................................................................................................... 26 
5. RISKS AND RISK MINIMALIZATION ................................................................................................. 27 
6. REGISTRY ORGANIZATION .............................................................................................................. 28 
6.1 Sponsor ........................................................................................................................................ 28 
6.2 Clinical Events Committee ........................................................................................................... 28 
7. REGISTRY MONITORING ................................................................................................................... 29 
7.1 Summary ...................................................................................................................................... 29 
7.2 Registry Monitors .......................................................................................................................... 29 
7.3 On-Site Monitoring Visits .............................................................................................................. 30 
7.4 Centralized Monitoring ................................................................................................................. 30 

 
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8. REGISTRY COMPLETION .................................................................................................................. 31 
9. ADVERSE EVENTS ............................................................................................................................. 32 
9.1 Reportable Adverse Events .......................................................................................................... 32 
9.1.1 Implant Procedure-Related Adverse Events ..................................................................... 32 
9.1.2 Pulse Generator-Related Adverse Events ........................................................................ 32 
9.1.3 Lead-Related Adverse Events .......................................................................................... 33 
9.1.4 Non-Procedure Non-System Related Adverse Events ..................................................... 33 
9.2 Endpoint Analysis ......................................................................................................................... 33 
9.3 Adverse Events for the Analysis of the Primary and Secondary Endpoints................................. 34 
9.3.1 Adverse Events for the Analysis of Primary Endpoint 1 and Secondary Endpoint 1 ........ 34 
9.3.2 Adverse Events for the Analysis of Secondary Endpoint 4 .............................................. 35 
9.3.3 Serious Adverse Events .................................................................................................... 35 
9.4 Adverse Event Reporting ............................................................................................................. 36 
10. OTHER GENERAL INFORMATION .................................................................................................... 37 
10.1 Protocol Compliance .................................................................................................................... 37 
10.1.1 Protocol Violations ............................................................................................................ 37 
10.1.2 Protocol Deviations ........................................................................................................... 37 
10.2 Study Terminations....................................................................................................................... 37 
10.2.1 Withdrawal of Consent ...................................................................................................... 37 
10.2.2 Subject Death .................................................................................................................... 38 
10.2.3 Plexa Lead or Pulse Generator Extraction ....................................................................... 38 
10.2.4 Lost to Follow-up ............................................................................................................... 38 
10.2.5 Registry Participation Complete ........................................................................................ 39 
10.3 Informed Consent ......................................................................................................................... 39 
10.4 IRB Approval ................................................................................................................................ 39 
10.5 Other Institutions and Physicians ................................................................................................. 39 
11. RECORDS AND REPORTS ................................................................................................................ 40 
11.1 Investigator Records..................................................................................................................... 40 
11.2 Investigator Reports ..................................................................................................................... 40 
11.3 Sponsor Records .......................................................................................................................... 41 
11.4 Sponsor Reports ........................................................................................................................... 41 
APPENDIX A: DEFINITION OF TERMS .................................................................................................... 43 
 
TABLE OF FIGURES 
Figure 1: GALAXY Freedom from Primary Endpoint Adverse Events (%) ................................................... 7 
Figure 2: Protego Freedom from Primary Endpoint Adverse Events (%) ..................................................... 9 
Figure 3: BIOTRONIK Home Monitoring® Transmission Path .................................................................... 11 
Figure 4: BIOTRONIK Home Monitoring® Quick View Summary Report ................................................... 13 
Figure 5: Registry Design Flowchart ........................................................................................................... 15 
Figure 6: Visit Schedule .............................................................................................................................. 16 
 
TABLE OF TABLES 
Table 1: All Linox Family ICD Lead-Related Adverse Events ....................................................................... 6 
Table 2: GALAXY Primary Endpoint Case Summary ................................................................................... 7 
Table 3: Protego ICD Lead-Related Adverse Events ................................................................................... 8 
Table 4: Protego Primary Endpoint Case Summary ..................................................................................... 9 
Table 5: Registry Visit Assessment Schedule ............................................................................................ 21 
Table 6: Investigator Reporting Responsibilities ......................................................................................... 41 
Table 7: Sponsor Reporting Responsibilities .............................................................................................. 42 

 
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Plexa Registry 
 
PROTOCOL SIGNATURE PAGE 
 
The signature below constitutes the receipt and review of the Plexa Registry 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 US federal regulations, 
ICH and GCP guidelines. 
 
 
PRINCIPAL INVESTIGATOR: 
 
 
Signed: 
 
 
 
 
Name (please print) 
 
 
 
 
 
Signature 
 
Date 
 

 
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SUMMARY 
Title: 
Plexa Registry 
Design: 
Prospective, single-arm, non-randomized, multi-center registry  
Purpose: 
To confirm the long-term safety and reliability of BIOTRONIK’s Plexa lead, as 
used in conjunction with a US market released BIOTRONIK implantable 
cardioverter defibrillator (ICD) or cardiac resynchronization therapy defibrillator 
(CRT-D) pulse generator. The evaluation of safety will be based on the 
analysis of Plexa lead-related adverse events. The Plexa Registry will provide 
data to permit characterization of Plexa lead failures contributing to loss of 
bradycardia pacing or shock therapy. Additionally, acute and chronic Plexa 
lead parameters will be evaluated. 
Subject Population: 
Subjects who are indicated for an ICD or a CRT-D. Subjects must be 
successfully implanted with a compatible US market released BIOTRONIK ICD 
or CRT-D. Subjects can be enrolled no more than 30 days after successful 
implantation of the Plexa system. 
Enrollment: 
This registry is designed to follow 1271 subjects implanted with the Plexa 
system through 5 years post-implant. 
Clinical Sites: 
Up to 75 US sites. 
Primary Endpoint: 
Overall incidence of adverse events (AEs) related to the Plexa lead 
Secondary Endpoints: 
1. Incidence of each individual type of AE that contributes to Primary 
Endpoint 1 
2. Pacing threshold, sensing, and impedance measurements for the Plexa 
lead through 5 years post-implant 
3. Shock impedance for the Plexa lead through 5 years post-implant 
4. AE rates for AEs excluded from primary safety endpoint 1, through 5 years 
post-implant 
Clinical Events 
Committee Chair: 
Dr. Gábor Duray 
State Health Center 
Róbert Károly krt. 44 
1134 Budapest 
Hungary 
Sponsor: 
BIOTRONIK, Inc. 
Clinical Studies Department 
6024 SW Jean Road 
Lake Oswego, Oregon 97035 
 

 
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1. INTRODUCTION 
1.1 
NAME OF DEVICE 
This protocol details the registry for BIOTRONIK’s Plexa implantable cardioverter defibrillator 
(ICD) lead, further referred to as the Plexa lead throughout this document. Currently, the 
following models are FDA approved: 
• Plexa SD (active fixation, DF4 connector, dual coil), 
• Plexa S (active fixation, DF4 connector, single coil), 
• Plexa DF-1 SD (active fixation, DF-1 connector, dual coil), 
• Plexa DF-1 S (active fixation, DF-1 connector, single coil), and 
• Plexa DF-1 S DX (active fixation, DF-1 connector, single coil with atrial sensing 
channel).  
1.2 
REGISTRY OVERVIEW 
The purpose of this registry is to confirm the safety and reliability of the Plexa lead as used in 
conjunction with any compatible US market released BIOTRONIK ICD or cardiac 
resynchronization therapy defibrillator (CRT-D). Data will be collected from no more than 1271 
subjects from implant through 5 years of follow-up.  
Subjects eligible for the registry include those that have been successfully implanted with a 
Plexa lead and a compatible US market released BIOTRONIK ICD or CRT-D no more than 30 
days prior to enrollment*. Prior to enrollment procedures, subjects will be screened to ensure 
eligibility and will provide written informed consent. Safety will be evaluated based on the 
analysis of all Plexa lead-related adverse events. Acute and chronic lead parameters for 
sensing, pacing thresholds, pacing impedance, and shock impedance will be evaluated for the 
Plexa lead. 
All devices included in the registry are legally marketed and prescribed by physicians according 
to approved indications for use. 
1.3 
BACKGROUND 
The Plexa Registry is designed to document the clinical experience of the Plexa ICD leads 
(P98023/S075, approved January 5, 2017).  
The Plexa lead is a transvenous ICD lead designed for permanent right ventricular pacing, 
sensing, and delivery of defibrillation / cardioversion shock therapies to the heart. Plexa is the 
successor of the Linoxsmart and Protego ICD lead (Linoxsmart SD / TD P980023/S038, approved 
September 17, 2010; Linoxsmart S / T P980023/S043, approved February 28, 2011; Linoxsmart S 
DX P980023/S049, approved February 13, 2013; Protego S / SD / T / TD P980023/S057, 
approved July 3, 2014). The Linox lead family has been extensively studied in the GALAXY 
registry. The Protego DF4 lead is being studied in the ongoing Protego DF4 Post-Approval 
Registry. 
                                                     
* For the purpose of the Plexa registry, the date of implant will be considered day 0. 

 
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1.3.1 GALAXY Lead Registry: Clinical Experience with Linox ICD Lead 
BIOTRONIK sponsored the GALAXY study, an after-market registry to confirm the long-term 
safety and reliability of the FDA approved Linox family of ICD leads. The GALAXY Registry is 
registered on clinicaltrials.gov, NCT00836589. This multi-center, prospective, non-randomized 
registry has been ongoing since enrollment began in January 2009 and has been closed to 
enrollment since November 2011. The final subject visit occurred in December 2016 and the 
final clinical report is pending.  There were 1997 subjects enrolled in the registry, 201 of which 
were implanted with Linoxsmart ICD leads.   
The sensing and pacing behavior was evaluated as well as the rate of lead-related 
complications over the available follow-up period. As of November 3, 2015, the mean pacing 
threshold across all Linox family ICD lead models was 0.64 ± 0.35 V, the mean sensing 
amplitude was 12.79 ± 5.44 mV, and the mean lead impedance was 553.0 ± 134.9 ohms. There 
were 61 (3.05%) subjects who experienced a primary AE related to the Linox family ICD leads.  
Details on reported ICD lead-related adverse events are provided in Table 1. The total number 
of subjects with an adverse event may not equal the sum of the number of subjects listed in 
each category because an individual subject may have experienced more than one adverse 
event. 
Table 1: All Linox Family ICD Lead-Related Adverse Events 
Adverse Event 
Subjects with 
AE, n 
% Subjects with 
AEs 
AEs, 
n 
Primary Endpoint AEs 
Other ICD lead related:  Lead noise or oversensing 
21 
1.05% 
21 
Lead impedance out of range, low impedance, potential 
insulation break. 
16 
0.80% 
16 
Lead impedance out of range, high impedance, potential 
conductor fracture. 
15 
0.75% 
15 
Lead dislodgement (> 180 days post-implant procedure) 
6 
0.30% 
6 
Lead undersensing or loss of sensing 
2 
0.10% 
2 
Inability to defibrillate or pace 
1 
0.05% 
1 
Other ICD lead related:  Noise consistent with probable 
fracture 
1 
0.05% 
1 
Other ICD lead related:  Lead migrated 
1 
0.05% 
1 
Other ICD lead related:  Tension pneumothorax 
1 
0.05% 
1 
Total Primary Endpoint AEs 
61 
3.05% 
64 
Secondary Endpoint AEs Related to the ICD Lead 
Lead dislodgement (≤ 180 days post-implant procedure) 
24 
1.20% 
25 
High pacing threshold, intermittent capture, no lead 
capture 
13 
0.65% 
14 
Cardiac perforation with or without tamponade 
5 
0.25% 
6 
Total Secondary Endpoint AEs (Related to ICD Lead) 
42 
2.10% 
45 
Total Primary or Secondary AEs (Related to ICD 
Lead) 
100 
5.01% 
109 
Total number of subjects = 1997 
 

 
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Figure 1 shows the calculated Kaplan-Meier actuarial graph demonstrating the freedom from all 
primary endpoint adverse events adjudicated by the Clinical Events Committee. Table 2 
displays the associated case summary. A common, final follow-up date of November 3, 2015, is 
assumed for all active subjects.  
The standard error (SE) for the estimated survival (freedom from primary endpoint AEs) was 
calculated using the method of Peto et al1. The last adverse event occurred on day 1809, and 
the current estimated freedom from adverse events is 95.0% (SE 1.0%) for implant times 1809 
days or longer. These estimates may change as additional follow-up data are collected.  
Figure 1: GALAXY Freedom from Primary Endpoint Adverse Events (%) 
      75.0%
      80.0%
      85.0%
      90.0%
      95.0%
     100.0%
Implant Time, days
I
0
I
 180
I
 360
I
 540
I
 720
I
 900
I
1080
I
1260
I
1440
I
1620
I
1826
Legend
-----   Peto  95% Confidence Bound
—     Survival Probability Estimate
AE = Cumulative Events
N = Number at Risk
AE: 0
5
11
15
25
30
37
44
53
55
  61
N: 1997
1853
1704
1558
1424
1265
1147
1036
944
755
     377
 
Table 2: GALAXY Primary Endpoint Case Summary 
Total Subjects, n Subjects with Adverse Events, n Censored 
n 
% 
1997 
61 
1936 96.9% 
 
 

 
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1.3.2 Protego Lead Registry: Clinical Experience with Protego ICD Lead 
BIOTRONIK is currently conducting the Protego Post-Approval Registry to confirm the long-term 
safety and reliability of the FDA approved Protego DF4 ICD leads. The Protego Post-Approval 
Registry is registered on clinicaltrials.gov, NCT02243696. This multi-center, prospective, non-
randomized registry has been ongoing since enrollment began in September 2014 and has 
been closed to enrollment since October 2016. There have been 1695 subjects enrolled in the 
registry as of October 10, 2016. 
As of May 31, 2016, the sensing and pacing behavior was evaluated as well as the rate of lead-
related complications over the available follow-up period. The mean pacing threshold across all 
Protego family ICD lead models was 0.62 ± 0.34 V, the mean sensing amplitude was 15.68 ± 
6.00 mV, and the mean lead impedance was 574.8 ± 122.3 ohms. There was one (0.08%) 
subject who experienced a primary AE reported as related to the Protego ICD lead and 16 
(0.23%) subjects who experienced a secondary AE reported as possibly related to the Protego 
ICD lead (Table 3). No subjects experienced a secondary AE adjudicated as related to the 
Protego ICD lead. 
Table 3: Protego ICD Lead-Related Adverse Events 
Adverse Event 
Subjects with 
AE, n 
% Subjects 
with AEs 
Number of AEs 
Primary Endpoint AEs 
Lead dislodgement (> 30 days post-implant 
procedure) 
1 
0.08% 
1 
Total Primary Endpoint AEs 
1 
0.08% 
1 
Secondary Endpoint AEs Possibly Related to the ICD Lead 
Lead dislodgement (≤ 30 days post-implant 
procedure) 
7 
0.54% 
7 
High pacing threshold 
3 
0.23% 
1 
Bent connector pin noted during implant 
procedure 
1 
0.08% 
1 
Cardiac perforation 
1 
0.08% 
1 
Inability to extend helix during implant 
procedure 
1 
0.08% 
1 
Intermittent capture / no lead capture 
1 
0.08% 
1 
Lead impedance out of range, high impedance 
1 
0.08% 
1 
Lead undersensing or loss of sensing 
1 
0.08% 
1 
Total Secondary Endpoint AEs (Possibly 
Related to ICD Lead) 
16 
0.23% 
16 
Total Primary or Secondary Endpoint AEs 
(Possibly Related to ICD Lead) 
17 
1.30% 
17 
Total number of subjects = 1305 
 
Figure 2 shows the calculated Kaplan-Meier actuarial graph demonstrating the freedom from all 
primary endpoint adverse events adjudicated by the Clinical Events Committee. Table 4 
displays the associated case summary. A common, final follow-up date of May 31, 2016, is 
assumed for all active subjects.  

 
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The standard error (SE) for the estimated survival (freedom from primary endpoint AEs) was 
calculated using the method of Peto et al1. The last adverse event occurred on the day of 
implant, and the current estimated freedom from adverse events is 99.91% (SE 0.16%) for 
implant times 94 day or longer. These estimates may change as additional follow-up data are 
collected.  
 
Figure 2: Protego Freedom from Primary Endpoint Adverse Events (%) 
      70.0%
      75.0%
      80.0%
      85.0%
      90.0%
      95.0%
     100.0%
Implant Time, days
0
90
180
270
360
450
540
628
Legend
-----   teto  95% Confidence .ound
—     Survival trobability 9stimate
A9 = Cumulative 9vents
N = Number at Risk
A9: 0
0
1
1
1
1
1
1
N: 1305
1180
962
706
477
240
74
1
 
Table 4: Protego Primary Endpoint Case Summary 
Total Subjects, n 
Subjects with 
Adverse Event, n 
Censored 
n 
% 
1305 
1 
1304 
99.9% 

 
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1.4 
DEVICE DESCRIPTION 
1.4.1 Plexa Lead Description 
The Plexa leads are 7.8 F transvenous, steroid-eluting, endocardial lead for use with any ICD or 
CRT-D. The Plexa DF-1 S and Plexa S leads have two RV sensing and pacing electrodes 
(distal tip and ventricular ring electrode) and one defibrillation electrode (ventricular shock coil). 
The Plexa DF-1 S DX lead has two RV sensing and pacing electrodes, two RA sensing 
electrodes, and one defibrillation electrode (ventricular shock coil). The Plexa DF-1 SD and 
Plexa SD leads have two sensing and pacing electrodes (distal tip and ventricular ring 
electrode) and two defibrillation electrodes (ventricular and superior vena cava shock coils).  
These leads, in conjunction with an ICD or CRT-D device, perform the following functions: 
• 
Sense electrical signals from cardiac tissue and conduct those signals to the ICD 
• 
Conduct bradycardia and anti-tachycardia pacing pulses emitted from the ICD to cardiac 
tissue 
• 
Conduct cardioversion / defibrillation shocks of both high and low energies from the ICD to 
cardiac tissue 
The Plexa leads are intended for permanent placement in the right ventricle. The tip and ring 
electrodes form the most distal portion of the lead and provide dedicated bipolar sensing and 
pacing. 
All Plexa leads have one shock electrode that is positioned in the right ventricle. The Plexa DF-1 
SD and Plexa SD dual-coil ICD leads have an additional shock electrode for placement in the 
superior vena cava (SVC). All Plexa leads feature Silglide® surface treatment, designed to 
reduce the force required to maneuver the lead during the implant procedure.  
All Plexa leads feature an electrically active extendable / retractable fixation helix for use in lead 
placement. The helix is extended and retracted by rotating the contact pin with a fixation tool. 
Both the fixation helix and ring electrode are comprised of a platinum / iridium alloy base with 
fractal iridium. 
The distal tip of all Plexa leads consists of a steroid eluting collar which contains the active 
ingredient dexamethasone acetate (DXA). Upon exposure to body fluids, the steroid elutes from 
the collar. Release of the steroid is intended to decrease the inflammatory response at the 
contact site between the lead tip and the endocardium, thereby decreasing the elevated pacing 
thresholds of the endocardial lead that often occur after lead implantation. 
The Plexa lead has a modified internal lead tip design, with a symmetric contact spring, and 
minor changes to the cut of the tip of the fixation screw as compared to the Linoxsmart and 
Protego leads. Additionally, the distal region, between the proximal end of the RV shock coil and 
the distal end of the SVC shock coil has a twisted cable design, where the lumens of the cables 
(peripheral lumens) are twisted around the inner lumen of the coil (helically wound around the 
longitudinal axis). All five lumens are coated with a lubricant, compared to only four peripheral 
lumens in the Linoxsmart and Protego leads. The color coding on the label tubing has been 
updated according to AAMI TIR41:2014. The steroid collar on the Plexa lead has a nominal 
value of 0.93 mg DXA. 
1.4.2 BIOTRONIK Home Monitoring® 
Current expert consensus advocates 3- to 6-month device evaluations either in-person or by 
remote monitoring for ICD or CRT-D devices2.  

 
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BIOTRONIK Home Monitoring® is a communication system which allows the automatic 
transmission of diagnostic patient data from the device to the physician at any time. The 
technology implements the use of wireless communications to provide the physician with daily 
patient monitoring and trend analysis information between office follow-up visits. A block 
diagram of the transmission path is shown in Figure 3, and the transmission steps are described 
as follows: 
1. Communication starts with the implant, which activates a very low power RF transmitter 
circuitry integrated within the pulse generator.  
2. The patient’s device accepts patient data from the implant and transfers this digital 
information using a cellular short messaging system (SMS) or telephone landline 
connection to a BIOTRONIK Service Center for evaluation. 
3. The BIOTRONIK Service Center receives incoming data and generates a customized 
summary which is available to the physician online via secure Internet access, or can be 
forwarded to the physician via fax. 
Figure 3: BIOTRONIK Home Monitoring® Transmission Path 
 
 
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. 
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. 

 
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In current US market released BIOTRONIK ICD and CRT-D devices, BIOTRONIK Home 
Monitoring® provides event and system information similar to what is currently available during 
office follow-up visits. The highlighted information in the BIOTRONIK Home Monitoring® Quick 
View Summary Report, Figure 4, displays the study related follow-up data automatically 
transmitted on a daily basis including: battery status, pacing impedance, pacing threshold, and 
sensing amplitude (mean / min) for both the atrial and ventricular leads. In addition, BIOTRONIK 
Home Monitoring® provides automatic daily information on arrhythmias, lead trends, current 
device programming, event episodes, therapy provided, and long term data trends. 

 
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Figure 4: BIOTRONIK Home Monitoring® Quick View Summary Report 
 
 

 
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2. REGISTRY DESIGN 
This multi-center, prospective, non-randomized registry is designed to gather safety data on 
BIOTRONIK’s Plexa leads. All subjects enrolled in the registry are implanted with a US market 
released BIOTRONIK ICD or CRT-D pulse generator and a Plexa lead. 
Potential subjects will be identified by the investigator from their general patient population. 
Additionally, potential subjects must satisfy the registry inclusion and exclusion criteria (Section 
3.1.3 and Section 3.1.4). After successful implantation of the Plexa lead with a US market 
released BIOTRONIK ICD or CRT-D pulse generator, if a subject satisfies the registry inclusion 
and exclusion criteria, written informed consent is obtained. After informed consent has been 
obtained, enrollment visit data will be collected. Informed consent and enrollment visit data 
collection may be obtained no more than 30 days after the date of implant. Device data and any 
adverse events since the date of the implant of the Plexa lead active at the time of consent will 
be collected retrospectively at the enrollment visit.  
After enrollment, any subjects who have the pulse generator explanted or Plexa lead explanted 
or capped must be re-implanted, or have plans to be re-implanted, with a Plexa lead connected 
to a US market released BIOTRONIK pulse generator to remain in the study.  
After enrollment, subjects will be evaluated at 3 months post-implant, 6 months post-implant, 
and every 6 months thereafter for 5 years. All subjects are required to be seen in-office once 
between the 24 and 36 month intervals and once at the 60 month interval. For all other visits, 
subjects may use BIOTRONIK Home Monitoring® follow-ups to meet the study visit schedule. 
The option to substitute a BIOTRONIK Home Monitoring® follow-up for an in-office follow-up 
may begin as early as the 3 month post-implant visit. Subjects should be seen in-office if not all 
information required during follow-up visits as noted in Section 3.2.4 can be obtained from 
BIOTRONIK Home Monitoring®. Subjects without a BIOTRONIK Home Monitoring® system 
should be seen in-office for all intervals per the study visit schedule.  
Figure 5 provides an overview of the clinical registry design. Details of subject eligibility 
requirements are noted in Section 3.1 and details of other registry specific procedures and data 
collection are noted in Section 3.2 and Section 4. Figure 6 provides the visit schedule for a 
subject using BIOTRONIK Home Monitoring®. 
BIOTRONIK may pool data from other prospective studies to supplement the Plexa Registry 
population to achieve the sample size of 1271 subjects needed for the primary endpoint 
analysis. The data collection would need to be sufficiently similar to the Plexa Registry data 
collection to allow pooling of the data. If data from other studies are used, the data will come 
from subjects who have a US market released BIOTRONIK ICD or CRT-D pulse generator and 
a successfully implanted Plexa lead. 

 
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Figure 5: Registry Design Flowchart 
SCREENING
Screen
Does subject satisfy the inclusion/exclusion criteria?
Study Evaluation
Collect required data from the following post-implant 
evaluations:
• 
Scheduled follow-up at 3 and 6 month post-
implant follow-up interval, and every 6 month 
follow-up interval thereafter for 5 years
• 
Interim follow-ups for AEs or system revisions
IMPLANT
VISITS
Subject is a 
screen failure.
Subject is not 
a candidate.
Enrollment Procedures
Subject provides written informed consent.
Once consented, collect demographics, medical 
history, and implant data (retrospectively).
Implant Procedure
Was the subject successfully implanted with a 
qualifying BIOTRONIK ICD / CRT-D system including 
the Plexa lead?
ENROLLMENT
Subject is a 
screen failure.
YES
NO 
NO 
NO 
YES
YES
 

 
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Figure 6: Visit Schedule 
Enrollment
3 Month
6 Month
12 Month
18 Month
24 Month
30 Month*
36 Month
42 Month
48 Month
54 Month
60 Month
Mandatory
In-Office Visit
BIOTRONIK Home 
Monitoring® Visit
* In-office visit may be performed at 24, 30, or 36 Month interval
 
 
2.1 
REGISTRY ENDPOINTS 
This registry includes the assessments of one primary safety endpoint related to the Plexa lead 
and several secondary endpoints that evaluate the safety and effectiveness of the Plexa 
system. 
2.1.1 Primary Endpoint 1 
The purpose of primary endpoint 1 is to evaluate the overall incidence of adverse events related 
to the Plexa lead (as defined in Section 9) from implant through 5 years. Assuming that the 
expected Plexa lead adverse event rate at 5 year post-implant (proportion of subjects with at 
least one AE in the timeframe from implant through 5 year post-implant) is 7.5% or less, then 
the primary safety endpoint will be evaluated in the following testable hypothesis in superiority 
format.  
Ho: The adverse event-free rate (AEFR) for subjects receiving the Plexa lead at 5 years post-
implant is less than or equal to 92.5% 
 
AEFR ≤ 92.5% 
Ha: The adverse event-free rate (AEFR) for subjects receiving the Plexa lead at 5 year post-
implant is greater than 92.5% 
 
AEFR > 92.5% 
If the two-sided, 95% lower confidence bound is greater than 92.5%, then the null hypothesis 
will be rejected. 
2.1.2 Secondary Endpoints 
There are no formal tests of hypotheses associated with secondary endpoints 1-4. 
1. Incidence of each individual type of AE that contributes to Primary Endpoint 1 
2. Pacing threshold, sensing and impedance measurements for the Plexa lead through 5 
years post-implant 
3. Shock impedance for the Plexa lead through 5 years post-implant 

 
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4. Adverse event rates for protocol defined, Clinical Events Committee (CEC) adjudicated 
AEs excluded from primary safety endpoint 1, through 5 years post-implant 
2.1.3 
Additional Data of Interest 
Additional information may be collected to characterize the registry population, implanted 
system, and progress of the registry. When available, the collected information may include 
baseline demographics, medical history, implanted system, system revisions, Plexa lead 
extractions, returned product analysis, and compliance. Specifically, data of interest may 
include: 
• 
Baseline demographics, such as date of birth, gender, height, weight, and New York Heart 
Association (NYHA) class (if available) 
• 
Medical history, including indication for device  
• 
Implanted device data from initial implant and / or revisions, including implant dates and 
manufacturers for all implanted pulse generator and leads. Additionally, models and serial 
numbers will be collected for BIOTRONIK pulse generator and leads.  
• 
Implant procedure data (collected retrospectively at enrollment) 
• 
Revision procedure data (may be collected retrospectively) 
• 
Plexa DX lead atrial dipole sensing measurement 
• 
Results from returned product analysis 
• 
Compliance to protocol requirements and registry visit schedule 
2.2 
REGISTRY SIZE AND DURATION 
To document the clinical experience of the Plexa lead, the Plexa Registry is designed to follow 
1271 subjects through the 60 month post-implant visit interval at up to 75 US sites.  
2.3 
SAMPLE-SIZE ANALYSIS 
The investigation is designed to limit the number of subjects involved while still exposing the 
device to a sufficiently large patient population in order to ensure a representative and 
statistically meaningful sample. 
The estimated sample size required to evaluate primary endpoint 1 is based on a superiority 
comparison of the overall Plexa lead AE-free rate to 92.5% at 5 years. The sample size for 
primary safety endpoint 1 was calculated based on the following assumptions:  
Assumptions for primary safety endpoint 1 
• 
Registry Design: nonrandomized registry 
• 
Test basis: exact binomial test 
• 
Type I error (alpha): 0.025 (one-sided for superiority) 
• 
Statistical power: 80% 
• 
Estimated AE-Free Rate at 5 years: 95.0% for Plexa leads 
• 
Performance goal for AE-Free Rate at 5 years: 92.5% 

 
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For primary safety endpoint 1, a total of 750 evaluable Plexa leads would be required to 
demonstrate superiority to an AE-free rate of 92.5%. Assuming a 10% loss to follow-up rate per 
year over 5 years of follow-up (average of 8.2% of original population per year), a total of 1271 
(= 750 / 0.95) subjects with an ICD lead would be required to be enrolled to evaluate primary 
safety endpoint 1.  
2.3.1 Attrition 
For the sample size calculation, a maximum loss to follow-up of 10% per year (41% over 5 
years) was assumed. The attrition rate encompasses all causes for subject exits prior to study 
completion and will include any subject exits where the subjects are not replaced per Section 
2.3.2.  
2.3.2 Replacement of Subjects 
A drop-out rate of 10% of subjects per year is expected in the Plexa Registry. The additional 
enrollment of 10% (total subject number: n = 750 / 0.95) is considered sufficient for the collection 
of the required primary endpoint 1 (n = 750). However, to ensure sufficient primary endpoint 1 
evaluable data, subjects who exit the clinical investigation due to death, device explants, subject 
directed withdrawals, physician directed withdrawals, or loss of contact with the subject may be 
replaced as long as enrollment is ongoing. Subjects who have had a protocol defined adverse 
event will not be replaced. The subjects replaced will not count towards the overall planned 
subject number of 1271. 
2.4 
DATA ANALYSES 
The analysis population for the primary endpoint in the registry will be the intention-to-treat (ITT) 
population. This population analysis will include all subjects who provided informed consent,met 
the enrollment criteria, and completed the five year follow-up period or exited the trial early with 
a primary endpoint event.  
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. 
2.4.1 Endpoint Analysis 
Primary safety endpoint 1 will be evaluated by performing an exact binomial test comparing the 
observed proportion (overall AE-free rate at 5 years) to 92.5%. The lower bound of the 95% 
confidence interval must be greater than 92.5%.  
The evaluation of secondary safety endpoint 1 will be based on the exact, two-sided 95% 
confidence interval for the observed, individual AE rates at 5 years. Secondary endpoints 2 and 
3, which summarize pacing thresholds, sensing, impedance measurements and shock 
impedance measurements for the Plexa lead, will be reported via standard measures, which 
can include means, standard deviations, medians, minimums, and maximums.  
Secondary endpoint 4, which includes AEs that were excluded from primary safety endpoint 1, 
through 5 years post-implant will also be summarized as AE rates together with their 
associated, exact 95% confidence intervals.  

 
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2.4.2 Trend Analyses 
The primary safety endpoint is evaluated at 5 years post-implant against pre-specified 
performance levels (92.5% for overall freedom from Plexa lead-rated AEs). To monitor the 
ongoing incidence of any potential AEs against the accumulating follow-up exposure post-
implant, Kaplan-Meier survival curves may be prepared at the reporting intervals for Primary 
Endpoint 1. Root causes for any failures, regardless of the incidence rates, may be investigated.  
2.4.3 Missing Data 
All possible steps will be taken to minimize missing data in the registry. This includes but is not 
limited to monitoring of registry electronic case report forms (eCRFs) for completeness and 
supporting efforts to track and maintain contact with registry subjects during the follow-up 
period.  
The reasons for any missing data in the registry should be documented.  BIOTRONIK Home 
Monitoring® can provide daily automatic sensing values, pacing thresholds, shock impedance, 
and pacing impedance, depending on the device programming. When available, missing data 
will be imputed with BIOTRONIK Home Monitoring® values obtained from the day of a 
completed follow-up, target date of a missed follow-up, or the next closest day in the visit 
window. 
For evaluation of primary endpoint1, only subjects who achieve 5 years of follow-up or have 
experienced an adverse event prior to 5 years will be included in the final evaluation of the 
associated hypotheses. The secondary endpoints 1 and 4 of other AEs at 5 yearswill be 
analyzed in a similar manner. There will be no imputation for these missing adverse event 
outcomes. 
For purposes of the final report Kaplan-Meier survival analyses,  all AE data on enrolled non-
replaced subjects will be included with follow-up times censored at the time of exit or last 
completed study visit representing the time of the last known AE status. 
Secondary endpoints 2 and 3, which include pacing thresholds, sensing, pacing impedance, 
and shock impedance measurements will be summarized by scheduled visit through the 5 years 
of registry follow-up 
2.4.4 Poolability Analysis 
The distribution in AE-free rates across centers will be examined. The significance of 
differences in rates between centers will be initially tested using a Kruskal-Wallis test statistic, 
with an associated p-value of 0.15 or less considered evidence of center differences.  
Additionally, a Cochran-Mantel-Haenszel test with continuity adjustment will be used to assess 
the poolability of data collected across the different centers. If evidence is found of center 
differences, then the reasons for the differences will be explored using Cox and logistic 
regression methods to determine if any baseline subject risk factors are explanatory. 
 

 
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3. PROTOCOL REQUIREMENTS 
3.1 
SUBJECT POPULATION  
The investigator is responsible for screening all potential patients and selecting those who are 
appropriate for study inclusion. The subject selected for participation should be from the 
investigator's general patient population according to the inclusion and exclusion criteria 
described below.  
3.1.1 Indications 
The Plexa steroid-eluting, bipolar transvenous lead system is intended for use in the right 
ventricle of patients for whom implantable defibrillators are indicated. For this registry, the Plexa 
lead is utilized in conjunction with any US market released ICD or CRT-D device. 
3.1.2 Contraindications 
Do not use the Plexa lead system in patients with severe tricuspid valve disease or patients who 
have a mechanical tricuspid valve implanted. The Plexa steroid-eluting leads are 
contraindicated for patients who cannot tolerate a single systemic dose of up to 1.02 mg 
dexamethasone acetate (DXA). 
3.1.3 Inclusion Criteria 
To support the objectives of this investigation, the inclusion criteria at the time of subject 
enrollment for this registry include the following requirements: 
• 
Successfully implanted with a BIOTRONIK ICD or CRT-D compatible system along with the 
Plexa lead no more than 30 days prior to consent† 
• 
Able to understand the nature of the registry and provide informed consent 
• 
Available for follow-up visits on a regular basis at the study site for the expected 5 years of 
follow-up 
• 
Accepts BIOTRONIK 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 subject 
enrollment include the following requirements: 
• 
Enrolled in any investigational cardiac device trial 
• 
Enrolled in BIOTRONIK’s QP ExCELs lead study 
• 
Planned cardiac surgical procedures or interventional measures within the next 6 months 
• 
Expected to receive heart transplantation or ventricular assist device within 1 year 
• 
Life expectancy of less than 1 year 
• 
Patients reporting pregnancy at the time of enrollment 
 
                                                     
† Sponsor may approve a site specific waiver upon written request to allow enrollment prior to implant per 
institution’s requirements. 

 
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3.2 
REGISTRY PROCEDURES 
Subjects will be enrolled no more than 30 days from implant of a BIOTRONIK ICD or CRT-D 
device and Plexa lead. BIOTRONIK Home Monitoring® should be activated in subjects who 
have a BIOTRONIK Home Monitoring® system. BIOTRONIK Home Monitoring® data can be 
utilized to assist in triage and diagnosis of lead-related adverse events between scheduled 
follow-ups. All subjects are required to be seen in-office once between the 24 and 36 month 
intervals and once at the 60 month interval. For all other visits, subjects may use BIOTRONIK 
Home Monitoring® follow-ups to meet the study visit schedule. Subjects without a BIOTRONIK 
Home Monitoring® system should be seen in-office for all intervals per the study visit schedule. 
Registry Procedure Visits: 
• 
Implant (collected retrospectively during enrollment) 
• 
Enrollment 
• 
Routine follow-up evaluations at 3 months post-implant, 6 months post-implant, and every 6 
months thereafter for 5 years 
• 
Interim follow-up information is only collected in support of AEs and is not required to be 
entered as a visit in the EDC  
• 
System revision (if applicable) 
Table 5 summarizes the visit assessment schedule. 
Table 5: Registry Visit Assessment Schedule 
 
Implant1 
 Enrollment 
Routine 
Follow-up 
Intervals2 
Interim 
Evaluation3 
System 
Revision 
Informed consent 
 
X 
 
 
 
Demographics and 
medical history1  
 
X 
 
 
 
Implant information1  
X1 
X1 
 
 
X1 
Device evaluation 
X 
 
X 
X 
X 
Adverse event 
assessment 
X 
X 
X 
X 
X 
Complete eCRFs 
X 
X 
X 
X 
X 
1 Data may be collected retrospectively. Implant data is collected retrospectively at the enrollment visit. Implant information is also 
collected at system revisions regardless of the location of the procedure. Demographics and medical history information may also 
be collected retrospectively during the enrollment visit. 
2 3, 6 months post-implant and every 6 months thereafter for 5 years post-implant. All subjects are required to be seen in-office once 
between the 24 and 36 month intervals and once at the 60 month interval. For all other visits, subjects may use BIOTRONIK Home 
Monitoring® follow-ups to meet the study visit schedule. Subjects without a BIOTRONIK Home Monitoring® system should be seen 
in-office for all intervals per the study visit schedule. 
3 Interim follow-up information is only collected in support of AEs and is not required to be entered as a visit in the EDC.  

 
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3.2.1 Registry Pre-Screening 
Prior to enrollment, the patient’s medical history must be reviewed in order to ensure the patient 
is an appropriate candidate for the registry. In addition, all patients must satisfy the registry 
inclusion and exclusion criteria prior to enrollment, including  having been implanted with a 
Plexa lead and BIOTRONIK ICD or CRT-D no more than 30 days before consent. 
3.2.2 Plexa Lead Implant 
Implant information is collected retrospectively during the enrollment visit. Implant details and 
device data will be collected retrospectively as follows: 
• 
Implant information 
− 
Date of implant 
− 
Implantation site (right or left) and, if available, implant approach (e.g. subclavian, 
axillary, etc.) 
• 
Information on implanted system (pulse generator and leads manufacturer / model, serial 
numbers, etc.) 
• 
Electrical parameters of the Plexa lead (if available, at least one pacing threshold 
measurement for each lead at 0.4 ms pulse width) 
• 
Any lead-related, pulse generator-related and procedure-related adverse events occurring 
during implant  
3.2.3 Enrollment Visit 
If the patient has been determined to be eligible for the registry, informed consent must be 
obtained from the patient prior to initiating any registry related data collection. The consent 
process, including discussion of the registry, should be documented in the patient’s medical 
record. A subject with a successfully implanted Plexa lead is considered enrolled in the registry 
upon signing the Informed Consent Form. The visit at which informed consent is obtained is the 
enrollment visit and occurs no more than 30 days after the date of implant. The system the 
subject has at the time of signing the Informed Consent Form will be considered the study 
system. Prior implanted systems will not count as part of the study and AEs will only be 
collected from the time of the study system implant. Subject demographics are to be obtained at 
the enrollment visit; however, some information may be historical if it is not available with proper 
source documentation. 
The following data collection and reporting procedures are performed at the enrollment visit: 
1. Obtain informed consent 
2. Collect subject demographics (date of birth, gender, etc.) 
3. Collected medical history of subject, including device implant indications 
4. Obtain data from the implant procedure as outlined in Section 3.2.2 
5. Perform routine device interrogation: 
• 
Determine ICD lead mean R-wave sensing amplitude 
• 
Determine ICD lead pacing threshold at 0.4 ms pulse width 
• 
Determine the ICD lead pacing impedance 
• 
Determine the ICD lead shock impedance 

 
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• 
If Plexa DX ICD lead, determine atrial dipole mean P-wave amplitude 
• 
Enable BIOTRONIK Home Monitoring® (if not already enabled) 
• 
Enable RV automatic threshold management (ATM) or RV ventricular capture 
control (VCC) 
6. Complete all required eCRFs 
3.2.4 Routine Follow-ups 
Subjects will undergo an assessment of their implanted system 3 months (± 30 days) post-
implant, 6 months (± 45 days) post-implant, and every 6 months (± 45 days) thereafter for 5 
years. All subjects are required to be seen in-office once between the 24 and 36 month intervals 
and once at the 60 month interval. For all other visits, subjects may use BIOTRONIK Home 
Monitoring® follow-ups to meet the study visit schedule. Subjects without a BIOTRONIK Home 
Monitoring® system should be seen in-office for all intervals per the study visit schedule. Figure 
6 provides the visit schedule for a subject using BIOTRONIK Home Monitoring®. 
Each site Principal Investigator (PI) will be trained to identify and schedule follow-ups to meet 
the required visit expectation. Additionally, the electronic data capture system (EDC) will provide 
assistance in identifying properly scheduled follow-ups according to this protocol. 
The following data should be collected: 
1. Perform routine device interrogation: 
• 
Determine ICD lead mean R-wave sensing amplitude 
• 
Determine ICD lead pacing threshold at 0.4 ms pulse width 
• 
Determine the ICD lead pacing impedance 
• 
Determine the ICD lead shock impedance 
• 
If Plexa DX ICD lead, determine atrial dipole mean P-wave amplitude 
2. Determine if there have been any study defined adverse events (see Section 9) 
3. Export and store the electronic device interrogation 
4. Complete all appropriate eCRFs 
The following data collection and reporting procedures are performed for a BIOTRONIK Home 
Monitoring® evaluation: 
1. Check “Last message” date on Quick View page to ensure the visit occurred within the 
visit window 
2. Review the data and save the Quick View page of the appropriate transmission 
3. Determine if there have been any study defined adverse events (see Section 9) 
4. Complete all appropriate eCRFs 

 
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3.2.4.1 
Device Programming 
If BIOTRONIK Home Monitoring® evaluations will be used for routine follow-up visits, atrial and / 
or ventricular capture control should be programmed to “ON” or “ATM,” and BIOTRONIK Home 
Monitoring® activated to allow collection and evaluation of pacing threshold data. If atrial and / or 
ventricular capture control is not programmed “ON” or “ATM,” the subject should be seen in-
office for study visits. If the atrial and / or ventricular capture control is disabled automatically 
due to AF, high intrinsic rate, or other reason, the reason should be documented in the EDC 
system and if the reason is unable to be resolved, the subject should be seen in-office for study 
visits. 
3.2.5 Interim Follow-ups 
Interim follow-ups may occur anytime during the registry. Data collected during interim follow-
ups should be the same as a routine in-office follow-up. Interim follow-up data is only collected 
in EDC in support of lead or system related AEs or system revisions and is not required to be 
entered as an interim follow-up in EDC. Other hospital or clinic visits that are unrelated to the 
device are not required to be collected. 
3.2.6 System Revisions 
For interim evaluations that involve a system revision (even if the Plexa lead is not directly 
affected), the following should be completed: 
1. Collect implant information 
• 
Date of revision 
• 
Implant site (right or left) and if available implant approach (e.g. subclavian, 
axillary, etc.) 
• 
Implant location of pulse generator and implanted leads 
• 
Whenever possible, devices that are explanted should be returned to 
BIOTRONIK for analysis 
2. Collect information on newly implanted system (pulse generator and leads manufacturer 
/ model, serial numbers, etc.) 
3. Record electrical parameters of the implanted leads (perform at least one pacing 
threshold measurement for each lead at 0.4 ms pulse width) 
4. Record any lead-related, pulse generator-related and procedure-related adverse events 
during implant and complete the Adverse Event eCRF 
5. Set programming parameters to best suit the needs of the subject 
6. Complete System Revision eCRF, as applicable 
If the Plexa lead is replaced with another Plexa lead attached to a US market released 
BIOTRONIK pulse generator, the subject may continue participation in the registry based on the 
original implant date and visit schedule. If the Plexa lead is explanted and the subject is not re-
implanted or will not be re-implanted with a new Plexa lead attached to a US market released 
BIOTRONIK pulse generator, the subject will be withdrawn from the registry. See Section 10.2.3 
for details on withdrawals due to lead or pulse generator extraction. 

 
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4. DATA COLLECTION 
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 registry 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 
access to reports for BIOTRONIK, specified study sites, and any other parties authorized by 
BIOTRONIK. 
4.2 
ELECTRONIC CASE REPORT FORMS (eCRFS) 
Original data will be collected at each study site and recorded into the EDC system, audited and 
monitored by BIOTRONIK, 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. 
Information from electronically delivered source data (e.g. programmers) will be captured and 
stored in a validated environment until the end of the registry. 
Subject follow-up is required for all subjects enrolled in this clinical registry. The required follow-
up visit dates are based on Plexa lead implant date, and are to be used for the calculation of the 
dates of the routine follow-up schedule. The following eCRFs will be available in the EDC 
system: 
• 
Informed Consent 
• 
Enrollment  
• 
Implant 
• 
Lead Values (used for implant lead values and revision lead values) 
• 
Follow-up (3 month ± 30 days post-implant, 6 months ± 45 days post-implant, and every 6 
months ± 45 days thereafter for 5 years) 
• 
Adverse Event 
• 
System Revision 
• 
Study Termination 
• 
Protocol Noncompliance 
4.3 
DATA QUALITY CONTROL 
BIOTRONIK will review registry data. At any time, reports may be generated on data completion 
and missing data for each study site. An 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 as well as to identify data completed, due, 
overdue, and backlogged. In addition, all registry data will undergo automatic edit and 
plausibility checks, which provide information to the study sites to help improve and maintain 
data quality control procedures, and is designed to detect inaccuracies and inconsistencies.  
To ensure protocol compliance at all participating study sites, BIOTRONIK monitors will conduct 
centralized and / or on-site monitoring throughout the course of the registry.  

 
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To ensure compliance with federal regulations, internal policies and procedures, and the registry 
protocol, the EDC vendor will also be audited by BIOTRONIK or a BIOTRONIK representative 
during the course of the registry. 
4.4 
SUBJECT RETENTION 
Although the registry sample size has been calculated with a 10% subject attrition rate per year 
(41% total in 5 years), subject retention in a 5 year registry may pose additional, unforeseen 
challenges. BIOTRONIK will provide additional tools to the sites in an effort to minimize the 
number of subjects that are lost to follow-up. The EDC system includes an overview of each 
subject’s follow-up schedule, including the windows for each follow-up.  
4.5 
SUBJECT DATA CONFIDENTIALITY 
All information sent to BIOTRONIK pertaining to each subject will be kept confidential at 
BIOTRONIK and is subject to FDA inspection. Source documents used to support endpoint 
adjudication by the CEC in the Plexa Registry will have all confidential subject and site 
identifiers redacted prior to transmission. Reports submitted to the physician or publications of 
registry results will not make any reference to subject names. 
In order to verify the registry data and ensure registry integrity, monitors from BIOTRONIK, the 
FDA, and the reviewing Institutional Review Board (IRB) may review and / or copy the registry 
records 

 
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5. RISKS AND RISK MINIMALIZATION 
All devices included in this registry are legally marketed and being prescribed by physicians 
according to FDA approved indications for use.  Additionally, all visits in this registry are 
standard of care. There are no new risks associated with participation in this study. Please refer 
to the product manuals for risks associated with the implanted leads, ICDs, or CRT-Ds. 

 
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6. REGISTRY ORGANIZATION 
6.1 
SPONSOR 
BIOTRONIK is the "sponsor" of the Plexa Registry. 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. As the investigator, the physician is responsible for conducting the study in 
accordance with the signed agreement, the protocol, applicable laws, FDA regulations, and any 
conditions of approval imposed by the reviewing IRB. The principal investigator must also 
accept responsibility for all aspects of the study including the actions of any co-investigators 
participating in the study at the study site. 
6.2 
CLINICAL EVENTS COMMITTEE  
A Clinical Events Committee (CEC) consisting of at least 3 independent electrophysiologists will 
review and adjudicate adverse events that occur during the registry. The CEC will be blinded to 
the clinical registry site and subject identity, and to minimize bias, members will not participate 
as investigators. The CEC will create a registry specific charter defining the adverse event 
adjudication process, specifically detailing review guidelines along with appropriate response 
timelines. 
All protocol defined adverse events included in the primary and secondary endpoint analysis 
(see Section 9.3.1 and Section 9.3.2) will be adjudicated by the CEC. The CEC will indicate 
whether the adverse event is related, possibly related, not related, or has an unknown relation 
to the Plexa lead. The CEC will have the responsibility to adjudicate the classification of each 
reported adverse event as implant procedure, implanted pulse generator, lead, or non-
procedure non-system related, to adjudicate the category of AE (e.g. Plexa lead dislodgement, 
major hematoma, etc.), and to assess the seriousness of each AE. 

 
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7. REGISTRY MONITORING 
7.1 
SUMMARY 
BIOTRONIK’s responsibility as the clinical registry sponsor is to ensure protocol and regulatory 
compliance through proper monitoring of the investigation. BIOTRONIK requires IRB review and 
a subject Informed Consent Form for all after-market research. Monitoring may be conducted 
on-site at the study site or remotely by BIOTRONIK monitors.  
Through on-site or centralized monitoring, BIOTRONIK will assess the site’s performance in the 
following areas:  
• 
Verification that informed consent was obtained 
• 
Adherence to protocol eligibility criteria and requirements 
• 
Conduct and documentation of procedures and assessments related to: 
− 
Study endpoints 
− 
Protocol required safety assessments 
− 
Evaluating, documenting, and reporting AEs, subject deaths, and withdrawals, especially 
when a withdrawal may be related to an adverse event. 
• 
Investigator oversight and delegation of authority to study personnel 
• 
Verification of study-specific required documentation 
• 
Conduct and documentation of procedures essential to trial integrity 
• 
Adherence to the applicable FDA regulations regarding the obligations of the investigator 
and maintenance of records. 
As the investigator, the physician is responsible for conducting the registry in accordance with 
the signed agreement, the protocol, applicable laws, FDA regulations, and any conditions of 
approval imposed by the reviewing IRB. The principal investigator must also accept 
responsibility for all aspects of the registry including the actions of any sub-investigators 
participating in the registry at the study site. 
7.2 
REGISTRY MONITORS 
Study monitors are trained, qualified, and designated by BIOTRONIK management to oversee 
the progress of an investigation at the study site. Additional monitors may be appointed as 
necessary. 
The address to submit registry information to BIOTRONIK is: 
BIOTRONIK, Inc. 
Clinical Studies Department 
6024 Jean Road 
Lake Oswego, Oregon 97035 
For technical assistance 24 hours a day, call: 
(800) 547-0394 
 

 
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7.3 
ON-SITE MONITORING VISITS 
A monitor will conduct monitoring visits at study sites in accordance with the Monitoring Plan. 
Sites are required to support these visits and the study monitoring effort. On-site monitoring 
visits will also provide an assessment of the continued acceptability of the facilities to continue 
participation in the registry.  
7.4 
CENTRALIZED MONITORING 
Centralized monitoring will be conducted throughout the course of the study in accordance with 
the Monitoring Plan. Some examples of data that may be monitored remotely include un-
redacted, signed informed consent forms, enrollment, implant information, device data, adverse 
events reported in the EDC system, etc. Sites are required to support centralized monitoring by 
providing source documents to BIOTRONIK in order to source data verify data reported in the 
EDC system and resolving queries in a timely manner.  
 

 
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8. REGISTRY COMPLETION 
BIOTRONIK will notify the registry site upon completion or termination of the registry or 
investigator’s participation in the registry. At BIOTRONIK’s request, an investigator will return 
any pertinent information in their possession. Whenever possible, BIOTRONIK will provide a 
final report to each study site that has closed since the previous report. Upon termination of this 
registry, BIOTRONIK personnel may conduct a registry closure visit according to the Monitoring 
Plan. If a closure visit occurs, during the visit, BIOTRONIK will verify registry records and ensure 
that the investigator understands any applicable regulatory requirements including those related 
to record retention. The investigator must retain records related to the registry for a period of 2 
years after the registry is completed. 
In the event that the registry is suspended or terminated, the investigator must inform all 
enrolled subjects who at that time have not yet exited the registry. Standard patient care will be 
ensured by the study site.  

 
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9. ADVERSE EVENTS 
An adverse event (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 each reported 
adverse event as related to either the implant procedure, implanted pulse generator, Plexa lead, 
RV lead (separate from Plexa lead), right atrial lead, left ventricular lead, or as non-procedure 
non-system related. All reportable adverse events occurring after informed consent are 
collected. Reportable adverse events occurring prior to consent will only be collected beginning 
from the date of implant of the study system (the Plexa system active at the time of enrollment).  
The study site should report each adverse event via an Adverse Event eCRF and if the IRB is 
notified, provide a copy of the IRB adverse event notification to BIOTRONIK.  
9.1 
REPORTABLE ADVERSE EVENTS 
The following AEs (sorted by classification) will be reported if they meet the definition of a 
primary or secondary endpoint as defined in Section 9.3. The classifications listed below are 
general classifications for site reporting purposes. Detailed information for some classifications 
is located in Appendix A. The CEC charter may include alternate classifications for some 
adverse events. 
9.1.1 Implant Procedure-Related Adverse Events 
An AE will be classified as procedure-related if any one of the following occurred as a result of 
the implant procedure: 
• 
Arrhythmias associated with the implant procedure 
• 
Cardiac perforation with or without tamponade  
• 
Coronary sinus dissection 
• 
Damage to lead during procedure (e.g. accidental cut to lead body during pocket revision, 
device replacement, etc.) 
• 
Incorrect lead connection with pulse generator 
• 
Lead dislodgement during a procedure (e.g. during pocket revision, device replacement, 
etc.) 
• 
Loose set-screw 
• 
Major hematoma 
• 
Non-healing pocket dehiscence requiring intervention 
• 
Pneumothorax associated with the implant procedure 
• 
Primary infection  
• 
Pulmonary embolism associated with the implant procedure 
• 
Venous occlusion associated with the implant procedure 
• 
Other major implant procedure related adverse event 
9.1.2 Pulse Generator-Related Adverse Events 
An AE will be classified as pulse generator-related if any one of the following occurred: 
• 
Inability to defibrillate or pace 

 
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• 
Premature battery depletion 
• 
Pulse generator failure 
• 
Pulse generator migration 
• 
Skin erosion 
• 
Other pulse generator related adverse event 
9.1.3 Lead-Related Adverse Events 
An AE will be classified as lead-related if any one of the following occurred: 
• 
Abnormal defibrillation impedance 
• 
Abnormal pacing impedance 
• 
Cardiac perforation occurring post-implant 
• 
Extracardiac stimulation 
• 
Failure to capture / intermittent capture 
• 
Failure to sense / undersensing 
• 
High pacing threshold 
• 
Lead conductor fracture 
• 
Lead dislodgement  
• 
Lead insulation breach 
• 
Lead oversensing due to external noise 
• 
Lead oversensing not due to external noise 
• 
Lead-related thrombosis 
• 
Other lead-related adverse event (not specified above) 
9.1.4 Non-Procedure Non-System Related Adverse Events 
An AE will be classified as non-procedure non-system related if any of the following occur and 
require a system revision or explant: 
• 
Ablation sequelae 
• 
Secondary infection 
• 
Twiddler’s syndrome 
• 
Other non-elective invasive intervention 
9.2 
ENDPOINT ANALYSIS 
All protocol defined adverse events included in the primary and secondary endpoint analysis will 
be adjudicated by the Clinical Events Committee (CEC) (see Section 2.1, Section 6.2, and 
section 9.3). For each adverse event, the CEC will indicate whether the adverse event 
relatedness to the Plexa lead is: not related, related, possibly related, or unknown.  

 
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In evaluation of primary endpoint 1 and secondary endpoint 1 for the registry, the estimates of 
AE rates will be based on the number of subjects with at least one “related” AE as a proportion 
of total subjects. Subjects with a final adjudicated related AE classification of “possibly related”, 
“not related” or “unknown” will not have that individual event contribute to or be included in the 
evaluation of primary safety endpoint. The same rules will be used for purposes of Kaplan-Meier 
survival analyses, described in Section 2.4.2.  
Secondary endpoint 4, which includes AEs that were excluded from primary safety endpoint 1 
through 5 years post-implant, will also be summarized as AE rates along with their associated, 
exact 95% confidence intervals. 
9.3 
ADVERSE EVENTS FOR THE ANALYSIS OF THE PRIMARY AND 
SECONDARY ENDPOINTS 
9.3.1 
Adverse Events for the Analysis of Primary Endpoint 1 and Secondary 
Endpoint 1 
If any of the following invasive interventions occur in order to resolve an above listed Plexa lead-
related AE, the AE will be included in the primary safety endpoint analysis: 
• 
Lead surgically repositioned 
• 
Lead surgically explanted 
• 
Lead surgically replaced 
• 
Lead surgically abandoned 
• 
Other lead-related surgery performed  
Additionally, if any of the following non-invasive interventions occur in order to resolve an above 
listed Plexa lead-related AE, the Plexa lead-related AE will be included in the primary endpoint 
analysis: 
• 
Lead pacing polarity or pacing mode reprogrammed in response to a problem with the 
mechanical or electrical integrity of the lead  
• 
Lead programmed off in response to a problem with the mechanical or electrical integrity of 
the lead 
• 
Lead use continued based on medical judgment despite a known clinical performance issue 
AEs that are corrected by reprogramming the pulse generator (other than the above) and 
resolved without invasive intervention will not be considered an adverse event. For example, 
electrical reprogramming of the pacing polarity to eliminate extracardiac stimulation will not be 
considered an adverse event if not in response to a problem with the mechanical or electrical 
integrity of the lead. Similarly, increasing pacing output as a result of an elevated threshold 
without further intervention will not be considered an adverse event. 
Subject deaths as a result of a Plexa lead-related AE will be included in the primary endpoint 
analysis. 
Primary endpoint 1 and secondary endpoint 1 will exclude 1) lead dislodgements that occur less 
than or equal to 30 days after lead implant or a lead revision procedure and 2) high pacing 
threshold, failure to capture, or intermittent capture that occurs less than or equal to 30 days 
after lead implant or a lead revision procedure. However, these will count towards secondary 
endpoint 4. 

 
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9.3.2 
Adverse Events for the Analysis of Secondary Endpoint 4 
All major implant procedure-related adverse events are included in the secondary endpoint 4 
analysis, as well as Pulse Generator-related and Non-Procedure Non-System-related adverse 
events that require invasive intervention to resolve. 
If any of the following invasive interventions occur in order to resolve an above listed RV 
(separate from Plexa) lead-related, RA lead-related, LV lead-related AE, or an AE related to the 
Plexa lead and excluded from primary endpoint 1 and secondary endpoint 1 as listed in Section 
9.3.1, the AE will be included in the secondary endpoint 4 analysis: 
• 
Lead surgically repositioned 
• 
Lead surgically explanted 
• 
Lead surgically replaced 
• 
Lead surgically abandoned 
• 
Other lead-related surgery performed  
Additionally, if any of the following non-invasive interventions occur in order to resolve an above 
listed RV (separate from Plexa) lead-related, RA lead-related, LV lead-related AE, or an AE 
related to the Plexa lead and excluded from primary endpoint 1 and secondary endpoint 1 as 
listed in Section 9.3.1, the AE will be included in the secondary endpoint 4 analysis: 
• 
Lead pacing polarity or pacing mode reprogrammed in response to a problem with the 
mechanical or electrical integrity of the lead  
• 
Lead programmed off in response to a problem with the mechanical or electrical integrity of 
the lead 
• 
Lead use continued based on medical judgment despite a known clinical performance issue 
AEs that are corrected by reprogramming the pulse generator (other than the above) and 
resolved without invasive intervention will not be considered an adverse event. For example, 
electrical reprogramming of the pacing polarity to eliminate extracardiac stimulation will not be 
considered an adverse event if not in response to a problem with the mechanical or electrical 
integrity of the lead. Similarly, increasing pacing output as a result of an elevated threshold 
without further intervention will not be considered an adverse event. 
9.3.3 
Serious Adverse Events 
All adverse events included in the primary and secondary endpoint analysis are adjudicated by 
the CEC for seriousness. Adverse events are classified as serious if one or more of the 
following occurs: 
• 
death 
• 
serious deterioration in the health of the subject, that resulted in one of the following: 
• 
life threatening illness or injury 
• 
permanent impairment of a body structure or body function 
• 
in-patient or prolonged hospitalization 
• 
medical or surgical intervention to prevent life threatening illness or injury or permanent 
impairment to a body structure or body function 
• 
congenital anomaly / birth defect 

 
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Note: planned hospitalization or 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. 
9.4 
ADVERSE EVENT REPORTING 
The adverse events that an IRB considers reportable are dependent on the particular IRB. To 
avoid underreporting, BIOTRONIK recommends that, at a minimum, the investigator reports the 
Plexa lead-related adverse events that occur during the Plexa Registry to BIOTRONIK and the 
IRB. 
The registry site will report the adverse event on the Adverse Event eCRF. Additionally, registry 
sites may report adverse events through MedWatch, FDA’s adverse event reporting tool for 
market-released devices. As defined in BIOTRONIK’s internal procedures, these adverse 
events may be reported by BIOTRONIK through manufacturer’s MedWatch reports. 

 
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10. OTHER GENERAL INFORMATION 
10.1 PROTOCOL COMPLIANCE 
The investigator is responsible for conducting the registry in accordance with the signed 
agreement, the protocol, applicable laws, FDA regulations, and any conditions of approval 
imposed by the reviewing IRB. The investigator shall notify BIOTRONIK and the reviewing IRB 
in writing no later than 5 working days after any significant deviation from the investigational 
plan 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 
investigational plan.  
BIOTRONIK categorizes protocol noncompliance instances as either violations or deviations. 
Both protocol violations and deviations will be reported during interim reports and the final 
report. 
10.1.1 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 
• 
Subject inclusion / exclusion violations and protocol requirement violations that affect the 
primary endpoint of the registry design 
These violations will be reported and the site must notify the reviewing IRB per the IRB’s 
reporting requirements. The site should provide a copy of the IRB protocol noncompliance 
notification (as applicable) to BIOTRONIK. Protocol violations must also be reported to 
BIOTRONIK via Protocol Noncompliance eCRFs. 
10.1.2 Protocol Deviations 
Protocol deviations are deviations from the requirements of the protocol in such a manner 
whereby data is unusable or not available. Protocol deviations are less serious in nature and do 
not require IRB notification as long as they do not have an effect on the rights, safety, or welfare 
of the registry subject. Protocol deviations include, but are not limited to: 
• 
Procedure not performed within the allowed timeframe 
• 
Required data not obtained 
The site must report protocol deviations to BIOTRONIK via Protocol Noncompliance eCRFs. 
Both protocol deviations and violations will be reported in progress reports. 
10.2 STUDY TERMINATIONS 
Once a subject is enrolled, every effort should be made to continue to follow the subject in the 
registry. However, it is inevitable that some subjects will decline to participate further, change 
geographic location, or become non-compliant with the visit schedule. 
10.2.1 Withdrawal of Consent  
If consent is withdrawn, obtain the date of withdrawal and reason for withdrawal of consent, then 
complete a Study Termination eCRF. 

 
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10.2.2 Subject Death 
In the event of subject death during registry participation, personnel at the study site are asked 
to notify BIOTRONIK as soon as possible by completing a Study Termination eCRF. If subject 
death was associated with an adverse event, an Adverse Event eCRF will also be required.  
The following information should be reported for any subject death: 
• 
Death certificate, death report signed by the investigator, or relevant medical records that 
includes: 
− 
Date and time of death 
− 
Place death occurred 
− 
Identification of the rhythm at the time of death, if known (include any available 
documentation) 
− 
Immediate cause of death 
− 
Any other circumstances surrounding the death 
• 
Whether death was related to Plexa lead 
• 
Plexa lead return status 
Whenever possible, devices that are explanted should be returned to BIOTRONIK for analysis. 
10.2.3 Plexa Lead or Pulse Generator Extraction 
Any subject who has the Plexa lead explanted or capped, and is not re-implanted or will not be 
re-implanted with another Plexa lead attached to a US market released BIOTRONIK pulse 
generator, will be withdrawn from the registry. Additionally, any subject who has their 
BIOTRONIK pulse generator explanted and is not re-implanted with a US market released 
BIOTRONIK pulse generator will also be withdrawn from the registry (even if the Plexa lead 
remains). Only complete a Study Termination eCRF after documentation of the system revision 
procedure (see Section 3.2.5) is available. For example, if the Plexa lead and pulse generator 
are explanted due to infection, the subject should not be exited until a non-registry lead / system 
is implanted or documentation is available stating that the subject will not be re-implanted with a 
registry qualifying lead / system. Report the exit on the Study Termination eCRF and any 
adverse events resulting from the system revision. 
Whenever possible, BIOTRONIK devices that are explanted should be returned to BIOTRONIK 
for analysis. 
10.2.4 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. Registry sites should attempt to contact these subjects in order to 
maintain registry 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 registry by completing a Study Termination eCRF.  

 
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10.2.5 Registry Participation Complete 
All subjects are expected to be followed for 5 years with a final visit interval at 60 months (± 45 
days). After a subject completes their final routine visit in this time interval, their study 
participation is complete and the subject should be exited from the registry by completing a 
Study Termination eCRF. 
10.3 INFORMED CONSENT 
Prior to the subject’s participation in the investigation, informed consent is required from all 
subjects. The investigator is required to inform BIOTRONIK and the reviewing IRB within 5 days 
if any subject was not appropriately consented to participate in the registry. In order to assist 
with the consent process, BIOTRONIK will provide a template subject consent form to sites 
participating in the registry. 
10.4 IRB APPROVAL 
IRB approval is required from each institution prior to participation in this registry. Subject 
enrollment may not begin until the IRB and BIOTRONIK have granted approval for the study 
site. IRB approval is also required throughout the duration of this clinical investigation. If IRB 
approval is withdrawn, BIOTRONIK must be notified within 5 working days.  
10.5 OTHER INSTITUTIONS AND PHYSICIANS 
This registry is not transferable to other institutions attended by the investigator unless prior 
approval is obtained from both BIOTRONIK and the appropriate IRB. Additional study sites may 
be included in this study. Only approved investigators are authorized to participate in the study. 
However, there are certain situations where an investigator might not be immediately available 
to provide the necessary medical care for a subject enrolled in this registry (e.g. when a subject 
goes to the emergency room for medical treatment). In these instances a protocol deviation 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 subject’s medical care and rights as a 
research subject. 

 
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11. RECORDS AND REPORTS 
11.1 INVESTIGATOR RECORDS 
Investigators are required to maintain on file the following accurate, complete and current 
records relating to this investigation: 
• 
All correspondence relating to the registry with another investigator, an IRB, BIOTRONIK, a 
monitor, or the FDA, or any other regulatory authority (e.g., a letter sent from the investigator 
to the IRB). 
• 
A copy of the Plexa Registry protocol 
• 
Signed investigator or research agreement 
• 
Signed Financial Disclosure Form 
• 
A copy of the IRB letter approving the research registry 
• 
A copy of the IRB approved subject Informed Consent Form 
• 
All clinical forms and documentation, including: 
− 
A copy of the signed subject Informed Consent Form 
− 
All supporting documentation for data entered into the EDC system 
− 
Records of any adverse events, including supporting documentation 
− 
Records pertaining to subject deaths during the investigation 
− 
Documentation and rationale for any deviations from the clinical protocol 
− 
Any other records required by BIOTRONIK 
11.2 INVESTIGATOR REPORTS 
Investigators are required to prepare and submit to BIOTRONIK the following complete, 
accurate, and timely reports on this investigation when necessary: 
• 
Notification of a subject death during the registry 
• 
Notification of the withdrawal of IRB approval 
• 
Annual progress reports prepared for the IRB 
• 
Notification of any deviations from the registry plan 
• 
Notification that an informed consent was not obtained from the subject 
• 
Final summary report prepared for the IRB 
• 
Any other information upon the request of an IRB, the FDA, or BIOTRONIK 
Table 6 outlines the responsibilities, including time constraints, for submitting the above reports.  

 
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Table 6: Investigator Reporting Responsibilities 
Type of Report 
Report to 
BIOTRONIK 
Report to 
IRB 
Time Constraints of Notification 
Subject Death During 
Registry 
Required 
Required 
BIOTRONIK as soon as possible and as 
required by reviewing IRB 
Adverse Event 
Required 
IRB 
dependent 
Within 10 calendar days after 
notification of the event 
Subject Withdrawal 
Required 
Required 
BIOTRONIK as soon as possible and as 
required by reviewing IRB. 
Withdrawal of IRB 
Approval 
Required 
N/A 
Within 5 working days 
Progress Report 
Required 
Required 
Submitted not less often than yearly 
Significant Deviations from 
Registry Plan 
Required 
Required 
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 
Required 
Required 
As soon as possible after discovery and 
no more than 5 working days 
 
11.3 SPONSOR RECORDS 
BIOTRONIK will maintain the following records: 
• 
All correspondence that pertains to the registry with the investigator(s), IRB, and the FDA 
• 
Investigator agreements, financial disclosures, and curriculum vitae 
• 
Name and address of each investigator and each IRB that is involved with the investigation 
• 
Adverse events and complaints 
• 
Adverse device effects  
• 
Electronic case report form data 
• 
Clinical investigation plan and report of prior investigations 
• 
Monitoring reports 
• 
Clinical progress reports 
11.4 SPONSOR REPORTS 
Table 7 outlines the responsibilities, including time constraints, for sponsor reports. 

 
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Table 7: Sponsor Reporting Responsibilities 
Type of Report 
Prepared by 
BIOTRONIK for 
Time Constraints 
of Notification 
Withdrawal of IRB Approval 
Reviewing IRBs and 
participating investigators 
Within 5 working days of receipt of 
notice of withdrawal of approval 
Progress Report 
All reviewing IRBs 
A progress report will be submitted at 
least annually 
Recall and Disposition 
All reviewing IRBs 
Notification will be made within 30 
working days and will include the 
reasons for any request that an 
investigator return, repair or otherwise 
dispose of any devices. 
Final Report 
All reviewing IRBs and 
participating investigators 
A final report will be submitted within 6 
months after completion or 
termination of the registry. 

 
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APPENDIX A: DEFINITION OF TERMS 
Abnormal defibrillation impedance – Defibrillation impedance is typically considered 
abnormal if a measurement is < 25 Ω or > 150 Ω (based on lead model and measurement range 
of the device). Includes high or low shock impedance when attempting to deliver a shock. 
Abnormal pacing impedance – Pacing impedance is typically considered abnormal if a 
measurement is <200 Ω or >3000 Ω (based on lead model and measurement range of the 
device). 
ACC / AHA – American College of Cardiology / American Heart Association 
AE (Adverse Event) – An unwanted affect detected in participants either implant procedure 
related, lead related, or other. The term is used whether or not the effect can be attributed to the 
leads in the study. For the purposes of this study, the CEC will indicate whether the adverse 
event’s relation to the Plexa lead is: related, possibly related, not related, or unknown. 
Cardiac perforation associated with a lead – Penetration of the lead tip through the 
myocardium (including microperforation), clinically suspected and confirmed by chest X-ray, 
fluoroscopy, echocardiogram, intracardiac electrogram, or visual observation. 
CFR – Code of Federal Regulations  
Chronic threshold – Chronic threshold is defined as the pacing threshold determined at the 
subject’s 3 month follow-up visit. If a 3 month follow-up visit is not completed, the chronic 
threshold is considered the first available threshold after the 3 month follow-up interval. 
Clinical failure – Inability of the lead to correctly sense or pace in the heart, not attributable to a 
physiologic reason (e.g. new onset atrial fibrillation) or a mechanical malfunction of the lead or 
pulse generator that remains unresolved despite reprogramming and / or repositioning.  
DF-1 – the international standard whereby leads and generators from different manufacturers 
are assured a basic fit [Reference ISO 5841-3:2013] 
DF4 – the international standard for defibrillation lead connectors [Reference ISO 27186:2010] 
Exit block – The failure of an intact pacing system to capture the heart because the stimulation 
threshold exceeds the output of the pacemaker. 
Explantation – Surgical removal of a lead during the acute implant stage, whereby the lead has 
not been chronically implanted and can be easily removed by simple traction. 
Extracardiac stimulation – Clinical observation of inadvertent nerve / muscle stimulation other 
than cardiac muscle, such as the diaphragm or pectoral muscles..  
Extraction of a lead – Surgical removal of a chronically implanted lead.  
Failure to capture or intermittent capture – Intermittent or complete failure to achieve cardiac 
stimulation at programmed output delivered outside of the cardiac refractory period. This will be 
considered an AE if invasive intervention is taken. In the absence of invasive intervention, this 
will only be considered an AE if there is failure to capture the permanently programmed output 
with a minimum 2:1 safety margin. Sudden and significant increase in the pacing threshold 
value (elevated threshold compared to previous measured value) at which 2:1 safety margin 
can no longer be achieved.  

 
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Failure to sense or undersensing – Intermittent or complete loss of sensing or failure to detect 
intended intrinsic cardiac signals (atrial or ventricular) during non-refractory periods at 
programmed sensitivity settings. This will be considered and AE if invasive intervention is taken. 
In the absence of invasive intervention, this will only be considered an AE if the loss of sensing 
is not due to a medical reason and cannot be resolved with reprogramming. 
Hematoma – A localized collection of extravasated blood, usually clotted, in an organ, space, or 
tissue. A hematoma is not considered a protocol defined AE unless it is a major hematoma 
related to the implant procedure. See major hematoma. 
High pacing threshold – High lead pacing threshold resulting in invasive intervention. In 
absence of invasive intervention, at follow-up, lead threshold that has increased two fold from 
the chronic threshold value, and is unable to achieve a 2:1 safety margin. 
IS-1 – the international standard whereby leads and generators from different manufacturers are 
assured a basic fit [Reference ISO 5841-3:2013] 
Lead conductor fracture – A mechanical break within the lead conductor (includes connectors, 
coils and / or electrodes) observed visually, electrically, or radiographically. 
Lead dislodgment – Radiographic, electrical, or electrocardiographic evidence of electrode 
displacement from the original implant site or electrode displacement that adversely affects 
pacing, and / or lead performance. 
Lead insulation breach or insulation break – A disruption or break in lead insulation 
observed visually, electrically, or radiographically. 
Loose set screw – Header set screw not properly tightened prior to end of implant or revision 
procedure. 
LV lead – Left ventricular lead 
Major hematoma – Hematoma requiring evacuation, drainage, blood transfusion, 
hospitalization, or extension of hospital stay to treat hematoma 
Mechanical failure – Malfunction of the lead through a break in the conductor, insulation, or 
connector pin leading to loss of pacing / sensing observed visually, electrically, or 
radiographically. Confirmed or suspected mechanical failures induced by intervention, such as 
lead damage caused during a procedure, are not protocol defined adverse events. 
Non-healing pocket dehiscence – Separation of wound edges around the pocket of the 
implanted pulse generator that has not healed. 
Oversensing – Misinterpretation of cardiac or non-cardiac events as cardiac depolarization, 
such as T-waves, skeletal muscle potentials, and extracardiac electromagnetic interference 
(EMI). 
Pneumothorax – Air or fluid in the pleural space surrounding the lung leading to collapse or 
partial collapse of the lung. 
Premature battery depletion – Reaching Elective Replacement Indicator (ERI) before reaching 
75% of the predicted date. 
Pulmonary embolism – Blockage of the main artery of the lung or one of its branches by a 
substance that has travelled from elsewhere in the body through the bloodstream. 

 
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Version 01-Mar-2017 
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CONFIDENTIAL: Do not copy or distribute without BIOTRONIK approval 
 
Pulse Generator Failure – Confirmed or suspected pulse generator issue that is due to a 
mechanical failure or electrical malfunction, such as inability to communicate with pulse 
generator, electrical circuit failure, or inability to deliver therapy, that is not attributable to 
another component of the system or caused by an external source. 
RA lead – Right atrial lead 
Skin erosion – Deterioration of tissue over an implanted device or the movement of a lead 
through the skin. 
Suspected lead failure – Lead issue that is potentially a mechanical or electrical malfunction. 
Tamponade – Compression of the heart caused by blood accumulation in the space between 
the myocardium and the pericardium. 
Thrombosis – The development of a blood clot in a vein or artery that leads to the obstruction 
of blood flow. 
Twiddler’s syndrome – A condition where the pulse generator leads are dislodged by the 
subject unwittingly rotating the subcutaneous pulse generator. 
Venous occlusion – Blockage of a vein causing a reduction of blood supply and associated 
symptoms. 
                                                     
REFERENCES 
 
1 Peto R, et al. Design and Analysis of Randomized Clinical Trials Requiring Prolonged Observation of 
Each Patient. II. Analysis and Examples. Br J Cancer 1977;35:1-39 
2 Slotwiner D, et al. HRS Expert Consensus Statement on remote interrogation and monitoring for 
cardiovascular implantable electronic devices. Heart Rhythm 2015;12:e69-100