Safety and Performance Study of the Siello S Pacing Lead
Conditions: Safety and Effectiveness of the Siello S Lead
Sponsor: Biotronik, Inc.

 
 
Protocol for the 
SIELLO 
Clinical Study 
 
 
 
NCT01791127 
IDE # G110221 
October 2, 2012  
 
 
 
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 .................................................................................................................................... 7 
1.1 Name of Device .............................................................................................................................. 7 
1.2 Overview and Background ............................................................................................................. 7 
1.2.1 Overview ............................................................................................................................. 7 
1.2.2 Background ......................................................................................................................... 7 
1.2.3 Prior Clinical Experience ..................................................................................................... 8 
1.2.3.1 Setrox OUS Study ........................................................................................................................ 8 
1.2.3.2 CELESTIAL and GALAXY Studies ............................................................................................... 8 
1.2.3.3 Siello European Study .................................................................................................................. 8 
1.2.3.4 Other Studies ................................................................................................................................ 9 
1.3 Device Descriptions ...................................................................................................................... 10 
1.3.1 Siello Leads ....................................................................................................................... 10 
1.3.2 BIOTRONIK Home Monitoring .......................................................................................... 11 
2. STUDY DESIGN ................................................................................................................................... 14 
2.1 Study Endpoints ........................................................................................................................... 16 
2.1.1 Primary Endpoint 1: Atrial Siello Lead Safety – 12-Month Adverse Event-Free Rate (Pre-
Market Analysis) ........................................................................................................................... 16 
2.1.2 Primary Endpoint 2: Ventricular Siello Lead Safety – 12-Month Adverse Event-Free Rate 
(Pre-Market Analysis) ................................................................................................................... 16 
2.1.3 Primary Endpoint 3: Siello Lead Effectiveness – Success rate of the implanted system 
including one or two Siello leads to sense and deliver pacing at 12-months post-implant (Pre-
Market Analysis) ........................................................................................................................... 17 
2.1.4 Primary Endpoint 4: Siello Lead Safety – 5-Year Adverse Event-Free Rate for Primary 
(RV) Lead Position (Post-Approval Analysis) ............................................................................... 18 
2.1.5 Primary Endpoint 5: Siello Ventricular Lead Safety – Individual Adverse Event Rates for 
Primary (RV) Lead Position (Post-Approval Analysis) ................................................................. 18 
2.1.6 Secondary Endpoints ........................................................................................................ 19 
2.1.7 Additional Data of Interest ................................................................................................. 19 
2.2 Study Size .................................................................................................................................... 19 
2.3 Protocol Requirements ................................................................................................................. 22 
2.3.1 Subject Population ............................................................................................................ 22 
2.3.2 Siello S Indications ............................................................................................................ 23 
2.3.3 Siello S Contraindications ................................................................................................. 23 
2.3.4 Inclusion Criteria ............................................................................................................... 23 
2.3.5 Exclusion Criteria .............................................................................................................. 23 
2.4 Study Design ................................................................................................................................ 24 
2.4.1 Study Procedures .............................................................................................................. 24 
2.4.2 Study Visits ....................................................................................................................... 24 
2.4.3 Study Pre-screening.......................................................................................................... 25 
2.4.4 Study Enrollment Visit ....................................................................................................... 25 
2.4.5 Siello Implant ..................................................................................................................... 26 
2.4.6 3-Month Follow-up ............................................................................................................ 26 
2.4.7 6-Month, 12-Month and Subsequent Routine Follow-ups ................................................ 27 
2.4.8 Interim Unscheduled Follow-Ups ...................................................................................... 27 
2.4.9 System Revision ............................................................................................................... 28 
2.5 Subject Withdrawals, Lost-To-Follow-Up ..................................................................................... 29 

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2.5.1 Withdrawal of Enrolled Subjects ....................................................................................... 29 
2.5.2 Enrolled Subjects Lost-to-Follow-up ................................................................................. 29 
2.6 Data Analysis ................................................................................................................................ 29 
2.7 Trend Analyses ............................................................................................................................. 30 
2.8 Missing Data ................................................................................................................................. 31 
2.9 Poolability Analyses...................................................................................................................... 31 
3. DATA COLLECTION ........................................................................................................................... 32 
3.1 Electronic Data Capture (EDC) .................................................................................................... 32 
3.2 Electronic Case Report Forms (eCRFs)....................................................................................... 32 
3.3 Data Quality Control ..................................................................................................................... 33 
3.4 Subject Retention ......................................................................................................................... 33 
4. SUBJECT CONSENT .......................................................................................................................... 33 
5. SUBJECT DATA CONFIDENTIALITY ................................................................................................ 34 
6. RISKS AND RISK MINIMIZATION ...................................................................................................... 34 
7. MONITORING ...................................................................................................................................... 35 
7.1 Summary ...................................................................................................................................... 35 
7.2 Monitors ........................................................................................................................................ 35 
8. STUDY COMPLETION ........................................................................................................................ 36 
9. DEVIATION FROM THE INVESTIGATIONAL PLAN ......................................................................... 36 
10. ADVERSE EVENTS ............................................................................................................................. 37 
10.1 Procedure-Related Adverse Events ............................................................................................. 37 
10.2 Pulse Generator-Related Adverse Events ................................................................................... 38 
10.3 Lead-Related Adverse Events ...................................................................................................... 38 
10.4 Adverse Events for the Analysis of the Primary Safety Endpoints 1 and 2.................................. 38 
10.5 Adverse Events for the Analysis of the Primary Safety Endpoints 4 and 5.................................. 39 
10.6 Adverse Event Reporting ............................................................................................................. 41 
10.7 Unanticipated Adverse Device Effects ......................................................................................... 41 
10.8 Subject Death ............................................................................................................................... 42 
10.9 Clinical Events Committee ........................................................................................................... 42 
11. IRB APPROVAL................................................................................................................................... 43 
12. OTHER GENERAL INFORMATION .................................................................................................... 43 
12.1 Labeling ........................................................................................................................................ 43 
12.2 Control of the Device .................................................................................................................... 43 
13. OTHER INSTITUTIONS AND PHYSICIANS ....................................................................................... 43 
14. RECORDS AND REPORTS ................................................................................................................ 44 
14.1 Investigator Records..................................................................................................................... 44 
14.2 Investigator Reports ..................................................................................................................... 44 
14.3 Sponsor Records .......................................................................................................................... 45 
14.4 Sponsor Reports ........................................................................................................................... 46 

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APPENDIX A: DEFINITION OF TERMS .................................................................................................... 47 
APPENDIX B: TIMELINE ........................................................................................................................... 50 
 
 
 
Table of Figures 
Figure 1: Siello Lead ..................................................................................................... 10 
Figure 2: Home Monitoring Transmission Path ............................................................. 11 
Figure 3: Home Monitoring Quick View Summary Report ............................................. 13 
Figure 4: Flowchart of Study Design ............................................................................. 15 
Table of Tables 
Table 1: Historical Adverse Events.................................................................................. 9 
Table 2: Primary Endpoints Sample Sizes (Pre-Market Analysis) ................................. 21 
Table 3: Primary Safety Endpoints Sample Sizes (Post-Market Analysis) .................... 22 
Table 4: Study Visit Assessment Schedule ................................................................... 25 
Table 5: Endpoint Related Adverse Events ................................................................... 40 
Table 6: Investigator Reports ........................................................................................ 45 
Table 7: Sponsor Reports ............................................................................................. 46 
 

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SIELLO Clinical Study 
 
PROTOCOL SIGNATURE PAGE 
 
The signature below constitutes the receipt and review of the SIELLO Clinical Study 
protocol and any attachments, and provides the necessary assurances that this study 
will be conducted according to all stipulations of the protocol, including all statements 
regarding confidentiality, and according to local legal and regulatory requirements and 
applicable U.S. federal regulations, ICH and GCP guidelines. 
 
 
PRINCIPAL INVESTIGATOR: 
 
 
Signed: 
 
 
 
 
Name (please print) 
 
 
 
 
 
Signature 
 
Date 
 

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SUMMARY 
Title: 
SIELLO Clinical Study 
Design: 
This clinical study is a combined Pre-Market Study and Post-Approval Registry 
that will enroll up to 2124 subjects implanted with BIOTRONIK’s Siello pacing 
lead in the atrium and/or ventricle. 
The Pre-Market study is designed to follow a total of 986 leads (430 atrial and 
556 ventricular) in up to 986 subjects from implant through 12 months post 
implant.  The pre-market analysis will occur once 387 Siello atrial leads and 
500 Siello ventricular leads have reached the 12-month follow-up time point.  
In order to meet FDA’s objective of a large subject cohort prospectively 
followed to confirm long-term safety of the Siello pacing lead, BIOTRONIK will 
continue enrollment for a long-term Post-Approval Registry designed to follow 
a total of 2124 leads (combined atrial and  ventricular) in up to 2124 subjects 
for a target follow-up time of 5 years post implant. A minimum number of 1694 
right ventricular leads will be enrolled in the study. 
Purpose: 
The purpose of the Pre-Market Study is to demonstrate the safety and 
effectiveness of the BIOTRONIK Siello pacing lead. The evaluation of safety 
will be based on the analysis of the Siello lead-related adverse events in a 
follow-up time of 12 months post implant. The evaluation of effectiveness will 
be based on the analysis of the success rate of the implanted system including 
one or two Siello leads to sense and deliver pacing at 12 months post-implant. 
The purpose of the Post-Approval Registry is to confirm long-term safety of the 
BIOTRONIK Siello pacing lead. The evaluation of safety will be based on the 
analysis of Siello pacing lead-related adverse events in a follow-up time of 5 
years post implant. Additionally, acute and chronic lead parameters for pacing 
and sensing thresholds and impedance will be evaluated.  
Subject Population: 
Subjects who require treatment for bradycardia requiring the implantation of a 
pacemaker system including an atrial and/or a ventricular pacing lead. 
Subjects need to be enrolled in the study before implantation of a BIOTRONIK 
system, including one or two Siello leads.  
Enrollment: 
The Pre-Market Study will include up to 986 subjects from up to 75 centers. 
Data on a total of a minimum of 887 leads (387 atrial and 500 ventricular) will 
be collected for 12 months post implant. Subjects enrolled in the Pre-Market 
Study will continue to be followed in the Post-Approval Registry. 
The Post-Approval Registry will include up to 2124 subjects from up to 75 
centers. The collection of data on a total of a minimum of 1253 leads 
(combined atrial and ventricular) will continue for five years post implant. 
Clinical Sites: 
Up to 75 sites in the United States. 

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Primary Endpoints: 
The purpose of primary endpoints 1 and 2 for pre-market analysis is to 
evaluate the overall incidence of adverse events related to the atrial and 
ventricular Siello leads within 12 months post-implant. The purpose of primary 
endpoint 3 is to evaluate the overall success rate of the implanted system 
including one or two Siello leads to sense and deliver pacing at 12 months 
post-implant. Primary endpoints 1, 2 and 3 will be evaluated once 387 Siello 
atrial leads and 500 Siello ventricular leads have reached the 12-month follow-
up time point.  
The purpose of primary endpoint 4 is to evaluate the overall incidence of 
adverse events related to the Siello lead in the primary RV lead position within 
5 years post implant. The purpose of primary endpoint 5 is to evaluate the 
incidence of each type of adverse event that contributes to primary endpoint 4, 
within 5 years post implant.  
Secondary Endpoint: 
The following secondary endpoints will also be evaluated during the study: 
1. 5-year Adverse Event-Free Rate for the Secondary (RA) lead position 
2. Individual Adverse Event Rates for the Secondary (RA) lead position at 
5-years 
3. Pacing threshold, sensing and impedance measurements for the atrial 
and ventricular Siello leads at 12-months post-implant 
4. Success rate of the implanted system including a Siello lead to deliver 
long-term pacing through 5 years post-implant 
5. Adverse event rates for AEs excluded from primary safety endpoint 
through 5 years post-implant. 
6. Pacing threshold, sensing and impedance measurements for the Siello 
leads through 5 years post-implant 
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 includes a Pre-Market Study (IDE) phase and an FDA required Post-
Approval Registry phase for BIOTRONIK’s Siello S (active fixation), further referred to 
as Siello lead throughout this protocol. Under this protocol, the Siello lead is utilized in 
conjunction 
with 
any 
market-released 
BIOTRONIK 
Evia 
pacemaker 
device 
(P950037/S72, dated May 7, 2010 and P950037/S92, dated February 11, 2011). 
1.2 OVERVIEW AND BACKGROUND 
1.2.1 Overview 
The purpose of this observational study is to confirm safety and reliability of the Siello 
lead as used in conjunction with any BIOTRONIK Evia pacemaker device. The study 
will provide data to characterize lead-related adverse events, from implant through 12 
months post implant to support a pre-market analysis.  In addition, the study will provide 
data to fully characterize Siello lead failures, from implant through 5 years as a post-
approval registry. Safety will be evaluated based on the analysis of all Siello lead-
related adverse events. Acute and chronic lead parameters for sensing, pacing 
thresholds, and impedance will be evaluated from implant through 12 months post 
implant for the pre-market analysis and 5 years post implant for a post-approval registry 
analysis. Reporting of all adverse events will be performed twice a year in order to 
identify and characterize any trend in adverse events, failure modes or failure rates. Up 
to 2124 subjects will be enrolled in this Post-Approval Registry, to gather data on a 
minimum total of 253 atrial and 1000 ventricular leads followed for five years post 
implant. 
In this study the Siello lead is considered an investigational device. All other devices 
included in the study are legally marketed. All devices are being prescribed by 
physicians according to approved indications for use. 
All subjects will be pre-screened to ensure they are eligible to participate, and will sign 
an informed consent prior to enrollment into the study.  The informed consent form will 
inform the subject regarding the collection of all pertinent subject, device and lead data 
from implant through 5 years post implant. 
1.2.2 Background 
The Siello S lead (active fixation) is a transvenous, bipolar, endocardial lead designed 
for permanent atrial or ventricular stimulation and sensing. The Pre-Market Study and 
Post-Approval Registry are designed to document the clinical experience of the Siello 
lead in the United States as required by the FDA. 

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1.2.3 Prior Clinical Experience 
The Siello lead is similar to BIOTRONIK’s Setrox lead. Data from the previous clinical 
studies including the Siello lead and the Setrox lead are presented in this section. 
1.2.3.1 Setrox OUS Study 
BIOTRONIK conducted a Post Market Surveillance study outside the United States on 
the Setrox S active fixation lead. The Post Market Surveillance (PMS) study was 
designed to evaluate the long term performance of the Setrox S lead based on a large 
subject population (n = 414 subjects). The sensing and pacing behavior was evaluated 
as well as the rate of device related complications over a period of at least 2 years (and 
up to 3 years). From the first implant in September 2006, 627 Setrox S leads (283 atrial, 
344 ventricular) were implanted in 414 subjects.  The mean atrial and ventricular pacing 
threshold at 24 months was 0.8 V and 0.9 V, respectively. The study reported a 
complication rate of 2.1% (13 lead-related complications) with 9 complications occurring 
within the first 4 days after implantation. 
1.2.3.2 CELESTIAL and GALAXY Studies 
BIOTRONIK is currently conducting two studies in the US on FDA approved leads 
(CELESTIAL, a post-approval study for the Corox OTW BP family of LV leads; and 
GALAXY, an after-market study for the Linox family of ICD leads), both of which include 
patients with the Setrox S lead implanted as the brady lead for the pacing system.  The 
Setrox S data collected to date from these two studies was extracted and summarized 
in an interim report. The report contains data from the 956 CELESTIAL and 960 
GALAXY subjects who have been implanted with a right atrial Setrox S lead enrolled as 
of September 16, 2011 for CELESTIAL and March 26, 2012 for GALAXY. The sensing 
and pacing behavior was evaluated as well as the rate of device related complications 
over the available follow-up period.  The mean atrial pacing threshold ranges from 0.6V 
to 0.8V. The mean atrial sensing amplitude ranges from 2.4 to 2.8 mV.  The mean atrial 
lead impedance ranges from 541 to 613 Ohms. The reported complication rate at this 
interim analysis is 1.4% (27 lead-related complications) with 11 complications occurring 
within 90 days of implant. 
1.2.3.3 Siello European Study 
BIOTRONIK completed a Post Market Evaluation in Europe which was designed to 
demonstrate the clinical effectiveness and safety of the Siello S active and Siello JT/T 
passive pacemaker lead family. This summary includes data on the Siello S active 
fixation lead.  From July 30, 2009 (first implant procedure) to November 15, 2010 (day 
of last follow-up in the report), data was collected on 191 Siello S leads in 126 subjects. 
The sensing and pacing behavior was evaluated as well as the rate of device related 
complications over a period of 1 year. 
 
The mean atrial pacing threshold at the 12 month follow-up of the Siello S lead was 0.8 
V ± 0.3 V. The mean atrial sensing amplitude at 12 months was 4.2 mV ± 2.0 mV and 

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the mean atrial impedance at 12 months was 573 Ohm ± 98 Ohm. All atrial lead 
measurements also showed stable performance over the 12 month study period. 
 
The mean ventricular pacing threshold at the 12 month follow-up of the Siello S lead 
was 0.9 V ± 0.5 V. The mean ventricular sensing amplitude at 12 months was 14.1 mV 
± 8.2 mV and the mean ventricular impedance at 12 months was 624 Ohm ± 94 Ohm. 
All ventricular lead measurements also showed stable performance over the 12 month 
study period. 
 
The Siello S complication free rate at 3 months was 96.8% with a confidence interval of 
[91.9%, 99.0%].  All complications were ventricular lead dislocations with successful 
repositioning of the lead within 3 months of implant. Five subjects died, but according to 
the investigators these deaths were not related to the Siello lead. 
1.2.3.4 Other Studies 
The following adverse events on active fixation leads have been collected and reported 
in several Summary of Safety and Effectiveness Data Reports and manuscripts.  
Table 1: Historical Adverse Events  
Adverse Events Exclusions 
Estimates of rates 
from prior studies 
(Atrial) 
Estimates of rates 
from prior studies 
(Ventricle) 
Estimates of rates 
from prior studies (A 
or V - no distinction) 
Lead dislodgement 
0 - 7.8% 
4.00% 
0 - 7.8% 
Elevated pacing threshold, 
undersensing, oversensing, loss 
of capture 
1.9 - 10.68% 
9.04% 
0.08 - 10.68% 
Implant procedure-related lead 
complications (lead reversed in 
header, loss of slack in leads) 
2.60% 
 
2.60% 
Implant procedure-related 
medical complications (e.g. 
Pleural effusion, pneumothorax, 
tamponade, cardiac perforation, 
edema, pericardial effusion, 
hematoma of the pocket, chest 
pain, venous occlusion) 
0.63 - 6% 
0.47 - 5.06% 
0.01 - 6% 
Pocket infection 
2.06% 
 
0.56% 
Extracardiac stimulation 
0.5 - 0.56% 
1.13% 
0.01 - 1.13% 
VA Crosstalk 
 
 
3.10% 
Atrial fibrillation 
0.56 - 14.29% 
 
 
Pulmonary embolism 
0.50% 
 
0.50% 
Non lead-related death 
0 - 9.2% 
0.00% 
0 - 37.86% 
Sources: 
- Summary of Safety and Effectiveness Data Report P020030 
- Summary of Safety and Effectiveness Data Report P030036 
- Boston Scientific CRM Product Performances Report, published Nov 30, 2009 
- Kistler P. M., Liew G. and Mond H. G., Long-term performance of active-fixation pacing leads: a prospective study, Pacing Clin Electrophysiol 2006; 
29: 226–230.  
- Luria D., Bar-Lev D., Gurevitz O., Granit H., Rotstein Z., Eldar M. and Glickson M., Long-term performance of screw-in atrial pacing leads: a 
randomized comparison of J-shaped and straight leads, Pacing Clin Electrophysiol 2005; 28: 898–902.  
- Sterlinski M, Przybylski A, Maciag A, Syska P, Pytkowski M, Lewandowski M, et al. Subacute cardiac perforations associated with active fixation 
leads. Europace. 2009;11: 206-212. 

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1.3 DEVICE DESCRIPTIONS 
1.3.1 Siello Leads 
The Siello S is a family of 6F, steroid-eluting, transvenous, endocardial and bipolar 
active-fixation leads with an extendable/retractable and electrically active screw. The 
Siello S is manufactured, like its predecessor the Setrox S lead, in three different 
models (45, 53 and 60 cm length). It has an isodiametric structure and silicone 
insulation. The inner and outer conductors consist of quadruple wire coils. Siello S has a 
diameter of 5.9 F and is covered by a polyurethane overlay for improved gliding. It has 
an IS-1 connector and a 10 mm pole distance. The area between tip and ring is flexible 
in order to minimize the perforation risk. The fixation screw of the Siello S is electrically 
active and has a fractal iridium coating. The screw can be extended by 1.8 mm and has 
an active surface area of 4.5 mm2. The ring electrode of Siello S has a surface area of 
approximately 17.4 mm2 and is fractally coated with iridium. The Siello S has a 
dexamethasone eluting steroid collar containing 0.85 mg dexamethasone acetate. The 
accessories that are delivered with the lead are identical to the accessories of the 
Setrox S.  
Figure 1: Siello Lead 
 
 
 
 

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1.3.2 BIOTRONIK Home Monitoring 
Current expert consensus advocates 3- to 12-month device evaluations either in-person 
or by remote monitoring1.   
Home Monitoring is a communication system which allows the automatic transmission 
of diagnostic subject data from the device to the physician at any time.  The technology 
implements the use of wireless communications to provide the physician with daily 
subject monitoring and trend analysis information between office follow-up visits.  A 
block diagram of the transmission path is shown in Figure 2, and the transmission steps 
are described as follows: 
• Communication starts with the implant, which activates a very low power RF 
transmitter circuitry integrated within the pulse generator.   
• The subject device accepts subject 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. 
• 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 2: Home Monitoring Transmission Path 
 
 
 
BIOTRONIK conducted the TRUST study to evaluate the safety and effectiveness of 
Home Monitoring. BIOTRONIK received FDA approval (P050023/S020, approved May 
12, 2009) of the following labeling claims regarding Home Monitoring: 
• BIOTRONIK Home Monitoring information may be used as a replacement for 
device interrogation during in-office follow-up visits. 
• 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. Home 
Monitoring data is helpful in determining the need for additional in-office 
follow-up. 
                                            
1 Wilkoff BL, et al. HRS/EHRA expert consensus on the monitoring of cardiovascular implantable 
electronic devices (CIEDs): description of techniques, indications, personnel, frequency and ethical 
considerations. Heart Rhythm 2008;5:907-25 

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• 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. 
• BIOTRONIK Home Monitoring provides early detection of arrhythmias. 
• BIOTRONIK Home Monitoring provides early detection of silent, asymptomatic 
arrhythmias. 
• Automatic early detection of arrhythmias and device system anomalies by 
BIOTRONIK Home Monitoring allows for earlier intervention than conventional 
in-office follow-ups. 
• 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. 
 
In the Evia pacemakers, Home Monitoring provides event and system information 
similar to what is currently available during office follow-up visits.  The highlighted 
information in the Home Monitoring Quick View Summary Report, Figure 3, displays the 
study related follow-up data automatically transmitted on a daily basis including: battery 
status, pacing impedance, pacing threshold, sensing amplitude (mean/min) for both the 
atrial and ventricular leads.  In addition, Home Monitoring provides automatic daily 
information on arrhythmias, lead trends, current device programming, event episodes, 
and long term trends.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Figure 3: Home Monitoring Quick View Summary Report 
 
 

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2. STUDY DESIGN 
This is a multi-center, prospective, non-randomized study designed to gather safety 
data on BIOTRONIK’s Siello S leads. All subjects enrolled into the study will have an 
implanted legally marketed BIOTRONIK Evia pacemaker system including one or two 
Siello leads.  
At enrollment, information will be collected regarding subject medical history and 
demographics. Implant data will include lead measurements, implant technique and 
lead positioning. Subjects will be seen for an in-office follow-up at 3, 6, and 12 months 
post-implant. At these follow-ups, a determination will be made whether the system is 
able to provide appropriate pacing and sensing. Additionally, the electrical parameters 
of the Siello leads will be collected, and any Siello lead-related adverse events will be 
documented.  
Subjects will continue to be followed for 5 years post-implant. Subjects with a Home 
Monitoring system may be seen for an in-office follow-up at least every 12 months and 
be followed by Home Monitoring between in-office follow-ups at least every 6 months. 
Subjects without a Home Monitoring system will be seen for an in-office follow-up at 
least every 6 months. At each follow-up, a determination will be made whether the 
system is able to provide appropriate pacing and sensing. Additionally, the electrical 
parameters of the Siello leads will be collected, and any Siello lead-related adverse 
event will be documented.  
The primary safety endpoints are constructed to capture all Siello lead-related adverse 
events (AEs) that require additional invasive intervention to resolve within 12 months 
post-implant (premarket analysis), and 5 years post-implant (post-approval analysis). 
Individual analysis of each adverse event (AE) will be conducted and reported 
throughout the study.  Primary endpoint 3 will analyze the success rate of the implanted 
system including a Siello lead to deliver long-term pacing through 12 months post 
implant.  Analysis for the pre-market primary endpoints will occur once 387 Siello atrial 
leads and 500 Siello ventricular leads have reached the 12-month follow-up time point.  
In order to meet FDA’s objective of a large subject cohort prospectively followed to 
confirm long-term safety of the Siello pacing lead, BIOTRONIK will continue enrollment 
for a long-term Post-Approval Registry designed to follow a minimum total of 1253 leads 
(combined  atrial and  ventricular) in up to 2124 enrolled subjects for a target follow-up 
time of 5 years post implant.  A minimum number of 1694 right ventricular leads will be 
enrolled in the study. 
Secondary endpoints will analyze the success rate of the implanted system including a 
Siello lead to deliver long-term pacing through 5 years post-implant, adverse event rates 
for AEs excluded from primary safety endpoint through 5 years post-implant, as well as 
pacing threshold, sensing and impedance measurements for the Siello leads through 
5 years post-implant.  The low probability of AE mandates the study size of a minimum 
of 1253 total atrial and ventricular leads in up to 2124 enrolled subjects. 
The study design is summarized in Figure 4. 
 

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Figure 4: Flowchart of Study Design 
 
 
 
 
IDE Approval 
Enroll “Pre-Market” Cohort: 430 
Atrial and 556 Ventricular Leads 
Enrollment Completed When 
2124 Siello Leads are Implanted 
(Minimum 1694 RV Leads) 
”Post-Approval” Reporting 
Phase Begins 
387 Atrial and 500 Ventricular 
Leads Complete 12 Month 
Follow-up 
Analysis of Primary 
Endpoints 1-3.  
FDA Approval of the Siello Lead 
Initial Enrollment 
Continue Enrollment 
Continue Follow-up 

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2.1 STUDY ENDPOINTS 
This study includes the assessments of four primary safety endpoints related to the 
atrial and ventricular Siello leads, and several secondary endpoints that evaluate the 
effectiveness of the BIOTRONIK system including one or two Siello leads. The 
hypotheses associated with the primary safety endpoint are presented below. 
Success Criteria 
The Pre-Market evaluation at 12 months will be considered a success, if the safety 
endpoints (Primary Endpoints 1 and 2) and effectiveness endpoint (Primary Endpoint 3) 
are met. 
The Post-Market evaluation at 5 years will be considered a success, if the Pre-Market 
evaluation is successful and the long-term safety endpoints (Primary Endpoints 4 and 5) 
are met. 
2.1.1 Primary Endpoint 1: Atrial Siello Lead Safety – 12-Month Adverse 
Event-Free Rate (Pre-Market Analysis) 
The purpose of primary endpoint 1 is to evaluate the overall incidence of adverse 
events related to the Siello leads (as defined in Section 10.4) implanted in the atrium 
with a BIOTRONIK Evia pacemaker device.   
Assuming that the expected atrial Siello lead-related adverse event rate at 12 months 
post-implant (proportion of subjects with at least one AE in the timeframe from implant 
through 12 months post-implant), excluding the adverse events listed above, is 6.0% 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 the atrial Siello leads at 12 months post-
implant is less than or equal to 94.0% 
 
AEFR ≤ 94.0% 
Ha: The adverse event-free rate (AEFR) for the atrial Siello leads at 12 months post-
implant is greater than 94.0% 
 
AEFR > 94.0% 
A rejection of the null hypothesis would demonstrate evidence that the adverse event-
free rate is greater than 94.0%. 
2.1.2 Primary Endpoint 2: Ventricular Siello Lead Safety – 12-Month 
Adverse Event-Free Rate (Pre-Market Analysis) 
The purpose of primary endpoint 2 is to evaluate the overall incidence of adverse 
events related to the Siello leads (as defined in Section 10.4) implanted in the ventricle 
with a BIOTRONIK Evia pacemaker device.   

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Assuming that the expected ventricular Siello lead-related adverse event rate at 12 
months post-implant (proportion of subjects with at least one AE in the timeframe from 
implant through 12 months post-implant), excluding the adverse events listed above, is 
6.0% 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 the ventricular Siello leads at 12 months 
post-implant is less than or equal to 94.0% 
 
AEFR ≤ 94.0% 
Ha: The adverse event-free rate (AEFR) for the ventricular Siello leads at 12 months 
post-implant is greater than 94.0% 
 
AEFR > 94.0% 
A rejection of the null hypothesis would demonstrate evidence that the adverse event-
free rate is greater than 94.0%. 
2.1.3 Primary Endpoint 3: Siello Lead Effectiveness – Success rate of the 
implanted system including one or two Siello leads to sense and 
deliver pacing at 12-months post-implant (Pre-Market Analysis) 
The purpose of primary endpoint 3 is to evaluate the overall success rate of the 
implanted system including one or two Siello leads to sense and deliver pacing at 12-
months post-implant.  
Successful sensing performance at 12 months is the demonstrated ability to 
appropriately sense without an intervention for undersensing (i.e. Siello lead-related 
adverse event for lead undersensing or loss of sensing) in the period from implant to 12 
months, except for normal pulse generator reprogramming.   Successful pacing is the 
demonstrated ability at 12 months to deliver a stimulation pulse with capture, without an 
intervention (i.e. Siello lead-related adverse event for intermittent capture or no lead 
capture) other than normal pulse generator reprogramming.  Success is determined at 
the subject level.  If both atrial and ventricular leads have been implanted, then both 
must have successful sensing and pacing performance.   The success rate will be 
tested in the following hypotheses: 
 
Ho: The rate of successful sensing and pacing (Rate) in subjects receiving the Siello 
leads at 12 months post-implant is less than or equal to 97% 
Rate ≤ 97% 
Ha: The rate of successful sensing and pacing (Rate) in subjects receiving the Siello 
leads at 12 months post-implant is greater than 97% 
Rate > 97% 

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A rejection of the null hypothesis would demonstrate that the rate of successful sensing 
and pacing is greater than 97%. 
2.1.4 Primary Endpoint 4: Siello Lead Safety – 5-Year Adverse Event-Free 
Rate for Primary (RV) Lead Position (Post-Approval Analysis) 
The purpose of primary endpoint 4 is to evaluate the overall incidence of adverse 
events related to the Siello leads (as defined in Section 10.5) implanted in the primary 
RV position with a BIOTRONIK pacemaker device.   
Assuming that the expected Siello lead-related 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 Siello leads 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 Siello leads at 5 year 
post-implant is greater than 92.5% 
 
AEFR  > 92.5% 
A rejection of the null hypothesis would demonstrate that the adverse event-free rate is 
greater than 92.5%. 
2.1.5 Primary Endpoint 5: Siello Ventricular Lead Safety – Individual 
Adverse Event Rates for Primary (RV) Lead Position (Post-Approval 
Analysis) 
Each of the individual types of adverse events contributing to primary safety endpoint 4 
will be evaluated separately in the following superiority hypotheses: 
Ho: The individual adverse event rate (AEIndividual) for a given type of AE for the Siello 
Ventricular Leads at 5 years post-implant is equal to 1% 
 
AEIndividual =  1% 
Ha: The individual adverse event rate (AEIndividual) for a given type of AE for the Siello 
Ventricular Leads at 5 years post-implant is not equal to 1% 
 
AEIndividual ≠  1% 
If the two-sided, 95% upper confidence bound is no more than 1% for individual adverse 
events, then the null hypothesis will be rejected for that AE type.  

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2.1.6 Secondary Endpoints 
There are no formal tests of hypotheses associated with secondary endpoints 1-6. 
1. 5-year Adverse Event-Free Rate for Secondary (RA) lead position 
2. Individual Adverse Event Rates for Secondary (RA) lead position at 5-years 
3. Pacing threshold, sensing and impedance measurements for the atrial and 
ventricular Siello leads at 12-months post-implant. 
4. Success rate of the implanted system including one or two Siello leads to deliver 
long-term pacing through 5 years post-implant. 
5. Adverse event rates for AEs excluded from primary safety endpoint 4; through 5 
years post-implant. 
6. Pacing threshold, sensing and impedance measurements for the Siello leads 
through 5 years post-implant. 
2.1.7 Additional Data of Interest 
In addition to the data collected in order to support the pre-defined endpoints, the 
SIELLO Pre-Market Study will also collect other data of interest: 
1. Subject implant data 
2. Demographic information 
3. Returned product analyses 
4. Extraction experience 
2.2 STUDY SIZE 
The estimated sample size requirement for primary safety endpoints 1 and 2 are based 
on a superiority comparison of the overall AE free-rate to 94.0% at 12 months.  The 
sample size for primary safety endpoint 1 and 2 was calculated based on the following 
assumptions:   
Assumptions for primary safety endpoints 1 and 2  
• Study Design:  nonrandomized study 
• Test basis:  exact binomial test 
• Type I error (alpha):  0.025 (one-sided for superiority) 
• Statistical power:  80% 
• Estimated AE-Free Rate at 12 months:  97.0% for both RV and RA Siello Leads 
• Performance goal for AE-Free Rate at 12 months:  94.0% 
For primary safety endpoint 1, a total of 387 evaluable subjects implanted with an atrial 
Siello lead would be required to demonstrate superiority to an AE free-rate of 94.0%. 
Assuming a 10% loss to follow-up rate over 12 months of follow-up, a total of 430 
(387/0.9) subjects with an atrial lead would be required to be enrolled to evaluate 
primary safety endpoint 1. 
For primary safety endpoint 2, a total of 387 evaluable subjects implanted with a 
ventricular Siello lead would be required to demonstrate superiority to an AE free-rate of 
94.0%.  

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Since the RV position is the primary lead position, the sample size will be increased to 
500 evaluable subjects as recommended by the FDA. Assuming a 10% loss to follow-up 
rate over 12 months of follow-up, a total of 556 (500/0.9) subjects with a ventricular lead 
would be required to be enrolled to evaluate primary safety endpoint 2.   As subjects 
may have an atrial and/or ventricular lead implanted, the total number of enrolled 
subjects may be less than the total of 986 Siello leads (430 + 556). 
The estimated sample size for primary effectiveness endpoint 3 is based on a 
superiority comparison of the overall sensing and pacing success rate to 97% at 12 
months. The samples size for primary endpoint 3 was calculated based on the following 
assumptions:   
Assumptions for primary effectiveness endpoint 1 
• Study Design:  nonrandomized registry 
• Test basis:  exact binomial test 
• Type I error (alpha):  0.025 (one-sided for superiority) 
• Statistical power:  80% 
• Estimated Successful Sensing and Pacing Rate at 12 months:  99.0% for Siello 
Leads 
• Performance goal for Success Rate at 12 months:  97% 
For primary endpoint 3, a total of 432 evaluable subjects would be required to 
demonstrate superiority to a success rate of 97%. Assuming a 10% loss to follow-up 
rate over 12 months of follow-up, a total of 480 (432/0.9) subjects would be required to 
be enrolled to evaluate primary endpoint 3. 
The estimated sample sizes required to evaluate primary endpoints 4 and 5 are based 
on a superiority comparison of the overall primary RV lead position AE free-rate to 
92.5% at 5 years, and a non-powered, superiority comparison for those individual lead-
related AE to 1% at 5 years. The sample size for primary safety endpoint 4 was 
calculated based on the following assumptions:   
Assumptions for primary safety endpoint 4 
• Study 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 Siello Leads 
• Performance goal for AE-Free Rate at 12 months:  92.5% 
 
For primary safety endpoint 4, a total of 750 evaluable Siello leads in the primary RV 
lead position 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 a RV lead 
would be required to be enrolled to evaluate primary safety endpoint 4.  

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Assumptions for primary safety endpoint 5 
• Estimated individual AE rate at 5 years:  0.4% 
• Allowable two-sided, upper 95% confidence bound:  1% 
For primary safety endpoint 5, a total of 1000 evaluable subjects with Siello leads in the 
primary RV position would be required to demonstrate a two-sided, upper 95% 
confidence bound of 1%, assuming an expected individual AE rate of 0.4%. 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 1694 (1000/0.95) Siello RV leads would be 
required for evaluation of primary safety endpoint 5. As stated above, a total of 430 
subjects with Siello leads in the RA position will be enrolled for evaluation of Primary 
Endpoint 1.  Of these, 253 (430/0.95) are expected to have follow-up data available at 5 
years.  As subjects may have an atrial and/or ventricular lead implanted, the total 
number of enrolled subjects may be less than the total of 2124 Siello leads (1694 + 
430). 
The required sample sizes for the five primary endpoints are summarized in Table 2 and 
Table 3.  The total eventual study enrollment will be determined by the number of 
subjects and leads required to evaluate primary endpoints 1-5.  
Table 2: Primary Endpoints Sample Sizes (Pre-Market Analysis) 
 
Primary Safety 
Endpoint 1: 
Overall Atrial 
AE free-rate 
(12 months) 
Primary Safety 
Endpoint 2: 
Overall 
Ventricular AE 
free-rate 
(12 months) 
Primary 
Effectiveness 
Endpoint 3: 
Overall Siello 
Lead Pacing 
and Sensing 
success rate  
(12 months) 
Sample Size of Evaluable 
Siello leads / subjects 
387 leads 
500 leads 
432 subjects 
Total adjusted for 
Potential Losses to 
Follow-Up  
430 leads 
556 leads 
480 subjects 

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Table 3: Primary Safety Endpoints Sample Sizes (Post-Market Analysis) 
 
Primary Safety 
Endpoint 4: 
Overall AE 
free-rate of 
primary (Right 
Ventricular) 
lead position 
(5 years) 
Primary 
Safety 
Endpoint 5: 
Individual  
AE rates for 
primary 
(Right 
Ventricular) 
lead position 
(5 years) 
Sample Size of Evaluable 
Siello leads / subjects 
750 leads 
1000 leads 
Total adjusted for 
Potential Losses to 
Follow-Up  
1271 leads 
1694 leads 
 
Attrition 
For the sample size calculation, a maximum loss to follow-up of 10% per year (41% 
over 5 years) was assumed. The loss to follow-up rate encompasses all causes for 
subjects to be exited from the study, including subject death, device explants, subject 
directed withdrawals, physician directed withdrawals, and loss of contact with the 
subject. 
2.3 PROTOCOL REQUIREMENTS 
2.3.1 Subject Population 
The study will enroll up to 2124 subjects from up to 75 centers. After the collection of 
data for evaluation of the Pre-Market Study endpoints, enrollment and follow-up will 
continue in preparation of the Post-Approval Registry.   Expected enrollment at a single 
site should be at least 20 subjects and will be limited to no more than 15% of the 
projected total study enrollment (approximately 320 subjects).  
The investigator is responsible for pre-screening all potential subjects and selecting 
those who are appropriate for study inclusion. The subjects selected for participation will 
be from the investigator's general subject population according to the inclusion and 
exclusion criteria described below. Subjects declining participation will be documented 
on a screen failure log describing the primary reason. 

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Investigators are strongly encouraged to seek an equal enrollment of both men and 
women at their sites, to ensure that women are adequately represented in the study 
population and to enable meaningful analyses of results by gender.  If less than 40% 
women are enrolled when the prespecified enrollment is reached, open enrollment will 
be maintained for women until a proportion of 40% is obtained. 
2.3.2 Siello S Indications 
The BIOTRONIK Siello S lead is a 5.6 French (6F introducer), transvenous, steroid-
eluting (0.85 mg DXA), bipolar, IS-1 compatible, active fixation lead intended for 
permanent sensing and pacing in either the right atrium or right ventricle when used 
with a compatible pulse generator. 
 
In this study, any currently and future legally-marketed BIOTRONIK Evia pacemaker 
device (e.g. DR-T, SR-T, HF-T) in combination with one or two Siello leads may be 
used. 
2.3.3 Siello S Contraindications 
Transvenous endocardial pacing leads are contraindicated in the presence of severe 
tricuspid valvular disease and in subjects with mechanical heart valves. The Siello S 
pacing lead is additionally contraindicated for subjects who cannot tolerate a single 
systemic dose of up to 0.85 mg of dexamethasone acetate (DXA). 
2.3.4 Inclusion Criteria 
To support the objectives of this study, subjects are required to meet the following 
inclusion criteria prior to enrollment: 
• Candidate for de novo implantation of a BIOTRONIK Evia pacemaker system, 
including one or two Siello leads. Candidate meets recommendation for 
pacemaker system implant put forth by guidelines of relevant professional 
societies. 
• Able to understand the nature of the study and provide informed consent  
• Available for follow-up visits on a regular basis at the investigational site for the 
expected 5 years of follow-up 
• Age greater than or equal to 18 years 
2.3.5 Exclusion Criteria 
To support the objectives of this study, the exclusion criteria at the time of subject 
enrollment include: 
• Enrolled in any other investigational clinical study 
• Currently implanted with a pacemaker or ICD device  

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• Planned cardiac surgical procedures or interventional measures within the next 6 
months 
• Expected to receive a heart transplant within 1 year 
• Life expectancy less than 1 year 
• Presence of another life-threatening, underlying illness separate from their 
cardiac disorder 
• Pregnant at the time of enrollment 
2.4 STUDY DESIGN 
2.4.1 Study Procedures 
The study will involve up to 2124 subjects from up to 75 centers. Subjects will be 
enrolled before implantation of a BIOTRONIK system including one or two Siello leads. 
BIOTRONIK Home Monitoring should be activated in subjects who have a Home 
Monitoring system. Home Monitoring data can be utilized to assist in triage and 
diagnosis of lead-related adverse events between scheduled follow-ups.  Following the 
12-month follow-up, subjects with a Home Monitoring system will be seen for a routine 
in-office follow-up at least every 12 months and will be followed by Home Monitoring 
between routine in-office follow-ups at least every 6 months.  Subjects without a Home 
Monitoring system will be seen for a routine in-office follow-up at least every 6 months. 
 
2.4.2 Study Visits 
The specific visits for the study are: 
• Enrollment  
• Implant 
• 3-Month Follow-up  
• 6-Month Follow-up  
• 12-Month Follow-up  
• Routine Follow-up evaluations (every subsequent six months) 
• Interim Follow-ups for Siello lead-related visits 
• System Revision 
Table 4 summarizes the visit assessment schedule. 
 
 
 
 
 
 
 

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Table 4: Study Visit Assessment Schedule 
 
Enrollment 
Implant1 
3 Month 
Follow-up  
(± 1 month) 
6 Month 
Follow-up  
(± 1 month) 
12 Month 
Follow-up 
(± 1 month) 
Routine  
Follow-up 
18-60 
Months 
(every 6 
months ± 1 
month)3 
System 
Revision (if 
applicable) 
Informed Consent 
(enrollment) 
X 
 
 
 
 
 
 
Demographics and 
Medical History 
X 
 
 
 
 
 
 
Collect Implant 
Information 
 
X2 
 
 
 
 
X 
Device Evaluation 
 
X 
X 
X 
X 
X 
X 
Adverse Event 
Assessment 
 
X 
X 
X 
X 
X 
X 
Complete eCRF 
X 
X 
X 
X 
X 
X 
X 
1Implant must be completed within 30 days of informed consent. 
2If the system was planned to be implanted with a Siello lead, but the Siello lead could not implanted, the subject will exit the study 
after being followed for a period of 30-days in order to capture any adverse events possibly related to the implant procedure. 
3Following the 12-month follow-up, subjects using Home Monitoring will be seen for a routine in-office follow-up at least every 12 
months and may be followed by Home Monitoring between routine in-office follow-ups at least every 6 months.  Subjects not using 
Home Monitoring will be seen for a routine in-office follow-up at least every 6 months.  If a study visit is conducted via home 
monitoring the site is required to call the subject on the date of the home monitoring data collect and document the Investigators 
assessment of possible Adverse Events since the last study visit. 
2.4.3 Study Pre-screening   
Prior to enrollment, the subject’s background and history must be reviewed in order to 
ensure they are an appropriate candidate for the study. In addition, all subjects must 
satisfy the study inclusion and exclusion criteria prior to enrollment, including being a 
candidate for an implanted BIOTRONIK Evia pacemaker system utilizing one or two 
Siello leads.   
2.4.4 Study Enrollment Visit 
If the subject has been determined to be eligible for the study, informed consent must 
be obtained from the subject prior to initiating any study related procedures.  The 
consent process, including discussion of the study, will be documented in the subject’s 
medical record.  A subject is considered enrolled in the study upon signing the Informed 
Consent Form. 
After Informed Consent has been obtained, data is gathered during the Enrollment visit. 
The following are required at the Enrollment Visit: 
• Obtain Informed Consent 

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• Collect subject demographics (gender, height, weight, etc.) 
• Medical history of subject 
• Device implant indications 
• Complete all appropriate eCRFs  
2.4.5 Siello Implant 
Implant may be completed on the same day enrollment procedures are completed.  
Otherwise, implant will be completed within 30 days of informed consent being 
obtained.   
The following are required at Implant: 
• Collect implant information 
• Date of implant 
• Implant approach/method, and venous access 
• Implant location of pulse generator and implanted leads 
• Implant success 
• Collect information on implanted system (pulse generator and leads 
manufacturer/model, serial numbers, etc.) 
• Record electrical parameters of the implanted leads. Perform all pacing 
threshold measurements at 0.4 ms or 0.5 ms pulse width when feasible. 
• Record any lead-related, pulse generator-related and procedure-related 
adverse events during implant. If any are recorded, complete the Adverse 
Event eCRF. 
• Programming parameters should be set to best suit the needs of the subject. 
• Complete all appropriate eCRFs.  
If the system was planned to include a Siello lead, but the subject could not be 
implanted with a lead, the subject will exit the study after being followed for a period of 
30-days in order to capture any adverse events possibly related to the implant 
procedure. 
2.4.6 3-Month Follow-up  
Three months (± 1 month) after implant, subjects will undergo an assessment of their 
implanted system.  The following are required at the 3-month follow-up visit: 
• Interrogate programmed parameters. 
• Record electrical parameters of the implanted leads. Perform all pacing 
threshold measurements at 0.4 ms or 0.5 ms pulse width when feasible. 

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• Evaluate device diagnostics, electrical parameters and programmed 
parameters to ensure the device is correctly pacing and sensing. 
• Determine if there are any lead-related, pulse generator-related or procedure-
related adverse events. If any are recorded, complete the Adverse Event 
eCRF. 
• Complete all appropriate eCRFs. 
2.4.7 6-Month, 12-Month and Subsequent Routine Follow-ups  
Six months (± 1 month) after implant and every six months thereafter, subjects will 
undergo an assessment of their implanted system.  Following the 12-month follow-up, 
subjects using Home Monitoring may be seen for a routine in-office follow-up at least 
every 12 months and will be followed by Home Monitoring between routine in-office 
follow-ups at least every 6 months.  Subjects not using Home Monitoring will be seen for 
a routine in-office follow-up at least every 6 months. Additionally, each Home Monitoring 
follow-up will be accompanied by a follow-up patient-doctor telephone call documenting 
clinical signs and symptoms.   
Each site Principal Investigator (PI) will be trained to identify and schedule follow-ups to 
meet the required visit expectation. Additionally, the EDC will provide assistance in 
identifying properly scheduled follow-ups according to this protocol. 
The following are required at the 6-month follow-up, 12-month follow-up, and all 
subsequent routine follow-ups: 
• Assess programmed parameters. 
• Record electrical parameters of the implanted leads. Perform all pacing 
threshold measurements at 0.4 ms or 0.5 ms pulse width when feasible. 
• Evaluate device diagnostics, electrical parameters and programmed 
parameters to ensure the device is correctly pacing and sensing. 
• Determine if there are any lead-related, pulse generator-related or procedure-
related adverse events. If any are recorded, complete the Adverse Event 
eCRF. 
• Complete all appropriate eCRFs. 
2.4.8 Interim Unscheduled Follow-Ups 
Interim unscheduled follow-ups may occur anytime during the study.  Data collection is 
only required for such visits when due to Siello lead-related reasons. 
The following should be performed at each interim unscheduled follow-up visit: 
• Assess programmed parameters. 

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• Record electrical parameters of the implanted leads. Perform all pacing 
threshold measurements at 0.4 ms or 0.5 ms pulse width when feasible. 
• Evaluate device diagnostics, electrical parameters and programmed 
parameters to ensure the device is correctly pacing and sensing. 
• Determine if there are any lead-related, pulse generator-related or procedure-
related Adverse Events. If any are recorded, complete the Adverse Event 
eCRF. 
• Complete all appropriate eCRFs.  
2.4.9 System Revision 
If a pulse generator and/or lead replacement occurs during the course of the study, 
information will be collected on the extraction experience (if applicable) and the newly 
implanted generator or lead(s).   
The following are required at a system revision: 
• Collect implant information 
• Date of revision 
• Implant approach/method, and venous access 
• Implant location of pulse generator and implanted leads 
• Extraction experience (if applicable) 
• Collect information on newly implanted system (pulse generator and leads 
manufacturer/model, serial numbers, etc.) 
• Record electrical parameters of the implanted leads. Perform all pacing 
threshold measurements at 0.4 ms or 0.5 ms pulse width when feasible. 
• Record any lead-related, pulse generator-related and procedure-related 
adverse events during implant. If any are recorded, complete the Adverse 
Event eCRF. 
• Programming parameters should be set to best suit the needs of the subject. 
• Complete System Revision and Out of Service (OOS) eCRF for explanted 
components.  

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2.5   SUBJECT WITHDRAWALS, LOST-TO-FOLLOW-UP 
2.5.1 Withdrawal of Enrolled Subjects 
Once a subject is enrolled, every effort should be made to continue to follow the subject 
in the study.  However, in a trial of this duration, it is inevitable that some subjects will 
decline to participate further, change geographic location, or become non-compliant 
with the follow-up schedule.  Subjects who are implanted with one or two Siello leads 
and have all Siello leads explanted that are not replaced with another Siello lead will be 
withdrawn from the study.  However, if a subject is re-implanted with a new Siello lead, 
the subject will continue to participate in the study based on their original implant date 
and follow-up schedule. 
2.5.2 Enrolled Subjects 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.   Subjects with Home Monitoring systems where 
contact is lost may continue to be followed via Home Monitoring despite failed efforts to 
locate the subject for in-office follow-up. 
2.6 DATA ANALYSIS 
The primary analysis population for the study is the intention-to-treat (ITT) population.  
All subjects who provide informed consent, meet the enrollment criteria, and in whom an 
attempt is made to implant a Siello lead will be included in the ITT population.     
The characteristics of the study population will be described using summary descriptive 
statistics appropriate to the type of parameter, continuous or discrete, being reported.   
Confidence intervals for Adverse Event-Free Rate (AEFR) will be based on Kaplan-Meier 
estimates for freedom from adverse events together with the associated standard errors. 
Primary safety endpoints 1 and 2 will be evaluated by performing an exact, binomial test 
comparing a binomial proportion (overall AE free-rate at 12 months) to 94.0%. 
Equivalently, the lower, two-sided 95% confidence bound for the absolute difference 
between the overall AE free-rate and 94.0% must exceed zero.  Primary endpoints 1 
and 2 will be evaluated once 387 Siello atrial leads and 500 Siello ventricular leads 
have reached the 12-month follow-up time point.  
Primary effectiveness endpoint 3 of successful sensing and pacing will be evaluated by 
performing an exact binomial test comparing a binomial proportion (success sensing 
and pacing rate) to 97.0%.  It will also be summarized as a success rate at the 12-
month follow-up visit post-implant, together with the associated exact, 95% confidence 
intervals.  Primary endpoints 1, 2 and 3 must all be met for the Pre-market evaluation at 
12-months to be considered as success.   

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The secondary endpoints of pacing threshold, sensing and impedance measurements 
for the Siello leads at the 12-month visit will be summarized, using standard measures, 
including means, standard deviations, medians, minimums, and maximums.  
Primary safety endpoint 4 will be evaluated by performing an exact binomial test 
comparing the observed proportion (overall AE free-rate at 5 years) to 92.5%. 
Equivalently, the two-sided 95% lower confidence bound for the absolute difference 
between the overall AE free-rate and 92.5% must exceed zero. 
The evaluation of primary safety endpoint 5 will be based on the exact, two-sided 95% 
confidence interval for the observed, individual AE rates at 5 years.  The upper bound of 
these 95% confidence intervals must be less than 1%. 
The secondary endpoint of the 5-year adverse event-free rate for the secondary (RA) 
lead position will summarized in a Kaplan-Meier survival curve for the follow-up period, 
with the associated 95% confidence bounds. 
The secondary endpoint of the individual adverse event rates for the secondary (RA) 
lead position will be summarized by the observed, individual AE rates at 5 years and the 
associated exact, two-sided 95% intervals.  
The secondary endpoint of successful pacing through 5 years will be summarized as a 
success rate at each of the scheduled follow-up visits through 5 years post-implant, 
together with the associated exact, 95% confidence intervals.  
The secondary endpoint of other AEs at 5 years, which were excluded from the primary 
safety analyses, will also be summarized as AE rates together with their associated 
exact, 95% confidence intervals.  
The secondary endpoints of pacing threshold, sensing and impedance measurements 
for the Siello leads will be summarized at scheduled visits where they were evaluated, 
using standard measures, including means, standard deviations, medians, minimums, 
and maximums.  
2.7 TREND ANALYSES 
The primary safety endpoints are evaluated at 5 years post-implant against pre-
specified performance levels (92.5% for overall freedom from Siello lead-rated AEs, 1% 
for individual AE rates). To monitor the ongoing incidence of any potential AEs against 
the accumulating follow-up exposure post-implant, Kaplan-Meier survival curves will be 
prepared at the reporting intervals for these safety outcomes. Root causes for any 
failures, regardless of the incidence rates, will be investigated.   

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If the observed cumulative survival rates fall below the 5-year target values (92.5% of 
overall freedom from AEs, 99% for individual AEs) at any time during the study, or are 
projected to fall below the target values, then BIOTRONIK will summarize the observed 
data and the results of its failure investigations, and report the findings to the FDA at or 
before the next scheduled status report. If at any time a single unanticipated adverse 
event or device failure, or combination of events, is believed to have implications 
regarding the safety of current or future subjects, then this will be reported to the FDA 
within the statutory timeframes. 
2.8 MISSING DATA 
All possible steps will be taken to minimize missing data in the study, including 
monitoring of data forms for completeness and efforts to track and maintain contact with 
study subjects during the follow-up period.   
The reasons for any missing data in the study will be documented. BIOTRONIK will 
examine both missing-data patterns, which describe which values are observed and 
which are missing, and the missing-data mechanisms, which concerns the relationship 
between missingness and the values of variables in the study data set2. 
For evaluation of the long-term primary study endpoints (safety endpoints 4 and 5), only 
subjects who achieve 5 years of follow-up or have experienced an adverse event prior 
to 5 years will be included in the evaluation of the associated hypotheses. The 
secondary endpoint of other AEs at 5 years, excluded from the primary safety analyses, 
will be analyzed in similar manner. There will be no imputation for these missing 
adverse event outcomes. 
For purposes of Kaplan-Meier survival analyses, described in Section 2.7. Trend 
Analyses, all AE data on enrolled subjects will be included with follow-up time censored 
at the time of withdrawal or last completed follow-up visit. 
Secondary endpoints, which include successful sensing and pacing, pacing thresholds, 
sensing and impedance measurements will be analyzed in two ways. Initially, all 
available results will be summarized by scheduled visit through the 5 years of study 
follow-up. Afterwards, a last value carried forward (LVCF) will be used to estimate the 
values at the final 5-year follow-up evaluation. 
2.9 POOLABILITY ANALYSES 
The distribution in AEFR 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.  In addition, a Cochran-Mantel-Haenszel test with continuity adjustment will 
be used to assess the poolability across 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. 
                                            
2 R.J.A. Little and D.B. Rubin, 2002, Statistical Analysis with Missing Data, 2nd edition, Wiley and Sons 

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BIOTRONIK is not aware of differences in baseline and clinical characteristics 
between patients with and without Home Monitoring.  However, the potential 
difference between the patients with and without Home Monitoring will be analyzed 
to demonstrate poolability of the data. 
 
3.  DATA COLLECTION 
3.1 ELECTRONIC DATA CAPTURE (EDC) 
MedNet Solutions Incorporated is a privately-held company that specializes in web-
based clinical data management technology. MedNet will host the EDC system and 
provide a secure environment that is accessible to authorized individuals through the 
internet.  BIOTRONIK will implement a study specific configuration using this software 
to meet the data collection requirements of the protocol. The EDC system is 21 CFR 
Part 11 compliant and is the platform for electronic case report form (eCRF) data entry, 
clinical data discrepancy resolution, and access to reports for BIOTRONIK, specified 
investigational sites, and any other parties authorized by BIOTRONIK. 
3.2 ELECTRONIC CASE REPORT FORMS (ECRFS) 
Original data will be collected from each investigational 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 study. 
Subject follow-up is required for all subjects enrolled in this clinical study. The required 
follow-up visit dates are based on the Siello 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: 
• Pre-screening  
• Enrollment  
• Implant 
• 3-month follow-up (± 1 month) 
• Routine follow-ups (± 1 month) 
• Interim Unscheduled follow-up 
• Final 5 Year follow-up (± 1 month) 
• Adverse Events 
• System Revision 
• Out of Service 

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• Study Exit 
• Protocol Non-Compliance 
• Data Clarification 
3.3 DATA QUALITY CONTROL 
BIOTRONIK will review study data. At any time, reports can be generated on data 
completion and missing data by BIOTRONIK and by approved research personnel at 
each investigational site. The EDC system will be used to track received and expected 
follow-up data and eCRFs for each participant. This system provides the capability to 
monitor the status, volume, and disposition of data as well as to identify data completed, 
due, overdue, and in process. In addition, all study data will undergo extensive 
automatic edit and plausibility checks which provide information to the investigational 
sites to help improve and maintain data quality control procedures designed to detect 
inaccuracies and inconsistencies.  
3.4 SUBJECT RETENTION 
Although the study sample size has been calculated with a 10% subject attrition rate per 
year (41% total in 5 years), subject retention in a 5 year study 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. The EDC system also provides a subject follow-up scheduling tool in the form of a 
Visit Scheduler Report. This report allows research personnel to become alerted to and 
track all study subjects that should be scheduled for upcoming follow-ups. The EDC 
system will automatically provide a bi-weekly action item list to each site coordinator in 
the form of email, which includes all subjects that are due for scheduling. 
To ensure protocol and follow-up compliance at all participating investigational sites, 
BIOTRONIK monitors will conduct monitoring visits (see Section 8). Monitoring visits 
include a review of subjects that may be lost to follow-up.  
4. SUBJECT CONSENT 
Subject participation in this study is voluntary. It is required that all subjects sign an 
Institutional Review Board (IRB) approved Subject Information and Consent Form (ICF) 
prior to participation in the study. Subject informed consent must be obtained before 
enrollment and any protocol related procedures. To assist with the consent process, 
BIOTRONIK will provide a template subject ICF to participating sites. 
The investigator is required to inform BIOTRONIK and the reviewing IRB within 5 days if 
any subject did not provide appropriate consent to participate in the study. BIOTRONIK 
is then required to report any failure to obtain subject consent to the FDA within 5 
working days of learning of such an event.  

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5. SUBJECT DATA CONFIDENTIALITY 
All information sent to BIOTRONIK pertaining to each subject will be kept confidential at 
BIOTRONIK and is subject to FDA audit. Reports submitted to the physician or 
publications of study results will not make any reference to subject names. 
In order to verify the study data and ensure study integrity, monitors from BIOTRONIK, 
the FDA, and the reviewing Investigational Review Board (IRB) may review and/or copy 
the study records. 
6. RISKS AND RISK MINIMIZATION 
During the Pre-Market Study, the Siello lead is considered an investigational device. All 
other devices included in the study are legally marketed. All devices are being 
prescribed by physicians according to FDA approved indications for use. 
As with any implantable device, there are always potential risks that accompany the 
device.  The following list provides the potential risks that may occur with the Siello lead 
in combination with a pacemaker device. 
• Air embolism 
• Allergic reactions to contrast media 
• Arrhythmias 
• Bleeding or bruising in the area of the pacemaker implant 
• Body rejection phenomena 
• Cardiac tamponade 
• Chronic nerve damage 
• Damage to heart valves 
• Device migration 
• Elevated pacing thresholds 
• Embolism 
• Extrusion 
• Fluid accumulation 
• Hematoma 
• Infection 
• Keloid formation 
• Lead dislodgment 
• Lead fracture/ insulation damage 
• Lead perforation 
• Lead-related thrombosis 
• Local tissue reaction / fibrotic tissue formation 
• Muscle or nerve stimulation 

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• Myocardial damage 
• Myopotential sensing 
• Pacemaker mediated tachycardia 
• Pneumothorax 
• Pocket erosion 
• Swelling in the area of the pacemaker implant 
• Ventricular ectopy 
BIOTRONIK foresees no additional risks associated with this study beyond those stated 
in the labeling for the respective pulse generators and leads. 
7. MONITORING 
7.1 SUMMARY 
BIOTRONIK is the "sponsor" of the clinical investigation. A sponsor is 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. BIOTRONIK is required to ensure that the investigational 
device is used under the immediate direction of an investigator. As the investigator, the 
physician is responsible for conducting the study in accordance with the signed 
agreement, the investigational plan (protocol), applicable laws, FDA regulations, and 
any conditions of approval imposed by the reviewing IRB. The primary investigator must 
also accept responsibility for all aspects of the study including the actions of any co-
investigators participating in the study at the investigational site. 
7.2 MONITORS 
Monitors are trained, qualified, and designated by BIOTRONIK management to oversee 
the progress of a study at the clinical site. 
The address for submitting clinical data to BIOTRONIK for this study is: 
BIOTRONIK, Inc. 
Attn: Siello Clinical Study 
Clinical Studies Department 
6024 Jean Road 
Lake Oswego, Oregon 97035 
 
Clinical data may also be submitted by fax to: (800) 723-9220 
For technical assistance 24 hours a day, call: (800) 284-6689 
A monitor will visit the study site periodically throughout the study. BIOTRONIK may 
also require the presence of personnel from BIOTRONIK at follow-up procedures 
outlined by this protocol in order to assist the investigator and other site personnel. 
During periodic monitoring visits, assessment of the study site will include the following: 

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• Completion and submission of the required eCRFs and other applicable study 
documentation 
• Continued acceptability of the facilities 
• Adherence to the clinical protocol 
• Adherence to the applicable FDA regulations regarding the obligations of the 
investigator and maintenance of records 
8. STUDY COMPLETION 
BIOTRONIK will notify the study site upon completion or termination of the study or of 
the investigator’s participation. At BIOTRONIK’s request, an investigator will return any 
investigational devices, equipment and pertinent information in their possession. 
BIOTRONIK will provide a final report to each investigational site as required by FDA 
regulations. After FDA has agreed to terminate this study, BIOTRONIK personnel will 
conduct a study closure visit. During this final visit, BIOTRONIK will verify 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 study for a period of 2 years after the study is completed. 
9. DEVIATION FROM THE INVESTIGATIONAL PLAN 
The investigator is required to conduct this study in accordance with the signed 
investigator agreement and clinical protocol. The investigator shall notify BIOTRONIK 
and reviewing IRB in writing no later than 5 working days after any significant deviation 
from the clinical protocol that has occurred to protect the life or physical well being of a 
subject in an emergency. Except in such emergency, prior approval by BIOTRONIK is 
required for significant deviations from the clinical protocol.   
BIOTRONIK categorizes protocol non-compliance instances as either violations or 
deviations. Both protocol violations and deviations will be reported to FDA in the form of 
progress reports as necessary. 
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 
study and/or the rights, safety, or welfare of subjects. Protocol violations include, but are 
not limited to, failure to obtain consent and subject inclusion/exclusion violations. These 
violations will be reported to FDA in accordance with applicable regulatory timelines, 
and the investigator must notify the reviewing IRB per the IRB’s reporting requirements. 
Protocol violations must also be reported to BIOTRONIK via eCRFs. 
Protocol deviations are deviations from the requirements of the protocol in such a 
manner whereby data may not be usable or is not available. Protocol deviations are less 
serious in nature and may not require IRB notification as long as they do not affect the 
rights, safety, or welfare of the study subject. Protocol deviations during the study must 
be reported to BIOTRONIK via eCRFs.   

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10. ADVERSE EVENTS 
The investigator will be required to assess and classify each reported adverse event 
related to either the implant procedure, implanted pulse generator, or lead. For each 
adverse event, the investigator will indicate whether the Adverse Event relatedness to 
the Siello lead is: not related, related, possibly related, or unknown.  
All protocol defined Adverse Events will be adjudicated by the Clinical Events 
Committee (see Section 10.9 Clinical Events Committee). The Clinical Events 
Committee (CEC) will have the responsibility to adjudicate the classification of each 
reported adverse event to either the implant procedure, implanted pulse generator, or 
lead. For each adverse event, the CEC will indicate whether the Adverse Event 
relatedness to the Siello lead is: not related, related, possibly related, or unknown.  
In evaluation of the four primary safety endpoints for the Pre-Market Study and the 
Post-Approval 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 with no AEs, 
related AEs, or unrelated AEs. Subjects with a final adjudicated related AE classification 
of unknown will not have that individual unknown event contribute to or be included in 
the evaluation of primary safety endpoints. However, for purposes of Kaplan-Meier 
survival analyses, described in Section 2.7 Trend Analyses and Section 2.8 Missing 
Data, all AE data on enrolled subjects will be included, with follow-up time censored at 
the time of withdrawal or last completed follow-up visit. 
10.1 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: 
• Pneumothorax associated with the lead 
• Arrhythmias associated with the lead 
• Infection  
• Cardiac Perforation with or without tamponade associated with the lead 
• Non-healing pocket dehiscence requiring intervention 
• Hematoma  
• Pocket pain 
• Lead reversed in header 
• Loose set-screw 
• Venous occlusion 
• Pulmonary embolism  
• Damage to lead during procedure (e.g. accidental cut to lead body during pocket 
revision, device replacement, etc.) 
• Lead dislodgement during a procedure (e.g. during pocket revision, device 
replacement, etc.) 

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10.2 PULSE GENERATOR-RELATED ADVERSE EVENTS 
An AE will be classified as pulse generator-related if any one of the following occurred: 
• Premature battery depletion 
• Pulse Generator failure 
• Skin erosion 
• Twiddler’s syndrome 
10.3 LEAD-RELATED ADVERSE EVENTS 
An AE will be classified as lead-related if any one of the following occurred: 
• Lead conductor fracture 
• Lead insulation failure 
• Lead dislodgment  
• High pacing threshold 
• Intermittent capture 
• No lead capture 
• Extracardiac stimulation 
• Lead impedance out of range, high impedance 
• Lead impedance out of range, low impedance 
• Lead-related thrombosis 
• Suspected lead failure 
• Lead undersensing or loss of sensing 
 
10.4 ADVERSE EVENTS FOR THE ANALYSIS OF THE PRIMARY SAFETY ENDPOINTS 
1 AND 2 
If any of the following invasive actions occur in order to resolve an above listed Siello 
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  
 
Alternatively, if any of the following non-invasive actions occur in order to resolve an 
above listed Siello lead-related AE, the AE will be included in the primary endpoint 
analysis: 
• Lead pacing polarity or pacing mode reprogrammed due to suspected lead 
failure  
• Lead abandoned and pacing disabled due to clinical failure or suspected lead 
failure 
• Lead use continued based on medical judgment despite a known clinical failure  
or suspected lead failure 

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AEs that are corrected by reprogramming the pulse generator (other than the above) 
and resolved without invasive action, will not be considered an adverse event counted 
towards the primary endpoints. For example, electrical reprogramming of the pacing 
polarity to eliminate extracardiac stimulation will not be considered an adverse event. 
 
Siello lead-related adverse events meeting the criteria above occurring post implant 
procedure and prior to hospital discharge (i.e. lead dislodgement post procedure) will be 
counted as Primary Endpoint adverse events. 
 
Subject deaths as a result of a Siello lead-related AE will be included in the primary 
endpoint analysis. 
 
In addition, the following two procedure-related adverse events will be included in the 
analysis of primary endpoints 1 and 2: Pneumothorax associated with the Siello lead 
and Cardiac Perforation with or without tamponade associated with the Siello lead. 
 
10.5 ADVERSE EVENTS FOR THE ANALYSIS OF THE PRIMARY SAFETY ENDPOINTS 
4 AND 5  
If any of the following invasive actions occur in order to resolve an above listed Siello 
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  
 
Alternatively, if any of the following non-invasive actions occur in order to resolve an 
above listed Siello lead-related AE, the Siello lead-related AE will be included in the 
primary endpoint analysis: 
• Lead pacing polarity or pacing mode reprogrammed due to suspected lead 
failure.  
• Lead abandoned and pacing disabled due to clinical failure or suspected lead 
failure 
• Lead use continued based on medical judgment despite a known clinical failure  
or suspected lead failure 
 
AEs that are corrected by reprogramming the pulse generator (other than the above) 
and resolved without invasive action, will not be considered an adverse event counted 
towards the primary endpoints. For example, electrical reprogramming of the pacing 
polarity to eliminate extracardiac stimulation will not be considered an adverse event. 
 
Subject deaths as a result of a Siello lead-related AEs will be included in the primary 
endpoint analysis. 
 

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Primary endpoints 4 and 5 will exclude 1) lead dislodgements that occur within 30 days 
after lead implant or a lead revision procedure and 2) high pacing threshold, intermittent 
capture, no lead capture within 30 days after lead implant or a lead revision procedure 
 
In addition, the following two procedure-related adverse events will be included in the 
analysis of primary endpoints 4 and 5: Pneumothorax associated with the Siello lead 
and Cardiac Perforation with or without tamponade associated with the Siello lead. 
 
Table 5 summarizes the adverse events collected and analyzed for the primary 
endpoints.  Adverse event rates for AEs excluded from primary safety endpoint 4 will be 
evaluated as secondary endpoint 5. 
 
Table 5: Endpoint Related Adverse Events 
Adverse Event 
Relationship 
Adverse Event 
Primary 
Endpoints 
1 and 2 
Primary 
Endpoints 
4 and 5 
Procedure- 
Related Adverse 
Events 
Pneumothorax associated with the 
Siello lead 
X 
X 
Arrhythmias associated with the Siello 
lead 
 
 
Infection  
 
 
Cardiac Perforation with or without 
tamponade associated with the Siello 
lead 
X 
X 
Non-healing pocket dehiscence 
requiring intervention 
 
 
Hematoma  
 
 
Pocket pain 
 
 
Lead reversed in header 
 
 
Loose set-screw 
 
 
Venous occlusion 
 
 
Pulmonary embolism  
 
 
Damage to Siello lead during 
procedure (e.g. accidental cut to lead 
body during pocket revision, device 
replacement, etc.) 
 
 
Lead dislodgement during a 
procedure (e.g. during pocket 
revision, device replacement, etc.). 
 
 
Pulse Generator-
Related Adverse 
Events 
Premature battery depletion 
 
 
Pulse Generator failure 
 
 
Skin erosion 
 
 
Twiddler’s syndrome 
 
 

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Adverse Event 
Relationship 
Adverse Event 
Primary 
Endpoints 
1 and 2 
Primary 
Endpoints 
4 and 5 
Siello Lead-
Related Adverse 
Events3 
Lead conductor fracture 
X 
X 
Lead insulation failure 
X 
X 
Lead dislodgment 
X 
X4 
High pacing threshold 
X 
X5 
Intermittent capture  
X 
X 
No lead capture 
X 
X 
Extracardiac stimulation 
X 
X 
Lead impedance out of range, high 
impedance 
X 
X 
Lead impedance out of range, low 
impedance 
X 
X 
Lead-related thrombosis 
X 
X 
Suspected lead failure 
X 
X 
Lead undersensing or loss of sensing 
X 
X 
10.6 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 procedure-related, lead-related, and pulse generator-related 
adverse events that occur during the SIELLO Pre-Market Study and Post-Approval 
Registry to BIOTRONIK and the IRB. 
The study site will report the Adverse Event on the Adverse Event eCRF. Additionally, 
study 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. 
10.7 UNANTICIPATED ADVERSE DEVICE EFFECTS 
All devices are subject to problems or failures.  As defined in the IDE regulations 
(21CFR, Part 812.3): "Unanticipated adverse device effect" means any serious adverse 
effect on health or safety or any life-threatening problem or death caused by, or 
associated with, a device, if that effect, problem or death was not previously identified in 
nature, severity or degree of incidence in the investigational plan or application 
(including a supplementary plan or application), or any other unanticipated serious 
problem associated with a device that relates to the rights, safety or welfare of 
subjects.”  It is important to note that random component failures or problems caused by 
misuse of the product are not considered unanticipated adverse device effects. 
                                            
3 Lead-Related Adverse Events must meet one of the invasive or non-invasive actions defined in sections 
8.5.4 or 8.5.5 to be included in the primary endpoint analyses. 
4 Analysis of endpoints 4 and 5 exclude lead dislodgements that occur within 30 days after lead implant or 
a lead revision procedure 
5 Analysis of endpoints 4 and 5 exclude all high pacing threshold, intermittent capture, no lead capture 
within 30 days after lead implant or a lead revision procedure 

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If an unanticipated adverse device effect occurs, then the investigator is required to 
notify the sponsor and the reviewing IRB as soon as possible but no later than 10 
working days after the investigator first learns of the event.  If the event is serious or life 
threatening, the sponsor must be notified within 2 calendar days.  The sponsor will 
conduct an immediate evaluation of any unanticipated adverse device effects.  Devices 
that are returned will be sent to BIOTRONIK GmbH in Berlin, Germany for analysis.  
Those analyses will be trended (as appropriate) and reported to FDA as soon as they 
are available.  The sponsor will notify the FDA, all reviewing IRBs, and participating 
investigators within 10 working days after notification of the event by the investigator, as 
required by FDA regulations. 
10.8 SUBJECT DEATH 
Personnel at the investigational site will notify BIOTRONIK as soon as possible 
concerning any subject death during the investigation.  This notification should include a 
completed out-of-service eCRF, study exit eCRF death certificate, and a copy of the 
notification of the death sent to the IRB.  If a death certificate is not available, a detailed 
statement (death report) signed by the investigator must be written. The death report 
must include all of the following, if available: 
• 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 it was device- or procedure-related 
Any implanted devices that are explanted, including the Siello lead and any legally 
BIOTRONIK marketed device must be returned to BIOTRONIK for analysis, if possible. 
10.9 CLINICAL EVENTS COMMITTEE 
A Clinical Events Committee (CEC) consisting of at least 3 independent 
Electrophysiologists will be established to review and adjudicate all adverse events that 
occur during the study according to the protocol definitions. The CEC will be blinded to 
the clinical study site and the subject identity.  The CEC members will not participate as 
investigators, in order to minimize any potential bias. 
The CEC will create a study specific charter defining the adverse event adjudication 
process, specifically detailing review guidelines along with appropriate response 
timelines. 

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11. IRB APPROVAL 
Institutional Review Board (IRB) approval is required from each investigator prior to 
participation in this clinical study. Subject enrollment may not begin until both the IRB 
and BIOTRONIK have granted approval for the investigator. IRB approval is also 
required throughout the duration of this clinical study. If IRB approval is withdrawn, 
BIOTRONIK must be notified within 5 working days.  
12. OTHER GENERAL INFORMATION 
12.1 LABELING 
The study device and its associated components will have a label that will be visible on 
the pertinent shipping cartons and storage containers.  The required labels or manuals 
will bear the following information: 
• Model and serial number of the device (where appropriate) 
• Name of the device and the address of BIOTRONIK SE & Co. KG as the 
manufacturer 
• Labeling statement: “Caution: Investigational Device.  Limited by United States 
law to investigational use.”  
• All relevant contraindications, hazards, adverse device effects, interfering 
substances or devices, warnings and precautions. 
12.2 CONTROL OF THE DEVICE 
BIOTRONIK will control the distribution of devices by distributing those devices only to 
approved investigational centers and approved investigators.  BIOTRONIK will also 
keep records that indicate the place and date of shipment.  Devices are not transferable 
between investigators unless prior approval is obtained from BIOTRONIK. 
 
13.  OTHER INSTITUTIONS AND PHYSICIANS 
This clinical study is not transferable to other institutions attended by the investigator 
unless prior approval is obtained from both BIOTRONIK and the appropriate IRB. Only 
approved investigators are authorized to participate in the clinical 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 the study (such as a 
subject emergency room visit for medical treatment). In such situations, the IRB and 
investigator must continue to provide oversight for that subject’s medical care and rights 
as a research subject. BIOTRONIK will ensure that the necessary support personnel 
are available to any physician providing immediate care for a subject enrolled in the 
study in order to answer questions about the device and provide guidance in collecting 

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the necessary documentation required for the clinical study. Documentation obtained 
will then be forwarded to the approved investigator for review and signature. 
14. RECORDS AND REPORTS 
14.1 INVESTIGATOR RECORDS 
Investigators are required to maintain the following accurate, complete and current 
records relating to this study: 
• All correspondence relating to the study with another investigator, an IRB, 
BIOTRONIK, a monitor, the FDA (e.g., a letter sent from the investigator to the 
IRB), or any other regulatory agency. 
• Records showing receipt, use and disposition of all investigational devices, 
including: 
− date, quantity, and serial numbers of devices and equipment received  
− names of patients implanted with the investigational device 
− information and serial numbers of devices returned to BIOTRONIK and the 
reason(s) for return 
− information and serial numbers of  devices that are discarded (not returned to 
BIOTRONIK) 
• All clinical forms and documentation, including: 
• A copy of the signed subject consent form 
• All procedure and follow-up report forms, including supporting documents 
• Records of any adverse device effect, including supporting documentation 
• Records pertaining to subject deaths during the study 
• Documentation and rationale for any deviations from the clinical protocol 
• Any other records required by BIOTRONIK 
14.2 INVESTIGATOR REPORTS 
Investigators are required to prepare and submit to BIOTRONIK the following complete, 
accurate and timely reports on this study, when necessary: 
• Notification of a subject death during the study 
• Any unanticipated adverse device effects 
• Notification of the withdrawal of IRB approval 
• Annual progress reports prepared for the IRB notifying of any deviations from the 
study 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, FDA, or BIOTRONIK 

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The table below outlines the responsibilities, including time constraints, for submitting 
the above reports.  For further detailed description of the content and nature of these 
reports, please refer to the IDE regulations 21CFR, Part 812.150. 
 
Table 6: Investigator Reports 
Type of Report 
Prepared by 
Investigator for: 
Time Constraints of Notification 
Subject death during study 
BIOTRONIK, IRB 
As soon as possible and as required by 
reviewing IRB 
Unanticipated adverse 
device effect 
BIOTRONIK, IRB 
Within 10 working days after notification of 
effect 
Serious or life-threatening 
unanticipated adverse 
device effect 
BIOTRONIK, IRB 
Within 2 working days after notification of 
effect 
Subject withdrawal 
BIOTRONIK 
Within 5 working days 
Withdrawal of IRB approval 
BIOTRONIK 
Within 5 working days of receipt of notice of 
withdrawal of approval 
Progress report 
BIOTRONIK, IRB 
Submitted not less than yearly 
Significant deviations from 
study plan 
BIOTRONIK, IRB 
Within 5 working days after emergency to 
protect life or physical well-being of subject, 
otherwise prior approval by BIOTRONIK 
required 
Informed consent not 
obtained 
BIOTRONIK, IRB 
Within 5 working days of use 
Final summary report 
BIOTRONIK, IRB 
Within 3 months after completion or 
termination of study 
 
14.3 SPONSOR RECORDS 
BIOTRONIK will maintain the following records: 
• All correspondence pertaining to the study with the investigator(s), IRBs and FDA 
• Investigational device shipment and inventory reconciliation reports 
• Investigator agreements, financial disclosures, and current curriculum vitae 
• Name and address of each investigator and each IRB involved with the study 
• Adverse events and complaints 
• Adverse device effects (whether anticipated or unanticipated) 
• Electronic Case Report Form data 
• Confirmation of completed subject informed consent forms 
• Clinical study plan and report of prior studies 
• Pre-screening reports 
• Monitoring reports 
• Clinical progress reports 

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• Statement of the extent to which the good manufacturing practice regulation Part 
21 CFR 820 will be followed in manufacturing the Siello lead 
14.4 SPONSOR REPORTS 
BIOTRONIK is responsible for preparing the following reports, when necessary:  
Table 7: Sponsor Reports 
Type of Report 
Prepared by 
BIOTRONIK for: 
Time Constraints of Notification 
Unanticipated 
adverse device 
effect 
FDA, all reviewing IRBs 
and participating 
investigators 
Within 10 working days after notification of effect 
Withdrawal of IRB 
approval 
FDA, all reviewing IRBs 
and participating 
investigators 
Within 5 working days of receipt of notice of 
withdrawal of approval 
Withdrawal of FDA 
approval 
Reviewing IRBs and 
participating investigators 
Within 5 working days 
Current investigator 
list 
FDA 
Names and addresses of participating investigators at 
6 month intervals (starting at 6 months after FDA 
approval) 
Progress report 
FDA, all reviewing IRBs 
Submitted not less than yearly 
Recall and 
disposition 
FDA, all reviewing IRBs 
Within 30 working days and will include reasons for 
request that an investigator return, repair or otherwise 
dispose of any investigational leads 
Final report 
FDA, all reviewing IRBs 
and participating 
investigators 
Within 30 working days of completion or termination 
of study. A final report will be submitted within 6 
months after completion or termination of study. 
Informed consent 
not obtained 
FDA 
Within 5 working days of notification of use 

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APPENDIX A: DEFINITION OF TERMS 
 
AE (Adverse Event) - An unwanted effect detected in participants either procedure-
related, pulse generator-related, or lead-related. The term is used whether or not the 
effect can be attributed to the leads in the study. For the purposes of this study, 
BIOTRONIK classifies an AE as either related to the Siello lead or not-related to the 
lead.  
ACC/AHA – American College of Cardiology/American Heart Association 
Cardiac Perforation – Penetration of the lead tip through the myocardium (including 
microperforation), either clinically suspected or confirmed by chest x-ray, fluoroscopy, 
echocardiogram, intracardiac electrogram and/or visually. 
Clinical Failure – Inability of the Siello lead to correctly sense or pace in the heart, not 
attributable to a mechanical malfunction of the lead or pulse generator that remains 
unresolved despite reprogramming and/or repositioning.  
CFR – Code of Federal Regulations  
Conductor Fracture – See Lead Fracture  
Confirmed Failure – A Siello lead having clinically relevant characteristics that are 
outside the performance limits established by BIOTRONIK while implanted and in 
service, as confirmed by analysis, except for changes in characteristics that are due to 
induced malfunctions.  Lead damage caused during or after explant is not considered a 
failure. 
Chronic Threshold – Chronic threshold is defined as the pacing threshold determined 
at the subject’s 3 month follow-up visit. 
eCRF – Electronic Case Report Form 
EDC – Electronic Data Capture system 
Exit Block – The failure of an intact pacing system to capture the heart because the 
stimulation threshold exceeds the output of the pacemaker. 
Explantation of a Lead – 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 Loss of Capture – Intermittent or complete failure to achieve 
cardiac stimulation at programmed output delivered outside of the cardiac refractory 
period. 
High Pacing Threshold - One of the following definitions must be met: 
1. At implant thresholds for the Siello S lead that are greater than 3.0 Volts at 0.4ms 
or 0.5ms., or 

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2. At follow-up, pacing thresholds for the Siello S lead that are greater than 3.5V at 
0.4ms or 0.5ms. 
 
IDE – Investigational Device Exemption 
Insulation Breach/Break – Visual, electrical, or radiographic evidence of a disruption 
or break in the insulation of a lead. 
Intermittent Capture - Ineffective and inconsistent cardiac stimulation at irregular 
intervals in response to cardiac pacing delivered outside of the cardiac refractory period 
with a pacing output that exceeds the safety margin (which is 2 times the measured 
pacing threshold).  
IRB – Investigational Review Board 
Lead 
Dislodgment 
or 
Lead 
Migration 
– 
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 Fracture – Visual, electrical and/or radiographic evidence of mechanical break 
within the lead conductor (connectors, coils and/or electrodes). 
Lead Impedance Out of Range – Pacing impedance is considered abnormal if a 
measurement is ≤ 200 Ohms or ≥ 2000 Ohms. 
Loss of Sensing– Complete failure to sense any intrinsic events that occur outside the 
programmed refractory periods at programmed sensitivity settings. 
Non-healing Pocket Dehiscence – Separation of wound edges around the pocket of 
the implanted pulse generator that have 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 
the predicted date. 
Mechanical Failure – Malfunction of the Siello lead through a break in the conductor, 
insulation or connector pin leading to loss of pacing/sensing. 
RV/RA lead – Right Ventricular/ Right Atrial Lead 
Skin Erosion – Deterioration of tissue over an implanted device or the movement of a 
lead toward or through the skin. 
Suspected Generator Failure – Pulse generator issue that is potentially an electrical 
malfunction. 
Suspected Lead Failure – Siello Lead issue that is potentially a mechanical or 
electrical malfunction. 

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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. 
Twiddler’s Syndrome – A condition where the pulse generator leads are dislodged by 
the subject unwittingly rotating the subcutaneous pulse generator. 
Undersensing– Intermittent failure to sense any intrinsic events that occur outside the 
programmed refractory periods at programmed sensitivity settings. 

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APPENDIX B: TIMELINE 
Study Timeline 
The timeline of the Pre-Market Study is dependent on the IDE approval date, 
September 12, 2012. 
Additionally, BIOTRONIK made the following assumptions: 
• Ability to recruit sufficient number of interested centers (75) and enroll subjects 
with 556 ventricular and 430 atrial leads within 12 months 
• 70% local IRB, 30% central IRB 
 
Estimated Timeline 
Date 
Siello S IDE approval  
IDE date 
First IRB Approval of Pre-Market Study Clinical Site 
IDE date +4 months 
First Subject Enrolled 
IDE date +6 months 
5 Clinical Sites open, 25 ventricular leads enrolled 
IDE date +7 months 
25 Sites open, 200 ventricular leads enrolled 
IDE date +12 months 
12 Month Interim Pre-Market Study Report submitted 
IDE date +12 months 
50-75 Sites open, 556 ventricular and 430 atrial leads enrolled 
IDE date +19 months 
50-75 Sites open, 800 ventricular leads enrolled 
IDE date +24 months 
24 Month Interim Pre-Market Study Report submitted 
IDE date +24 months 
Last 12 month follow-up on first 500 ventricular and 387 atrial leads 
IDE date +31 months 
Pre-Market Approval Report submitted 
IDE date +33 months 
50-75 Sites open, 1400 ventricular leads enrolled 
IDE date +36 months 
FDA Approval 
IDE date +38 months 
Up to 75 Sites open, 2124 leads enrolled (minimum 1694 RV leads) 
IDE date +42 months 
6 Month Interim Post-Approval Registry Status Report submitted 
IDE date +44 months 
12 Month Interim Post-Approval Registry Status Report submitted 
IDE date +50 months 
18 Month Interim Post-Approval Registry Status Report submitted 
IDE date +56 months 
24 Month Interim Post-Approval Registry Status Report submitted 
IDE date +62 months 
30 Month Interim Post-Approval Registry Status Report submitted 
IDE date +68 months 
36 Month Interim Post-Approval Registry Status Report submitted 
IDE date +74 months 
42 Month Interim Post-Approval Registry Status Report submitted 
IDE date +80 months 
48 Month Interim Post-Approval Registry Status Report submitted 
IDE date +86 months 
54 Month Interim Post-Approval Registry Status Report submitted 
IDE date +92 months 
60 Month Interim Post-Approval Registry Status Report submitted 
IDE date +98 months 
Last follow-up on last enrolled subject 
IDE date +102 months 
Final Post-Approval Registry Status Report submitted 
IDE date +105 months