Sentus QP - Extended CRT Evaluation With Quadripolar Left Ventricular Leads
Phase: NA
Conditions: Heart Failure
Sponsor: Biotronik SE & Co. KG

 
  
  
 
 
Clinical Investigation Plan for  
QP ExCELs U.S. 
 
 
 
Sentus QP – Extended CRT Evaluation with Quadripolar          
Left Ventricular Leads 
NCT02290028 
 
 
IDE#G150147 
February 1, 2017 
 
 
 
BIOTRONIK, Inc. 
6024 Jean Road, Lake Oswego, OR 97035 
 
This document contains confidential information for use only by investigators and 
clinical sites participating in the clinical study. Therefore, this document should be 
maintained in a secure location and should not be copied or made available for 
review by any unauthorized personnel. 

 
  
  
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Table of Contents 
1. INTRODUCTION .................................................................................................................................. 12 
1.1 Background .................................................................................................................................. 12 
1.2 Devices ........................................................................................................................................ 14 
1.3 Investigational Device Description ............................................................................................... 14 
1.3.1 Sentus QP Lead Design ................................................................................................... 14 
1.3.2 Pacing and Sensing Vector Options ................................................................................. 17 
1.4 Prior Clinical Performance ........................................................................................................... 18 
1.4.1 Primary Endpoint 1 Results .............................................................................................. 18 
1.4.2 Primary Endpoint 2 Results .............................................................................................. 19 
2. STUDY DESIGN .................................................................................................................................. 21 
2.1 Objectives .................................................................................................................................... 21 
2.2 Study Endpoints and Hypotheses ................................................................................................ 21 
2.2.1 Primary Endpoint 1: Sentus QP Related Complication-Free Rate through 6 
Months (Pre-Market Analysis) ...................................................................................................... 21 
2.2.2 Primary Endpoint 2: Percentage of Subjects with Acceptable Pacing Threshold in 
Permanently Programmed Vector at 3 Months (Pre-Market Analysis) ........................................ 22 
2.2.3 Primary Endpoint 3: Sentus QP Related Complication-Free Rate through 5 years 
(Post-Approval Analysis) .............................................................................................................. 22 
2.2.4 Secondary Endpoints ....................................................................................................... 22 
2.2.4.1 Sentus QP pacing threshold in permanently programmed vector at 3 months per lead 
model 23 
2.2.4.2 Sentus QP pacing threshold in novel vectors at 3 months .......................................................... 23 
2.2.4.3 Sentus QP R-wave sensed amplitude at 3 months per lead model ............................................ 23 
2.2.4.4 Sentus QP pacing impedance at 3 months per lead model ........................................................ 23 
2.2.4.5 Sentus QP Time to first complication .......................................................................................... 23 
2.2.4.6 Percentage of subjects successfully reprogrammed to resolve phrenic nerve 
stimulation or high pacing threshold during the study period .................................................................. 24 
2.2.4.7 Sentus QP Related Complication-Free Rate through 5 years per lead model ............................ 24 
2.2.4.8 Sentus QP Lead Safety – Individual 5-year adverse event rates ................................................ 24 
2.2.5 Additional Data of Interest ................................................................................................ 24 
2.3 Statistical Design, Method, and Analytical Procedures ............................................................... 25 
2.3.1 Pre-Market Analyses Cohort ............................................................................................ 25 
2.3.2 Primary Endpoint 1 Analysis ............................................................................................ 25 
2.3.3 Primary Endpoint 2 Analysis ............................................................................................ 26 
2.3.4 Primary Endpoint 3 Analysis ............................................................................................ 26 
2.3.5 Secondary Endpoints ....................................................................................................... 26 
2.3.6 Additional Data of Interest Analysis .................................................................................. 27 
2.3.7 Trend Analyses ................................................................................................................. 27 
2.4 Estimated Sample Size ................................................................................................................ 28 
2.4.1 Pre-Market Analyses ........................................................................................................ 28 
2.4.2 Post-Approval Analysis ..................................................................................................... 28 
2.4.3 Replacement of Subjects.................................................................................................. 29 
2.5 Other Statistical Considerations .................................................................................................. 29 
2.5.1 Success Criteria ............................................................................................................... 29 
2.5.2 Provision for a Pivotal and Interim Analysis ..................................................................... 29 
2.5.3 Specification of Subgroups ............................................................................................... 30 

 
  
  
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2.5.4 Handling of Missing, Unused, or Spurious Data............................................................... 30 
2.5.5 Maximum Number of Subjects per Site ............................................................................ 31 
3. PROTOCOL REQUIREMENTS ........................................................................................................... 32 
3.1 Subject Population ....................................................................................................................... 32 
3.1.1 Indications for Use ............................................................................................................ 32 
3.1.2 Contraindications .............................................................................................................. 32 
3.1.3 Inclusion Criteria ............................................................................................................... 33 
3.1.4 Exclusion Criteria .............................................................................................................. 33 
3.2 Methods ....................................................................................................................................... 33 
3.2.1 eCRFs ............................................................................................................................... 33 
3.2.2 Subject Demographics, Comorbidities and Medications .................................................. 34 
3.2.3 Implantation Information ................................................................................................... 35 
3.2.4 Device Settings ................................................................................................................. 35 
3.2.5 CRT Based Lead Measurements ..................................................................................... 35 
3.2.6 LV Pacing Threshold Measurement in Novel Vectors ...................................................... 36 
3.2.7 Adverse Events and Device Complaints .......................................................................... 36 
3.3 Number of Investigational Devices to be Used ............................................................................ 36 
3.4 Study Procedures ........................................................................................................................ 37 
3.4.1 Overview of Study Procedures ......................................................................................... 39 
3.4.2 Enrollment......................................................................................................................... 40 
3.4.3 Implantation ...................................................................................................................... 41 
3.4.4 Pre-hospital Discharge/Wound Check and 3-month Follow-up ....................................... 42 
3.4.5 6-month Follow-up and 12-month Follow-up .................................................................... 43 
3.4.6 Additional Visits Required Every 6 Months to 60 Months ................................................ 44 
3.4.7 Interim Follow-up .............................................................................................................. 45 
3.4.7.1 Adverse event related interim follow-up ...................................................................................... 45 
3.4.7.2 System Revision ......................................................................................................................... 45 
3.4.8 Study Termination ............................................................................................................ 46 
3.5 Study Participation Expectations ................................................................................................. 46 
3.5.1 Point of Enrollment ........................................................................................................... 46 
3.5.2 Reasons for Study Termination ........................................................................................ 46 
3.5.2.1 No implant attempt...................................................................................................................... 46 
3.5.2.2 Unsuccessful implant .................................................................................................................. 46 
3.5.2.3 Withdrawal of subject consent .................................................................................................... 47 
3.5.2.4 Subject death .............................................................................................................................. 47 
3.5.2.5 Sentus QP lead extraction .......................................................................................................... 47 
3.5.2.6 Lost to follow-up ......................................................................................................................... 47 
3.5.3 Date of Study Termination ................................................................................................ 48 
4. ADDITIONAL STUDY CONDITIONS .................................................................................................. 49 
4.1 IRB Approval ................................................................................................................................ 49 
4.2 Subject Consent ........................................................................................................................... 49 
4.3 Data Collection ............................................................................................................................. 49 
4.3.1 Electronic Data Capture (EDC) ........................................................................................ 49 
4.3.2 Electronic Case Report Forms (eCRFs) ........................................................................... 49 
4.3.3 BIOTRONIK Home Monitoring® Data ............................................................................... 49 
4.4 Confidentiality of Subject Data ..................................................................................................... 50 
4.5 Data Quality Control ..................................................................................................................... 50 

 
  
  
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4.6 Deviations from Clinical Investigation Plan .................................................................................. 50 
4.6.1 Protocol Violations ............................................................................................................ 51 
4.6.2 Protocol Deviations ........................................................................................................... 51 
4.7 Subject Retention ......................................................................................................................... 51 
4.8 Study Completion ......................................................................................................................... 51 
4.9 Labeling and Control of the Investigational Devices .................................................................... 51 
5. STUDY OVERSIGHT ........................................................................................................................... 53 
5.1 Clinical Events Committee ........................................................................................................... 53 
6. ADVERSE EVENTS ............................................................................................................................ 55 
6.1 Definitions .................................................................................................................................... 55 
6.1.1 Definition of Adverse Event .............................................................................................. 55 
6.1.2 Definition of Adverse Device Effect .................................................................................. 55 
6.1.3 Definition of Unanticipated Adverse Device Effect ........................................................... 56 
6.1.4 Serious AEs, ADEs, and UADEs ...................................................................................... 56 
6.1.5 Definition of Device Complaint ......................................................................................... 56 
6.2 Reporting Adverse Events ........................................................................................................... 57 
6.3 Examples of Reportable Adverse Events .................................................................................... 58 
6.4 Adverse Event Reporting Timelines ............................................................................................ 59 
6.5 Sponsor Reporting ....................................................................................................................... 59 
6.6 Adverse Events for Primary Endpoint Analysis ........................................................................... 59 
6.6.1 Adverse Events Included in Primary Endpoint 1 .............................................................. 59 
6.6.2 Adverse Events Included in Primary Endpoint 3 .............................................................. 61 
7. OTHER INSTITUTIONS AND PHYSICIANS....................................................................................... 64 
8. RISKS AND BENEFITS OF THE DEVICE AND CLINICAL INVESTIGATION .................................. 65 
8.1 Anticipated Clinical Benefits ........................................................................................................ 65 
8.2 Anticipated Risks ......................................................................................................................... 66 
8.2.1 Anticipated Adverse Events.............................................................................................. 66 
8.2.2 Risk Associated with Participation in the Clinical Investigation ........................................ 66 
8.2.3 Possible Interactions with Concomitant Medical Treatments ........................................... 67 
8.3 Steps to Control or Mitigate the Risks ......................................................................................... 67 
8.4 Risk-to-benefit Rationale.............................................................................................................. 67 
9. MONITORING ...................................................................................................................................... 69 
9.1 Summary ...................................................................................................................................... 69 
9.2 Monitors ....................................................................................................................................... 70 
10. RECORDS AND REPORTS ................................................................................................................ 71 
10.1 Investigator Records .................................................................................................................... 71 
10.2 Investigator Reports ..................................................................................................................... 71 
10.3 Sponsor Records and Reports .................................................................................................... 72 
11. MULTIPOLE PACING SUB-STUDY ................................................................................................... 74 
11.1 Introduction .................................................................................................................................. 74 
11.1.1 Sub-Study Overview ......................................................................................................... 74 
11.1.2 MultiPole Pacing (MPP) Description ................................................................................ 75 

 
  
  
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11.1.3 Published Results for Multipoint LV Pacing...................................................................... 78 
11.2 Sub-Study Design ........................................................................................................................ 79 
11.2.1 Study Endpoints ............................................................................................................... 80 
11.2.1.1 
Primary Endpoint 1 ................................................................................................................ 81 
11.2.1.2 
Secondary Endpoint 1- Freedom from MPP system related adverse events 
requiring additional invasive intervention to resolve at 6 months ............................................................ 81 
11.2.1.3 
Secondary Endpoint 2 - Evaluate CCS + PGA Responder Status utilizing a modified 
CCS that incorporates the Patient Global Assessment .......................................................................... 82 
11.2.1.4 
Secondary Endpoint 3: Evaluate CCS Responder Status utilizing a modified 
Responder Classification ........................................................................................................................ 82 
11.2.1.5 
Additional Data of Interest ..................................................................................................... 83 
11.2.2 Study Size and Duration ................................................................................................... 83 
11.2.3 Sample-Size Analysis ....................................................................................................... 83 
11.2.4 Data Analyses .................................................................................................................. 84 
11.2.4.1 
Adjustments to Overall Study Sample Size ........................................................................... 85 
11.2.4.2 
Replacement of Missing Data ............................................................................................... 85 
11.2.4.3 
MPP Programming ................................................................................................................ 85 
11.3 Protocol Requirements ................................................................................................................ 85 
11.3.1 Patient Population ............................................................................................................ 85 
11.3.1.1 
Inclusion Criteria ................................................................................................................... 85 
11.3.1.2 
Exclusion Criteria .................................................................................................................. 86 
11.3.2 Specific Testing ................................................................................................................ 86 
11.3.2.1 
New York Heart Association (NYHA) Classification .............................................................. 87 
11.3.2.2 
Patient Global Assessment (PGA) ........................................................................................ 87 
11.3.3 Sub-Study Procedures ..................................................................................................... 88 
11.3.3.1 
Enrollment into MultiPole Pacing Sub-Study ......................................................................... 90 
11.3.3.2 
9-Month MPP Follow-up ........................................................................................................ 91 
11.3.3.3 
12-Month MPP Follow-up ...................................................................................................... 91 
11.3.4 Clinical Events Committee – MPP Sub-Study Events ...................................................... 91 
11.4 Benefits and Risks ....................................................................................................................... 92 
11.4.1 Potential Benefits .............................................................................................................. 92 
11.4.2 Potential Risks .................................................................................................................. 92 
11.5 Other General Information ........................................................................................................... 93 
11.5.1 Subject Death ................................................................................................................... 93 
11.5.2 Reporting Hospitalizations ................................................................................................ 93 
11.5.3 Definition of Heart Failure Hospitalization ........................................................................ 94 
11.5.4 Adverse Events ................................................................................................................ 94 
11.5.5 Adverse Events for Secondary Endpoint Analysis ........................................................... 95 
11.5.6 Consent Materials (MPP Sub-Study) ............................................................................... 95 
11.5.7 IRB Approval .................................................................................................................... 95 
11.5.8 MPP Sub-Study References ............................................................................................ 95 
12. JUSTIFICATION FOR THE DESIGN OF THE PRE-MARKET CLINICAL INVESTIGATION ............ 97 
12.1 EveresT ........................................................................................................................................ 97 
12.2 CELESTIAL Study: Clinical Experience with Corox LV Lead ...................................................... 98 
12.3 Complication-free Rate in the EchoCRT Trial............................................................................ 100 
12.4 Eluna Family /Sentus BP Master Study ..................................................................................... 100 
12.5 Iperia Family / Sentus QP Master Study .................................................................................... 101 
12.6 Published Results for Competitive Quadripolar Leads .............................................................. 101 

 
  
  
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13. BIBLIOGRAPHY ................................................................................................................................ 102 
14. APPENDIX A: DEFINITION OF TERMS ........................................................................................... 104 
15. APPENDIX B: PREVIOUSLY IDENTIFIED ADVERSE EVENTS .................................................... 108 
 

 
  
  
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Table of Figures 
Figure 1: Sentus OTW QP Left Ventricular Lead (L model) .......................................................... 14 
Figure 2: IS4 Connector of the Sentus QP Lead ........................................................................... 15 
Figure 3: Sentus QP Lead Tip Design ........................................................................................... 15 
Figure 4: Pole Spacing with Sentus OTW QP S Models ............................................................... 16 
Figure 5: Pole Spacing with Sentus OTW QP L Models ............................................................... 16 
Figure 6: Programmer Display of LV Pacing Polarity .................................................................... 18 
Figure 7: Sentus QP Pacing Threshold Values at the 3 Month Follow-up .................................... 20 
Figure 8: Clinical Study Design ..................................................................................................... 38 
Figure 9: Programming MultiPole Pacing ...................................................................................... 76 
Figure 10: Programming 1st LV Stimulus ....................................................................................... 76 
Figure 11: Programming 2nd LV Stimulus ...................................................................................... 77 
Figure 12: V-V Delay, LV First ....................................................................................................... 77 
Figure 13: V-V Delay, RV First ...................................................................................................... 78 
Figure 14: MPP Sub-Study Design ................................................................................................ 89 
 
Table of Tables 
Table 1: LV Pacing and Sensing Configurations ........................................................................... 17 
Table 2: Primary Endpoint 1 Adverse Event Summary ................................................................. 19 
Table 3: Recommended Device Settings ...................................................................................... 35 
Table 4: Novel Pacing Vectors ...................................................................................................... 36 
Table 5: Required Visit Windows................................................................................................... 39 
Table 6: Procedures by Visit Type................................................................................................. 40 
Table 7: Adverse Event/Resolution Combinations for Primary Endpoint 1 Analysis .................... 60 
Table 8: Adverse Event/Resolution Combinations for Primary Endpoint 3 Analysis .................... 62 
Table 9: Investigator Reports ........................................................................................................ 72 
Table 10: Sponsor Reporting Responsibilities .............................................................................. 73 
Table 11: Programmable Parameters for MultiPole Pacing .......................................................... 75 
Table 12: Reasons for Corox BP Implantation Failure .................................................................. 98 
Table 13: CELESTIAL Study Supporting Data .............................................................................. 99 
Table 14: EchoCRT Supporting Data .......................................................................................... 100 
Table 15: Competitive Quadripolar LV Lead Performance.......................................................... 101 
Table 16a-d: Expected Perioperative Events .............................................................................. 108 
 
 

 
  
  
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U.S. specific amendment of 
QP ExCELs 
Sentus QP – Extended CRT Evaluation with Quadripolar  
Left Ventricular Leads 
Protocol Version – February 1, 2017 
PROTOCOL SIGNATURE PAGE 
The signature below documents receipt and review of the QP ExCELs study 
protocol and any attachments, and provides assurance that this study will be 
conducted according to all stipulations of the protocol, including all statements 
regarding confidentiality, and according to local legal and regulatory 
requirements and applicable guidelines. 
 
 
Principal Investigator: 
 
 
 
 
Name (please print) 
 
 
 
 
Signature 
 
Date 
 

 
  
  
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Summary 
Title 
Sentus QP – Extended CRT Evaluation with Quadripolar Left 
Ventricular Leads 
Acronym 
QP ExCELs 
Subject collective 
Heart failure subjects with standard CRT-D indication according 
to clinical routine. Subjects need to be enrolled in the QP 
ExCELs clinical investigation prior to implantation with a 
BIOTRONIK Sentus QP left ventricular lead and US market 
released BIOTRONIK CRT-D with an IS4 port for the LV lead. 
Design 
Prospective, non-randomized, multi-center clinical investigation 
to satisfy FDA requirements for pre-market submission and 
post-approval registry of the Sentus OTW QP left ventricular 
leads. 
Investigational 
device(s) 
Sentus OTW QP L, Sentus OTW QP S, Sentus OTW QP S/49, 
and Sentus OTW QP L/49 left ventricular lead. 
Objectives 
Pre-market: Confirm the safety and effectiveness of the 
BIOTRONIK Sentus OTW QP left ventricular pacing leads. The 
evaluation of safety will be freedom from Sentus QP related 
complications at 6 months post-implant. The evaluation of 
effectiveness will be based on LV pacing capture thresholds. 
Post-approval: Confirm long-term safety of the BIOTRONIK 
Sentus OTW QP left ventricular pacing leads.  The evaluation 
of safety will be freedom from Sentus QP related complications 
at 5 years post-implant. 
Primary endpoints  
Pre-market: 
1. Sentus QP related complication-free rate through 6 
months 
2. Percentage of subjects with acceptable pacing threshold 
of Sentus QP lead in permanently programmed vector at 3 
months 
Post-approval: 
3. Sentus QP related complication-free rate through 5 years 
post-implant 
 

 
  
  
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Secondary endpoints Pre-market: 
1. Sentus QP pacing threshold in permanently programmed 
vector at 3 months per lead model 
2. Sentus QP pacing threshold in novel vectors at 3 months 
3. Sentus QP R-wave sensed amplitude at 3 months per 
lead model 
4. Sentus QP pacing impedance at 3 months per lead model 
5. Sentus QP time to first complication 
6. Percentage of subjects successfully reprogrammed to 
resolve phrenic nerve stimulation or high LV pacing 
threshold during the study period 
Post-approval: 
7. Sentus QP related complication-free rate through 5 years 
post-implant per lead model 
8. Sentus QP Lead Safety – Individual 5-year adverse event 
rate  
 
MultiPole 
Pacing 
(MPP) 
Sub-study: 
Primary Endpoint 
Evaluation of the CRT responder status with the MPP feature 
MultiPole 
Pacing 
Sub-Study: 
Secondary 
Endpoints 
1. Freedom from MPP system-related complications at 6 
months post MPP enrollment. 
2. Clinical composite score + patient global assessment 
responder status 
3. Clinical composite score responder status utilizing a 
modified responder classification 
Sample Size 
Pre-market study: up to 314 subjects enrolled worldwide 
Post-approval study: up to 1,754 subjects enrolled in U.S 
MPP sub-study: up to 100 subjects at up to 75 sites within the 
U.S. who are participating in the QP ExCELs study. 
Investigational Sites 
Pre-market: Up to 75 sites within the United States, up to 125 
sites worldwide 
Post-approval: Up to 75 sites within the United States 

 
  
  
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Inclusion criteria 
• Standard CRT-D indication according to clinical routine 
• De novo implantation or upgrade from existing ICD or 
pacemaker implant utilizing a BIOTRONIK CRT-D system 
with IS4 LV port and Sentus QP LV lead 
• Patient is able to understand the nature of the clinical 
investigation and provide written informed consent 
• Patient is able and willing to complete all routine study 
visits at the investigational site through 5 years of follow-
up 
• Patient accepts BIOTRONIK Home Monitoring® concept 
• Age ≥ 18 years 
Exclusion criteria 
• Contraindication to CRT-D therapy 
• Currently implanted with an endocardial or epicardial left 
ventricular lead or had prior attempt to place a left 
ventricular lead 
• Cardiac surgical procedure, such as coronary artery 
bypass graft or valve surgery that is planned to occur 
within 6 months after implant or ablation that is planned to 
occur within 90 days after implant (ablations planned to 
occur prior to or at implant are not exclusionary) 
• Expected to receive a heart transplant or ventricular assist 
device within 6 months 
• Life expectancy less than 12 months 
• Participation in any other investigational cardiac clinical 
investigation during the course of the study 
• Presence of another life-threatening, underlying illness 
separate from their cardiac disorder 
• Pregnant or breast-feeding at time of enrollment 

 
  
  
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MultiPole 
Pacing 
Sub-Study: Inclusion 
Criteria 
• Currently enrolled in the ongoing QP ExCELs study 
• Successfully implanted with a BIOTRONIK Ilivia 7 HF-T 
QP family CRT-D system, or future U.S. marketed CRT-
D system with the MPP feature. Successful implantation 
is defined as having at least two LV pacing vectors with 
a measured pacing threshold of ≤ 5.0 V @ any pulse 
width (allowing for a minimum 2.5 V safety margin) 
without 
phrenic 
nerve 
stimulation 
at 
the 
final 
programmed pacing output at the time of enrollment into 
the MPP sub-study.   
• CRT 
Responder 
Assessment 
classification 
as 
“Worsened” or “Unchanged”. 
• Standard continuous biventricular (BiV) pacing from 
implant until the 6-Month QP ExCELs follow-up visit. 
(Implant to 3-Month QP ExCELs follow-up for subjects 
with a HF hospitalization event prior to 3-Month follow-
up) 
• Able to understand the nature of the sub-study and give 
informed consent 
• Available for an additional follow-up visit specific to the 
MPP sub-study at the investigational site 
• No evidence of non-compliance to their ongoing 
commitment in the QP ExCELs study 
MultiPole 
Pacing 
Sub-Study Exclusion 
Criteria 
• Have a life expectancy of less than 6 months 
• Expected to receive heart transplantation or ventricular 
assist device within 6 months 
• Chronic atrial fibrillation 
• Presence of another life-threatening, underlying illness 
separate from their cardiac disorder 
• Received MPP pacing prior to enrollment into the MPP 
sub-study 
Follow-up period: 
All subjects will be followed for 5 years post-implant of the 
Sentus QP LV lead 
Sponsor 
BIOTRONIK, Inc. 
Clinical Studies Department 
6024 Jean Road 
Lake Oswego, Oregon 97035 
 

 
  
  
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1. 
INTRODUCTION 
This clinical study protocol includes a pre-market study phase and an FDA 
required post-approval registry phase for BIOTRONIK’s Sentus QP lead. During 
the study safety and effectiveness data will be collected and evaluated for the 
Sentus QP lead. The pre-market phase will enroll up to 314 subjects at up to 125 
clinical study sites worldwide for pre-market analyses. Up to 75 study sites are 
planned within the United States.  U.S. sites will enroll up to 1,754 subjects as 
part of a post-approval study.  This clinical protocol additionally includes an FDA 
required post-approval MultiPole Pacing (MPP) sub-study to demonstrate the 
MPP feature can effectively convert a percentage of CRT non-responders to 
responders.      
Subjects eligible for the study are receiving a new (de novo) implant or 
undergoing an upgrade from an existing ICD or pacemaker implant with no prior 
attempt at LV lead placement. Prior to enrollment, eligible subjects will be 
identified and will provide written informed consent. Post implant, subjects will be 
seen for a pre-hospital discharge or wound check evaluation plus in-office follow-
ups at 3, 6, and 12 months. Thereafter, subjects enrolled in U.S. sites will 
continue to have follow-up visits every 6 months until 5 years post-implant.    
Within the U.S., the Sentus QP LV leads are considered investigational devices. 
All other devices utilized in conjunction with this study are U.S. market approved 
and prescribed by physicians according to approved indications for use. 
This clinical study protocol is a U.S. specific amendment for the QP ExCELs 
study and is only for U.S. study sites. The study sponsor for all U.S. sites is 
BIOTRONIK, Inc., Lake Oswego, OR, USA. Enrollment at non-U.S sites has 
ended with the last subject enrolled on February 29, 2016. It is anticipated that 
the Sentus QP LV lead will receive FDA approval during the course of the trial.  
BIOTRONIK will notify all sites when FDA approval is granted.  The non-US 
subjects were enrolled and followed for the pre-market cohort only.  These 
subjects end their study participation at the 12-month follow-up. The sponsor for 
all non-U.S. sites is BIOTRONIK SE & Co. KG, Berlin, Germany. 
1.1 
Background 
Heart failure (HF) is a major public health issue with a current prevalence of 2-
3% in the total and 10-20% in the aged population (Lloyd-Jones et al., 2010). The 
overall prevalence for heart failure is increasing due to aging population. 
Additional factors are the success of the modern therapies in prolongation of 
survival of patients suffering from coronary events and the effective prevention of 
death for patients being at high risk. 
The overall mortality for the population is 50% in the first 4 years and 40% of the 
patients with HF-related hospitalizations have to be readmitted to hospital or die 
within one year (Dickstein et al., 2008). 

 
  
  
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Cardiac Resynchronization Therapy (CRT) is used in order to synchronize 
interventricular and intraventricular contraction pattern of the heart in patients 
with heart failure in whom there is evidence of electrical dyssynchrony (QRS 
width ≥120 ms). CRT with defibrillator function (CRT-D) is recommended to 
reduce morbidity and mortality in patients in NYHA class III-IV who are 
symptomatic despite optimal medical therapy and suffer from a reduced left 
ventricular ejection fraction (LVEF ≤ 35%, (Dickstein et al., 2008)). This indication 
has been recently extended to patients in NYHA class II (Dickstein et al., 2010). 
Despite many improvements in techniques and equipment for this device 
therapy, phrenic nerve stimulation (PNS) or elevated pacing thresholds are still 
frequent issues (Crossley et al., 2010; Romeyer-Bouchard et al., 2010).  
Phrenic nerve stimulation occurs when a device's electrical output inadvertently 
activates the diaphragm muscle and causes muscle twitching, hiccup, or 
shortness of breath. Phrenic nerve stimulation is found in 2 to 37% of implanted 
patients, depending on different factors including the type of the left ventricular 
lead (Moubarak et al., 2014). A higher incidence of PNS is found in the standard 
pacing configuration as compared to alternative configurations (Goetze et al., 
2013).  With unipolar and bipolar left ventricular leads, PNS may require surgery 
to reposition the lead or disable the CRT.  With four electrodes on the left 
ventricular (LV) lead and 12 programmable pacing configurations, available with 
the Sentus QP left ventricular lead in combination with a corresponding CRT-D 
device, an occurrence of PNS or increased LV pacing thresholds may be 
resolved by non-invasive optimization of CRT delivery. Goetze et al., 2013 have 
shown that in 98% of patients presenting with phrenic nerve stimulation a 
reprogramming of the pacing vector could successfully terminate phrenic nerve 
stimulation without re-operation. Therefore, by using leads with multiple pacing 
options, the risk of surgical revision during follow up may be reduced. 
Apart from limiting risks of CRT, quadripolar (QP) leads with multiple additional 
pacing vectors can also increase cardiac output compared to conventional 
bipolar LV leads (Cabrera-Bueno et al., 2013; Thibault et al., 2013) and thus 
enhance the overall benefit of CRT. 
The combination of the new BIOTRONIK left ventricular lead family Sentus QP, 
containing 
4 
separate 
electrodes, 
with 
the 
corresponding 
Cardiac 
Resynchronization Therapy devices (CRT), provides additional pacing options to 
optimize cardiac resynchronization therapy, based on the individual anatomy and 
needs of heart failure patients as well as the occurrence of PNS and increased 
thresholds. 
The QP ExCELs study aims to gather safety and effectiveness data on 
BIOTRONIK Sentus QP leads which will be used to satisfy US FDA requirements 
for pre-market submission of the Sentus over-the-wire (OTW) quadripolar (QP) 
left ventricular (LV) leads. 

 
  
  
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1.2 
Devices 
The investigational devices used in this clinical investigation are the Sentus OTW 
QP L LV lead, Sentus OTW QP S LV lead, Sentus OTW QP S/49 LV lead, and 
Sentus OTW QP L/49 LV lead.  
Sentus OTW QP L, Sentus OTW QP S, Sentus OTW QP S/49, and Sentus OTW 
QP L/49 are quadripolar coronary sinus leads with IS4 connector. The leads are 
intended for permanent implantation in the coronary venous system and for left 
ventricular pacing with an appropriate triple chamber implantable pulse 
generator. The Sentus OTW QP L, Sentus OTW QP S, Sentus OTW QP S/49, 
and Sentus OTW QP L/49 will be further referred to as Sentus QP leads 
throughout this protocol. The Sentus QP leads will be utilized in conjunction with 
a US market released BIOTRONIK CRT-D with an IS4 port for the LV lead.  
1.3 
Investigational Device Description 
1.3.1 
Sentus QP Lead Design 
The Sentus QP leads are 4.8 F transvenous, steroid-eluting, quadripolar 
coronary sinus leads intended for permanent pacing and sensing of the left 
ventricle during cardiac resynchronization therapy. The development of the 
Sentus QP lead (Figure 1) is based on the predecessor product Corox OTW BP. 
The new elements of the development include two additional ring electrodes 
along the distal portion of the lead, a standard IS4 quadripolar lead connector 
(Figure 2) and a small diameter.  
 
Figure 1: Sentus OTW QP Left Ventricular Lead (L model) 
 
 

 
  
  
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Figure 2: IS4 Connector of the Sentus QP Lead 
A single steroid collar with 0.5 mg dexamethasone acetate (DXA) is located 
proximal to the lead tip. In the Sentus OTW QP L and Sentus OTW QP S models 
the distance between LV1-tip and LV2-ring is 21 mm, between LV2-ring and LV3-
ring 20 mm and between LV3-ring and LV4-ring 20 mm. The additional Sentus 
OTW QP S/49 and Sentus OTW QP L/49 models have shorter pole spacing for 
short target vein anatomies with a distance of 21 mm between LV1-tip and LV2-
ring, 15 mm between LV2-ring and LV3-ring, and 10 mm between LV3-ring and 
LV4-ring (Figure 3, Figure 4, and Figure 5).  The tip and ring electrodes are 
coated with fractal iridium. The tantalum and platinum/iridium conductor coil is 
insulated with silicone, and then externally coated with polyurethane. 
Polyurethane improves the gliding capabilities of the lead when advanced 
through a left ventricular lead delivery catheter and through the coronary 
vasculature. The Sentus QP leads can be positioned in the target vein by using a 
guide wire via the over-the-wire technique or by using a stylet. 
The Sentus QP has an outer diameter of 4.8 F and can be implanted with a CS 
lead delivery system. 
Four Sentus QP lead models will be evaluated in this clinical investigation: 
• Sentus OTW QP L and L/49 models are passive fixation leads utilizing a 
2D dual-curve to achieve a stable position within the target vein.  
• Sentus OTW QP S and S/49 models utilize a bend in the distal end 
enhanced with a silicone screw to provide passive fixation within the target 
vein. 
 
Figure 3: Sentus QP Lead Tip Design 

 
  
  
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Figure 4: Pole Spacing with Sentus OTW QP S Models 
 
Figure 5: Pole Spacing with Sentus OTW QP L Models 

 
  
  
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The Sentus OTW QP is available in three lengths; L-75 (77 cm), L-85 (87 cm), 
and L-95 (97 cm). All three length variants carry a green marker ring to identify 
them as left ventricular CRT leads (Figure 2). 
1.3.2 
Pacing and Sensing Vector Options  
When connected to a CRT-D device with an IS4 LV port, the Sentus QP leads 
offer more options in pacing and sensing configurations as compared with 
conventional bipolar systems.  
The vectors are built between a cathode (From -) to an anode electrode (To +). 
Besides the four consecutively numbered LV electrodes of the quadripolar LV 
lead (LV1 tip, LV2 ring, LV3 ring, LV4 ring) the distal shock coil of the RV lead 
(RV coil) or the ICD housing (CRT-D) can be used as additional anode 
electrodes for the LV pacing and sensing configuration. This gives the Sentus QP 
leads a total of 12 LV pacing and 7 LV sensing vector options as described in 
Table 1.  
 
 
Table 1: LV Pacing and Sensing Configurations 
Pacing Vectors 
Sensing Vectors 
# 
From (-) →  To (+) 
# 
From (-) → 
To (+) 
1 
LV1 tip  → 
LV2 ring 
1 
LV1 tip  → 
LV2 ring 
2 
LV1 tip  → 
LV4 ring 
2 
LV1 tip  → 
ICD 
3 
LV1 tip  → 
RV coil 
3 
LV2 ring  → 
LV3 ring 
4 
LV1 tip  → 
ICD 
4 
LV2 ring  → 
ICD 
5 
LV2 ring  → 
LV1 tip 
5 
LV3 ring  → 
LV4 ring 
6 
LV2 ring  → 
LV4 ring 
6 
LV3 ring  → 
ICD 
7 
LV2 ring  → 
RV coil 
7 
LV4 ring  → 
ICD 
8 
LV3 ring  → 
LV2 ring 
 
 
 
9 
LV3 ring  → 
LV4 ring 
 
 
 
10 
LV3 ring  → 
RV coil 
 
 
 
11 
LV4 ring  → 
LV2 ring 
 
 
 
12 
LV4 ring  → 
RV coil 
 
 
 
 
The vectors are chosen by selecting a cathode (From -) and an anode electrode 
(To +) during device interrogation and programming (Figure 6). 

 
  
  
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Figure 6: Programmer Display of LV Pacing Polarity 
1.4 
Prior Clinical Performance 
BIOTRONIK, Inc. submitted the QP ExCELs Pre-Market Approval (PMA) Clinical 
Report in support of the PMA application to the FDA on November 23, 2016 and 
it is currently under FDA review. The PMA Clinical Report included all data 
collected since the first subjects were enrolled on December 16, 2014 (O.U.S.) 
and October 15, 2015 (U.S.) through September 9, 2016. A total of 635 subjects 
were enrolled and 576 successfully implanted with a Sentus QP lead. The 
cumulative implant duration was 341.8 years (mean implant duration: 0.6 ± 0.3 
years). 
The analyzed pre-market cohort is comprised of 299 subjects who were 
implanted on or before January 29th, 2016; the implant date for the 282nd subject 
to complete a 3 month follow-up. All pre-market primary endpoints were met with 
statistical significance and the results are summarized below.  
1.4.1 
Primary Endpoint 1 Results 
The purpose of primary endpoint 1 is to evaluate the Sentus QP related 
complication-free rate through 6 months post-implant. Reported adverse events 
that were related to the implanted CRT-D system and/or implant procedure were 
adjudicated by the CEC. Events that occurred prior to or on the date of the 6 
month follow-up and were adjudicated by the CEC as meeting the primary 
endpoint criteria were included in the calculation of the primary endpoint 1 
complication-free rate. For the purposes of the primary endpoint 1 analysis, 
evaluable subjects are those who were included in the pre-market cohort and 
either completed a 6 month follow-up visit (n = 274), experienced an endpoint 
related adverse event but exited the study prior to reaching the 6 month follow-up 

 
  
  
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(n = 2), did not complete a 6 month follow-up visit but did complete a subsequent 
visit (n = 3), or had an unsuccessful implant due to a Sentus QP lead related 
complication (n = 0). Subjects in the pre-market cohort that did not have a 
successful Sentus QP implant were not included in the endpoint 1 analysis 
(unless, as noted above, the unsuccessful implant was due to a Sentus QP lead 
related complication). The total number of evaluable subjects for primary 
endpoint 1 was 279. 
Analysis 
Primary endpoint 1 was evaluated by performing an exact, binomial test 
comparing the observed proportion (complication-free rate at 6 months) to 
90.0%.  
Of the 279 evaluable subjects for primary endpoint 1, eight subjects had an event 
that met the primary endpoint criteria, were adjudicated by the CEC as related to 
the Sentus QP lead, and occurred prior to or on the date of the 6 month follow-
up. The complication-free rate through 6 months post-implant is 97.1% 
(271/279), 95% CI of 94.4% to 98.8%, p<0.0001. 
Table 2 provides a summary of the eight primary endpoint 1 adverse events. 
Table 2: Primary Endpoint 1 Adverse Event Summary 
Adverse Event Type 
Subjects 
with AE 
% with AE 
Number of 
AEs 
Rate (per 
subject 
year) 
Lead dislodgement 
4 
1.43% 
4 
0.028 
Extracardiac stimulation 
3 
1.08% 
3 
0.021 
Lead impedance out of range, high 
1 
0.36% 
1 
0.007 
Total 
8 
2.87% 
8 
0.055 
Total number of implanted subjects = 279; Subject years since successful implant = 144.7 
Conclusion 
The results indicate that the complication-free rate through 6 months post-implant 
is greater than 90.0%; therefore, primary endpoint 1 is met. 
 
1.4.2 
Primary Endpoint 2 Results 
The purpose of primary endpoint 2 is to evaluate the LV lead pacing threshold for 
the permanently programmed pacing vector at 3 months post-implant. 
Specifically, the percentage of subjects with an acceptable LV pacing threshold 
in the permanently programmed vector at the 3 month follow-up will be 
determined. An acceptable LV threshold was defined as being ≤ 2.5 V at a pulse 
width of 0.4 ms in the pacing vector programmed at the beginning of the 3 month 
follow-up.  

 
  
  
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For the purposes of the primary endpoint 2 analysis, evaluable subjects are 
those who were included in the pre-market cohort and either completed a 
threshold test at a pulse width of 0.4 ms at the 3 month follow-up (n = 276), did 
not have a threshold test at or missed the 3 month follow-up but had Home 
Monitoring data meeting specific consistency criteria available for imputation (n = 
3), had a subsequent follow-up visit with threshold test at a pulse width of 0.4 ms 
(n = 7), or were not successfully implanted due to a Sentus QP lead related 
adverse event (n = 0). A total of 286 subjects were included in the evaluation of 
primary endpoint 2. 
 
Analysis 
Primary endpoint 2 was evaluated by performing an exact, binomial test 
comparing the observed proportion (rate of acceptable LV pacing thresholds at 3 
months) to 88.0%.  
Of the 286 evaluable subjects for primary endpoint 2, 267 subjects had an 
acceptable LV threshold for a rate of 93.4%, 95% CI of 89.8% to 96.0%, p=0.002. 
Figure 7 provides a histogram showing the Sentus QP pacing threshold values in 
the permanently programmed vector at 3 months. The acceptable threshold 
maximum of 2.5 V is indicated by the vertical line. Three subjects had a result of 
no capture possible during the threshold test and are not displayed in Figure 7. 
These three subjects were considered as failures in the analysis of primary 
endpoint 2. 
Figure 7: Sentus QP Pacing Threshold Values at the 3 Month Follow-up 
 
Conclusion 
The results indicate that the proportion of subjects with an acceptable threshold 
value in the permanently programmed vector at the 3 month follow-up is greater 
than 88.0%; therefore, primary endpoint 2 is met. 

 
  
  
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2. 
STUDY DESIGN 
This is a multi-center, prospective, non-randomized clinical investigation. To 
document the clinical experience of the Sentus QP lead as required by the FDA 
to satisfy requirements for pre-market submission, the pre-market clinical 
investigation is designed to enroll up to 314 subjects whom will be followed for at 
least 12 months post-implant at up to 125 sites in total including up to 75 
investigational sites within the United States.  To satisfy U.S. requirements for a 
long term post-approval registry, the clinical investigation is designed to enroll up 
to 1754 U.S. subjects whom will be followed for 5 years post-implant.  A sub-
study is included (Section 11) to satisfy an FDA required post-approval study of 
the Multi-Pole Pacing feature (PMA P050023/S107) of the Ilivia HF-T QP family 
CRT-D system (PMA  P050023/S103). 
2.1 
Objectives 
The objective of this clinical investigation is to confirm the safety and efficacy of 
BIOTRONIK’s Sentus QP leads in a clinical investigation to support regulatory 
approval as well as a long term post-approval evaluation of the devices in the 
United States. The safety objective of the clinical investigation is to assess the 
safety of the Sentus QP lead by the analysis of the lead related complications 
during 6 months after implantation. The efficacy (performance) objective of the 
clinical investigation is to assess if pacing thresholds of the lead are in an 
acceptable range at 3 months after implantation.  The post-approval objective of 
the clinical investigation is to assess the safety of the Sentus QP lead by the 
analysis of the lead related complications through 5 years post-implant. 
2.2 
Study Endpoints and Hypotheses 
The following endpoints have been defined to confirm the safety and efficacy of 
the investigational devices. 
2.2.1 
Primary Endpoint 1: Sentus QP Related Complication-Free Rate 
through 6 Months (Pre-Market Analysis) 
The purpose of primary endpoint 1 is to evaluate the Sentus QP related 
complication-free rate through 6 months post-implant. The Sentus QP related 
complications that will be assessed in this primary endpoint are defined in 
Section 6.6.1. The parameter of interest 
SentusQP
on
Complicati
p
 is the complication-free rate 
per subject, which will be calculated by (1 - the number of subject with one or more 
complications divided by the number of subjects) in percent. The period of 
observation starts after successful implantation of the Sentus QP lead. 
The following hypotheses have been defined to evaluate the primary endpoint 
“Sentus QP related complication-free rate through 6 months”: 
Ho: Complication-free rate through 6 months post-implant is ≤ 90.0% 
Ha: Complication-free rate through 6 months post-implant is > 90.0% 

 
  
  
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A rejection of the null hypothesis (Ho) would demonstrate evidence that the 
complication-free rate is greater than 90.0%. 
2.2.2 
Primary Endpoint 2: Percentage of Subjects with Acceptable Pacing 
Threshold in Permanently Programmed Vector at 3 Months (Pre-
Market Analysis) 
The purpose of primary endpoint 2 is to evaluate the LV lead pacing threshold for 
the permanently programmed pacing vector at 3 months post-implant. 
Specifically, the percentage of subjects with an acceptable LV pacing threshold 
in the permanently programmed vector at the 3-month visit (
PaThres
acceptable
p
) will be 
determined. LV threshold values of ≤ 2.5V at 0.4 ms in the permanently 
programmed vector, defined as the permanent pacing vector at the beginning of 
the 3-month visit interrogation, will be considered acceptable.  
The following hypotheses have been defined to evaluate the primary endpoint 
“Percentage of subjects with acceptable pacing threshold in permanently 
programmed vector at 3 months”: 
Ho: Acceptable LV threshold rate at 3 months post-implant is ≤ 88.0% 
Ha: Acceptable LV threshold rate at 3 months post-implant is > 88.0% 
A rejection of the null hypothesis (Ho) would demonstrate evidence that the rate 
of acceptable LV pacing thresholds is greater than 88.0%. 
2.2.3 
Primary Endpoint 3: Sentus QP Related Complication-Free Rate 
through 5 years (Post-Approval Analysis) 
The purpose of primary endpoint 3 is to evaluate the long-term Sentus QP 
related complication-free rate through 5 years post-implant. The Sentus QP 
related complications that will be assessed in this primary endpoint are defined in 
Section 6.6.2. The parameter of interest 
SentusQP
on
Complicati
p
 is the complication-free rate 
per subject, which will be calculated by (1 - the number of subject with one or more 
complications divided by the number of subjects) in percent. The period of 
observation starts after successful implantation of the Sentus QP lead. 
The following hypotheses have been defined to evaluate the primary endpoint 
“Sentus QP related complication-free rate through 5 years”: 
Ho: Complication-free rate through 5-years post-implant is ≤ 92.5% 
Ha: Complication-free rate through 5-years post-implant is > 92.5% 
A rejection of the null hypothesis (Ho) would demonstrate evidence that the 
complication-free rate is greater than 92.5%. 
2.2.4 
Secondary Endpoints 
The following secondary endpoints will be evaluated during this clinical 
investigation. There are no formal tests of hypothesis associated with the 
secondary endpoints.  Secondary endpoints 1 through 6 will only be evaluated as 

 
  
  
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part of the pre-market analyses.  Secondary endpoint 7 and 8 will be evaluated 
as part of the post-approval analyses.   
2.2.4.1 
Sentus QP pacing threshold in permanently programmed vector at 3 
months per lead model 
The purpose of the secondary endpoint is to evaluate the LV lead pacing 
threshold for the permanently programmed pacing vector at 3 months post-
implantation in the four different lead types, Sentus OTW QP L, Sentus OTW QP 
S, Sentus OTW QP S/49, and Sentus OTW QP L/49. Specifically, the percentage 
of subjects with an acceptable LV pacing threshold in the permanently 
programmed vector at the 3-month visit will be determined for both leads. LV 
pacing threshold values of ≤ 2.5V at 0.4 ms in the permanently programmed 
vector, defined as the permanent pacing vector at the beginning of the 3-month 
visit interrogation, will be considered acceptable.  
2.2.4.2 
Sentus QP pacing threshold in novel vectors at 3 months 
The purpose of this secondary endpoint is to evaluate the LV lead pacing 
threshold for the novel pacing vector at 3 months post-implantation. Specifically, 
the percentage of subjects with at least one acceptable LV pacing threshold in 
the novel vectors at the 3-month visit will be determined. LV pacing threshold 
values of ≤ 2.5V at 0.4 ms in the novel vectors will be considered acceptable. 
Novel vectors are defined as all vectors utilizing one of the two distal LV rings 
(LV3 or LV4). 
2.2.4.3 
Sentus QP R-wave sensed amplitude at 3 months per lead model 
The purpose of this secondary endpoint is to evaluate the LV lead sensing 
amplitude at 3 months post-implantation. Specifically, the percentage of subjects 
with acceptable LV sensing amplitude at the 3-month visit will be determined. R-
wave sensed mean amplitude of ≥ 2mV will be considered acceptable.  
2.2.4.4 
Sentus QP pacing impedance at 3 months per lead model 
The purpose of this secondary endpoint is to evaluate the LV lead pacing 
impedance at 3 months post-implantation. Specifically, the percentage of 
subjects with acceptable LV pacing impedance at the 3-month visit will be 
determined. LV impedance values of >200 Ohms and <2000 Ohms will be 
considered acceptable.  
2.2.4.5 
Sentus QP Time to first complication 
The purpose of this secondary endpoint is to evaluate the Sentus QP related 
complication-free rate through 6 months post-implant by the Kaplan-Meier 
method. 

 
  
  
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2.2.4.6 
Percentage of subjects successfully reprogrammed to resolve phrenic 
nerve stimulation or high pacing threshold during the study period 
The purpose of this secondary endpoint is to evaluate the effectiveness of 
electrical lead repositioning to resolve phrenic nerve stimulation or high LV 
pacing thresholds. Specifically, the percentage of subjects in which phrenic nerve 
stimulation or high LV pacing thresholds which could be resolved by vector 
reprogramming during the study period will be determined in relation to all 
subjects in which it was attempted to resolve phrenic nerve stimulation or high LV 
pacing thresholds by electrical repositioning. 
2.2.4.7 
Sentus QP Related Complication-Free Rate through 5 years per lead 
model 
The purpose of this secondary endpoint is to evaluate the long-term Sentus QP 
related complication-free rate through 5 years post-implant per lead model. The 
Sentus QP related complications that will be assessed in this endpoint will be 
those defined in Section 6.6.2  
2.2.4.8 
Sentus QP Lead Safety – Individual 5-year adverse event rates 
The purpose of this secondary endpoint is to evaluate each of the individual 
types of adverse events contributing to primary safety endpoint 3.  The Sentus 
QP related complications that will be assessed in this endpoint will be those 
defined in Section 6.6.2.  
2.2.5 
Additional Data of Interest 
Additional information will be collected to characterize the study population, 
implanted system, and progress of the clinical investigation. The collected data 
will include baseline demographics, comorbidities, implanted system and 
implantation experience, system revision, Sentus QP extractions, returned 
product analysis, and compliance. The data will be statistically analyzed, where 
appropriate. Specifically, further data of interest will include: 
• Demographics, including age and gender 
• Baseline New York Heart Association (NYHA) class 
• Historical left ventricular ejection fraction (LVEF), if obtained within 6 
months prior to enrollment 
• Implanted devices, including pulse generator and other leads 
• Implantation site and, if available, implant approach 
• Approximate vessel diameter at Sentus QP lead tip (at final lead position, 
when this information is available from a routine venogram performed 
during implant) 
• Reason for inability to place Sentus QP lead 

 
  
  
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• Adverse events related to implant procedure, pulse generator, or other 
implanted leads 
• Sentus QP lead performance at 6 and 12 months post-implant plus at 
additional required follow-up visits (i.e., 18 months, 24 months), including 
R-wave sensing, pacing impedance, and pacing threshold 
• Revisions to implanted system and reason for revision 
• Results from returned product analysis 
• Compliance to protocol requirements and study visit schedule 
• Sentus QP pacing threshold in novel vectors (optional) 
2.3 
Statistical Design, Method, and Analytical Procedures 
2.3.1 
Pre-Market Analyses Cohort 
A pre-market cohort for analysis of primary endpoints 1 and 2 and secondary 
endpoints 1 through 6 will be comprised at the time when 231 completed 6 month 
follow-ups and 282 completed 3 month follow-ups have occurred.  Follow-ups will 
be considered complete once entered in the EDC system and case report forms 
are electronically signed by the investigator.   
The pre-market analyses cohort is defined as the population of subjects who 
were implanted (or had an implant attempt) on or before the implant date of the 
last subject to reach the latter of the 231st completed 6 month follow-up or 282nd 
completed 3 month follow-up. 
2.3.2 
Primary Endpoint 1 Analysis 
The analysis population for primary endpoint 1 will include all subjects who 
provided informed consent, met the enrollment criteria, and in whom a Sentus 
QP lead was successfully implanted. The common scenarios listed below will be 
taken into account for analysis of primary endpoint 1: 
• Subjects who completed a 6 month follow-up or experienced an adverse 
event (as defined in Section 6.6.1) prior to reaching the 6 month follow-up 
time point will be included in the endpoint evaluation. 
• Subjects without an adverse event (as defined in Section 6.6.1) who exit 
the study prior to the 6-month follow-up are excluded from the analysis 
population to avoid an overestimation of the complication-free rate.  
• Subjects that were not successfully implanted due to a Sentus QP lead 
related complication (such as coronary sinus dissection caused by the 
Sentus QP lead) will be included in the population.  
• Any subject with a missing 6 month follow-up, who completes a 
subsequent follow-up (e.g. 12 month follow-up or interim follow-up) will be 
included in the evaluation.   

 
  
  
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Primary endpoint 1 will be evaluated by performing an exact, binomial test 
comparing the observed proportion (overall complication-free rate at 6 months) to 
the performance goal of 90.0%. The lower, two-sided 95% confidence bound for 
the overall complication-free rate must be greater than 90.0%.  
2.3.3 
Primary Endpoint 2 Analysis 
For primary endpoint 2, only subjects who provide informed consent, met the 
enrollment criteria, and in whom a Sentus QP lead was successfully implanted 
will be included. The common scenarios listed below will be taken into account 
for analysis of primary endpoint 2.  
• Any subjects not successfully implanted due to a Sentus QP lead related 
adverse event will be included in the analysis for primary endpoint 2 as a 
failure. 
• For successfully implanted subjects that missed a 3 month visit or did not 
undergo threshold testing of the LV lead at the 3 month visit, or completed 
threshold testing at a pulse width other than 0.4 ms, missing data points 
will be imputed according to Section 2.5.4.  
Primary endpoint 2 will be evaluated by performing an exact, binomial test 
comparing an observed proportion (rate of acceptable LV pacing thresholds at 
the permanently programmed pacing vector at 3 months) to 88.0%. The lower, 
two-sided 95% confidence bound for the percentage of subjects with an 
acceptable LV pacing threshold in the permanently programmed pacing vector 
must be greater than 88.0%.  
2.3.4 
Primary Endpoint 3 Analysis 
The analysis population for primary endpoint 3 will include all subjects who 
provided informed consent, met the enrollment criteria, and in whom a Sentus 
QP lead was successfully implanted.   Only subjects who were successfully 
implanted and completed a 60-month month visit will be included in the endpoint 
analysis  
Primary endpoint 3 will be evaluated by performing an exact, binomial test 
comparing the observed proportion (overall complication-free rate at 5 years) to 
the performance goal of 92.5%. The lower, two-sided 95% confidence bound for 
the overall complication-free rate must be greater than 92.5%.  
2.3.5 
Secondary Endpoints 
The secondary endpoints of pacing threshold (programmed and novel pacing 
vectors), sensed amplitude, and impedance at the 3 month visit will be 
summarized using standard measures, including means, standard deviations, 
medians, minimum and maximums. In addition, the percentage of subjects with 
values within the acceptable range per lead model will be provided. Acceptable 
ranges for the lead measurements are provided in Section 3.2.5. 

 
  
  
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For secondary endpoints 1-4 only subjects who were successfully implanted, 
completed a 3 month visit, and have data for the specific endpoint being 
evaluated will be included in the endpoint analysis; however, additional data 
resources may be used for supplemental analysis.  
For the endpoint 5, time-to-first-complication, the analysis set of the primary 
endpoint 1 and additionally also those subjects who drop out prior to the 6-month 
follow-up is used. Confidence intervals based on Kaplan-Meier estimates for 
freedom from complications together with the associated standard errors will be 
provided. For this estimate, subjects exiting the clinical investigation prior to the 6 
month visit will be censored at the time of study termination. 
For endpoint 7 and 8, only subjects who were successfully implanted and 
completed a 60-month month visit will be included in the endpoint analysis; 
however, additional data resources may be used for supplemental analysis.  
2.3.6 
Additional Data of Interest Analysis 
For additional data of interest, descriptive summary statistics appropriate to the 
type of parameter, continuous or discrete, will be reported.  
Pacing threshold, R-wave sensing and impedance measurements for the Sentus 
QP leads at pre-hospital discharge/wound check, 3, 6, and 12 months, plus 
additional required follow-up visits (i.e., 18 months, 24 months) will be 
summarized using standard measures, including means, standard deviations, 
medians, minimums, and maximums. Data will be provided as a total at each visit 
interval and per lead model at each visit interval. 
2.3.7 
Trend Analyses 
The primary post-approval safety endpoint is evaluated at 5 years post-implant 
against a prespecified performance level (92.5% for overall freedom from Sentus 
QP related complications). To monitor the ongoing incidence of any potential AEs 
against the accumulating follow-up exposure post-implant, a Kaplan-Meier 
survival curve will be prepared at the reporting intervals for this safety outcome. 
Root causes for any failures, regardless of the incidence rates, will be 
investigated. 
If the observed cumulative survival rate falls below the 5-year target value 
(92.5% of overall freedom from complications) at any time during the study, or is 
projected to fall below the target value, then BIOTRONIK will summarize the 
observed data and the results of the failure investigations, and report the findings 
to the FDA at or before the next scheduled reporting interval. If at any time a 
single unanticipated adverse event or device failure, or combination of events, is 
believed to have implications regarding the safety of current or future subjects, 
then this will be reported to the FDA within the statutory timeframes. 

 
  
  
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2.4 
Estimated Sample Size 
2.4.1 
Pre-Market Analyses 
The sample size required to evaluate primary hypotheses 1 and 2 was estimated 
using the following design criteria: 
• Study design: non-randomized 
• Test basis: exact binomial test 
• Type I error, alpha: 2.5% (one-sided) 
• Statistical power: 80% for acceptance of both primary Alternative 
hypotheses 
For primary safety hypothesis (complication-free rate), the following assumptions 
apply: 
• Expected complication-free rate through 6 months: 95.0% 
• HA: Complication-free rate through 6 months post-implant > 90.0% 
For primary efficacy hypothesis (LV pacing threshold for permanently 
programmed vector), the following assumptions apply: 
• Expected rate of acceptable LV pacing thresholds at 3 months: 93.0% 
• HA: Acceptable LV pacing threshold rate at 3 months > 88.0% 
Based on the above criteria, a total of 231 evaluable subjects assessed at 6 
months would be required to accept the primary safety alternative hypothesis 
(endpoint 1). For primary endpoint 2, a total of 282 evaluable subjects assessed 
at 3 months would be required to accept the primary efficacy alternative 
hypothesis.  
An adjustment of 10% is used in the sample size estimation for both primary 
endpoints 1 and 2 to account for subjects that exit the clinical investigation prior 
to having a 6 month evaluation. Reasons that subjects may exit the clinical 
investigation include withdrawal of consent, mortality, device explant, change in 
physician, or subject moving. Therefore, up to 314 subjects (=282/.9) will need to 
be enrolled to account for premature study terminations. 
2.4.2 
Post-Approval Analysis 
The sample size required to evaluate primary hypotheses 3 was estimated using 
the following design criteria: 
• Study design: non-randomized 
• Test basis: exact binomial test 
• Type I error, alpha: 2.5% (one-sided) 
• Statistical power: 80%  
• Expected complication-free rate through 5-years: 94.75% 

 
  
  
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• HA: Complication-free rate through 5-years post-implant > 92.5% 
Based on the above criteria, a total of 979 evaluable subjects assessed at 5 
years would be required to accept the primary 5-year safety alternative 
hypothesis.  
An adjustment of 11% per year is used in the sample size estimation for primary 
endpoint 3 to account for subjects that exit the clinical investigation prior to 
having a 5-year (60-month) evaluation. Reasons that subjects may exit the 
clinical investigation include withdrawal of consent, mortality, device explant, 
change in physician, or subject moving. Therefore, up to 1754 evaluable subjects 
(=979/0.89^5) will need to be enrolled to account for premature study 
terminations. 
2.4.3 
Replacement of Subjects 
For this study, a drop-out rate of 11% of subjects per year is expected in the QP 
ExCELs study. The additional enrollment of 11% (total subject number: 
n=979/0.89^5) is considered sufficient for the collection of the required primary 
endpoint 3 (n=979). However, to ensure sufficient primary endpoint 3 evaluable 
data, subjects who exit the clinical investigation prior to implantation of the LV 
lead, or by death, explant, lost-to-follow up may be replaced as long as 
enrollment is ongoing. This includes subjects in which it is determined that they 
are not eligible for the Sentus QP lead during implantation, as long as the subject 
did not come in contact with the Sentus QP lead. These subjects do not count to 
the overall U.S. planned subject number of 1754. 
2.5 
Other Statistical Considerations 
2.5.1 
Success Criteria 
The proposed study will be considered a success (pre-approval) if the 
requirements set by the FDA for regulatory approval of the Sentus QP leads are 
fulfilled. The post-approval study will be considered a success if the post-
approval requirements of the Sentus QP leads are fulfilled. 
2.5.2 
Provision for a Pivotal and Interim Analysis 
An FDA pivotal analysis of the pre-market endpoint relevant data is planned after 
the minimum sample size for Primary Endpoints 1 and 2 has been met (Section 
2.3.1). All enrolled subjects will be considered in an OUS Final Clinical 
Investigation Report, which is planned after all enrolled subjects outside of the 
U.S. have completed the 12 month follow-up period.  Further interim analyses 
are not planned and there are no statistical criteria to stop the clinical 
investigation for superiority. Thus, no adjustment of the significance level is 
planned. 

 
  
  
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2.5.3 
Specification of Subgroups 
For primary endpoints, pooling of data from the Sentus OTW QP S, Sentus OTW 
QP S/49, Sentus OTW QP L, and Sentus OTW QP L/49 leads will be justified as 
part of the final data analysis. Potential differences in primary endpoint outcomes 
for the S lead models (Sentus OTW QP S or S/49) and the L lead models 
(Sentus OTW QP L or L/49) will be tested using an exact, Chi-square test. If no 
evidence is found of differences between the S and L lead models (p > 0.05), 
then the results will be considered poolable for the purposes of testing the 
hypothesis associated with each applicable primary endpoint. Based on the 
model mix of the Corox OTW-S and OTW-L in the CELESTIAL study, at least 
30% of implants are expected to include the Sentus OTW QP S or S/49 lead 
models. However, as a minimum target, at least 100 subjects should be 
implanted with each of the two fixation curves (L or S) for the pre-market 
analyses, and at least 400 subjects with each fixation curve for the post-approval 
analyses (Note: the Sentus OTW QP L/49 lead model was not included in the 
study protocol prior to the pre-market analysis and will only contribute to the post-
approval analysis). Additionally, gender subgroup analysis of the primary 
endpoints will be conducted with a p-value of 0.15 or less considered evidence of 
gender differences. 
The distribution in complication-free rates across study centers will also be 
examined. The significance of differences in rates between centers will be initially 
tested using a Kruskal-Wallis test statistic, with an associated p-value of 0.15 or 
less considered evidence of center differences. In addition, a Cochran-Mantel-
Haenszel test with continuity adjustment will be used to assess the poolability of 
data collected across the different centers. If evidence is found of center 
differences, then the reasons for the differences will be explored using Cox and 
logistic regression methods to determine if any baseline subject risk factors are 
explanatory.    
Details on the data analysis plan for all endpoints and additional data of interest 
is provided in Section 2.3. 
2.5.4 
Handling of Missing, Unused, or Spurious Data 
All possible steps will be taken to minimize missing data in the clinical 
investigation. This includes but is not limited to monitoring of study forms for 
completeness and supporting efforts to track and maintain contact with study 
subjects during the study period. If any data is missing, the reason will be 
documented.  
In cases of missing data, a pre-planned supplemental procedure using 
BIOTRONIK Home Monitoring® data to impute the missing data points will be 
followed. When active, BIOTRONIK Home Monitoring® provides daily automatic 
LV pacing thresholds, R-wave sensing, and pacing impedance. When available, 
missing data will be imputed with BIOTRONIK Home Monitoring® values 
obtained from the day of a completed follow-up, due date of a missed follow-up, 
or the next closest day before or after. 

 
  
  
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For values imputed in support of primary endpoint 2, the consistency of the 
imputed value will be examined by comparing the selected value to the average 
value of the surrounding 6 values (typically 3 values prior to the selected value 
and 3 values after the selected value). The imputed value will be considered 
consistent if it is contained within the 95% confidence interval for the surrounding 
6 values or if the difference between the minimum and maximum of the imputed 
value and surrounding values is ≤ 0.2 V.   
Where BIOTRONIK Home Monitoring® data is not available for imputation of 
missing 3-month follow-up data in support of primary endpoint 2, the LV pacing 
threshold from the next completed follow-up after the 3-month time point may be 
used to impute the missing data. 
Multiple analyses will be conducted as needed to assess the impact of missing 
and imputed data. 
For purposes of the Kaplan-Meier survival analysis, described in Section 2.3.7, 
enrolled subjects exiting the clinical investigation prior to the 5 year visit will be 
censored at the time of study termination. 
2.5.5 
Maximum Number of Subjects per Site 
For U.S. investigational sites, the maximum number of subjects per 
investigational site is 15% of the expected total number of subjects to be enrolled 
(n=1754), thus a maximum of n=263 subjects can be enrolled per center.  OUS 
sites may enroll a maximum of 43 subjects per center for the pre-market 
analyses. 

 
  
  
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3. 
PROTOCOL REQUIREMENTS 
3.1 
Subject Population 
The subject population consists of heart failure subjects with CRT-D indication 
according to clinical routine.  
Up to 1754 subjects will be enrolled in the clinical investigation. The investigator 
is responsible for screening all potential subjects and selecting those who are 
appropriate candidates for implantation of a BIOTRONIK CRT system with 
Sentus QP lead. The subjects selected for participation should be from the 
investigator’s general patient population with documented evidence of an 
indication for implantation of a BIOTRONIK CRT-D system according to clinical 
routine and according to the inclusion and exclusion criteria described below. 
Decision for implantation of the respective BIOTRONIK devices is based on 
medical decisions alone and should not be influenced by the possible enrollment 
to this clinical trial. If a Sentus QP implantation was planned but the investigator 
decided after depiction of the coronary sinus system that the Sentus QP lead is 
not suitable for the vessel anatomy he/she is not bound to the lead choice. 
The implanting investigator is responsible for choosing the fixation and length 
variant. For the indications, we recommend following the respective current 
guidelines of the Heart Rhythm Society (HRS), the American College of 
Cardiology (ACC), and the American Heart Association (AHA), as well as those 
of other national cardiology associations. 
Investigators are strongly encouraged to seek equal enrollment between men 
and women at their site. This will help ensure women are adequately represented 
in the study population and enable meaningful analyses of results by gender.  
3.1.1 
Indications for Use 
The Sentus OTW QP left ventricular pacing lead is a 4.8 French (5 F introducer) 
quadripolar steroid-eluting lead intended for permanent implantation in the left 
ventricle via the coronary veins to provide pacing and/or sensing when used in 
conjunction with a compatible IS4 pulse generator. 
3.1.2 
Contraindications 
Implantation of this lead is contraindicated in the following cases: 
• Coronary sinus anomalies 
• Tissue in the coronary sinus area that has been damaged by an infarction 
• Any anomalies of the venous system that preclude transvenous 
implantation of the lead 
• Patient cannot tolerate a single systemic dose of up to 0.5 mg of 
dexamethasone acetate (DXA) 

 
  
  
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3.1.3 
Inclusion Criteria 
All of the following inclusion criteria have to be fulfilled for study participation: 
• Standard CRT-D indication according to clinical routine 
• De novo implantation or upgrade from existing ICD or pacemaker implant  
utilizing a BIOTRONIK CRT-D system with IS4 LV port and Sentus QP LV 
lead 
• Patient is able to understand the nature of the clinical investigation and 
provide written informed consent 
• Patient is able and willing to complete all routine study visits at the 
investigational site through 5 years of follow-up 
• Patient accepts BIOTRONIK Home Monitoring® concept 
• Age ≥ 18 years 
3.1.4 
Exclusion Criteria 
None of the following exclusion criteria can be fulfilled for study participation: 
• Contraindication to CRT-D therapy 
• Currently implanted with an endocardial or epicardial left ventricular lead 
or had prior attempt to place a left ventricular lead 
• Cardiac surgical procedure, such as coronary artery bypass graft or valve 
surgery that is planned to occur within 6 months after implant or ablation 
that is planned to occur within 90 days after implant (ablations planned to 
occur prior to or at implant are not exclusionary) 
• Expected to receive a heart transplant or ventricular assist device within 6 
months 
• Life expectancy less than 12 months 
• Participation in any other investigational cardiac clinical investigation 
during the course of the study 
• Presence of another life-threatening, underlying illness separate from their 
cardiac disorder 
• Pregnant or breast-feeding at time of enrollment 
3.2 
Methods 
3.2.1 
eCRFs 
During the course of the clinical investigation all clinical procedures are 
performed according to clinical routine. All parameters and measurements that 
are recorded within the clinical investigation are described in this section and are 
documented on the following electronic Case Report Forms (eCRFs). Information 

 
  
  
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from electronically delivered source data (e.g. programmer interrogations, 
adverse event documentation) will be uploaded to the appropriate eCRF, then 
captured and stored in a validated environment until the end of the study. The 
investigator will be required to use an electronic signature to approve the content 
of the data reported in the eCRFs listed below.  
• Informed Consent 
• Enrollment  
• Demographics Indications 
• Comorbidities Medication 
• Implantation 
• Device Measurements 
• Follow-up Visit (routine and interim) 
• Threshold Test 
• Study Termination 
• Adverse Event 
• Device Complaint 
• Informed Consent Update 
• Protocol Noncompliance 
• Study Termination 
• System Revision 
BIOTRONIK, Inc. will audit and monitor the content of the eCRFs as described in 
Section 9.  The required procedures and corresponding time schedule for eCRF 
completion is described in Section 3.4  
All data have to be available for source data verification during monitoring visits 
of the sponsor. Subjects have to consent to the use of their medical data prior to 
enrollment by signing the informed consent form. 
3.2.2 
Subject Demographics, Comorbidities and Medications 
After the informed consent has been obtained, demographic information 
including year of birth, gender, height and weight should be gathered for all 
subjects. 
Furthermore, details regarding illnesses, ECG diagnostics (if obtained within 6 
months prior to enrollment), most recent LVEF, the assessment of the current 
NYHA class, the device therapy indication, comorbidities and current 
cardiovascular medication should be collected. 

 
  
  
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3.2.3 
Implantation Information 
All devices are identifiable by a unique 8-digit serial number which will be 
collected on the implantation eCRF. In addition, the following implantation 
information will also be collected: 
• Implanted devices (manufacturer, model, serial number) 
• Implantation site and, if available, implant approach 
• Upgrade information from pacemaker/ICD 
• Information about LV lead implantation (date of implantation) 
• Sentus QP lead implant success  
• Approximate vessel diameter at Sentus QP lead tip (at final lead position, 
when this information is available from a routine venogram performed 
during implant) 
Note: The implantation of the Sentus QP LV lead is considered ‘unsuccessful’ if an attempt was 
made to place the lead but it could not be placed in a stable position for any reason. 
3.2.4 
Device Settings 
The device programming must be medically reasonable. Recommended device 
settings for participation in this clinical trial are summarized in the following table 
(Table 3): 
Table 3: Recommended Device Settings 
Parameter 
Recommended device settings 
BIOTRONIK Home Monitoring® 
ON 
Capture control LV lead 
ON or ATM 
Pacing configuration 
BiV 
LV MultiPole Pacing 
OFF* 
*In order to support the CRT responder assessment for enrollment into the 
MPP sub-study, the MPP feature should not be programmed ON prior to the 
6-month follow-up (or the 3-Month follow-up for subjects consented for the 
MPP sub-study due to a HF hospitalization event).   
3.2.5 
CRT Based Lead Measurements 
At implantation, pre-hospital discharge/wound check, 3-, 6- and 12-month follow-
up, and the additional required visits every 6 months to 60 months post-implant, 
documentation of the mean sensing amplitude, the pacing threshold and the 
impedance is required for the LV channel at beginning of device interrogation. 
The pacing threshold can be measured either manually or triggered 
automatically.  

 
  
  
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The LV pacing threshold is considered elevated if the threshold is greater than 
2.5 V at 0.4 ms. The LV lead impedance is considered ‘out of range’ if a 
measurement is < 200 Ohms or > 3000 Ohms. The LV sensing threshold is 
considered ‘out of range’ if a measurement is lower than 2 mV.  
The electronic programmer file with the stored measurements is used for source 
data verification.  
3.2.6 
LV Pacing Threshold Measurement in Novel Vectors 
At pre-hospital discharge/wound check and 3-month follow-up the LV pacing 
threshold at each of the following novel pacing vectors (vectors utilizing the two 
proximal LV rings) at 0.4 ms may be determined (optional).  
Table 4: Novel Pacing Vectors 
Sentus QP Novel 
Pacing Vectors 
From (-) → To (+) 
LV1 tip → LV4 ring 
LV2 ring → LV4 ring 
LV3 ring → LV2 ring 
LV3 ring → LV4 ring 
LV3 ring → RV coil 
LV4 ring → LV2 ring 
LV4 ring → RV coil 
The physician is free to test the other vectors, including the available standard 
vectors. All measured values can be documented in the eCRF. A maximum of 12 
vectors are available for testing (see Section 1.3.2). 
Please note: Following completion of the pacing threshold test, the permanent pacing vector can 
be programmed according to physicians’ medical opinion independent of the threshold 
measurement test. 
3.2.7 
Adverse Events and Device Complaints 
The investigator has to record any reportable adverse event, or device complaint 
which occurs during study duration on the corresponding eCRF. The adverse 
event will be classified according to the seriousness, the relation to the 
investigational devices and to the procedure. Reportable adverse events and the 
definitions  event classification are described in Section 6.  
3.3 
Number of Investigational Devices to be Used 
In the QP ExCELs study, 314 Sentus QP leads are expected to be successfully 
implanted for the pre-market cohort, which equals one device per subject. 
However, additional investigational devices may be used due to left ventricular 
lead exchange during the study. Additional Sentus QP leads will be implanted 

 
  
  
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during the IDE to satisfy the post-approval cohort.  All Sentus QP leads 
implanted during the ongoing IDE are considered investigational until FDA 
approval of the Sentus QP lead is received. 
3.4 
Study Procedures 
Subjects who have a successful lead implant will be evaluated at pre-hospital 
discharge or wound check and then seen for in-office evaluations at 3, 6, and 12 
months post-implant. Thereafter, subjects enrolled will be seen for follow-up visits 
every 6 months until 60 months post implant. 
Figure 8 provides an overview of the clinical study design. Details of subject 
eligibility requirements are noted in Sections 3.1.3 and 3.1.4. Details of other 
specific study procedures and collected data are noted in Section 3.2.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
  
  
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Figure 8: Clinical Study Design 
 
Assessments of the lead performance are required at pre-hospital discharge or 
wound check, 3 months post-implant, 6 months post-implant, 12 months post-
implant, and every 6 months until 60 months post-implant. The windows 
associated with each visit are provided below in Table 5. This schedule should 
be followed as closely as possible. If circumstances prevent the presence of the 
subject at the follow-up visit, the reason for the missed follow-up has to be 
indicated on the eCRF. In addition interim evaluations for Sentus QP lead-related 
complications or system revisions will be performed. 

 
  
  
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Table 5: Required Visit Windows 
Visit Type 
Window 
Days post-implant 
Pre-hospital discharge or wound check 
N/A 
0 to 45 
3 months post-implant 
± 30 days 
61 to 121 
6 months post-implant 
± 45 days 
137 to 227 
12 months post-implant 
± 45 days 
320 to 410 
18 months post-implant 
± 45 days 
503 to 593 
24 months post-implant 
± 45 days 
685 to 775 
30 months post-implant 
± 45 days 
868 to 958 
36 months post-implant 
± 45 days 
1051 to 1141 
42 months post-implant 
± 45 days 
1234 to 1324 
48 months post-implant 
± 45 days 
1417 to 1507 
54 months post-implant 
± 45 days 
1600 to 1690 
60 months post-implant 
± 45 days 
1783 to 1873 
3.4.1 
Overview of Study Procedures 
Table 6 displays an overview about the study procedures at the different visits 
which are described in detail afterwards.  
 

 
  
  
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Table 6: Procedures by Visit Type 
Procedures 
Enrollment  
Implant 
 
Pre-
hospital 
discharge 
& 3 Month 
Follow-up 
6 Month 
Follow-up 
through 60 
Month 
Follow-up* 
Interim 
Follow-
up† 
Informed consent 
X 
 
 
 
 
Verification of inclusion and 
exclusion criteria 
X 
 
 
 
 
Demographic data and 
comorbidities 
X 
 
 
 
 
NYHA class and heart failure 
symptoms 
X 
 
 
 
 
ECG and ECHO values (if 
performed routinely) 
X 
 
 
 
 
Co-morbidities 
X 
 
 
 
 
Cardiovascular medication 
X 
 
 
 
 
CRT-D implantation 
 
X 
 
 
 
Implantation information 
 
X 
 
 
X 
Vessel diameter at lead tip 
 
X 
 
 
 
Programming of device settings 
 
X 
 
 
 
Standard device evaluation 
 
X 
X 
X 
X 
Extended device evaluation with 
novel pacing vector (optional) 
 
 
X 
 
 
Adverse event reporting  
X 
X 
X 
X 
X 
Completion of eCRFs 
X 
X 
X 
X 
X 
† Interim follow-ups may be collected when related to an AE or a system revision. Implant 
information only needs to be collected if a system revision has occurred. 
3.4.2 
Enrollment 
Prior to enrollment, the physician selects potential candidates which are eligible 
for the clinical investigation. If the potential subject meets all inclusion and 
exclusion criteria (see Sections 3.1.3 and 3.1.4), the potential subject is informed 
on the study and asked to read and sign an Informed Consent Form. The 
potential subject should be provided with sufficient time to consider participation 
in the trial. Afterwards a detailed recording of data being evaluated during the 
clinical investigation is possible. A subject is considered enrolled in the QP 
ExCELs study upon signing the Informed Consent Form and meeting the 
inclusion/exclusion criteria at time of consent. Enrolled subjects must be entered 
in the subject enrollment log. The consent process should be documented within 
the subject’s medical record. 

 
  
  
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After informed consent has been obtained, the following data should be collected 
for baseline evaluation: 
1. 
Demographic characteristics (year of birth, gender, height, weight) 
2. 
Device therapy indication 
3. 
ECG diagnosis, if routinely performed 
4. 
Current NYHA class and most recent LVEF 
5. 
Comorbidities and cardiac medications 
The Enrollment eCRF needs to be completed using the data collected during the 
enrollment visit.  
3.4.3 
Implantation 
Implantation occurs after enrollment of the subject. 
At implantation, the following procedures/data are required: 
1. 
Implanted devices (manufacturer, model, serial number). 
2. 
Implantation procedure information (see Section 3.2.3). 
3. 
Sentus QP lead implant success. 
4. 
Approximate vessel diameter at Sentus QP lead tip (at final lead position, 
when this information is available from a routine venogram performed 
during implant). 
5. 
Activation of the recommended device settings as listed in Section 3.2.4. 
6. 
Sentus QP lead  evaluation from implant procedure: 
• Determine LV lead impedance 
• Determine LV mean R-wave sensing amplitudes 
• Determine LV pacing threshold at 0.4 ms pulse width for the pacing 
vector programmed at the end of implantation 
7.  
Plexa ICD lead evaluation from implant procedure (if Plexa ICD lead is 
implanted with initial Sentus QP lead): 
• Determine Plexa ICD lead R-wave sensing amplitude 
• Determine Plexa ICD lead pacing threshold at 0.4 ms pulse width 
• Determine Plexa ICD lead pacing impedance 
• Determine Plexa ICD lead shock impedance 
8. 
9. 
Device programming and settings at end of implantation procedure. 
Store the electronic procedure data (including final device settings, 
measurements, episodes) of the BIOTRONIK programmer on an 
appropriate USB flash drive. 

 
  
  
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10. Complete the Implantation eCRF using data collected during implant and 
information from the end of procedure device evaluation. 
11. Document any reportable adverse event (e.g. phrenic nerve stimulation, 
high LV pacing threshold, etc.) or device complaint during the procedure by 
using the respective eCRF. Please adhere to the reporting timelines listed in 
Section 10.2. 
Please note: 
1. 
If a Sentus QP implantation was planned but not performed or the implant procedure was 
initiated but the Sentus QP lead did not come in contact with the subject, the subject will be 
exited from the clinical investigation using a Study Termination eCRF. 
2. 
If an attempt to implant a Sentus QP lead was made and the lead came in contact with 
subject but implantation was not successful, reportable adverse events related to the 
implant attempt will be collected and the subject will be exited from the clinical investigation 
using a Study Termination eCRF. 
3. 
If the investigator decided to repeat the implantation of the Sentus QP lead, the final 
successful implantation is documented on the Implantation eCRF. Please complete 
Adverse Event or Device complaint eCRF for the first unsuccessful attempt (attempt = 
Sentus QP lead came in contact with subject). 
3.4.4 
Pre-hospital Discharge/Wound Check and 3-month Follow-up 
As the analysis of secondary endpoint 2 is complete, additional LV pacing 
threshold testing using the novel pacing vectors is optional at the pre-hospital 
discharge/wound check and the 3 month post-implant follow-up. The pre-hospital 
discharge/wound check visit occurs after successful device system implantation 
and either prior to the subject’s discharge from the hospital or at a routine wound 
check visit (occurring no later than 45 days after implantation). Three (3) months 
(± 30 days) after implantation, subjects return to the investigational site for an in-
office assessment of their implanted system. For both visits the CRT-D system 
should be assessed.  
The following requirements have to be fulfilled and the data have to be 
documented on the Pre-hospital Discharge/Wound Check eCRF or 3-month 
Follow-up eCRF, respectively: 
1. 
Standard Sentus QP lead evaluation: 
• Determine LV lead impedance 
• Determine LV lead R-wave sensing 
• Determine LV pacing threshold at 0.4 ms pulse width for the pacing 
vector programmed at the beginning of the device interrogation 
2. 
Plexa ICD lead evaluation from implant procedure (if Plexa ICD lead is 
implanted with initial Sentus QP lead): 
• Determine Plexa ICD lead R-wave sensing amplitude 
• Determine Plexa ICD lead pacing threshold at 0.4 ms pulse width 

 
  
  
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• Determine Plexa ICD lead pacing impedance 
• Determine Plexa ICD lead shock impedance  
 
3. 
Novel pacing vector evaluation, if performed 
• Measure the LV pacing threshold with 0.4 ms pulse width 
4. 
Check the activation of the recommended device settings (Section 3.2.4). 
5 
 
Screen/Enroll subject for MPP Sub-Study if prior HF Hospitalization event 
(3-month Follow-up Only) → Refer to Protocol Section 11 
6. 
7. 
Device programming and settings at end of follow-up. 
At pre-hospital discharge or wound check, register the subject in the 
Home Monitoring Service Center. 
8. 
Store the electronic procedure data (including final device settings, 
measurements, episodes) of the BIOTRONIK programmer on an 
appropriate USB flash drive. 
9. 
Complete the electronic Pre-hospital Discharge/Wound Check or 3-month 
Follow-up eCRF. 
10. 
Document any reportable adverse event (e.g. phrenic nerve stimulation, 
high LV pacing threshold, etc.) or  device complaint by using the 
respective eCRF. Please adhere to the reporting timelines listed in 
Section 10.2. 
Please note: Phrenic nerve stimulation occurring during the left ventricular threshold test and not 
leading to any serious medical symptoms are not considered adverse events and thus do not 
need to be reported in an Adverse Event eCRF. 
 
 
In order to support the CRT responder assessment for enrollment into the 
MPP sub-study, the MPP feature should not be programmed ON prior to the 
6-month follow-up (or the 3-month follow-up for subjects consented for the 
MPP sub-study due to a HF hospitalization event).   
3.4.5 
6-month Follow-up and 12-month Follow-up 
Six (6) months (± 45 days) and 12 months (± 45 days) after implantation, 
subjects return to the investigational site for an in-office assessment of their 
implanted system.  
The following data should be collected: 
1. 
Standard Sentus QP lead evaluation: 
• Determine LV lead impedance 
• Determine LV lead R-wave sensing amplitude  
• Determine the LV pacing threshold at 0.4 ms pulse width for the 

 
  
  
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programmed pacing vector  
2. 
 
 
 
 
 
3. 
Plexa ICD lead evaluation from implant procedure (if Plexa ICD lead is 
implanted with initial Sentus QP lead): 
• Determine Plexa ICD lead R-wave sensing amplitude 
• Determine Plexa ICD lead pacing threshold at 0.4 ms pulse width 
• Determine Plexa ICD lead pacing impedance 
• Determine Plexa ICD lead shock impedance 
Screen/Enroll Subject for MPP Sub-Study (6-Month Follow-up Only) → 
Refer to Protocol Section 11 
4. 
Device programming and settings at end of follow-up. 
5. 
Store the electronic procedure data (including final device settings, 
measurements, episodes) of the BIOTRONIK programmer on an 
appropriate USB flash drive. 
6. 
Complete the appropriate Follow-Up eCRF. 
7. 
Document any reportable adverse event (e.g. phrenic nerve stimulation, 
high LV pacing threshold, etc.), or device complaint by using the respective 
eCRF. Please adhere to the reporting timelines listed in Section 10.2. 
Any subject not enrolled into the MPP sub-study may only have the MPP 
feature activated at the investigator’s discretion any time after the 6-Month 
follow-up if the subject is determined by the investigator to be a non-
responder. 
3.4.6 
Additional Visits Required Every 6 Months to 60 Months 
After completion of the 12-month follow-up visit, subjects enrolled at U.S. study 
sites will be followed every 6 months until 60 months post-implant. For subjects 
utilizing BIOTRONIK Home Monitoring®, study sites will have the option to 
substitute a BIOTRONIK Home Monitoring® evaluation for up to every other of 
these additional visits. BIOTRONIK Home Monitoring® evaluations will be 
accompanied by a phone assessment that is designed to document clinical signs 
and symptoms that identify a potential reportable adverse event, or device 
complaint. The phone assessment should occur within 7 days of the date of the 
BIOTRONIK Home Monitoring® report. Subjects utilizing BIOTRONIK Home 
Monitoring® assessments are still expected to be evaluated in-office at least once 
per year. 
The data collected for these additional visits is the same as required for the 6 and 
12 month evaluations (Section 3.4.5). For BIOTRONIK Home Monitoring® 
evaluations, a Summary Report created in the Home Monitoring Service Center 
will be used to store the required electronic procedure data. 

 
  
  
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3.4.7 
Interim Follow-up 
Interim follow-ups may occur anytime during the clinical investigation; however, 
those interim evaluations in support of lead or system related adverse events or 
system revisions may be collected in the clinical investigation. Interim follow-ups 
can be visits scheduled by physicians according to clinical routine, visits 
scheduled by the physician due to BIOTRONIK Home Monitoring® alerts or 
trends, or visits initiated by the subject. 
3.4.7.1 
 Adverse event related interim follow-up 
For interim follow-ups related to an adverse event, the data collected on the 
Interim Follow-up eCRF is the same as the 6 and 12 month evaluations (Section 
3.4.50). 
3.4.7.2 
System Revision 
For interim evaluations that involve a system revision (even if the Sentus QP lead 
is not directly affected), the following data is required: 
1. 
Implantation procedure information (date of intervention, information about 
new implanted devices). 
2 
Revised device (manufacturer, model, serial number). 
3. 
Sentus QP lead measurements during procedure: 
• Determine LV lead impedance 
• Determine LV lead R-wave sensing amplitudes 
• Determine LV pacing threshold at 0.4 ms pulse width for the pacing 
vector programmed at the end of intervention.  
4. 
Device programming and settings at end of intervention. 
5. 
Plexa ICD lead measurements during procedure (if Plexa ICD lead is 
implanted with initial Sentus QP lead): 
• Determine Plexa ICD lead R-wave sensing amplitude 
• Determine Plexa ICD lead pacing threshold at 0.4 ms pulse width 
• Determine Plexa ICD lead pacing impedance 
• 
Determine Plexa ICD lead shock impedance 
6. 
Store the electronic procedure data (including final device settings, 
measurements, episodes) of the BIOTRONIK programmer on an 
appropriate USB flash drive. 
7. 
Complete the electronic System Revision eCRF. 
8. 
Document any reportable adverse event (e.g. phrenic nerve stimulation, 
high LV pacing threshold, etc.), or device complaint during the procedure by 
using the respective eCRF. Please adhere to the reporting timelines listed in 

 
  
  
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Section 10.2. 
Please note: 
1. 
If the Sentus QP lead is explanted and the subject does not receive a new Sentus QP lead, 
the subject will be withdrawn from the clinical investigation. 
2. 
If the Sentus QP lead is replaced with another Sentus QP lead, the subject will continue 
participation in the clinical investigation based on the original implantation date and visit 
schedule. 
3. 
The subject will continue participation and time schedule will be unchanged if any other 
lead is replaced or if the CRT-D is replaced (even if replacement CRT-D is not 
BIOTRONIK). 
4. 
Please notice, whenever possible, BIOTRONIK devices that are explanted must be 
returned to BIOTRONIK, Inc. for analysis. 
3.4.8 
Study Termination 
The Study Termination eCRF must be completed to determine the end date and 
reason for study termination of the individual subject. The expected study 
termination for all subjects should not be earlier than the 60 month follow-up visit. 
Reasons for early study termination are described in Section 3.5.2. 
3.5 
Study Participation Expectations 
3.5.1 
Point of Enrollment  
A subject is considered enrolled in the QP ExCELs study upon signing the 
Informed Consent Form and meeting the inclusion/exclusion criteria at time of 
consent. 
3.5.2 
Reasons for Study Termination 
Once a subject is enrolled and successfully implanted, every effort should be 
made to continue to follow the subject in the clinical investigation. However, it is 
inevitable that some subjects will decline to participate further, change 
geographic location, or become non-compliant with the visit schedule. 
3.5.2.1 
No implant attempt  
If a Sentus QP implantation was planned but not performed or the implant 
procedure was initiated but the Sentus QP did not come in contact with the 
subject, the subject is exited. The reason for study termination must be provided.   
3.5.2.2 
Unsuccessful implant 
If a Sentus QP lead came in contact with the subject but could not be implanted, 
an adverse event or device complaint should be completed and the subject 
exited. Data for subjects that have a Sentus related adverse event according to 
the listing provided in Section 6 will be included in analysis.  

 
  
  
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3.5.2.3 
Withdrawal of subject consent 
Subjects may withdraw their consent for study participation at any time without 
stating the reason and without any unfavorable consequences. All data, which 
are collected until the date of withdrawal will be used for analysis. A Study 
Termination eCRF has to be completed by the investigator in which the reasons 
for withdrawal should be documented if willingly provided by the subject. 
3.5.2.4 
Subject death 
In the event of subject death during study participation, personnel at the 
investigational site are requested to notify BIOTRONIK, Inc. immediately by 
completing an Adverse Event eCRF (if applicable) and a Study Termination 
eCRF.  
The following information will be required for any subject death: 
• Death certificate, death report signed by the investigator, or relevant 
medical records that include: 
o Date of death 
o Primary cause of death 
o Any other circumstances surrounding the death 
o Whether death was device or procedure related 
• Sentus QP lead return status, if available 
Whenever possible, devices that are explanted must be returned to BIOTRONIK, 
Inc. for analysis. 
3.5.2.5 
Sentus QP lead extraction 
Any subject who has the Sentus QP lead explanted and not replaced with 
another Sentus QP lead will be withdrawn from the clinical investigation. After 
documentation of the system revision procedure (see Section 3.4.7.2), a Study 
Termination eCRF should be completed.  
Whenever possible, devices that are explanted must be returned to BIOTRONIK, 
Inc. for analysis. 
3.5.2.6 
Lost to follow-up 
Subjects lost to follow-up are those for whom contact is lost despite the 
investigator’s best efforts to locate the subject. Study sites should attempt to 
contact these subjects in order to maintain study visit compliance and all contact 
attempts should be documented. At a minimum, the site should make two 
attempts to contact the subject by phone and one attempt by certified mail. 
In the event the subject cannot be contacted using the above methods, the 
subject is terminated from the clinical investigation by completing a Study 
Termination eCRF.  

 
  
  
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3.5.3 
Date of Study Termination 
The expected study termination for all subjects should not be earlier than the 60 
month follow-up visit.  
For all early study terminations, the following rules apply: 
• In case of withdrawal of consent, date of study termination is the date of 
withdrawal of consent. 
• In case of subject death, the date of study termination is the date of death.  
• If subject is lost to follow-up, date of termination is the date of last 
documented contact with the subject. 
• If a Sentus QP implantation was planned but was never attempted, the 
date of termination is the date of decision not to implant. 
• If a Sentus QP implantation was initiated but not completed and the 
Sentus QP did not come in contact with the subject, date of unsuccessful 
implantation is date of study termination.  
• If an attempt to implant Sentus QP lead was made and lead came in 
contact with subject but implantation was ultimately not successful, date of 
study termination is date of unsuccessful implantation. 
• If the Sentus QP is explanted and not replaced with another Sentus QP, 
the date of study termination is the date the lead is explanted. 
Study related procedures and documentation should end at the day of study 
termination for the respective subject.  

 
  
  
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4. 
ADDITIONAL STUDY CONDITIONS 
4.1 
IRB Approval 
Institutional Review Board (IRB) approval is required for each study site 
according to local requirements and investigator prior to participation in this 
clinical study. Subject enrollment may not begin until both the IRB and 
BIOTRONIK, Inc. have granted approval for the study site. If IRB approval is 
withdrawn, BIOTRONIK, Inc. must be notified by the investigator within 5 working 
days.  
4.2 
Subject Consent 
Subject participation in this study is voluntary. All subjects must sign an IRB 
approved Informed Consent Form (ICF) prior to participation in the study. Subject 
informed consent must be obtained prior to enrollment or any protocol related 
procedures. To assist with the consent process, BIOTRONIK, Inc. will provide a 
template subject ICF to participating sites.  Subjects that qualify for the MPP sub-
study (Section 11) must sign a separate ICF prior to participating in the MPP sub-
study. 
4.3 
Data Collection 
4.3.1 
Electronic Data Capture (EDC) 
MedNet Solutions Incorporated is a privately-held company that specializes in 
web-based clinical data management technology. MedNet will host the EDC 
system and provide a secure environment that is accessible to authorized 
individuals through the internet. BIOTRONIK, Inc. will implement a study specific 
configuration using this software to meet the data collection requirements of the 
protocol. It is the platform for electronic case report form (eCRF) data entry, 
query management, and access to clinical data for parties authorized by 
BIOTRONIK, Inc.  
4.3.2 
Electronic Case Report Forms (eCRFs) 
Original data will be collected from each investigational site and recorded into the 
EDC system via completion of eCRFs. The investigator will be required to use an 
electronic signature to approve the content of the data reported in the eCRFs. 
BIOTRONIK, Inc. will audit and monitor the content of the eCRFs as described in 
Section 9. 
Information from electronically delivered source data (e.g. programmers) will be 
captured and stored in a validated environment until the end of the study. 
4.3.3 
BIOTRONIK Home Monitoring® Data 
In the QP ExCELs study, data of the study subjects will be accessible to the 
sponsor via transfer from the Home Monitoring Service Center during the course 

 
  
  
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of study participation of the respective subject. BIOTRONIK Home Monitoring® 
data might be used for evaluation and publication if desired by the sponsor. 
All data are transferred to the sponsor in a pseudonymized form. Data includes 
all information transmitted from the device (e.g. IEGMs, statistics, lead 
information). 
4.4 
Confidentiality of Subject Data 
Information sent to BIOTRONIK, Inc. pertaining to study subjects will be kept 
confidential at BIOTRONIK, Inc. and is subject to audit by IRB and other 
regulatory authorities. For reporting purposes, data collected from U.S. sites will 
be shared with BIOTRONIK SE & Co. KG. Information shared with BIOTRONIK 
SE & Co. KG will be kept confidential. Reports submitted to physicians and data 
presented in publications of study results will not make any reference to subject 
name. 
In order to verify the study data and ensure study integrity, monitors from 
BIOTRONIK, Inc., authorized personnel from BIOTRONIK SE & Co. KG, 
regulatory authorities, and the reviewing IRB may review and/or copy the study 
records.  
4.5 
Data Quality Control 
BIOTRONIK, Inc. will regularly review study data. At any time, reports can be 
generated on entered or missing data by BIOTRONIK, Inc. or by approved 
research personnel at each investigational site. The EDC system will be used to 
track received and expected visit data and eCRFs for each subject. This system 
also provides the capability to monitor the status, volume, and disposition of data. 
In addition, all study data will undergo extensive automatic edit and plausibility 
checks that provide information to the investigational sites to help improve and 
maintain data quality control procedures designed to detect inaccuracies and 
inconsistencies.  
4.6 
Deviations from Clinical Investigation Plan 
The investigator is required to conduct this study in accordance with the signed 
investigator agreement and clinical protocol. The investigator shall notify 
BIOTRONIK, Inc. and reviewing IRB in writing no later than 5 working days after 
any significant deviation from the clinical protocol that has occurred to protect the 
life or physical well-being of a subject in an emergency. Except in such 
emergency situations, prior approval by BIOTRONIK, Inc. is required for 
significant deviations from the clinical protocol.   
BIOTRONIK, Inc. categorizes protocol non-compliance instances as either 
protocol violations or protocol deviations. Both protocol violations and deviations 
will be reported in the interim and final clinical progress reports. 

 
  
  
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4.6.1 
Protocol Violations 
Protocol violations are defined as instances where the protocol requirements 
and/or regulatory guidelines were not followed, and are generally more serious in 
nature. Protocol violations are considered to potentially affect the scientific 
soundness of the study and/or the rights, safety, or welfare of subjects. Protocol 
violations include, but are not limited to, failure to obtain consent, unapproved 
investigator implanting an investigational device, and subject inclusion/exclusion 
violations.  
The investigator must notify the reviewing IRB of all protocol violations per the 
reporting requirements. In some instances, such as failure to obtain consent, the 
investigator should also seek guidance from the IRB to ensure the subject 
received appropriate information to consider their participation in the study.  
4.6.2 
Protocol Deviations 
Protocol deviations are defined as instances where the requirements of the 
protocol were not followed in such a manner whereby data is unusable or 
unavailable. Protocol deviations are less serious in nature and may not require 
IRB notification as long as they do not affect the rights, safety, or welfare of the 
study subject.  
4.7 
Subject Retention 
BIOTRONIK, Inc. will provide additional tools to the sites in an effort to minimize 
the number of subjects that are lost to follow-up. This includes an overview of 
each subject’s visit schedule, including the windows for each visit as they 
become due. The visit schedule reporting allows research personnel to become 
alerted to and track all study subjects that should be scheduled for upcoming 
study evaluations.  
In addition, BIOTRONIK, Inc. monitors will review subjects, including those that 
may be lost to follow-up, to ensure protocol and study visit compliance. 
4.8 
Study Completion 
BIOTRONIK, Inc. will notify the U.S. study site upon completion or termination of 
the clinical investigation or of the investigator’s participation. BIOTRONIK, Inc. 
will provide a Clinical Investigation Report to each investigational site. 
BIOTRONIK, Inc. will also determine which sites will have an on-site close out 
visit and provide details on closure activities to all investigators to ensure the 
investigator understands any applicable regulatory requirements, including those 
related to record retention.  
4.9 
Labeling and Control of the Investigational Devices 
For all sites, the investigational leads and associated components will have a 
label that will be visible on the pertinent shipping cartons and storage containers. 
The required labels or manuals will bear the following information: 

 
  
  
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• Model and serial number of the investigational device (where appropriate) 
• Name of the investigational device and the address of BIOTRONIK SE & 
Co. KG as the manufacturer 
• Labeling statement: Caution: Investigational Device. Limited by United 
States law to investigational use. 
• All relevant contraindications, hazards, adverse device effects, interfering 
substances or devices, warning and precautions. 
BIOTRONIK, Inc. will control the investigational devices within the U.S. by 
distributing those devices only to approved investigational centers and approved 
investigators. BIOTRONIK, Inc. will also keep records that indicate the place and 
date of shipment. Devices are not transferrable between investigators unless 
prior approval is obtained from BIOTRONIK, Inc. 
Upon receipt of FDA approval of the Sentus QP lead, this section will no longer 
be applicable. 
 
 
 
 
 
 
 
 
 
 
 

 
  
  
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5. 
STUDY OVERSIGHT 
5.1 
Clinical Events Committee 
A Clinical Events Committee (CEC) consisting of at least 3 independent 
Electrophysiologists or Cardiologists (with CRT experience) will be established to 
review and adjudicate all protocol defined adverse events reported by the 
investigational sites related to:  
1. Lead or generator adverse event resolved by surgical reposition, surgical 
explanation, surgical replacement, surgical abandonment, or if other lead-
related surgery is performed 
2. Adverse event related to clinical lead failure, electrical lead failure, or 
mechanical lead failure, regardless of action taken.  This includes PNS 
resolved by electrical abandonment and disabled pacing 
3. Any major implant procedure related event that meets the criteria of a 
serious adverse event 
4. (MPP Sub-Study Only, see Section 11.3.4) MPP sub-study related events. 
Protocol defined adverse events that do not meet these criteria for CEC 
adjudication (e.g. reprogramming pacing output due to high LV threshold without 
a suspected or confirmed lead failure) will be included in the clinical report based 
on site-reported information.   
The CEC will be blinded to the investigational site and subject identity, and to 
minimize bias members will not participate as investigators. The CEC will create 
a study specific charter defining the adverse event adjudication process, 
specifically detailing review guidelines along with appropriate response timelines. 
Adverse events meeting the criteria described above will be adjudicated by the 
Clinical Events Committee. The Clinical Events Committee (CEC) will have the 
responsibility to adjudicate the classification, category, seriousness, and 
resolution of each reported adverse event In addition, the CEC will also indicate 
whether the adverse event is related, possibly related, not related, or has an 
unknown relation to the Sentus QP lead or Plexa ICD lead. The CEC will decide 
for each event on the inclusion to the primary endpoint 3 analysis according to 
the definition for endpoint 3 relevant adverse events as documented in Section 
6.6.2. 
The Clinical Events Committee is responsible for: 
• Endpoint adjudication of adverse events meeting the criteria above 
• Adjudication meetings, as needed, via telephone conference or face-to-
face 
• Final decision on inclusion of each adverse event in the primary endpoint 
3 analysis according to the definition provided in Section 6.6.2. 
• Regular reporting of adjudication results to the sponsor 

 
  
  
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The Clinical Events Committee will be supported by members of the sponsor in 
pre-selection of device complications from non-device related adverse events 
(e.g. broken leg, headache, cancer) and in organizational tasks. 

 
  
  
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6. 
ADVERSE EVENTS 
In the course of the clinical investigation, undesired medical events can occur in 
participating subjects, which are called adverse events (AEs). Furthermore, 
device deficiencies (DD) or complaints may also be observed. All AEs and device 
complaints of the investigational device shall be assessed by the investigator and 
shall be documented and reported throughout the clinical investigation.  
The investigator shall submit to the sponsor all reportable events using the 
respective eCRFs provided within the EDC system.  
Based on literature research, the adverse events listed in Appendix B may 
possibly occur as medical complications of a cardiac rhythm management 
system implant. 
6.1 
Definitions 
6.1.1 
Definition of Adverse Event 
An AE is defined as any untoward medical occurrence, unintended disease or 
injury, or untoward clinical signs (including abnormal laboratory findings) in 
subjects, users or other persons whether or not related to the investigational 
medical device. This includes: 
• Events related to the investigational medical device or the comparator 
• Events related to the procedures involved  
• For users or other persons, this definition is restricted to events related to 
the investigational medical devices.  
6.1.2 
Definition of Adverse Device Effect 
An adverse device effect (ADE) is an AE that is related to the use of an 
investigational medical device. This includes any AE resulting from insufficient or 
inadequate instructions for use or the deployment, implantation, installation, or 
operation, or any malfunctioning of the investigational device and any event 
resulting from use error or from unintentional misuse of the investigational 
device.  
Adverse events, which result from the required medical procedures involved, 
when implanting, using or testing the respective investigational device, even if 
not directly related to the device (e.g. anesthetic complications, wound healing 
disturbances, lead perforation, etc) are considered ADEs. 
Three categories for classification of relationship to the investigational device 
and/or procedure are available: 
• Clearly not related: A relationship of the AE to the investigational device 
and / or procedure can be excluded. 

 
  
  
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• Possibly related:  
It cannot be excluded that there is a connection with 
the device under investigation and / or the procedure.  
• Clearly related:  A relationship of the AE to the investigational device 
and/or procedure is likely/sure. 
6.1.3 
Definition of Unanticipated Adverse Device Effect 
As defined in 21 CFR Part 812.3, an unanticipated adverse device effect is any 
serious adverse effect on health or safety or any life-threatening problem or 
death caused by, or associated with, a device, if that effect, problem or death 
was not previously identified in nature, severity or degree of incidence in the 
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. 
A listing of previously identified adverse events along with anticipated frequency 
is provided in Appendix B. It is important to note that random component failures 
or problems caused by misuse of the product are not considered unanticipated 
adverse device effects.  
6.1.4 
Serious AEs, ADEs, and UADEs 
AEs, ADEs, and UADEs are classified as serious if one or more of the following 
consequences are fulfilled: 
• led to death 
• led to serious deterioration in the health of the subject, that either resulted 
in 
o a life-threatening illness or injury, or 
o a permanent impairment of a body structure or a body function, or 
o in-patient or prolonged hospitalization, or 
o medical or surgical intervention to prevent life-threatening illness or 
injury or permanent impairment to a body structure or a body 
function. 
• led to fetal distress, fetal death or a congenital abnormality or birth defect. 
Note: Planned hospitalization for a pre-existing condition, or a procedure required by the 
protocol, without serious deterioration in health, is not considered a serious adverse event. 
In-patient hospitalization is defined as at least one overnight stay (change of 
date) in a hospital. Events for which subjects are hospitalized for less than 24 
hours without change of date will not be documented as serious, unless one or 
more of the other seriousness criteria are fulfilled.  
6.1.5 
Definition of Device Complaint 
Device complaint is defined as any written, electronic, or oral communication that 
alleges deficiencies related to the identity, quality, durability, reliability, safety, 

 
  
  
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effectiveness, or performance of a device after it is released for distribution [21 
CRF 820 3(b)].  
6.2 
Reporting Adverse Events 
The investigator shall report to the sponsor, by completing the appropriate eCRF, 
the following types of events: 
• all adverse events related to or possibly related to 
o investigational device 
o implanted system 
• any major adverse events related to procedures involved with implanting, 
using, or testing the investigational device (see examples in Section 6.3 
and definitions in Appendix A: Definition of Terms) 
• any adverse device effects, regardless of severity and including both 
previously reported and unanticipated adverse events  
• (MPP Sub-Study Only, see Section 11.5.4) any cardiovascular 
hospitalizations and any other hospitalizations in which cardiovascular 
symptoms occur on or before the date of the 12-Month follow-up  
•  (MPP Sub-Study Only, see Section 11.5.4) all adverse events that require 
additional invasive intervention to resolve, specifically related to the MPP 
feature of the CRT-D.  These adverse events include any software issues 
related to MPP programming for any adverse event that occurs while MPP 
is enabled and that may be attributed to the use of the MPP feature. 
 (Please note: Phrenic nerve stimulation is an expected event during left ventricular threshold 
testing. As the Sentus QP lead allows for measurements in up to 12 different vectors, phrenic 
nerve stimulation might be a common observation in this study. Therefore phrenic nerve 
stimulation during threshold testing is only considered a reportable adverse event if serious 
medical symptoms occur. 
 
Events will be reported on an Adverse Event eCRF or a Device Complaint eCRF, 
as appropriate. Events should be reported as information is available, even if this 
results in an incomplete eCRF. The investigator must follow-up all ongoing 
reportable events either as long as the subject participates in the clinical 
investigation, the clinical investigation is terminated, or until the event has been 
resolved, whatever comes first. 
The investigator must characterize each event by a single primary diagnosis. The 
primary diagnosis may describe an event consisting of several clinically 
recognizable features, symptoms or secondary diagnoses. Note: The observed 
symptoms and secondary diagnoses must be properly documented in the 
respective eCRF.  
Multiple events may occur simultaneously in one subject. For each medically 
independent event with a primary diagnosis an individual report must be 
provided. 

 
  
  
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In addition, the action taken/treatment should also be provided with any 
supportive documentation available.  
The investigator has to ensure that all relevant information is available. This also 
includes information from other parties (family, other hospitals, etc.).  
If a patient dies during the clinical investigation, the investigator shall document 
the cause of death, circumstances and place of death. All actions taken, which 
were initiated to gain further information must be documented in writing and 
provided to BIOTRONIK, Inc. 
Investigators are required to adhere to applicable regulations and reviewing IRB 
reporting requirements for adverse events. 
6.3 
Examples of Reportable Adverse Events 
The following are examples of potential reportable adverse events and do not 
limit the required adverse event reporting as defined in Section 6.2. 
 
Examples of reportable lead related events 
o Ablation sequelae (such as lead dislodgement or 
damage during an ablation) 
o Cardiac perforation occurring post implant 
o Clinical lead failure 
o High pacing threshold 
o Extracardiac stimulation (e.g. phrenic nerve 
stimulation) 
o Electrical lead failure 
o Intermittent capture 
o Lead abrasion 
o Lead dislodgement or migration (not occurring 
during a procedure) 
o Lead impedance out of range, high impedance 
o Lead impedance out of range, low impedance 
 
o Lead fracture or insulation damage 
o Lead undersensing 
o Lead-related thrombosis 
o Loss of sensing 
o No capture 
o Mechanical lead failure 
o Muscle or nerve stimulation 
o Twiddler’s syndrome 
o Unsuccessful Sentus QP lead implant (unless due to a device 
complaint not leading to AE) 
o Lead repositioned, explanted, or replaced for any other reason 
Examples of reportable system or pulse generator related 
events 
o Device extrusion 
o Device migration 
o Inappropriate detection of arrhythmias 
o Inappropriate therapy or shocks 
o Inability to defibrillate or pace 
o Myopotential sensing 
o Pacemaker mediated tachycardia 
 
o Premature battery depletion 
o Pulse generator failure 
o Shunting current or insulating myocardium during defibrillation 
with internal or external paddles 
o Skin erosion 
o Pulse generator repositioned, explanted, or replaced for any 
other reason 
Examples of reportable major implant related events 
o Air embolism 
o Anesthetic complications 
o Allergic reaction to components used at implant or 
during lead testing,  
or to components of the lead 
o Arrhythmias associated with implant 
o Arteriovenous fistula 
o Body rejection phenomena 
o Cardiac perforation with or without tamponade 
associated with lead implant 
o Chronic nerve damage 
o Coronary sinus dissection 
o Damage to lead during a procedure 
o Fluid accumulation 
o Heart valve damage 
o Major Hematoma 
o Infection 
o Keloid formation/fibrotic tissue formation 
o Lead dislodgement of chronic leads that occurs during a 
procedure 
o Loose set-screw 
o Myocardial damage 
o Non-healing pocket dehiscence or other wound healing 
disturbance 
o Pericardial effusion 
o Pericarditis 
o Phlebitis 
o Pleural effusion 
o Pneumothorax associated with lead implant 
o Pulmonary embolism associated with the implant procedure 
o Respiratory arrest 
o Venous occlusion associated with the implant procedure 

 
  
  
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o Hemothorax 
o Incorrect lead connection with pulse generator 
 
 
6.4 
Adverse Event Reporting Timelines 
If an unanticipated adverse device effect occurs, then the investigator is required 
to notify the sponsor and the reviewing IRB as soon as possible but no later than 
10 working days after the investigator first learns of the event. If the event is 
serious or life threatening, the sponsor must be notified within 2 calendar days. 
The sponsor will conduct an immediate evaluation of any unanticipated adverse 
device effects. Devices that are returned to BIOTRONIK, Inc. will be sent to 
BIOTRONIK SE & Co. KG in Berlin, Germany for analysis.  Those analyses will 
be trended (as appropriate) and reported to FDA as soon as they are available. 
The sponsor will notify the FDA, all reviewing IRBs, and participating 
investigators within 10 working days after notification of the event by the 
investigator, as required by FDA regulations. 
All other events should be reported to the sponsor as soon as information is 
available.  
6.5 
Sponsor Reporting 
To ensure reporting requirements are met during the study, adverse event 
information reported for all study sites, will be reviewed by BIOTRONIK to ensure 
specific reporting requirements are met.  
As such, unanticipated adverse device effects identified will be reported to FDA, 
all reviewing IRBs, and participating investigators per the standard requirements 
and timelines. 
6.6 
Adverse Events for Primary Endpoint Analysis 
The complication-free rate calculated for primary endpoint 1 will be based on the 
total number of subjects with at least one ADE. For the primary endpoint 
analysis, the AE classification, category, resolution and relation to the 
investigational device (Sentus QP lead) for each individual event will be 
determined by the Clinical Events Committee (CEC) (see Section 5.1). 
All adverse events that meet the primary endpoint criteria (Section 6.6.1) and for 
which the CEC determines the event is related or possibly related to the Sentus 
QP lead will be included in the primary endpoint event analysis. Adverse events 
with a final CEC adjudicated relation of not related or unknown will not contribute 
to or be included in the evaluation of the primary safety endpoint.  
6.6.1 
Adverse Events Included in Primary Endpoint 1 
ADEs related to the Sentus QP lead and resolution combinations that will be 
analyzed as part of the primary endpoint 1 (
SentusQP
on
Complicati
p
) are presented in Table 7. 

 
  
  
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Combinations marked with an “X” will be included but are not limited to the 
primary endpoint 1 analysis. All Sentus QP related ADEs meeting the below 
criteria occurring after successful implantation until the 6-month post-implantation 
visit will be included. 
 
Table 7: Adverse Event/Resolution Combinations for Primary Endpoint 1 Analysis 
Resolution 
Clinical lead failure 
Electrical lead failure 
High pacing threshold 
Extracardiac stimulation 
Intermittent capture 
Lead dislodgement 
Lead impedance out of range, high 
Lead impedance out of range, low 
Lead undersensing 
Lead-related thrombosis 
Loss of sensing 
Mechanical lead failure 
No capture 
Lead surgically repositioned 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lead surgically explanted 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lead surgically replaced 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lead surgically abandoned 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Other lead-related surgery performed 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lead pacing polarity or mode 
reprogrammed* 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Lead electrically abandoned and pacing 
disabled 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
Lead use continued based on medical 
judgment 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
*Adverse events resolved by reprogramming of pacing polarity or pacing mode are only included 
in primary endpoint 1 analysis in cases of electrical or mechanical lead failure. Other adverse 
events, such as extracardiac stimulation, which are resolved by reprogramming are excluded. 
In addition, the following procedure-related adverse events will be included in the 
analysis of primary endpoint 1: 
• Pneumothorax directly associated with the Sentus QP lead 

 
  
  
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• Cardiac perforation with or without tamponade caused by the Sentus QP 
lead 
• Coronary sinus dissections directly caused by the Sentus QP lead (e.g., 
dissections caused by lead delivery device are excluded) 
Finally, subject deaths resulting from a Sentus QP lead-related AE will be 
included in the primary endpoint analysis. 
 
6.6.2 
Adverse Events Included in Primary Endpoint 3 
ADEs related to the Sentus QP lead and resolution combinations that will be 
analyzed as part of the primary endpoint 3 (
SentusQP
on
Complicati
p
) are presented in Table 8. 
Combinations marked with an “X” will be included but are not limited to the 
primary endpoint 3 analysis. All Sentus QP related ADEs meeting the below 
criteria occurring after successful implantation until the 60-month post-
implantation visit will be included. 

 
  
  
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Table 8: Adverse Event/Resolution Combinations for Primary Endpoint 3 Analysis 
Resolution 
Clinical lead failure 
Electrical lead failure 
High pacing threshold excluding 
events within 45 days of implant or 
lead revision 
Extracardiac stimulation 
Intermittent capture excluding events 
within 45 days of implant or lead 
revision 
Lead dislodgement >45 days post-
implant or lead revision 
Lead impedance out of range, high 
Lead impedance out of range, low 
Lead undersensing 
Lead-related thrombosis 
Loss of sensing 
Mechanical lead failure 
No capture excluding events within 
45 days of implant or lead revision 
Lead surgically repositioned 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lead surgically explanted 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lead surgically replaced 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lead surgically abandoned 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Other lead-related surgery 
performed 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lead pacing polarity or mode 
reprogrammed* 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Lead electrically abandoned 
and pacing disabled 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
Lead use continued based on 
medical judgment 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
*Adverse events resolved by reprogramming of pacing polarity or pacing mode are only included 
in primary endpoint 3 analysis in cases of electrical or mechanical lead failure. Other adverse 
events, such as extracardiac stimulation, which are resolved by reprogramming are excluded. 
In addition, the following adverse events will be included in the analysis of 
primary endpoint 3: 
• Pneumothorax directly associated with the Sentus QP lead 
• Cardiac perforation with or without tamponade caused by the Sentus QP 
lead 
• Coronary sinus dissections directly caused by the Sentus QP lead (e.g., 
dissections caused by lead delivery device are excluded) 

 
  
  
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Finally, subject deaths resulting from a Sentus QP lead-related AE will be 
included in the primary endpoint analysis. 
 

 
  
  
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7. 
OTHER INSTITUTIONS AND PHYSICIANS 
This clinical study is not transferable to other institutions attended by the 
investigator unless prior approval is obtained from both BIOTRONIK, Inc. and the 
appropriate IRB. Only approved investigators are authorized to participate in the 
clinical investigation. However, there are certain situations where an investigator 
might not be immediately available to provide the necessary medical care for a 
subject enrolled in the clinical investigation (such as a subject emergency room 
visit for medical treatment) in these instances a protocol deviation will not be 
issued and all available data will be utilized. 
In case technical support is needed the service hotline of BIOTRONIK, Inc. is 
available 24 hours a day. Phone: 1-800-547-0394. 

 
  
  
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8. 
RISKS AND BENEFITS OF THE DEVICE AND 
CLINICAL INVESTIGATION 
8.1 
Anticipated Clinical Benefits 
With the participation in this clinical investigation, the subject receives a modern 
device with many clinical benefits. The clinical status of the subject will be 
intensively supervised within study participation. The different available LV 
sensing and pacing configurations of the QP systems will be tested in order to 
find the best suitable setting for the CRT therapy. The investigational devices 
meet the current state of medical science and technology and are used 
according to their intended use. 
With the CRT therapy, a significant improvement in quality of life is achieved in 
75-85% of patients (Bristow et al., 2004).  
CRT devices are three chamber devices, requiring the implantation of the left 
ventricular lead. As a standard, left ventricular leads are implanted in a 
transvenous approach through the coronary sinus. Due to the diversity of the 
individual venous anatomy a range of different coronary sinus leads is required, 
e.g. leads with a larger diameter for larger caliber target veins and smaller 
diameter leads for small caliber target veins (Hansky et al., 2006; Minden, 2011). 
The Sentus OTW QP L, Sentus OTW QP S, Sentus OTW QP S/49, and Sentus 
OTW QP L/49 are quadripolar, 4.8 F left ventricular leads, which can be used in 
combination with CRT devices. Due to the thin diameter, this leads might allow 
easier left ventricular positioning in patients with small coronary arteries 
compared to leads with a larger diameter. 
However, since the establishment of CRT in the last 10 years some pitfalls are 
still remaining as there are notable non-responder rates, high pacing thresholds 
and phrenic nerve stimulation (PNS). Electronic repositioning as discussed for 
the first time by Gurevitz et al., 2005 has been revealed as means of choice to 
overcome at least high pacing thresholds and PNS adequately. The available 
approach to extend the choice of pacing vectors due to the use of a quadripolar 
LV lead has shown the superiority over a standard bipolar system in several 
studies (Goetze et al., 2013; Moubarak et al., 2014). The quadripolar left 
ventricular leads like the Sentus QP together with the corresponding CRT-D 
device offer more pacing and sensing configuration for CRT therapy compared to 
the bipolar LV leads. Due to multiple pacing options, the treating physician is able 
to overcome most cases of high pacing thresholds and PNS during implantation 
or at follow-up. A very important benefit of the QP system is the option to 
maintain lead stability in case of distal PNS and to avoid pacing from within scar 
areas by selecting near-site stimulation. Therefore the number of re-intervention 
procedures can be reduced with the new systems which may lead to reduce 
patient risks and costs. 
The use of Home Monitoring® functionality offers the physicians the possibility to 
monitor their patients remotely whenever it is deemed necessary. The automatic 

 
  
  
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early detection of arrhythmia and device anomalies allows earlier medical 
intervention as compared to conventional in-office follow-ups. The results of the 
TRUST clinical study demonstrated the safety and effectiveness of the remote 
monitoring (Varma et al., 2010).  
The individual benefit of study participation for the subject is an intensified 
medical supervision of his clinical status, an optimal adaptation of the left 
ventricular pacing configuration and the supervision of the success of the CRT 
therapy. 
8.2 
Anticipated Risks 
8.2.1 
Anticipated Adverse Events 
Implantation of the Sentus QP LV lead does not differ from the procedures 
applicable for comparable devices. Thus, no additional risks or burdens 
concerning device implantation derive from participation in the clinical 
investigation.  
8.2.2 
Risk Associated with Participation in the Clinical Investigation 
Subjects included in the QP ExCELs study have an indication for CRT-D therapy 
and will be implanted with an implantable cardiac rhythm management device as 
well as a left ventricular lead independently from the clinical investigation. As 
implantation of the investigational devices used in this clinical investigation does 
not differ from standard operation procedure, no study specific risks are 
associated with the implantation procedure. 
In some cases the Sentus QP might not be suitable for implantation due to the 
individual anatomy of the coronary venous system. The physician will determine 
if the lead is appropriate for a specific subject during the implantation procedure. 
In most cases the decision can be made during visualization of the coronary 
veins, thus the Sentus QP lead will only be implanted in those subjects most 
likely eligible for the LV lead. However, in single cases unsuccessful positioning 
of a Sentus QP lead might occur, requiring lead exchange during implantation. 
Unsuccessful positioning of a left ventricular lead and exchange of the lead 
during implantation is common in about 7% to 19% of subjects during CRT 
implantation (Nof et al., 2008) and can therefore not be accounted for as 
additional risk of Sentus QP implantation. 
At pre-hospital discharge/wound check and 3-month follow-up testing of the 
pacing threshold of the Sentus QP lead is planned for a pre-specified testing 
order. These measurements will increase the duration of the follow-up by about 
10 minutes. Furthermore threshold tests of the left ventricular lead in some cases 
may lead to reversible phrenic nerve stimulation, therefore potentially resulting in 
hiccups or muscle contractions (Metha et al., 2012; Shetty et al., 2011). In 
addition, palpitations during the measurements might be experienced. However, 
threshold tests are a common procedure at device follow-ups and are therefore 
also expected during device implantation outside of clinical studies. 

 
  
  
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All other conducted examinations are part of clinical routine. Depending on the 
specific clinics’ routine, the timing of the in-office follow-ups might deviate slightly 
from the routine. However, otherwise no additional burden for the subject due to 
the study participation is expected. 
8.2.3 
Possible Interactions with Concomitant Medical Treatments 
For CRT-D therapy, no interactions with concomitant medication or other medical 
treatment are expected.  
The subject’s individual cardiovascular medication may have to be adapted to the 
subject’s needs. 
8.3 
Steps to Control or Mitigate the Risks 
As with any implantable device, there are always potential risks that accompany 
the device. The risks can be minimized through the utilization of strict aseptic 
technique, compliance with the technical manual, compliance with this clinical 
investigation plan and technical procedures, adhering to the guidelines for 
selection of subjects, close monitoring of the subject’s physiologic status during 
the procedures, and by promptly supplying BIOTRONIK, Inc. with all pertinent 
information required by this clinical investigation plan. 
8.4 
Risk-to-benefit Rationale 
Subjects are provided with the new quadripolar left ventricular lead which will be 
implanted in combination with the newest available BIOTRONIK CRT-D 
technology. Only the Sentus QP LV leads are investigational. All other devices 
used in this study are approved for the U.S. market. The implantation procedure 
does not differ from other comparable CRT-D system implantations, thus 
resulting in no additional risk for the subject. 
The Sentus QP lead is the successor of the well-proven Corox OTW BP LV lead.  
The use of the quadripolar Sentus QP LV lead and the corresponding CRT-D 
device with IS4 connection offers more programming options due to 12 available 
pacing vectors. This might be beneficial in avoiding phrenic nerve stimulation. It 
also offers more possibilities to reprogram the device in case of elevated pacing 
thresholds. The testing of the enhanced LV pacing options during the study visits 
is reduced as testing is only performed until a suitable pacing configuration is 
determined. Hence, the measurement of the LV pacing thresholds in all 12 
pacing vectors is not required. However, the measurements might increase 
duration of the follow-ups by about 10 minutes and may result in reversible 
hiccup or palpitations. As threshold tests are common procedures during device 
follow-up, this cannot be counted as additional burden due to the study 
participation. Beyond the predefined measurements, the physician is not limited 
in testing other vectors during follow-up. The physician can test and program the 
CRT-D system according to the subjects’ individual needs.  

 
  
  
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The implantation of a Sentus QP lead is limited to those subjects with an 
appropriate structural anatomy of the coronary veins. The thin, flexible lead might 
allow easy and successful implantation in small diameter coronary veins and thus 
might be beneficial for a specific subset of subjects with the respective structural 
properties of the coronary veins. 
In total, no additional burden for the subject exists during the clinical 
investigation, besides potential slight time changes of follow-ups in the clinical 
routine, increase of follow-up duration at pre-hospital discharge/wound check and 
3-month follow-up, and possible hiccup or palpitation experiences during 
threshold measurements. 
In summary the potential benefits of the study participation of the subject exceed 
the potential risks, which is for the most part limited to a possible exchange of the 
LV lead during implantation, which is a common procedure during CRT 
implantation.  
 
 

 
  
  
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9. 
MONITORING 
9.1 
Summary 
The responsibility of BIOTRONIK, Inc. as sponsor is to ensure protocol and 
regulatory compliance through proper monitoring of the clinical investigation in 
sites. BIOTRONIK, Inc. is also required to ensure that the investigational device 
is used under the immediate direction of an investigator. As the investigator, the 
physician is responsible for conducting the clinical investigation in accordance 
with the signed Investigator Agreement, the study protocol, applicable laws, and 
FDA and/or local regulations and any conditions of approval imposed by the 
reviewing IRB. The principal investigator must also accept responsibility for all 
aspects of the clinical investigation including the actions of any co-investigators 
participating in the clinical investigation at the investigational site. 
BIOTRONIK utilizes a risk-based monitoring strategy consistent with FDA’s 
Guidance for Industry:  Oversight of Clinical Investigations – A Risk-Based 
Approach to Monitoring, August 2013. Risk-based monitoring starts with 
performing a study risk assessment of the identified critical data and processes. 
The resulting monitoring plan focuses on targeted source data verification and 
trend analyses to improve oversight and data quality, while integrating predefined 
triggers for additional on-site monitoring. The detailed QP ExCELs risk-based 
monitoring plan developed by BIOTORNIK, Inc. focuses on a combination of 
centralized and on-site monitoring.  
Monitors will visit the study site periodically during the clinical investigation in 
accordance with the monitoring plan. Sites are required to support these on-site 
monitoring visits and the study monitoring effort. On-site monitoring visits will also 
provide an assessment of the continued acceptability of the facilities to continue 
participation in the study.  
Centralized monitoring is conducted via investigator locked electronic case report 
forms (eCRFs) through the source data verification of source documents 
uploaded to the eCRF. Some examples of data that may be monitored remotely 
include: informed consent forms, enrollment, eligibility, implant, study termination, 
device data and adverse events reported in the EDC system. Sites are required 
to support centralized monitoring by providing source documents to BIOTRONIK 
in order to source data verify data reported in the EDC system and resolving 
queries in a timely manner. Uploaded source documents should meet ALCOA 
principles of attributable, legible, contemporaneous, original, and accurate. It is 
critical that the fully executed informed consent form and all necessary source 
documentation are uploaded to the EDC in a timely manner. 
The entries in the eCRF will be reviewed and source data verified by on-site or 
centralized monitors (authorized BIOTRONIK, Inc. personnel, or by authorized 
BIOTRONIK, Inc. designees) to ensure that the investigator and the clinical 
investigation team conducts the clinical investigation in accordance with the 
clinical investigation protocol and applicable FDA and local laws and regulations 

 
  
  
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to ensure adequate protection of the rights, safety and wellbeing of subjects and 
the quality and integrity of the resulting data. In addition, BIOTRONIK, Inc. may 
require the presence of personnel from BIOTRONIK, Inc. at implant and/or 
follow-up visits outlined in this protocol in order to assist the investigator and 
other site personnel. 
9.2 
Monitors 
Monitors are trained, qualified, and designated by BIOTRONIK, Inc. management 
to oversee the progress of a study at the clinical site. Additional monitors may be 
appointed as necessary.  
If a monitor becomes aware that an investigator is not complying with the signed 
Investigator Agreement, the study protocol, applicable laws, and FDA and/or 
local regulations and any conditions of approval imposed by the reviewing IRB, 
the monitor is obliged to notify BIOTRONIK, Inc. study management. 
BIOTRONIK, Inc. will evaluate the non-compliance and issue corrective actions, 
discontinue enrollment or as a last measure close the clinical investigation site. 

 
  
  
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10. RECORDS AND REPORTS 
10.1 
Investigator Records 
Investigators are required to maintain the following accurate, complete and 
current records relating to this study: 
• All correspondence relating to the study with another investigator, an IRB, 
BIOTRONIK, Inc., a monitor, or any regulatory agency (e.g., a letter sent 
from the investigator to the IRB) 
• Records showing receipt, use, and disposition of all investigational 
devices, including: 
o Date, quantity, and serial numbers of devices received 
o Names of subjects implanted with the investigational device 
o Information and serial numbers of devices return to BIOTRONIK, 
Inc. and the reason(s) for return 
o Information and serial numbers of devices that are discarded (not 
returned to BIOTRONIK, Inc.) 
• All clinical forms and documentation, including: 
o A copy of all signed Informed Consent Forms 
o All procedure and visit report forms, including supporting 
documents 
o Records of any adverse device effect, including supporting 
documentation 
o Records pertaining to subject deaths during the study 
o Protocol with documentation and rationale for any deviations from 
the clinical protocol 
o Any other records required by BIOTRONIK, Inc. 
The investigator must retain records related to the study according to FDA 
regulations and IRB requirements. 
10.2 
Investigator Reports 
Investigators are required to prepare and submit to BIOTRONIK, Inc. the 
following complete, accurate and timely reports on this study, when necessary: 
• Notification of a subject death during the study 
• Any unanticipated adverse device effects 
• Notification of the withdrawal of IRB approval 
• Annual progress reports prepared for the IRB  

 
  
  
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• Notification that informed consent was not obtained from a subject 
• Final summary report prepared for the IRB 
• Any other information upon the request of an IRB, regulatory authority, or 
BIOTRONIK, Inc. 
Table 9 outlines the responsibilities, including time constraints, for submitting the 
above reports.  
Table 9: Investigator Reports 
Type of Report 
Prepared by 
Investigator for: 
Time Constraints of Notification 
Subject death during study 
BIOTRONIK, Inc., 
IRB 
As soon as possible and as required by reviewing 
IRB 
Unanticipated adverse 
device effect 
BIOTRONIK, Inc., 
IRB 
Within 10 working days after notification of effect 
Serious or life-threatening 
unanticipated adverse 
device effect 
BIOTRONIK, Inc., 
IRB 
Within 2 working days after notification of effect 
Subject withdrawal 
BIOTRONIK, Inc. 
Within 5 working days after notification of 
withdrawal 
Withdrawal of IRB approval 
BIOTRONIK, Inc. 
Within 5 working days of receipt of notice of 
withdrawal of approval 
Progress report(s) 
BIOTRONIK, Inc., 
IRB 
Submitted no less than yearly 
Significant deviations from 
study plan 
BIOTRONIK, Inc.,  
IRB 
Within 5 working days after emergency to protect 
life or physical well-being of subject, otherwise 
prior approval by BIOTRONIK, Inc. is required 
Informed consent not 
obtained 
BIOTRONIK, Inc.,  
IRB 
Within 5 working days of occurrence 
Final summary report 
BIOTRONIK, Inc.,  
IRB 
Within 3 months after completion or termination of 
the study 
10.3 
Sponsor Records and Reports 
BIOTRONIK, Inc. will maintain the following records: 
• All correspondence with the investigator(s), IRBs, and FDA that pertains to 
the study 
• Investigational device shipment and inventory reconciliation reports 
• Investigator agreements, financial disclosures, and current curriculum 
vitae 
• Name and address of each investigator and each IRB that is involved with 
the investigation 
• Adverse events and complaints 

 
  
  
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• Adverse device effects (whether anticipated or unanticipated) 
• Electronic Case Report Form data 
• Confirmation of completed subject informed consent forms 
• Clinical investigation protocol and report of prior investigations 
• Screening visit reports 
• Monitoring reports 
• Clinical progress reports 
• Statement of the extent to which the good manufacturing practice 
regulation in part 21 CFR 820 will be followed in manufacturing the device 
BIOTRONIK, Inc. is responsible for preparing the following reports, when 
necessary: 
Table 10: Sponsor Reporting Responsibilities 
Type of Report 
Prepared by 
BIOTRONIK for 
Time Constraints 
of Notification 
Unanticipated adverse 
device effect 
FDA, all reviewing IRBs, 
participating investigators 
Within 10 working days after notification of 
effect 
Withdrawal of IRB 
approval 
FDA, all reviewing IRBs, 
participating investigators 
Within 5 working days of receipt of notice of 
withdrawal of approval 
Withdrawal of FDA 
approval 
Reviewing IRBs, 
participating investigators 
Within 5 working days 
Current investigator list 
FDA 
Names and addresses of participating 
investigators at 6 month intervals 
Progress report 
FDA, all reviewing IRBs 
Submitted at least annually 
Recall and disposition 
FDA, all reviewing IRBs 
Within 30 working days and will include 
reasons for any request that an investigator 
return, repair, or otherwise dispose of any 
investigational leads 
Final report 
FDA, all reviewing IRBs, 
participating investigators 
Notification within 30 working days of the 
completion or termination of the 
investigation. A final report will be submitted 
within 6 months after completion or 
termination of the study. 
Informed consent not 
obtained 
FDA 
Within 5 working days of notification of 
occurrence 
 
 

 
  
  
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11. MULTIPOLE PACING SUB-STUDY 
11.1 
Introduction 
This QP ExCELs clinical sub-study is an FDA required post-approval study for 
the US market released BIOTRONIK MultiPole Pacing (MPP) feature (PMA 
P050023/S107) 
of 
the 
Ilivia 
HF-T 
QP 
family 
CRT-D system 
(PMA 
P050023/S103).  
11.1.1 Sub-Study Overview 
Since the initial PMA approvals of Cardiac Resynchronization Therapy (CRT) 
devices, features have evolved to provide additional programmability designed to 
maximize patient benefit.  Despite the proven benefit of CRT in the indicated 
population, up to one-third of patients do not respond to the therapy.1 
In the field of CRT, the adaption of the IS4 connector standard was the most 
prominent improvement within the recent past. This IS4 connector allows the 
usage of left ventricular (LV) leads that offer four separate poles which results in 
an increased number of effectively different pacing polarities. Along with the 
quadripolar (QP) LV lead comes the possibility of stimulating more than one LV 
pacing site within one cardiac cycle. 
Studies have shown that multiple point LV pacing via a QP LV lead may be an 
alternative approach to improve CRT response by delivering multiple LV pacing 
pulses, simultaneously recruiting a larger volume of myocardium.2  A recent IDE 
study from St. Jude Medical showed that quadripolar multiple point LV pacing 
(MultiPointTM Pacing algorithm) was non-inferior to standard quadripolar 
biventricular pacing.3   
QP ExCELs is a prospective, non-randomized, multi-center clinical investigation 
designed to satisfy U.S. Food and Drug Administration (FDA) requirements for 
pre-market submission of the Sentus OTW QP LV leads. The QP ExCELs study 
enrolls subjects with a standard CRT-D indication prior to implantation with a 
BIOTRONIK Sentus QP LV lead and US a market released BIOTRONIK CRT-D 
with an IS4 port for the LV lead. 

 
  
  
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11.1.2 MultiPole Pacing (MPP) Description 
The US market released MultiPole Pacing feature of the Ilivia HF-T QP family 
CRT-D systems allows left ventricular pacing in two different vectors within a 
single cardiac cycle using the same quadripolar lead in order to improve 
synchronization of the contraction pattern. Both left ventricular stimuli will either 
be before the right ventricular pace (1st LV – 2nd LV - RV) or after the right 
ventricular pace (RV-1st LV – 2nd LV). The second LV stimulus will only be 
capable of delivering the second pacing stimulus in the left ventricle; sensing and 
timing will not be affected by 2nd LV. The delay between the two left ventricular 
paces is programmable between 0 ms and 50 ms in 5 ms steps. All 12 currently 
approved pacing configurations are available for both pacing stimuli. However, 
the same pacing vector cannot be used for both stimuli. Pacing output and 
interventricular delays can be programmed independently. There is no change to 
the same parameter ranges available for pacing amplitude and pulse width (0.5 
to 7.5 V and 0.4 to 1.5 ms, respectively). The programmable parameters for the 
MultiPole Pacing feature are listed in 11. 
Table 11: Programmable Parameters for MultiPole Pacing 
Parameter 
Programmable range 
LV MultiPole stimulation 
OFF, 1st LV-2nd LV-RV, RV-1st LV-
2nd LV 
LV stimulation amplitude (1st LV and 
2nd LV) 
0.5 to 7.5 V 
LV stimulation width (1st LV and 2nd 
LV) 
0.4 to 1.5 ms 
Interval 1st LV – 2nd LV 
0 to 50 ms 
Stimulation configuration (1st LV and 
2nd LV)  
LV1 Tip → LV2 Ring 
LV1 Tip → LV4 Ring 
LV1 Tip → RV Coil 
LV1 Tip → ICD 
LV2 Ring → LV1 Tip 
LV2 Ring → LV4 Ring 
LV2 Ring → RV Coil 
LV3 Ring → LV2 Ring 
LV3 Ring → LV4 Ring 
LV3 Ring → RV Coil 
LV4 Ring → LV2 Ring 
LV4 Ring → RV Coil 
 

 
  
  
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MultiPole Pacing is programmable using programmer software that can be used 
with one of BIOTRONIK’s programmers, either the ICS 3000 (P950037/S035, 
dated May 18, 2005) or the Renamic (P950037/S089, dated April 15, 2011). The 
user accesses the feature from the Bradycardia/CRT parameters tab (Figure 9). 
 
Figure 9: Programming MultiPole Pacing 
 
As shown in Figure 9 and Figure 10 the polarity, pulse amplitude, and pulse 
width for the two LV stimuli can be programmed independently. 
 
Figure 10: Programming 1st LV Stimulus  
 
 
 

 
  
  
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Figure 11: Programming 2nd LV Stimulus 
 
 
Figure 11 and Figure 12 compare the timing of the ventricular stimuli depending 
on which chamber is selected to be initially paced.  When the right ventricle is 
paced first, the LV-LV delay starts after the V-V delay, whereas the V-V and LV-
LV delays start simultaneously when the left ventricle is paced first. 
Figure 12: V-V Delay, LV First 
 
 

 
  
  
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Figure 13: V-V Delay, RV First 
 
 
11.1.3 Published Results for Multipoint LV Pacing 
Forleo et. al, 2016 evaluated the experience of the St. Jude Medical MPP-capable 
CRT-D devices (Unify Quadra MP or Quadra Assura MP) connected to a 
quadripolar LV lead (Quartet™).  A total of 507 patients in whom these devices had 
been successfully implanted were enrolled between August 2013 and May 2015. 
The analyses included: (i) current clinical practices for the management of such 
patients, and (ii) the impact of MPP on heart failure clinical composite response 
and on the absolute change in ejection fraction (EF) at 6 months. Multipoint pacing 
was programmed to ‘ON’ in 46% of patients before discharge. Methods of 
optimizing MPP programming were most commonly based on either the greatest 
narrowing of the QRS complex (38%) or the electrical delays between the 
electrodes (34%). Clinical and echocardiographic follow-up data were evaluated in 
232 patients whom data were available both at the baseline and the 6-month 
follow-up examination. These patients were divided into two groups according to 
whether MPP was programmed to ‘ON’ (n = 94) or ‘OFF’ (n = 138) at the time of 
discharge. At 6 months, EF was significantly higher in the MPP group than in the 
biventricular-pacing group (39.1 ± 9.6 vs. 34.7 ± 7.6%; P < 0.001). Even after 
adjustments, early MPP activation remained an independent predictor of absolute 
increase in LVEF of ≥5% (odds ratio 2.5; P = 0.001). At 6 months, an improvement 
in clinical composite score was recorded in a greater proportion of patients with 
MPP-ON than in controls (56 vs. 38%; P = 0.009). On comparing optimal MPP and 
conventional vectors, QRS was also seen to have decreased significantly (P < 
0.001).2 
 

 
  
  
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The recent MultiPoint™ Pacing (MPP) IDE Study from St. Jude Medical showed 
that quadripolar multiple point LV pacing (MultiPointTM Pacing algorithm) was non-
inferior to standard quadripolar biventricular pacing. The multicenter study enrolled 
and followed 506 subjects with a standard CRT-D indication who were implanted 
with a CRT-D system (Quartet™ LV lead with a Quadra CRT-D) capable of 
delivering either quadripolar biventricular pacing or MPP.  Quadripolar Bi-V pacing 
was activated at implant.  At 3 months post-implant, patients’ responder status was 
assessed, both responders and non-responders were randomized, and 1:1 
randomization (Bi-V or MPP) was stratified by responder status.  The primary 
efficacy endpoint (freedom from system-related complications through 9 months) 
was 93.2%, (97.5% lower confidence bound 90.4%) was greater than the objective 
performance criterion of 75%.  The primary efficacy endpoint was met for both 
intention-to-treat and as-treated populations in 381 randomized patients (ITT, 
p=0.013 and as-treated, p=0.008, respectively).  For patients in the MPP arm 
programmed with wide cathode spacing and the shortest intraventricular timing 
delay (5ms), MPP provided significantly higher clinical responder rate (between 3 
and 9 months) up to 87% (p=0.003 vs <30mm) and converted 100% non-
responders to responders (p=0.006 vs <30mm).3 
11.2 
Sub-Study Design 
The objective of this MultiPole Pacing sub-study is to demonstrate that the MPP 
feature is effective by converting a percentage of CRT non-responders to 
responders.  Each subject’s responder status will be assessed using a Clinical 
Composite Score (CCS)4 including three components: NYHA Class, heart failure 
(HF) hospitalizations, and cardiovascular death.  
The MPP sub-study is a single-arm, multi-center, prospective trial within the 
ongoing QP ExCELs study.  Eligible patients will have been enrolled in QP ExCELs 
and successfully implanted with the BIOTRONIK Ilivia HF-T QP family CRT-D 
system, or future-marketed CRT-D system with the MPP feature, and have 
received standard biventricular (BiV) pacing (i.e. without MPP) prior to a 6-Month 
CCS assessment or at the time of the QP ExCELs 3-month follow-up with a HF  
hospitalization event.  
Visit intervals below are specified according to time since implant to minimize 
confusion between the differing enrollment timing into the QP ExCELs study and 
MPP sub-study.   
At the QP ExCELs 6-month Follow-up, a CCS assessment will be completed for all 
QP ExCELs enrolled subjects who are currently receiving BiV pacing, including 
NYHA class and HF hospitalization status.  Additionally, a Patient Global 
Assessment (PGA) will be collected. A responder status will be derived classifying 
these subjects as “Improved”, “Worsened”, or “Unchanged” using the following 
definitions: 

 
  
 
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CRT Responder Classification at QP ExCELs 6-Month Follow-up (evaluated 
compared to QP ExCELs Enrollment Visit)*: 
• “Improved”:   
o No HF hospitalization has occurred, AND  
o NYHA class is improved 
• “Unchanged”:   
o No HF hospitalization has occurred, AND  
o NYHA class is unchanged 
• “Worsened”: 
o HF hospitalization has occurred, OR  
o NYHA class is worsened 
Classification of prior “HF hospitalization” event at the time of MPP 
screening/enrollment and NYHA class will be determined and reported by the 
investigator.   
Those subjects responder classification determined to be “Worsened” or 
“Unchanged” may be approached for enrollment into the MPP sub-study. These 
subjects must sign a separate MPP sub-study Informed Consent prior to 
enrollment.  Those that decline enrolling into the MPP sub-study will continue to be 
followed according to the primary QP ExCELs protocol. 
After enrollment into the MPP sub-study, the MPP feature will be programmed ON 
and an MPP optimization procedure may be performed for all subjects according to 
the site’s optimization method (see Section11.3.3.1).   
At a 9-Month Follow-up† (90 ± 30 days post-MPP enrollment), each subject will 
repeat the NYHA classification, PGA, and HF hospitalization status, in addition to 
the standard QP ExCELs required lead testing.  
At a 12-Month Follow-up† (180 ± 30 days post-MPP enrollment), each subject will 
repeat the NYHA classification, PGA, and HF hospitalization status. Following the 
12-Month Follow-up, all subjects may be programmed to MPP or standard BiV 
pacing, per physician discretion. 
Subjects enrolled in the MPP sub-study will rejoin the main QP ExCELs study at 
the 12-Month Follow-up†; however, no further CCS will be assessed. 
11.2.1 Study Endpoints 
This sub-study includes the assessment of one primary effectiveness endpoint, as 
well as three secondary endpoints. The hypothesis associated with the primary 
endpoint is in a superiority format.   
 
* Subjects may be enrolled in the MPP sub-study at the 3-Month QP ExCELs follow-up if the subject 
received continuous standard biventricular (BiV) pacing from implant to the 3-Month follow-up with a 
HF hospitalization event and will be followed for 6 months in the MPP sub-study with MPP sub-
study data collected at a 6-month follow-up and 9-month follow-up. 

 
  
 
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11.2.1.1 
Primary Endpoint 1 
The purpose of primary endpoint 1 is to evaluate the CRT responder status with 
the MPP feature within the Ilivia 7 HF-T QP family CRT-D, or future-marketed CRT-
D system, compared to a pre-specified performance goal. 
The associated hypothesis is evaluated based on a CCS determining a responder 
classification based on changes in NYHA class, HF hospitalization, and 
cardiovascular death. 
A responder status will be derived classifying these subjects as “Improved”, 
“Worsened”, or “Unchanged” using the following definitions: 
Responder Classification at 12-Month Follow-up (evaluated compared to MPP 
Enrollment Visit occurring at 6 months)†: 
• “Improved”:   
o No HF hospitalization or cardiovascular death, AND 
o NYHA class is improved  
• “Unchanged”:   
o No HF hospitalization or cardiovascular death, AND 
o NYHA class is unchanged 
•  “Worsened”:  
o HF hospitalization or cardiovascular death has occurred, OR  
o NYHA class is worsened 
Ho: The proportion of subjects (P) who are classified as “Improved” is not superior 
to a performance goal (PG) of 3%.  
 
PG ≥ P 
Ha: The proportion of subjects who are classified as “Improved” is superior to a 
performance goal of 3%. 
 
PG < P 
A rejection of the null hypothesis would indicate that the proportion of subjects 
classified as “Improved” is superior to 3%. 
11.2.1.2 
Secondary Endpoint 1- Freedom from MPP system related adverse 
events requiring additional invasive intervention to resolve at 6 months 
The purpose of Secondary Endpoint 1 is to evaluate adverse events that require 
additional invasive intervention to resolve, specifically related to the MPP feature of 
the Ilivia HF-T QP family, or future-marketed CRT-D system with the MPP feature. 
These adverse events include any software issues related to MPP programming or 
any adverse event that occurs while MPP is enabled and that may be attributed to 
the use of the MPP feature. 
 
† Evaluated at 9-month follow-up if MPP sub-study enrollment visit occurred at 3 months. 

 
  
 
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11.2.1.3 
Secondary Endpoint 2 - Evaluate CCS + PGA Responder Status 
utilizing a modified CCS that incorporates the Patient Global 
Assessment  
The purpose of Secondary Endpoint 2 is to evaluate a modified CCS, determining 
a responder classification based on changes in NYHA class, Patient Global 
Assessment (PGA), HF hospitalization, and cardiovascular death, where the PGA 
will ask subjects to assess how their overall status has changed since prior to 
receiving CRT therapy (markedly better, better, unchanged, worse, markedly 
worse). 
 
Modified Responder Classification (CCS + PGA) at 12-Month Follow-up‡: 
• “Improved”:   
o No HF hospitalization or cardiovascular death, AND 
o Neither NYHA class is worsened or PGA is worsened (“worse” or 
“markedly worse”), AND 
o NYHA class is improved or PGA is improved (“better” or “markedly 
better”) 
•  “Unchanged”:   
o No HF hospitalization or cardiovascular death, AND 
o NYHA class is unchanged, AND  
o PGA is unchanged (“unchanged”) 
•  “Worsened”:  
o HF hospitalization or cardiovascular death has occurred, OR  
o NYHA class is worsened or PGA is worsened (“worse” or “markedly 
worse”) 
11.2.1.4 
Secondary Endpoint 3: Evaluate CCS Responder Status utilizing a 
modified Responder Classification 
The purpose of Secondary Endpoint 3 is to evaluate a modified Responder 
Classification in which both “Improved” and “Unchanged” subjects will be classified 
as responders.  At the time of enrollment into the MPP sub-study, MPP sub-study 
subjects have already been found to have no change or worsening in their HF 
status with BiV pacing.  Since HF is a chronic and progressive condition, these 
subjects may be expected to continue to worsen during the MPP follow-up period 
or remain stable with careful management.  In this secondary endpoint, a status of 
“Unchanged” (in addition to “Improved”) during the MPP follow-up period will be 
considered a responder to MPP. 
 
‡ Evaluated at 9-month follow-up if MPP sub-study enrollment visit occurred at 3 months. 

 
  
 
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11.2.1.5 
Additional Data of Interest  
Additional information will be collected to characterize the study population, 
implanted system, and progress of the clinical investigation.  The data will be 
statistically analyzed, where appropriate.  Further data of interest will include: 
• Patient Global Assessment (PGA) at each visit 
• MPP programmed settings 
• Adverse events attributed to MPP feature 
• Device initial and final programmed settings 
• 
Methods utilized to optimize MPP, AV and/or V-V timing 
11.2.2 Study Size and Duration 
The MPP sub-study will enroll up to 100 subjects at up to 75 sites within the United 
States who are participating in the QP ExCELs study.  Subjects in the MPP sub-
study will be followed for 6 months (180 ± 30 days post-MPP enrollment).  Subjects 
enrolled in the MPP sub-study will rejoin the main QP ExCELs study after 
completion of their 12-month MPP follow-up§. 
11.2.3 Sample-Size Analysis 
The investigation is designed to limit the number of patients involved while still 
exposing the device to a sufficiently large patient population in order to ensure a 
representative and statistically meaningful sample. 
Primary Endpoint 1 Sample Size 
The estimated sample size requirements are based on a superiority comparison of 
the proportion of responders to a performance goal of 3%, chosen based on the 
assumption that any conversion of non-responders to responders is clinically 
relevant.  A performance goal of 3% was chosen rather than 0% to account for 
variability (“noise”) around 0%, for example, due to infrequent subjects who are late 
responders to CRT or improve regardless of MPP.  The expected result is 
estimated at a 10% conversion of non-responders to responders.   
There is limited published data available for mid- to long-term follow-up CRT 
response with multiple point LV pacing in any population.  Additionally, no 
published data could be found related to CRT response with multiple point LV 
pacing in an “all-comer non-responder” population.  The St. Jude Medical 
MultiPoint Pacing IDE Study3,5 (“St. Jude IDE study”, NCT01786993) evaluated 
CRT response based on a Clinical Composite Score (CCS) after 3 months of BiV 
pacing.  Subjects were then randomized to the MultiPointTM Pacing treatment arm 
 
§ If an MPP sub-study subject was enrolled at the 3-Month QP ExCELs follow-up, they will re-join 
the main QP ExCELs study after completion of their 9-month MPP follow-up. 

 
  
 
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or to continue on with BiV pacing.  The study showed that 70.1% of subjects were 
responders to MultiPointTM Pacing.  However, both responders and non-responders 
after 3 months of BiV pacing were included in the MultiPointTM Pacing treatment 
arm.  Additionally, the St. Jude IDE study only randomized subjects with acute 
"equal or better" EA velocity time integral (VTI) with MultiPointTM Pacing vs. BiV 
pacing per echocardiogram at the 3-Month Visit.  There were 52 subjects that did 
not meet this criterion and were not randomized.  Thus, subjects that may likely 
have not responded to multiple point LV pacing therapy were not randomized 
which certainly led to a higher response rate to MultiPointTM Pacing. 
BIOTRONIK proposes to allow enrollment of any QP ExCELs subject meeting non-
responder criteria (“all-comer non-responders”) at the 6-Month Follow-up into the 
MPP sub-study as it is not standard of care to perform echocardiograms on CRT 
subjects to determine if they are responding to standard CRT therapy. As such, we 
estimate that the proportion of non-responders at 6-months that will be converted 
to responders at 12-months will be less than that observed in the St. Jude IDE 
study.  There are three additional studies which have published results for CRT 
response with MPP measured via CCS or NYHA improvement with mid- to long-
term follow-up (6 to 12 months)2,6,7.  However, these studies also did not limit 
multiple point LV pacing treatment to non-responders, and thus the results are not 
directly applicable to the proposed BIOTRONIK study design. 
Assumptions: 
• Study Design:  Superiority Trial 
• Type I error (alpha):  0.025 (one-sided) 
• Statistical power:  80% 
• Performance Goal: 3% 
• Expected: 10% 
A total of 90 evaluable subjects would be required to demonstrate superiority to a 
performance goal of 3%. 
11.2.4 Data Analyses 
Classification of “HF hospitalization” and “cardiovascular death” events for use in 
primary endpoint 1, secondary endpoint 2, and secondary endpoint 3 analyses will 
be determined by a Clinical Events Committee (Section 11.3.4).  
Descriptive statistics will be used to present and summarize the data collected in 
the clinical study.  Frequency distributions and cross tabulations will be presented 
for discrete variables.  Means, standard errors, and ranges will be presented for 
continuous variables. 
For primary endpoint 1, the lower, one-sided, exact 97.5% bound for the observed 
proportion of responders (“improved”) would have to exceed 3% for rejection of the 
null hypothesis. 
Additional related analyses to be performed for the endpoint include: 

 
  
 
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• Descriptive statistics for observed changes in NYHA class and frequency 
tabulations for the other components of the Clinical Composite Score.  
11.2.4.1 
Adjustments to Overall Study Sample Size 
Assuming a 10% loss to follow-up rate during the study for reasons unrelated to the 
study outcomes, a total enrollment of 100 subjects (90/0.9) would be required to 
achieve an evaluable study population of 90 subjects. 
11.2.4.2 
Replacement of Missing Data 
The last observation carried forward (LOCF) principle will be utilized for the 
analysis of NYHA Classification and Patient Global Assessment for primary 
endpoint 1 and secondary endpoints 2 and 3. 
Missing NYHA and patient global assessment data at either the enrollment or 
follow-up visits affects the number of subjects that can be included in the analysis.  
It is possible that subjects or investigational personnel may either forget or choose 
not to answer one or more of the questions related to NYHA classification or 
patient global assessment.   
11.2.4.3 
MPP Programming 
Subjects are expected to remain programmed with the MPP feature ON from MPP 
enrollment through the completion of the sub-study.  Subjects who have the MPP 
feature permanently turned OFF prior to completion of the sub-study will be 
required to report a protocol violation.  Subjects with MPP permanently turned OFF 
prior to completion of the stub-study will be analyzed as intent to treat.  
Subjects may have the MPP feature temporally turned OFF due to a lead revision 
procedure and these short durations with MPP will not be reported as a protocol 
violation or analyzed differently.  Additionally, any QP ExCELs subject that does 
not enroll into the MPP sub-study but receives MPP due to the physician’s 
determination will not be analyzed towards the MPP study endpoints. 
11.3 
Protocol Requirements 
11.3.1 Patient Population 
The investigator is responsible for screening all potential patients and selecting 
those who are appropriate for study inclusion.  The patients selected for 
participation should be from the investigator's general patient population currently 
participating in the QP ExCELs study according to the inclusion and exclusion 
criteria described below. 
11.3.1.1 
Inclusion Criteria 
To support the objectives of this investigation, the inclusion criteria at the time of 
patient enrollment for this investigational study include the following requirements: 

 
  
 
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• 
Currently enrolled in the ongoing QP ExCELs study 
• 
Successfully implanted with a BIOTRONIK Ilivia 7 HF-T QP family CRT-D 
system, or future-marketed CRT-D system with the MPP feature. Successful 
implantation is defined as having at least two LV pacing vectors with a 
measured pacing threshold of ≤ 5.0 V @ any pulse width (allowing for a 
minimum 2.5 V safety margin) without phrenic nerve stimulation at the final 
programmed pacing output at the time of enrollment into the MPP sub-study.  
• 
CRT Responder Assessment classification as “Worsened” or “Unchanged” 
• 
Standard continuous biventricular (BiV) pacing from implant until the 6-Month 
QP ExCELs follow-up visit. (Implant to 3-Month QP ExCELs follow-up who 
qualify due to a HF hospitalization event) 
• 
Able to understand the nature of the sub-study and give informed consent 
• 
Available for an additional follow-up visit specific to the MPP sub-study at the 
investigational site 
• 
No evidence of non-compliance to their ongoing commitment in the QP ExCELs 
study 
11.3.1.2 
Exclusion Criteria 
To support the objectives of this investigation, the exclusion criteria at the time of 
patient enrollment include the following requirements: 
• Have a life expectancy of less than 6 months 
• Expected to receive heart transplantation or ventricular assist device within 6 
months 
• Chronic atrial fibrillation 
• Presence of another life-threatening, underlying illness separate from their 
cardiac disorder 
• Received MPP pacing prior to enrolment into the MPP sub-study 
11.3.2 Specific Testing 
This sub-study protocol involves very specific inclusion and exclusion criteria.  
Therefore, detailed evaluation of all patients before enrollment is important to the 
success of the trial.   
The specific visits that are part of the study are provided below.  Specific 
Procedures are described in more detail in the following sections.   
• MPP Enrollment (QP ExCELs 6-Month follow-up or 3-Month follow-up with 
HF hospitalization) 
• 9-Month MPP Follow-up  
• 12-Month MPP Follow-up 

 
  
 
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Subjects enrolled in the QP ExCELs MPP sub-study will be evaluated at the MPP 
enrollment visit, then 3- and 6-months post MPP enrollment.  Subjects enrolled in 
the MPP sub-study will rejoin the main QP ExCELs study after the 12-Month** 
Follow-up; however, no further specific MPP related data will be assessed.  
Subjects with a HF Hospitalization event, as classified by investigator, prior to 90 
days post implant may be enrolled into the MPP sub-study at the 3-Month follow-up 
visit. 
11.3.2.1 
New York Heart Association (NYHA) Classification 
During the course of the study, the NYHA classification will be utilized for 
evaluation of the specific level of cardiac disease.  The NYHA class will be 
evaluated and reported by the study investigator.  The NYHA will be evaluated at 
all protocol-defined follow-ups.  The following bullets provide the definitions for 
each class: 
• Class I: Subjects with cardiac disease, but without resulting limitation of 
physical activity. Ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnea, or anginal pain. 
• Class II: Subjects with cardiac disease resulting in slight limitation of physical 
activity. They are comfortable at rest. Ordinary physical activity results in 
fatigue, palpitation, dyspnea, or anginal pain. 
• Class Ill: Subjects with cardiac disease resulting in marked limitation of physical 
activity. They are comfortable at rest. Less than ordinary activity causes fatigue, 
palpitation, dyspnea, or anginal pain. 
• Class IV: Subjects with cardiac disease resulting in inability to carry on any 
physical activity without discomfort. Symptoms of cardiac insufficiency or of 
anginal syndrome may be present even at rest. If any physical activity is 
undertaken, discomfort is increased. 
The description for each of the classes was taken from the ACC/AHA Guidelines 
for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices8.  
11.3.2.2 
Patient Global Assessment (PGA) 
During the course of the study a patient global assessment will be given to assess 
how the subject’s overall status has changed since prior to receiving CRT therapy 
(markedly better, better, unchanged, worse, markedly worse). It is important to 
minimize the influence on the respondent by limiting their interaction and verbal 
exchanges with spouses or other individuals who may affect results while the 
assessment form is being completed.   
 
** Subjects enrolled in the MPP sub-study at the 3-Month QP ExCELs follow-up, qualifying with a HF 
hospitalization event, will rejoin the main QP ExCELs study after the 9-Month Follow-up 

 
  
 
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11.3.3 Sub-Study Procedures 
Figure 13 provides an overview of the MPP sub-study design as part of the QP 
ExCELs study.  Details of subject eligibility requirements and specific study 
procedures are noted in Section 11.3.1.  While participating in the MPP sub-study, 
all subjects will continue to complete all required QP ExCELs study follow-ups. 

 
  
 
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Figure 14: MPP Sub-Study Design 
 
* 3 Month follow-up if heart failure hospitalization event occurred. 
A subject may qualify as a CRT non-responder and be enrolled at the 3-month 
follow-up if a HF hospitalization has occurred while receiving standard bi-
ventricular pacing. 

 
  
 
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11.3.3.1 
Enrollment into MultiPole Pacing Sub-Study 
Prior to enrollment, the patient’s background and history must be reviewed in order 
to ensure that the patient is an appropriate candidate for this sub-study.  In 
addition, as part of the clinical study, informed consent must be obtained from the 
patient prior to initiating any study-related procedures.   
Subjects enrolled in the QP ExCELs study evaluation who reach the 6-month post-
implant follow-up with a CRT Responder Assessment as Unchanged or Worsened 
and meet the sub-study inclusion/exclusion may be enrolled into the sub-study.  
Subjects at the 3-month QP ExCELs follow-up with a HF hospitalization event 
since the QP ExCELs implant will be considered worsened and may be enrolled at 
the 3-month visit. Subjects are considered enrolled in the sub-study once MPP 
sub-study informed consent is obtained.   
MPP optimization may be performed or not performed per investigator discretion at 
the time of enrollment into the MPP sub-study.  The investigator will determine if 
MPP optimization will be performed for each subject and which method will be 
used (e.g. QRS width, electrical delay, echocardiography, etc.). MPP programmed 
parameters may be adjusted as needed during the follow-up period for MPP sub-
study subjects.   
 
The following data will be collected at the MPP enrollment visit: 
1. Collect all lead testing data for standard QP ExCELs study follow-up 
2. Turn MPP ON and collect MPP programmed settings 
3. Document MPP optimization method 
4. Obtain NYHA classification and HF hospitalization status 
5. Obtain Patient Global Assessment 
6. Collect device initial and final programmed settings 
7. Document any reportable Adverse Events 
8. Review and complete the appropriate eCRFs 
The MPP feature must be programmed ON from MPP enrollment until the 
subject exits the sub-study.  Subjects who have the MPP feature permanently 
turned OFF prior to completion of the sub-study will be required to report a 
protocol violation.   
 
MPP follow-up windows are ± 30 days.  Care should be given to ensure 
scheduling of MPP study visits fall within the corresponding QP ExCELs visit 
windows (± 45 days). 

 
  
 
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11.3.3.2 
9-Month MPP Follow-up†† 
At a 9-month follow-up (90 ± 30 days post-MPP enrollment), subjects return to the 
investigational site for an in-office assessment of their heart failure status and 
implanted system.  
The following data should be collected: 
1. Collect MPP programmed settings 
2. Obtain NYHA classification and HF hospitalization status 
3. Obtain Patient Global Assessment 
4. Collect device initial and final programmed settings 
5. Document any reportable Adverse Events 
6. Review and complete the appropriate eCRFs 
11.3.3.3 
12-Month MPP Follow-up‡‡ 
At the QP ExCELs 12-month follow-up (180 ± 30 days post-MPP enrollment), 
subjects return to the investigational site for an in-office assessment of their heart 
failure status and implanted system. 
1. Collect all lead testing data for standard QP ExCELs study follow-up 
2. Collect MPP programmed settings 
3. Obtain NYHA classification and HF hospitalization status 
4. Obtain Patient Global Assessment 
5. Collect device initial and final programmed settings 
6. Document any reportable Adverse Events 
7. Review and complete the appropriate eCRFs 
Following the 12-month follow-up, all subjects may be programmed to MPP or 
standard BiV pacing, per physician discretion. 
11.3.4 Clinical Events Committee – MPP Sub-Study Events 
The QP ExCELs Clinical Events Committee (CEC) described in Section 5.1 will 
adjudicate all adverse events that require additional invasive intervention to resolve 
which may be related to the MPP feature.  These events include any software 
issues related to MPP programming or any adverse event that occurs while MPP is 
enabled and that may be attributed to the use of the MPP feature.   The CEC will 
 
†† Subjects enrolled at the 3-Month follow-up due to a prior HF hospitalization event will be followed at 6-months 
(90 ± 30 days post-MPP enrollment).   
‡‡ Subjects enrolled at the 3-Month follow-up due to a prior HF hospitalization event will be seen at 9-months (180 ± 30 days 
post-MPP enrollment) and join the main QP ExCELs study at the 12-Month visit.  

 
  
 
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indicate whether the adverse event is related, possibly related, not related, or has 
an unknown relation to the MPP feature.     
In addition, the CEC will adjudicate all deaths reported while participating in the 
MPP sub-study and classify each death as cardiovascular, vascular, non-
cardiovascular/vascular, or unknown.   
The CEC will adjudicate all reported protocol-defined hospitalizations while a 
subject is enrolled in the MPP sub-study.  Hospitalization events will be classified 
as 
cardiovascular, 
vascular, 
non-cardiovascular/vascular, 
or 
unknown.  
Additionally, hospitalizations classified as cardiovascular will be further classified 
as a HF hospitalization, non-HF hospitalization, or unknown. Hospitalization events 
reported by the investigator as part of the initial responder classification for 
enrollment into the MPP sub-study will not be adjudicated by the CEC.  
11.4 
Benefits and Risks 
11.4.1 Potential Benefits 
The clinical benefit of the Ilivia HF-T CRT-D is similar to that of standard CRT-Ds.  
Subjects taking part in this sub-study will receive additional and detailed 
examinations of their CRT system. 
Although the participating study subjects might benefit from the new CRT-D system 
with MPP feature, currently there is only limited benefit for enrolled study subjects.  
Studies have shown that multiple point LV pacing via a QP LV lead may be an 
alternative approach to improve CRT response by delivering multiple LV pacing 
pulses, simultaneously recruiting a larger volume of myocardium.2   A recent IDE 
study showed that quadripolar multiple point LV pacing was non-inferior to 
standard quadripolar biventricular pacing.3 The medical community, as well as 
future subjects, may benefit from these study results, which will enable a better 
understanding of the safety and efficacy of the MPP feature. 
 
11.4.2 Potential Risks 
During the course of this sub-study subjects may experience potential adverse events 
related to the MPP feature.  Although not expected these risks may include excessive 
battery drain or phrenic nerve stimulation.  There is no current data to support 
superiority of MPP to conventional BiV pacing and it is not known if this feature will 
turn a non-responder into a responder. Adverse events will be determined by the 
investigator during subject follow-ups, documented in the subject medical record, and 
reported in the EDC system. Documentation includes the evaluation of the relation 
between the adverse event and the MPP feature. The date of the adverse event and 
resolution must be recorded. When an adverse event is noted in the EDC system, 
corrective action will also be provided with any supportive documentation available. 
Corrective actions may include, for example: drug therapy changes, programming 
changes, lead repositioning, new lead implants, or CRT-D explant.  

 
  
 
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Study sites may report adverse events through MedWatch, FDA’s adverse event 
reporting tool for market-released devices. As defined in BIOTRONIK’s internal 
procedures, these adverse events may be reported by BIOTRONIK through 
manufacturer’s MedWatch reports. 
11.5 
Other General Information 
11.5.1 Subject Death 
Personnel at the investigational site should notify BIOTRONIK as soon as possible 
concerning any subject death during the investigation.  This notification should 
include a completed study termination eCRF, death certificate, and a copy of the 
notification of the death sent to the IRB.  If a death certificate is not available, a 
detailed statement (death report) signed by the investigator should be written in 
addition to the termination eCRF. The death report should include all of the 
following, if available: 
• date and time of death 
• place death occurred 
• identification of the rhythm at the time of death, if known (include any available 
documentation) 
• immediate cause of death 
• any other circumstances surrounding the death 
• whether it was device or procedure related 
All implanted devices that are involved with the investigational study should be 
removed and returned to BIOTRONIK. 
All deaths occurring while enrolled in the MPP study will be reviewed by the CEC. 
11.5.2 Reporting Hospitalizations 
To eliminate possible bias at the site level related to possible endpoint events of 
the MPP sub-study, adverse events requiring hospitalization for any cardiovascular 
hospitalizations and any other hospitalizations in which cardiovascular symptoms 
occur will be collected while subjects are enrolled in the MPP sub-study. Each 
hospitalization will be adjudicated to determine whether it meets the MPP sub-
study endpoint criteria as a heart failure hospitalization by the Clinical Events 
Committee (CEC). 
BIOTRONIK will be responsible for verifying completeness of the initial reported 
event and coordinating with sites to obtain any missing or additional source 
documentation required by the CEC to adjudicate the case.  Additional 
documentation will be requested from the enrolling site as needed. The hospital 
report should include the following, if available: 
 

 
  
 
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• 
Discharge summary 
• 
History and physical and admission summary. 
• 
Diagnostic and laboratory test results. 
• 
Chest X-ray, echocardiography, ultrasound or other imaging test results, as 
appropriate. 
• 
Consultations, operation reports, progress notes and discharge summaries from 
the subject medical records. 
• 
Investigator description and assessment of the event. 
11.5.3 Definition of Heart Failure Hospitalization 
Hospitalization for worsening heart failure is defined as a hospitalization that 
includes increased signs and/or symptoms of worsening heart failure requiring the 
administration or augmentation of intravenous or oral heart failure therapy (e.g., 
inotropes, diuretics, and/or vasodilators).  
A hospitalization classification will be based on the primary admission diagnosis, 
not on the development of new events that occur during the hospitalization.   
For each hospital admission, the investigator will be requested to state whether or 
not the subject experienced worsening heart failure at the time of admission or 
during the admission, and if so, whether or not this was the primary reason for 
admission or secondary to an obvious precipitating factor such as atrial fibrillation. 
The investigator will also be asked to state whether or not the subject received an 
intravenous medication for heart failure including diuretics, vasodilators or inotropic 
agents or a substantial increase in oral diuretic therapy for heart failure. 
11.5.4 Adverse Events 
In addition to the adverse events reportable for the main QP ExCELs study, 
Section 6.2, the investigator shall report to the sponsor by completing the 
appropriate eCRF, the following type of events specific to the MPP sub-study: 
• Any cardiovascular hospitalizations and any other hospitalizations in which 
cardiovascular symptoms occur on or before the date of the 12-Month 
follow-up§§.  
• All adverse events that required additional invasive intervention to resolve, 
specifically related to the MPP feature of the CRT-D.  These adverse events 
include any software issues related to MPP programming for any adverse 
event that occurs while MPP is enabled and that may be attributed to the 
use of the MPP feature. 
 
§§ 9-month follow-up for subjects enrolled at the 3-month follow-up. 

 
  
 
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11.5.5 Adverse Events for Secondary Endpoint Analysis 
The AE-free rate calculated for secondary endpoint 1 will be based on the total 
number of subjects with at least one MPP related adverse event requiring 
additional invasive intervention to resolve.  For the secondary endpoint analysis, 
the AE classification, category, resolution, and relation to the MPP feature for each 
individual event will be determined by the Clinical Events Committee (Section 
11.3.4) 
All adverse events which the CEC determines the event is related or possibly 
related to the MPP feature will be included in the secondary endpoint event 
analysis.  Adverse events with a final CEC adjudicated relation of not related or 
unknown will not contribute to or be included in the evaluation of the secondary 
endpoint.   
11.5.6 Consent Materials (MPP Sub-Study) 
Prior to the patient's participation in the sub-study, informed patient consent is 
required from all patients.  Informed consent should be obtained in accordance with 
the FDA regulations (21CFR, Part 50).  The investigator is required to inform 
BIOTRONIK and the reviewing IRB within 5 days if any patient was not 
appropriately consented to participate in the study.  BIOTRONIK is then required to 
report any failure to obtain patient consent to the FDA within 5 working days of 
learning of such an event.  In order to assist with the consent process, BIOTRONIK 
will provide a template patient consent form to investigational sites participating in 
the study. 
11.5.7 IRB Approval 
Institutional Review Board (IRB) approval is required from each institution prior to 
participation in this clinical investigation (sub-study).  Patient enrollment may not 
begin until the IRB and BIOTRONIK have granted approval for the investigational 
site.  IRB approval is also required throughout the duration of this clinical 
investigation.  If IRB approval is withdrawn, BIOTRONIK must be notified within 5 
working days.  
11.5.8 MPP Sub-Study References 
1. Rinaldi CA, Burri H, Thibault B, Curnis A, Rao A, Gras D, Sperzel J, Singh JP, Biffi M, 
Bordachar P, Leclercq C:  A review of multisite pacing to achieve cardiac resynchronization 
therapy. Europace 2015;17:7-17. 
2. Forleo GB, Santini L, Giammaria M, Potenza D, Curnis A, Calabrese V, Ricciardi D, D’agostino 
C, Notarstefano P, Ribatti V, Morani G, Mantica M, Di Biase L, Bertaglia E, Calo L, Zanon F. 
Multipoint pacing via a quadripolar left-ventricular lead:  preliminary results from the Italian 
registry on multipoint left-ventricular pacing in cardiac resynchronization therapy (IRON-MPP). 
Europace 2016, doi:10.1093/europace/euw094 
3. Tomassoni GF, Baker J, Corbisiero R, Love CJ, MD, Martin DT, Sheppard RC, Worley SJ, 
Varma N, Niazi I.  Safety and efficacy of Multipoint Pacing in Cardiac Resynchronization 
Therapy: The MultiPoint Pacing (MPP) IDE Study.  Heart Rhythm Society 2016 LBCT01-03, 
http://www.abstractsonline.com/pp8/#!/3934/presentation/16311.    

 
  
 
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4. Packer M. Proposal for a new clinical end point to evaluate the efficacy of drugs and devices in 
the treatment of chronic heart failure. J Card Fail 2001;7:176–182. 
5. Bradycardia and Tachycardia Devices Merlin™ Patient Care System Help Manual, St. Jude 
Medical, Sylmar, CA, 2016, pp. 418-431, https://manuals.sjm.com 
6. Pappone C, Calovic Z, Vicedomini G, Cuko A, McSpadden LC, Ryu K, Jordan CD, Romano E, 
Baldi M, Saviano M, Pappone A, Vitale R, Catalano C, Ciaccio C, Giannelli L, Ionescu B, 
Petretta A, Fragakis N, Fundaliotis A, Tavazzi L, Santinelli V. Improving cardiac 
resynchronization therapy response with multipoint left ventricular pacing:  Twelve-month follow-
up study. Heart Rhythm 2015;12:1250-1258. 
7. Zanon F, Marcantoni L, Baracca E, Pastore G, Lanza D, Fraccaro C, Picariello C, Conte L, 
Aggio S, Roncon L, Pacetta D, Badie N, Noventa F, Prinzen F. Optimization of left ventricular 
pacing site plus multipoint pacing improves remodeling and clinical response to cardiac 
resynchronization therapy at 1 year. Heart Rhythm 2016;13:1644-1651. 
8. Gregoratos G, Cheitlin MD, Conill A et al. ACC/AHA 1998 Guideline for Implantation of Cardiac 
Pacemakers 
and 
Antiarrhythmia 
Devices: 
a 
report 
of 
the 
American 
College 
of 
Cardiology/American Heart Association Task Force on Practice. J Am Coll Cardiol 1998; 
31:1175-1209. 
 

 
  
 
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12. JUSTIFICATION FOR THE DESIGN OF THE PRE-
MARKET CLINICAL INVESTIGATION 
The Sentus QP leads are 4.8 French (F) quadripolar left ventricular leads designed 
for use with biventricular pacing systems. Sentus QP is the successor of the Corox 
OTW bipolar (BP) LV leads. The Corox LV leads are market approved in the U.S. 
and internationally. They have been extensively studied in the ongoing CELESTIAL 
Post Approval Registry (NCT#00810264). Quadripolar LV leads are relatively new 
to the market. In the U.S., the first quadripolar LV lead received market approval 
November 2011 and is currently undergoing evaluation in a post-approval study. A 
second quadripolar LV lead more recently received approval for the U.S. market. 
The results of CELESTIAL, summarized below, along with data collected during the 
EchoCRT study and available results from competitive quadripolar lead studies 
were used to support the expected performance goals and design for the pre-
market endpoints of this clinical study. 
Several clinical investigations conducted by BIOTRONIK Inc. or BIOTRONIK SE & 
Co. KG were relevant for the design of this clinical investigation: 
• EveresT 
• CELESTIAL Post Approval Registry 
• EchoCRT 
• Eluna Family/Sentus BP Master Study 
• Iperia Family / Sentus QP Master Study 
12.1 
EveresT 
The clinical study everesT was conducted by BIOTRONIK SE & Co. KG to assess 
the clinical safety and efficacy of the Corox OTW BP steroid polyurethane coated 
bipolar left ventricular lead and of Lumax HF-T 300/340 CRT-D devices. Two 
different fixation types of the Corox BP were investigated: a three dimensional pre-
shaped helical tip to achieve a stable position in larger veins (Corox OTW BP) and 
a straight tip ‘wedge position’ (Corox OTW-S BP) for placement in smaller veins.  
148 subjects in 25 sites from Austria, Germany, Italy, Israel, Switzerland and 
United Kingdom were enrolled in this prospective, non-randomized investigation. 
The first implantation was conducted on August 2, 2006 and the analysis consists 
of clinical data until September 30, 2007.  
Summary of results: 
• Corox LV lead implantation was attempted in 144 of 148 study subjects 
(97%) 
• 131 of the attempted Corox implants were successful (91%)  
• Implantation efficacy of Corox OTW BP helix was 91.5% (89/97) 

 
  
 
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• Implantation efficacy of Corox OTW-S BP straight was 89.5% (30/34) 
• Out of 131 study subjects with a successful Corox implantation, a total of 2 
Corox BP LV lead related complications were seen in 2 subjects within 90 
days post implantation 
• 1.5% of the study subjects with a successful Corox BP implantation 
experienced an LV lead related complication at 3 months post implantation 
(lead dislodgement, loss of capture) 
• One Lumax HF-T device related complication occurred due to a pocket 
infection 
• Corox BP LV lead measurements demonstrated good results in known 
ranges at implantation, pre-hospital discharge/wound check, and 1-, 3- and 
6- month follow-up visits 
Table 9 lists the reasons for the 13 unsuccessful Corox BP lead implantations:  
Table 12: Reasons for Corox BP Implantation Failure 
Reasons for implant failure 
NFailure* 
Inability to find stable position 
6 (46%) 
Anatomical difficulties 
5 (38%) 
Inability to advance the lead 
4 (31%) 
Lead dislodged while removing guide catheter 
4 (31%) 
High threshold 
3 (23%) 
Dissection of coronary sinus 
1 (8%) 
Phrenic nerve stimulation 
1 (8%) 
No reason given 
1 (8%) 
Total Corox BP implant failures 
13 
*Percentages total over 100% because multiple answers could be given for reason 
of implant failure. 
The data received and analyzed during the everesT clinical study demonstrate the 
safety and efficacy of the Lumax HF-T CRT-D device and Corox OTW (-S) BP 
Steroid. 
12.2 
CELESTIAL Study: Clinical Experience with Corox LV Lead 
BIOTRONIK, Inc. is currently conducting the CELESTIAL post-approval study 
(P070008) to confirm the long-term safety and reliability of the Corox OTW BP LV 
leads. This multi-center, prospective, non-randomized registry has been ongoing 
since December 2008 with enrollment of 2,499 subjects completed on October 16, 
2013. As of the May 2014 bi-annual report, the cumulative follow-up duration was 
5,741 years (mean duration 2.3 years). 

 
  
 
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Data from the May 2014 bi-annual report is summarized below. In one column, 
results from all three Corox LV lead models included in the CELESTIAL Study 
(OTW, OTW-S, and OTW-L) are provided, as the materials and lead body design 
are similar to Sentus QP. In a separate column, data from the Corox OTW-L and 
OTW-S leads are presented as these lead tip shapes are similar to those leads 
included in this study. 
The CELESTIAL Study permits enrollment up to 180 days post-implant and the 
visit schedule permits 3, 4, or 6 month visit intervals depending on the 
investigator’s standard of care for CRT subjects. The complication-free rate at 6 
months was calculated using the implant date and any qualifying adverse events 
occurring within 6 months post-implant. Lead measurements are from the actual 3 
month evaluation; therefore, the number of subjects is less than the total study 
population. 
Table 13: CELESTIAL Study Supporting Data 
 
All Corox models 
Corox OTW-L and 
Corox OTW-S 
Data supporting safety endpoint 
 
 
Subjects with safety data through 6 months post-implant, n 
2,128 
1,520 
Corox related complication-free rate at 6 months post-
implant* 
97.4% 
97.6% 
Total subjects with Corox related complication, n (%) 
56 (2.6%) 
37 (2.4%) 
  Lead dislodgement 
35 (1.6%) 
21 (1.4%) 
  Diaphragmatic/pectoral stimulation 
13 (0.6%) 
10 (0.7%) 
  High pacing threshold/intermittent or no capture 
7 (0.3%) 
5 (0.3%) 
  Lead impedance out of range. Potential conductor  
  fracture. 
1 (0.0%) 
1 (0.1%) 
  Procedure-related events 
0 (0.0%) 
0 (0.0%) 
Data supporting efficacy endpoint 
 
 
Subjects with efficacy data at 3 months post-implant, n 
1,475 
1,095 
Elevated threshold† free rate at 3 months post-implant 
93.2% 
93.0% 
Total subjects with elevated threshold, n (%) 
101 (6.8%) 
77 (7.0%) 
Corox lead performance at 3 months post-implant 
 
 
R-wave sensing, mean (±SD) in mV 
13.6 (±7.3) 
13.5 (±7.3) 
Pacing threshold, mean at 0.5 ms (±SD) in V 
1.4 (±1.1) 
1.4 (±1.1) 
Impedance, mean (±SD) in ohms 
732 (±251) 
730 (±248) 
*Includes all Corox related events resolved with an invasive action or for which the lead was 
abandoned, continued to be used despite a known clinical performance issue, or when polarity or 
mode reprogramming was utilized for suspected lead failures. In addition, procedure-related events 

 
  
 
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(such as cardiac perforation, pneumothorax, and coronary sinus dissection) that were directly 
caused by the LV lead were included. 
†Elevated threshold is defined as an LV pacing threshold > 3.5 V in any standard bipolar pacing 
vector. 
12.3 
Complication-free Rate in the EchoCRT Trial 
To further refine the expected complication-free rate, adverse events collected as 
part of the EchoCRT trial (IDE# G080067) were evaluated. The EchoCRT trial was 
a randomized control trial conducted at 115 sites in 17 different countries 
conducted by BIOTRONIK, Inc. At study termination, 821 narrow QRS subjects 
had been implanted with a CRT-D system (mean implant duration of 1.7 years). 
Though the LV leads implanted in EchoCRT were not exclusively manufactured by 
BIOTRONIK, the data is informative because subjects were consented prior to 
implant, which limits subject selection bias and ensures reporting of all adverse 
events that occur at or immediately after device implant.  
Table 14: EchoCRT Supporting Data 
Data supporting safety endpoint 
All LV leads 
Subjects with safety data through 6 months post-randomization, n 
670 
LV lead related complication-free rate at 6 months post-randomization* 
94.5% 
Total subjects with LV lead related complication, n (%) 
37 (5.5%) 
  Lead dislodgement 
24 (4.3%) 
  Diaphragmatic/pectoral stimulation 
4 (0.6%) 
  High pacing threshold/intermittent or no capture 
2 (0.3%) 
  Procedure-related events 
2 (0.3%) 
*Includes all LV lead related events resolved with an invasive action or for which the lead was 
abandoned, continued to be used despite a known clinical performance issue, or when polarity 
or mode reprogramming was utilized for suspected lead failures, or events in which these 
actions would have been taken if subject had been randomized to CRT ON treatment arm. In 
addition, procedure-related events (such as cardiac perforation, pneumothorax, and coronary 
sinus dissection) that were directly caused by the LV lead were included. 
12.4 
Eluna Family /Sentus BP Master Study 
This Master Study is performed by BIOTRONIK SE & Co. KG to confirm the safety 
and efficacy of the Eluna pacemaker family and the Sentus BP left ventricular lead. 
The Sentus BP left ventricular lead is the bipolar model of the Sentus leads and is 
similar in design to the quadripolar QP lead variants. After implantation of the 
Sentus BP lead, 2 in-hospital follow-ups are part of the study (pre-hospital 
discharge and 3 months after implantation). The data will be used to support the 
regulatory process in Japan. The study has enrolled 166 subjects and is currently 
in the follow-up phase. 

 
  
 
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12.5 
Iperia Family / Sentus QP Master Study 
This Master Study is performed by BIOTRONIK SE & Co. KG to confirm the safety 
and efficacy of the Iperia ICD family. The CRT-D devices of the Iperia Family are 
implanted in combination with the Sentus QP left ventricular lead. After 
implantation of the device system, 2 in-hospital follow-ups are part of the study 
(pre-hospital discharge and 3 months after implantation). The data will be used to 
support the regulatory process in Japan. The study has enrolled 152 subjects and 
is currently in the follow-up phase. 
12.6 
Published Results for Competitive Quadripolar Leads 
Tomassoni et al., 2013 evaluated the safety and efficacy of the St. Jude Medical 
Promote® Q device system (Promote® Q CRT-D and Quartet® LV lead) in a 
clinical investigation. The CRT-D device is equipped with an IS4 connector to 
facilitate the implantation of the corresponding LV lead. The Quartet® LV lead is a 
quadripolar lead and has an over-the-wire design. In total 178 subjects were 
enrolled in the study. The device system was implanted successfully in 170 
subjects (95.5%). The primary safety endpoint was designed to show the freedom 
from LV lead related complications from implantation to the 3-month post-
implantation visit. The complication free rate was calculated to 96%. The 97.5% 
lower confidence interval of 93% is greater than the success criterion of 85%. The 
LV capture thresholds and pacing impedances in all 10 vectors remained stable 
during follow-up. LV lead dislodgment occurred in 6 subjects and phrenic nerve 
stimulation (PNS) was observed in 23 subjects. PNS was resolved non-invasively 
in all cases by reprogramming of the device. 
Performance criteria and results from this IDE study are presented in Table 15. 
Table 15: Competitive Quadripolar LV Lead Performance 
 
Safety 
Efficacy 
Performance criteria 
85% 
75% 
Outcome 
96%  
(97.5% LCB = 93%) 
79.7%  
(97.5% LCB = 73%) 
Source: Review Memo for P030054-S173 from FDA.gov. Efficacy is from the per protocol analysis 
(percentage of subjects with threshold < 2.5 V in Vector 1 and at least one nonstandard vector). 

 
  
 
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13. BIBLIOGRAPHY 
Bristow,M.R., Saxon,L.A., Boehmer,J., Krueger,S., Kass,D.A., De Marco,T., 
Carson,P., 
DiCarlo,L., 
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and the European Heart Rhythm Association. Eur. Heart J. 31, 2677-2687. 
Goetze,S., Defaye,P., Bauer,A., Merkel,M., Bizeau,O., Treusch,S., Contzen,K., 
Juenger,C., and Winter,J. (2013). Phrenic nerve stimulation in CRT patients and 
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Gurevitz,O., Nof,E., Carasso,S., Luria,D., Bar-Lev,D., Tanami,N., Eldar,M., and 
Glikson,M. (2005). Programmable multiple pacing configurations help to overcome 
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Hansky,B., 
Vogt,J., 
Gueldner,H., 
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Horstkotte,D., 
and 
Koerfer,R. (2006). Left ventricular pacing and CRT. What CV fits into which vein? 
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Lloyd-Jones,D., Adams,R.J., Brown,T.M., Carnethon,M., Dai,S., de Simone,G., 
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stroke statistics--2010 update: a report from the American Heart Association. 
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Metha,P.A., Shetty,A.K., Squirrel,M., Bostock,J., and Rinaldi,A. (2012). Elimination 
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Minden,H.H. (2011). Technische Innovationen und Limitationen im Bereich der 
Elektrotherapie. Herzschr. Elektrophys 1, 11-15. 
Moubarak,G., Bouzeman A., Ollitrault,J., Anselme,F., and Cazeau,S. (2014). 
Phrenic nerve stimulation in cardiac resynchronisation therapy. J Interv Card 
Electrophysiol epub ahead of print. 
Nof,E., Gurevitz,O., Carraso,S., Bar-Lev,D., Luria,D., Bachar,S., Eldar,M., and 
Glikson,M. (2008). Comparison of results with different left ventricular pacing leads. 
Europace 10, 35-39. 
Romeyer-Bouchard,C., 
Da 
Costa 
A., 
Dauphinot,V., 
Messier,M., 
Bisch,L., 
Samuel,B., Lafond,B., Ricci,P., and Isaaz,K. (2010). Prevalence and risk factors 
related to infections of cardiac resynchronization therapy devices. Eur. Heart J. 31, 
203-210. 
Shetty,A.K., Duckett,S.G., Bostock,J., Roy,D., Ginks,M., Hamid,S., Rosenthal,E., 
Razavi,R., and Rinaldi,C.A. (2011). Initial single-center experience of a quadripolar 
pacing lead for cardiac resynchronization therapy. Pacing Clin. Electrophysiol. 34, 
484-489. 
Thibault,B., Dubuc,M., Khairy,P., Guerra,P.G., Macle,L., Rivard,L., Roy,D., 
Talajic,M., Karst,E., Ryu,K. et al. (2013). Acute haemodynamic comparison of 
multisite and biventricular pacing with quadripolar left ventricular lead. Europace 
15, 984-991. 
Tomassoni,G., Baker,J., Corbisiero,R., Love,C., Martin,D., Niazi,I., Sheppard,R., 
Worley,S., Beau,S., Greer,S. et al. (2013). Postoperative performance of the 
Quartet left ventricular heart lead. J Cardiovasc Electrophysiol 24, 449-456. 
Varma,N., Epstein,A.E., Irimpen,A., Schweikert,R., and Love,C. (2010). Efficacy 
and safety of automatic remote monitoring for implantable cardioverter-defibrillator 
follow-up: the Lumos-T Safely Reduces Routine Office Device Follow-up (TRUST) 
trial. Circulation 122, 325-332. 
 

 
  
 
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14. APPENDIX A: DEFINITION OF TERMS 
Abnormal Defibrillation Impedance – Defibrillation impedance is typically 
considered abnormal if a measurement is < 25 Ω or > 150 Ω (based on lead model 
and measurement range of the device). Includes high or low shock impedance 
when attempting to deliver a shock. 
Abnormal Pacing Impedance – Pacing impedance is typically considered 
abnormal if a measurement is <200 Ω or >3000 Ω (based on lead model and 
measurement range of the device). 
Cardiac Perforation associated with a lead – Penetration of the lead tip through 
the myocardium (including microperforation), clinically suspected and confirmed by 
chest x-ray, fluoroscopy, echocardiogram, intracardiac electrogram and/or visually. 
Clinical Lead Failure – Inability of the lead to correctly sense or pace in the heart, 
not attributable to a mechanical or electrical failure of the lead or pulse generator 
and that remains unresolved despite reprogramming and/or repositioning. 
Coronary Sinus Dissection – A tear that occurs in the wall of the coronary sinus. 
Electrical Lead Failure – Confirmed or suspected lead issue that is due to an 
electrical failure of the lead, such as electrical noise not attributable to other 
causes, and that leads to loss of pacing and/or sensing. Specific types of confirmed 
or suspected electrical lead failures, such as high impedance values, no capture, 
and loss of sensing, are separate adverse event categories and should only be 
reported once. Confirmed or suspected electrical lead failures caused by induced 
malfunctions, such as lead damage caused during a procedure, are excluded. 
Elevated Pacing Threshold – Either of the following is considered an elevated 
pacing threshold for the Sentus QP lead: 
• At implant: pacing threshold > 3.0 V at 0.4 ms or 0.5 ms 
• At routine evaluation: pacing threshold > 2.5 V at 0.4 ms or 0.5 ms 
These thresholds are less than half of the maximum output in BIOTRONIK CRT 
devices and allow for an adequate safety margin. 
Extracardiac Stimulation – Clinical observation of inadvertent nerve/muscle 
stimulation other than cardiac muscle, such as phrenic nerve stimulation. 
Failure to Capture or Intermittent Capture – Intermittent or complete failure to 
achieve cardiac stimulation at programmed output delivered outside of the cardiac 
refractory period. This will be considered an AE if invasive intervention is taken. In 
absence of invasive intervention, this will only be considered an AE if there is 
failure to capture at the permanently programmed output with a minimum 2:1 safety 
margin. Sudden and significant increase in the pacing threshold value (elevated 
threshold compared to previous measured value) at which 2:1 safety margin can 
no longer be achieved.  

 
  
 
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Failure to Sense or Undersensing – Intermittent or complete loss of sensing or 
failure to detect intended intrinsic cardiac signals (atrial or ventricular) during non-
refractory periods at programmed sensitivity settings. In absence of additional 
invasive intervention, this will only be considered an AE if the loss of sensing is not 
due to a medical reason and cannot be resolved with reprogramming. 
Hematoma – A localized collection of extravasated blood, usually clotted, in an 
organ, space, or tissue. A hematoma is not considered a protocol defined AE 
unless it is a major hematoma related to the implant procedure. See major 
hematoma. 
High Pacing Threshold – High lead pacing threshold resulting in invasive 
intervention. In absence of invasive intervention, at follow-up, lead threshold that 
has increased two fold from the chronic threshold value, and is unable to achieve a 
2:1 safety margin. 
Incorrect Lead/Header Connection – Lead connector pin connected to wrong 
header port, such as swapping leads or reversing connector pins, that is not 
identified and corrected prior to the end of the implant/revision procedure. 
Infection – An invasion and multiplication of microorganisms in body tissues 
causing local cellular injury and requiring intravenous antibiotics and or system 
removal/extraction. 
Lead Conductor Fracture – A mechanical break within the lead conductor 
(includes connectors, coils and / or electrodes) observed visually, electrically, or 
radiographically. 
Lead Dislodgment – Radiographic, electrical or electrocardiographic evidence of 
electrode displacement from the original implant site or electrode displacement that 
adversely affects pacing, and/or lead performance. 
Lead Explant – Surgical removal of a lead either by simple traction (such as 
occurs during the acute implant stage) or using manipulation and tools (as can be 
required for chronically implanted leads). 
Lead Insulation Breach or Insulation Break – A disruption or break in lead 
insulation observed visually, electrically, or radiographically. 
Loose Set Screw – Header set screw not properly tightened prior to end of 
implant/revision procedure. 
Major Hematoma – Hematoma requiring evacuation, drainage, blood transfusion, 
hospitalization or extension of hospital stay to treat hematoma. 
Mechanical Failure – Malfunction of the lead through a break in the conductor, 
insulation, or connector pin leading to loss of pacing / sensing observed visually, 
electrically, or radiographically. Confirmed or suspected mechanical failures 
induced by intervention, such as lead damage caused during a procedure, are not 
protocol defined adverse events. 

 
  
 
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New York Heart Association (NYHA) Functional Classification – A recognized 
system of classifying the extent of heart failure.  
NYHA 
Class 
Symptoms 
I 
Subjects with cardiac disease, but without resulting limitation of 
physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain. 
II 
Subjects with cardiac disease resulting in slight limitation of 
physical activity. They are comfortable at rest. Ordinary physical 
activity results in fatigue, palpitation, dyspnea, or anginal pain. 
III 
Subjects with cardiac disease resulting in marked limitation of 
physical activity. They are comfortable at rest. Less than ordinary 
activity causes fatigue, palpitation, dyspnea, or anginal pain. 
IV 
Subjects with cardiac disease resulting in inability to carry on any 
physical activity without discomfort. Symptoms of cardiac 
insufficiency or of anginal syndrome may be present even at rest. If 
any physical activity is undertaken, discomfort is increased. 
Non-healing Pocket Dehiscence – Separation of wound edges around the pocket 
of the implanted pulse generator that have not healed. 
Pneumothorax – Air or fluid in the pleural space surrounding the lung leading to 
collapse or partial collapse of the lung requiring observation or chest tube 
placement 
Premature Battery Depletion – Reaching elective replacement indicator (ERI) 
before the predicted date. 
Pulmonary Embolism – Blockage of the main artery of the lung or one of its 
branches by a substance that has travelled from elsewhere in the body through the 
bloodstream. 
Pulse Generator Failure – Confirmed or suspected pulse generator issue that is 
due to a mechanical failure or electrical malfunction, such as inability to 
communicate with pulse generator, electrical circuit failure, or inability to deliver 
therapy, that is not attributable to another component of the system or caused by 
an external source.  
Skin Erosion – Deterioration of tissue over an implanted device or the movement 
of a lead toward or through the skin. 
Tamponade – Compression of the heart caused by blood accumulation in the 
space between the myocardium and the pericardium. 
Thrombosis – The development of a blood clot in a vein or artery that leads to the 
obstruction of blood flow. 

 
  
 
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Twiddler’s Syndrome – A condition where the pulse generator leads are 
dislodged by the subject unwittingly rotating or otherwise moving the subcutaneous 
pulse generator. 
Venous Occlusion – Blockage of a vein causing a reduction of blood supply and 
associated symptoms. 
 

 
  
 
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15. APPENDIX B: PREVIOUSLY IDENTIFIED ADVERSE 
EVENTS  
Based on literature research, the following adverse events may possibly occur as 
medical complications of a cardiac rhythm management system implant. The most 
common adverse events related to the implantation procedure are listed in Table 
16a. Expected adverse events related to the left ventricular pacing threshold test in 
the novel vectors are listed in Table 16d. All references used for this chapter refer 
to the list at the end of this section. 
Adverse events listed below are considered expected unless not previously 
identified in nature, severity or degree of incidence. 
Table 16a: Expected Perioperative Events  
Frequency 
Percentage (%) 
Risk 
Very frequent 
>1 out of 10 patients 
7-1945 
LV lead exchange due to unsuccessful positioning 
3-2732 
Atelectasis (when thoracotomy necessary) 
3-2732 
Pleural effusion (when thoracotomy necessary) 
3-2732 
Pneumonia (when thoracotomy necessary) 
Up to 1732 
VT/VF exacerbation8,32 
Frequent 
1 to 10 patients out of 100 
1-732 
Infection (general) 
5.255,56 - 632 
Lead perforation 
3-432 
Pericarditis (when patch lead placement necessary) 
Up to 332 
Embolism 
Up to 349 
Phrenic nerve stimulation 
0.6 – 2.049 
Infection requiring reoperation 
0.07*-332,54 
Pericardial tamponade (2-3% during patch lead placement) 
0.9331-10.62,49 
Lead dislodgement 
0.1231–3.449 
Coronary sinus dissection 
Occasionally 
1 to 10 patients out of 
1.000 
0.9331 
Hematoma 
0.754 
Loosening of set screw 
0.0231 -130 
Myocardial infarction 
0.0631-232 
Cerebrovascular 
accident, 
stroke 
(1-2% 
during 
thoracotomy) 
0.630 
Lead dysfunction 
0.530 – 0.757 
Mortality 
0.530 
Severe pocket hematoma 
0.554 
Pericardial tamponade (2-3% during patch lead placement) 
0.4231 -130 
Pneumothorax 
0.331 – 0.449 
Cardiac arrest 
0.230 
Arrhythmia 
0.2 – 0.349 
Respiratory arrest 
0.249 
Tamponade 

 
  
 
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0.1 - 0.451 
Allergic reaction to ionic contrast material 
0.1450 
Air embolism 
0.149 
Lead fracture/ insulation failure 
0.159 
Ventricular fibrillation 
Rare 
1 to 10 patients out of 
10.000 
0.0931 
Drug reaction 
0.0831 
Hemothorax 
0.0731 
Cardiac perforation 
0.0431 
Phlebitis, superficial 
0.0331 
Conduction block 
0.0331 
Infection related to device 
0.0331 
Peripheral embolus 
0.0252– 0.0453 
Allergic reaction to non-ionic contrast material 
0.0231 
Phlebitis, deep 
0.0231 
Transient ischemic attack 
Very rare 
<1 patient out of 10.000 
<0.0131 
Cardiac valve injury 
<0.0131 
Peripheral nerve injury 
<0.0131 
AV-fistula 
Not known 
Frequency not assessable 
on the  basis of the 
available data 
 
Allergic reaction to dexamethasone acetate, bleeding32, 
brachial plexus injury32, device migration30,41, diaphragmatic 
stimulation32, discomfort, erosion, exit block32, failure to 
insulate set screw32, hemoptysis32, injury to vagus nerve32, 
lead malpositioning32, lead microdislocation32, local tissue 
reaction30, muscle stimulation30, nerve stimulation (general) 
30, myocardial lesion30, pocket seroma32, subclavian artery 
puncture32, higher x-ray load due to extended fluoroscopy 
times34, failing of shock test40, injury due to implantation 
accessories42,44 
Table 16b: Expected Postoperative Events 
Frequency 
Percentage (%) 
Risk 
 
9.720 -3723 
Lead failure20,22,23 
Very frequent 
>1 out of 10 patients 
2.97–25.424 
Inappropriate shocks7,24,25,54 
Up to 1329 
Device 
explantation 
(manufacturers` 
advisory: 
4%29, 
electronic failure: 2%29, housing defects: 1%29) 
0.31 – 13.64 
Phrenic nerve stimulation 
126,21 
Lead dysfunction 
1.219 –10.62 
Lead dislodgement 
Frequent 
1 to 10 patients out of 100 
1.72 – 9.52 
Formation of clinical significant hematomas 
7.615 – 9.51 
Hematoma1,3,15,16,17 
746 
Subclavian vein occlusion ≥ 75% 
0.15 - 71 
Infections1,5,14 (CRT-D related: 1.91,4,13 - 1.9%1,4; in-hospital 
infections: 0.7%12; infections after replacement: 1.9%13) 
0.1 – 4.260 
Lead fracture 
1.67 – 3.94 
Elevated pacing threshold/ loss of capture/ failure to capture 
2.430 
Aggregate perforation 

 
  
 
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3.430 
Pocket erosion 
02 – 1.57 
Mortality within 30 days after implant (0.4% related to 
implant procedure7) 
1.530 
Premature depletion of battery  
1.47 
Diaphragmatic muscular stimulation 
0.32 – 1.35 
Lead perforation 
1.31 
Pericarditis requiring anti-inflammatory agents 
0.057 –1,212,57,61 
Pneumothorax 
0.91 
High LV threshold 
0.75 
Oversensing 
0.67 
Discomfort 
0.67 
Pain at device pocket 
0.61 
Pericardial effusion requiring intervention 
0.67 
Seroma 
0.67 
Shoulder pain 
0.54 
Lead conductor fracture 
0.530 
M. pectoralis tremor 
0.35 – 0.518 
Post-operative perforation 
0.754 
Thrombosis of brachial, subclavian or jugular veins 
0.312 
Acute renal failure requiring hemodialysis 
0.31 
Ipsilateral venous thrombosis 
0.37 
System- or lead-related arrhythmia 
0.24 
Elevated lead impedance 
0.263 
Site pain 
0.254 
Thrombosis of deep femoral vein 
Rare 
1 to 10 patients out of 
10.000 
0.0935 
Fluid accumulation due to heart perforation 
0.17 
Cardiac/ cardiac vein/ coronary sinus dissection 
0.17 
Hypotension 
0.0739 
Twiddlers syndrome 
Not known 
Frequency not assessable 
on the  basis of the 
available data 
 
Farfield sensing or crosstalk leading to pacemaker 
malfunction30, 
Pacemaker 
Mediated 
Tachycardia30,  
isolation 
deficiency30, 
connector 
deficiency30, 
undersensing30, chronic nerve damage30, fibrotic tissue 
formation30, keloid formation30, formation of cysts30, sensing 
of myopotentials30, pulse generator failures26, device 
extrusion36, 
43, vein occlusion37, occlusion of coronary 
sinus38 
Table 16c: Expected Psychological Events 
Frequency 
Percentage (%) 
Risk 
Very frequent 
>1 out of 10 patients 
259,10 - 509 
Anxiety or depression9,10,11,27 
Occasionally 
Up to 16 
Psychological intolerance 

 
  
 
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1 to 10 patients out of 
1.000 
Psychosomatic impairment 
Not known 
Frequency not assessable 
on the  basis of the 
available data 
 
Decreased energy levels28, sleep disturbances28, loss of 
libido28, fatigue28, reduced physical capacity28, change in 
body perception28, decreased activity level28, sense of 
impending danger and uncertainty about the future28, 
sensation of losing control28, sensation of isolation28, 
cognitive impairment28, decline in social interaction28, fear of 
shock 
delivery28, 
fear 
of 
death28, 
fear 
of 
device 
malfunction28, alteration of social relationships28, obsessive 
thinking about shocks28 
Tale 16d: Expected Events due to Pacing Threshold Test of the LV Lead 
Frequency 
Percentage (%) 
Risk 
Very frequent 
>1 out of 10 patients 
3247- 4148 
Phrenic nerve stimulation in 1 or more pacing vectors 
Not known 
Frequency not assessable 
on the  basis of the 
available data 
 
palpitations 
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lead 
for 
cardiac 
resynchronization 
therapy. 
Pacing  
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