Evaluation of ACUITY™ X4 Quadripolar Coronary Venous Leads and RELIANCE™ 4-FRONT Defibrillation Leads: NAVIGATE X4
Phase: NA
Conditions: Cardiac Resynchronization Therapy
Sponsor: Boston Scientific Corporation

THESE DOCUMENTS ARE THE PROPERTY OF BOSTON SCIENTIFIC CORP. AND SHALL NOT BE REPRODUCED, 
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December 17, 2013 
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Evaluation of ACUITY™ X4 Quadripolar Coronary Venous Leads and 
RELIANCE™ 4-FRONT Defibrillation Leads 
 
NAVIGATE X4 Clinical Study 
 
 
 
 
CLINICAL PROTOCOL 
 
NAVIGATE X4 IDE#: G130222 
 
 
Sponsored By 
Boston Scientific, CRM 
4100 Hamline Avenue North 
St. Paul, MN 55112 
 
 
 
 
 
 
 
 
 
 
This protocol contains confidential information for use by the Investigators and their 
designated representatives participating in this clinical investigation. It should be held 
confidential and maintained in a secure location. 
Do not copy or distribute without written permission from Boston Scientific Corporation. 
 
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NAVIGATE X4 IDE# G130222 
 
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Contact Information 
Role 
Contact 
Clinical 
Contact 
Julie Ecklund, MA 
Senior Clinical Trial Manager 
Cardiac Rhythm Management 
Clinical Department,  
     Mail Stop 9-321 
4100 Hamline Avenue North 
St. Paul, MN 55112-5798 
 
Phone: (651)-582-4721 
Email: Julie.Ecklund@bsci.com 
 
Eszter Pais, MD, PhD 
Clinical Trial Manager 
Cardiac Rhythm Management 
Clinical Department,  
     Mail Stop 9-321 
4100 Hamline Avenue North 
St. Paul, MN 55112-5798 
 
Phone: (770)-512-0693 
Email: Eszter.Pais@bsci.com 
 
Coordinating  
Co-Principal 
Investigator 
Suneet Mittal, MD FACC, FHRS 
Director, Electrophysiology 
Valley Health System of NY and NJ 
 
1790 Broadway, Suite 800 
New York, NY 10019 
(212)-432-7837 
 
223 N Van Dien Avenue 
Ridgewood, NJ 07450 
(201)-432-7837  
 
Email: mittsu@valleyhealth.com 
Coordinating 
Co-Principal 
Investigator 
Martin Burke, DO  
Associate Professor of Medicine 
University of Chicago Medical Center 
5758 S. Maryland MC9024 
Chicago, IL 60637 
(773)-520-8322 
 
Email: mburke@medicine.bsd.uchicago.edu 
 
 
 
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NAVIGATE X4 IDE# G130222 
 
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Revision History 
Revision 
Number 
Release Date 
Change, Including Reason for Change 
Version AB 
December 17, 2013 
Changes to implement FDA feedback and 
clarifications 
Version AA 
August 1, 2013 
Original Version, not released for study use 
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2. PROTOCOL SYNOPSIS 
NAVIGATE X4 Clinical Study 
Evaluation of ACUITY™ X4 Quadripolar Coronary Venous Leads and RELIANCE™ 4-FRONT Defibrillation 
Leads
Objective(s) 
The objective of the NAVIGATE X4 Clinical Study is to gather data to establish the safety, 
performance and effectiveness of the ACUITY™ X4 quadripolar coronary venous leads and 
the RELIANCE 4-FRONT™ ventricular defibrillation leads to satisfy FDA requirements for pre-
market submission. Additionally, data from this study will be used to support post-market 
approval requirements for the ACUITY X4 and RELIANCE 4-FRONT leads. 
Test Leads 
ACUITY™ X4 Quadripolar Coronary Venous Leads 
RELIANCE 4-FRONT™ Ventricular Defibrillation Leads 
Model Numbers of 
Leads included in 
NAVIGATE X4 
ACUITY™ X4 Quadripolar Coronary Venous Leads* 
Tip 
Configuration 
Electrode 
Spacing 
Length 
86cm  
95cm  
Model Number 
Straight 
Even  
4671 
4672 
Spiral  
Short tip  
4674 
4675 
Long tip  
4677 
4678 
*ACUITY X4 will be investigational in the US during a portion of the study 
RELIANCE 4-FRONT™ Ventricular Defibrillation Leads* 
 
 
Lead Length 
 
 
59cm 
64cm 
70cm 
Lead 
Fixation 
Type 
Lead Type 
Model Number 
Active 
Dual Coil  
0675 
0676 
NA 
Single Coil  G 
0692 
0693 
0657 
Dual Coil  G 
0695 
0696 
0658 
Passive 
Dual Coil  
0665 
0636 
NA 
Single Coil  G 
0682 
0683 
0654 
Dual Coil  G 
0685 
0686 
0655 
*RELIANCE 4-FRONT will be investigational in the US during a portion of the study 
G= Gore ePTFE  (expanded-polytetrafluoroethylene) covered coil(s) 
 
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NAVIGATE X4 Clinical Study 
Evaluation of ACUITY™ X4 Quadripolar Coronary Venous Leads and RELIANCE™ 4-FRONT Defibrillation 
Leads 
Model Numbers of 
BSC X4 CRT-Ds 
that may be used 
in NAVIGATE X4 
Boston Scientific (BSC) X4 CRT-Ds 
Device Name 
US  
Model Numbers 
International  
Model Numbers 
Description of Port 
RV/ LV/ RA 
AUTOGEN™ X4 
G166*  
G177 
DF1/ IS4/ IS1 
AUTOGEN™ X4 
G168*  
G179 
DF4/ IS4/ IS1 
DYNAGEN™ X4 
G156 
G156 
DF1/ IS4/ IS1 
DYNAGEN™ X4 
G158 
G158 
DF4/ IS4/ IS1 
INOGEN™ X4 
G146 
G146 
DF1/ IS4/ IS1 
INOGEN™ X4 
G148 
G148 
DF4/ IS4/ IS1 
ORIGEN™ X4 
G056 
G056 
DF1/ IS4/ IS1 
ORIGEN™ X4 
G058 
G058 
DF4/ IS4/ IS1 
*AUTOGEN X4 will be investigational in the US during a portion of the study 
Additional Devices 3140 Zoom Wireless Transmitter (ZWT) 
3141 USB Cable Accessory 
2909 Multiple Application Utility (MAU) 
NOTE: the 3140 ZWT, and 2909 MAU are investigational devices in the USA only and may 
become approved for commercial use during the study 
Study Design 
The NAVIGATE X4 Clinical Study is a prospective, non-randomized, multi-center, single-arm, 
global clinical study. 
Planned Number of 
Subjects 
NAVIGATE X4 is a clinical study that will support data collection for  ACUITY X4 quadripolar 
coronary venous leads and RELIANCE 4-FRONT ventricular defibrillation leads. 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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NAVIGATE X4 Clinical Study 
Evaluation of ACUITY™ X4 Quadripolar Coronary Venous Leads and RELIANCE™ 4-FRONT Defibrillation 
Leads 
Planned Number of 
Centers/ Countries 
Up to 125 centers located in the United States, Israel, and Canada.  
ACUITY X4 
Primary Safety 
Endpoint 
Lead-related Complication-Free Rate from Implant through 6 Months Post-Implant (
 
 
ACUITY X4 
Primary 
Effectiveness 
Endpoint 1 
Pacing capture thresholds in the programmed configuration, evaluated at 3 months post-
implant (
 Responders are defined as subjects with PCT ≤ 2.5 V in the 
programmed configuration. 
ACUITY X4 
Primary 
Effectiveness 
Endpoint 2 
Pacing capture thresholds (PCT) in the proximal zone (E2, E3, or E4) for 
 analyzed 
at 3 Months post-implant. 
ACUITY X4 
Secondary 
Effectiveness 
Endpoint 1 
Sensed amplitude in the programmed configuration, analyzed at 3 Months post-implant 
ACUITY X4 
Secondary 
Effectiveness 
Endpoint 2 
Pacing impedances in the programmed configuration, analyzed at 3 months post-implant. 
RELIANCE 4-
FRONT Primary 
Safety Endpoint 1 
Lead-related Complication-Free Rate (CFR) from Implant through 3 Months Post-Implant 
RELIANCE 4-
FRONT Primary 
Safety Endpoint 2 
Lead-related Complication-Free Rate from 3 Months through 24 Months Post-Implant 
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NAVIGATE X4 Clinical Study 
Evaluation of ACUITY™ X4 Quadripolar Coronary Venous Leads and RELIANCE™ 4-FRONT Defibrillation 
Leads 
RELIANCE 4-
FRONT Secondary 
Safety Endpoint  
Detection of Ventricular Tachyarrhythmia’s (VT/VF) within 30 days of implant 
RELIANCE 4-
FRONT Primary 
Effectiveness 
Endpoint 
Pacing Thresholds at 0.5 ms pulse width, analyzed at 3 Months Post-Implant 
RELIANCE 4-
FRONT Secondary 
Effectiveness 
Endpoint 1 
Sensed Amplitude, analyzed at 3 Months Post-Implant 
RELIANCE 4-
FRONT Secondary 
Effectiveness 
Endpoint 2 
Pacing Impedance, analyzed at 3 Months Post-Implant 
RELIANCE 4-
FRONT Secondary 
Effectiveness 
Endpoint 3 
Ventricular Tachyarrhythmia (VT/VF) Shock Conversion, analyzed within 30 days of implant 
Follow-up 
Schedule 
Study procedures or clinic visits will occur at the following time periods. 
- 
Enrollment Visit (less than or equal to 30 days from implant procedure) 
- 
Implant Procedure (Day 0; all future follow ups based on this date) 
- 
Pre-Discharge Clinic Visit (3 – 72 hours) 
- 
3 Month Clinic Visit (91 ± 21 days) 
- 
6 Month Clinic Visit (182 ± 21 days) 
- 
12 Month Clinic Visit (365 ± 45 days) 
- 
18 Month Clinic Visit (547 ± 45 days) 
- 
24 Month Clinic Visit (730 ± 45 days) 
- 
30 Month Clinic Visit (913 ± 45 days) 
- 
36 Month Clinic Visit (1095 ± 45 days) 
- 
42 Month Clinic Visit (1278 ± 45 days) 
- 
48 Month Clinic Visit (1461 ± 45 days) 
- 
54 Month Clinic Visit (1643 ± 45 days) 
- 
60 Month Clinic Visit (1826 ± 45 days) 
The study will be considered complete after all subjects have completed the 5 year follow-up. 
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NAVIGATE X4 Clinical Study 
Evaluation of ACUITY™ X4 Quadripolar Coronary Venous Leads and RELIANCE™ 4-FRONT Defibrillation 
Leads 
Study Duration 
Study completion is anticipated in 2019. Primary endpoint completion and US regulatory 
submission for ACUITY X4 is anticipated after all subjects 
 have completed the 6-
Month follow-up visit. For RELIANCE 4-FRONT, primary endpoint completion and US 
regulatory submission is anticipated after all subjects implanted with the RELIANCE 4-FRONT 
lead have completed the 24-Month follow-up visit. All study required visits will be completed 
during clinic visits. 
Key Inclusion 
Criteria 
• Subjects indicated for a CRT-D that fulfill one of the following 5 criteria[1]: 
1. Subject with LVEF less than or equal to 35%, sinus rhythm, LBBB with a QRS 
duration greater than or equal to 150 ms, and a NYHA class II, III or ambulatory IV 
symptoms on GDMT* 
2. Subject with LVEF less than or equal to 35%, sinus rhythm, LBBB with a QRS 
duration 120 to 149 ms, and NYHA class II, III, or ambulatory IV symptoms on GDMT* 
3. Subject with LVEF less than or equal to 35%, sinus rhythm, a non-LBBB pattern with a 
QRS duration greater than or equal to 150 ms, and NYHA class III/ ambulatory class 
IV symptoms on GDMT* 
4. Subject with atrial fibrillation and LVEF less than or equal to 35% on GDMT* if a) the 
subject requires ventricular pacing or otherwise meets CRT criteria and b) AV nodal 
ablation or pharmacologic rate control will allow near 100% ventricular pacing with 
CRT 
5. Subject on GDMT* who have LVEF less than or equal to 35% and are undergoing 
new device placement with anticipated requirement for significant (>40%) ventricular 
pacing  
*GDMT= Guideline-directed medical therapy (formerly known as optimal pharmaceutical 
therapy (OPT)), represents optimal medical therapy as defined by ACCF/ AHA guideline-
recommended therapies (primarily Class I) 
• Subject is intended to receive the ACUITY X4 LV lead and RELIANCE 4-FRONT RV lead 
(optional in Study Phase 1) and BSC CRT-D with quad header as their initial (de novo) 
cardiac implants 
• Subject is willing and capable of providing informed consent (which can include the use of a 
legally authorized representative (LAR) for documentation of informed consent) and 
participating in all testing associated with this investigation at an approved center and at the 
intervals defined by this protocol  
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NAVIGATE X4 Clinical Study 
Evaluation of ACUITY™ X4 Quadripolar Coronary Venous Leads and RELIANCE™ 4-FRONT Defibrillation 
Leads 
• Subject is age 18 or above, or of legal age to give informed consent specific to state and 
national law 
Key Exclusion 
Criteria 
• Subject has a known or suspected sensitivity to dexamethasone acetate (DXA)  
• Subject has a mechanical tricuspid heart valve  
• Subject is enrolled in any other concurrent study, with the exception of local mandatory 
governmental registries and observational studies/registries* that are not in conflict and do 
not affect the following: 
o 
Schedule of procedures for the Study (i.e. should not cause additional or missed 
visits); 
o 
Study outcome (i.e. involve medications that could affect the heart rate of the 
subject); 
o 
Conduct of the Study per GCP/ ISO 14155:2011/ 21 CFR 812, local regulations  
• Subject is currently on the active heart transplant list 
• Subject has a documented life expectancy of less than twelve months  
• Women of childbearing potential who are or might be pregnant at the time of study 
enrollment or CRT-D System implant (method of assessment upon physician’s discretion) 
• Subjects currently requiring chronic dialysis 
*Sponsors of such studies/registries should be informed and Boston Scientific must be 
informed by the investigator about the parallel conduct of these projects in the subject and of 
the project’s basic nature. The decision if a desired mandatory governmental registry or 
observational study/ registry is in conflict with this exclusion criterion is up to the enrolling 
investigator. 
 
 
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Statistical Methods  
Endpoint Hypotheses 
and Statistical Test 
Methods 
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Sample Size 
Justification 
The overall study sample size is in accordance with current FDA requirements for lead 
approval. All endpoints for each lead (ACUITY X4 and RELIANCE 4-FRONT) are 
adequately powered to at least 80%. 
 
 
 
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2. TABLE OF CONTENTS 
1. Title Page………………………………………………………….......……………………1 
2. 
Protocol Synopsis.................................................................................................................... 4 
2. 
Table of Contents .................................................................................................................. 12 
3. 
Introduction ........................................................................................................................... 18 
4. 
Device Description................................................................................................................ 20 
4.1. 
Programming System .................................................................................................... 20 
4.1.1. 
2909 Multiple Application Utility (MAU) ........................................................... 20 
4.1.2. 
2868 PRM Software Application .......................................................................... 20 
4.2. 
Zoom Wireless Transmitter .......................................................................................... 21 
4.3. 
ACUITY X4 Quadripolar Coronary Venous LV Lead................................................. 21 
4.4. 
ACUITY X4 Quadripolar Coronary Venous Lead and Associated Accessory Models 22 
4.5. 
RELIANCE 4-FRONT Ventricular Defibrillation Leads ............................................. 22 
4.6. 
RELIANCE 4-FRONT Lead and Associated Accessory Models ................................ 23 
4.7. 
Boston Scientific X4 CRT-Ds ...................................................................................... 23 
4.7.1. 
PaceSafe Feature Overview .................................................................................. 24 
4.7.1. 
RightRate Feature Overview ................................................................................. 25 
5. 
Objectives ............................................................................................................................. 25 
6. 
Endpoints .............................................................................................................................. 25 
6.1. 
ACUITY X4 Endpoints ................................................................................................ 25 
6.1.1. 
Safety Endpoints ................................................................................................... 25 
6.1.2. 
Effectiveness Endpoints ........................................................................................ 25 
6.2. 
RELIANCE 4-FRONT Endpoints ................................................................................ 26 
6.2.1. 
Safety Endpoints ................................................................................................... 26 
6.2.2. 
Effectiveness Endpoints ........................................................................................ 26 
7. 
Design ................................................................................................................................... 26 
7.1. 
Scale and Duration ........................................................................................................ 26 
7.2. 
Justification for the Study Design ................................................................................. 28 
8. 
Subject Selection ................................................................................................................... 29 
8.1. 
Study Population and Eligibility ................................................................................... 29 
8.2. 
Inclusion Criteria .......................................................................................................... 29 
8.3. 
Exclusion Criteria ......................................................................................................... 30 
9. 
Subject Accountability .......................................................................................................... 30 
9.1. 
Point of Enrollment ....................................................................................................... 30 
9.2. 
Withdrawal .................................................................................................................... 30 
9.3. 
Subject Status and Classification .................................................................................. 31 
9.4. 
Enrollment Controls ...................................................................................................... 32 
9.5. 
End-of-Study Action Plan ............................................................................................. 32 
10. 
Study Methods .................................................................................................................. 32 
10.1. Data Collection ............................................................................................................. 32 
10.2. Study Candidate Screening ........................................................................................... 34 
10.3. Informed Consent.......................................................................................................... 34 
10.4. Enrollment Visit ............................................................................................................ 34 
10.4.1. 
Source Documentation Requirements................................................................... 34 
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10.5. Implant Visit ................................................................................................................. 34 
10.5.1. 
Pulse Generator Selection ..................................................................................... 34 
10.5.2. 
Atrial Lead Selection ............................................................................................ 35 
10.5.3. 
Right Ventricular Lead Selection.......................................................................... 35 
 
 
 
 35 
10.5.3.3. 
RELIANCE 4-FRONT ................................................................................... 35 
10.5.4. 
ACUITY X4 Left Ventricular Lead Selection ...................................................... 35 
10.5.5. 
LV Lead Delivery Method Selection .................................................................... 36 
10.5.6. 
Baseline ACUITY X4 Lead Measurements with PSA 
 ............... 36 
10.5.7. 
Baseline PSA Measurements for RA and RV Leads; 
 ..... 38 
10.5.8. 
Loss of Capture and Threshold Definition............................................................ 38 
10.5.9. 
ACUITY X4 Lead Measurements with PG .......................................................... 38 
10.5.9.1. 
Phrenic Nerve Stimulation (PNS) Testing .................................................... 40 
10.5.10. 
RA and RV Lead Measurements with PG ........................................................ 40 
10.5.11. 
Optional Ventricular Tachyarrhythmia Induction ............................................ 41 
10.5.12. 
Source Documentation Requirements............................................................... 41 
10.6. Pre-Discharge Visit ....................................................................................................... 41 
10.6.1. 
ACUITY X4 Lead Measurements with PG .......................................................... 42 
10.6.1.1. 
PNS Testing ................................................................................................... 42 
10.6.2. 
RA and RV Lead Measurements with PG ............................................................ 42 
10.6.3. 
Optional Ventricular Tachyarrhythmia Induction ................................................ 43 
10.6.4. 
Shock Therapy for Spontaneous Ventricular Tachyarrhythmia ........................... 43 
10.6.5. 
Source Documentation Requirements................................................................... 43 
10.7. Three-Month Visit ........................................................................................................ 43 
10.7.1. 
ACUITY X4 Lead Measurements with PG .......................................................... 43 
10.7.1.1. 
PNS Testing ................................................................................................... 44 
10.7.2. 
RA and RV Lead Measurements with PG ............................................................ 44 
10.7.3. 
Shock Therapy for Spontaneous Ventricular Tachyarrhythmia ........................... 44 
10.7.4. 
Source Documentation Requirements................................................................... 44 
10.8. Semi-Annual Clinic Visits from 6 months through 5 years (6, 12, 18, 24, 30, 36, 42, 
48, 54, and 60 months) .............................................................................................................. 44 
10.8.1. 
ACUITY X4, RA and RV Lead Measurements with PG ..................................... 45 
10.8.2. 
Shock Therapy for Spontaneous Ventricular Tachyarrhythmia ........................... 45 
10.8.3. 
Source Documentation Requirements................................................................... 45 
10.9. Additional Visits ........................................................................................................... 45 
10.9.1. 
Source Documentation Requirements................................................................... 46 
10.10. 
LATITUDE Remote Follow-up ................................................................................ 46 
10.11. 
Source Documents from All Study-Required Visits ................................................. 46 
10.12. 
Study Completion ..................................................................................................... 47 
10.13. 
Exceptions for Use of Investigational Software (associated with the AUTOGEN 
CRT-D) at Non-Investigational Sites........................................................................................ 47 
11. 
Statistical Considerations .................................................................................................. 48 
11.1. ACUITY X4 Endpoints ................................................................................................ 48 
11.1.1. 
ACUITY X4 Primary Safety Endpoints ............................................................... 48 
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11.1.1.1. 
Hypotheses .................................................................................................... 48 
11.1.2. 
Sample Size ........................................................................................................... 49 
11.1.3. 
Statistical Methods ................................................................................................ 49 
11.1.4. 
ACUITY X4 Primary Effectiveness Endpoint 1 .................................................. 50 
11.1.4.1. 
Hypotheses .................................................................................................... 50 
11.1.4.2. 
Sample Size ................................................................................................... 50 
11.1.4.3. 
Statistical Methods ........................................................................................ 51 
11.1.5. 
ACUITY X4 Primary Effectiveness Endpoint 2 .................................................. 51 
11.1.5.1. 
Hypotheses .................................................................................................... 51 
11.1.5.2. 
Sample Size ................................................................................................... 51 
11.1.5.3. 
Statistical Methods ........................................................................................ 52 
11.1.6. 
ACUITY X4 Secondary Effectiveness Endpoint 1 .............................................. 52 
11.1.6.1. 
Hypotheses .................................................................................................... 52 
11.1.6.2. 
Sample Size ................................................................................................... 52 
11.1.6.3. 
Statistical Methods ........................................................................................ 53 
11.1.7. 
ACUITY X4 Secondary Effectiveness Endpoint 2 .............................................. 53 
11.1.7.1. 
Hypotheses .................................................................................................... 53 
11.1.7.2. 
Sample Size ................................................................................................... 53 
11.1.7.3. 
Statistical Methods ........................................................................................ 53 
11.1.8. 
ACUITY X4 Ancillary Analyses .......................................................................... 54 
11.1.8.1. 
ACUITY X4 Ancillary Safety Objective ........................................................ 54 
11.1.8.2. 
ACUITY X4 Ancillary Data Collection ......................................................... 54 
11.2. RELIANCE 4-FRONT Endpoints ................................................................................ 54 
11.2.1. 
RELIANCE 4-FRONT Primary Safety Endpoint 1.............................................. 54 
11.2.1.1. 
Hypotheses .................................................................................................... 55 
11.2.1.2. 
Sample Size ................................................................................................... 55 
11.2.1.3. 
Statistical Methods ........................................................................................ 55 
11.2.2. 
RELIANCE 4-FRONT Primary Safety Endpoint 2.............................................. 56 
11.2.2.1. 
Hypotheses .................................................................................................... 56 
11.2.2.2. 
Sample Size ................................................................................................... 56 
11.2.3. 
Statistical Methods ................................................................................................ 56 
11.2.4. 
RELIANCE 4-FRONT Secondary Safety Endpoint............................................. 57 
11.2.4.1. 
Hypotheses .................................................................................................... 57 
11.2.4.2. 
Sample Size ................................................................................................... 57 
11.2.4.3. 
Statistical Methods ........................................................................................ 58 
11.2.5. 
RELIANCE 4-FRONT Primary Effectiveness Endpoint ..................................... 58 
11.2.5.1. 
Hypotheses .................................................................................................... 58 
11.2.5.2. 
Sample Size ................................................................................................... 58 
11.2.5.3. 
Statistical Methods ........................................................................................ 59 
11.2.6. 
RELIANCE 4-FRONT Secondary Effectiveness Endpoint 1 .............................. 59 
11.2.6.1. 
Hypotheses .................................................................................................... 59 
11.2.6.2. 
Sample Size ................................................................................................... 59 
11.2.6.3. 
Statistical Methods ........................................................................................ 60 
11.2.7. 
RELIANCE 4-FRONT Secondary Effectiveness Endpoint 2 .............................. 60 
11.2.7.1. 
Hypotheses .................................................................................................... 60 
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11.2.7.2. 
Sample Size ................................................................................................... 60 
11.2.7.3. 
Statistical Methods ........................................................................................ 60 
11.2.8. 
RELIANCE 4-FRONT Secondary Effectiveness Endpoint 3 .............................. 61 
11.2.8.1. 
Hypotheses .................................................................................................... 61 
11.2.8.2. 
Sample Size ................................................................................................... 61 
11.2.8.3. 
Statistical Methods ........................................................................................ 62 
11.2.9. 
RELIANCE 4-FRONT Ancillary Analyses.......................................................... 62 
11.2.9.1. 
RELIANCE 4-FRONT Ancillary Safety Objective ........................................ 62 
11.2.9.2. 
Additional Analyses for RELIANCE 4-FRONT ............................................ 62 
11.3. General Statistical Methods .......................................................................................... 62 
11.3.1. 
Study Success Criteria .......................................................................................... 62 
11.3.2. 
Analysis Sets ......................................................................................................... 62 
11.3.3. 
Control of Systematic Error/Bias .......................................................................... 63 
11.3.4. 
Control of Type-I Error ......................................................................................... 63 
11.3.5. 
Number of Subjects per Investigative Site............................................................ 64 
11.4. Data Analyses ............................................................................................................... 64 
11.4.1. 
Interim Analyses ................................................................................................... 64 
11.4.2. 
Pooling Analyses .................................................................................................. 65 
11.4.2.1. 
RELIANCE 4-FRONT Pooling of Cohorts ................................................... 65 
11.4.2.2. 
ACUITY X4 Pooling of Cohorts .................................................................... 65 
11.4.2.3. 
Pooling of Geographies ................................................................................ 66 
11.4.2.4. 
Pooling of investigational centers ................................................................ 66 
11.4.3. 
Subgroup Analyses ............................................................................................... 67 
11.4.4. 
Multivariate Analyses ........................................................................................... 68 
11.4.5. 
Early Projection of Ancillary Safety Endpoint Results ........................................ 68 
11.4.6. 
Accuracy of Projection Estimates for Long-term Lead-Related Complication-Free 
Rates 
68 
11.4.7. 
Changes to Planned Analyses ............................................................................... 69 
12. 
Data Management ............................................................................................................. 69 
12.1. Data Collection, Processing, and Review ..................................................................... 69 
12.2. Data Retention .............................................................................................................. 69 
13. 
Amendments ..................................................................................................................... 70 
14. 
Deviations ......................................................................................................................... 70 
15. 
Investigational Device/ Equipment Accountability .......................................................... 70 
16. 
Compliance ....................................................................................................................... 71 
16.1. Statement of Compliance .............................................................................................. 71 
16.2. Investigator Responsibilities ......................................................................................... 71 
16.2.1. 
Delegation of Responsibility................................................................................. 73 
16.3. Institutional Review Board/ Ethics Committee ............................................................ 73 
16.4. Sponsor Responsibilities ............................................................................................... 74 
16.4.1. 
Role of Boston Scientific Representatives ............................................................ 74 
16.5. Insurance ....................................................................................................................... 75 
17. 
Monitoring ........................................................................................................................ 75 
18. 
Potential Risks and Benefits ............................................................................................. 75 
18.1. Anticipated Adverse Events .......................................................................................... 75 
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18.2. Risks associated with Participation in the Clinical Study ............................................. 77 
18.3. Risk Minimization Actions ........................................................................................... 77 
18.4. Anticipated Benefits...................................................................................................... 77 
18.5. Risk to Benefit Rationale .............................................................................................. 78 
19. 
Safety Reporting ............................................................................................................... 78 
19.1. Definitions and Classification ....................................................................................... 78 
19.2. Relationship to Study Device(s) or Investigational Device Implant Procedure ........... 80 
19.3. Definition for Lead-related Adverse Events ................................................................. 80 
19.3.1. 
Definition for Lead-related Complication ............................................................ 81 
19.4. Adverse Event Classification ........................................................................................ 81 
19.5. Boston Scientific Device Deficiencies.......................................................................... 82 
19.6. Investigator Reporting Requirements ........................................................................... 83 
19.7. Reporting to Regulatory Authorities / IRBs / ECs / Investigators ................................ 84 
19.8. Subject Death Reporting ............................................................................................... 84 
19.9. Subject Death Classification ......................................................................................... 85 
20. 
Informed Consent.............................................................................................................. 88 
21. 
Committees ....................................................................................................................... 89 
21.1. NAVIGATE X4 Clinical Events Committee (CEC) .................................................... 89 
22. 
Suspension or Termination ............................................................................................... 90 
22.1. Premature Termination of the Study ............................................................................. 90 
22.1.1. 
Criteria for Premature Termination of the Study .................................................. 90 
22.2. Termination of Study Participation by the Investigator or Withdrawal of IRB/ EC 
Approval ................................................................................................................................... 90 
22.3. Requirements for Documentation and Subject Follow-up............................................ 90 
22.4. Criteria for Suspending/Terminating a Study Center ................................................... 91 
23. 
Publication Policy ............................................................................................................. 91 
24. 
Abbreviations and Definitions .......................................................................................... 92 
24.1. Abbreviations ................................................................................................................ 92 
24.2. Definitions of Terms ..................................................................................................... 93 
25. 
Investigational Device Description ................................................................................... 95 
25.1. ACUITY X4.................................................................................................................. 95 
25.2. RELIANCE 4-FRONT ................................................................................................. 96 
25.2.1. 
Active Fixation...................................................................................................... 96 
25.2.2. 
Passive Fixation .................................................................................................... 97 
25.2.3. 
Single Coil Electrode ............................................................................................ 97 
25.2.4. 
Dual Coil Electrode............................................................................................... 97 
25.2.5. 
Silicone Adhesive Backfilled Coils ...................................................................... 98 
25.2.6. 
ePTFE Covered Coils ........................................................................................... 98 
25.2.7. 
Iridium Oxide Coated Electrode ........................................................................... 98 
26. 
References ......................................................................................................................... 99 
Table of Figures 
Figure 1: ACUITY X4 Leads and Electrode Placement ............................................................... 22 
Figure 2: NAVIGATE X4 Clinical Study Phases......................................................................... 27 
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Figure 3: NAVIGATE X4 Clinical Study Design ........................................................................ 28 
Figure 4: Fluoroscopic Views of the RELIANCE 4-FRONT Active Fixation Lead Helix .......... 35 
Figure 5: ACUITY X4 Lead Selection ......................................................................................... 36 
Figure 6: Relationship between the terminal pin and ring contacts with the distal tip electrodes 
E1 – E4 ...................................................................................................................... 37 
Figure 7: ACUITY X4 Configurations to be Tested with PSA .................................................... 38 
Figure 8: ACUITY X4 Lead Measurements Required at Implant, Pre-D and 3 Months ............. 40 
Table of Tables 
Table 1: ACUITY X4 Lead Models ............................................................................................. 22 
Table 2: ACUITY X4 Lead Accessories ...................................................................................... 22 
Table 3: RELIANCE 4-FRONT Lead Models ............................................................................. 23 
Table 4: RELIANCE 4-FRONT Accessories ............................................................................... 23 
Table 5: Boston Scientific X4 CRT-Ds Allowed in NAVIGATE X4 .......................................... 24 
Table 6: ACUITY X4 and RELIANCE 4-FRONT
 ......................................................... 28 
Table 7: Data Collection Schedule for NAVIGATE X4 Clinical Study ...................................... 33 
Table 8: ACUITY X4 PSA Testing Required during Implant ..................................................... 37 
Table 9: ACUITY X4 Pacing Configuration Required for PCT Testing at Implant, Pre-D and 
Three Months Post Implant ....................................................................................... 39 
Table 10: Source Documentation Requirements .......................................................................... 46 
Table 11: Historical Complication-Free Rates from 0 to 6 Months ............................................. 48 
Table 12: Sample Size Estimates for Primary Safety Endpoint ................................................... 49 
Table 13: Sample Size Estimates for Primary Safety Endpoint ................................................... 49 
Table 14: Potential Adverse Events for Pulse Generator and/ or Lead System Implants............. 75 
Table 15: Potential Adverse Events for Coronary Venous Lead Implants ................................... 77 
Table 16: Potential Adverse Events for Implant of a Pulse Generator ......................................... 77 
Table 17: Adverse Event Definitions ............................................................................................ 78 
Table 18: Criteria for Assessing Relationship of Study Device to Adverse Event ...................... 80 
Table 19: Adverse Event Types I-V to be Used for BSC AE Classification ................................ 81 
Table 20: Definition of Observation and Complication ............................................................... 82 
Table 21: Investigator Reporting Requirements ........................................................................... 83 
Table 22: Abbreviations ................................................................................................................ 92 
Table 23: Definitions .................................................................................................................... 94 
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3. INTRODUCTION 
Cardiac resynchronization therapy (CRT) has demonstrated immediate acute hemodynamic 
improvement[2, 3] as well as long-term improvement in functional capacity, quality of life, 
symptomatic heart failure severity and mortality.[2, 4-7] Typically, CRT is administered by means 
of bi-ventricular pacing in which right ventricular (RV) pacing is delivered through standard 
endocardial leads and left ventricular (LV) stimulation is achieved through a coronary venous 
lead within a branch of the coronary sinus (CS) or great cardiac vein. LV stimulation using 
coronary venous leads and endocardial defibrillation and pace/sense leads are used as an integral 
part of an implantable cardiac resynchronization therapy (CRT-D) system. CRT-Ds are intended 
to provide ventricular anti-tachycardia pacing and ventricular defibrillation for automated 
treatment of life-threatening ventricular arrhythmias. A lead provides the insulated electrical 
conductor between the implantable pulse generator (PG) and the cardiac tissue and conducts 
sensed intrinsic cardiac electrical signals to the PG and delivers to the heart, as necessary, 
artificial stimulation from the PG. The lead is a complex mechanical structure that has to 
withstand biodegradation in the environment of the body, repetitive flexural cycles of the heart, 
and compressive and tensile forces in the extravascular space. To be successful, LV leads must 
not only be able to navigate through the vasculature to a potential target site, but they must also 
achieve good contact with viable myocardium, allow repositioning if needed, and then remain in 
a stable position over time to allow therapy delivery. Maintaining myocardial contact and stable 
positioning are often achieved by pre-shaping the distal tip of a lead or adding a feature to wedge 
it within the vessel.[8-12] Further, design requirements may be related to ease of implant handling, 
fluoroscopic visualization, diameter of the lead body, durability to last beyond the replacement 
of several PGs, performance to stimulate the cardiac tissue with low energy, ability to reliably 
sense intrinsic cardiac activity, ability to defibrillate, and a design with consideration of future 
lead extraction.  
In recent years there has been considerable focus on lead malfunctions.[13-19] As a result of this, 
Boston Scientific has continued to leverage reliable lead design attributes from currently 
marketed products and refine its design controls process to create validated, in vitro test methods. 
These test methods have informed design changes that will produce a more robust lead. There 
has also been an increase in regulatory requirements for testing of the leads both in pre-market 
clinical trials and post-market follow-up studies.  
Boston Scientific has leveraged previous design attributes, conducted in vivo pre-clinical studies, 
completed an acute human study (LILAC), and evaluated the design with validated, in vitro 
bench tests to ensure the safety and efficacy of its next generation LV lead. The ACUITY™ X4 
lead family utilizes many attributes of the current EASYTRAK 2 and ACUITY Spiral coronary 
venous leads (i.e. tine and spiral fixation, IROX coated electrodes, steroid, tapered distal tip, and 
lead body materials). The notable design changes for ACUITY X4 from the predecessor leads is 
the addition of cable conductors, an IS4 terminal and four electrodes to make a quadripolar lead.  
Although it may seem that the somewhat tortuous path of a lead within the coronary venous 
system should be enough to hold it in place, reported experiences with lead dislodgement suggest 
that some type of passive fixation is needed to counter heart motion and retrograde blood flow.[8] 
Historically, the mode of fixation has been a passive one although active fixation coronary 
venous leads are currently available. These active fixation leads have positive results in terms of 
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lead dislodgment[20-22] although extraction may be a difficult. Some implanters have reported 
success with stent implantation in order to stabilize the LV.[23-25] While others have reported 
implanting an over-the-wire LV lead, inserting a stiff stylet into the lead, and then cutting the 
stylet with no lead dislocations observed in 35 patients after 12 months of follow-up.[26] Risk 
factors for lead dislodgments may include large lead-to-vein diameter mismatch, rapid 
myocardial motion and superficial insertion.[27] 
Phrenic nerve stimulation (PNS) is a known complication of resynchronization therapy and may 
hinder LV pacing. PNS has been detected in approximately 30% of patients treated with CRT.[28] 
The ability of implanted devices to allow flexible LV pacing configurations is a useful feature 
for preventing PNS.[28-30] This essentially allows “electronic repositioning” and limits the need 
for surgical lead revision. The optimal LV pacing configuration should be determined on the 
basis of individual patient testing and can lead to successful and effective outcomes of CRT 
therapy.[31] Recent developments in LV lead design have resulted in quadripolar leads to allow 
more choices in lead placement and programming capability. 
Boston Scientific has also designed, bench tested, and animal tested a new defibrillation lead 
based on the ENDOTAK RELIANCE family of defibrillation leads, called RELIANCE 4-
FRONT™. The RELIANCE family of leads has a proven track record of performance over the 
last ten years. RELIANCE 4-FRONT maintains many of the robust design aspects from the 
RELIANCE lead family (i.e. fixation, electrode surface area and spacing, lead body 
configuration, insulation thickness and materials). The notable design change for RELIANCE 4-
FRONT from the predecessor lead is a reduced lead body diameter, enabled by a new high 
voltage conductor cable. Additional dimensional changes were made to some components in the 
lead to accommodate the smaller lead body size; while insulation thicknesses did not change 
from the RELIANCE lead family for abrasion and dielectric strength performance. The outside 
diameter allows all leads in the family to fit through an 8 French introducer when implanted 
without a retained guidewire. The lead includes an active fixation method (identical to the 
RELIANCE lead family) using an extendable/ retractable helix and a passive fixation method 
using tines. 
The objective of this study is to obtain US regulatory approval of both ACUITY X4 and 
RELIANCE 4-FRONT by gathering data to establish the safety, performance and effectiveness 
of the ACUITY X4 Quadripolar Coronary Venous Leads and RELIANCE 4-FRONT 
Defibrillation leads. Subjects enrolled into this clinical study will be indicated for a CRT-D and 
will be implanted with a RELIANCE 4-FRONT lead. Because the RELIANCE 4-FRONT leads 
have the same indications for use as existing defibrillation leads, the clinical study will seek no 
new indications for use. The endpoints related to RELIANCE 4-FRONT lead performance 
include the ability to stimulate cardiac tissue, the ability to record intrinsic cardiac activity, and 
pacing lead impedance in the normal range. Subject safety will be monitored with attention 
focused on lead-related complications throughout the study. Subjects who enroll into the 
NAVIGATE X4 Clinical Study, will be consented for 5 years of follow-up evaluation. The data 
will contribute to the total sample size necessary to satisfy post-market regulatory data collection 
requirements. 
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4. DEVICE DESCRIPTION 
The devices included in the NAVIGATE X4 Clinical Study are the ACUITY X4 LV lead 
(description included in Section 4.3), RELIANCE 4-FRONT RV lead (description included in 
Section 4.5), AUTOGEN X4 CRT-D (description included in Section 4.7), or market-released 
BSC CRT-D with quad header, 2868 PRM software application, 2909 multiple application utility 
(MAU), and the 3140 Zoom Wireless Transmitter (ZWT) that provides Medical Implantable 
Communication Services (MICS) telemetry with the market approved 3120 Zoom LATITUDE 
programmer/recorder/monitor (PRM). Devices to be used in the study that are investigational are 
summarized below.  
4.1. Programming System 
The programming system consists of the 3120 Zoom LATITUDE PRM, 2909 MAU, 2868 
software application, and the 3140 ZWT with a 3141 USB cable. The 3120 Zoom LATITUDE 
PRM is approved for commercial use. The 2909 MAU, 2868 software application and 3140 
ZWT will all be investigational in the US at the start of the NAVIGATE X4 Study.  
At the start of the NAVIGATE X4 Study a dedicated clinical 3120 Zoom LATITUDE PRM and 
investigational ZWT will be provided to US centers after they are approved to enroll. The 
dedicated clinical 3120 Zoom LATITUDE PRM, used in the US, will contain the investigational 
2909 MAU and 2868 software application and will be labeled for use only with an AUTOGEN 
X4 PG. Do not interrogate any market released PGs with the dedicated clinical 3120 Zoom 
LATITUDE PRM. During the course of the NAVIGATE X4 Study, the 2909 MAU, 2868 
software application, and the 3140 ZWT may become approved for commercial use in the US. If 
this occurs: 
• there will be no change to the protocol;  
• the dedicated clinical 3120 Zoom LATITUDE PRM will be returned to BSC after the 
market approved 2909 MAU and 2868 software version are available;  
• the 3140 ZWT labeled as investigational will be returned to BSC after the market 
approved device is available; and  
• the 3140 ZWT and 3120 Zoom LATITUDE PRM will no longer be tracked as an 
investigational device through this study after the investigational device/ equipment 
accountability log is reconciled (see Section 15). 
4.1.1. 
2909 Multiple Application Utility (MAU) 
The 2909 MAU Version 9.02 is the operational system used to launch software applications on 
the 3120 Zoom LATITUDE PRM, including the 2868 software application. 
4.1.2. 
2868 PRM Software Application 
The Model 2868 PRM Software Application is used to support the communication with the BSC 
X4 CRT-Ds in conjunction with the 2909 MAU. 
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NOTE: the version of the 2909 MAU or 2868 software application may be updated during the 
study. If this occurs, investigational centers will be notified of the new software version(s) and a 
BSC representative will update the software on the PRM. 
A programmer key (dongle) is required to interrogate the investigational (US versions) 
AUTOGEN X4 model G166-100 and G168-100 CRT-Ds. A programmer key is only available 
for use by a Boston Scientific representative. Therefore a BSC representative will need to be 
present any time the investigational AUTOGEN X4 CRT-D (G166-100, G168-100) is 
interrogated. This will continue to be a requirement during the NAVIGATE X4 Study (in 
the US) until the AUTOGEN X4 device is FDA-approved. 
During the course of the NAVIGATE X4 Study, the AUTOGEN X4 CRT-D may become 
approved for commercial use. If this occurs: 
• there will be no change to the protocol and 
• the programmer key will no longer be required to interrogate the device  
Note: Subjects in NAVIGATE X4 who are implanted with a BSC X4 CRT-D other than 
AUTOGEN X4 (INOGEN X4, ORIGEN X4, DYNAGEN X4 once they are commercially 
available) or international subjects implanted with devices outside the US, will not need to have 
their devices interrogated using the programmer key.  
4.2. Zoom Wireless Transmitter 
The ZWT, model 3140, provides radio frequency (RF) telemetry using the MICS band. The 
ZWT is connected to a 3120 Zoom LATITUDE PRM using the 3141 USB cable.  
MICS telemetry operates over a range of 402 MHz – 405 MHz using 10 channels. The ZWT is 
available for use with the 2868 software application. Inductive telemetry is also available to 
interrogate, program and communicate with the Boston Scientific X4 CRT-Ds using the wired 
telemetry wand. 
4.3. ACUITY X4 Quadripolar Coronary Venous LV Lead 
The Boston Scientific ACUITY X4 quadripolar coronary venous leads are intended for chronic 
left ventricular pacing and sensing. These steroid-eluting leads have an over-the-wire design and 
an IS41 four-pole connector. A variety of pace/sense configurations are possible with the four 
distal, IROX-coated electrodes that can function as cathodes (all four electrodes) or anodes (all 
except E1, the most distal electrode) when used with a compatible pulse generator. ACUITY X4 
leads are available in three tip configuration designs (straight tip, short tip spiral, long tip 
spiral)—intended to provide choices for a variety of patient anatomies. A small diameter, 
atraumatic tip with small diameter silicone distal sections on all lead models is designed to track 
into tortuous vasculature. 
 
1. IS4 refers to the international standard ISO 27186:2010. 
See Figure 1 below for a picture of the ACUITY X4 leads as well as the layout of the electrodes 
on the lead. Refer to Section 25.1 for a more detailed description of the ACUITY X4 leads. 
 
 
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Figure 1: ACUITY X4 Leads and Electrode Placement 
Note: Nomenclature of electrodes on the lead (E1, E2, E3, E4) is an industry standard. The 
corresponding nomenclature on the BSC PRM is as follows: 
• 
E1: LV Tip 1 
• 
E2: LV Ring 2 
• 
E3: LV Ring 3 
• 
E4: LV Ring 4 
4.4. ACUITY X4 Quadripolar Coronary Venous Lead and Associated Accessory Models 
Table 1 includes the model numbers and lead lengths of the ACUITY X4 leads.  
Table 1: ACUITY X4 Lead Models 
Tip 
Configuration 
Electrode 
Spacing 
Length 
86cm  
95cm  
Model Number 
Straight 
Even  
4671 
4672 
Spiral  
Short tip  
4674 
4675 
Long tip  
4677 
4678 
Table 2 includes the accessories used with ACUITY X4 leads. 
Table 2: ACUITY X4 Lead Accessories 
Component 
Model Number** 
ACUITY X4 Flushing Tool* 
4604 
ACUITY X4 Connector Tool* 
4625 
Vein Pick* 
6541 
Quadripolar Connector Lead Cap 
7007 
Slit Suture Sleeve (optional)  
4603 
*These accessories packaged with ACUITY X4 leads (model numbers do 
not apply) 
**Model numbers to order components as accessories  
4.5. RELIANCE 4-FRONT Ventricular Defibrillation Leads 
The RELIANCE 4-FRONT lead is designed for right-side heart applications within the ventricle, 
atrium, and superior vena cava. It is equipped with one quadripolar connector defined by ISO 
27186 [Active Implantable medical devices – Four-pole connector system for implantable 
cardiac rhythm management devices], which contains both high and low voltage connections. 
RELIANCE 4-FRONT is intended for permanent sensing, pacing, and defibrillation when used 
with a compatible Implantable Cardioverter Defibrillator (ICD) (not for the NAVIGATE X4 
Study) or Cardiac Resynchronization Therapy Defibrillator (CRT-D). For the purpose of the 
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NAVIGATE X4 Clinical Study, only commercially available or investigational BSC CRT-Ds 
with quad headers are allowed. The RELIANCE 4-FRONT lead is designed to be placed into the 
venous anatomy through an 8 Fr introducer. 
Refer to Section 25.2 for a more detailed description of this lead. 
4.6. RELIANCE 4-FRONT Lead and Associated Accessory Models 
Table 3 contains the model numbers and lead lengths of the RELIANCE 4-FRONT Leads.  
Table 3: RELIANCE 4-FRONT Lead Models 
 
 
Lead Length 
 
 
59cm 
64cm 
70cm 
Lead 
Fixation 
Type 
Lead Type 
Model Number 
Active 
Dual Coil  
0675 
0676 
NA 
Single Coil  G 
0692 
0693 
0657 
Dual Coil  G 
0695 
0696 
0658 
Passive 
Dual Coil  
0665 
0636 
NA 
Single Coil  G 
0682 
0683 
0654 
Dual Coil  G 
0685 
0686 
0655 
G= Gore ePTFE  (expanded-polytetrafluoroethylene) covered coil(s) 
Table 4 includes the accessories used with RELIANCE 4-FRONT Leads.  
Table 4: RELIANCE 4-FRONT Accessories 
Component 
Accessory Model 
Number 
Soft Straight Stylets 
6601 (59cm), 6964 
(70cm), 6972 (64cm) 
Firm Straight Stylets 
6602 (59cm), 6963 (70 
cm), 6971 (64cm) 
Vein Pick 
6541 
Quadripolar Connector Lead Cap 
7007 
EZ-4 Connector Tool 
7001 
Tunneler Accessory Kit 
6888 
Quadripolar Lead Pulling Tip 
7006 
Slit Suture Sleeve (optional) 
6403 
4.7. Boston Scientific X4 CRT-Ds 
Boston Scientific’s new family of CRT-D devices include several models as listed in Table 5. 
They provide a variety of therapies including: 
• Ventricular tachyarrhythmia therapy used to treat rhythms associated with sudden 
cardiac death such as VT and VF,  
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• CRT which treats heart failure by resynchronizing ventricular contractions through 
biventricular electrical stimulation, and  
• Bradycardia pacing, including adaptive rate pacing, to detect and treat bradyarrhythmias 
and to provide cardiac rate support after defibrillation therapy.  
This family of CRT-Ds includes models that are not intended to accept quadripolar coronary 
venous LV leads (they accept IS-1 or LV-1 coronary venous leads). Those models in the family 
that are compatible with quadripolar coronary venous leads include “X4” in their name and are 
listed in Table 5 below. As a family of devices, they will be referred to as BSC X4 CRT-Ds. All 
models in the BSC X4 CRT-D family may be implanted in NAVIGATE X4 once commercially 
available. The AUTOGEN X4 CRT-D devices are investigational in the US until approval of 
AUTOGEN (non X4) CRT-D devices; they may be used in NAVIGATE X4 while 
investigational. Therefore, there is one algorithm included in the AUTOGEN X4 that is 
investigational in the US until approval of AUTOGEN; it is PaceSafe, which is described further 
in Section 4.7.1.    
Table 5: Boston Scientific X4 CRT-Ds Allowed in NAVIGATE X4 
Device Name 
US  
Model Numbers 
International  
Model Numbers 
Description of Port 
RV/ LV/ RA 
AUTOGEN™ X4 
G166*  
G177 
DF1/ IS4/ IS1 
AUTOGEN™ X4 
G168*  
G179 
DF4/ IS4/ IS1 
DYNAGEN™ X4 
G156 
G156 
DF1/ IS4/ IS1 
DYNAGEN™ X4 
G158 
G158 
DF4/ IS4/ IS1 
INOGEN™ X4 
G146 
G146 
DF1/ IS4/ IS1 
INOGEN™ X4 
G148 
G148 
DF4/ IS4/ IS1 
ORIGEN™ X4 
G056 
G056 
DF1/ IS4/ IS1 
ORIGEN™ X4 
G058 
G058 
DF4/ IS4/ IS1 
*AUTOGEN X4 will be investigational in the US during a portion of the study 
4.7.1. 
PaceSafe Feature Overview 
The PaceSafe feature consists of two independent automatic pacing threshold determination 
algorithms: Right Atrial AutoThreshold (RAAT), and Right Ventricular AutoThreshold (RVAT) 
in AUTOGEN X4. The PaceSafe feature is designed to dynamically adjust the pacing output, 
independently in each chamber, to ensure capture by optimizing the output voltage to an 
adequate safety margin. 
The PaceSafe algorithm will be studied in a separate clinical study.  
Please refer to the AUTOGEN X4 Physician’s Technical Guide for more information regarding 
PaceSafe. 
Note: Although PaceSafe will be investigational in the US during a portion of the NAVIGATE 
X4 Study, investigators may program the feature ON at their discretion. Programming of these 
features will be collected for NAVIGATE X4.   
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4.7.1. RightRate Feature Overview 
The international AUTOGEN X4 models (G177, G179) will also include the RightRate feature 
that uses the minute ventilation sensor as a rate driver for subjects with chronotropic 
incompetence. The RightRate feature is not available in AUTOGEN X4 models in the US 
(G166, G168).  
Please refer to the AUTOGEN X4 Reference Guide for additional information on the RightRate 
feature. 
5. OBJECTIVES 
The objective of the NAVIGATE X4 Clinical Study is to gather data to establish the safety, 
performance and effectiveness of the ACUITY X4 quadripolar coronary venous leads and the 
RELIANCE 4-FRONT ventricular defibrillation leads to satisfy FDA requirements for pre-
market submission. Additionally, data from this study will be used to support post-market 
approval requirements for the ACUITY X4 and RELIANCE 4-FRONT leads. 
6. ENDPOINTS 
6.1. ACUITY X4 Endpoints 
The following endpoints will be evaluated to establish safety, performance, and effectiveness of 
the ACUITY X4 leads to satisfy US regulatory requirements. 
6.1.1. 
Safety Endpoints 
• Primary Safety Endpoint: Lead-related CFR from Implant through 6 Months Post-
Implant.  
• Ancillary Safety Objective:  Chronic Lead-related CFR through 60 Months Post-
Implant (Data from the NAVIGATE X4 Clinical Study will be pooled with data from 
a separate Post-Market Approval Study for analysis of this objective) 
6.1.2. 
Effectiveness Endpoints 
• Primary Effectiveness Endpoint 1: LV Lead Pacing Capture Thresholds in the 
programmed configuration at 3 months post-implant for ACUITY X4 
 
Responders are defined as subjects with PCT ≤ 2.5 V in the programmed 
configuration 
• Primary Effectiveness Endpoint 2:  LV Lead Pacing Capture Thresholds in the 
proximal zone (E2, E3, or E4) at 3 months post-implant for ACUITY X4 
 
• Secondary Effectiveness Endpoint 1:  Sensed Amplitude in the programmed 
configuration at Three Months Post-Implant 
• Secondary Effectiveness Endpoint 2:  Pacing Impedance in the programmed 
configuration at Three Months Post-Implant 
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6.2. RELIANCE 4-FRONT Endpoints 
The following endpoints will be evaluated to establish safety, performance, and effectiveness of 
the RELIANCE 4-FRONT leads, to satisfy US regulatory requirements. 
6.2.1. 
Safety Endpoints 
• Primary Safety Endpoint 1:  Lead-related CFR from Implant through 3 Months Post-
Implant  
• Primary Safety Endpoint 2:  Lead-related CFR from 3 through 24 Months Post-
Implant  
• Secondary Safety Endpoint:  Detection of VT/VF within 30 days of implant 
• Ancillary Safety Objective:  Chronic Lead-related CFR through 60 Months Post-
Implant (Data from the NAVIGATE X4 Clinical Study will be pooled with data from 
a separate Post-Market Approval Study for analysis of this objective) 
6.2.2. 
Effectiveness Endpoints 
• Primary Effectiveness Endpoint:  RV Lead Pacing Capture Threshold at 0.5 ms pulse 
width at Three Months Post-Implant 
• Secondary Effectiveness Endpoint 1:  Sensed Amplitude at Three Months Post-
Implant 
• Secondary Effectiveness Endpoint 2:  Pacing Impedance at Three Months Post-
Implant 
• Secondary Effectiveness Endpoint 3:  VT/ VF Shock Conversion, analyzed within 30 
days of implant 
7. DESIGN 
The NAVIGATE X4 Clinical Study is a prospective, single-arm, non-randomized, multi-center, 
global clinical study, utilizing performance goals, to demonstrate the safety, performance and 
effectiveness of the ACUITY X4 LV and RELIANCE 4-FRONT RV Leads. 
 
 
  
7.1. Scale and Duration 
The NAVIGATE X4 Clinical Study will 
 to enroll between 1542 and 
2290 subjects at up to 125 centers in the United States, Israel, and Canada. 
 
 ACUITY X4 leads are required to be implanted or attempted, whereas RELIANCE 4-
FRONT is 
 
 
  
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Subjects will be consented and followed for 5 years following implant to fulfill worldwide 
regulatory post-market approval requirements. See Figure 3.   
Figure 3: NAVIGATE X4 Clinical Study Design 
7.2. Justification for the Study Design 
To appropriately characterize performance of new lead families, the United States Food and 
Drug Administration (FDA) requires that the various leads in a lead family be studied 
 
 with minimum sample sizes for each 
depending on the type of lead.   
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
restrictions.  
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8. SUBJECT SELECTION  
8.1. Study Population and Eligibility  
Subjects included in the NAVIGATE X4 Clinical Study should be selected from the 
investigator’s general patient population indicated for CRT-D implantation. Investigators are 
responsible for screening all potential subjects and selecting those who meet the eligibility 
criteria for the study as described in Sections 8.2 and 8.3 below. 
8.2. Inclusion Criteria 
Subjects who meet all of the following criteria may be given consideration for inclusion in this 
clinical study, provided no exclusion criterion (see Section 8.3) is met. 
• Subjects indicated for a CRT-D that fulfill one of the following 5 criteria[1]: 
1. Subject with LVEF less than or equal to 35%, sinus rhythm, LBBB with a QRS 
duration greater than or equal to 150 ms, and a NYHA class II, III or ambulatory IV 
symptoms on GDMT* 
2. Subject with LVEF less than or equal to 35%, sinus rhythm, LBBB with a QRS 
duration 120 to 149 ms, and NYHA class II, III, or ambulatory IV symptoms on 
GDMT*  
3. Subject with LVEF less than or equal to 35%, sinus rhythm, a non-LBBB pattern 
with a QRS duration greater than or equal to 150 ms, and NYHA class III/ 
ambulatory class IV symptoms on GDMT* 
4. Subject with atrial fibrillation and LVEF less than or equal to 35% on GDMT* if a) 
the subject requires ventricular pacing or otherwise meets CRT criteria [listed here] 
and b) AV nodal ablation or pharmacologic rate control will allow near 100% 
ventricular pacing with CRT 
5. Subject on GDMT* who have LVEF less than or equal to 35% and are undergoing 
new device placement with anticipated requirement for significant (>40%) 
ventricular pacing  
*GDMT = Guideline-directed medical therapy (formerly known as optimal 
pharmaceutical therapy (OPT)), represents optimal medical therapy as defined by 
ACCF/ AHA guideline-recommended therapies (primarily Class I) 
• 
Subject is intended to receive the ACUITY X4 LV lead and RELIANCE 4-FRONT RV 
lead (optional in Study Phase 1) and BSC CRT-D with quad header as their initial (de 
novo) cardiac implants 
• 
Subject is willing and capable of providing informed consent (which can include the use 
of a legally authorized representative (LAR) for documentation of informed consent) and 
participating in all testing associated with this investigation at an approved center and at 
the intervals defined by this protocol  
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• 
Subject is age 18 or above, or of legal age to give informed consent specific to state and 
national law 
8.3. Exclusion Criteria 
Subjects who meet any one of the following criteria will be excluded from this clinical study. 
• 
Subject has a known or suspected sensitivity to dexamethasone acetate (DXA)  
• 
Subject has a mechanical tricuspid heart valve  
• 
Subject is enrolled in any other concurrent study, with the exception of local mandatory 
governmental registries and observational studies/registries* that are not in conflict and 
do not affect the following: 
• 
Schedule of procedures for the Study (i.e. should not cause additional or missed 
visits); 
• 
Study outcome (i.e. involve medications that could affect the heart rate of the 
subject); 
• 
Conduct of the Study per GCP/ ISO 14155:2011/ 21 CFR 812, local regulations  
• 
Subject is currently on the active heart transplant list 
• 
Subject has a documented life expectancy of less than twelve months  
• 
Women of childbearing potential who are or might be pregnant at the time of study 
enrollment or CRT-D System implant (method of assessment upon physician’s 
discretion) 
• 
Subjects currently requiring chronic dialysis 
*Sponsors of such studies/registries should be informed and Boston Scientific must be 
informed by the investigator about the parallel conduct of these projects in the subject and of 
the project’s basic nature. The decision if a desired mandatory governmental registry or 
observational study/ registry is in conflict with this exclusion criterion is up to the enrolling 
investigator. 
9. SUBJECT ACCOUNTABILITY 
9.1. Point of Enrollment 
Subjects will be considered enrolled into the NAVIGATE X4 Clinical Study at the time of 
informed consent form execution. All subject enrollments will be counted against the enrollment 
ceiling for the study.  
9.2. Withdrawal 
All subjects enrolled in the clinical study (including those withdrawn from the clinical study or 
lost to follow-up) shall be accounted for and documented. If a subject withdraws from the 
clinical investigation, the reason(s) shall be reported. If such withdrawal is due to problems 
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related to investigational device safety or performance, the investigator shall ask for the subject’s 
permission to follow his/her status/condition outside of the clinical study.   
Reasons for withdrawal may include physician discretion, subject choice to retire consent, loss to 
follow-up, or death. While study withdrawal is discouraged, subjects may withdraw from the 
study at any time, with or without reason, and without prejudice to further treatment. All 
applicable electronic case report form (eCRFs) up to the point of subject withdrawal and an “End 
of Study” eCRF must be completed. For subjects who are “lost-to-follow-up” the investigator/ 
center should have at least three documented attempts to contact the subject prior to completion 
of the “End of Study” eCRF. Additional data may no longer be collected after the point at which 
a subject has been withdrawn from the study or withdraws his/her consent, for whatever reason. 
All open adverse events should be closed or documented as chronic. Data collected up to the 
point of subject withdrawal may be used. 
9.3. Subject Status and Classification 
All patients who sign the Informed Consent form are considered enrolled in the study and count 
towards the enrollment ceiling. Subjects will be classified in the study database as follows: 
Intent - refers to a subject who has been enrolled, but then does not undergo an implant 
procedure. The original Informed Consent form and screening documentation for intent 
patients should be maintained in the Center’s files. There are no follow-up requirements for 
intent subjects; intent subjects must be withdrawn from the study. 
Partial Attempt – refers to a subject who has been enrolled and has had anesthesia 
administered in preparation for the surgical implant procedure, but does not have an 
ACUITY X4 or RELIANCE 4-FRONT lead introduced into their vasculature. There are no 
follow-up requirements for partial attempt subjects; partial attempt subjects must be 
withdrawn from the study. 
Note: In this case since neither study lead was implanted, US subjects may not be 
implanted with an AUTOGEN X4 CRT-D (while it is investigational) 
Attempt - refers to a subject who 1) has been enrolled in the NAVIGATE X4 Study, 2) has 
had anesthesia administered in preparation for the surgical implant procedure, 3) has had 
either the ACUITY X4 or RELIANCE 4-FRONT lead introduced into the subject’s 
vasculature, but 4) is not successfully implanted with either the ACUITY X4 lead or 
RELIANCE 4-FRONT lead.  
Note: In this case since neither the RELIANCE 4-FRONT lead nor the ACUITY X4  
lead was implanted, US subjects may not be implanted with an AUTOGEN X4 
CRT-D (while it is investigational) 
Attempt subjects must be followed 30 ± 7 days post-attempted ACUITY X4 and/or 
RELIANCE 4-FRONT lead implant to assure there are no associated adverse events, or to 
assure the resolution of any adverse events associated with the attempted ACUITY X4 and/ 
or RELIANCE 4-FRONT lead implants. These subjects must be withdrawn from the study 
after satisfying the 30 ± 7 day follow up. 
Implant - refers to a subject who is successfully implanted and/or tested with the ACUITY 
X4 and/or RELIANCE 4-FRONT Lead(s) per the study protocol. These subjects are 
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followed in accordance with the follow-up schedule included in this protocol and included 
in all analyses of safety, effectiveness, and performance. 
9.4. Enrollment Controls 
To support regulatory requirements approximately 1840 subjects 
 
 
 will be enrolled per this protocol. Investigational sites will be notified when the 
enrollment goal for each cohort is close to being reached and once enrollment for each cohort is 
complete. See Section 7.2 for more information on the study cohorts. 
9.5. End-of-Study Action Plan 
Boston Scientific Corporation reserves the right to terminate the study, or discontinue implanting 
one of the two study leads at any stage but intends to exercise this right only for valid scientific 
or administrative reasons and reasons related to protection of subjects. In the event of this 
occurrence, BSC will communicate to the investigators of the NAVIGATE X4 Clinical Study. 
The investigators will be responsible for communicating any information necessary to the 
subjects. BSC will support the physicians by providing recommendations for ensuring the safety 
of the subjects and the handling of the investigational devices (AUTOGEN X4 CRT-D, 
ACUITY X4 leads, and/or RELIANCE 4-FRONT leads) which may include, but are not limited 
to: 
• 
Standard of care procedures 
• 
More frequent follow ups of the subject and the lead(s) than per standard procedures 
• 
Longer term follow up (beyond consented 5-year period) 
• 
Explantation of ACUITY X4 and/ or RELIANCE 4-FRONT leads 
• 
Explantation of AUTOGEN X4 CRT-D 
• 
Other possible actions 
10. STUDY METHODS 
10.1. Data Collection 
The data collection schedule for this study is shown in Table 7 below. A reminder that the 
NAVIGATE X4 Clinical Study is 
 ACUITY X4 is required to be 
implanted or attempted 
 and RELIANCE 4-FRONT is 
 
required to be implanted or attempted 
  
 
 
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Table 7: Data Collection Schedule for NAVIGATE X4 Clinical Study 
Procedure/ 
Assessment 
Enroll-
ment 
Implant 
Pre- 
Discharge 
3 Months 
6 Months 
Semi-annual Visits 
through 5 Years 
Add’l Visits 
Timeframe 
 
≤ 30 d 
prior to 
Implant 
Implant 
3-72 h* 
Clinic Visit 
91±21 d* 
Clinic Visit 
182±21 d* 
Clinic Visit 
12 Mo: 365±45 d* 
18 Mo: 547±45 d* 
24 Mo: 730±45 d* 
2 ½ Yr: 913±45 d* 
3 Yr: 1095±45 d* 
3 ½ Yr: 1278±45 d* 
4 Yr: 1461±45 d* 
4 ½ Yr: 1643±45 d* 
5 Yr: 1826±45 d* 
Clinic Visit 
Not specified 
ICF Process 
X 
-- 
-- 
-- 
-- 
-- 
-- 
Subject demographics 
X 
-- 
-- 
-- 
-- 
-- 
-- 
Physical assessment 
X 
-- 
-- 
-- 
-- 
-- 
-- 
Medical history 
X 
-- 
-- 
-- 
-- 
-- 
-- 
PSA measurements for 
all leads (pacing 
threshold(s) @ 0.5ms) 
-- 
X (X4 
leads, 
 
else O 
-- 
-- 
-- 
-- 
-- 
PA and lateral CXR 
and/or fluoro image of 
X4 and  4-FRONT lead 
distal tip fixation 
-- 
X  
(Either/ or, not both) 
-- 
-- 
-- 
-- 
Ventricular 
tachyarrhythmia 
induction 
-- 
O 
-- 
-- 
-- 
-- 
Shock Therapy for 
Spontaneous 
Ventricular Arrhythmias 
-- 
X 
X 
X 
X 
X 
O 
Class I/ III 
Antiarrhythmic 
Medications including 
updates and changes 
X 
X 
X** 
X** 
X** 
X** 
O** 
Documentation of 
PaceSafe Programming 
-- 
X 
X 
X 
X 
X 
O 
PG lead measurements 
(sensed amplitude, 
impedance, shock lead 
impedance and PCT) 
for all implanted leads 
(pacing threshold(s) for 
RV and LV @ 0.5ms 
through 3 Month follow 
up) 
-- 
X 
X 
X 
X 
X 
X  
(if lead-
related AE), 
else O 
ECG from PRM 
documenting LOC 
-- 
X 
X 
X 
-- 
-- 
O 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
Protocol Deviations 
X 
X 
X 
X 
X 
X 
X 
Legend: X = Required; - - = Not required/ Not applicable; O = Optional;  
*Clock Starts after end of implant procedure, day of implant is day 0 and hour 0 is pocket closure 
**Collection of Class I/III antiarrhythmic medications for lead-related adverse events 
 h = hours; d = days; yr = year; AE = Adverse Event;  ECG = Electrocardiogram; LOC = Loss of Capture; PG = Pulse Generator; PSA = Pacing 
System Analyzer  
 
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10.2. Study Candidate Screening 
Boston Scientific will collect information to document potential subjects who are considered as 
NAVIGATE X4 Study candidates but are determined not to meet inclusion criteria prior to 
signing informed consent. 
10.3. Informed Consent 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria and agree to 
participate in the NAVIGATE X4 Clinical Study must give written informed consent approved 
by the regional regulatory body and the investigational center’s Institutional Review Board (IRB) 
or Ethics Committee (EC) prior to study participation and use of any investigational leads or 
testing/ data collection. The Informed Consent Form (ICF) must be in a language understandable 
to the subject and if needed, Boston Scientific will assist the center in obtaining a written consent 
translation. Translated consent forms must also have IRB/EC approval prior to their use. 
Subjects will be considered enrolled into the NAVIGATE X4 Clinical Study at the time the 
subject signs and dates the ICF. 
10.4. Enrollment Visit 
The data to be collected during enrollment into the NAVIGATE X4 Clinical Study includes 
patient demographic data, a physical assessment of the subject, including height and weight, vital 
signs, arrhythmia history, cardiac disease history, indications, and current cardiovascular 
medications. No study-specific procedures, device implant, or data collection may be conducted 
prior to consent.   
Implant or attempted implant of the ACUITY X4 and/ or RELIANCE 4-FRONT Lead(s) must 
occur within 30 days of the subject signing informed consent. 
10.4.1. Source Documentation Requirements 
See Table 10 for required source documentation of the enrollment visit. 
10.5. Implant Visit 
The PG, investigational leads (ACUITY X4 and/ or RELIANCE 4-FRONT), and any other 
commercially available leads should be implanted and tested per standard procedures and in 
accordance with the Physician’s Manuals for the associated PG and leads. 
10.5.1. Pulse Generator Selection 
Only a commercially available Boston Scientific Cardiac Resynchronization Therapy 
Defibrillator (CRT-D) with a quad header, or AUTOGEN X4 CRT-D (investigational in the US, 
see Section 4.7 for more detail) may be used in the NAVIGATE X4 Clinical Study*.   
*Note: in the event ACUITY X4 is attempted but not successfully implanted, BSC PGs 
(including ICDs) are allowed. 
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10.5.2. Atrial Lead Selection 
Any commercially available atrial pace/sense lead may be used. Boston Scientific leads are 
preferred and recommended. 
10.5.3. Right Ventricular Lead Selection 
10.5.3.1. 
 NAVIGATE X4 
Any commercially available Boston Scientific cardioversion/defibrillation lead may be used 
 NAVIGATE X4. BSC recommends the use of RELIANCE 4-FRONT. 
Documentation of RV lead choice will be collected 
 NAVIGATE X4.  
10.5.3.2. 
 NAVIGATE X4 
RELIANCE 4-FRONT is required in 
 NAVIGATE X4. If RELIANCE 4-FRONT is 
attempted, but not successfully implanted, the subject may still be a part of the study 
 
 and a commercially available RV lead 
is acceptable. Boston Scientific RV leads are required. 
10.5.3.3. RELIANCE 4-FRONT  
When implanting RELIANCE 4-FRONT Active Fixation Leads, view the radiopaque markers 
under fluoroscopy to identify when the fixation helix is fully extended. Full extension is 
achieved when the radiopaque markers are joined and the fixation helix is extended outside the 
distal fluoroscopy markers (the expected number of rotations is 11 turns for 59 and 64 cm and 12 
turns for 70 cm). Refer to Figure 4.   
 
Figure 4: Fluoroscopic Views of the RELIANCE 4-FRONT Active Fixation Lead Helix 
10.5.4. LV Lead Selection 
Subjects enrolled in the NAVIGATE X4 study are required to be implanted and/ or attempted 
with an ACUITY X4 lead. In the event an ACUITY X4 lead is attempted, but not successfully 
implanted, only a market-released BSC unipolar or bipolar coronary venous lead is acceptable.  
Note: In the event a BSC LV lead other than ACUITY X4 is implanted, data collected on these 
leads must follow that of sections 10.5.8, 10.5.11, 10.6.2, 10.7.2, and 10.8.1 (for RA and RV 
leads).  
10.5.5. ACUITY X4 Left Ventricular Lead Selection 
When selecting the appropriate ACUITY X4 lead for a subject, use the following guidelines.  
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Use venogram to identify a suitable target vein for lead implantation.  
The three ACUITY X4 lead tip configurations (Spiral S, Spiral L, and Straight) are available to 
provide appropriate choice for a variety of coronary veins. See below and Figure 5.  
• 
ACUITY X4 Spiral L is recommended when a target vein reaches the apical-third region 
of the heart, or mid-third of a severely dilated heart  
• 
ACUITY X4 Spiral S is recommended when a target vein reaches only the mid-third of 
the heart 
• 
ACUITY X4 Straight is recommended when a target vein is short, narrow, or torturous 
 
Figure 5: ACUITY X4 Lead Selection 
10.5.6. LV Lead Delivery Method Selection 
The choice of the LV lead delivery system is left to physician discretion. Data regarding LV lead 
delivery method will be collected as a part of the NAVIGATE X4 Study database. Boston 
Scientific LV lead delivery systems are preferred and recommended.    
10.5.7. Baseline ACUITY X4 Lead Measurements with PSA 
 
Documentation of PSA measurements for ACUITY X4 leads will be required as described below 
for NAVIGATE X4 Study 
. 
 
  
The required data to be collected from the implant procedure for all ACUITY X4 includes PCT 
at 0.5 ms pulse width, sensed amplitude, and pacing impedance, measured with a pacing system 
analyzer (PSA) to verify adequate signals. Refer to Figure 6 below for a picture of the 
relationship between the terminal pin and ring contacts on the ACUITY X4 quadripolar lead.  
As stated in the ACUITY X4 Physician’s Lead manual as a warning, only use the ACUITY X4 
Connector Tool for electrical connections to PSAs or similar monitors. Do not attach alligator 
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clips directly to the lead terminal or damage could occur. During 
 NAVIGATE X4, it 
is required to perform a minimum of 6 threshold measurements as summarized in Table 8 and 
Figure 7 below. First, test 4 extended bipolar or 4 unipolar configurations (per physician 
discretion) to determine adequate electrode-myocardium contact. Test for the presence of 
extracardiac or phrenic nerve stimulation (PNS) for each electrode by pacing the lead at a high 
voltage output, using professional medical judgment to select the output voltage. If extracardiac 
stimulation is detected, measure stimulation PNS threshold. The four extended bipolar, or 
unipolar, measurements provide a relative threshold ranking among the electrodes which is 
associated to the proximity of each electrode to viable myocardium. Although thresholds may 
change, the relative ranking will be the same for bipolar measurements. Then select 2 bipolar 
measurements (one pair from E1 as the cathode (E2, E3, or E4 as the anode) and the other pair 
from E2, E3 or E4 as the cathode) to confirm the preferred distal and proximal pacing options. 
Use the best extended bipolar or unipolar ring electrode (from E2, E3, E4) as a cathode to any 
other ring electrode as an anode. Again, test for the presence of extracardiac or phrenic nerve 
stimulation for each electrode. If stimulation is detected, measure a PNS threshold. Refer to 
Table 8, Figure 6 and Figure 7 below. 
The final test results of this testing must be printed from the PSA or documented on the Implant 
technical source documentation form and must be recorded on the Implant eCRF. BSC will also 
collect the PSA manufacturer and model number. Use the following figure to assist in connecting 
the ACUITY X4 lead to the PSA using the ACUITY X4 connector tool.  
 
 
 
Figure 6: Relationship between the terminal pin and ring contacts with the distal tip 
electrodes E1 – E4 
Table 8: ACUITY X4 PSA Testing Required during Implant  
Pacing Configurations 
# of Configurations 
and PNS Testing 
Unipolar or extended bipolar 
measurements from each electrode, E1 
through E4 
4 
Bipolar measurements between 2 of the 
electrodes: 
E1 →E2 
E1 →E3  
E1 →E4 
 2 
Total configurations tested with PSA 
6 
2
3
4
1
E2
E1
E4
E3
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Figure 7: ACUITY X4 Configurations to be Tested with PSA 
10.5.8. Baseline PSA Measurements for RA and RV Leads
 
The optional data to be collected from the implant procedure for RA and RV leads, as well as 
ACUITY X4 
 includes pacing threshold, sensed amplitude, and pacing 
impedance, measured with a PSA to verify adequate signals before attaching the lead to the PG. 
10.5.9. Loss of Capture and Threshold Definition 
During the NAVIGATE X4 Study PCT measurements from the PG are collected from leads 
implanted in the LV, RA and RV in the standard manual fashion. At least 3 cardiac cycles at a 
given voltage level shall be obtained before stepping down to the next voltage level. A count of 
two non-capture beats is required at a given voltage level to declare a loss of capture (LOC) for 
any of these tests. The threshold is defined as one voltage level above the level where two non-
captured beats are observed.  
10.5.10. ACUITY X4 Lead Measurements with PG 
Lead measurements, including pacing threshold (at 0.5 ms pulse width), sensed amplitude, and 
pacing impedance, are required to be collected using the CRT-D at implant for all implanted 
ACUITY X4 Leads. Pacing and sensing evaluation using the PG must be performed and the 
results recorded on the Implant eCRF. Lead measurements are required unless the testing is 
prohibited by a subject’s condition (subject has no intrinsic rhythm). The following 
measurements are to be taken utilizing the PG to ensure adequate sensing and pacing function of 
all ACUITY X4 Leads: 
• Intrinsic amplitude (mV)* 
• Pacing threshold (V, at 0.5 ms pulse width), details below in Table 9 and Figure 8 
• Pacing lead impedance (Ω)* 
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*Note: the configuration used for sensed amplitude and lead impedance measurements is upon 
physician discretion. The nominal sensing configuration for ACUITY X4 is E1 →E2 (LV Tip 1 
→LV Ring 2). 
The pacing configurations that require PCT testing at the implant (through three-month follow 
up) are listed in Table 9 below and shown in Figure 8. If the investigator chooses to conduct 
multiple pacing threshold tests or on configurations not listed below on the ACUITY X4 Lead, 
only the final measurement and none of the initial measurements taken at 0.5 ms pulse width 
must be indicated on the eCRF. 
Table 9: ACUITY X4 Pacing Configuration Required for PCT Testing at Implant, Pre-D 
and Three Months Post Implant 
Pacing Configurations 
# of Configurations tested 
Unipolar or extended bipolar measurements from each 
electrode, E1 through E4 
4 
Bipolar between electrodes∆: 
E1 →E2 
E1 →E3  
E1 →E4 
 3 
Bipolar from the best electrode* on the lead to another electrode 
on the lead (excluding E1) 
 1 
Total configurations tested 
8 
* Best electrode is the one that has the lowest threshold without phrenic nerve stimulation (PNS). In the event of a “tie” for 
best electrode, the investigator should use their medical judgment to select the best.  
∆Nomenclature of electrodes on the lead (E1, E2, E3, E4) is an industry standard. The corresponding nomenclature on 
the BSC PRM is as follows: 
• 
E1: LV Tip 1 
• 
E2: LV Ring 2 
• 
E3: LV Ring 3 
• 
E4: LV Ring 4 
Figure 8 below depicts the measurements required for the ACUITY X4 leads as described in the 
table above. 
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Figure 8: ACUITY X4 Lead Measurements Required at Implant, Pre-D and 3 Months 
10.5.10.1. Phrenic Nerve Stimulation (PNS) Testing 
Test for PNS in all aforementioned configurations and measure the PNS threshold if detected in 
the programmed configuration. The PNS threshold must be documented on the Implant technical 
source documentation form and must be recorded on the Implant eCRF. 
10.5.11. RA and RV Lead Measurements with PG 
Lead measurements, including pacing threshold, sensed amplitude, pacing impedance, and shock 
impedance are required at implant for all implanted RA (regardless of model) and RV Leads 
(RELIANCE 4-FRONT or commercially available RV lead). Pacing and sensing evaluation 
using the PG must be performed and the results recorded on the Implant eCRF. Lead 
measurements are required unless the testing is prohibited by a subject’s condition (subject has 
no intrinsic rhythm or is in atrial fibrillation). The following measurements are to be taken 
utilizing the PG to ensure adequate sensing and pacing function of all RA and RV Leads: 
• Intrinsic amplitude (mV) 
• Pacing threshold (V, at 0.5 ms pulse width; pulse width requirement for RELIANCE 
4-FRONT leads only) 
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• Pacing impedance and  
• Shock lead impedance (Ω) 
If the investigator chooses to conduct multiple pacing threshold tests on the RA and/or RV Lead, 
only the final measurement and none of the initial measurements must be indicated on the eCRF. 
10.5.12. Optional Ventricular Tachyarrhythmia Induction 
Subjects are not required to undergo induction testing. Those subjects that undergo induction 
testing within 30 days of implant, per the discretion of the investigator, will be included in the 
analysis of the 4-FRONT Secondary Safety Endpoint and the 4-FRONT Secondary Effectiveness 
Endpoint 3. See Sections 11.2.4 and 11.2.8, respectively, for more information on these 
endpoints. The method of induction is per the physician’s discretion but BSC strongly 
recommends the programmer/ PRM electrogram be run continuously during induction and 
delivery of therapy. VT/VF will be induced and the device allowed to sense and detect the 
arrhythmia (VT/VF Detection Time) and deliver programmed therapy (VT/VF Shock 
Conversion). The investigator shall allow the device to deliver at least one shock prior to external 
rescue, if appropriate. If multiple shock lead configurations (different shock vectors, polarities or 
lead positions) are tested, data from the final configuration must be used to document both 
detection time and shock conversion. VT/VF Detection Time is defined as the interval starting 
250 ms after the last induction artifact (the time of the post induction ventricular refractory 
period) and ending at the “V-Episode Declared” marker. Programming of detection and duration 
should remain at nominal settings .  
Steps for VT/VF induction: 
1. Run programmer/PRM paper 
2. Induce VT/VF 
3. Allow device to sense and detect arrhythmia. Measure and record detection time. 
4. Allow device to deliver therapy. Record conversion efficacy from final configuration. 
If not done at implant, the physician may complete the optional VT/VF induction testing at pre-
discharge or within 30 days of implant (at an additional follow up). Subjects may have additional 
VT/VF testing done if deemed appropriate. 
10.5.13. Source Documentation Requirements 
See Table 10 for required source documentation of the implant procedure. 
10.6. Pre-Discharge Visit 
The pre-discharge follow-up visit must be performed between 3 hours and 72 hours after 
implant. If the subject needs to stay more than 72 hours in the hospital after implant for any 
reason, the pre-discharge procedure should still be performed within 72 hours of implant. Any 
reasons for a prolonged or ongoing hospitalization need to be appropriately documented (i.e. 
Adverse Event Form, if applicable). 
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10.6.1. ACUITY X4 Lead Measurements with PG 
Lead measurements, including pacing threshold (at 0.5 ms pulse width), sensed amplitude, and 
pacing impedance, are required to be collected at the pre-discharge visit for all implanted 
ACUITY X4 Leads. Pacing and sensing evaluation using the PG must be performed and the 
results recorded on the Pre-Discharge eCRF. Lead measurements are required unless the testing 
is prohibited by a subject’s condition (subject has no intrinsic rhythm). The following 
measurements are to be taken utilizing the PG to ensure adequate sensing and pacing function of 
all ACUITY X4 Leads: 
• Intrinsic amplitude (mV)* 
• Pacing threshold (V, at 0.5 ms pulse width), details below in Table 9 and Figure 8 
• Pacing lead impedance (Ω)* 
*Note: the configuration used for sensed amplitude and lead impedance measurements is upon 
physician discretion. The nominal sensing configuration for ACUITY X4 is E1 →E2 (LV Tip 1 
→LV Ring 2). 
If the investigator chooses to conduct multiple pacing threshold tests or on configurations not 
listed below, on the ACUITY X4 Lead, only the final measurement and none of the initial 
measurements taken at 0.5 ms pulse width must be indicated on the eCRF. The pacing 
configurations that require testing at the Pre-Discharge visit are listed in Table 9 and Figure 8. 
10.6.1.1. PNS Testing 
Test for PNS in all aforementioned configurations and measure the PNS threshold if detected in 
the programmed configuration. The PNS threshold must be documented on the Pre-Discharge 
technical source documentation form and must be recorded on the Pre-Discharge eCRF. 
10.6.2. RA and RV Lead Measurements with PG 
Lead measurements, including pacing threshold, sensed amplitude, pacing impedance, and shock 
impedance are required at the pre-discharge visit for all implanted RA (regardless of model) and 
RV Leads (RELIANCE 4-FRONT or commercially available RV lead). Pacing and sensing 
evaluation using the PG must be performed and the results recorded on the Pre-Discharge Visit 
eCRF. Lead measurements are required unless the testing is prohibited by a subject’s condition 
(subject has no intrinsic rhythm or is in atrial fibrillation). The following measurements are to be 
taken utilizing the PG to ensure adequate sensing and pacing function of all RA and RV Leads: 
• Intrinsic amplitude (mV) 
• Pacing threshold (V, at 0.5 ms pulse width; pulse width requirement for RELIANCE 
4-FRONT RV leads only) 
• Pacing impedance and  
• Shock lead impedance (Ω)  
If the investigator chooses to conduct multiple pacing threshold tests on the RA and/or RV Lead, 
only the final measurement and none of the initial measurements must be indicated on the eCRF. 
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10.6.3. Optional Ventricular Tachyarrhythmia Induction 
If not done at implant, the physician may complete the optional VT/VF induction testing at Pre-
Discharge or within 30 days of implant (at an additional follow up), as described in Section 
10.5.12. Subjects may have additional VT/VF testing done if deemed appropriate.  
10.6.4. Shock Therapy for Spontaneous Ventricular Tachyarrhythmia 
Record the following information for any spontaneous ventricular tachyarrhythmia that is treated 
with shock therapy: episode number, episode date, episode attempt number, episode type, 
therapy delivered, energy delivered, device classification, investigator classification, and return 
to normal sinus rhythm. 
10.6.5. Source Documentation Requirements 
See Table 10 for required source documentation for the Pre-Discharge visit. 
10.7. Three-Month Visit 
The three-month visit must be performed as a clinic visit at 91 ± 21 days after implant. 
10.7.1. ACUITY X4 Lead Measurements with PG 
Lead measurements, including pacing threshold (at 0.5 ms pulse width), sensed amplitude, and 
pacing impedance, are required to be collected at the three-month visit for all implanted 
ACUITY X4 Leads. Pacing and sensing evaluation using the PG must be performed and the 
results recorded on the three-month visit eCRF. Lead measurements are required unless the 
testing is prohibited by a subject’s condition (subject has no intrinsic rhythm). The following 
measurements are to be taken utilizing the PG to ensure adequate sensing and pacing function of 
all ACUITY X4 Leads: 
• Intrinsic amplitude (mV)* 
• Pacing threshold (V, at 0.5 ms pulse width), details below in Table 9 and Figure 8 
• Pacing lead impedance (Ω)* 
*Note: the configuration used for sensed amplitude and lead impedance measurements is upon 
physician discretion. The nominal sensing configuration for ACUITY X4 is E1 →E2 (LV Tip 1 
→LV Ring 2). 
If the investigator chooses to conduct multiple pacing threshold tests or on configurations not 
listed below, on the ACUITY X4 Lead, only the final measurement and none of the initial 
measurements taken at 0.5 ms pulse width must be indicated on the eCRF. The pacing 
configurations that require testing at the three-month visit are listed in Table 9 and Figure 8 in 
Section 10.5.10.  
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10.7.1.1. PNS Testing 
Test for PNS in all aforementioned configurations and measure the PNS threshold if detected in 
the programmed configuration. The PNS threshold must be documented on the Three-Month 
technical source documentation form and must be recorded on the Three-Month eCRF. 
10.7.2. RA and RV Lead Measurements with PG 
Lead measurements, including pacing threshold, sensed amplitude, pacing impedance, and shock 
impedance are required at the three-month visit for all implanted RA (regardless of model) and 
RV Leads (RELIANCE 4-FRONT or commercially available RV lead). Pacing and sensing 
evaluation using the PG must be performed and the results recorded on the three-month visit 
eCRF. Lead measurements are required unless the testing is prohibited by a subject’s condition 
(subject has no intrinsic rhythm or is in atrial fibrillation). The following measurements are to be 
taken utilizing the PG to ensure adequate sensing and pacing function of all RA and RV Leads: 
• Intrinsic amplitude (mV) 
• Pacing threshold (V, at 0.5 ms pulse width; pulse width requirement for RELIANCE 
4-FRONT RV leads only) 
• Pacing impedance and  
• Shock lead impedance (Ω) 
If the investigator chooses to conduct multiple pacing threshold tests on the RA and/or RV Lead, 
only the final measurement and none of the initial measurements must be indicated on the eCRF. 
10.7.3. Shock Therapy for Spontaneous Ventricular Tachyarrhythmia 
Record the following information for any spontaneous ventricular tachyarrhythmia that is treated 
with shock therapy: episode number, episode date, episode type, therapy delivered, device 
classification, investigator classification, return to normal sinus rhythm. 
10.7.4. Source Documentation Requirements 
See Table 10 for required source documentation for the three-month visit. 
10.8. Semi-Annual Clinic Visits from 6 months through 5 years (6, 12, 18, 24, 30, 36, 42, 48, 
54, and 60 months) 
Semi-annual visits are required to be conducted as clinic visits for NAVIGATE X4 subjects, 
starting at six months post implant and continuing until 5 years post implant. Specifically, timing 
for each follow up is based on the subject’s implant date: 
• 6 Month Follow-up: 182 ± 21 days 
• 12 Month Follow-up: 365 ± 45 days 
• 18 Month Follow-up: 547 ± 45 days 
• 24 Month Follow-up: 730 ± 45 days 
• 30 Month Follow-up: 913 ± 45 days 
• 36 Month Follow-up: 1095 ± 45 days 
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• 42 Month Follow up: 1278 ± 45 days 
• 48 Month Follow-up: 1461 ± 45 days 
• 54 Month Follow-up: 1643 ± 45 days 
• 60 Month Follow-up: 1826 ± 45 days 
10.8.1. ACUITY X4, RA and RV Lead Measurements with PG 
Lead measurements, including pacing threshold, sensed amplitude, pacing impedance, and shock 
impedance are required to be collected for all implanted LV, RA and RV leads at each semi-
annual visit, starting at the six-month visit, through 5 years post-implant. Pacing and sensing 
evaluation using the PG must be performed and the results recorded on the appropriate semi-
annual visit eCRF. Lead measurements are required unless the testing is prohibited by a subject’s 
condition (subject has no intrinsic rhythm or is in atrial fibrillation). The following 
measurements are to be taken utilizing the PG to ensure adequate sensing and pacing function of 
all implanted LV, RA and RV leads: 
• Intrinsic amplitude (mV) 
• Pacing threshold (V, pulse width at physician discretion) 
• Pacing impedance (Ω) and  
• Shock lead impedance (Ω) 
If the investigator chooses to conduct multiple pacing threshold tests on the implanted LV, RA or 
RV leads, only the final measurement and none of the initial measurements must be recorded on 
the eCRF. 
10.8.2. Shock Therapy for Spontaneous Ventricular Tachyarrhythmia 
Record the following information for any spontaneous ventricular tachyarrhythmia that is treated 
with shock therapy: episode number, episode date, episode type, therapy delivered, device 
classification, investigator classification, return to normal sinus rhythm.  
10.8.3. Source Documentation Requirements 
See Table 10 for required source documentation for all semiannual follow-ups. 
10.9. Additional Visits 
All follow-ups outside of the designated follow-up windows or multiple visits inside any one 
follow-up window need to be reported as an additional follow-up if a lead-related adverse event 
(as defined in Section 19.3) occurred, or the device was interrogated and there was a resulting 
programming change. If possible, a device evaluation and lead measurements should be 
performed and the results recorded on the Additional Follow-up eCRF.  
In the event of a lead-related adverse event, a device evaluation and lead measurements are 
required and the results must be recorded on the Additional Follow-up eCRF. 
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10.9.1. Source Documentation Requirements 
See Table 10 for required source documentation for additional follow-ups. 
10.10. LATITUDE Remote Follow-up  
Subjects may be followed on the LATITUDE system (which may include weight scale and blood 
pressure sensors) from the time they are implanted, if commercially available. However, required 
NAVIGATE X4 Clinical Study follow ups cannot be substituted with a LATITUDE remote 
follow up. 
10.11. 
Source Documents from All Study-Required Visits 
Table 10 below summarizes the source data requirements for this clinical study. Original source 
documents are required to be retained at the center. On the rare occasion where the original is not 
available, copies of the original source document must be signed and dated by a member of the 
investigational center team with a statement that it is a true reproduction of the original source 
document. 
 
Table 10: Source Documentation Requirements 
Requirement 
Visit 
Disposition 
Informed consent documentation process 
Enrollment 
Retain at Center 
Assessment of pregnancy for women of child bearing potential: 
method of assessment per physician discretion 
Enrollment 
Retain at Center 
Documentation of the following: 
 
• 
Demographics: age at implant, gender 
• 
Heart Failure assessment: LVEF, QRS width, GDMT  
• 
Vital signs: heart rate, blood pressure 
• 
Class I/III Antiarrhythmic medications  
• 
Subject’s height and weight 
• 
Arrhythmia history 
• 
Cardiac disease history 
Enrollment 
Retain at Center 
Documentation of the following: 
• 
Time of first incision 
• 
Time of pocket closure, to document time 0 
• 
Class I/III antiarrhythmic medications that the subject 
is prescribed prior to, but not including the implant 
procedure 
• 
Model and serial number of implanted cardiac devices 
• 
Manufacturer and model number of PSA 
Implant 
Retain at Center 
Printout of ACUITY X4 PSA measurements or signed Implant 
Technical Source Form 
Implant 
Retain at Center 
Printout of PG measurements (sensed amplitude, pacing 
impedance, shock lead impedance, and pacing capture 
threshold results) either from PRM printout or a signed 
Technical Source Form (from applicable visit) 
Implant, 
Follow-ups 
Retain at Center 
Printout of ECG strip (from PRM) documenting LOC for all 
implanted leads threshold tests  
Implant, Pre-
Discharge, 3-
Month Follow up 
Retain at Center 
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Table 10: Source Documentation Requirements 
PA and lateral chest X-ray or fluoroscopic image of ACUITY 
X4 and RELIANCE 4-FRONT (as applicable) Lead distal tip 
fixation 
Implant or Pre-
Discharge 
Retain at Center 
Real time programmer/ PRM strip documenting induced VT/VF 
(if conducted and strip available) 
Implant through 
30 days post-
implant 
Retain at Center 
Initial Quick Notes report to document programming of 
PaceSafe features  
Implant through 
24 Month Follow 
up 
Retain at Center 
Class I/III Antiarrhythmic medications 
Any applicable 
visit with a Lead-
related Adverse 
Event 
Retain at Center 
Documentation of spontaneous shock therapy  by saving all to 
disk (USB drive required); PRM strips are optional: 
• 
“Selected Episodes Report” (counters and EGMs 
required), 
• 
“Arrhythmia Logbook”,  
• 
“Quick Notes” 
• 
“Follow up Report” 
Any applicable 
visit 
Retain at Center 
Adverse events 
Any applicable 
visit 
Retain at Center 
In the event of subject death:  
• 
Death narrative 
• 
Relative medical records 
• 
Death certificate (if available) 
• 
Autopsy report (if available) 
Any applicable 
visit 
Submit one copy to 
Boston Scientific 
CRV, 
Retain one copy at 
center 
Abbreviations: PSA = Pacing System Analyzer; PG = Pulse Generator; PA = Posterior-Anterior; CRF = 
Case Report Form; EGM= Electrogram  
10.12. 
Study Completion 
Each subject will complete the study when they have been followed for 5 years after their 
implant procedure. See Section 12.2 for details on data retention. 
10.13. Exceptions for Use of Investigational Software (associated with the AUTOGEN 
CRT-D) at Non-Investigational Sites 
While geographic stability is an inclusion criterion at the time of enrollment, it is possible for 
conditions to change for the subject in which continuing follow-up at the investigational center 
may pose a challenge. Every attempt should be made to keep the patient at the investigational 
center and under care of a trained investigator. 
In order to protect patient safety, use of investigational software at non-investigational sites may 
be permitted in exceptional situations with prior sponsor approval. Sponsor approval for use of 
investigational software will be considered for the following conditions: 
• Patient has sought unplanned urgent medical attention at a non-investigational site and 
software use is intended to protect the health and welfare of the patient 
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• Health of the patient prevents reasonable safe travel to an investigational site 
• Travel to investigational site presents a significant hardship on the patient (e.g. physical 
distance to an approved investigational site is too great, limited access to transportation to 
the investigational site, patient is under inpatient care , or patient is seen frequently for 
recurring treatment, such as dialysis or chemotherapy, at another sites and the 
investigator agrees to allow device interrogations at that site) 
Upon use of the investigational software at a non-investigational site, information is to be 
collected surrounding the circumstances of use of the investigational software and reported to 
Boston Scientific CRM within 5 business days.  
11. STATISTICAL CONSIDERATIONS 
11.1. ACUITY X4 Endpoints 
11.1.1. ACUITY X4 Primary Safety Endpoints 
Safety of the ACUITY X4 lead will be evaluated by the lead-related complication-free rate 
(CFR) over a six-month follow-up period. 
. 
Lead-related complications are lead-related adverse events resulting in permanent loss of pacing 
therapy, invasive intervention, injury or death. Lead-related adverse events are further defined in 
Section 19.3. Lead-related complications associated with attempted ACUITY X4 Lead implants 
will count toward this safety endpoint.  
11.1.1.1. Hypotheses 
The following hypotheses will be used to evaluate the Primary Safety Endpoint 
 
Ho:  The Implant through 6-month lead-related complication-free rate ≤ 87% 
Ha:  The Implant through 6-month lead-related complication-free rate > 87% 
The following hypotheses will be used to evaluate the Primary Safety Endpoint 
 
Ho:  The Implant through 6-month lead-related complication-free rate ≤ 85% 
Ha:  The Implant through 6-month lead-related complication-free rate > 85% 
 
 
 
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11.1.2. Sample Size  
The overall sample size required for ACUITY X4 is determined by the Primary Safety Endpoint. 
Table 12 contains the sample size estimates 
 based on the outlined assumptions. 
The sample size estimates were obtained using the normal approximation to the binomial and 
verified through simulations based on Kaplan-Meier methodology; Kaplan-Meier methodology 
will be used for the analyses. 
 
 
   
 
 
 
 
 
 
 
 
11.1.3. Statistical Methods 
To assess safety of the ACUITY X4 leads, the Kaplan-Meier six month (180-day) complication-
free rate will be calculated. 
 
The analysis will be conducted when the last 6-month follow-up is completed 
 
 Data from all implanted or attempted 
 
 leads will be included in the 
endpoint analysis.  
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The exact follow-up time for each ACUITY X4 lead in the 180-day post-implant period will be 
included in the analysis via Kaplan-Meier methodology. The leads that fail to reach 180 days of 
follow-up (without experiencing an endpoint event prior to their end of follow-up in the period) 
will be censored at the time of their end of follow-up in the period. Because non-informative 
censoring cannot be assumed for these leads, a tipping point analysis will be performed to 
determine the potential effects these censored leads could have on the results if full information 
on each lead was present. The tipping point analysis will assign each lead that was censored prior 
to 180 days as either having or not having an endpoint event. The tipping point will be 
determined by the point at which the endpoint results turn from passing (null hypothesis) to 
failing (null hypothesis rejected). An exact binomial test will be performed for the tipping point 
analysis.  
11.1.4. ACUITY X4 Primary Effectiveness Endpoint 1 
The first effectiveness endpoint for ACUITY X4 is pacing capture thresholds (PCT) in the 
programmed configuration. This endpoint will be evaluated at 3 months post-implant. 
 
 For this endpoint, responders will be defined as 
subjects with PCT ≤ 2.5 V in the programmed configuration. 
11.1.4.1. Hypotheses 
The following hypotheses will be used to evaluate Primary Effectiveness Endpoint 1 for X4 
: 
Ho:  3 month responder rate ≤ 75% 
Ha:  3 month responder rate > 75% 
11.1.4.2. Sample Size 
 
 
 
 
 
 
 
 
 
 
 
. 
. 
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11.1.4.3. Statistical Methods 
ACUITY X4 Primary Effectiveness Endpoint 1 will be analyzed 
 Subjects eligible for this analysis includes all 
 subjects who are successfully implanted with an ACUITY X4 lead. Subjects with LV 
pacing threshold data in the programmed configuration collected at the 3-month follow-up visit 
will contribute data to the endpoint analysis. 
 
 
 
   
Subjects that do not have LV pacing threshold data in the programmed configuration collected at 
the three month follow-up visit will be considered to have missing data. A tipping point analysis 
will be used to determine the potential effects subjects with missing data could have had on the 
results. The tipping point analysis will consider a range of possible responder rates in the 
subjects with missing data. The tipping point will be determined by the point at which the 
endpoint results turn from passing (null hypothesis rejected) to failing (null hypothesis not 
rejected). 
11.1.5. ACUITY X4 Primary Effectiveness Endpoint 2 
The second effectiveness endpoint for ACUITY X4 is pacing capture thresholds (PCT) in in the 
proximal zone (E2, E3, or E4) for 
. This endpoint will be evaluated at 3 months 
post-implant.  
Clustering electrodes on the spiral is expected to position at least one electrode adjacent to the 
myocardium. Physician investigators will therefore be instructed to use the “best” proximal 
electrode (E2, E3 or E4) as the cathode and the RV lead coil as the anode. For this endpoint 
“best” will be defined as the electrode with the lowest PCT without PNS. The PG may be used as 
an anode depending on the clinical scenario or physician preference. For this endpoint, 
responders will be defined as patients with PCT ≤ 2.5 V in the best proximal zone at 3 months 
post-implant. 
11.1.5.1. Hypotheses 
The following hypotheses will be used to evaluate Primary Effectiveness Endpoint 2 
 
 
Ho:  3 month responder rate ≤ 75% 
Ha:  3 month responder rate > 75% 
11.1.5.2. Sample Size 
: 
• 
 
• 
 
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• 
 
• 
 
 
 
 
 
11.1.5.3. Statistical Methods 
ACUITY X4 Primary Effectiveness Endpoint 2 will be analyzed when the last 3-month follow-
up visit 
 is completed. All 
 subjects who are successfully implanted 
with an ACUITY X4 spiral lead 
 eligible for inclusion in this analysis. Subjects 
with a best proximal zone LV pacing threshold measurement collected at the 3-month follow-up 
visit will contribute data to the endpoint analysis. 
 
 
  
Subjects that do not have a best proximal zone LV pacing threshold measurement collected at the 
three month follow-up visit will be considered to have missing data. A tipping point analysis will 
be used to determine the potential effects subjects with missing data could have had on the 
results. The tipping point analysis will consider a range of possible responder rates that could 
have been observed in the subjects with missing data. The tipping point will be determined by 
the point at which the endpoint results turn from passing (null hypothesis rejected) to failing 
(null hypothesis not rejected). 
11.1.6. ACUITY X4 Secondary Effectiveness Endpoint 1 
The first secondary effectiveness endpoint for ACUITY X4 is sensed amplitudes in the 
programmed configuration. This endpoint will be evaluated at 3 months post-implant.  
11.1.6.1. Hypotheses 
The following hypotheses will be used to evaluate the sensed amplitude Secondary Effectiveness 
Endpoint 1 
: 
Ho:  The three -month mean R-wave amplitude is ≤ 3.0 mV 
Ha:  The three -month mean R-wave amplitude is > 3.0 mV 
11.1.6.2. Sample Size 
 
: 
• 
 
• 
 
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• 
 
• 
 
. 
11.1.6.3. Statistical Methods 
ACUITY X4 Secondary Effectiveness Endpoint 1 will be analyzed when the last 3-month 
 
 follow-up visit is complete. This analysis will include 
 subjects with an ACUITY 
X4 LV sensed amplitude measurement at three months, and the analysis will be done 
 
 Sensed amplitude measurements in the programmed configuration 
from the three-month follow-up visit will be analyzed using a one-sided t-test with an alpha of 
2.5%. A histogram of three month LV sensed amplitudes in the programmed configuration will 
also be provided. 
11.1.7. ACUITY X4 Secondary Effectiveness Endpoint 2 
The second secondary effectiveness endpoint for ACUITY X4 is pacing impedances in the 
programmed configuration. This endpoint will be evaluated at 3 months post-implant.  
11.1.7.1. Hypotheses 
The following hypotheses will be used to evaluate the pacing impedance Secondary 
Effectiveness Endpoint for 
: 
Ho:  The three -month mean LV lead impedance is ≤ 300 Ω  
Ha:  The three -month mean LV lead impedance is > 300 Ω 
11.1.7.2. Sample Size 
 
: 
• 
  
 
   
 
 
 
 
. 
11.1.7.3. Statistical Methods 
ACUITY X4 Secondary Effectiveness Endpoint 2 will be analyzed when the last 3-month 
follow-up visit 
 is complete. This analysis will include all 
 patients 
with an ACUITY X4 LV pacing impedance at three months, and the analysis will be done 
 LV lead pacing impedance measurements in the 
programmed configuration from the three-month follow-up visit will be analyzed using a one-
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sided t-test with an alpha of 2.5%. A histogram of three month LV pacing impedances in the 
programmed configuration will also be provided. 
11.1.8. ACUITY X4 Ancillary Analyses 
11.1.8.1. ACUITY X4 Ancillary Safety Objective  
The ACUITY X4 Ancillary Safety Objective will be used to prospectively determine the chronic 
five year complication-free rate of the ACUITY X4 LV lead. 
 
 
 
 
. 
11.1.8.2. ACUITY X4 Ancillary Data Collection  
The following data will be collected and summarized: 
• Implant success 
• Lead measurements in all tested configurations 
• Dislodgment rate (post-implant) 
• Skin-to-skin time 
• Feedback from the site investigator regarding final ACUITY X4 programmed 
configuration if the physician chooses a configuration other than the best configuration; 
(best electrode is the one that has the lowest threshold without phrenic nerve stimulation 
(PNS). In the event of a “tie” for best electrode, the investigator should use their medical 
judgment to select the best) 
• ACUITY X4 Lead placement time  
• Interoperative repositioning and rationale for selection of multiple veins/branches  
• Method of lead delivery (inner or outer sheath) 
• Vein used to implant LV lead – Right-sided vs. left-sided and axillary, cephalic, or 
subclavian 
11.2. RELIANCE 4-FRONT Endpoints 
11.2.1. RELIANCE 4-FRONT Primary Safety Endpoint 1  
Safety of the RELIANCE 4-FRONT Leads will be evaluated by the lead-related complication-
free rate (CFR) from lead implant through the 3-month follow-up visit, based on complications 
that are related to the RELIANCE 4-FRONT Lead. Lead-related complications are defined as 
lead-related adverse events resulting in permanent loss of pacing therapy, invasive intervention, 
injury or death. Lead-related adverse events are further defined in Section 19.3 and lead-related 
complications are further defined in Section 19.3.1. 
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Lead-related complications associated with attempted RELIANCE 4-FRONT Lead implants will 
count toward this safety endpoint.  
11.2.1.1. Hypotheses 
The following hypotheses will be used to evaluate the RELIANCE 4-FRONT Primary Safety 
Endpoint 1 
: 
Ho:  The lead-related complication-free rate from implant to 3 months ≤ 93.0% 
Ha:  The lead-related complication-free rate from implant to 3 months > 93.0% 
 
 
 
 
 
 
11.2.1.2. Sample Size 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
11.2.1.3. Statistical Methods 
Data from all subjects implanted or attempted with a RELIANCE 4-FRONT lead will be eligible 
for inclusion in the endpoint analysis. All RELIANCE 4-FRONT leads 
 will be 
pooled for this analysis.  
The lead-related complication-free rate from date of implant (or date of attempt, for leads 
attempted but not implanted) through 91 days post-implant will be calculated using Kaplan-
Meier methodology. The 95% one-sided lower pointwise confidence limit of the complication-
free rate will be calculated via log-log methodology for all eligible subjects contributing to the 
analyses and compared to the performance goal of 93%. If the lower confidence limit exceeds 
93%, the null hypothesis will be rejected. 
Each lead’s exact follow-up time in the 91 days post-implant will be included in the analysis via 
Kaplan-Meier methodology. The leads that fail to reach 91 days of follow-up (without 
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experiencing an endpoint event prior to their end of follow-up in the period) will be censored at 
the time of their end of follow-up in the period. Because non-informative censoring cannot be 
assumed for these leads, a tipping point analysis will be performed to determine the potential 
effects these censored leads could have on the results if full information on each lead was 
present. The tipping point analysis will assign each lead that was censored prior to 91 days as 
either having or not having an endpoint event. The tipping point will be determined by the point 
at which the endpoint results turn from passing (null hypothesis) to failing (null hypothesis 
rejected). An exact binomial test will be performed for the tipping point analysis.  
11.2.2. RELIANCE 4-FRONT Primary Safety Endpoint 2 
To satisfy the safety assessment requirements of the US Food and Drug Administration (FDA), 
safety of the RELIANCE 4-FRONT Leads will also be evaluated by the lead-related CFR from 
three months post-implant through 24 months post implant based on complications that are 
related to the RELIANCE 4-FRONT Lead during that period. The same definition of lead-related 
complication will be used for both RELIANCE 4-FRONT Primary Safety Endpoint 1 and 
Primary Safety Endpoint 2.  
11.2.2.1. Hypotheses 
The following hypotheses will be used to evaluate RELIANCE 4-FRONT Primary Safety 
Endpoint 2 
: 
Ho:  The lead-related complication-free rate from 3 to 24 months ≤ 94% 
Ha:  The lead-related complication-free rate from 3 to 24 months > 94% 
11.2.2.2. Sample Size 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
11.2.3. Statistical Methods 
Data from all RELIANCE 4-FRONT leads that have been followed for at least 
days post-
implant at the time of endpoint analysis will be eligible for inclusion in the endpoint analysis. All 
RELIANCE 4-FRONT leads 
 will be pooled for this analysis.  
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The lead-related complication-free rate from 
 days through 
 days post-implant will be 
calculated using Kaplan-Meier methodology. The 95% one-sided lower pointwise confidence 
limit of the complication-free rate will be calculated via log-log methodology for all eligible 
subjects and compared to the performance goal of 94%. If the lower confidence limit exceeds 
94%, the null hypothesis will be rejected. 
Each lead’s exact follow-up time in the period between 
 days post-implant will be 
included in the analysis due to the rate being calculated via Kaplan-Meier methodology. The 
leads that reach 
 of follow-up but fail to reach 
 of follow-up (without 
experiencing an endpoint event in the period prior to their end of follow-up) will be censored at 
the time of their end of follow-up in the period. Because non-informative censoring cannot be 
assumed for these leads, a tipping point analysis will be performed to determine the potential 
effects these censored leads could have on the results if full information on each lead was 
present. The tipping point analysis will assign each lead that was censored between the 
 
 post-implant as either having or not having an endpoint event. The tipping point will be 
determined by the point at which the endpoint results turn from passing (null hypothesis) to 
failing (null hypothesis rejected). An exact binomial test will be performed for the tipping point 
analysis.  
11.2.4. RELIANCE 4-FRONT Secondary Safety Endpoint  
The purpose of this endpoint is to confirm that the RELIANCE 4-FRONT lead and its associated 
PG system have the ability to appropriately sense and detect VT/VF. Historically, this endpoint 
has been used to evaluate system performance; the lead is part of the system and therefore will 
be evaluated in this study. Subjects will not be required to undergo induction testing. Those 
subjects with a RELIANCE 4-FRONT lead that undergo induction testing within 30 days of 
implant, per the discretion of the investigator, will be included in the analysis and the time to 
detection of VT/VF will be measured.  
11.2.4.1. Hypotheses 
The time it takes for the device to detect VT/VF will be compared to performance goal of 4.5 
seconds, 
 
 
]
 
.   
Ho:  Induced mean VT/VF detection time ≥ 4.5 seconds 
Ha:  Induced mean VT/VF detection time < 4.5 seconds 
11.2.4.2. Sample Size 
 
 
 
 
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• 
 
 
 
 
  
 
 
 
 
.  
11.2.4.3. Statistical Methods 
Data from all subjects with a RELIANCE 4-FRONT lead that have undergone an induction test 
within 30 days of implant will contribute to the analysis of this endpoint.  
If multiple tests or multiple configurations are tested in the 30 day post-implant period, the last 
induction test in its final configuration will be used in the analysis. A one-sided one-sample t-test 
will be performed, using an alpha equal to 
. If the t-test is deemed to be inappropriate based 
on the data, then a data transformation or a non-parametric test will be performed. If the p-value 
for the one-sided test is less than 
, the null hypothesis will be rejected. 
11.2.5. RELIANCE 4-FRONT Primary Effectiveness Endpoint 
Effectiveness of the RELIANCE 4-FRONT Leads will be established by demonstrating that the 
leads provide clinically acceptable pacing thresholds at a 0.5 ms pulse width at three months post 
implant. 
. 
11.2.5.1. Hypotheses 
The following hypotheses will be used to evaluate the RELIANCE 4-FRONT Primary 
Effectiveness Endpoint 
: 
Ho:  The pacing threshold at 0.5 ms at three months post-implant ≥ 1.5 V 
Ha:  The pacing threshold at 0.5 ms at three months post-implant < 1.5 V 
11.2.5.2. Sample Size 
 
 
• 
 
 
 
 
 
 
 
 
 
 
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11.2.5.3. Statistical Methods 
All RV lead pacing threshold data from subjects with the RELIANCE 4-FRONT lead collected 
at the 3-month follow-up visit will be included in the endpoint analysis.   
A one-sided one-sample t-test will be performed, using an alpha equal to %. If the t-test is 
deemed to be inappropriate based on the data, then a data transformation or a non-parametric test 
will be performed. If the p-value for the one-sided test is less than %, the null hypothesis will be 
rejected. 
Subjects that do not have pacing threshold data collected at the three month follow-up visit will 
not contribute any data to the endpoint analysis. A tipping point analysis will be used to 
determine the potential effects these subjects could have had on the results if they would have 
had endpoint data for inclusion in the analysis. The tipping point analysis will consider a range 
of possible mean pacing threshold values that could have been observed in the subjects with 
missing data. The observed mean and the possible mean from the subjects with missing data will 
be pooled for the tipping point analysis. The tipping point will be determined by the possible 
mean value (
) at which the endpoint results turn from passing 
(null hypothesis rejected) to failing (null hypothesis failed to be rejected). 
11.2.6. RELIANCE 4-FRONT Secondary Effectiveness Endpoint 1 
The purpose of this secondary effectiveness endpoint is to establish that the RELIANCE 4-
FRONT Lead leads provide clinically acceptable sensing amplitudes at three months post 
implant. 
. 
11.2.6.1. Hypotheses 
The following hypotheses will be used to evaluate Secondary Effectiveness Endpoint 1 for 
: 
Ho:  R-wave sensed amplitude at three months post-implant ≤ 5 mV 
Ha:  R-wave sensed amplitude at three months post-implant > 5 mV 
11.2.6.2. Sample Size 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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11.2.6.3. Statistical Methods 
All R-wave sensed amplitude data collected at the 3-month follow-up visit will be included in 
the endpoint analysis.  
A one-sided one-sample t-test will be performed, using an alpha equal to %. If the t-test is 
deemed to be inappropriate based on the data, then a data transformation or a non-parametric test 
will be performed. If the p-value for the one-sided test is less than %, the null hypothesis will be 
rejected.  
11.2.7. RELIANCE 4-FRONT Secondary Effectiveness Endpoint 2 
The purpose of this secondary effectiveness endpoint is to establish that the RELIANCE 4-
FRONT Lead provides clinically acceptable pacing impedance at three months post-implant. 
. 
11.2.7.1. Hypotheses 
The following hypotheses will be used to evaluate the Secondary Effectiveness Endpoint 2 
: 
Ho:  Pacing impedance ≤ 300 Ω, or pacing impedance ≥ 1200 Ω 
Ha:  300 Ω < Pacing impedance < 1200 Ω 
11.2.7.2. Sample Size  
 
 
  
  
 
 
  
  
 
 
 
 
 
 
 
  
11.2.7.3. Statistical Methods 
Endpoint analysis will be performed 
 4-FRONT 
. Leads will not be 
pooled for the hypothesis testing, due to expected differences in performance for this endpoint 
between the active and passive fixation leads. Results will be presented split by fixation type, but 
will not be split by coil type. Two one-sided t-tests (TOST) will be performed, using an alpha 
equal to % for each test. If the TOST is deemed to be inappropriate based on the data, a data 
transformation or a non-parametric test will be performed. If both of the p-values for the two 
one-sided tests are less than %, the null hypothesis will be rejected. 
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11.2.8. RELIANCE 4-FRONT Secondary Effectiveness Endpoint 3 
The purpose of this secondary endpoint is to confirm that the RELIANCE 4-FRONT lead and its 
associated PG system have the ability to successfully convert VT/VF. Historically, this endpoint 
has been used to evaluate system performance; the lead is part of the system and therefore will 
be evaluated in this study. Subjects will not be required to undergo induction testing. Those 
subjects that undergo induction testing within 30 days of implant, per the discretion of the 
investigator, will be included in the analysis and the time to detection of VT/VF will be 
measured. Success will be considered if the device converts the subject’s last induced episode in 
its final configuration without the need for external defibrillation. 
11.2.8.1.  Hypotheses 
The percent of successful VT/VF conversions with a RELIANCE 4-FRONT lead will be 
compared to a performance goal of 93%, 
 
 
]. The null hypothesis will therefore be rejected 
in favor of the alternative if the upper confidence limit of the observed percent of successful 
conversions is greater than 93%. The conversion will be considered successful if the device 
converts the subject without the need for external defibrillation. 
 
 
 
 
 
 
  
Ho:  Percent of successful conversion ≤ 93% 
Ha:  Percent of successful conversion > 93% 
11.2.8.2.  Sample Size 
 
 
 
 
• 
 
 
 
 
  
 
 
 
 
.  
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11.2.8.3.  Statistical Methods 
All subjects with a RELIANCE 4-FRONT lead that undergo an induction test within 30 days of 
implant will contribute to the analysis of this endpoint. If multiple tests or multiple 
configurations are tested in the 30 day post-implant period, the last induction test in its final 
configuration will be used in the analysis. A one-sided exact binomial test will be performed on 
all subjects with induction data (regardless of lead fixation or coil type) and the resulting lower 
exact (Clopper-Pearson) confidence interval will be calculated, using an alpha equal to %. If the 
lower one-sided 95% confidence limit for the conversion rate is greater than 93%, the null 
hypothesis will be rejected. 
11.2.9. RELIANCE 4-FRONT Ancillary Analyses 
11.2.9.1. RELIANCE 4-FRONT Ancillary Safety Objective  
The RELIANCE 4-FRONT Ancillary Safety Objective will be used to prospectively determine 
the chronic five year complication-free rate of the RELIANCE 4-FRONT RV lead. The overall 
sample size required for this endpoint is greater than the sample size of this NAVIGATE X4 
study. The remaining leads will be enrolled under a separate post-market approval study 
protocol. Data from this study and data from the post-approval study protocol will be pooled for 
purposes of analysis. 
11.2.9.2. Additional Analyses for RELIANCE 4-FRONT  
To assess the long term performance of electrical measurements, pacing threshold, sensed 
amplitude, and pacing impedance at 24 months will be summarized using descriptive statistics. 
Spontaneous VT/VF events will also be summarized with descriptive statistics. 
11.3. General Statistical Methods 
All sample size calculations were performed and all statistical analyses will be done with SAS 
version 9.1 or higher. 
11.3.1. Study Success Criteria 
The study success will be determined 
for ACUITY X4 and RELIANCE 4-FRONT. 
Each study will be considered successful if all primary endpoints specific to that lead are passed 
11.3.2. Analysis Sets 
The following analysis sets will be used for each endpoint. Note that for all analyses, the final 
lead implanted or attempted from the initial procedure will contribute to the analysis. 
Endpoint 
Analysis Sets 
ACUITY X4 Primary Safety Endpoint 
All subjects implanted or attempted with ACUITY X4 
ACUITY X4 Primary Effectiveness 
Endpoint 1 
All ACUITY X4 leads with measurements taken at the three-
month follow-up visit 
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Endpoint 
Analysis Sets 
ACUITY X4 Primary Effectiveness 
Endpoint 1 
All ACUITY X4 
 leads with measurements taken at 
the three-month follow-up visit 
ACUITY X4 Secondary Effectiveness 
Endpoints 1 & 2 
All ACUITY X4 leads with measurements taken at the three-
month follow-up visit 
ACUITY X4 Ancillary Safety Objective 
Analysis will not be performed at the time of report 
submission since 60-month data from this study will be 
pooled with data from an ACUITY X4 Post-Market Approval 
Study 
RELIANCE 4-FRONT Primary Safety 
Endpoint 1 
All subjects implanted or attempted with RELIANCE 4-
FRONT 
RELIANCE 4-FRONT Primary Safety 
Endpoint 2 
All subjects implanted with RELIANCE 4-FRONT that have 
been followed for at least 
days post-implant  
RELIANCE 4-FRONT Secondary Safety 
Endpoint 
All subjects implanted with RELIANCE 4-FRONT that 
undergo an induction test within 30 days of implant will 
contribute to the analysis of this endpoint 
RELIANCE 4-FRONT Ancillary Safety 
Objective 
Analysis will not be performed at the time of report 
submission since 60-month data from this study will be 
pooled with data from a RELIANCE 4-FRONT Post-Market 
Approval Study 
RELIANCE 4-FRONT Primary 
Effectiveness Endpoint 
All RELIANCE 4-FRONT leads with measurements taken at 
three month follow-up visit 
RELIANCE 4-FRONT Secondary 
Effectiveness Endpoints 1 &2 
All RELIANCE 4-FRONT leads with measurements taken at 
three month follow-up visit 
RELIANCE 4-FRONT Secondary 
Effectiveness Endpoint 3: 
All subjects implanted with RELIANCE 4-FRONT that 
undergo an induction test within 30 days of implant will 
contribute to the analysis of this endpoint 
11.3.3.  Control of Systematic Error/Bias 
Selection of subjects for enrollment will be made from the Investigator’s usual patient load. All 
subjects meeting the eligibility criteria and having signed the ICF will be eligible for enrollment 
in the study.  
11.3.4.  Control of Type-I Error 
Control of type-I Error will be handled separately for ACUITY X4 and RELIANCE 4-FRONT.  
ACUITY X4 
Each primary endpoint can be tested at the significance level specified in Section 11.1 (
 
). 
For each lead, due to the requirement that each applicable endpoint must be passed, each 
applicable endpoint can be tested at the specified significance level while still maintaining the 
overall type-I error level at no greater than %.This follows the methodology of the Intersection-
Union Test (IUT).  
If all primary endpoints are passed, then a gating approach will be employed to test the following 
secondary endpoints in this order: 
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• Secondary Effectiveness Endpoint 1 
• Secondary Effectiveness Endpoint 2 
RELIANCE 4-FRONT 
Each primary endpoint can be tested at the significance level of % while still maintaining the 
overall type-I error level of no more than %. This follows the methodology of the Intersection-
Union Test (IUT). If all primary endpoints are passed, then a gating approach will be employed 
to test the following secondary endpoints in this order: 
• Secondary Effectiveness Endpoint 1 
• Secondary Effectiveness Endpoint 2 
• Secondary Safety Endpoint  
• Secondary Effectiveness Endpoint 3 
11.3.5. Number of Subjects per Investigative Site 
To avoid any center effect and bias, one center will not be authorized to enroll more than 20% of 
the maximum number of 
 of this protocol, without approval from Boston 
Scientific. Similarly, and with the same rationale, one center will not be authorized to enroll 
more than 20% of the maximum number of 
subjects 
 this protocol, without 
approval from Boston Scientific. 
11.4. Data Analyses 
11.4.1. Interim Analyses  
Analyses of adverse events and device deficiencies will occur at frequent intervals during the 
course of the study.  Results of these analyses will be reviewed by the Boston Scientific Medical 
Safety Group to evaluate the safety of the subjects under study. 
A futility analysis for each investigational lead – ACUITY X4 and RELIANCE 4-FRONT – will 
be conducted for each effectiveness endpoint.  The futility analyses for ACUITY X4 leads will 
occur at the point at which 
 subjects have been enrolled for 3 
months. 
 
 
 If a futility 
analysis reveals that the conditional power to pass an effectiveness endpoint is sufficiently low 
(less than 20%), Boston Scientific may consider terminating enrollment for one (or both) leads. 
To reduce the potential for biasing the results, the futility analyses will be performed by a BSC 
statistician independent from the NAVIGATE X4 Study. 
No formal interim analyses are planned for the purpose of stopping the study early for declaring 
effectiveness. The hypothesis test for each endpoint will be performed when all applicable data 
for that endpoint has been collected.  
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11.4.2. Pooling Analyses 
11.4.2.1. RELIANCE 4-FRONT Pooling of Cohorts 
It is expected that results will not differ 
 for any endpoint, with the exception of 
Secondary Effectiveness Endpoint 2. In order to confirm the poolability for each endpoint, a 
pooling analysis will be performed. Specifically, a likelihood ratio test from a regression model 
will be conducted. The type of regression model used for each of the following endpoints is as 
follows: 
• Primary Safety Endpoint 1 (CFR from Implant to 3 Months):  Logistic Regression 
• Primary Safety Endpoint 2 (CFR from 3 to 24 Months):  Logistic Regression 
• Secondary Safety Endpoint (Detection of VT/VF):  Linear Regression 
• Primary Effectiveness Endpoint (Pacing Threshold at 3 Months): Linear Regression 
• Secondary Effectiveness Endpoint 1 (Sensed Amplitude at 3 Months): Linear Regression 
• Secondary Effectiveness Endpoint 3 (VT/VF Shock Conversion): Logistic Regression 
The regression model will include additional baseline covariates to attempt to adjust for any 
imbalances between baseline data. The following baseline covariates will be considered: age, 
gender, etiology, CRT-D indication, LVEF, NYHA classification, medications, arrhythmia 
history, associated diseases/risk factors, height, weight and geography. 
 
 
. 
 
 
 
 
 
11.4.2.2. ACUITY X4 Pooling of Cohorts 
It is expected that results will not differ 
 for any endpoint, with the exception of 
Secondary Effectiveness Endpoint 2. In order to confirm the poolability for each endpoint, a 
pooling analysis will be performed. Specifically, a likelihood ratio test from a regression model 
will be conducted. The type of regression model used for each of the following endpoints is as 
follows: 
• Primary Safety Endpoint (CFR from Implant to 6 Months):  Logistic Regression 
• Primary Effectiveness Endpoint 1 (Pacing Threshold at 3 Months, programmed): Logistic 
Regression  
• Primary Effectiveness Endpoint 2 (Pacing Threshold at 3 Months, best proximal): 
Logistic Regression  
• Secondary Effectiveness Endpoint 1 (Sensed Amplitude at 3 Months): Linear Regression  
• Secondary Effectiveness Endpoint 2 (Pacing Impedance at 3 Months): Linear Regression  
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The regression model will include additional baseline covariates to attempt to adjust for any 
imbalances between baseline data. The following baseline covariates will be considered: age, 
gender, etiology, CRT-D indication, LVEF, NYHA classification, medications, arrhythmia 
history, associated diseases/risk factors, height, weight and geography. 
 
 
. 
 
 
 
  
11.4.2.3. Pooling of Geographies 
It is expected that results will not differ by geographic regions for any of the endpoints for either 
lead. In order to confirm the poolability of the data from the geographic regions for each 
endpoint, a pooling analysis will be performed. Specifically, a likelihood ratio test from a 
regression model will be conducted. 
 
 
 
 
11.4.2.4. Pooling of investigational centers 
Center-to-center heterogeneity will be assessed for each endpoint by performing random effects 
regression analyses. Centers with less than five enrollments will be combined to form 
“supercenters”. Small centers will be combined until the newly created supercenter has five 
enrollments, and then a new supercenter will be created. The following regression models for 
each of the following endpoints will be used: 
ACUITY X4 
• Primary Safety Endpoint (CFR from Implant to 6 Months):  Random Effects Logistic 
Regression 
• Primary Effectiveness Endpoint 1 (Pacing Threshold at 3 Months, programmed): 
Random Effects Logistic Regression  
• Primary Effectiveness Endpoint 2 (Pacing Threshold at 3 Months, best proximal): 
Random Effects Logistic Regression  
• Secondary Effectiveness Endpoint 1 (Sensed Amplitude at 3 Months): Random Effects 
Linear Regression  
• Secondary Effectiveness Endpoint 2 (Pacing Impedance at 3 Months): Random Effects 
Linear Regression  
RELIANCE 4-FRONT 
• Primary Safety Endpoint 1 (CFR from Implant to 3 Months):  Random Effects Logistic 
Regression 
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• Primary Safety Endpoint 2 (CFR from 3 to 24 Months):  Random Effects Logistic 
Regression 
• Secondary Safety Endpoint (Detection of VT/VF):  Random Effects Linear Regression  
• Primary Effectiveness Endpoint  (Pacing Threshold at 3 Months): Random Effects Linear 
Regression  
• Secondary Effectiveness Endpoint 1 (Sensed Amplitude at 3 Months):  Random Effects 
Linear Regression  
• Secondary Effectiveness Endpoint 2 (Pacing Impedance at 3 Months):  Random Effects 
Linear Regression  
• Secondary Effectiveness Endpoint 3 (VT/VF Shock Conversion):  Random Effects 
Logistic Regression 
Investigational center will be added into the model as a random effect. Centers will be deemed to 
be heterogeneous if the variance of the random center effect is found to significantly differ from 
zero. A significance level of 
% will be used for each test. If it determined that the center 
random effect is significant for an endpoint, then the results from the random effects model for 
that endpoint will be presented. Regardless of the results of the random effects model, results by 
investigational center will be presented for each endpoint.   
11.4.3. Subgroup Analyses 
Analyses will be performed for each endpoint to determine whether significant differences exist 
in endpoint results between subgroups. Results will be presented for each subgroup, regardless of 
whether significant differences exist between the subgroups. The list of baseline covariates (with 
applicable subgroups in parentheses) includes, but is not necessarily limited to: 
• Sex (Female vs. Male) 
• Geography (International vs. United States) 
• Age (< 65 years vs. ≥ 65 years) 
• NYHA Class 
• LVEF (< 25% vs. ≥ 25%) 
• QRS width (< 150 ms vs. ≥ 150 ms) 
• Bundle Branch Block Morphology (LBBB vs. non-LBBB) 
For ACUITY X4, the following additional baseline covariates will be assessed: 
• Spiral length (Short vs. Long) 
• Lead shape (Spiral vs. Straight) 
For RELIANCE 4-FRONT, the following additional baseline covariates will be assessed: 
• Fixation type (Active vs. Passive) 
• Coil type (Dual vs. Single) 
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The baseline covariate will be added to a univariate regression model and a test for significance 
at the 
% level will be performed. The regression models used for each endpoint will be 
identical to those specified in Section 11.4.2.1.   
In addition to subgroup analyses, descriptive statistics of patient demographic and baseline 
characteristics will be presented for each subgroup listed in this section. Descriptive statistics 
will also be presented for the overall study population. 
11.4.4. Multivariate Analyses 
Univariate analyses of various baseline covariates and their relationship to each endpoint are 
outlined in Section 11.4.3. For each endpoint, all baseline characteristics found to be 
significantly associated with the outcome will be included as covariates in a multivariate 
regression model. The impact of each baseline characteristic’s subgroups will be presented along 
with the multivariate model results.  
11.4.5. Early Projection of Ancillary Safety Endpoint Results 
At the time of the submission of the Clinical Report for each lead (
 
 it is desired to obtain an estimate of the chronic 
complication-free rate at 60-months. To obtain such an estimate, two methods will be employed: 
1. 
 
 
 
   
2. 
 
 
 
 
 
 
 
 
 
Through the interpretation of the results of both analysis methods, an understanding of the 
expected 60-month results will be obtained. 
11.4.6. Accuracy of Projection Estimates for Long-term Lead-Related Complication-
Free Rates  
As stated in the previous section, parametric survival models (such as the Weibull and log-
logistic) provide the ability to project survival curves and yield survival estimates beyond the 
evaluation time period. The objective of this ancillary analysis is to evaluate the ability of these 
parametric survival models to provide accurate long-term estimates using data collected through 
a shorter-term follow-up. This analysis will be performed separately for ACUITY X4 and 
RELIANCE 4-FRONT. Actual complication rates observed at long-term time points (e.g. 24, 36, 
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48, 60 months) will be compared to the corresponding projected/estimated complication rates 
produced using data collected through earlier time points (e.g. 3, 6, 12 months). 
The risk period for the events of interest for these analyses may begin at implant or at some later 
time point (e.g. 3 months), depending on the type of event being considered.  For example, a 
survival projection for dislodgments may start at implant, while a survival projection for chronic 
lead fractures may start at 3 months. 
A parametric survival analysis can provide unreliable estimates if an insufficient sample size or 
insufficient number of events is present. 
 
 
 
 
11.4.7. Changes to Planned Analyses 
Any changes to the planned statistical analyses outlined in this protocol will be documented in 
the statistical analysis plan and/ or clinical study reports along with a reason for the deviation. 
12. DATA MANAGEMENT 
12.1. Data Collection, Processing, and Review 
Subject data will be recorded in a limited access secure electronic data capture (EDC) system.  
The clinical database will reside on a production server hosted by Medidata. All changes made to 
the clinical data will be captured in an electronic audit trail and available for review by BSC or 
its representative. The associated RAVE software and database have been designed to meet 
regulatory compliance for deployment as part of a validated system compliant with laws and 
regulations applicable to the conduct of clinical studies pertaining to the use of electronic records 
and signatures. Database backups are performed regularly. 
The Investigator provides his/her electronic signature on the appropriate eCRFs in compliance 
with local regulations. A written signature on printouts of the eCRFs must also be provided if 
required by local regulation. Changes to data previously submitted to the sponsor require a new 
electronic signature by the Investigator acknowledging and approving the changes. 
Visual and/or electronic data review will be performed to identify possible data discrepancies. 
Manual and/or automatic queries will be created in the EDC system and will be issued to the site 
for appropriate response. Site staff will be responsible for resolving all queries in the database. 
12.2. Data Retention 
The Investigator or Investigational site will maintain, at the investigative site, in original format 
all essential study documents and source documentation that support the data collected on the 
study subjects in compliance with International Conference on Harmonisation (ICH)/ Good 
Clinical Practice (GCP) guidelines. Documents must be retained for at least 2 years after the last 
approval of a marketing application or until at least 2 years have elapsed since the formal 
discontinuation of the clinical investigation of the product. These documents will be retained for 
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a longer period of time by agreement with BSC or in compliance with other local regulations. It 
is BSC’s responsibility to inform the Investigator when these documents no longer need to be 
maintained. The Investigator will take measures to ensure that these essential documents are not 
accidentally damaged or destroyed. If for any reason the Investigator withdraws responsibility 
for maintaining these essential documents, custody must be transferred to an individual who will 
assume responsibility and BSC must receive written notification of this custodial change.  
13. AMENDMENTS  
If a protocol revision is necessary which affects the rights, safety or welfare of the subject or 
scientific integrity of the data, an amendment is required. Appropriate approvals (e.g., 
IRB/EC/FDA/CA) of the revised protocol must be obtained prior to implementation. 
14. DEVIATIONS 
An Investigator must not make any changes or deviate from this protocol, except to protect the 
life and physical well-being of a subject in an emergency. An investigator shall notify the 
sponsor and the reviewing IRB/EC of any deviation from the investigational plan to protect the 
life or physical well-being of a subject in an emergency, and those deviations which affect the 
scientific integrity of the clinical investigation. Such notice shall be given as soon as possible, 
but no later than 5 working days after the emergency occurred, or per prevailing local 
requirements, if sooner than 5 working days.  
All deviations from the investigational plan, with the reason for the deviation and the date of 
occurrence, must be documented and reported to the sponsor using the EDC system. Sites may 
also be required to report deviations to the IRB/EC, per local guidelines and government 
regulations.  
Deviations will be reviewed and evaluated on an ongoing basis and, as necessary, appropriate 
corrective and preventive actions put into place by the sponsor (including notification, center re-
training, or discontinuation). 
15. INVESTIGATIONAL DEVICE/ EQUIPMENT ACCOUNTABILITY 
This section applies to sites in the US, as the only geography with investigational devices/ 
equipment. The investigational products used in the NAVIGATE X4 Study must be securely 
maintained, controlled, and used only as a part of this clinical study. Investigational products in 
this study include the AUTOGEN X4 CRT-D, ACUITY X4 quadripolar coronary venous leads, 
and associated flushing tool (tracked only if used as separate accessory Model 4604), connector 
tool (tracked only if used as separate accessory Model 4625) and accessory slit suture sleeve 
(Model 4603), the RELIANCE 4-FRONT defibrillator leads and associated accessory slit suture 
sleeve, (Model 6403), as well as 2909 MAU, 2868 software application, and 3140 ZWT. Current 
Boston Scientific processes will be used to track investigational device/ equipment allocations 
during the study. 
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Boston Scientific shall keep records to document the physical location of all investigational 
devices from shipment of investigational devices to the investigation sites until return or 
disposal. 
The principal investigator or an authorized designee shall keep records documenting the receipt, 
use, return and disposal of the investigational devices/equipment, which shall include the 
following: 
• Date of receipt 
• Identification of each investigational device/piece of equipment (model number and serial or 
lot number) 
• Expiration date, as applicable 
• Date or dates of use (for implantable devices only, not PRM) 
• Subject identification 
• Date on which the investigational device/piece of equipment was returned/explanted from 
subject, if applicable 
• Date of return of unused, expired, or malfunctioning investigational devices/equipment, if 
applicable. 
Written procedures may be required by national regulations. 
Upon completion of enrollment into the NAVIGATE X4 Clinical Study, or as directed by 
Boston Scientific, all unused investigational AUTOGEN X4 CRT-Ds, ACUITY X4 Leads, 
ACUITY X4 Connector Tool, ACUITY X4 Flushing Tool/ Wire Guide, RELIANCE 4-FRONT 
Leads and accessory suture sleeves must be returned to Boston Scientific. 
Also, at such time that the 2909 MAU, 2868 software application, and 3140 ZWT are approved 
for commercial use, or as directed by Boson Scientific, the clinical 3120 Zoom LATITUDE 
PRM must be returned to Boston Scientific.  
16. COMPLIANCE 
16.1. Statement of Compliance 
This study will be conducted in accordance with ISO 14155:2011, relevant parts of the ICH 
Guidelines for GCP, relevant parts of the Code of Federal Regulations (CFR), and ethical 
principles that have their origins in the Declaration of Helsinki, and pertinent individual country 
laws and regulations. The study shall not begin until the required approval/favorable opinion 
from the IRB/EC and/or regulatory authority has been obtained, if appropriate. Any additional 
requirements imposed by the IRB/EC or regulatory authority shall be followed, if appropriate. 
16.2. Investigator Responsibilities 
The Principal Investigator of an investigational center is responsible for ensuring that the study is 
conducted in accordance with the Clinical Study Agreement, the investigational plan/protocol, 
ISO 14155, ethical principles that have their origins in the Declaration of Helsinki, any 
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conditions of approval imposed by the reviewing IRB/EC, and prevailing local and/or country 
laws and/or regulations, whichever affords the greater protection to the subject. 
The Principal Investigator’s responsibilities include, but are not limited to, the following.  
• Prior to beginning the study, sign the Investigator Agreement and Protocol Signature page 
documenting his/her agreement to conduct the study in accordance with the protocol. 
• Provide his/her qualifications and experience to assume responsibility for the proper conduct 
of the study and that of key members of the center team through up-to-date curriculum vitae 
or other relevant documentation and disclose potential conflicts of interest, including 
financial, that may interfere with the conduct of the clinical study or interpretation of results. 
• Make no changes in or deviate from this protocol, except to protect the life and physical 
well-being of a subject in an emergency; document and explain any deviation from the 
approved protocol that occurred during the course of the clinical investigation. 
• Create and maintain source documents throughout the clinical study and ensure their 
availability with direct access during monitoring visits or audits; ensure that all clinical-
investigation-related records are retained per requirements. 
• Ensure the accuracy, completeness, legibility, and timeliness of the data reported to the 
sponsor in the CRFs and in all required reports. 
• Record, report, and assess (seriousness and relationship to the device/procedure) every 
adverse event and observed device deficiency. 
• Report to BSC, per the protocol requirements, all SAEs and device deficiencies that could 
have led to a SADE. 
• Report to the IRB/EC and regulatory authorities any SAEs and device deficiencies that could 
have led to a SADE, if required by the national regulations or this protocol or by the IRB/EC, 
and supply BSC with any additional requested information related to the safety reporting of a 
particular event. 
• Maintain the device accountability records and control of the device, ensuring that the 
investigational device/ equipment are used only by authorized/designated users and in 
accordance with this protocol and instructions/directions for use. 
• Allow the sponsor to perform monitoring and auditing activities, and be accessible to the 
monitor and respond to questions during monitoring visits. 
• Allow and support regulatory authorities and the IRB/EC when performing auditing 
activities. 
• Ensure that informed consent is obtained in accordance with this protocol and local IRB/EC 
requirements. 
• Provide adequate medical care to a subject during and after a subject’s participation in a 
clinical study in the case of adverse events, as described in the ICF. 
• Inform the subject of the nature and possible cause of any adverse events experienced. 
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• Inform the subject of any new significant findings occurring during the clinical investigation, 
including the need for additional medical care that may be required. 
• Provide the subject with well-defined procedures for possible emergency situations related to 
the clinical study, and make the necessary arrangements for emergency treatment, including 
decoding procedures for blinded/masked clinical investigations, as needed. 
• Ensure that clinical medical records are clearly marked to indicate that the subject is enrolled 
in this clinical study. 
• Ensure that, if appropriate, subjects enrolled in the clinical investigation are provided with 
some means of showing their participation in the clinical investigation, together with 
identification and compliance information for concomitant treatment measures (contact 
address and telephone numbers shall be provided). 
• Inform, with the subject’s approval or when required by national regulations, the subject’s 
personal physician about the subject’s participation in the clinical investigation. 
• Make all reasonable efforts to ascertain the reason(s) for a subject’s premature withdrawal 
from clinical investigation while fully respecting the subject’s rights. 
• Ensure that an adequate investigation site team and facilities exist and are maintained and 
documented during the clinical investigation. 
• Ensure that maintenance and calibration of the equipment relevant for the assessment of the 
clinical investigation is appropriately performed and documented, where applicable. 
16.2.1. Delegation of Responsibility 
When specific tasks are delegated by an investigator, including but not limited to conducting the 
informed consent process, the investigator is responsible for providing appropriate training and 
adequate supervision of those to whom tasks are delegated. The investigator is accountable for 
regulatory violations resulting from failure to adequately supervise the conduct of the clinical 
study.  
16.3. Institutional Review Board/ Ethics Committee 
Prior to gaining Approval-to-Enroll status, the investigational center will provide to the sponsor 
documentation verifying that their IRB/EC is registered or that registration has been submitted to 
the appropriate agency, as applicable according to national/regulatory requirements.   
A copy of the written IRB/EC and/or competent authority approval of the protocol (or 
permission to conduct the study) and Informed Consent Form, must be received by the sponsor 
before recruitment of subjects into the study and shipment of investigational product/equipment. 
Prior approval must also be obtained for other materials related to subject recruitment or which 
will be provided to the subject. 
Annual IRB/EC approval and renewals will be obtained throughout the duration of the study as 
required by local/country or IRB/EC requirements. Copies of the Investigator’s reports and the 
IRB/EC continuance of approval must be provided to the sponsor.  
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16.4. Sponsor Responsibilities 
All information and data sent to BSC concerning subjects or their participation in this study will 
be considered confidential by BSC. Only authorized BSC personnel or a BSC representative 
including Contract Research Organization (CRO) will have access to these confidential records. 
Authorized regulatory personnel have the right to inspect and copy all records pertinent to this 
study. Study data collected during this study may be used by BSC for the purposes of this study, 
publication, and to support future research and/or other business purposes. All data used in the 
analysis and reporting of this study will be without identifiable reference to specific subject 
name. 
Boston Scientific will keep subjects’ health information confidential in accordance with all 
applicable laws and regulations. Boston Scientific may use subjects’ health information to 
conduct this research, as well as for additional purposes, such as overseeing and improving the 
performance of its device, new medical research and proposals for developing new medical 
products or procedures, and other business purposes. Information received during the study will 
not be used to market to subjects; subject names will not be placed on any mailing lists or sold to 
anyone for marketing purposes.  
16.4.1. Role of Boston Scientific Representatives 
Boston Scientific personnel can provide technical support to the investigator and other health 
care personnel (collectively HCP) as needed during implant, testing required by the protocol, and 
follow-ups. Support may include HCP training, addressing HCP questions, or providing 
clarifications to HCPs concerning the operation of BSC equipment/devices (including 
programmers, analyzers, and other support equipment). 
At the request of the investigator and while under investigator supervision, BSC personnel may 
operate equipment during implant or follow-up, assist with the conduct of testing specified in the 
protocol, and interact with the subject to accomplish requested activities. Typical tasks may 
include the following. 
• Interrogating the device or programming device parameters to investigator-requested settings 
as well as operating investigational equipment 
• Performing lead diagnostic testing using a Pacing System Analyzer or programmer to obtain 
pacing and sensing thresholds and impedance measurements 
• Clarifying device behavior, operation or diagnostic output as requested by the investigator or 
other health care personnel 
• Assisting with the collection of study data from Pacing System Analyzers, programmers, and 
other equipment 
In addition, BSC personnel may perform certain activities to ensure study quality. These 
activities may include the following. 
• Observing testing or medical procedures to provide information relevant to protocol 
compliance 
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• Reviewing collected data and study documentation for completeness and accuracy 
Boston Scientific personnel will not do the following.  
• Practice medicine 
• Provide medical diagnosis or treatment to subjects 
• Discuss a subject’s condition or treatment with a subject without the approval and presence 
of the HCP 
• Independently collect critical study data (defined as primary or secondary endpoint data) 
• Enter data in electronic data capture systems or on paper case report forms 
16.5. Insurance  
Where required by local/country regulation, proof and type of insurance coverage, by BSC for 
subjects in the study will be obtained. 
17. MONITORING 
Monitoring will be performed during the study to assess continued compliance with the protocol 
and applicable regulations. In addition, the monitor verifies that study records are adequately 
maintained, that data are reported in a satisfactory manner with respect to timeliness, adequacy, 
and accuracy, and that the Investigator continues to have sufficient staff and facilities to conduct 
the study safely and effectively. The Investigator/institution guarantees direct access to original 
source documents by BSC personnel, their designees, and appropriate regulatory authorities. 
The study may also be subject to a quality assurance audit by BSC or its designees, as well as 
inspection by appropriate regulatory authorities. It is important that the Investigator and relevant 
study personnel are available during on-site monitoring visits or audits and that sufficient time is 
devoted to the process.  
18. POTENTIAL RISKS AND BENEFITS 
18.1. Anticipated Adverse Events  
Subjects participating in this study are subject to the same risks shared by all patients undergoing 
implantation of a CRT-D system.  
Based on the literature and on pulse generator implant experience, Table 14 includes an 
alphabetical list of the possible adverse events associated with implantation of a pulse generator 
and/or lead system.  
Table 14: Potential Adverse Events for Pulse Generator and/ or Lead System Implants 
Potential Adverse Events for Implantation of a Pulse Generator and/ or Lead System* 
Acceleration of arrhythmias 
Incisional pain  
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Table 14: Potential Adverse Events for Pulse Generator and/ or Lead System Implants 
Potential Adverse Events for Implantation of a Pulse Generator and/ or Lead System* 
Adverse reaction to procedure (e.g., 
bradycardia, general, respiratory, 
hypotension) 
Incomplete lead connection with pulse generator  
Air embolism  
Infection including endocarditis 
Allergic reaction  
Insulating myocardium during defibrillation with internal 
or external paddles 
Arterial damage with subsequent stenosis 
Lead dislodgment  
Bleeding  
Lead fracture  
Breakage/ failure of the implant instruments 
Lead insulation breakage or abrasion  
Cardiac perforation  
Lead perforation 
Cardiac tamponade  
Lead tip deformation and / or breakage  
Chronic nerve damage  
Local tissue reaction 
Component failure  
Loss of capture 
Conductor coil fracture 
Malignancy or skin burn due to fluoroscopic radiation  
Coronary venous spasm 
Myocardial necrosis 
Death  
Myocardial trauma (e.g.,irritability,injury, tissue 
damage, valve damage) 
Electrolyte imbalance/ dehydration  
Myopotential sensing  
Elevated thresholds  
Oversensing / undersensing  
Erosion  
Pacemaker-mediated tachycardia (PMT) 
Excessive fibrotic tissue growth  
Pericardial rub, effusion  
Extracardiac stimulation (muscle/ nerve 
stimulation) 
Pneumothorax 
Failure to convert an induced arrhythmia 
Pulse generator migration 
Fluid accumulation  
Shunting current during defibrillation with internal or 
external paddles 
Foreign body rejection phenomena  
Tachyarrhythmias, which include acceleration of 
arrhythmias and early, recurrent atrial fibrillation  
Formation of hematomas or seromas  
Thrombus, thromboemboli 
Heart block  
Valve damage  
Hemorrhage 
Venous occlusion  
Hemothorax 
Venous trauma (e.g. perforation, dissection, erosion) 
Inability to defibrillate or pace 
Worsening heart failure 
Inappropriate therapy (e.g., shocks, and 
antitachycardia pacing [ATP] where 
applicable, pacing) 
 
*From the ACUITY X4, RELIANCE 4-FRONT Physician’s Lead Manuals and/ or AUTOGEN, DYNAGEN, INOGEN, 
and ORIGEN CRT-D family (X4 and non-X4) Physician’s Technical Manual. 
In addition to the implantation of a PG and lead system, potential adverse events associated with 
implantation of a coronary venous lead system are listed in Table 15, below.  
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Table 15: Potential Adverse Events for Coronary Venous Lead Implants 
List of potential adverse events for coronary venous lead system* 
Allergic reaction to the contrast media 
Renal failure from contrast media used to 
visualize coronary veins  
Prolonged exposure to fluoroscopic radiation 
 
*From the ACUITY X4 Physician’s Lead Manuals and/ or AUTOGEN, DYNAGEN, INOGEN, and ORIGEN CRT-D 
family (X4 and non-X4) Physician’s Technical Manual 
 
Table 16: Potential Adverse Events for Implant of a Pulse Generator 
List of potential adverse events for implant of a pulse generator* 
Dependency 
Fear that shocking capability may be lost 
Depression 
Imagined shocking 
Fear of premature battery depletion 
Fear of device malfunction 
*From the AUTOGEN, DYNAGEN, INOGEN, and ORIGEN CRT-D family (X4 and non-X4) Physician’s Technical 
Manual 
18.2. Risks associated with Participation in the Clinical Study 
There are no specific tests outside of standard practice associated with this clinical study.   
Subjects who are implanted with an AUTOGEN X4 CRT-D in the US, have an added risk: 
Unavailability of a programmer/PRM with appropriate software to interrogate the AUTOGEN 
X4 device (this is in place until the programmer software is approved by FDA). Further, those 
US subjects implanted with an AUTOGEN X4 device will need a BSC representative at all 
follow ups as a programmer key (dongle key) is required to interrogate these devices until 
AUTOGEN devices are approved by FDA. This is the same risk shared by subjects in any new 
device IDE trial where only study programmers can interrogate the device. 
  
This information is also provided in Section 4.1.2. 
18.3. Risk Minimization Actions 
Additional risks may exist. Risks can be minimized through compliance with this protocol, 
performing procedures in the appropriate hospital environment, adherence to subject selection 
criteria, close monitoring of the subject's physiologic status during research procedures and/or 
follow-ups and by promptly supplying BSC with all pertinent information required by this 
protocol. 
18.4. Anticipated Benefits 
There may be no benefit to the subject. However, subjects participating in clinical studies may 
have better outcomes than the general population. The subject may benefit from closer device 
follow up due to the clinical protocol schedule. Subjects may be followed more carefully and 
their status, as well as their PG and lead status is checked by various persons and systems: 
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Investigators, data coordinators, monitors and automatic warning systems in the clinical study 
database set to monitor the data as it is submitted to Boston Scientific. 
18.5. Risk to Benefit Rationale 
Risk management activities, including hazard analyses and fault tree analysis, have been 
performed on the ACUITY X4 leads, RELIANCE 4-FRONT leads and BSC X4 CRT-Ds to 
identify and analyze known and foreseeable hazards (in both normal and fault conditions) and 
reasonably foreseeable sequences or combinations of events that could result from using this 
product and the risks associated with each hazard. Mitigations have been implemented in the 
design, processes, and/or labeling and instructions for use of the product to reduce the residual 
risk of each hazard as necessary and practicable. The hazard analysis has been reviewed and 
approved and the remaining risks are acceptable when weighed against the intended benefits to 
the patient. 
19. SAFETY REPORTING 
19.1. Definitions and Classification 
All Adverse Events reported to Boston Scientific during the study will be reviewed and 
adequately reported to comply with applicable regulations (ISO 14155: 2011 and/or 21 CFR Part 
812). Investigators will be asked to classify whether an adverse event is considered serious or 
non-serious, whether it is anticipated or unanticipated (meets USADE/ UADE definition) as 
defined in Table 17 below, and whether it is considered device or procedure related, as defined in 
Section 19.2. Any event that is determined to be an unanticipated serious adverse device effect 
(USADE; ISO 14155: 2011) will also be considered an unanticipated adverse device effect 
(UADE; CFR Part 812), as defined in Table 17 below. 
Table 17: Adverse Event Definitions 
Term 
Definition 
Adverse Event (AE) 
 
Ref: ISO 14155-2011 
 
Ref: MEDDEV 2.7/3 12/2010 
 
 
Any untoward medical occurrence, unintended disease or injury, or any 
untoward clinical signs (including an abnormal laboratory finding) in 
subjects, users or other persons, whether or not related to the 
investigational medical device.  
NOTE 1: This includes events related to the investigational medical 
device or comparator. 
NOTE 2: This definition includes events related to the procedures 
involved (any procedure in the clinical investigation plan). 
NOTE 3: For users or other persons, this definition is restricted to 
events related to the investigational medical device.  
Adverse Device Effect (ADE) 
 
Ref: ISO 14155-2011 
 
Ref: MEDDEV 2.7/3 12/2010 
Adverse event related to the use of an investigational medical device 
NOTE 1: This definition includes any adverse event resulting from 
insufficient or inadequate instructions for use, the deployment, the 
implantation, the installation, the operation, or any malfunction of the 
investigational medical device. 
NOTE 2: This definition includes any event resulting from use error or 
from intentional misuse of the investigational medical device. 
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Table 17: Adverse Event Definitions 
Term 
Definition 
Serious Adverse Event (SAE) 
 
Ref: ISO 14155-2011 
 
Ref: MEDDEV 2.7/3 12/2010 
Adverse event that: 
• Led to death, 
• Led to serious deterioration in the health of the subject, that either 
resulted in: 
o a life-threatening illness or injury, or 
o a permanent impairment of a body structure or a body function, or 
o in-patient or prolonged hospitalization of existing hospitalization, or 
o medical or surgical intervention to prevent life-threatening illness 
or injury or permanent impairment to a body structure or a body 
function 
• Led to fetal distress, fetal death, or a congenital abnormality or birth 
defect. 
NOTE 1: Planned hospitalization for a pre-existing condition, or a 
procedure required by the clinical investigational plan, without serious 
deterioration in health, is not considered a serious adverse event.  
Serious Adverse Device Effect 
(SADE) 
 
Ref: ISO 14155-2011Ref: 
MEDDEV 2.7/3 12/2010 
Adverse device effect that has resulted in any of the consequences 
characteristic of a serious adverse event. 
Unanticipated Adverse Device 
Effect (UADE) 
 
Ref: 21 CFR Part 812 
 
Note: For US IDE studies 
only, otherwise remove UADE 
from table 
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.   
Unanticipated Serious 
Adverse Device Effect 
(USADE) 
 
Ref: ISO 14155-2011 
 
Ref: MEDDEV 2.7/3 12/2010 
Note: For studies conducted 
outside the US only, otherwise 
remove USADE from table. 
Serious adverse device effect which by its nature, incidence, severity, or 
outcome has not been identified in the current version of the risk 
analysis report. 
NOTE 1: Anticipated serious adverse device effect (ASADE) is an effect 
which by its nature, incidence, severity or outcome has been identified 
in the risk analysis report. 
Device Deficiency 
 
Ref: ISO 14155-2011 
 
Ref: MEDDEV 2.7/3 12/2010 
A device deficiency is any inadequacy of a medical device with respect 
to its identity, quality, durability, reliability, safety or performance. 
NOTE 1: Device deficiencies include malfunctions, misuse or use errors, 
and inadequate labeling. 
 
Abbreviations: EC=Ethics Committee; IRB=Institutional Review Board 
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Underlying diseases are not reported as AEs unless there is an increase in severity or frequency 
during the course of the NAVIGATE X4 Clinical Study. Death should not be recorded as an AE, 
but should only be reflected as an outcome of a specific SAE (see Table 17 for AE definitions).  
Any AE experienced by the study subject after informed consent, whether during or subsequent 
to the procedure, must be recorded in the eCRF. 
Refer to Section 18 for the known risks associated with the study device(s). 
19.2. Relationship to Study Device(s) or Investigational Device Implant Procedure 
The Investigator must assess the relationship of the AE to the investigational devices 
(AUTOGEN X4, ACUITY X4, RELIANCE 4-FRONT) and to the implant procedure of the 
investigational devices as related or unrelated using the criteria in Table 18. 
Table 18: Criteria for Assessing Relationship of Study Device to Adverse Event 
Classification 
Description 
Unrelated 
The adverse event is determined to be due to a concurrent illness or effect of 
another device/drug and is not related to the investigational product or procedure 
related to the implant of the investigational device. 
Related 
• The adverse event is determined to be potentially related to the investigational 
product or procedure related to the implant of the investigational device, and 
an alternative etiology is equally or less likely compared to the potential 
relationship to investigational product, or 
• There is a strong relationship to investigational product or procedure related to 
the implant of the investigational device, or recurs on re-challenge, and 
another etiology is unlikely, or 
• There is no other reasonable medical explanation for the event. 
19.3. Definition for Lead-related Adverse Events 
Those adverse events deemed related to one of the investigational leads, ACUITY X4 or 
RELIANCE 4-FRONT, the following definitions will also be applied. Lead-related adverse 
events include, but are not limited to the following, based on the Advamed Industry Guidance for 
Uniform Reporting of Clinical Performance of Cardiac Rhythm Management of Pulse 
Generators and Leads[37] and FDA Guidance Document[38]: 
• Cardiac perforation requiring surgical intervention 
• Cardiac perforation not requiring surgical intervention 
• Conductor fracture/ helix damage 
• Lead dislodgment 
• Failure to capture 
• Oversensing 
• Failure to sense (undersensing) 
• Insulation breach 
• Abnormal pacing impedance 
• 
Extracardiac stimulation 
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19.3.1. Definition for Lead-related Complication 
Lead-related complications are defined as lead-related adverse events resulting in permanent loss 
of pacing therapy, invasive intervention*, injury or death. *See definition for invasive 
intervention within the definition of “complication” in Table 20. 
Lead-related complications associated with attempted ACUITY X4 and/ or RELIANCE 4-
FRONT lead implants will count toward the respective safety endpoints. Lead-related adverse 
events that are not a complication will be counted as a complication if intravenous (IV) drug 
therapy is necessary to treat the event. IV drug therapy that occurs concomitant but unrelated to 
the lead-related adverse event will not be counted as a lead-related complication. Complications 
involving an ACUITY X4 and/ or RELIANCE 4-FRONT lead that occur as a result of a 
procedure unrelated to that ACUITY X4 and/ or RELIANCE 4-FRONT lead will not count 
toward the safety endpoints. Two examples of this scenario are 1) an ACUITY X4 and/or 
RELIANCE 4-FRONT lead dislodgement resulting from a repositioning of an RA lead and 2) an 
ACUITY X4 and/ or RELIANCE 4-FRONT lead dislodgement resulting from a CABG 
procedure.  
19.4. Adverse Event Classification 
Following receipt of adverse event information, the investigator’s assessment of seriousness, 
relationship to the investigational device, and expectedness, will be reviewed and an internal 
BSC assessment will be documented. If the opinions between the investigator and BSC differ, 
both opinions will be reported, as appropriate. 
In addition, case report forms are reviewed by internal BSC personnel and adverse events are 
assigned a type, classified as a clinical observation or a clinical complication, and coded for 
reporting purposes. 
The adverse event is classified as one of the following Types:  
Table 19: Adverse Event Types I-V to be Used for BSC AE Classification 
Type 
Description 
Type I 
Related to an investigational device, investigational procedure, investigational therapy, or 
procedure related to the implant of the investigational device. 
Type II 
Related to the protocol or procedures specifically related to protocol testing that is not 
standard of care. 
Type III 
Related to commercially available implanted components or commercially available 
features of an investigational device, or the procedure of a commercially available device 
Type IV 
Related to a change in the patient’s condition or to therapies other than delivered by the 
implanted system.   
Type V 
Comments Only 
 
The adverse event is classified as a clinical observation or complication, defined  in Table 20. 
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Table 20: Definition of Observation and Complication 
Clinical Event 
Description 
Observation 
Adverse event that was transient or reversible and corrected with non-invasive 
interventions, such as reprogramming or oral medications, or was resolved with 
no intervention or monitoring 
Complication 
An adverse event that resulted in: death, serious injury a, correction using 
invasive interventionb, or permanent loss of device functions. 
a Per 21 CFR 803.3: Serious injury means an injury or illness that: 
• 
Is life-threatening 
• 
Results in permanent impairment of a body function or permanent damage 
to a body structure, or 
• 
Necessitates medical or surgical intervention to preclude permanent 
impairment of a body function or permanent damage to a body structure 
Permanent means irreversible impairment or damage to a body structure or 
function, excluding trivial impairment or damage 
b Invasive interventions are those in which treatment necessary to correct the 
adverse event is delivered by cutting or piercing of the skin or placing an 
instrument in a body cavity to provide therapy. Examples of invasive 
interventions (complication) include, but are not limited to: 
• 
Surgical revision of a lead 
• 
Electrophysiology study in which an ablation is performed 
• 
Angiogram in which angioplasty or stent placement is performed 
• 
Intravenous medications 
• 
Blood transfusions 
• 
Intubation to provide respiratory support 
• 
Chemical (pharmacologic) cardioversion with IV sedation (This is a 
complication due to the IV antiarrhythmic medication used for the 
cardioversion.) 
Invasive procedures that are purely diagnostic in nature should not be 
considered as a complication. Some examples of procedures that are invasive, 
but not considered to be an intervention include: 
• 
Blood draw for laboratory analysis  
• 
Cardiac catheterization in which pressures are recorded, but without 
therapeutic intervention 
• 
Electrophysiology study to map arrhythmias, but without therapeutic 
intervention  
• 
Transesophageal echo (TEE) 
• 
Electrical (external) cardioversion with IV sedation (the IV sedation used is 
for patient comfort and not part of the treatment) 
 
*See also definition for lead-related complication in Section 19.3.1. 
19.5. Boston Scientific Device Deficiencies 
All device deficiencies (including but not limited to failures, malfunctions, use errors, product 
nonconformities, and labeling errors) will be documented and reported to BSC. If possible, the 
device(s) should be returned to BSC for analysis. Instructions for returning the investigational 
device(s) will be provided. If it is not possible to return the device, the investigator should 
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document why the device was not returned and the final disposition of the device. Device 
failures and malfunctions should also be documented in the subject’s medical record. 
In addition, any Investigational Device Deficiency that might have led to a serious adverse event 
if a) suitable action had not been taken or b) intervention had not been made or c) if 
circumstances had been less fortunate should be reported. Following receipt, the investigator’s 
assessment is reviewed by internal BSC personnel. If the opinions between the investigator and 
BSC differ, both opinions will be reported, as appropriate. 
NOTE: Device deficiencies (including but not limited to failures, malfunctions, and product 
nonconformities) are not to be reported as adverse events. However, if there is an adverse event 
that results from a device failure or malfunction, that specific event would be recorded on the 
appropriate eCRF and reported, as appropriate. 
19.6. Investigator Reporting Requirements 
The communication requirements for reporting adverse events, device deficiencies, failures, 
malfunctions, and product nonconformities to Boston Scientific are listed in Table 21. 
Adverse events should always be reported through the EDC system for NAVIGATE X4. 
However, in case of any issues where an alternative method of reporting is necessary (i.e. the 
EDC is not available), please report the adverse event to Boston Scientific by sending the AE 
Notification Form via email to the following email address: 
NAVIGATEX4Safety@bsci.com  
Source documentation for UADE/USADE, SAE/SADE and BSC requested AE’s can either be 
uploaded in the EDC system or sent via email, with the accompanying source document 
checklist to the following email address: 
NAVIGATEX4Safety@bsci.com 
Table 21: Investigator Reporting Requirements 
Event Classification 
Communication Method  
Communication Timeline  
Unanticipated Adverse Device 
Effect (UADE) / Unanticipated 
Serious Adverse Device Effect 
(USADE)  
Complete AE eCRF page with all 
available new and updated 
information 
• Within 1 business day of first 
becoming aware of the event. 
• Terminating at the end of the 
study 
Provide all relevant source 
documentation (unidentified) for 
reported event 
• When documentation is 
available 
Serious Adverse Event 
including Serious Adverse 
Device Effects 
Complete AE eCRF page with all 
available new and updated 
information 
• Within 2 business days of first 
becoming aware of the event 
or as per local/regional 
regulations. 
• Reporting required through 
the end of the study 
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Table 21: Investigator Reporting Requirements 
Event Classification 
Communication Method  
Communication Timeline  
Provide all relevant source 
documentation (de-identified) for 
all subject deaths and any 
ACUITY X4 and/ or RELIANCE 
4-FRONT lead-related events 
• When documentation is 
available 
Adverse Event 
Complete AE eCRF page, which 
contains such information as 
date of AE, treatment of AE 
resolution, assessment of 
seriousness and relationship to 
the device 
• No later than 10 working days 
after becoming aware of the 
information 
• Reporting required through 
the end of the clinical study  
Device Deficiencies (including 
but not limited to failures, 
malfunctions, and product 
nonconformities) 
Note:  Any Investigational 
Device Deficiency that might 
have led to a serious adverse 
event if a) suitable action had 
not been taken or b) 
intervention had not been 
made or c) if circumstances 
had been less fortunate is 
considered a reportable event. 
 
Complete Device Deficiency 
section of the Adverse Event 
eCRF with all available new and 
updated information 
• Within 1 business day of first 
becoming aware of the event 
and as per local/regional 
regulations 
• Reporting required through 
the end of the study 
Abbreviations: AE=adverse event; CRF=case report form; IDE=Investigational Device Exemption; 
UADE=unanticipated adverse device effect
19.7. Reporting to Regulatory Authorities / IRBs / ECs / Investigators 
BSC is responsible for reporting adverse event information to all participating investigators, 
IRBs/ ECs, and regulatory authorities, as applicable.  
The Principal Investigator is responsible for informing the IRB/EC, of UADE and SAE as 
required by local/regional regulations. 
19.8. Subject Death Reporting 
A subject death during the study should be reported to Boston Scientific as soon as possible and, 
in any event, within two working days of center notification. The center’s IRB must be notified 
of any deaths in accordance with that center’s IRB policies and procedures. 
Notification of death should include a detailed narrative (death letter) that provides detailed 
information describing the circumstances surrounding the death and is signed by the Principal 
Investigator or authorized sub-Investigator. A death narrative in the local language is acceptable, 
if accompanied by a translation in English (signed by an authorized translator). The death 
narrative must include all of the following, if available: 
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• Date and time of death 
• Place death occurred 
• Immediate cause of death 
• Rhythm at the time of death, if known (include any available documentation) 
• Whether the death was related to the pulse generator, lead/catheter, clinical 
investigation, procedure, or patient condition 
• Whether or not the death was witnessed 
• Device status and/or activity at the time of death 
• Whether the subject had worsening heart failure 
• Any other circumstances surrounding the death 
• Approximate time interval from the initiating event to death (temporal course) 
• Investigator or co-Investigator signature and date 
Any information listed above that is unavailable or unknown must be specified as unavailable or 
unknown, as applicable, in the narrative. Also submit the following documentation: 
If the subject expired in the hospital: 
• A copy of the medical records for that admission (e.g., H & P, consults, test results, 
operative reports, and/or progress notes from the hospital chart) 
• Death certificate (if available) 
• Autopsy report (if applicable) 
If the subject expired outside of the hospital (e.g., home): 
• A copy of the most recent clinic visit (if not already submitted to Boston Scientific) 
• Death certificate (if available) 
Whenever possible, the PG should be interrogated. Investigational leads and related Boston 
Scientific system components (e.g., PGs) should be removed intact and returned promptly to 
Boston Scientific for analysis.  
The NAVIGATE X4 Clinical Events Committee (CEC) must review information regarding 
subject deaths (see Section 21.1).  
19.9. Subject Death Classification 
The following definitions of each category, along with the Epstein article[39], are to be used by 
the investigator when completing the Death Information section. 
I. 
Primary Organ Cause - The root problem that initiated the terminal event if multiple factors 
were involved, e.g., HF - primary, renal failure - secondary. 
A.  Cardiac 
1. Arrhythmic 
2. Pump Failure - Death occurring in a patient with severe heart failure, refractory to 
medical therapy, in whom death is anticipated within days to two months. Often such 
patients are referred for hospice care, comfort care is provided and aggressive treatment 
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is curtailed. The terminal event could be sudden and may be arrhythmic. This does not 
change the non-sudden, non-arrhythmic course that preceded the terminal event. 
3. Ischemic 
a. Acute MI - Symptoms compatible with an acute coronary syndrome (chest pain, 
acute dyspnea etc.), with evidence of myocardial necrosis as defined by: 
i. 
creatinine 
kinase 
(CK) 
≥ 
2x 
upper 
limit 
of 
normal 
(ULN)  
and CK MB isoenzyme percent > ULN  
ii. troponin level ≥ 2 x ULN 
Patients with an acute coronary syndrome and diagnostic ST-T wave changes (>2 
mm ST elevation in two contiguous leads) will be included if the death occurs 
prior to enzyme confirmation. 
b. No Acute MI - Patient has not met the enzymatic or electrocardiographic 
criteria for an acute myocardial infarction. The testing was done and came 
back negative. For example, a patient who survives an unstable angina 
episode long enough to provide documentation that they did NOT have an 
MI, e.g., cardiac enzyme confirmation. 
c. MI Unknown - Myocardial infarction suspected but data to prove or 
disprove are not available. Used to capture the patient who is suspected of 
having a probable MI but dies prior to the MI being documented. For 
example, chest pain > 20 minutes, or chest pain with a nondiagnostic EKG 
(LBBB), or chest pain of unknown duration. 
4. Other Cardiac 
5. Unknown 
B.  Noncardiac 
C.  Unknown 
II. 
Temporal Course 
A.  Sudden - death that occurred within one hour of onset of symptoms 
B.  Non-Sudden - death that occurred greater than one hour of onset of symptoms 
C.  Unknown/Presumed Sudden - This category should be used for patients who were not 
expected to die of other causes, and were not witnessed at the time of death. There must be 
documentation of the patient’s condition within 24 hours prior to the event and there should 
be no acute change in the patient’s condition or circumstances leading up to the event. An 
example would be a stable patient who dies in his sleep. Patients can have worsening heart 
failure prior to the event and be included in this category, as long as the severity of heart 
failure does not fit the definition of death due to pump failure. 
D. Unknown 
III. 
Antecedent Worsening Heart Failure - Patients with signs or symptoms of worsening heart 
failure within the two weeks prior to death or the event that led to death (e.g. cardiac arrest and 
hypoxic encephalopathy from which the patient does not recover). In order to avoid recall bias, 
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there must be documentation of a clinical evaluation documenting worsening signs or symptoms 
or a change in medication recommended for symptoms of worsening heart failure. 
A.  N/A (Not Applicable) 
B.  Yes 
C.  No 
D.  Unknown - Insufficient information to determine state of heart failure at time of the event 
IV. 
Death Witnessed - Someone witnessed the death event (in the same room or within earshot) 
A.  Yes 
B.  No 
C.  Unknown 
V. 
Monitored - The patient rhythm at the onset of the terminal event (just prior to death) was 
documented. This may or may not be related to the actual cause of death. Device stored 
electrograms may not be used for this determination (depending on the study, i.e., heart failure). 
A.  Yes 
1. Ventricular Tachyarrhythmia 
2. Bradyarrhythmia 
a.  Sinus Bradyarrhythmia 
b.  High degree AV block with slow ventricular response 
c.  Asystole 
3. PEA (Pulseless Electrical Activity) 
4. Other (AF, SVT, sinus tachycardia, normal sinus rhythm) 
5.  Unknown 
B.  No 
C.  Unknown 
VI. 
Operative Relationship 
A.  Pre-Operative - deaths that occur after the consent is signed, but before the procedure 
B.  Peri-Operative - deaths that occur ≤ 30 days post-op or prior to hospital discharge following 
any system related surgery including lead and pulse generator revisions.  
C.  Post-Operative - deaths that occur > 30 days post-implant or revision following discharge. 
VII. 
Procedure Related - includes events during, or as a result of, events from pre-op anesthesia 
through leaving the OR suite, the EP lab, or an office visit. 
A.  Yes 
B.  No 
C.  Unknown 
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VIII. 
Investigation Related - related specifically to differences in procedure or necessary equipment 
used or implanted used solely for the new or investigational aspects of the study. An example 
would be a coronary sinus perforation from a new left ventricular pacing lead introduced via the 
coronary sinus. 
A.  Yes 
B.  No 
C.  Unknown 
IX. 
Pulse Generator Related - includes events associated with pulse generator’s ability to detect and 
treat an arrhythmia. 
A.  Yes 
B.  No - including events where initiating event was nonarrhythmic 
C.  Unknown 
D.  N/A 
X. 
Lead/Catheter Related - includes events associated with the lead system’s ability to detect and 
treat an arrhythmia. 
A.  Yes 
B.  No - including events where initiating event was nonarrhythmic 
C.  Unknown 
20. INFORMED CONSENT 
Subject participation in this clinical study is voluntary. Informed Consent is required from all 
subjects or their legally authorized representative. The Investigator is responsible for ensuring 
that Informed Consent is obtained prior to the use of any investigational devices, study-required 
procedures and/or testing, or data collection.  
The obtaining and documentation of Informed Consent must be in accordance with the principles 
of the Declaration of Helsinki, ISO 14155, any applicable national regulations, and local Ethics 
Committee and/or Regulatory authority body, as applicable. The ICF must be approved by the 
center’s IRB/EC, or central IRB, if applicable. 
Boston Scientific will provide a study-specific template of the ICF to investigators participating 
in this study. The ICF template may be modified to meet the requirements of the investigative 
center’s IRB/EC. Any modification requires approval from BSC prior to use of the form. The 
ICF must be in a language understandable to the subject and if needed, BSC will assist the center 
in obtaining a written consent translation. Translated consent forms must also have IRB/EC 
approval prior to their use. Privacy language shall be included in the body of the form or as a 
separate form as applicable.   
The process of obtaining Informed Consent shall: 
• be conducted by the Principal Investigator or designee authorized to conduct the process,  
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• include a description of all aspects of the clinical study that are relevant to the subject’s 
decision to participate throughout the clinical study, 
• avoid any coercion of or undue influence of subjects to participate, 
• not waive or appear to waive subject’s legal rights, 
• use native language that is non-technical and understandable to the subject or his/her legal 
representative, 
• provide ample time for the subject to consider participation and ask questions if necessary, 
• ensure important new information is provided to new and existing subjects throughout the 
clinical study. 
The ICF shall always be signed and personally dated by the subject or legal representative and by 
the investigator or an authorized designee responsible for conducting the informed consent 
process. If a legal representative signs, the subject shall be asked to provide informed consent for 
continued participation as soon as his/her medical condition allows. The original signed ICF will 
be retained by the center and a copy of the signed and dated document and any other written 
information must be given to the person signing the form.  
Failure to obtain subject consent will be reported by BSC to the applicable regulatory body 
according to their requirements (e.g., FDA requirement is within 5 working days of learning of 
such an event). Any violations of the informed consent process must be reported as deviations to 
the sponsor and local regulatory authorities (e.g. IRB/EC), as appropriate. 
If new information becomes available that can significantly affect a subject's future health and 
medical care, that information shall be provided to the affected subject(s) in written form via a 
revised ICF or, in some situations, enrolled subjects may be requested to sign and date an 
addendum to the ICF. In addition to new significant information during the course of a study, 
other situations may necessitate revision of the ICF, such as if there are amendments to the 
protocol, a change in Principal Investigator, administrative changes, or following annual review 
by the IRB/EC. The new version of the ICF must be approved by the IRB/EC. Boston Scientific 
approval is required if changes to the revised ICF are requested by the center’s IRB/EC. The 
IRB/EC will determine the subject population to be re-consented. 
21. COMMITTEES 
21.1. NAVIGATE X4 Clinical Events Committee (CEC) 
A CEC is an independent group of individuals with pertinent expertise that reviews and 
adjudicates subject deaths reported by study investigators. The CEC will review a safety event 
dossier, which may include copies of subject source documents provided by study sites, for all 
reported  subject deaths from any cause.  
Committee members will include a minimum of three practitioners with training in 
Electrophysiology (EP), and/ or Cardiology with the necessary therapeutic and subject matter 
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expertise to adjudicate subject deaths. CEC responsibilities, qualifications, membership, and 
committee procedures are outlined in the CEC charter. 
22. SUSPENSION OR TERMINATION 
22.1. Premature Termination of the Study 
Boston Scientific Corporation reserves the right to terminate the study at any stage but intends to 
exercise this right only for valid scientific or administrative reasons and reasons related to 
protection of subjects. Investigators, associated IRBs/ECs, and regulatory authorities, as 
applicable, will be notified in writing in the event of study termination. 
22.1.1. Criteria for Premature Termination of the Study 
Possible reasons for premature study termination include, but are not limited to, the following. 
• The occurrence of unanticipated adverse device effects that present a significant or 
unreasonable risk to subjects enrolled in the study. 
• An enrollment rate far below expectation that prejudices the conclusion of the study.  
• A decision on the part of Boston Scientific to suspend or discontinue development of the 
device. 
22.2. Termination of Study Participation by the Investigator or Withdrawal of IRB/ EC 
Approval 
Any investigator, or IRB/ EC in the NAVIGATE X4 Study may discontinue participation in the 
study or withdrawal approval of the study, respectively, with suitable written notice to Boston 
Scientific. Investigators, associated IRBs/ECs, and regulatory authorities, as applicable, will be 
notified in writing in the event of these occurrences. 
22.3. Requirements for Documentation and Subject Follow-up 
In the event of premature study termination a written statement as to why the premature 
termination has occurred will be provided to all participating centers by Boston Scientific. The 
IRB/EC and regulatory authorities, as applicable, will be notified. Detailed information on how 
enrolled subjects will be managed thereafter will be provided.  
In the event an IRB or EC terminates participation in the study, participating investigators, 
associated IRBs/ECs, and regulatory authorities, as applicable, will be notified in writing. 
Detailed information on how enrolled subjects will be managed thereafter will be provided by 
Boston Scientific. 
In the event an investigator terminates participation in the study, study responsibility will be 
transferred to a co-investigator, if possible. In the event there are no opportunities to transfer 
investigator responsibility; detailed information on how enrolled subjects will be managed 
thereafter will be provided by Boston Scientific. 
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The investigator must return all documents and investigational product to Boston Scientific, 
unless this action would jeopardize the rights, safety, or welfare of the subjects. 
22.4. Criteria for Suspending/Terminating a Study Center 
Boston Scientific Corporation reserves the right to stop the inclusion of subjects at a study center 
at any time after the study initiation visit if no subjects have been enrolled at that center for a 
period beyond 3 months after center initiation, or if the center has multiple or severe protocol 
violations/non-compliance without justification and/or fails to follow remedial actions. 
In the event of termination of investigator participation, all study devices and testing equipment, 
as applicable, will be returned to BSC unless this action would jeopardize the rights, safety or 
well-being of the subjects. The IRB/ EC and regulatory authorities, as applicable, will be 
notified. Detailed information on how enrolled subjects will be managed thereafter will be 
provided by Boston Scientific. The Principal Investigator at the center must make provision for 
these follow-up visits unless BSC notifies the investigational center otherwise. 
23. PUBLICATION POLICY 
In accordance with the Corporate Policy on the Conduct of Human Subject Research, BSC 
requires disclosure of its involvement as a sponsor or financial supporter in any publication or 
presentation relating to a BSC study or its results. In accordance with the Corporate Policy for 
the Conduct of Human Subject Research, BSC will submit study results for publication 
(regardless of study outcome) following the conclusion or termination of the study. Boston 
Scientific Corporation adheres to the Contributorship Criteria set forth in the Uniform 
Requirements of the International Committee of Medical Journal Editors (ICMJE; 
http://www.icmje.org). In order to ensure the public disclosure of study results in a timely 
manner, while maintaining an unbiased presentation of study outcomes, BSC personnel may 
assist authors and investigators in publication preparation provided the following guidelines are 
followed. 
• All authorship and contributorship requirements as described above must be followed. 
• BSC involvement in the publication preparation and the BSC Publication Policy should be 
discussed with the Coordinating Principal Investigator(s) and/or Executive/Steering 
Committee at the onset of the project. 
• The First and Senior authors are the primary drivers of decisions regarding publication 
content, review, approval, and submission. 
 
 
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24. ABBREVIATIONS AND DEFINITIONS  
24.1. Abbreviations 
Abbreviations used in this protocol are shown in Table 22.   
Table 22: Abbreviations 
Acronym/Abbreviation 
Definition 
ACC 
American College of Cardiology 
ADE 
Adverse Device Effect 
AE  
Adverse Event 
AHA  
American Heart Association 
BBB/LBBB 
Bundle Branch Block/Left BBB 
BSC 
Boston Scientific 
CABG 
Coronary Artery Bypass Graft 
CEC 
Clinical Events Committee 
CFR 
Complication-free Rate 
CRM 
Cardiac Rhythm Management 
CRT-D 
Cardiac Resynchronization Therapy - Defibrillator 
CRT 
Cardiac Resynchronization Therapy 
CS 
Coronary Sinus 
DXA 
Dexamethasone Acetate 
EC/ IEC 
Ethics Committee/ Institutional Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
EGM 
Electrogram 
EP 
Electrophysiology 
ETFE 
Ethylene tetrafluoroethylene 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GDMT 
Guideline-directed medical therapy 
HCP 
Health Care Professional 
HRS 
Hearth Rhythm Society 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IRB 
Institutional Review Board 
IUT 
Intersection-Union Test 
IROX 
Iridium Oxide 
ISO 
International Standard Organization 
LBBB 
Left Bundle Branch Block 
LOC 
Loss of Capture 
LV 
Left Ventricle/ Ventricular 
LVEF 
Left Ventricular Ejection Fraction 
MAU 
Multiple Application Utility 
MEDDEV 
European Commission guidance on Medical 
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Table 22: Abbreviations 
Acronym/Abbreviation 
Definition 
Devices 
MICS 
Medical Implantable Communication Services 
mV 
Millivolts 
Ω 
Ohms 
OPT 
Optimal Pharmaceutical Therapy 
PA 
Posterior-Anterior 
PCT 
Pacing Capture Threshold 
PG 
Pulse Generator 
PNS 
Phrenic Nerve Stimulation 
PRM 
Programmer/ Recorder/ Monitor 
PSA 
Pacing System Analyzer 
ePTFE 
Expanded Polytetrafluoroethylene 
RA 
Right atrium/ atrial 
RF 
Radiofrequency 
RV 
Right ventricle/ ventricular 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
TOST 
Two one-sided t-tests  
UADE 
Unanticipated Adverse Device Effect 
USADE 
Unanticipated Serious Adverse Device Effect 
V 
Volts 
VT 
Ventricular Tachycardia 
VF 
Ventricular Fibrillation 
ZWT 
Zoom Wireless Transmitter 
24.2. Definitions of Terms 
Terms used in this protocol are defined in Table 23 below.  
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Table 23: Definitions 
Term 
Definition 
ACUITY X4 Best 
Electrode 
The best electrode configuration is the one that has the lowest 
threshold without phrenic nerve stimulation (PNS). In the event of a “tie” 
for best electrode, the investigator should use their medical judgment to 
select the best 
Guideline-directed 
medical therapy (GDMT) 
This term represents optimal medical therapy as defined by ACCF/AHA 
guidelines 
Lead-related adverse 
event 
Lead-related adverse events include, but are not limited to the 
following, based on the Advamed Industry Guidance for Uniform 
Reporting of Clinical Performance of Cardiac Rhythm Management of 
Pulse Generators and Leads: 
• 
Cardiac perforation requiring surgical intervention 
• 
Cardiac perforation not requiring surgical intervention 
• 
Conductor fracture/ helix damage 
• 
Lead dislodgment 
• 
Failure to capture 
• 
Oversensing 
• 
Failure to sense (undersensing) 
• 
Insulation breach 
• 
Abnormal pacing impedance 
• 
Extracardiac stimulation 
Lead-related complication 
Lead-related complications are defined as lead-related adverse events 
resulting in permanent loss of pacing therapy, invasive intervention, 
injury or death. 
Pacing impedance 
An assessment of the opposition to the flow of current by the pacing 
system; measured in ohms (Ω). 
Pacing threshold 
An assessment of the minimum electrical stimulation required to 
consistently initiate cardiac depolarization; measured in Volts (V). 
Sensed amplitude 
An assessment of how well the lead senses the heart’s intrinsic 
electrical activity; measured in millivolts (mV). 
Source Data (ISO 
14155:2011) 
All information in original records of clinical findings, observations, or 
other activities in a clinical investigation, necessary for the 
reconstruction and evaluation of the clinical study (Original records or 
certified copies).  
Source Document (ISO 
14155:2011) 
Printed, optical or electronic document containing source data. 
Examples: Hospital records, laboratory notes, device accountability 
records, radiographs, records kept at the investigation site, and at the 
laboratories involved in the clinical study.   
 
 
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25. INVESTIGATIONAL DEVICE DESCRIPTION 
25.1. ACUITY X4  
The ACUITY X4 lead family has the following characteristics: 
• Coronary venous pace/sense lead—intended for chronic left ventricular pacing and sensing. 
This transvenous lead offers various pace/sense configurations depending upon the 
programming options of a compatible device; refer to the pulse generator manual for 
instructions. Placement is achieved by inserting the lead through the coronary sinus and 
placing it into a branch of the cardiac vasculature. 
• Three tip configuration designs (straight tip, short tip spiral, long tip spiral)—intended to 
provide choices for a variety of patient anatomies. 
 
 
 
• IS4 four-pole connector—the industry standard connector to be used in conjunction with a 
compatible cardiac device with an IS4-LLLL port, where L indicates a connection to a low-
voltage pace/sense electrode. 
• IROX-coated electrodes—provide a pacing and sensing surface in the coronary venous 
system. The electrodes are coated with IROX (iridium oxide) to increase the microscopic 
surface area.  
• 3D electrode spiral—the spiral model leads were designed to overcome challenges in mid-
base (proximal) ventricular regions by clustering electrodes on the 3D spiral fixation, 
which is set back from the distal tip of the lead. The electrodes are spatially oriented on the 
spiral to increase the chance that at least one of the three electrodes will be placed adjacent 
to the myocardium in any coronary vasculature location. 
• Lead body—the distal electrode (E1) is connected to the terminal pin by means of a coil 
conductor, while the three proximal electrodes (E2, E3, E4) are connected to the three 
terminal rings by means of three individual low voltage cable conductors. The coil 
conductor filars and the cables are sheathed in Ethylene tetrafluoroethylene (ETFE) 
insulation. The conductor separation insulation and the outer lead body insulation material 
are polyurethane in the proximal region and silicone in the distal region adjacent to the 
electrodes and spiral fixation. 
• Protected IS4 terminal pin design—all proximal electrical connections occur within the 
terminal pin that fits safely inside the device header. There are no splice points in the lead 
body outside of the header. With this protected IS4 design, the absence of splice points in 
the lead body offers the following advantages: 
– protection from flex fatigue and fracture 
– protection from pulse generator-on-lead and lead-on-lead abrasion 
– protection from acute bending at splice points due to lead wrap 
– fewer connection points 
• Distal tip—the distal tip is protected by silicone rubber to allow lead advancement through 
the coronary venous system.  
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• Steroid-eluting—upon exposure to body fluids, the steroid elutes from the drug collar near 
the distal end of the lead to help reduce tissue inflammation response. The steroid 
suppresses the inflammatory response believed to cause threshold rises typically associated 
with implanted pacing electrodes. The nominal dose and structure of the steroid are listed 
in the specifications included in the Physician’s Lead Manual for ACUITY X4. 
• Radiopaque suture sleeve—the radiopaque suture sleeve is visible under fluoroscopy and is 
used to secure, immobilize, and protect the lead at the venous entry site after lead 
placement. The window feature is designed to aid compression of the sleeve onto the lead 
during suturing. 
• Tined fixation—silicone rubber tines located proximal to the distal electrode provide the 
option of passive fixation to the vasculature for all lead models. 
• Spiral fixation—a distal, 3D spiral shape provides an additional or alternative passive 
fixation option for the spiral tip models. 
• Fluoroscopic visibility—the platinum-iridium electrode design increases the visibility of the 
lead tip under fluoroscopy. 
• Fluoroscopic marker—a radiopaque marker on the spiral models can be seen under 
fluoroscopy to indicate the approximate proximal end of the spiral fixation. 
• Lubricious coating—the lead has a proprietary coating on the silicone distal region that 
makes the surface more lubricious. This reduces both the static and dynamic coefficients of 
friction, and makes the lead feel and handle like polyurethane while providing the 
flexibility of silicone. 
• Over-the-Wire delivery method—the design consists of an open-lumen conductor coil that 
tracks over a guide wire. 
 
25.2. RELIANCE 4-FRONT 
25.2.1. Active Fixation 
RELIANCE 4-FRONT leads with an active fixation electrode serving as the most distal tip 
electrode, consist of an IROX coated, platinum iridium alloy helix coil, which serves as the rate 
sensing bipolar cathode electrode and as a pacing tip. The distal tip electrode can be extended out 
of and retracted within the distal non-conductive rigid polymer components. A steroid drug 
collar impregnated with dexamethasone acetate (DXA) (an anti-inflammatory glucocorticoid) is 
placed at the distal end of the non-conductive housing. The distal tip contains a seal to limit the 
penetration of body fluids into the lumen during implant. 
The distal tip electrode is connected to an inner, multi-filar, rotatable conductor coil insulated by 
the pace/sense lumen of trilumen silicone rubber tubing. A layer of expanded-
polytetrafluoroethylene (ePTFE) tubing resides between the coil and the pace/sense lumen of the 
trilumen silicone tubing to aid rotational movement. The coil is continuous throughout the lead 
body, joining to the connector terminal. 
The terminal pin is connected to the inner conductor coil and the assembly is free to rotate. The 
terminal assembly is hollow to allow for stylet passage. Rotation of the terminal pin transmits 
torque through the inner conductor coil to the distal tip electrode/helix. In this manner the helix 
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can be extended out of the distal tip housing allowing for fixation into cardiac tissue. The 
exposed surface area of the most distal tip electrode is approximately 5.7 mm2. The helix may 
also be retracted into the distal tip housing if desired. 
25.2.2. Passive Fixation 
RELIANCE 4-FRONT leads with a passive fixation electrode serving as the most distal tip 
electrode, consist of a solid, IROX coated, platinum/iridium tip. It functions as the rate sensing 
bipolar cathode electrode and as a pacing tip. A steroid drug collar impregnated with DXA is 
placed at the distal end of the passive tip. Four molded elastomer tines adjacent to this tip 
electrode provide acute and chronic fixation. The exposed surface area of the distal electrode is 
approximately 3.5 mm2. 
25.2.3. Single Coil Electrode 
RELIANCE 4-FRONT leads with a single coil electrode (intermediate distal electrode) consist of 
two distally located electrodes, connective elastomeric lead body sections, and one proximally 
located terminal, containing both high and low voltage connections. The intermediate distal 
electrode is a smooth surfaced platinum coated multi-filar composite round wire coil electrode. It 
functions as the electrocardiogram rate sensing/pacing anode, and cardioversion/defibrillation 
cathode. The conductor cable passes continuously through a tri-lumen extruded elastomer tubing 
to the connector terminal. 
The distal tip electrode conductor coil proceeds to the inside tubing of the terminal body, and 
terminates with a tubular terminal connector pin located in the terminal connector assembly. This 
tubular connector pin allows a stylet wire to be inserted through the full length of the lead to the 
distal tip electrode as an aid in venous insertion and implant positioning. 
25.2.4. Dual Coil Electrode 
RELIANCE 4-FRONT leads with dual coil electrodes (intermediate distal electrode and most 
proximal electrode) consist of three distally located electrodes, connective elastomeric lead body 
sections, and one proximally located terminal, containing both high and low voltage connections. 
The intermediate distal electrode is a smooth surfaced platinum coated multi-filar composite 
round wire coil electrode. It functions as the electrocardiogram rate sensing/pacing anode, and 
cardioversion/defibrillation cathode. The most proximal electrode is also a smooth surfaced 
platinum coated multi-filar composite round wire coiled electrode. It functions as the 
cardioversion/defibrillation anode electrode. The proximal and distal conductor cables pass 
continuously through a tri-lumen extruded elastomer tubing to the connector terminal.  
The distal tip electrode conductor coil proceeds to the inside tubing of the terminal body, and 
terminates with a tubular terminal connector pin located in the terminal connector assembly. This 
tubular connector pin allows a stylet wire to be inserted through the full length of the lead to the 
distal tip electrode as an aid in venous insertion and implant positioning. 
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25.2.5. Silicone Adhesive Backfilled Coils 
RELIANCE 4-FRONT leads with dual coil electrodes contain an intermediate distal electrode 
and a most proximal electrode with silicone adhesive backfilled coils. The silicone adhesive 
backfill minimizes tissue ingrowth into the shocking coils. 
25.2.6. ePTFE Covered Coils 
RELIANCE 4-FRONT leads with a single coil electrode covered with expanded-
polytetrafluoroethylene (ePTFE) contain an intermediate distal electrode covered with ePTFE, 
which allows rapid wetting by body fluids. RELIANCE 4-FRONT leads with dual coil 
electrodes covered with ePTFE contain an intermediate distal electrode and a most proximal 
electrode covered with surface treated ePTFE, which allows rapid wetting by body fluids. The 
ePTFE prevents tissue ingrowth into the shocking coils. 
25.2.7. Iridium Oxide Coated Electrode 
Iridium Oxide (IROX) has been added to the active fixation helix and the passive fixation tip of 
the RELIANCE 4-FRONT Lead. An IROX coating creates a high electrochemical surface area 
to reduce afterpotential (polarization) and pacing thresholds as well as improve sensing 
performance.   
 
 
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26. REFERENCES 
1. 
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Guidelines for Device-Bassed Therapy of Cardiac Rhythm Abnormalities: A Report of the 
American College of Cardiology Foundation/ American Heart Association Task Force on 
Practice Guidelines. Heart Rhythm, 2012. 9(10): p. 1737-1753. 
2. 
Auricchio, A., et al., Effect of pacing chamber and atrioventricular delay on acute 
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3. 
Butter, C., et al., Effect of resynchronization therapy stimulation site on the systolic 
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Abraham, W.T., et al., Cardiac resynchronization in chronic heart failure. 
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Higgins, S.L., et al., Cardiac resynchronization therapy for the treatment of heart failure 
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6. 
Young, J.B., et al., Combined cardiac resynchronization and implantable cardioversion 
defibrillation in advanced chronic heart failure: the MIRACLE ICD Trial. JAMA: The 
Journal of the American Medical Association, 2003. 289(20): p. 2685-2694. 
7. 
Lozano, I., et al., Impact of biventricular pacing on mortality in a randomized crossover 
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Electrophysiology, 2000. 23(11 Pt 2): p. 1711-2. 
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Ollitrault, J., et al., Long-term experience with a preshaped left ventricular pacing lead. 
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Gras, D., et al., Multisite pacing as a supplemental treatment of congestive heart failure: 
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10. 
Fatemi, M., et al., Short and long-term single-centre experience with an S-shaped 
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Walker, S., et al., Initial results with left ventricular pacemaker lead implantation using a 
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Gras, D., P. Mabo, and P. Ritter, First experience with coronary sinus leads used for 
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Faulknier, B.A., et al., Time-dependent risk of Fidelis lead failure. Am J Cardiol, 2010. 
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Hauser, R.G. and D.L. Hayes, Increasing hazard of Sprint Fidelis implantable 
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Farwell, D., et al., Accelerating risk of Fidelis lead fracture. Heart Rhythm, 2008. 5(10): 
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Hauser, R.G., et al., Longevity of Sprint Fidelis implantable cardioverter-defibrillator 
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Maisel, W.H., et al., Recommendations from the Heart Rhythm Society Task Force on 
Lead Performance Policies and Guidelines: developed in collaboration with the 
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Heart Rhythm, 2009. 6(6): p. 869-85. 
18. 
Krebsbach, A., et al., Premature failure of a Riata defibrillator lead without impedance 
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19. 
Epstein, A.E., et al., Performance of the St. Jude Medical Riata leads. Heart Rhythm, 
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Nagele, H., et al., First experience with a new active fixation coronary sinus lead. 
Europace, 2007. 9(6): p. 437-41. 
21. 
Nagai, T., et al., Initial Japanese experience and long-term follow-up with a new active 
fixation coronary sinus lead, the StarFix 4195. Journal of Cardiology Cases, 2010. 1(3): 
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22. 
Hansky, B., et al., Implantation of active fixation leads in coronary veins for left 
ventricular stimulation: report of five cases. Pacing Clin Electrophysiol, 2007. 30(1): p. 
44-9. 
23. 
Szilagyi, S., et al., Stabilization of the coronary sinus electrode position with coronary 
stent implantation to prevent and treat dislocation. J Cardiovasc Electrophysiol, 2007. 
18(3): p. 303-7. 
24. 
Demir Ahmet, D., et al., Long-term follow-up data of coronary sinus stenting for the 
stabilization of the left ventricular leads. Pacing Clin Electrophysiol, 2010. 33(12): p. 
1485-9. 
25. 
Geller, L., et al., Long-term experience with coronary sinus side branch stenting to 
stabilize left ventricular electrode position. Heart Rhythm, 2011. 8(6): p. 845-50. 
26. 
Sharifkazemi Mohamad, B. and A. Aslani, Stabilization of the coronary sinus lead 
position with permanent stylet to prevent and treat dislocation. Europace, 2007. 9(10): p. 
875-7. 
27. 
Zhao, X., et al., Simulation of LV pacemaker lead in marginal vein: potential risk factors 
for acute dislodgement. Journal of biomechanical engineering, 2011. 133(3): p. 031006. 
28. 
Biffi, M., et al., Phrenic stimulation: a challenge for cardiac resynchronization therapy. 
Circ Arrhythm Electrophysiol, 2009. 2(4): p. 402-10. 
29. 
Seifert, M., et al., Influence of pacing configurations, body mass index, and position of 
coronary sinus lead on frequency of phrenic nerve stimulation and pacing thresholds 
under  cardiac resynchronization therapy. Europace, 2010. 12(7): p. 961-7. 
30. 
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