QP ExCELs: MultiPole Pacing (MPP) Sub-Study
Phase: NA
Conditions: Heart Failure
Sponsor: Biotronik, Inc.

 
  
 
 
 
 
Clinical Investigation Plan for  
QP ExCELs U.S. 
 
 
 
 
Sentus QP – Extended CRT Evaluation with 
Quadripolar Left Ventricular Leads 
EP PASSION/MPP Sub-Study Amendment 
NCT03155724 
 
 
September 6, 2019 
 
 
 
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 ........................................................................................................................ 7 
1.1 Study Overview .................................................................................................................. 7 
1.2 Background ........................................................................................................................ 7 
1.2.1 Published Results for Multipoint LV Pacing............................................................ 8 
1.3 Devices .............................................................................................................................. 9 
1.3.1 Sentus QP Lead ..................................................................................................... 9 
1.3.2 Pacing and Sensing Vector Options ..................................................................... 10 
1.3.3 MultiPole Pacing (MPP) Description .................................................................... 12 
2. STUDY DESIGN ...................................................................................................................... 16 
2.1 Objectives ........................................................................................................................ 17 
2.1.1 Primary Endpoint 1 ............................................................................................... 17 
2.1.2 Secondary Endpoint 1 .......................................................................................... 18 
2.1.3 Secondary Endpoint 2 .......................................................................................... 18 
2.1.4 Secondary Endpoint 3 .......................................................................................... 18 
2.1.5 Additional Data of Interest .................................................................................... 19 
2.2 Subject Status Definitions ................................................................................................ 19 
2.3 Study Size and Duration .................................................................................................. 20 
2.3.1 MPP Sub-Study Sample Size Analysis ................................................................ 21 
2.3.1.1 Primary Endpoint 1 Sample Size ................................................................................ 21 
2.4 Interim Analysis ................................................................................................................ 22 
2.5 Adjustments to Overall Sample Size ............................................................................... 22 
2.6 Data Analyses .................................................................................................................. 22 
2.6.1 Replacement of Missing Data .............................................................................. 23 
2.6.2 MPP Sub-Study Analysis Population ................................................................... 23 
3. PROTOCOL REQUIREMENTS ............................................................................................... 24 
3.1 Subject Population ........................................................................................................... 24 
3.1.1 Indications for Use ................................................................................................ 24 
3.1.2 Contraindications .................................................................................................. 24 
3.1.3 Inclusion Criteria ................................................................................................... 24 
3.1.4 Exclusion Criteria .................................................................................................. 25 
3.2 Methods ........................................................................................................................... 26 
3.2.1 eCRFs ................................................................................................................... 26 
3.2.2 Subject Demographics, Comorbidities and Medications ...................................... 26 
3.2.3 Device Settings ..................................................................................................... 27 
3.2.4 CRT Based Lead Measurements ......................................................................... 27 
3.2.5 New York Heart Association (NYHA) Classification ............................................. 27 
3.2.6 Patient Global Assessment (PGA) ....................................................................... 28 
3.3 Study Procedures ............................................................................................................ 28 
3.3.1 Overview of Study Procedures ............................................................................. 30 
3.3.2 QP ExCELs Enrollment ........................................................................................ 31 
3.3.3 Implantation .......................................................................................................... 31 
3.3.4 QP ExCELs 6-month Follow-up ........................................................................... 32 
3.3.5 MPP Sub-Study Enrollment .................................................................................. 33 

 
  
 
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3.3.6 3-Month MPP Follow-up ....................................................................................... 34 
3.3.7 6-Month MPP Follow-up ....................................................................................... 34 
3.3.8 Interim Follow-up .................................................................................................. 34 
3.3.8.1 MPP Sub-Study Heart Failure Hospitalization ............................................................ 35 
3.3.8.2 Adverse event related interim follow-up ..................................................................... 35 
3.3.8.3 System Revision ........................................................................................................ 35 
3.3.9 Study Termination ................................................................................................ 36 
3.4 Study Participation Expectations ..................................................................................... 36 
3.4.1 Point of Enrollment ............................................................................................... 36 
3.4.2 Reasons for Study Termination ............................................................................ 36 
3.4.2.1 No implant attempt ..................................................................................................... 36 
3.4.2.2 Withdrawal of subject consent .................................................................................... 37 
3.4.2.3 Subject death ............................................................................................................. 37 
3.4.2.4 Sentus QP lead or BIOTRONIK CRT-D extraction ..................................................... 37 
3.4.2.5 Lost to follow-up ......................................................................................................... 37 
3.4.2.6 MPP Sub-Study Completion ....................................................................................... 38 
3.4.3 Date of Study Termination .................................................................................... 38 
4. ADDITIONAL STUDY CONDITIONS ...................................................................................... 39 
4.1 IRB Approval .................................................................................................................... 39 
4.2 Subject Consent ............................................................................................................... 39 
4.3 Data Collection ................................................................................................................. 39 
4.3.1 Electronic Data Capture (EDC) ............................................................................ 39 
4.3.2 Electronic Case Report Forms (eCRFs) ............................................................... 39 
4.3.3 BIOTRONIK Home Monitoring® Data ................................................................... 40 
4.4 Confidentiality of Subject Data ......................................................................................... 40 
4.5 Data Quality Control ......................................................................................................... 40 
4.6 Deviations from Clinical Investigation Plan ...................................................................... 40 
4.6.1 Protocol Violations ................................................................................................ 41 
4.6.2 Protocol Deviations ............................................................................................... 41 
4.6.3 IRB Reporting of Non-Compliance ....................................................................... 41 
4.7 Subject Retention ............................................................................................................. 41 
4.8 Study Completion ............................................................................................................. 42 
5. STUDY OVERSIGHT ............................................................................................................... 43 
5.1 Clinical Events Committee ............................................................................................... 43 
5.1.1 Clinical Events Committee – MPP Sub-Study Events .......................................... 43 
6. ADVERSE EVENTS ................................................................................................................ 44 
6.1 Definitions ........................................................................................................................ 44 
6.1.1 Definition of Adverse Event .................................................................................. 44 
6.1.2 Definition of Adverse Device Effect ...................................................................... 44 
6.1.3 Serious AEs, ADEs ............................................................................................... 45 
6.1.4 Definition of Heart Failure Hospitalization ............................................................ 45 
6.2 Reporting Adverse Events ............................................................................................... 45 
6.3 Reportable Adverse Events ............................................................................................. 47 
6.3.1 Lead, System, and Procedure Related Event Examples ..................................... 47 
6.3.2 Reporting Hospitalizations .................................................................................... 48 

 
  
 
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6.3.3 MPP Feature Related Adverse Events ................................................................. 48 
6.4 Sponsor Reporting ........................................................................................................... 49 
7. OTHER INSTITUTIONS AND PHYSICIANS........................................................................... 50 
8. RISKS AND BENEFITS........................................................................................................... 51 
8.1.1 Potential Benefits .................................................................................................. 51 
8.1.2 Potential Risks ...................................................................................................... 51 
9. MONITORING .......................................................................................................................... 52 
9.1 Summary .......................................................................................................................... 52 
9.2 Monitors ........................................................................................................................... 53 
10. RECORDS AND REPORTS .................................................................................................... 54 
10.1 Investigator Records ........................................................................................................ 54 
10.2 Investigator Reports ......................................................................................................... 54 
10.3 Sponsor Records and Reports ........................................................................................ 55 
11. REFERENCES ......................................................................................................................... 57 
12. APPENDIX A: DEFINITION OF TERMS ................................................................................. 60 
13. APPENDIX B: PREVIOUSLY IDENTIFIED ADVERSE EVENTS .......................................... 64 
 

 
  
 
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Table of Figures 
Figure 1: Sentus QP Lead Tip Design ........................................................................................... 10 
Figure 2: Programmer Display of LV Pacing Polarity .................................................................... 12 
Figure 3: Programming MultiPole Pacing ...................................................................................... 13 
Figure 4: Programming 1st LV Stimulus ......................................................................................... 14 
Figure 5: Programming 2nd LV Stimulus ........................................................................................ 14 
Figure 6: V-V Delay, LV First ......................................................................................................... 15 
Figure 7: V-V Delay, RV First ........................................................................................................ 15 
Figure 8: Clinical Study Design ..................................................................................................... 29 
 
Table of Tables 
Table 1: LV Pacing and Sensing Configurations ........................................................................... 11 
Table 2: Programmable Parameters for MultiPole Pacing ............................................................ 13 
Table 3: Subject Status Definitions................................................................................................ 20 
Table 4: Recommended Device Settings ...................................................................................... 27 
Table 5: Required Visit Windows for MPP Sub-Study................................................................... 30 
Table 6: Procedures by Visit Type................................................................................................. 30 
Table 7: Investigator Reports ........................................................................................................ 55 
Table 8: Sponsor Reporting Responsibilities ................................................................................ 56 
Table 9: Expected Perioperative Events ....................................................................................... 64 
 
 
 

 
  
 
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QP ExCELs 
Sentus QP – Extended CRT Evaluation with Quadripolar  
Left Ventricular Leads 
EP PASSION/MPP Sub-Study Amendment 
 
Protocol Version – September 6, 2019 
 
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 
EP PASSION/MPP Sub-Study Amendment 
Acronym 
QP ExCELs 
Subject collective 
Heart failure subjects with standard CRT-D indication 
according to clinical routine.  
Design 
 
 
 
Single-arm, multi-center, and prospective trial. The MPP 
sub-study is designed to fulfill the FDA required post-
aproval 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),or Acticor/Rivacor HF-T QP family CRT-
D system (PMA P050023/S125). 
Objectives 
The primary objective of this clinical investigation is to 
convert a percentage of CRT non-reponders to 
responders using the MultiPole Pacing (MPP) feature.  
Primary Endpoint 
Evaluation of the CRT responder status with the MPP 
feature 
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 
QP ExCELs study: up to 1,754 subjects enrolled in U.S. 
MPP sub-study: up to 110 subjects within the U.S. who 
are participating in the QP ExCELs study. 
Investigational Sites 
Up to 75 sites within the United States 
Follow-up period 
All subjects will be followed up to 6 months for screening 
into the MPP sub-study. If the MPP inclusion/exclusion 
criteria are met at screening, the subject will be followed 
an additional 6 months.   
Sponsor 
BIOTRONIK, Inc. 
Clinical Studies Department 
6024 Jean Road 
Lake Oswego, Oregon 97035 
 

 
  
 
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1. 
INTRODUCTION 
1.1 
Study Overview 
The QP ExCELs study protocol was designed to support a pre-market study 
phase and an FDA required post-approval registry phase for BIOTRONIK’s 
Sentus QP lead. In addition, the QP ExCELs protocol supports 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.  
Upon completion of the pre-market analysis and approval of the Sentus QP LV 
lead (P070008/S079, approved May 4, 2017), enrollment into the QP ExCELs 
study was continued to fulfill the post-approval study requirements. On 
September 24th, 2019, BIOTRONIK received FDA approval to transition the QP 
ExCELs Study protocol to the Sentus QP EP PASSION Post-Approval Study 
Protocol. The purpose of this clinical study protocol amendment is to support the 
continuation of the MPP sub-study while the QP ExCELs Post-Approval Study 
protocol is transitioned to the Sentus QP EP PASSION Post-Approval Study 
protocol.  
Subjects eligible for the study are receiving or have recently received 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, which will 
include consent to participate in the QP ExCELs study and the MPP sub-study. 
Subjects will be screened for the MPP sub-study at the 6 month in-office follow-
up, or between 3 months and 6 months post-implant if the patient has a heart 
failure hospitalization. Those subjects satisfying the MPP sub-study inclusion and 
exclusion criteria will continue into the MPP sub-study and be seen for additional 
follow-up visits at 3 months and 6 months after MPP sub-study enrollment (See 
Section 3.3 for details). No further study visits will be completed for subjects that 
do not qualify for the MPP sub-study.  
All devices utilized in conjunction with this study are U.S. market approved and 
prescribed by physicians according to approved indications for use. 
1.2 
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 the proven benefit of CRT in the indicated population, up to one-third of 
patients do not respond to the therapy (Rinaldi et al., 2015). The combination of 
the BIOTRONIK left ventricular lead family Sentus QP 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 ability 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 (Forleo et al., 
2016). 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 (BiV) pacing (Tomassoni et al., 2016).  
The current protocol is designed to demonstrate the effectiveness of the MPP 
feature in BIOTRONIK CRT-D systems by converting a percentage of CRT non-
responders to responders.  
1.2.1 
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 

 
  
 
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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) (Forleo et al., 2016). 
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). 
1.3 
Devices 
This study utilizes the Ilivia 7 HF-T QP family and the Acticor/Rivacor HF-T QP 
family CRT-D systems with an IS4 port for connection to a Sentus OTW left 
ventricular lead. 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. 
1.3.1 
Sentus QP Lead 
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 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 and a small 
diameter.  
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 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 

 
  
 
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between LV2-ring and LV3-ring, and 10 mm between LV3-ring and LV4-ring. 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 are available: 
• 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 1: Sentus QP Lead Tip Design 
 
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. 
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 

 
  
 
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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. When implanted with an Acticor/Rivacor family device, the Sentus QP 
LV lead offers 20 programmable pacing configurations. 
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 
 
 
 
13 
LV3 ring → 
LV1 tip* 
 
 
 
14 
LV4 ring → 
LV1 tip* 
 
 
 
15 
LV1 tip  → 
LV3 ring* 
 
 
 
16 
LV2 ring → 
LV3 ring* 
 
 
 
17 
LV4 ring → 
LV3 ring* 
 
 
 
18 
LV2 ring → 
ICD* 
 
 
 
19 
LV3 ring → 
ICD* 
 
 
 
20 
LV4 ring → 
ICD* 
 
 
 
  
 
*Pacing vectors are only available in the Acticor/Rivacor family devices.  
The vectors are chosen by selecting a cathode (From -) and an anode electrode 
(To +) during device interrogation and programming (Figure 2). 

 
  
 
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Figure 2: Programmer Display of LV Pacing Polarity 
 
1.3.3 
MultiPole Pacing (MPP) Description 
The MultiPole Pacing feature of the Ilivia and Acticor/Rivacor HF-T QP family 
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 20 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 Table 2. 

 
  
 
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Table 2: 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) 
Any available pacing vector (Table 1) 
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 3). 
Figure 3: Programming MultiPole Pacing 
As shown in Figure 4 and Figure 5 the polarity, pulse amplitude, and pulse width 
for the two LV stimuli can be programmed independently. 

 
  
 
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Figure 4: Programming 1st LV Stimulus  
 
Figure 5: Programming 2nd LV Stimulus 
 
Figure 6 and Figure 7 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. 

 
  
 
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Figure 6: V-V Delay, LV First 
 
 
Figure 7: V-V Delay, RV First 
 
 

 
  
 
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2. 
STUDY DESIGN 
The QP ExCELs Study is a multi-center, prospective, non-randomized clinical 
investigation that includes a sub-study to satisfy an FDA required post-approval 
study of the MultiPole Pacing feature (PMA P050023/S107) of the Ilivia HF-T QP 
family CRT-D system (PMA P050023/S103) or Acticor/Rivacor HF-T QP family 
CRT-D system (PMA P050023/S125).  
Subjects enrolled into the QP ExCELs study are ‘provisionally enrolled’ in the MPP 
sub-study upon signing the Informed Consent Form. Once the subject meets all of 
the MPP sub-study inclusion and none of the exclusion criteria at the QP ExCELs 6 
month follow-up visit, or if a heart failure hospitalization has occurred, the subject 
may continue into the MPP sub-study, at which point they are ‘fully enrolled’ (as 
defined in Table 3). No additional subject follow-up is required once the QP 
ExCELs 6 month follow-up visit is completed, unless the subject is enrolled into the 
MPP sub-study.  
As part of the MPP sub-study inclusion and exclusion criteria, a CRT responder 
status will be determined for all QP ExCELs subjects. The CRT Responder 
Classification at QP ExCELs 6-month follow-up will be evaluated by comparing the 
subject status at the QP ExCELs Enrollment Visit and classified as documented 
below: 
• “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 
Those subjects determined to have a CRT Responder Classification of “Worsened” 
or “Unchanged” at the MPP enrollment visit may continue into the MPP sub-study if 
all other inclusion and exclusion criteria are met. 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 preferred 
optimization method.  
Evaluation at the 3-month MPP follow-up (90 ± 30 days post-MPP enrollment) and 
6-month MPP follow-up (180 ± 30 days post-MPP enrollment) will include NYHA 
classification, Patient Global Assessment (PGA), and HF hospitalization status, in 
addition to collection of the MPP programming. After completion of the 6-month 
MPP follow-up, subjects may be programmed to MPP or standard BiV pacing, per 

 
  
 
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physician discretion. Subjects participating in the MPP sub-study will be exited 
once the MPP sub-study 6 month visit has been completed. 
2.1 
Objectives 
The primary objective of this clinical investigation 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) including three components: NYHA Class, heart failure 
(HF) hospitalizations, and cardiovascular death (Packer et al., 2001). 
The MPP sub-study also includes three secondary endpoints.  
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 Acticor/Rivacor 7 HF-
T QP family 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 the 6-Month MPP Follow-up (evaluated compared to 
MPP enrollment visit): 
• “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 

 
  
 
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A rejection of the null hypothesis would indicate that the proportion of subjects 
classified as “Improved” is superior to 3%. 
2.1.2 
Secondary Endpoint 1 
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 or Acticor/Rivacor HF-T QP family. 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. 
2.1.3 
Secondary Endpoint 2  
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 the 6-Month MPP Follow-Up 
(evaluated compared to MPP enrollment visit): 
• “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”) 
2.1.4 
Secondary Endpoint 3 
The purpose of Secondary Endpoint 3 is to evaluate the Responder Classification 
(as defined in Section 2.1.1) 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, 

 
  
 
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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. 
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: 
• 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 
• Sentus QP lead performance up to 6 months post-implant including R-wave 
sensing, pacing impedance, and pacing threshold 
• 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 
• Adverse events related to implant procedure, pulse generator, or implanted 
leads 
• Revisions to implanted system and reason for revision 
• Compliance to protocol requirements and study visit schedule 
2.2 
Subject Status Definitions 
The subject status definitions utilized in this study are provided in Table 3. 

 
  
 
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Table 3: Subject Status Definitions 
Subject Status 
Definition 
Provisionally enrolled 
Subject has provided written informed consent but 
has not yet been screened against the MPP sub-
study specific inclusion and exclusion criteria. 
Provisionally enrolled subjects will become fully 
enrolled if they meet the MPP sub-study specific 
inclusion and exclusion criteria, and complete the 
MPP Enrollment visit.  
Provisionally enrolled subjects will not be included in 
the analysis population for the study objectives; 
however, they may be included in analysis of 
additional data of interest. 
Screen Failure 
Subject has signed consent, but at the time of 
consent it was identified the subject does not meet all 
inclusion/exclusion criteria,  
OR 
Subject consented prior to implant, but prior to 
implant the subject status changes. 
Subject will be exited and will not be included in the 
analysis population or count toward the enrollment 
maximum. 
Fully Enrolled 
Subject meets all of the MPP sub-study specific 
inclusion criteria and none of the exclusion criteria, 
and completes the MPP Enrollment visit.  
Fully enrolled subjects will be included in the analysis 
population for the study objectives, as well as in the 
analysis of the additional data of interest. 
2.3 
Study Size and Duration 
The MPP sub-study will enroll up to 110 subjects at up to 75 sites within the United 
States who are participating in the QP ExCELs study. Based on the previous 
sample size analysis for the post-approval QP ExCELs cohort, the sample size for 
the QP ExCELs study is 1754 and will remain unchanged to support continuation of 
the MPP sub-study (QP ExCELs protocol version February 1, 2017 provides the 
justification and sample size analysis).  
Subjects that enroll in the MPP sub-study will be followed 12 months post-implant, 
while subjects that do not continue in the MPP sub-study will be followed for 6 
months post-implant.  

 
  
 
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2.3.1 
MPP Sub-Study 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. 
2.3.1.1 
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. The St. Jude Medical 
MultiPoint Pacing IDE Study (“St. Jude IDE study”, NCT01786993) evaluated CRT 
response based on a Clinical Composite Score (CCS) after 3 months of BiV pacing 
(Tomassoni et al., 2016; System Help Manual, St. Jude Medical). Subjects were 
then randomized to the MultiPointTM Pacing treatment arm 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 post-implant 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) (Forleo et al., 2016; Pappone et al., 2015; 
Zanon et al., 2016). However, these studies also did not limit multiple point LV 
pacing treatment to non-responders, 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) 

 
  
 
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• 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%. 
2.4 
 Interim Analysis 
An interim analysis will be performed on the primary endpoint when 50% (n = 45) of 
subjects have completed participation in the MPP sub-study. An alpha spending 
function (DeMets et al., 1994) will be incorporated to make adjustments on alpha 
for the interim and final analyses. Boundaries will be computed based on the 
O’Brien-Fleming method. The MPP sub-study will be terminated early and a final 
report will be prepared if the evidence of benefit reaches significance of P<0.0026 
at the 50% interim analysis.  
Due to the conservative alpha spending for the interim analysis, the threshold for 
determining significance at the final analysis is impacted minimally, with a final 
nominal p-value required for significance being 0.0224. The required sample size is 
not affected to any meaningful extent by the interim analysis and the sample size 
for primary endpoint 1 remains unchanged (n = 90).  
Interim Analysis (50%), significance level, alpha=0.0026 
Type I Error, Final adjusted significance level, alpha = 0.0224 
2.5 
Adjustments to Overall Sample Size 
Due to the inclusion of interim analyses, a total of 90 evaluable subjects are 
required to demonstrate superiority to a performance goal of 3%. Assuming a 10% 
loss to follow-up rate during the study for reasons unrelated to the study outcomes, 
a total enrollment of 100 subjects would be required to achieve an evaluable study 
population of 90 subjects. 
2.6 
Data Analyses 
Descriptive statistics will be used to present and summarize the data collected in 
the clinical study. Frequency distributions and cross tabulations will be presented 
for discrete variables. Means, standard errors, and ranges will be presented for 
continuous variables. 
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 5.1.1.). 
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. Additionally, descriptive statistics will be provided for observed 

 
  
 
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changes in NYHA class and frequency tabulations provided for the other 
components of the Clinical Composite Score.  
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 (CEC) 
(Section 5.1.1). 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 1 
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. 
2.6.1 
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 study personnel may either forget or choose not to 
answer one or more of the questions related to NYHA classification or patient 
global assessment.  
2.6.2 
MPP Sub-Study Analysis Population 
The primary and secondary endpoint analyses will be conducted according to the 
intention-to-treat principle (IIT) utilizing all available data from fully enrolled 
subjects. 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; however, these subjects will be included 
in the analysis population. All available data from subjects that undergo a pulse 
generator change and no longer have an MPP eligible device will be included in the 
analysis. Subjects may have the MPP feature temporarily turned OFF due to a lead 
revision procedure and these short durations with MPP will not be reported as a 
protocol violation.  
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. 

 
  
 
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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 enrollment in the QP ExCELs clinical study. 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.  
The implanting physician 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) 
3.1.3 
Inclusion Criteria 
All of the following inclusion criteria have to be fulfilled for participation in the QP 
ExCELs Study:  

 
  
 
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• Standard CRT-D indication according to clinical routine 
• De novo implantation or upgrade from existing ICD or pacemaker implant 
utilizing a BIOTRONIK Ilivia 7 HF-T QP family CRT-D system or 
Acticor/Rivacor HF-T QP family CRT-D system. feature with IS4 LV port and 
Sentus QP LV lead, that meets one of the following criteria: 
o Implant planned to occur after enrollment 
o Enrollment occurs within 30 days after implant and NYHA from within 
30 days prior to implant is documented in subject medical record 
• 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 up to 12 months of follow-up 
• Able to understand the nature of the study and give informed consent 
• Available for follow-up visits at the investigational site, including those 
specific to the MPP sub-study 
• Age ≥ 18 years 
At the time of MPP screening for inclusion into the MPP sub-study, additional 
inclusion criteria have to be fulfilled for participation: 
• 
Successfully implanted with a BIOTRONIK Ilivia 7 HF-T QP family CRT-D 
system or Acticor/Rivacor HF-T QP family CRT-D system. 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 MPP 
enrollment 
3.1.4 
Exclusion Criteria 
None of the following exclusion criteria can be fulfilled for QP ExCELs study 
participation: 
• Chronic atrial fibrillation 
• 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) 

 
  
 
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• Expected to receive a heart transplant or ventricular assist device within 12 
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 
At the time of MPP screening for inclusion into the MPP sub-study none of the 
following exclusion criteria can be fulfilled: 
• Development of chronic atrial fibrillation since QP ExCELs enrollment 
• Received MPP pacing prior to MPP sub-study 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 appropriate electronic Case Report Forms (eCRFs). Information 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.  
A QP ExCELs Study Termination eCRF should only be completed for early study 
termination. A QP ExCELs Study Termination eCRF is not required for subjects 
who complete the 6 month QP ExCELs visit and who are not enrolled into the MPP 
sub-study. For subjects enrolled into the MPP sub-study, an MPP sub-study 
specific termination eCRF is required to record a study exit; however, a QP 
ExCELs Termination eCRF is not required. 
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 3.3  
All data have to be available for source data verification during monitoring 
conducted by 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. 

 
  
 
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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. 
3.2.3 
Device Settings 
The device programming must be medically reasonable. Recommended device 
settings for participation in this clinical trial are summarized in Table 4: 
Table 4: 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 enrollment in the MPP 
sub-study.  
3.2.4 
CRT Based Lead Measurements 
Documentation of the mean sensing amplitude, the pacing threshold and the 
impedance is required for the LV channel at beginning of device interrogation at 
implantation and the required 6 month follow-up post-implant. The pacing threshold 
can be measured either manually or triggered automatically.  
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.  
3.2.5 
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 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. 

 
  
 
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• 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 Devices (Gregoratos et 
al., 1998).  
3.2.6 
Patient Global Assessment (PGA) 
During the course of the MPP sub-study a PGA 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.  
3.3 
Study Procedures 
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 the QP ExCELs implant and 
6 months follow-up visits. If circumstances prevent the presence of the subject at 
the in-office follow-up visit, the reason for the missed follow-up has to be indicated 
on the eCRF. In addition, interim evaluations related to adverse events, system 
revisions, or heart failure hospitalizations for inclusion into the MPP sub-study will 
be performed. 

 
  
 
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Table 5: Required Visit Windows for MPP Sub-Study 
Visit Type 
Window 
Days post-implant 
QP ExCELs 6 month follow-up/ MPP Enrollment* 
+ 30 days 
137 to 227 
3 month MPP follow-up 
± 30 days 
198 to 228 
6 month MPP follow-up 
± 30 days 
288 to 318 
*MPP Enrollment may also occur after 3 months post-implant (90 days post-implant) if the subject 
has a heart failure hospitalization. 
3.3.1 
Overview of Study Procedures 
Table 6 displays an overview about the study procedures at the different visits 
which are described in detail afterwards.  
Table 6: Procedures by Visit Type 
Procedures 
Enrollment 
Implant 
 
QP ExCELs 
and MPP 
sub-study 
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* 
 
x 
x 
ECG and ECHO values (if 
performed routinely) 
x 
 
 
 
Co-morbidities 
x 
 
 
 
Cardiovascular medication 
x 
 
 
 
CRT-D implantation 
 
x 
 
 
Implantation information 
 
x 
 
 
Programming of device 
settings 
 
x 
x 
x 
Standard device evaluation 
 
x 
x 
x 
Adverse event reporting  
x 
x 
x 
x 
Completion of eCRFs 
x 
x 
x 
x 
† Interim follow-ups may be collected when related to an AE, system revision or for a heart failure 
hospitalization for enrolment into the MPP sub-study. Implant information only needs to be collected 
if a system revision has occurred. 
* NYHA collected within 30 days prior to implant if enrolled after implantation.  

 
  
 
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3.3.2 
QP ExCELs Enrollment 
Prior to enrollment, the physician selects potential candidates which are eligible for 
the clinical study. If the potential subject meets all inclusion and exclusion criteria 
(Sections 3.1.3 and 3.1.4), the potential subject is asked to read and sign an 
Informed Consent Form. The potential subject should be provided with sufficient 
time to consider participation in the trial.  
Subjects are ‘provisionally enrolled’ into the MPP sub-study upon signing the 
Informed Consent Form and meeting the inclusion/exclusion criteria at time of 
consent. All subjects enrolled in the study must be entered in the subject 
enrollment log. The consent process should be documented within the subject’s 
medical record. 
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. 
NYHA class 
a) For subjects enrolled prior to implant, current NYHA class as 
assessed by study personnel at the time of enrollment  
or 
b) NYHA class obtained within 30 days prior to implant for subjects 
enrolled after implant.   
5. 
Most recent LVEF, obtained prior to implant 
6. 
Comorbidities and cardiac medications 
The Enrollment eCRF needs to be completed using the data collected during the 
enrollment visit.  
3.3.3 
Implantation 
Implantation may occur after enrollment of the subject or may occur prior to 
enrollment if an NYHA assessment within 30 days prior to the implant date is 
available in the subject’s medical record. For subjects implanted prior to 
enrollment, implant details and device data will be collected retrospectively.  
At implantation, the following data is collected:  
1. 
Implanted devices (manufacturer, model, serial number), plus date of implant 
2. 
Implantation site, and if available, implant approach 
3. 
Sentus QP lead implant success 
5. 
Activation of the recommended device settings as listed in Section 3.2.3 
6. 
Sentus QP lead evaluation from implant procedure: 

 
  
 
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• 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. 
8. 
Device programming and settings at end of implantation procedure 
Store the electronic procedure data (including final device settings, 
measurements, episodes) from the BIOTRONIK programmer  
9. 
Complete the Implantation eCRF using data collected during implant and 
information from the end of procedure device evaluation 
10. Document any reportable adverse event (e.g. phrenic nerve stimulation, high 
LV pacing threshold, etc.) during the procedure on the respective eCRF. 
Please note: 
1. 
If the BIOTRONIK Ilivia 7 or Acticor/Rivacor HF-T QP family CRT-D and/or 
Sentus QP LV lead were not implanted, the subject will be exited from the 
clinical investigation using a Study Termination eCRF. 
2. 
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 
MPP sub-study enrollment.  
3.3.4 
QP ExCELs 6-month Follow-up  
Six (6) months (± 45 days) after implantation, subjects return to the investigational 
site for an in-office assessment of their implanted system. To support CRT 
Responder Assessment at 6-months post-implant, QP ExCELs 6-month follow-ups 
occurring prior to the visit window or more than 30 days after the visit window will 
not be allowed. 
The following data should be collected: 
1. 
Perform device interrogation: 
• Determine LV lead impedance 
• Determine LV lead R-wave sensing amplitude  
• Determine the LV pacing threshold at 0.4 ms pulse width for the 
programmed pacing vector  
• Determine LV pacing threshold @ any pulse width (allowing for a 
minimum 2.5 V safety margin) and document occurrence of phrenic 
nerve stimulation for additional LV pacing vectors. 
2. 
Obtain NYHA classification and HF hospitalization status to determine CRT 
Responder Assessment classification 

 
  
 
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3. 
 
Screen subject for MPP sub-study by confirming subject meets all of the 
MPP sub-study specific inclusion criteria and none of the MPP sub-study 
specific exclusion criteria (Sections 3.1.3 and 3.1.4). If the subject qualifies 
for the MPP sub-study, complete MPP sub-study enrollment procedures in 
Section 3.3.5.  
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.) using the respective eCRF.  
If subject does not qualify for the MPP sub-study, no further follow-up visits are 
required. A study termination eCRF is not required. 
3.3.5 
MPP Sub-Study Enrollment 
MPP sub-study enrollment occurs after a subject has been screened and 
determined to meet all MPP sub-study specific inclusion criteria and none of the 
exclusion criteria.  QP ExCELs subjects with a heart failure hospitalization will be 
considered to have a CRT Responder Assessment classification of worsened and 
are eligible for the MPP sub-study. Subjects with a heart failure  hospitalization 
occurring prior to the 6 month post-implant follow-up visit may be enrolled between 
3 and 6 months post-implant by completing an interim follow-up eCRF (Section 
3.3.8.1) or be enrolled at the QP ExCELs 6 month follow-up visit (Section 3.3.4).  
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.  
After a patient has been screened and determined to be eligible for the MPP sub-
study, the following data will be collected: 
1. 
Turn MPP ON and collect MPP programmed settings 
2. 
Document MPP optimization method 
3. 
Obtain Patient Global Assessment 
4. 
Document any reportable Adverse Events 
5. 
Review and complete the appropriate eCRFs 

 
  
 
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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.  
3.3.6 
3-Month MPP Follow-up 
At a 3-month MPP 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 
3.3.7 
6-Month MPP Follow-up 
At the 6-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 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 
7. 
Complete a study termination eCRF documenting MPP sub-study completion 
Following the 6-month MPP follow-up, all subjects may be programmed to MPP or 
standard BiV pacing, per physician discretion. 
3.3.8 
Interim Follow-up 
Interim follow-ups may occur anytime during the clinical investigation; however, 
only those interim evaluations in support of MPP sub-study enrollment due to a 
heart failure hospitalization between 3 and 6 months post-implant and those related 
to 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. 

 
  
 
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3.3.8.1 
MPP Sub-Study Heart Failure Hospitalization 
Subjects with a heart failure hospitalization meeting the definition in Section 6.1.4 
may be enrolled into the MPP sub-study between 3 and 6 months post-implant by 
completing an interim visit eCRF. The following procedures are required:  
1. 
Obtain NYHA classification and HF hospitalization status to determine CRT 
Responder Assessment classification 
2. 
Perform device interrogation: 
• Determine LV lead impedance 
• Determine LV lead R-wave sensing amplitude  
• Determine the LV pacing threshold at 0.4 ms pulse width for the 
programmed pacing vector  
Determine LV pacing threshold @ any pulse width (allowing for a minimum 
2.5 V safety margin) and document occurrence of phrenic nerve stimulation 
for additional LV pacing vectors. 
3. 
Screen subject for MPP sub-study by confirming subject meets all of the 
MPP sub-study specific inclusion criteria and none of the MPP sub-study 
specific exclusion criteria (Sections 3.1.3 and 3.1.4). If the subject qualifies 
for the MPP sub-study, complete MPP sub-study enrollment procedures in 
Section 3.3.5 
3.3.8.2 
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 3.3.4). 
3.3.8.3 
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. 

 
  
 
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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 electronic System Revision eCRF. 
7. 
Document any reportable adverse event (e.g. phrenic nerve stimulation, 
high LV pacing threshold, etc.) during the procedure by using the 
respective eCRF.  
Please note: 
1. 
If prior to MPP sub-study enrollment, the BIOTRONIK Ilivia 7 HF-T QP family 
CRT-D system or Acticor/Rivacor HF-T QP family CRT-D and/or Sentus QP 
LV lead were explanted and not replaced with an MPP sub-study eligible 
system, the subject will be exited from the clinical investigation using a Study 
Termination eCRF. 
2. 
Whenever possible, BIOTRONIK devices that are explanted must be returned 
to BIOTRONIK, Inc. for analysis. 
3.3.9 
Study Termination 
A QP ExCELs Study Termination eCRF should only be completed for early study 
termination. Reasons for early study termination are described in Section 3.4.2. A 
QP ExCELs Study Termination eCRF is not required for subjects who complete the 
6 month QP ExCELs visit and who are not enrolled into the MPP sub-study. For 
subjects enrolled into the MPP sub-study, an MPP sub-study specific termination 
eCRF is required to record a study exit; however a QP ExCELs Study Termination 
eCRF is not required. 
3.4 
Study Participation Expectations 
3.4.1 
Point of Enrollment  
Subjects are ‘provisionally enrolled’ into the MPP sub-study upon signing the 
Informed Consent Form and meeting the inclusion/exclusion criteria at time of 
consent. 
3.4.2 
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. 
3.4.2.1 
No implant attempt  
If BIOTRONIK Ilivia 7 HF-T QP family CRT-D system or Acticor/Rivacor HF-T QP 
family CRT-D system and/or Sentus QP LV lead was not implanted, the subject is 
exited. The reason for study termination must be provided.  

 
  
 
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3.4.2.2 
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. 
3.4.2.3 
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. 
3.4.2.4 
Sentus QP lead or BIOTRONIK CRT-D extraction 
If prior to MPP enrollment , any subject who has the BIOTRONIK Ilivia 7 HF-T QP 
family CRT-D system or Acticor/Rivacor HF-T QP family CRT-D system and/or 
Sentus QP LV lead explanted and not replaced with an MPP sub-study eligible 
system will be withdrawn from the clinical investigation. After documentation of the 
system revision procedure (Section 3.3.8.3), a Study Termination eCRF should be 
completed.  
Whenever possible, devices that are explanted must be returned to BIOTRONIK, 
Inc. for analysis. 
3.4.2.5 
Lost to follow-up 
Subjects lost to follow-up are those for whom contact is lost despite the 
investigator’s best efforts to locate the subject. Study sites should attempt to 
contact these subjects in order to maintain study visit compliance and all contact 

 
  
 
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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.  
3.4.2.6 
MPP Sub-Study Completion 
Subjects who complete the MPP 6 month follow-up visit will be exited with reason 
of MPP sub-study completion selected on the Study Termination eCRF; however a 
QP ExCELs Study Termination eCRF is not required.  
3.4.3 
Date of Study Termination 
The expected study termination for all subjects should not be earlier than the 6 
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 BIOTRONIK Ilivia 7 HF-T QP family CRT-D system or Acticor/Rivacor HF-
T QP family CRT-D system and/or Sentus QP LV lead was not implanted, 
the date of termination is the date of decision not to implant. 
• If prior to MPP enrollment, the BIOTRONIK Ilivia 7 HF-T QP family CRT-D 
system or Acticor/Rivacor HF-T QP family CRT-D system and/or Sentus QP 
LV lead was explanted and not replaced with an MPP sub-study eligible 
system, the date of study termination is the date of system revision.  
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. IRB approval is also required throughout the 
duration of this clinical investigation. 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.  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 subject was not appropriately consented 
to participate in the study. In order to assist with the consent process, BIOTRONIK 
will provide a template patient consent form to investigational sites participating in 
the 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. 

 
  
 
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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 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, and subject 
inclusion/exclusion violations.  
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.  
Informed Consent documentation issues are also considered protocol deviations. 
These include but are not limited to incomplete ICF, missing dates for signature(s), 
missing initials or illegible information, subject signature date completed by 
someone other than subject, utilization of an outdated or non-IRB approved ICF, or 
incomplete associated forms required at time of consent, etc. (this is not an 
exclusive list). 
4.6.3 
IRB Reporting of Non-Compliance 
The study site must notify the reviewing IRB of all non-compliance issues per the 
IRB and protocol reporting requirements. At a minimum, all violations and non-
compliance 
issues related 
to 
informed 
consent and 
informed 
consent 
documentation should be reported to the IRB.  
In some instances, such as failure to obtain consent, the study site should also 
seek guidance from the IRB to ensure the subject received appropriate information 
to consider her or his participation in the study. 
The site should provide a copy of the IRB protocol noncompliance notification (as 
applicable) to BIOTRONIK.  
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. 

 
  
 
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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.  
 
 
 
 
 
 

 
  
 
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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 MPP sub-study related events (Section 5.1). Protocol 
defined adverse events that are not MPP sub-study related 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. 
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 
• Regular reporting of adjudication results to the sponsor 
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. 
5.1.1 
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 
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.  
 
 

 
  
 
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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). All AEs 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 medical device. This 
includes: 
• Events related to the 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 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 a 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 a device and any event resulting from use error or from 
unintentional misuse of the device.  
Adverse events, which result from the required medical procedures involved, when 
implanting, using or testing the respective 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 device and/or procedure 
are available: 
• Clearly not related: A relationship of the AE to the device and / or procedure 
can be excluded. 
• 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 device and/or procedure is 
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6.1.3 
Serious AEs, ADEs 
AEs and ADEs 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.  
6.1.4 
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. 
6.2 
Reporting Adverse Events 
The investigator has to record any reportable adverse event which occurs during 
study duration. The adverse event will be classified according to the seriousness, 
the relation to the implanted devices, and to the procedure. The investigator shall 

 
  
 
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report to the sponsor, by completing the appropriate eCRF, the following types of 
events: 
• all adverse events related to or possibly related to the implanted system 
• any major adverse events related to procedures involved with implanting, 
using, or testing the implanted system (examples are provided in Section 
6.3.1 and definitions are provided in Appendix A: Definition of Terms) 
• any adverse device effects, regardless of severity  
• any cardiovascular hospitalizations and any other hospitalizations in which 
cardiovascular symptoms occur during participation in the MPP sub-study 
(Section 6.3.2 provides definitions) 
• most recent heart failure hospitalization that occurs after eligible system 
implant and before MPP sub-study enrollment (if subject participates in the 
MPP sub-study; Section 6.1.4 provides definition) 
• all adverse events that require additional invasive intervention to resolve, 
specifically related to the MPP feature of the CRT-D that occur during 
participation in the MPP sub-study (examples are provided in Section 6.3.3) 
Events will be reported on an Adverse Event eCRF. 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. 
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 (as defined in Section 3.4.2.3). 
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. 

 
  
 
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6.3 
Reportable Adverse Events 
6.3.1 
Lead, System, and Procedure Related Event Examples 
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 
• 
Ablation sequelae (such as lead 
dislodgement or damage during an 
ablation) 
• 
Cardiac perforation occurring post 
implant 
• 
Clinical lead failure 
• 
High pacing threshold 
• 
Extracardiac stimulation (e.g. phrenic 
nerve stimulation) 
• 
Electrical lead failure 
• 
Intermittent capture 
• 
Lead abrasion 
• 
Lead dislodgement or migration (not 
occurring during a procedure) 
• 
Lead impedance out of range, high 
impedance 
• 
Lead impedance out of range, low 
impedance 
• 
Lead fracture or insulation damage 
• 
Lead undersensing 
• 
Lead-related thrombosis 
• 
Loss of sensing 
• 
No capture 
• 
Mechanical lead failure 
• 
Muscle or nerve stimulation 
• 
Twiddler’s syndrome 
• 
Unsuccessful Sentus QP lead implant  
• 
Lead repositioned, explanted, or replaced for 
any other reason 
Examples of reportable system or pulse generator related events 
• 
Device extrusion 
• 
Device migration 
• 
Inappropriate detection of 
arrhythmias 
• 
Inappropriate therapy or shocks 
• 
Inability to defibrillate or pace 
• 
Myopotential sensing 
• 
Pacemaker mediated tachycardia 
• 
Premature battery depletion 
• 
Pulse generator failure 
• 
Shunting current or insulating myocardium 
during defibrillation with internal or external 
paddles 
• 
Skin erosion 
• 
Pulse generator repositioned, explanted, or 
replaced for any other reason 
Examples of reportable major implant related events 
• 
Air embolism 
• 
Anesthetic complications 
• 
Allergic reaction to components used 
at implant or during lead testing,  
• 
or to components of the lead 
• 
Arrhythmias associated with implant 
• 
Arteriovenous fistula 
• 
Body rejection phenomena 
• 
Cardiac perforation with or without 
tamponade associated with lead 
implant 
• 
Chronic nerve damage 
• 
Coronary sinus dissection 
• 
Damage to lead during a procedure 
• 
Fluid accumulation 
• 
Heart valve damage 
• 
Major Hematoma 
• 
Infection 
• 
Keloid formation/fibrotic tissue formation 
• 
Lead dislodgement of chronic leads that 
occurs during a procedure 
• 
Loose set-screw 
• 
Myocardial damage 
• 
Non-healing pocket dehiscence or other 
wound healing disturbance 
• 
Pericardial effusion 
• 
Pericarditis 
• 
Phlebitis 
• 
Pleural effusion 
• 
Pneumothorax associated with lead implant 
• 
Pulmonary embolism associated with the 
implant procedure 
• 
Respiratory arrest 
• 
Venous occlusion associated with the 

 
  
 
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• 
Hemothorax 
• 
Incorrect lead connection with pulse 
generator 
implant procedure 
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 20 
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. 
6.3.2 
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: 
• 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 
6.3.3 
MPP Feature Related Adverse Events 
All adverse events that required additional invasive intervention to resolve, 
specifically related to the MPP feature of the CRT-D will be reported. 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. 

 
  
 
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6.4 
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.  
 

 
  
 
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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  
8.1.1 
Potential Benefits 
The clinical benefit of the Ilivia 7 HF-T QP family or Acticor/Rivacor HF-T QP family 
CRT-D system, is similar to that of standard CRT-Ds. Subjects taking part in this 
study may receive additional 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 (Forleo et al., 
2016). A recent IDE study showed that quadripolar multiple point LV pacing was 
non-inferior to standard quadripolar biventricular pacing (Tomassoni et al., 2016). 
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. 
8.1.2 
Potential Risks 
All devices, device leads, device programmers, and Home Monitoring® systems 
included in the QP ExCELs study are legally marketed and being prescribed by 
physicians according to FDA approved indications for use. There are no new 
known risks associated with participation in this study. Please refer to the product 
manuals for risks associated with the implanted leads or CRT-Ds.  
During the course of this study subjects may experience potential adverse    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.  
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. 
Another research related risk is the potential loss of confidentiality that is minimized 
by PHI redaction in the study. 
 

 
  
 
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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. 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 
sub-investigators participating in the clinical investigation at the 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 monitoring visits and 
centralized monitoring.  
Monitors will conduct monitoring visits periodically during the clinical investigation 
in accordance with the monitoring plan. Sites are required to support these 
monitoring visits and the study monitoring effort. 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 signed 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-C principles of 
attributable, legible, contemporaneous, original, accurate, and complete. 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 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 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 

 
  
 
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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) 
• 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 
• Notification of the withdrawal of IRB approval 
• Annual progress reports prepared for the IRB  
• 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 7 outlines the responsibilities, including time constraints, for submitting the 
above reports.  

 
  
 
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Table 7: 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 
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 
• 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  
• Adverse device effects  
• 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 

 
  
 
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BIOTRONIK, Inc. is responsible for preparing the following reports, when 
necessary: 
Table 8: Sponsor Reporting Responsibilities 
Type of Report 
Prepared by 
BIOTRONIK for 
Time Constraints of Notification 
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 
Progress report 
FDA, all reviewing 
IRBs 
Submitted at least annually 
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. 
 
 
 

 
  
 
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11. REFERENCES 
Bradycardia and Tachycardia Devices Merlin™ Patient Care System Help Manual, 
St. Jude Medical, Sylmar, CA, 2016, pp. 418-431, https://manuals.sjm.com 
Bristow,M.R., Saxon,L.A., Boehmer,J., Krueger,S., Kass,D.A., De Marco,T., 
Carson,P., 
DiCarlo,L., 
DeMets,D., 
White,B.G. 
et 
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(2004). 
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resynchronization therapy with or without an implantable defibrillator in advanced 
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Ros,J.O., 
Fernandez-Lozano,I., 
Guerrero,J.J.G., Fernandez de la Concha,J., Madrid,A.H., Tolosana,J.M., 
Asensi,J.O., Cordero,A.B. et al. (2013). Improvement in hemodynamic response 
using a quadripolar LV lead. Pacing Clin. Electrophysiol. 36, 963-969. 
Crossley,G.H., Exner,D., Mead,R.H., Sorrentino,R.A., Hokanson,R., Li,S., and 
Adler,S. (2010). Chronic performance of an active fixation coronary sinus lead. 
Heart Rhythm 7, 472-478. 
DeMets DL, Lan KK. (1994). Interim analysis: the alpha spending function 
approach. Stat Med 13,1341-56. 
Dickstein,K., Cohen-Solal,A., Filippatos,G., McMurray,J.J., Ponikowski,P., Poole-
Wilson,P.A., Stromberg,A., van Veldhuisen,D.J., Atar,D., Hoes,A.W. et al. (2008). 
ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 
2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart 
Failure 2008 of the European Society of Cardiology. Developed in collaboration 
with the Heart Failure Association of the ESC (HFA) and endorsed by the 
European Society of Intensive Care Medicine (ESICM). Eur. Heart J. 29, 2388-
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Dickstein,K., Vardas,P.E., Auricchio,A., Daubert,J.C., Linde,C., McMurray,J., 
Ponikowski,P., Priori,S.G., Sutton,R., van Veldhuisen,D.J. et al. (2010). 2010 
Focused Update of ESC Guidelines on device therapy in heart failure: An update of 
the 2008 ESC Guidelines for the diagnosis and treatment of acute and chronic 
heart failure and the 2007 ESC guidelines for cardiac and resynchronization 
therapy Developed with the special contribution of the Heart Failure Association 
and the European Heart Rhythm Association. Eur. Heart J. 31, 2677-2687. 
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, 19, 1170-1177. 
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 
benefits of electronic lead repositioning: the ERACE trial. J Interv Card 
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Gregoratos G, Cheitlin MD, Conill A et al. (1998). 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 31, 1175-1209. 
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 
high left ventricular pacing thresholds and avoid phrenic nerve stimulation. Pacing 
Clin. Electrophysiol. 28, 1255-1259. 
Hansky,B., 
Vogt,J., 
Gueldner,H., 
Heintze,J., 
Lamp,B., 
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., 
Ferguson,T.B., Ford,E., Furie,K., Gillespie,C. et al. (2010). Heart disease and 
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 
of phrenic nerve stimulation occuring during CRT - Follow-up in patients implanted 
with a novel quadripolar pacing lead. J Interv Card Electrophysiol 33, 43-49. 
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 41, 
15-21. 
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. 
Packer M. (2001). 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 7, 176–182. 
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. (2015). Improving cardiac resynchronization therapy response with multipoint 
left ventricular pacing: Twelve-month follow-up study. Heart Rhythm 12, 1250-
1258. 
Rinaldi CA, Burri H, Thibault B, Curnis A, Rao A, Gras D, Sperzel J, Singh JP, Biffi 
M, Bordachar P, Leclercq C. (2015). A review of multisite pacing to achieve cardiac 
resynchronization therapy. Europace 17, 7-17. 
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, 
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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. 
Tomassoni GF, Baker J, Corbisiero R, Love CJ, MD, Martin DT, Sheppard RC, 
Worley SJ, Varma N, Niazi I. (2017). Safety and efficacy of Multipoint Pacing in 
Cardiac Resynchronization Therapy: The MultiPoint Pacing (MPP) IDE Study. 
JACC Clin Electrophysiol 3, 1510-1518. 
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. 
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. (2016). 
Optimization of left ventricular pacing site plus multipoint pacing improves 
remodeling and clinical response to cardiac resynchronization therapy at 1 year. 
Heart Rhythm 13, 1644-1651. 
 

 
  
 
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12. 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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13. 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 
9a. Expected adverse events related to the left ventricular pacing threshold test in 
the novel vectors are listed in Table 9d. 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 9a: Expected Perioperative Events  
Frequency 
Percent (%) 
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 

 
  
 
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placement) 
0.4231 -130 
Pneumothorax 
0.331 – 0.449 
Cardiac arrest 
0.230 
Arrhythmia 
0.2 – 0.349 
Respiratory arrest 
0.249 
Tamponade 
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 9b: Expected Postoperative Events 
Frequency 
Percentage (%) 
Risk 
 
9.720 -3723 
Lead failure20,22,23 
Very frequent 
2.97–25.424 
Inappropriate shocks7,24,25,54 

 
  
 
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>1 out of 10 patients 
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 
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 

 
  
 
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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 9c: Expected Psychological Events 
Frequency 
Percentage (%) 
Risk 
Very frequent 
>1 out of 10 patients 
259,10 - 509 
Anxiety or depression9,10,11,27 
Occasionally 
1 to 10 patients out of 
1,000 
Up to 16 
Psychological intolerance 
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 9d: 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 based on 
the available data 
 
palpitations 

 
  
 
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