Left Ventricular Synchronous Versus Sequential MultiSpot Pacing for CRT
Phase: NA
Conditions: Heart Failure
Sponsor: Medtronic Cardiac Rhythm and Heart Failure

CONFIDENTIAL
  
DOCUMENT/RECORD 
 
 
This document/record is electronically controlled; printed copies are considered uncontrolled. 
System of Record: Regulatory Affairs Domain 
 
Document Name
Version
Title
1.0
CIP SYNSEQ
CIP SYNSEQ

 
 
Clinical Investigation Plan 
 
 
 
 
 
Version 1.0 
SYNSEQ 
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SYNSEQ study 
Left Ventricular Synchronous versus 
Sequential MultiSpot Pacing for CRT 
Clinical Investigation Plan 
 
Version 1.0   
22 Oct 2015 
 
Sponsor
Bakken Research Center BV, 
Medtronic  
Endepolsdomein 5 
 6229 GW Maastricht,  
The Netherlands  
 
 
 
 
 
 

 
 
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Change History record 
 
 
CIP Change History 
Version 
Summary of Changes 
Author 
1.0
Initial version 
Laurence Hogge 
 
 
 

 
 
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TABLE OF CONTENTS 
 
A 
SYNOPSIS ......................................................................................................... 6 
B 
GENERAL INFORMATION ................................................................................ 9 
B.1 
Introduction ......................................................................................................................... 9 
B.2 
Device information ............................................................................................................ 11 
 Pacing devices ........................................................................................................ 11 
B.2.1
 Leads and electrophysiological catheters ............................................................... 11 
B.2.2
 Acquisition system .................................................................................................. 12 
B.2.3
B.3 
Comparator information .................................................................................................... 16 
C 
STUDY PLAN ................................................................................................... 17 
C.1 
Study objectives ................................................................................................................ 17 
 Primary objectives .................................................................................................. 17 
C.1.1
C.1.1.1 
Primary objective 1 .................................................................................. 17 
C.1.1.2 
Primary objective 2 .................................................................................. 17 
 Secondary objectives .............................................................................................. 17 
C.1.2
C.1.2.1 
Secondary objective 1 ............................................................................. 17 
C.1.2.2 
Secondary objective 2 ............................................................................. 17 
C.1.2.3 
Secondary objective 3 ............................................................................. 17 
C.2 
Clinical endpoints .............................................................................................................. 18 
 Primary endpoints ................................................................................................... 18 
C.2.1
 Secondary endpoints .............................................................................................. 18 
C.2.2
C.3 
Study hypothesis ............................................................................................................... 18 
C.4 
Study population ............................................................................................................... 18 
C.5 
Study design ..................................................................................................................... 19 
 Minimization of bias ................................................................................................ 19 
C.5.1
C.6 
Randomization and blinding .............................................................................................. 19 
C.7 
Sample size ....................................................................................................................... 19 
C.8 
Number of investigation sites and study duration ............................................................. 20 
D 
SUBJECT SELECTION .................................................................................... 21 
D.1 
Inclusion criteria ................................................................................................................ 21 
D.2 
Exclusion criteria ............................................................................................................... 21 
E 
STUDY PREPARATION PROCEDURES ........................................................ 21 
E.1 
Investigator/Investigation site selection ............................................................................ 21 
 Clinical Investigation Agreement ............................................................................ 22 
E.1.1
 Curriculum Vitae ..................................................................................................... 22 
E.1.2
E.2 
Ethics................................................................................................................................. 22 
 EC approval ............................................................................................................ 22 
E.2.1
 Informed consent process ...................................................................................... 22 
E.2.2
 Revisions in Patient Information and Informed Consent Form ............................... 23 
E.2.3
 Regulatory notification / approval ........................................................................... 23 
E.2.4
E.3 
Regulatory compliance...................................................................................................... 23 
E.4 
Training requirements ....................................................................................................... 24 
E.5 
Study materials and study-specific equipment ................................................................. 24 
E.6 
Study device/product traceability ...................................................................................... 24 

 
 
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 Supply of investigational devices ............................................................................ 24 
E.6.1
 Storage and handling of investigational devices .................................................... 25 
E.6.2
 Device explant and return procedures .................................................................... 25 
E.6.3
F 
STUDY METHODS .......................................................................................... 25 
F.1 
Point of enrollment ............................................................................................................ 25 
F.2 
Implant or procedure aspects ........................................................................................... 25 
 Baseline visit ........................................................................................................... 25 
F.2.1
F.2.1.1 
Magnetic Resonance Imaging (MRI) ....................................................... 26 
 Electrophysiological (EP) study visit ....................................................................... 26 
F.2.2
F.3 
Data collection requirements ............................................................................................ 30 
F.4 
Role of the sponsor’s representatives ............................................................................... 31 
F.5 
Source documents ............................................................................................................ 31 
F.6 
Adverse events and Device Deficiencies .......................................................................... 32 
 Definition/classification ........................................................................................... 32 
F.6.1
 Recording and reporting of Adverse Events ........................................................... 34 
F.6.2
 Recording and reporting of Device Deficiencies ..................................................... 34 
F.6.3
 Adverse Event and Device Deficiency review process........................................... 35 
F.6.4
 Adverse Event Advisory Committee ....................................................................... 36 
F.6.5
 Emergency contact details in case of serious AEs ................................................. 37 
F.6.6
 Subject Death ......................................................................................................... 37 
F.6.7
F.7 
Subject accountability ....................................................................................................... 37 
F.8 
Study deviations and CIP changes ................................................................................... 38 
 Request for approval of study deviations ............................................................... 38 
F.8.1
 Reporting requirements for study deviations .......................................................... 38 
F.8.2
 Amendments to the Clinical Investigation Plan ...................................................... 39 
F.8.3
G 
QUALITY CONTROL PROCEDURES ............................................................. 39 
G.1 
Procedures for database management ............................................................................. 39 
 Data collection ........................................................................................................ 39 
G.1.1
 Source data to be directly recorded on the Case Report Forms ............................ 39 
G.1.2
 Data review and processing ................................................................................... 40 
G.1.3
G.2 
Monitoring procedures ...................................................................................................... 40 
 Accessibility of investigation site staff and study materials .................................... 40 
G.2.1
 Audits and investigation site inspections ................................................................ 40 
G.2.2
G.3 
Study suspension or early termination .............................................................................. 40 
 Early study suspension or termination .................................................................... 40 
G.3.1
 Early investigation site suspension or termination.................................................. 41 
G.3.2
 Subject follow-up in case of termination ................................................................. 41 
G.3.3
G.4 
Study close out .................................................................................................................. 41 
H 
DATA ANALYSIS AND REPORTING ............................................................... 41 
H.1 
Analysis of clinical data ..................................................................................................... 41 
 Primary objective 1 ................................................................................................. 42 
H.1.1
 Primary objective 2 ................................................................................................. 43 
H.1.2
 Secondary objective 1 ............................................................................................ 43 
H.1.3
 Secondary objective 2 ............................................................................................ 43 
H.1.4
 Secondary objective 3 ............................................................................................ 43 
H.1.5
H.2 
Publication Policy .............................................................................................................. 44 

 
 
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I 
STUDY MANAGEMENT ................................................................................... 45 
I.1 
Study staff ......................................................................................................................... 45 
I.2 
Advisory committees ......................................................................................................... 45 
 Data Monitoring Committee .................................................................................... 45 
I.2.1
 Publication Committee ............................................................................................ 45 
I.2.2
I.3 
Records and reports .......................................................................................................... 45 
 Investigator records ................................................................................................ 45 
I.3.1
 Investigator reporting responsibilities ..................................................................... 46 
I.3.2
 Sponsor records...................................................................................................... 47 
I.3.3
 Sponsor reporting responsibilities .......................................................................... 48 
I.3.4
 Record retention ..................................................................................................... 49 
I.3.5
I.4 
Miscellaneous ................................................................................................................... 49 
 Insurance and warranty .......................................................................................... 49 
I.4.1
 Subject confidentiality ............................................................................................. 49 
I.4.2
 Subject compensation ............................................................................................ 49 
I.4.3
J 
RISKS AND BENEFITS .................................................................................... 50 
J.1 
Anticipated Clinical Benefits .............................................................................................. 50 
J.2 
Risks.................................................................................................................................. 50 
J.3 
Risk-to-benefit rationale .................................................................................................... 51 
K 
REFERENCES ................................................................................................. 52 
L 
APPENDICES .................................................................................................. 54 
L.1 
Case Report Forms ........................................................................................................... 54 
L.2 
Foreseeable adverse event and anticipated adverse device effects ................................ 54 
L.3 
Abbreviations .................................................................................................................... 57 
 
 
Figures 
Figure 1: SYNSEQ equipment set-up 
Figure 2: MultiSpot electrophysiological catheters 
Figure 3: Start of protocol description 
Figure 4: Different ventricular lead positions 
Figure 5: Description of the pacing protocol 
 
Tables 
Table 1: Devices and accessories 
Table 2: Data Collection Requirements 
Table 3: Adverse Event reporting requirements 
Table 4: Sponsor Contact Information 
Table 5: Investigator Reports  
Table 6: Sponsor Reports  
Table 7: Observed LV Lead Related Adverse Events  
 

 
 
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A SYNOPSIS 
Left Ventricular Synchronous versus Sequential 
MultiSpot Pacing for CRT 
SYNSEQ study 
Purpose 
The SYNSEQ study intends to assess the positive left ventricular dP/dt 
max achieved by multipoint LV pacing (either simultaneously or 
sequentially) in comparison to the response achieved by the current 
(standard) BiV pacing configuration in patients indicated/recommended 
for cardiac resynchronization therapy. 
Design 
This study is a prospective, interventional, non-randomized, multi-center 
research study. 
Medical 
device 
• 
Pacing system Analyzer 2290 
• 
CareLink Programmer 2090 
• 
Hand-held pacers 5388D or 5392 
• 
Endocardial or transvenous leads (atrial, right ventricular and 
left ventricular leads) 
• 
Guiding catheters ATTAIN or ATTAIN SELECT II 
• 
LV pressure wire Millar (825-0101) 
• 
Invasive Blood pressure Codan PVB transducer (17.8059) and 
contact board (75.1068.00) 
• 
Electrophysiological catheters and pacing wires: Soloist, 
TORQR-CS, Map-iT or VisionWire 
• 
Surgical connection cables 5114, 5832S, 5833S or 5487 
• 
Adaptor 5103 
• 
Reference lead F7830S or F7832S 
• 
Catheter connecting cable 05518SP or 901957 
• 
Motion sensing input device: Kinect camera or similar 
• 
Connection box and connectors 09083 
The connection box (and its connectors) is investigational. All other 
products used in the present study (leads and pacing devices) are 
commercially released (and CE-marked) and used within their intended 
purpose. 
Primary 
objectives 
• 
Compare the hemodynamic response of a MultiSpot-SYN Left 
Ventricular pacing configuration (simultaneous LV pacing) to a 
single spot LV pacing configuration in patients undergoing a 
research study, an EP exploratory procedure or CRT implant 
using the contractility parameter positive LV dP/dt max. 
• 
Compare the hemodynamic response of a MultiSpot-SEQ Left 
Ventricular pacing configuration (sequential LV pacing) to a 
single spot LV pacing configuration in patients undergoing a 
research study, an EP exploratory procedure or CRT implant 
using the contractility parameter positive LV dP/dt max.
Secondary 
objectives 
• 
Compare the positive LV dP/dt max from a MultiSpot-SEQ LV 
pacing configuration is non-inferior to a MultiSpot-SYN LV 
pacing configuration. 
• 
Correlate the (non)invasive measures (blood pressure, 
electrocardiographic mapping and RV/LV EGM timings) 
obtained during the different pacing configurations to the 
positive LV dP/dt max measures obtained. 
• 
Evaluate the (non)invasive measures ability to identify the 
pacing configuration with the highest positive LV dP/dt max.

 
 
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Primary 
endpoint 
The contractile ability of LV is characterized by the positive LV dP/dt 
max. It is a measure of the initial velocity of myocardial contraction and 
is a derivative of the LV-pressure. LV pressure is measured invasively 
using a high-fidelity micromanometer catheter inside the LV. 
Secondary 
endpoint 
Besides the contractility index, other hemodynamic/electrical 
parameters will also be used as endpoints.  
Blood pressure (systolic and diastolic) is measured by invasive arterial 
blood line connected to a sensitive membrane displacement sensor. 
Non-invasive blood pressure (systolic/diastolic) is acquired through 
finger volume clamp.  
The electrical signals (Q-LV timings, QRS width) are derived from intra-
cardiac leads (invasive) and surface electrodes (non-invasive) 
respectively.  
Subject 
population 
Only “difficult” CRT patients are selected in order to adequately address 
the potential benefit of MultiSpot Pacing in this patient population. The 
term “difficult” represent those patients with an increased likelihood of 
non-response to conventional cardiac resynchronization therapy (e.g. 
ischemic patients or non-LBBB left ventricular dyssynchrony patients).  
The study will enroll up to 40 subjects who fulfill the eligibility criteria and 
who have completed the EP study procedure. 
Number of 
sites 
The study is expected to be conducted in approximately 10 centers in 
Europe. 
Study 
duration 
It is anticipated that this study will require approximately 12 to 18 
months for subject enrollment. Patients’ participation in this study is 
expected to last approximately between 1 day and 3 months, depending 
on the time between enrollment and the EP study and the duration of 
hospital stay after the research study, or EP related procedure, or the 
CRT-implant. 
Subjects will be exited from the study just before the moment of hospital 
discharge. There will be no further follow-up required for subjects that 
are exited from the study. 
Inclusion 
criteria 
• 
Subject is indicated or recommended for CRT-P or CRT-D 
device according to current applicable ESC/AHA guidelines 
• 
Subject is in sinus rhythm 
• 
Subject receives optimal heart failure oral medical therapy  
• 
Subject is willing to sign the informed consent form 
•
Subject is 18 years or older
Exclusion 
criteria 
• 
Subject has permanent atrial fibrillation/flutter or tachycardia 
• 
Subject has pure right bundle branch block (= no additional left 
ventricular conduction delays) 
• 
Subject has left bundle branch block and QRS-duration of > 
150 ms and no sign of myocardial scar indicated by late 
gadolinium enhancement MRI 
• 
Subject experienced recent myocardial infarction, within 40 
days prior to enrollment  
• 
Subject underwent valve surgery, within 90 days prior to 
enrollment 
• 
Subject is post heart transplantation, or is actively listed on the 
transplantation list 
• 
Subject is implanted with a left ventricular assist device 
• 
Subject has severe renal disease (up to physicians discretion) 
• 
Subject is on continuous or uninterrupted infusion (inotropic) 
therapy for heart failure ( 2 stable infusions per week) 

 
 
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• 
Subject has severe aortic stenosis (with a valve area of <1.0 
cm2 or significant valve disease expected to be operated within 
study period) 
• 
Subject has complex and uncorrected congenital heart disease  
• 
Subject has a mechanical heart valve 
• 
Pregnant or breastfeeding women, or women of child bearing 
potential and who are not on a reliable form of birth control 
• 
Subject is enrolled in another study that could confound the 
results of this study, without documented pre-approval from 
Medtronic study manager
Clinical 
Procedures 
Enrollment:  
A subject is enrolled in the study when he/she signs and dates the 
Patient Informed Consent. 
Baseline: 
• 
Verification of all inclusion and all exclusion criteria 
• 
Enrollment 
• 
Demographics (age, gender) 
• 
Physical examination (height, weight, heart rate, blood 
pressure) 
• 
Left ventricular ejection fraction (within last 3 months, otherwise 
a new measurement should be performed) 
• 
Multi-lead ECG (within last 3 months, otherwise a new ECG 
should be performed) 
• 
Echocardiographic evaluation (if available within last 3 months, 
otherwise not collected ) 
• 
NYHA classification 
• 
Medical history (cardiovascular or related) 
• 
Cardiovascular medications 
• 
Pregnancy test for women with child-bearing potential 
• 
Magnetic Resonance Imaging (MRI) to identify the location and 
transmurality of any myocardial scar. If the patient has a LBBB 
conduction pattern and QRS-width above 150ms, the MRI 
images should be analyzed to quantify the presence of scar. If 
no scar is present (as indicated by gadolinium enhancement), 
the patient should not be included in the study.  
EP visit: 
The EP study visit should take place within 3 months after the 
MRI has been obtained.  
The following LV pacing configurations will be evaluated:  
Biventricular pacing (BiV)  
Pacing will be performed on one LV electrode pair, (at 3 different 
longitudinal locations), and on the tip of the RV-lead. In total, 
three different pacing BiV settings will be evaluated. 
Configuration 1: RV + LV lateral Apex 
Configuration 2: RV + LV lateral Mid 
Configuration 3: RV + LV lateral Base (Reference: Standard 
CRT) 
 
MultiSpot simultaneous LV-ventricular pacing (MultiSpot-
SYN) 
Pacing will be performed on 3 electrodes on the LV wall, placed 
at different longitudinal locations, and on the tip of the RV-lead 
simultaneously.  

 
 
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Configuration 4: RV + LV lateral Apex + LV lateral Mid + LV 
lateral Base 
 
MultiSpot sequential LV-ventricular pacing (MultiSpot-SEQ) 
3 electrodes on the LV wall will be paced sequentially. The RV-
electrode will be paced simultaneously with last paced LV-
electrode. The timing-sequence and the amount of spots will 
depend on the electrical delays measured during the 
experiments.  
Configuration 5: LV lateral Apex  LV lateral Mid  LV lateral 
Base + RV 
    
The protocol procedures will result in an additional 30 to 45 minutes to 
the standard procedure time, and up to an additional 10 minutes to the 
fluoroscopy exposure. Once the configurations have been evaluated the 
investigational procedures will end and the EP/CRT-implant-procedure 
will continue as per standard practice.  
Non-invasive sensor data include the measurements of arterial pressure 
performed from the finger volume clamp and the surface ECG.  
Invasive sensor data will be derived from the electrocardiogram timing, 
i.e. the electrical delay between the RV and different LV sites from the 
implanted leads/catheters. Invasive blood pressure will also be 
collected. 
 
 
B GENERAL INFORMATION 
B.1 
Introduction 
Cardiac Resynchronization Therapy (CRT) has been one of the most important 
advancements in the past decade for patients with systolic heart failure (HF) and a wide 
QRS. Several clinical trials have shown improvements in mortality, exercise capacity, 
clinical symptoms, and quality of life 1, 2. However, a considerable amount of CRT patients 
show only limited benefit from the therapy 3. Multiple reasons for a low responder rate have 
been proposed, such as underlying HF severity and etiology, suboptimal device 

 
 
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programming, inadequate viable myocardium, lack of baseline dyssynchrony, and non-
optimal Left Ventricular (LV) lead position 4.  
 
Recent efforts to increase the responder rate is to pace from multiple sites on the left 
ventricle (LV). Multi-site pacing can be achieved either by stimulating on a second LV lead 
or right ventricular (RV) lead or by stimulating additional electrodes on one lead (e.g. 
Quadripolar system). The use of one-lead with multiple electrodes stimulated has recently 
been investigated in more detail with regard to improving (hemodynamic) response in CRT 
patients. The results are inconclusive. Several studies have shown acute hemodynamic 
benefit from multipoint pacing 5-7 while others have failed or only showed marginal benefit 
(own data (iSPOT-study) and 8-10). It might be that the current inter-electrode distance or 
the sequence of RV and LV activation is suboptimal.  
 
It is shown that besides synchrony the sequence of electrical/mechanical activation is a 
major determinant of cardiac function. Activating the LV lateral wall first (before septum and 
RV lateral wall) prevents paradoxical movement of the septum initiated by RV-pacing. In 
addition, a physiological apex-to-base sequence of activation is induced by LV apical 
pacing in children, which results in synchronous electrical activation and contraction at the 
circumferential level of the LV 11. Moreover, LV apical pacing preserved septal to lateral LV 
synchrony and systolic function, as well as maintaining cardiac function at a normal level 12, 
13. 
More studies have shown the possible mechanisms involved in proper sequence of cardiac 
stimulation 15, 16. The relative contribution of these different cardiac properties (like torsion, 
vortex and different strains) in hemodynamic function in the heart failure patient is unknown 
although it seems intuitive to mimic the physiological propagation of electrical conduction.  
 
LV sequential pace has now become more easily achievable with the new Quadripolar LV 
lead systems. The use of one-lead with multiple paced electrodes (i.e. MultiSpot or 
MultiPoint) to improve CRT-response has recently been investigated in more detail. The 
overall outcome of these studies is difficult to interpret scientifically. Some studies have 
failed to prove additional benefit 8, 17 while others show acute benefit but are difficult to 
interpret because of their methodology, like using non-optimal atrioventricular (AV)-delays 6, 
7, 9, 18. Other studies show only borderline but significant better hemodynamic response to 
multipoint pacing than to standard biventricular (BiV) pacing 10.  
The inconclusiveness might be attributed to the patient population. In a recent study of 
multisite pacing in humans it was shown that MultiSpot pacing had no incremental 
hemodynamic effect in responders to CRT with strict criteria for left bundle branch block 
(LBBB) 19. However, in hemodynamic non-responders who did not have strict LBBB there 
was a significant hemodynamic benefit with multisite pacing. These findings are in keeping 
with the iSPOT study in that all the patients studied had LBBB. It is possible that multisite 
pacing may have a role but for patients with non-strict LBBB. 
 
The SYNSEQ study intends to assess the positive LV dP/dt max achieved by multiple LV 
pacing either simultaneously or sequentially in comparison to the response achieved by the 
current (standard) BiV pacing configuration. The protocol includes rigorous methodology to 
decrease measurement variability and to be patient-tailored (e.g. AV-delay) in order to 
provide a justified conclusion to the acute hemodynamic benefit of MultiSpot Pacing (MSP) 
20. In addition, only “difficult” CRT patients are selected in order to adequately address the 
potential benefit of MSP in this patient population. The term “difficult” represent those 
patients with an increased likelihood of non-response to conventional CRT (e.g. ischemic 
patients or non-LBBB LV dyssynchrony patients). In addition to the hemodynamic 
evaluation, electrical parameters such as Q-LV/RV timing and QRS-width will be measured. 
The study will also evaluate the feasibility of non-invasive sensors to assist with optimal 
lead placement and pacing sequence. Additionally, it is anticipated that this study will 
provide data that can be used to design future studies. 

 
 
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For further literature review, pre-clinical testing and previous clinical experience please 
refer to the Investigator’s Brochure.  
B.2 
Device information 
 
Pacing devices 
B.2.1
 
In order to deliver pacing on 4 different regions on the heart a system was developed which 
consists of a “master” pacer and four “slaves” pacers (Figure 1 and Table 1).  
The master pacer is the 2290 analyzer (in the 2090 Programmer) which will be used to 
pace the right atrium (RA). The other pacing output (i.e. the ventricular) of the 2290 
analyzer will be used as an atrial input for the up to four “slaves”. The “slaves” are used to 
pace the right ventricle (RV) and the three LV electrodes. The master pacer can be used to 
adjust AV-delay for all “slaves”. The “slaves” are hand-held pacers (Medtronic model 
number: 5388 DDD or 5392) and can be programmed independently. In this study the 
“slaves” will be programmed to specific settings before start of the experimental protocol. 
During the entire protocol the “slaves” will be either turned “on” or “off”. No additional intra-
protocol settings will be changed. Benchmark testing performed has found that upon 
pacing, i.e using all four “slaves” the delay between them was ~1 ms (range 0-2 ms).  
 
 
Figure 1: SYNSEQ equipment set-up. Green depicts the connection box.  
 
Leads and electrophysiological catheters 
B.2.2
 
Only commercial market released leads and EP catheters will be used within their intended 
use to test the feasibility of MSP simultaneous or sequential pacing for increased acute 
hemodynamic response to CRT.  
In this study we will use Medtronic or other commercially available intra-cardiac electrode 
catheters for the delivery of MSP pacing (see Table 1). These catheters are designed for 
recording intracardiac electrograms and temporary pacing associated with EP studies 
(Figure 2). For adequate delivery of these EP-catheters into the coronary veins specially 
designed Medtronic tools can be used (ATTAIN SELECT II and ATTAIN). For the part of 

 
 
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the study which requires two separate leads/catheters, standard Medtronic over-the-wire 
passive leads will be used (e.g. 4196) in addition to the possible replacement from a lateral 
position to a more anterior or posterior position of the EP-catheters. 
 
Figure 2: MultiSpot electrophysiological catheters. Left to right:  TORQR-CS, MAP-
iT Duo-Decapolar and VisionWire.   
 
Acquisition system 
B.2.3
 
All data–acquisition will be done using a multi-channel ambulatory system for (electro)-
physiological research (porti-system by TMSI or CardioTek EP-tracer system). It will be 
possible to time-aligned acquire all parameters measured in the study. This includes up to 
7 bipolar or unipolar electrograms (EGMs), a 12-lead electrocardiograms (ECG) and up to 
3 pressure signals. After a recording is ended the PC reads out the memory card, making 
the measurement data available for further analysis. During the entire experimental 
protocol, the following will be measured continuously: 
- 
Unipolar/bipolar EGMs for all the different leads in the heart (if not paced) 
- 
Ventricular pressure (using a left ventricular Millar pressure catheter) 
- 
Multi-lead ECG  
- 
(Optional) Non-invasive blood pressure (using finger volume clamp)  
- 
Invasive blood pressure (through an arterial access line available because of LV 
pressure measurement) 
The devices that will be involved in the conduct of this study are listed in Table 1. Medtronic 
may incorporate additional Medtronic devices, programmers, software and accessories into 
this clinical study as they receive appropriate license or regulatory approval or/and are 
commercially released by Medtronic, providing the scientific soundness of the study is not 
adversely affected. 
 
 

 
 
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Table 1: Devices and accessories 
Component 
Model Number 
(or latest Medtronic or 
other company release) 
Investigational or  
commercially released 
Pacing system 
Analyzer 
(Medtronic) 
2290 
Commercially Released  
CareLink® 
Programmer 
(Medtronic) 
2090  
Commercially Released  
Hand-held pacers 
(Medtronic)  
 
5388 DDD or 5392 
Commercially Released  
Leads  
Endocardial or 
transvenous leads 
(Medtronic or other 
company)  
Atrial lead 
RV lead 
LV lead 
Commercially Released  
Guiding catheters 
(Medtronic) 
ATTAIN (all available) 
ATTAIN SELECT II (all 
available) 
Commercially Released  
LV pressure wire 
(Millar Instruments) 
Millar (825-0101) 
or similar 
Commercially Released  
Invasive Blood 
pressure 
(Codan) 
Codan PVB transducer 
(17.8059) and contact board 
(75.1068.00) 
or similar 
Commercially Released 
EP catheters and 
pacing wires  
(Medtronic) 
 
(AP technologies) 
 
 
Soloist (all available) 
TORQR-CS (all available) 
Map-iT (903256) 
Commercially Released  

 
 
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Table 1: Devices and accessories 
(Biotronik) 
VisionWire 
or similar 
Surgical connection 
cables 
(Medtronic) 
5114, 5832S 
5833S, 5487 
Commercially Released  
Adaptor 
(Medtronic) 
5103 
Commercially Released  
Reference lead  
(Fiab) 
Recommended: F7830S 
F7832S 
Commercially Released 
Catheter connecting 
cable 
(Medtronic) 
(AP Technologies) 
(Millar) 
 
 
05518SP 
901957 
TEC-10D 
Commercially Released  
Motion sensing input 
device  
Kinect camera or similar 
Commercially Released 
External 
computerized 
electrophysiology 
measurement system 
TMSi porti (Twente 
Medical Systems 
Enschede NL) or 
Cardiotek EPTracer38 
(Schwarzer Germany 
Cardiotek) 
TMSi porti: porti7-16e12b4at
Cardiotek: 00SYS01  
 
Commercially Released 
Connection Box and 
connectors 
(Medtronic) 
09083 
Investigational 
 
The connection box and its connectors are investigational. All other products used in the 
present study (leads and pacing devices) are commercially released (and CE-marked) and 
used within their intended purpose. 
 

 
 
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More detail on the basic components of the system: 
 
The Medtronic Analyzer 2290 is intended for use by a clinician to analyze the pacing and 
sensing performance of the cardiac lead system during the implant of a cardiac arrhythmia 
management device, or during invasive troubleshooting of a cardiac lead system.  
 
The Medtronic or competitor catheters are intended for use in diagnostic EP procedures. 
The catheter is designed for recording intracardiac EGMs and temporary pacing associated 
with EP studies. 
 
The Medtronic Model 5388 DDD or 5392 hand-held pacemaker is a dual chamber 
temporary pacemaker. A dual pacemaker has the ability to sense and pace in both 
chambers of the heart.  
 
Reference lead (recommended F7830S and F7832S): Extension cable for threshold 
analysis for permanent or temporary cardiac pacing  
 
Catheter connecting cable (05518SP and 901957) is used during EP studies to connect 
electrode catheter to ECG recording/stimulation equipment. 
 
LV Pressure wire (825-0101): The Mikro-Cath is a single-use cardiovascular catheter 
intended to be used for medical research and diagnostic purposes. The catheter is used to 
measure hemodynamic cardiac pressures in the human body to allow physicians to better 
understand cardiac performance. 
 
Invasive blood pressure monitoring (DPT9003): The sample line of the sheath used to 
guide the LV pressure wire is connected to the xtrans pressure transducer. 
 
The motion sensing camera is used to visualize the 3-dimension location of the 12-lead 
ECG on the thorax. The 3-dimensional information of the ECG electrodes is needed to 
obtain reliable estimates of the ventricular activation (e.g. ventricular activation isochrones) 
by solving the inverse ECG problem. The total image recording time of the chest area 
approximates 30 seconds. 
 
The Cardiotek EPTracer38 system is a computerized electrophysiology measurement 
system with CE Mark and designed for both regular and experimental electrophysiology 
(EP) studies. An EPTracer system consists of an EPTracer unit and a Personal Computer. 
The EPTracer unit is connected to the computer by an USB cable. The EPTracer unit 
contains a two-channel stimulator and a multi-channel amplifier which can replace and is 
similar in function as the Medtronic analyzer. The system is used to display the 
electrocardiogram (ECG) traces and to inspect, command and control the EPTracer unit. 
EPTracer38 provides the acquisition of the 12 lead Surface ECG, 20 intracardiac channels 
and 6 auxiliary channels. Cardiotek EPTracer38 will be used in the SYNSEQ study as the 
master-pacer and acquisition system. 
 
The Model 09083 Connection Box: 
The Medtronic Model 09083 Connection Box connects pacing electrodes or temporary 
stimulation electrodes to external pacemakers during the pre-implant EP testing procedure. 
The connection box allows easy, flexible and safe connection of pacing electrodes to 
external stimulators, while simultaneously offering the possibility to feed ECG signals 
obtained from the pacing electrodes into an EP monitoring and recording system. The 
connection box contains six channels. Each channel can be individually switched on or off, 

 
 
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connecting the stimulator to the connected pacing electrode, as needed. Each of the six 
channels can be switched to unipolar of bipolar cardiac stimulation independently. 
 
The connection box has been designed to facilitate connection during the EP pre-implant 
testing procedure, when multiple electrodes are used. The connection box improves the 
management of the intervention and helps thereby to minimize the prolongation of the 
procedure and improve safety. Additionally the connection box helps to minimize the 
likelihood of arrhythmias as a result of setups. 
The connection box is designed such that the setup is intuitive. Connections to the 
monitoring system are located on one side, all connections to external pacemakers are 
located at another side of the box, and all connections towards the stimulation electrodes 
are located at a third site of the device. All switches are placed on the top of the device. 
Switches are consistently physically linked to the switched stimulation channel, connecting 
an external stimulator and a stimulation electrode. 
 
All the recommended devices connecting to the connection box have CE-mark with clear 
defined functionality and electrical standards. Inserting the connection box into the 
electrical pathway does not significantly change the electrical characteristics (impedance, 
capacitance) of the pacing system. 
 
The connection box will be accompanied with cabling to connect to recommended 
Medtronic equipment. The box nor its pacing connection cables are in direct contact with 
the patient, or will be in the sterile patient field, and do not need to be sterilized.  
 
The intended use of the connection box is to facilitate, the CRT pre-implant physiological 
testing procedure, involving multiple cardiac stimulation sites in the right and/or LV. The 
box facilitates the interconnection between pacing devices and selected pacing locations in 
the patient’s right and/or LV. It increases the safety of the patient while undergoing the 
procedure and will only indirectly (through a specific clinical protocol) aid in the diagnosis. 
The device is reusable, non-invasive, non-sterile box with no direct contact to the patient. 
The box will not be used in a magnetic resonance imaging (MRI) environment. 
 
The connection box has been used in a previous study without any complications (iSPOT-
study: Clinical Trial Registration:  NTC01883141). In total 31 patients were included with 
successful therapy delivery and data collection. A similar protocol as was done in the 
iSPOT-study will be investigated in this study. 
 
The non-CE marked devices will be labeled ‘exclusively for clinical investigations’ and 
labelling will be in English (unless otherwise required for local regulations). 
For all other CE marked products the manual can be used for review and labeling is 
available in local languages. 
B.3 
Comparator information 
This study does not involve any comparators. 
 
 

 
 
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C STUDY PLAN 
C.1 
Study objectives 
The SYNSEQ study intends to assess the positive LV dP/dt max achieved by multipoint LV 
pacing (either simultaneously or sequentially) in comparison to the response achieved by 
the current (standard) BiV pacing configuration in patients indicated/recommended for 
CRT. The protocol includes rigorous methodology to decrease measurement variability and 
to be patient-tailored (e.g. AV-delay) in order to provide a justified conclusion to the acute 
hemodynamic benefit of MSP 20. In addition, only “difficult” CRT patients are selected in 
order to adequately address the potential benefit of MSP in this patient population. The 
term “difficult” represent those patients with an increased likelihood of non-response to 
conventional CRT (e.g. ischemic patients or non-LBBB LV dyssynchrony patients). In 
addition to the hemodynamic evaluation, electrical parameters such as Q-LV/RV timing and 
QRS-width will be measured. 
The study will also evaluate the feasibility of non-invasive sensors to assist with optimal 
lead placement and pacing sequence. Additionally, it is anticipated that this study will 
provide data that can be used to design future studies. 
 
Primary objectives 
C.1.1
C.1.1.1 
Primary objective 1 
 
Compare the hemodynamic response of a MultiSpot-SYN Left Ventricular pacing 
configuration (simultaneous LV pacing) to a single spot LV pacing configuration in patients 
undergoing a research study, an EP exploratory procedure or CRT implant using the 
contractility parameter positive LV dP/dt max. 
C.1.1.2 
Primary objective 2 
 
Compare the hemodynamic response of a MultiSpot-SEQ Left Ventricular pacing 
configuration (sequential LV pacing) to a single spot LV pacing configuration in patients 
undergoing a research study, an EP exploratory procedure or CRT implant using the 
contractility parameter positive LV dP/dt max. 
 
Secondary objectives 
C.1.2
C.1.2.1 
Secondary objective 1 
Compare the positive LV dP/dt max from a MultiSpot-SEQ LV pacing configuration to a 
MultiSpot-SYN LV pacing configuration in patients undergoing a research study, an EP 
exploratory procedure or CRT-implant using the contractility parameter positive LV dP/dt 
max. 
C.1.2.2 
Secondary objective 2 
Correlate the (non)invasive measures (blood pressure, electrocardiographic mapping and 
RV/LV EGM timings and QRS width) obtained during the different pacing configurations to 
the positive LV dP/dt max measures obtained. 
C.1.2.3 
Secondary objective 3 
Evaluate the (non)invasive measures ability to identify the pacing configuration with the 
highest positive LV dP/dt max 

 
 
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C.2 
Clinical endpoints 
 
Primary endpoints 
C.2.1
The contractile ability of LV is characterized by +dP/dt max of LV. It is a measure of the 
initial velocity of myocardial contraction and is a derivative of the LV-pressure. Left 
ventricular pressure is measured invasively using a high-fidelity micromanometer catheter 
inside the LV. The primary endpoint for primary objectives 1 and 2 and secondary objective 
1 will be the % change LV dP/dt max from baseline (AAI setting). 
 
Secondary endpoints 
C.2.2
Besides the contractility index, other hemodynamic/electrical parameters will also be used 
as endpoints. Blood pressure (systolic and diastolic) is measured by invasive arterial blood 
line connected to a sensitive membrane displacement sensor. Non-invasive blood pressure 
(systolic and diastolic) is acquired through finger volume clamp. The electrical signals (Q-
LV timings, QRS width) are derived from intra-cardiac leads (invasive) and surface 
electrodes (non-invasive) respectively.  
 
In summary, the following secondary endpoints might be determined: 
• 
Invasively measured systolic blood pressure 
• 
Invasively measured diastolic blood pressure 
• 
Non-invasively measured systolic blood pressure 
• 
Non-invasively measured diastolic blood pressure 
• 
Q-LV timings 
• 
QRS width 
• 
RV/LV timings 
 
All the mentioned secondary endpoints will be used to calculate the pairwise correlation 
with the contractility endpoint (+LV dP/dt max) acquired during the different configurations. 
C.3 
Study hypothesis 
• 
It is hypothesized that MultiSpot pacing simultaneously is superior to BiV pacing  
• 
It is hypothesized that MultiSpot pacing sequentially (from apex to mid and then to 
base) is superior to BiV pacing  
• 
It is hypothesized that MultiSpot pacing sequentially (from apex to mid and then to 
base) is non-inferior to MultiSpot pacing simultaneously. 
 
Hypothesis testing will be performed at significance level of 0.05 expect for non-inferiority 
testing which will be performed at a significance level of 0.025. Statistical hypotheses are 
further described in section H.1 
C.4 
Study population 
Subjects indicated or recommended for a CRT-P or CRT-D device (according to the current 
applicable ESC/AHA guidelines) are potential subjects for this study. Only “difficult” CRT 
patients are selected in order to adequately address the potential benefit of MSP in this 
patient population. The term “difficult” represent those patients with an increased likelihood 
of non-response to conventional CRT. They should be 18 or older, they should receive 
optimal heart failure oral medical therapy and they should be in stable sinus rhythm at the 
time of the EP visit. Subjects must meet all of the inclusion criteria and none of the 
exclusion criteria to be included in the study. There is no control group in this study. Since 
all configurations are planned to be measured longitudinally within each subject, subjects 
will serve as their own control. 

 
 
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C.5 
Study design 
This clinical trial is a prospective, interventional, non-randomized, multi-center research 
study designed to assess augmentation of contractility as measured by positive LV dP/dt 
max across LV pacing site(s) in patients indicated/recommended for CRT.  
Therefore, the force of contraction during MultiSpot simultaneous or MultiSpot sequential 
pacing is compared to standard BiV pacing. Standard BiV pacing is defined as pacing from 
a (postero-) laterally placed lead with the electrode between the base and mid position of 
the LV with individually optimized AV delay and a VV-delay of zero or 20 or 40 ms.  
In addition, the feasibility of (non)invasive sensors to identify site(s) of maximal positive 
dP/dt max values is assessed. Rationale for the study design is to aim for maximizing the 
acute hemodynamic response on a per patient basis in a patient population which is known 
to be more at risk for less response to conventional CRT.  
The sample size calculation is based on the primary objective 1 and the primary endpoint, 
i.e.% change LV dP/dt max from baseline (AAI setting). More details can be found in 
Section C.7. 
 
Minimization of bias 
C.5.1
Potential sources of bias in this study may result from selection of subjects, treatment of 
subjects, and evaluation of study data. Methods incorporated in the study design to minimize 
potential bias include but are not limited to:  
• 
Subjects will be their own control, and study measurements have been designed to 
minimize the impact of within-subject temporal variation. 
• 
Subjects will be screened to confirm eligibility for enrollment with defined 
inclusion/exclusion criteria prior to enrollment  
• 
Subject demographics will be collected at the enrollment visit on possible differences 
that may affect primary endpoints. 
• 
Data collection requirements and study procedures (such as AV-optimization) will be 
standardized across all study centers, including identical and calibrated equipment. 
• 
All implanters in the study will be experienced in the placement of LV leads, performing 
EP procedures, performing LV pressure measurements.  
• 
To ensure a widespread distribution of data between centers, the maximum number of 
enrolled subjects per center is 15 subjects. 
• 
A Statistical Analysis Plan will be developed prior to analyzing data which will document 
all pre-specified analyses and analysis methods. 
• 
All study center personnel and Medtronic personnel will be trained on their respective 
aspects of the study using standardized training materials. All study clinicians will be 
trained on and required to follow the Clinical Investigational Plan. 
In summary, potential sources of bias that may be encountered in this clinical investigation 
have been considered and minimized by careful study design. 
C.6 
Randomization and blinding 
No randomization and no blinding are used in this study. 
C.7 
Sample size 
The sample size calculation is based on the primary objective 1. This study is powered to 
show superiority of MultiSpot SYN pacing to BiV pacing (standard CRT) for the primary 
endpoint % change + LV dP/dt max from baseline (AAI pacing). Assuming an expected 
difference in % change between MultiSpot and BiV pacing of 3.5% and standard deviation 

 
 
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of 7%, 34 patients would have 80% power to demonstrate superiority.  The total sample 
size is increased to 40 patients to accommodate for data collection problems during the EP 
procedure. The following null-hypothesis H0 and alternative hypothesis H1 will be evaluated 
at a significance level of 0.05: 
 
  H0: MultiSpot SYN -  BiV = 0% 
  H1: MultiSpot SYN -  BiV ≠ 0 %, 
    
where  indicates percentage change from baseline for the corresponding configuration. 
Previous literature and results from the iSPOT study suggests that the average difference 
in percentage change between MultiSpot SYN and BiV pacing is 2.5% in a normal HF 
population  (iSPOT-study, 9, 19). For the standard deviation of the difference in % change 
between MultiSpot and BiV pacing we assume 7% based on previous literature and the 
iSPOT study. 
Not much literature is available for the difference in % change between MultiSpot and BiV 
pacing for the study population targeted in this study. This study selects “difficult” CRT 
patients in order to adequately address the potential benefit of MultiSpot Pacing in this 
patient population. The term “difficult” represent those patients with an increased likelihood 
of non-response to conventional cardiac resynchronization therapy (e.g. ischemic patients 
or non-LBBB left ventricular dyssynchrony patients). Based on few small subgroup 
analyses  (iSPOT study, 19), we expect that the difference in % change between MultiSpot 
SYN and BiV pacing will be slightly higher in the targeted study population, namely 3.5%. 
The sample size calculation is based on this difference of 3.5% and a standard deviation of 
7%. 
 
For the second primary objective, previous literature suggests that the average difference 
in % change  LV dP/dt max between MultiSpot SEQ and BiV pacing is 3% (6, 17) in a normal 
HF population. Assuming an increased difference between MultiSpot SEQ pacing and BiV 
pacing within the targeted study population similar to the increase for the difference 
between MultiSpot SYN pacing, i.e., 1 %, the expected difference between MultiSpot SEQ 
pacing and BiV pacing is 4%. Assuming this difference and a standard deviation of 7%, a 
sample size of 34 patients has 90 % power to demonstrate superiority. 
 
For the secondary objective 1, a power of 80% is achieved with 34 patients. Based on 
previous research (iSPOT study,19), we assume that the lower-border of the 95 % 
confidence interval for % change MultiSpot SYN to baseline (AAI mode) in the targeted 
patient population is 12.6. In this study we consider MultiSpot SEQ non-inferior to MultiSpot 
SYN if the difference in their means is less than a quarter of the difference between 
MultiSpot SYN pacing and baseline. The non-inferiority margin is thus chosen to be – 3%. 
Assuming the expected difference in percentage change dP/dt max between MultiSpot SEQ 
and MultiSpot SYN pacing is 0.5% and a standard deviation in differences of 7%, 34 
patients would have 80% power to demonstrate non-inferiority of MultiSpot SEQ to 
MultiSpot SYN. 
C.8 
Number of investigation sites and study duration 
The study is expected to be conducted in approximately 10 centers in Europe. At the time 
this Clinical Investigation Plan was finalized, not all participating investigation sites were 
identified. A list of participating investigation sites and investigators will be available under a 
separate cover. The study will enroll up to 40 subjects who fulfill the eligibility criteria and 
who have completed the EP study procedure. It is anticipated that this study will require 
approximately 12 to 18 months for subject enrollment. Patients’ participation in this study is 
expected to last approximately between 1 day and 3 months, depending on the time 
between enrollment and the EP study and the duration of hospital stay after this research 
study, or EP related procedure, or the CRT-implant. Subjects must meet all of the inclusion 
criteria and none of the exclusion criteria to be included in the study.  

 
 
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There will be no minimum limit that each investigator must enroll. To ensure a widespread 
distribution of data between centers, the maximum number of enrolled subjects per center 
is 15 subjects. 
D SUBJECT SELECTION 
D.1 
Inclusion criteria 
• 
Subject is indicated or recommended for CRT-P or CRT-D device according to the 
current ESC/AHA guidelines 
• 
Subject is in sinus rhythm 
• 
Subject receives optimal heart failure oral medical therapy  
• 
Subject is willing to sign the informed consent form 
• 
Subject is 18 years or older 
D.2 
Exclusion criteria 
• 
Subject has permanent atrial fibrillation/flutter or tachycardia 
• 
Subject has pure right bundle branch block (= no additional left ventricular conduction 
delays) 
• 
Subject has left bundle branch block and QRS-duration of > 150 ms and no sign of 
myocardial scar indicated by late gadolinium enhancement MRI 
• 
Subject experienced recent myocardial infarction, within 40 days prior to enrollment  
• 
Subject underwent valve surgery, within 90 days prior to enrollment 
• 
Subject is post heart transplantation, or is actively listed on the transplantation list 
• 
Subject is implanted with a left ventricular assist device 
• 
Subject has severe renal disease (up to physicians discretion) 
• 
Subject is on continuous or uninterrupted infusion (inotropic) therapy for heart failure 
( 2 stable infusions per week) 
• 
Subject has severe aortic stenosis (with a valve area of <1.0 cm2 or significant valve 
disease expected to be operated within study period) 
• 
Subject has complex and uncorrected congenital heart disease  
• 
Subject has a mechanical heart valve 
• 
Pregnant or breastfeeding women, or women of child bearing potential and who are 
not on a reliable form of birth control 
• 
Subject is enrolled in another study that could confound the results of this study, 
without documented pre-approval from Medtronic study manager 
E STUDY PREPARATION PROCEDURES 
E.1 
Investigator/Investigation site selection 
The role of the principal investigator is to implement and manage the day-to-day conduct of 
the clinical study as well as ensure data integrity and the rights, safety and well-being of the 
subjects involved in the clinical study. 
An investigator/investigation site may be included in the investigation, if the 
investigator/investigation site complies with the following requirements:  
• 
Investigator is qualified by training, education, and relevant experience appropriate to 
the use of the product and associated procedures (EP procedures and CRT- pacing) 
• 
The center has adequate resources, facilities and equipment to conduct this trial 
• 
The investigator/center  has adequate volume of patients fulfilling the eligibility criteria 
to meet a monthly enrollment rate of 0.4 patient per month which can be maintained 
over a period of 12 to 18 months 

 
 
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• 
Investigator has experience in conducting clinical research trials 
• 
Site has dedicated/qualified trial site team and/or Medtronic personnel available to 
support, activation, protocol compliance, data collection and record retention 
requirements 
• 
Site has computer with high speed internet access and Microsoft Internet Explorer 
available for data entry 
• 
Market released Medtronic programmer (Model 2090), Pacing System Analyzer 
(Model 2290) and MRI scanner (that has the ability to quantify scar amount) are 
available at the site for the study 
• 
CRT implant reimbursement for the study patient population is secured 
 
Clinical Investigation Agreement 
E.1.1
A Clinical Investigation Agreement shall be in place, signed by the participating 
investigation site and/or principal investigator of each investigation site, as per the local 
legal requirements, and returned to Medtronic prior to the commencement of any clinical 
study activities. The investigator is indicating approval of the Clinical Investigation Plan and 
subsequent amendments, by a fully executed agreement. Amendments to this Clinical 
Investigation Plan shall be agreed upon between Medtronic and investigator(s) and be 
recorded with a justification for the amendments. 
 
Curriculum Vitae 
E.1.2
An up to date signed and dated curriculum vitae from each investigator participating in this 
clinical study, evidencing the required qualifications, including the year and where obtained, 
and shall include their current position at the investigation site. The signature on the CV 
must be dated within 3 years prior to the date of activation of the site.  
E.2 
Ethics 
 
EC approval 
E.2.1
Prior to enrolling subjects in this clinical study, each investigation site’s EC will be required 
to approve the current Clinical Investigation Plan, the Patient Information and Informed 
Consent form, including any other written information to be provided to the subjects and, if 
applicable, the Investigator’s Brochure and materials used to recruit subjects. EC approval 
of the clinical study must be received in the form of a letter and provided to Medtronic 
before commencement of the clinical study at an investigation site. The approval letter must 
contain enough information to identify the version or date of the documents approved. If 
this information is not contained in the approval letter, it must be retrievable from the 
corresponding submission letter. In addition, the approval letter needs to be accompanied 
by an EC roster or letter of compliance, to allow verification that the investigator, other 
investigation site personnel, and/or Medtronic personnel are not members of the EC. If they 
are members of the EC, written documentation is required stating that he/she did not 
participate in the approval process. If the EC imposes any additional requirements (e.g. 
safety reports, progress reports etc.), Medtronic will prepare the required documents and 
send them to the investigator for reporting to the EC. Investigators must inform Medtronic of 
any change in status of EC approval once the investigation site has started enrolment. If 
any action is taken by an EC with respect to the investigation, that information will be 
forwarded to Medtronic by the respective investigator. 
 
Informed consent process 
E.2.2
The investigator or authorized designee must obtain written informed consent before any 
clinical study related activity takes place.  
Well in advance of the consent discussion, the subject should receive the EC approved 
Patient Information and Informed Consent Form. During the consent discussion, the 
investigator or his/her authorized designee must fully inform the patient of all aspects of the 
clinical study that are relevant to the patient’s decision to participate in the clinical study. If 
a patient is illiterate, an impartial witness must be present during the entire informed 

 
 
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consent discussion. All items addressed in the Patient Information and the Informed 
Consent Form must be explained. The language used shall be as non-technical as possible 
and must be understandable to the patient and the impartial witness, where applicable.  
The patient must have ample time and opportunity to read and understand the Patient 
Information and the Informed Consent Form, to inquire about details of the clinical study, 
and to decide whether or not to participate in the clinical study. All questions about the 
clinical study should be answered to the satisfaction of the patient. 
Neither the investigator, nor the investigation site staff shall coerce or unduly influence a 
patient to participate or to continue to participate in the clinical study. The informed consent 
process shall not waive or appear to waive the patient’s rights. 
When the patient decides to participate in the clinical study, the Informed Consent Form 
must be signed and personally dated by the patient and investigator or authorized 
designee. If applicable, the witness shall also sign and personally date the consent form to 
attest that the information in the Patient Information and Informed Consent Form was 
accurately explained and clearly understood by the subject, and that informed consent was 
freely given. 
After all persons have signed and dated the Informed Consent Form, the investigator must 
provide the subject with a copy of the Patient Information and the signed and dated 
Informed Consent Form. 
 
Revisions in Patient Information and Informed Consent Form 
E.2.3
Medtronic will inform the investigators whenever information becomes available that may 
be relevant to the subject’s confirmed participation in the clinical study. The investigator or 
his/her authorized designee should inform the subject in a timely manner.  
Medtronic will revise the written Patient Information and Informed Consent Form whenever 
new information becomes available that may be relevant to the subject’s confirmed 
participation in the clinical study. The revised information will be sent to the investigator for 
approval by the EC. After approval by the EC, a copy of this information must be provided 
to the participating subjects, and the informed consent process as described above needs 
to be repeated.   
 
Regulatory notification / approval 
E.2.4
In countries where submission to the regulatory authority is required per local law, no 
patients will be enrolled in the clinical study until the particular regulatory authority has 
approved the current Clinical Investigation Plan of the clinical study and other documents 
as required according to the local requirements. 
E.3 
Regulatory compliance 
The SYNSEQ clinical study is a prospective, interventional, non-randomized, multi-center 
research study.  
This clinical study will be conducted in compliance with the latest version of the Declaration 
of Helsinki, Good Clinical Practices (GCP), laws and regulations of the country/ies in which 
the clinical study is conducted, including data protection laws, the Clinical Investigation 
Agreement and the Clinical Investigation Plan.  
All principles of the Declaration of Helsinki have been implemented in this clinical study by 
means of the patient informed consent process, EC approval, clinical study training, clinical 
trial registration, preclinical testing, risk benefit assessment, publication policy, etc.  
The study was designed to reflect the good clinical practice principles outlined in ISO 
14155:2011 (so the study is not fully ISO 14155:2011 compliant). These include the 
protection of the rights, safety and well-being of human subjects, controls to ensure the 
scientific conduct and credibility of the clinical investigation and the definition of 
responsibilities of the sponsor and investigators.     
Prior approval of the CIP and any subsequent amendments is required from the following 
groups prior to any study procedures at a study center: Medtronic, geography-specific 

 
 
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regulatory authorities (if regulatory approval or notification is required) and an independent 
medical ethics committee or institutional review board. 
The legally incompetent persons are not going to be included in the study. 
If the regulatory authority imposes any additional requirements (e.g. safety reports, 
progress reports etc.), Medtronic will prepare the required documents and send them to the 
respective authority. 
E.4 
Training requirements 
Prior to investigation site activation or subsequent involvement in clinical study activities, 
Medtronic will provide clinical study training relevant and pertinent to the involvement of 
personnel conducting clinical study activities and investigator responsibilities. 
Training will be given as a minimum on the CIP, the PIC process, the use of data collection 
tools, applicable local regulations, as well as device training are required. Study-specific 
training will be documented prior to investigation site activation. 
Investigator and/or study coordinator meeting(s) or conference call(s) may be held to 
discuss the CIP, provide training, discuss study results, etc. Continued training may occur 
through interim meetings or conference calls to discuss relevant study issues. 
Trained clinical site personnel can provide training to other site study personnel on study 
documents and procedures. 
E.5 
Study materials and study-specific equipment 
The following study equipment must be available at each center to support study activities: 
• 
Computer with high speed internet access and Microsoft Internet Explorer available 
for data entry 
• 
Market released Medtronic programmer (Model 2090) 
• 
Pacing System Analyzer (Model 2290) 
• 
MRI scanner (that has the ability to quantify scar amount) 
It is preferable that the following study equipment is available at a center to support study 
activities: 
• 
Non-invasive beat-to-beat blood pressure monitor (such as Finapres, Finapres 
Medical Systems, Amsterdam, the Netherlands; Nexfin, Bmeye, Amsterdam, the 
Netherlands, or similar). 
All study equipment must be properly maintained and calibrated if required. Programmer 
calibration and maintenance will be performed at the Medtronic office in Heerlen, the 
Netherlands. Only calibrated programmers may be used. Centers are responsible for 
maintaining and calibrating other equipment not provided by Medtronic and used in the 
course of this study in accordance with established center practice.  
Each investigational site will be provided with study materials (e.g. Investigator Site File 
and electronic Case Report Forms access). 
E.6 
Study device/product traceability 
The connection box and its connectors are investigational.  
All other products used in the present study (leads and pacing devices) are commercially 
released (and CE-marked) and used within their intended purpose. Therefore, no 
accountability is needed for these products. 
 
Supply of investigational devices 
E.6.1
Medtronic will only allow shipment of investigational devices/products to the investigation 
site or investigator, after the Clinical Study Manager has declared the investigation site 
ready to start the clinical study. 

 
 
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The connection box can only be sent/brought to a center by Medtronic personnel for use 
during the EP study visit. Medtronic personnel will take the connection box back to 
Medtronic after completion of the EP study visit.    
 
Storage and handling of investigational devices 
E.6.2
Investigational devices/products must be stored in a secured area. The method of storage 
shall prevent the use of investigational devices/products for other applications than 
mentioned in this Clinical Investigation Plan. The connection box will be used only in the 
study according to the CIP. 
 
Device explant and return procedures 
E.6.3
Medtronic personnel will take the connection box back to Medtronic after completion of the 
EP study visit. The connection box will remain in the possession of Medtronic personnel 
and will not be stored at the site between EP study visits.    
The connection box will be traced during the clinical study. The investigator is responsible 
for maintenance of a Device Tracking Log in the Investigator Site File. The distribution logs 
are provided to the center and will be used for tracking the presence of a connection box at 
the site by assignment of serial numbers. The logs will contain the date of receipt, the name 
of person who receives it, the date of use, the subject ID of the subjects paced with the 
connection box, the date of return and the name of the person who complete the log. The 
logs must be maintained at each investigational center and updated when a connection box 
is brought to the site for an EP study visit and taken back to Medtronic after the EP study 
visit. The log should be sent to Medtronic each time they are updated. 
At the end of the clinical study the principal investigator must sign and date the original 
Device Tracking Log.  
F STUDY METHODS 
F.1 
Point of enrollment 
A subject is enrolled in the study when he/she signs and dates the PIC. At this point, the 
patient will be assigned a subject number and is considered a subject in the investigation. 
The investigator will maintain a log of all subjects enrolled in the clinical investigation, 
assigning an identification code linked to their names, alternative subject identification or 
contact information.  
F.2 
Implant or procedure aspects 
 
Baseline visit 
F.2.1
The baseline visit can be a standalone visit or occur on the same day as the EP study. 
The following procedures/data collection will be conducted during the baseline visit: 
• 
Verification of all inclusion and all exclusion criteria 
• 
Enrollment 
• 
Demographics (age, gender) 
• 
Physical examination (height, weight, heart rate, blood pressure) 
• 
Left ventricular ejection fraction (within last 3 months, otherwise a new 
measurement should be performed) 
• 
Multi-lead ECG (within last 3 months, otherwise a new ECG should be 
performed) 
• 
Echocardiographic evaluation (if available within last 3 months, otherwise not 
collected ) 
• 
NYHA classification 
• 
Medical history (cardiovascular or related) 
• 
Cardiovascular medications 

 
 
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• 
Pregnancy test for women with child-bearing potential 
• 
MRI as explained in paragraph below  
F.2.1.1 
Magnetic Resonance Imaging (MRI) 
 
Patients will undergo a baseline MRI before scheduled CRT-related surgery (i.e. dedicated 
research study or EP procedure or actual CRT implant) to identify the location and 
transmurality of any myocardial scar using late gadolinium enhancement-magnetic 
resonance imaging according to standard hospital practice. During the MRI a thorax scan is 
required to be able to reconstruct the thorax and lungs, i.e. a transverse scan with neck and 
liver visible. An appropriate marker should be placed on the xyphoid and 10 cm above the 
xyphoid during this scan.  In addition, left ventricular end systolic volume (LVESV), left 
ventricular end diastolic volume (LVEDV) and left ventricular ejection fraction (LVEF) will be 
determined. MRI can be performed as standard of care or solely for the study. If the patient 
has a LBBB conduction pattern and QRS-width above 150ms, the MRI images should be 
analyzed before the EP study to detect the presence of scar. If no scar is present on late 
gadolinium enhancement MRI, the LBBB patient with QRS > 150ms should not be included 
in the study (if MRI done as standard of care) or should be exited from the study (if MRI 
done solely for the study). 
 
Electrophysiological (EP) study visit 
F.2.2
 
The EP study visit can be a standalone visit or can occur on the same day as the baseline 
visit. The EP study visit should take place within 3 months after the MRI has been obtained. 
Patients will undergo standard implant of a biventricular pacing system (CRT-P or CRT-D) 
or will undergo the EP study (data for this research study will be collected) before possible 
CRT-implant or will participate in this dedicated research study as a standalone visit 
(without any concomitant procedure).  
 
If available in the center, a finger volume clamp system (e.g. model Nexfin, BMEYE B.V.) 
will be connected to one of the subject’s fingers to measure the blood pressure non-
invasively. In addition, a multi-lead surface ECG is collected during the whole procedure.   
 
Pacing electrodes (cardiac leads or EP catheters) will be placed in the right atrium (RA) 
and right ventricle (RV). The coronary sinus will be cannulated, a venogram will be 
obtained and target vessels for LV stimulation will be identified. An EP-catheter (“Multi-
electrode lead”) or LV lead will be used for LV pacing. The temporary LV pacing electrodes 
(e.g. EP catheter or LV lead) will be inserted into the coronary sinus and then sequentially 
into the suitable target vein. Targeted myocardial regions for LV lead/catheter placement 
are: lateral or posterolateral vein (standard vein), and the vein displaying the most promise 
to reach the true LV apical position (to be anticipated the anterior vein). To reach the most 
LV apical position small EP-catheters or pacing guide wire will be used. 
 
Pacing will be performed at up to three electrodes simultaneously or sequentially within the 
(standard) vein(s) (MultiSpot-SYN and MultiSpot-SEQ), covering the LV basal to apical 
locations when feasible (see figures 4, 5 and 6). A lateral LAO, RAO and/or AP fluoro-
screen shot will be taken to document the different (temporary) electrode positions. A 
marker is placed on the xyphoid to register the fluoroscopy images. 
 
A Millar pressure catheter or similar will be introduced via the femoral artery retrograde 
across the aortic valve into the LV for hemodynamic pressure monitoring. Heparin will be 
administered to ensure that the activated clotting time is monitored per standard hospital 
practice.  
 

 
 
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The following LV pacing configurations will be evaluated:  
Biventricular pacing (BiV)  
Pacing will be performed on one LV electrode pair, (at 3 different longitudinal locations), 
and on the tip of the RV-lead. In total, three different pacing BiV settings will be evaluated. 
Configuration 1: RV + LV lateral Apex 
Configuration 2: RV + LV lateral Mid 
Configuration 3: RV + LV lateral Base (Reference: Standard CRT) 
 
MultiSpot simultaneous LV-ventricular pacing (MultiSpot-SYN) 
Pacing will be performed on 3 electrodes on the LV wall, placed at different longitudinal 
locations, and on the tip of the RV-lead simultaneously.  
Configuration 4: RV + LV lateral Apex + LV lateral Mid + LV lateral Base 
 
MultiSpot sequential LV-ventricular pacing (MultiSpot-SEQ) 
3 electrodes on the LV wall will be paced sequentially. The RV-electrode will be paced 
simultaneously with last paced LV-electrode. The timing-sequence and the amount of spots 
will depend on the electrical delays measured during the experiments.  
Configuration 5: LV lateral Apex  LV lateral Mid  LV lateral Base + RV 
 
The different pacing settings include simultaneous and sequential RV and LV pacing and 
are in bipolar or unipolar mode. At each pacing site, the evaluation of the effect of CRT will 
be performed approximately 4 times (repetition) in order to increase signal to noise ratio. 
Each setting lasts about 20 beats (10-15 sec) interspersed with baseline (AAI; also 20 
beats, 10-15 sec) pacing. The heart rate will be elevated by atrial pacing to a base rate 
about 10 beats above intrinsic or maximally tolerable rate, to ensure a constant heart rate. 
The RV-LV and the LV-LV (= VV-timing) intervals will be zero (MultiSpot-SYN) or will be 
sequential with VV-delay depending on the per patient measured electrical timing between 
the different electrode positions (MultiSpot-SEQ). For the latter, the VV-delay between 
Apical and Mid electrode position will be similar to the VV-delay between Mid and Basal 
electrode position. Optimal AV-delay will be calculated using CardioSyncTM formulas 
(PAVECG=min (Ap-Pend + 30 ms, Ap-RVs – 50 ms)) derived from a correlation study 
between electrocardiographic measures such as the intrinsic AV interval and P-wave 
duration. The method aims at absence of truncation of the E/A waves. Up to five different 
AV-delays will be evaluated in this study (i.e. the optimal AV-delay and optimal AV-delay +/- 
30 and +/- 60 ms). Hemodynamic measurements of positive LV dP/dt max, LV end diastolic 
pressure and arterial pressures will be measured during baseline and CRT. Additionally, at 
each pacing setting, the electrical delay from RV-pace to the different LV activations will be 
measured. 
 
The signals from the LV pressure catheter, finger volume clamp system, internal 
electrograms, and surface ECG will be collected in real time and stored for later analysis as 
explained earlier. The CRT implant or EP procedure will be completed as per standard 
practice.  
 
The protocol procedures will result in an additional 30 to 45 minutes to the standard 
procedure time. Pacing will be achieved by using a Medtronic 2290 analyzer and temporary 
pacemaker (5388DDD or 5392) stimulators or equipment present in the operating room of 
the participating physicians.  
 
All patients should be followed up according to standard of care after the end of the 
protocol procedures.  
 

 
 
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Figure 3:  Start of protocol description.  
 
 
 
Figure 4: Different ventricular lead positions. MultiSpot pacing at 3 electrodes at 
targeted LV locations synchronously or sequentially and RV. The mid and basal LV 
electrodes are placed in lateral or posterolateral vein. To reach the LV apex an alternative 
than the lateral vein can be used (to be anticipated the anterior vein). The delay between 
the different LV-electrodes will be determined during the experiment as it will be patient-
dependent. AV-delay will be calculated using CardiosyncTM 
 
 
 
 
 
 
 
 

 
 
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Part A: 
 
 
Part B: 
 
 
 
 
 
 
 
 

 
 
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Part C: 
 
                                      
 
Figure 5: Description of the pacing protocol. Part A is depicting the MultiSpot-SYN 
protocol while Part B is depicting the MultiSpot-SEQ protocol. Both protocols require the 
determination of the patient-specific AV-delay while Part B also requires the determination 
of patient-specific VV-delays. Part C is displaying the pacing procedure for 1 out of 5 total 
AV delays during which the positive dP/dt max will be measured. Each pacing ON and OFF 
setting will last 10-15 sec. The repetition of steps is used to increase sensitivity of the 
positive dP/dt max measurements. Five AV delays will be assessed: optimal AV, optimal 
AV delay +/- 30 and +/-60 ms. 
F.3 
Data collection requirements 
Clinical data will be collected at enrollment, baseline and during the study procedure. Table 
2 summarizes the data requirements. Patients’ participation in this study is expected to last 
approximately between 1 day and 3 months, depending on the time between 
enrollment/baseline and the EP study and the duration of hospital stay after the research 
study, or EP related procedure or the CRT-implant. The EP study visit should take place 
within 3 months after the MRI has been obtained. In case the EP study visit is not done 
within 3 months after the MRI, the patient should be exited from the study. 
Subjects, who complete all study procedures, will be exited from the study just before the 
moment of hospital discharge. This will be documented on the Study Exit eCRF. There will 
be no further follow-up required for subjects that are exited from the study since no 
investigational products will be implanted or used in the study. 
 
 
 

 
 
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Table 2: Data Collection Requirements 
Data 
Baseline 
EP Visit 
Inclusion/Exclusion Criteria 
x
Subject Informed Consent 
x
Demographics     
x
Physical examination 
x
LVEF 
Within 3 months prior to enrollment, 
otherwise a new measurement should 
be performed 
x 
  
Surface ECG 
Within 3 months prior to enrollment, 
otherwise a new ECG should be 
performed 
x 
x 
Echocardiogram 
If available within last 3 months, 
otherwise not collected  
x 
  
NYHA Class 
x
Medical history 
x
Cardiovascular medications 
x
MRI (structural and functional) 
x
Non-invasive blood pressure 
x
x
Venogram 
x
Invasive blood pressure  
x
LV pressure 
x
LV lead implant location (Chest X-ray) 
x
Unipolar and Bipolar electrograms 
x
Adverse events 
x
x
Device deficiency 
x
Deviation 
x
x
Exit 
x1
x
1 In case the MRI is done solely for the study:  If the patient has ischemic etiology and a LBBB 
conduction pattern and QRS-width above 150ms, the MRI images should be analyzed immediately 
to detect scar. If scar is not present on late gadolinium enhanced MRI, the patient should be exited 
from the study prior to EP visit 
F.4 
Role of the sponsor’s representatives 
Sponsor’s representatives (e.g. Field Clinical Engineer, Field CRS, Technical Consultant) 
may provide support as required for the clinical study, including technical support during 
implant/procedure including completion of a technical support sheet and/or technical 
support. Documentation of study training and qualification of sponsor representatives will 
be maintained by Medtronic. The sponsor’s representatives providing technical support 
may be listed on the sponsor technical support list.   
F.5 
Source documents 
Source documents may be the PIC, hospital/clinic files, Electronic Media (MRI images, 
Echo images), programmer or ECG printouts, worksheets, MRI images and eCRFs. 
The investigator will clearly mark the clinical records to indicate that the subject is enrolled 
in this clinical study.  
Data that could be recorded directly on the eCRF and considered as source data are listed 
in section G.1.2. 

 
 
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F.6 
Adverse events and Device Deficiencies 
 
Definition/classification 
F.6.1
Timely, accurate, and complete reporting and analysis of safety information for clinical 
studies are crucial for the protection of subjects, investigators, and the sponsor. Reporting 
and analysis of safety data are mandated by regulatory authorities worldwide. All events 
and deaths for the SYNSEQ study will be collected, classified, reviewed and reported from 
enrollment up till study exit. Documented pre-existing conditions are not considered AEs 
unless the nature or severity of the condition has worsened.  
For the purposes of the clinical report, Medtronic will classify each Adverse Event 
according to ISO 14155:2011. 
Where the definition indicates “device”, it refers to any device used in the study. This might 
be the device under investigation, or any market released component of the system. 
Adverse Event (AE): (ISO14155:2011 3.2) 
Any untoward medical occurrence, unintended disease or injury, or untoward clinical signs 
(including abnormal laboratory findings) in subjects, users or other persons, whether or not 
related to the investigational medical device 
 
NOTE 1:  This definition includes events related to the investigational medical device or the 
comparator. 
NOTE 2:  This definition includes events related to the procedures involved. 
NOTE 3:  For users or other persons, this definition is restricted to events related to investigational 
medical devices. 
Adverse Device Effect (ADE): (ISO14155:2011 3.1) 
Adverse event related to the use of an investigational medical device 
 
NOTE 1: This definition includes adverse events resulting from insufficient or inadequate 
instructions for use, deployment, implantation, installation, or operation, or any malfunction of the 
investigational medical device. 
NOTE 2: This definition includes any event resulting from use error or from intentional misuse of 
the investigational medical device 
Serious Adverse Event (SAE): (ISO 14155:2011 3.37) 
Adverse event that  
a) 
led to death, 
b) 
led to serious deterioration in the health of the subject, that either resulted in  
1) 
a life-threatening illness or injury, or  
2) 
a permanent impairment of a body structure or a body function, or 
3) 
in-patient or prolonged hospitalization, or  
4) 
medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function, 
c) 
led to foetal distress, foetal death or a congenital abnormality or birth defect.   
 
NOTE:  Planned hospitalization for a pre-existing condition, or a procedure required by the CIP, 
without serious deterioration in health, is not considered a serious adverse event. 
Serious Adverse Device Effect (SADE): (ISO 14155:2011 3.36) 
Adverse device effect that has resulted in any of the consequences characteristic of a 
Serious Adverse Event  
Unanticipated Serious Adverse Device Effect (USADE): (ISO 14155:2011 
3.42) 

 
 
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Serious adverse device effect which by its nature, incidence, severity or outcome has not 
been identified in the current version of the risk analysis report 
 
NOTE:  Anticipated serious adverse device effect (ASADE) is an effect which by its nature, incidence, 
severity or outcome has been identified in the risk analysis report. 
Device deficiency: (ISO 14155:2011 3.15) 
Inadequacy of a medical device with respect to its identity, quality, durability, reliability, 
safety or performance 
 
NOTE: Device deficiencies include malfunctions, use errors, and inadequate labelling. 
Unavoidable Adverse Event: 
An adverse event inherent to a surgical procedure that is expected to occur in all subjects 
for a projected duration according to the Investigator’s opinion, including, but not limited to:  
 
Event Description 
 
Time Frame 
(Hours) from the 
Surgical 
Procedure 
Anesthesia related nausea / vomiting  
24 
Low-grade fever (<100°F or 37.8°C) 
48 
Pocket site / Incisional pain 
72 
Mild to moderate bruising / ecchymosis
168 
Sleep problems (insomnia) 
72 
Back pain related to laying on table 
72 
Shoulder pain/discomfort/stiffness 
related to shoulder immobilization 
during procedure 
72 
 
Further adverse event definitions: 
 
Relatedness 
Procedure Related  
An adverse event that occurs due to any procedure related to the 
investigational study procedure/protocol   
System Related  
• 
Pacing system Related:  An adverse event that results from the 
presence or performance (intended or otherwise) of the Pacing system 
(Connection Box, hand-held pacers and connection cables) 
• 
Lead Related: An adverse event that results from the presence or 
performance (intended or otherwise) of the right atrial, right ventricular 
or left ventricular lead 
• 
Implant or Introduction Tool Related: An adverse event that results 
from the presence or performance (intended or otherwise) of the 
implant or introduction tool 
• 
LV Catheter Related: An adverse event that results from the 
presence or performance (intended or otherwise) of the LV Catheter 
Timing 

 
 
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Pre-study procedure 
testing AE 
An adverse event that occurs after the patient informed consent form has 
been signed but before the skin incision related to the investigational study 
procedure/protocol 
During study 
procedure testing AE 
An adverse event that occurs during investigational study procedure 
testing/protocol 
Post study procedure 
testing AE 
An adverse event that occurs between  the completion of skin closure for 
the investigational study procedure testing/protocol and before hospital 
discharge of the patient 
 
Other 
Hospitalization 
A therapeutic inpatient hospitalization (excludes outpatient and emergency 
room visits) lasting greater than or equal to 24 hours. 
 
 
Recording and reporting of Adverse Events 
F.6.2
 
Adverse Event (AE) information will be collected throughout the study and reported to 
Medtronic on an Adverse Event Form, one for each Adverse Event. This Adverse Event 
form must be entered in the database.  
In the event the database is unavailable an alternative data collection system may be 
implemented such as an email notification to the sponsor. Upon database (re)-instatement, 
the data contained in the email notification to the sponsor will be entered in to the database 
by the investigator or authorized designee. The email notification must be sent to the study 
contact person as listed in Table 4. 
 
All Adverse Events, regardless of relatedness or outcome, must be reported. 
See the Adverse Event eCRF for the information to be reported for each Adverse Event. 
 
For Adverse Events that require immediate reporting (see table 3), initial reporting may be 
done on the eCRF completing as much information as is available. The completed AE 
eCRF must be sent to Medtronic as soon as possible. 
 
In case the investigator requires information from the sponsor in an emergency situation, 
the investigator can contact the study contact person as listed in Table 4. 
 
In case the Adverse Event is related to a market released device used during the study, 
post market surveillance is also applicable and the investigator is responsible for immediate 
reporting of the product complaint via the regular channels for market released products. 
The reporting of product complaints, abuse, and misuse of these CE-labeled devices is not 
part of the clinical study and should be done in addition to the AE reporting requirements. 
 
 
Recording and reporting of Device Deficiencies 
F.6.3
 
Device Deficiency information will be collected throughout the study and reported to 
Medtronic. Device Deficiencies that did not lead to an Adverse Event should be reported on 
a Device Deficiency Form, one for each Device Deficiency. This Device Deficiency form 
must be entered in the database.  
In the event the database is unavailable an alternative data collection system may be 
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the data contained in the email notification to the sponsor will be entered in to the database 
by the investigator or authorized designee. The email notification must be sent to the study 
contact person as listed in Table 4. 
 
See the Device Deficiency eCRF for the information to be reported for each Device 
Deficiency that did not lead to an Adverse Event.   
 
Device deficiencies that did not lead to an Adverse Event but could have led to an SADE 
a) if either suitable action had not been taken, 
b) if intervention had not been made, or 
c) if circumstances had been less fortunate, 
require immediate reporting (see table 3). Initial reporting may be done by on the eCRF by 
completing as much information as is available. The original completed Device Deficiency 
eCRF must be sent to Medtronic as soon as possible. 
 
Adverse Event and Device Deficiency review process 
F.6.4
 
All Adverse Events and Device Deficiencies will be reviewed by a Medtronic responsible 
person. This review will include the determination whether the Adverse Event/Device 
Deficiency meets regulatory reporting requirements (see table 3). The sponsor will ensure 
timely Adverse Event/Device Deficiency reporting to meet global regulatory requirements. 
A list of anticipated adverse events that are expected in nature is included in Appendix L.2 
of this CIP. 
In case the Adverse Event/Device Deficiency is related to a market released device used 
during the study, the Medtronic responsible person will immediately report this device 
related Adverse Event/Device Deficiency to the Medtronic internal Complaint Handling Unit. 
The Medtronic internal Complaint Handling Unit will ensure prompt review, and appropriate 
reporting.  
 
Table 3: Adverse Event reporting requirements 
Serious Adverse Device Effects (SADE), including Unanticipated Serious Adverse Device 
Effect (USADE): 
Investigator submit to: 
 
Medtronic 
Immediately after the investigator first learns of the event or of new 
information in relation with an already reported event.  
Regulatory Authority 
As per local reporting requirement 
EC 
Reporting timeframe as per local EC/IRB requirement.  
Sponsor submit to: 
 
Regulatory Authorities  
Reporting timeframe as per local requirement. 
EC 
Submit to EC/IRB per local reporting requirement. 
Serious Adverse Events (SAE)
Investigator submit to: 
 
Medtronic 
Immediately after the investigator first learns of the event or of new 
information in relation with an already reported event.  
Regulatory Authority 
As per local reporting requirement 
EC 
Submit to EC/IRB per local reporting requirement. 
Sponsor submit to: 
 

 
 
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Regulatory Authorities  
Reporting timeframe as per local requirement. 
EC 
Submit to EC/IRB per local reporting requirement. 
Adverse Device Effects (ADE) 
Investigator submit to: 
 
Medtronic 
Immediately after the investigator first learns of the event.  
Regulatory Authority 
As per local reporting requirement 
EC 
Submit to EC/IRB per local reporting requirement. 
Sponsor submit to: 
 
Regulatory Authorities 
Reporting timeframe as per local requirement 
EC 
Submit to EC/IRB per local reporting requirement. 
All other AEs
Investigator submit to: 
 
Medtronic 
Submit in a timely manner after the investigator first learns of the event. 
Regulatory Authority 
As per local reporting requirement 
EC 
Submit to EC/IRB per local reporting requirement. 
Device Deficiency with SADE potential 
Investigator submit to: 
 
Medtronic 
Immediately after the investigator first learns of the deficiency or of new 
information in relation with an already reported deficiency.  
Regulatory Authority 
As per local reporting requirement 
EC 
Submit to EC/IRB per local reporting requirement. 
Sponsor submit to: 
 
Regulatory Authorities 
Reporting timeframe as per local requirement 
EC 
Submit to EC/IRB per local reporting requirement. 
All other Device Deficiencies 
Investigator submit to: 
 
Medtronic 
Submit in a timely manner after the investigator first learns of the 
deficiency. 
Regulatory Authority 
As per local reporting requirement 
EC 
Submit to EC/IRB per local reporting requirement. 
 
Adverse Event Advisory Committee 
F.6.5
 
An independent Adverse Event Advisory Committee (AEAC) will review all Adverse Events, 
all deaths and all Device Deficiencies with SADE potential. 
The AEAC will consist of a minimum of three non-Medtronic physicians.   This committee 
will determine the relatedness of all adverse events and deaths to the device, system, and 
testing procedure. 
All Adverse Events, all deaths and Device Deficiencies with SADE potential will be 
reviewed by a minimum of three members of the committee.  

 
 
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The responsibilities of an AEAC committee are:  
• 
to review all reported all Adverse Events, all deaths and all Device Deficiencies with 
SADE potential and its classification on a periodic basis 
• 
upon request advise Medtronic about the potential clinical impact of an observed 
unintended device performance 
• 
advise Medtronic in cases of SADE’s, Device Deficiencies with SADE potential  
 
Emergency contact details in case of serious AEs 
F.6.6
In case of an immediately reportable Adverse Event the investigators can contact the study 
contact person as listed in table 4. 
 
Subject Death 
F.6.7
All subject deaths must be reported by the investigator to Medtronic on a Subject Death 
form as soon as possible after the investigator first learns of the death.  
A copy of the death certificate, if available and allowed by state/local law, should be sent to 
the Medtronic clinical study team. When a death occurs in a hospital, a copy of the death 
summary report and all relevant hospital records should be sent to the Medtronic clinical 
study team, if available. If an autopsy is conducted, the autopsy report should also be sent 
to the Medtronic clinical study team if available and allowed by state/local law. When the 
death occurs at a remote site, it is the investigative center’s responsibility to attempt 
retrieval of information about the death. In summary, the following data will be collected:  
• 
Date of death  
• 
Detailed description of death  
• 
Cause of death 
• 
Relatedness to system and/or procedure  
• 
Death summary/hospital records (if available and allowed by state/local law)  
• 
Autopsy report (if available and allowed by state/local law)  
• 
Death certificate (if available and/or allowed by state/local law)  
 
Sufficient information will be required in order to properly classify the subject’s death. The 
Investigator shall classify each subject death per the following definitions:  
• 
Cardiac Death: A death directly related to the electrical or mechanical dysfunction 
of the heart.  
• 
Sudden Cardiac Death (SCD): Natural death due to cardiac causes, indicated by 
abrupt loss of consciousness within one hour of the onset of acute symptoms; 
preexisting heart disease may have been known to be present, but the time and 
mode of death are unexpected. If time of onset cannot be determined, SCD will 
alternatively be defined as any unexpected cardiac death occurring out of the 
hospital or in the emergency room as dead on arrival.  
• 
Non-sudden Cardiac Death: All cardiac deaths that are not classified as sudden 
deaths, including all cardiac deaths of hospitalized subjects on inotropic support.  
• 
Non-cardiac Death: A death not classified as a cardiac death.  
• 
Unknown Cardiac Classification: Unknown death classification is intended for use 
only when there is insufficient or inadequate information to classify the death.  
The AEAC will review deaths and provide a final adjudication of the primary cause of death, 
relatedness, and cardiac classification.  
F.7 
Subject accountability 
A subject will be exited from the study in the event that he or she is unable to participate, 
expresses a desire to withdraw, or is unwilling to continue participation in the study. The 
reason for withdrawal needs to be documented in the subject’s hospital record and in the 
eCRF. The subject should be informed that their future care or treatment will not be 
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alternative treatments and medical consequences of exiting the study should be discussed 
with the subject. Any significant new findings related to the study that may develop, which 
may relate to the subject’s willingness to continue participation, should be communicated to 
the subject. Unless the patient explicitly revokes informed consent, available data will be 
reported. 
A subject may be exited from the study if an investigator feels it is necessary to withdraw 
the subject from the study due to a medical condition or other reason. In such cases, the 
subject will be notified and provided an explanation regarding the reasons for the study exit. 
Unless the patient explicitly revokes informed consent, available data will be reported. 
Upon withdrawal from the study, no further study data will be collected for the subject. 
If discontinuation is because of safety or lack of effectiveness, the subject shall be asked to 
be followed for collecting safety data outside the clinical study. 
The subjects who withdraw or who are withdrawn are not replaced.  
If the subject is determined to be lost to follow-up, the details regarding a minimum of two 
attempts and the method of attempt (e.g., one letter and one phone record or two letters) to 
contact the subject must be documented in the patient medical record.  Any additional 
regulations set forth by the governing MEC must be followed.  
F.8 
Study deviations and CIP changes 
A study deviation is an event where the investigator or site personnel did not conduct the 
clinical study according to the Clinical Investigational Plan or Clinical Investigation 
Agreement. The investigator is not allowed to deviate from the above mentioned 
documents except with prior approval and under emergency circumstances. All deviations 
shall be documented and explained, regardless the reason for the deviation. 
Medtronic will assess the significance of all deviations and evaluate the need to amend the 
Clinical Investigation Plan or to early terminate the investigation, in accordance with 
Medtronic SOPs. 
 
Request for approval of study deviations 
F.8.1
The investigator shall obtain documented approval from Medtronic and, if required, from EC 
and regulatory authority, before implementation of any change in- or deviation from the 
Clinical Investigation Plan. The investigator shall timely contact the Clinical Study Manager 
for review of the proposed change/deviation. 
In any emergency situation the investigator shall exercise his/her judgment to safeguard 
the subject’s interest. Such deviations from the Clinical Investigation Plan do not require the 
prior approval of Medtronic. The investigator shall report the deviation as soon as possible 
to Medtronic and the reviewing EC, if applicable. Medtronic will inform the regulatory 
authorities, if required. 
 
Reporting requirements for study deviations 
F.8.2
Study deviations directly related to a subject, including informed consent violations, will be 
documented in the subject’s case history record and recorded on the Deviation eCRF.  
The investigator shall adhere to EC requirements and procedures, local laws and 
regulatory agency for reporting study deviations. 
Medtronic is responsible for analyzing deviations, assessing their significance, and 
identifying any additional corrective and/or preventive actions (e.g. amend the CIP, 
additional training, terminate the study, etc.). Repetitive or serious investigator compliance 
issues may result in the need to initiate a corrective action plan, and in some cases freeze 
enrolment or ultimately terminate the investigator’s participation in the clinical study. 
Medtronic will provide investigation site-specific reports to the investigators on a periodic 
basis summarizing information on deviations that occurred at the investigational site.  

 
 
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Amendments to the Clinical Investigation Plan 
F.8.3
The investigator may propose any appropriate modification(s) of the Clinical Investigation 
Plan or investigational device or investigational device use. Medtronic will review this 
proposal and decide whether the modification(s) will be implemented.  
Medtronic will submit any significant amendment to the Clinical Investigation Plan, including 
a justification for this amendment, to the appropriate regulatory authorities and to the 
investigators to obtain approval from their EC, if applicable. Administrative amendments to 
the Clinical Investigation Plan will be submitted to the EC and appropriate regulatory 
authorities for notification, if applicable. 
G QUALITY CONTROL PROCEDURES 
G.1 
Procedures for database management 
 Data collection 
G.1.1
The investigator must ensure accuracy, completeness and timeliness of the data reported 
in the eCRFs and in all other required reports. Data reported on the eCRFs which are 
derived from source documents must be consistent with the source documents and 
discrepancies need to be justified in a documented rationale, signed and dated by the 
(principal) investigator and filed in the patient medical file. 
Only authorized persons can complete eCRFs. eCRFs shall be signed by investigators 
(physicians only) as specified on the Delegated Tasks List included in the Investigator Site 
File. 
The Electronic Data Capture system is used for study visit data, adverse event data, device 
deficiency data, study deviations and exits collection. This system maintains an audit trail 
on entries, changes or corrections in eCRFs. If a person is only authorized to complete 
eCRFs or make changes to an already signed eCRF, the investigator shall re-sign this 
eCRF. 
The data collected during the EP study visit coming from the heart, chest or finger (i.e. 
surface ECG, (non-)invasive blood pressure, LV pressure, unipolar and bipolar 
electrograms) will be collected simultaneously on the universal data acquisition system (i.e.  
PORTI-system is a multi-channel ambulatory and stationary system for physiological 
research). The raw data from the PORTI-system will not be processed during the 
experiment, and no data will be used to guide patient care. The data from the PORTI-
system, MRI images, echo images (if available) and venogram will be brought to the 
Medtronic office by attending Medtronic personnel. A copy of the data will remain at the 
site. Offline analyses include standard calculations of first time derivative of left ventricular 
pressure (filter settings), and timing between the different electrodes on the heart or on the 
chest.  
All data will be stored in a secure, password-protected database which will be backed up 
nightly. Study management reports may be generated to monitor data quality and study 
progress. At the end of the study, the data will be frozen and retained indefinitely by 
Medtronic. 
All data shall be secured against unauthorized access. The privacy of each subject and 
confidentiality of his/her information shall be preserved in reports and when publishing any 
data. 
 Source data to be directly recorded on the Case Report Forms 
G.1.2
The following data will be recorded directly on the eCRF and is considered as source data: 
• 
Baseline form: the subject number 
• 
Baseline form: exclusion criteria “Pregnant of breast feeding women, or women of 
child bearing potential and who are not on a reliable form of birth control” and 
”Subject is enrolled in one or more concurrent studies that would confound the 
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• 
AE form and death form: the date the study center became aware of the AE/Death 
• 
AE form: check box “Device interrogation” and  “Device reprogramming”  
• 
Death form: “Location of subject at time of death”  
Even when the eCRF may be considered as source, an alternate method of source 
documentation is always strongly encouraged. 
 Data review and processing 
G.1.3
Data management will be done according to Medtronic SOPs and the Data Management 
Plan for this clinical study. These documents will be made available on request. 
All collected data will be reviewed for completeness, correctness and consistency. In case 
of issues, queries will be sent to the investigator to complete, correct or comment the data.  
G.2 
Monitoring procedures 
Monitoring visits will be conducted before site activation, during the study and at the closure 
of the clinical study in accordance with Medtronic SOPs and the Monitoring Plan. 
Frequency of monitoring visits may be based on subject enrollment, duration of the study 
and study compliance. 
During the monitoring visit, it will be verified whether signed and dated Informed Consent 
Forms have been obtained from each subject before any clinical-study-related procedures 
are undertaken. 
Regulatory documents (e.g., EC approval letters, Competent Authorities approval letters 
and CTAs) will be reviewed at each study center. Subject data will be monitored against 
source documentation (e.g., clinic and hospital charts). Center study progress, 
investigator’s adherence to the CIP and maintenance of records and reports will also be 
checked. 
 Accessibility of investigation site staff and study materials 
G.2.1
The principal investigator(s), his/her delegate(s) and the study coordinator(s) shall be 
accessible to Medtronic field personnel and the Clinical Study Manager. This accessibility is 
of particular importance for reviewing data in the eCRF. Direct access to patient medical 
files for source data verification (if applicable) will need to be granted and prepared prior to 
any monitoring visits. 
 Audits and investigation site inspections 
G.2.2
In addition to regular monitoring visits, Medtronic may conduct audits at participating 
investigation sites. The purpose of an audit is to verify the adequate performance of the 
clinical study related activities. Independent of the employees involved in the clinical study. 
Regulatory authorities may also perform inspections at participating investigation sites. Any 
regulatory authority inspection announcements shall be forwarded immediately to the 
sponsor contact person (e.g. Clinical Study Manager). 
The investigator and/or institution shall permit Medtronic and regulatory bodies direct 
access to source data and documents, taking into account any restrictions due to local law, 
to perform clinical study-related monitoring, audits, EC review, and regulatory inspections. 
G.3 
Study suspension or early termination 
 Early study suspension or termination 
G.3.1
Medtronic or Regulatory Authority may decide to suspend or prematurely terminate the 
clinical study (e.g. adverse event and device deficiencies associated with the EP study 
procedure under investigation which might endanger the safety or welfare of subjects). If 
the clinical study is terminated prematurely or suspended, Medtronic shall promptly inform 
the regulatory authorities and the clinical investigators of the termination or suspension and 
the reason(s) for this. The investigator shall then promptly inform the reviewing EC, if 
required, and the study subjects or their legal representative.  

 
 
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 Early investigation site suspension or termination 
G.3.2
Medtronic, EC or Regulatory Authority may decide to suspend or prematurely terminate an 
investigation site. Possible reasons include but are not limited to: 
• 
Failure to obtain initial Ethics Board approval or annual renewal of the study 
• 
Consistent non-compliance to the CIP (e.g. failure to adhere to inclusion/exclusion 
criteria, failure to schedule subjects for study visit, etc.) 
• 
Lack of enrollment 
• 
Noncompliance to regulations and the terms of the Clinical Trial Agreement (e.g. 
failure to submit data in a timely manner, failure to follow-up on data queries and 
monitoring findings in a timely manner, etc.) 
• 
Ethics Board suspension of the center 
• 
Fraud or fraudulent misconduct (as defined by local law and regulations) 
• 
Investigator request (e.g. no longer able to support the study).  
If an investigation site is suspended or prematurely terminated, Medtronic shall promptly 
inform the investigator(s) of the termination or suspension and the reason(s) for this. The 
investigator shall then promptly inform the reviewing EC, if required, the study subjects or 
their legal representative. 
When the risks are found to outweigh the potential benefits or when there is conclusive 
proof of definite outcomes, investigators must assess whether to continue, modify or 
immediately stop the clinical study in the respective investigation site and immediately 
inform the sponsor and EC, if applicable. 
 Subject follow-up in case of termination 
G.3.3
In the case of a study suspension, enrolled subjects should continue to be followed out of 
consideration of their safety, rights and welfare. 
 
G.4 
Study close out 
Study closure is defined as closure of a clinical study that occurs when Medtronic and/or 
regulatory requirements have been satisfied per the Clinical Investigational Plan and/or by 
a decision by Medtronic or regulatory authority, whichever occurs first. Continued MEC 
oversight is required until the overall study closure process is complete. 
Study closure is a process initiated by distribution of an initial study closure letter to all 
investigators. In all geographies, the study closure process is complete upon distribution of 
the Final Report or after final payments, whichever occurs last. Study closure will also be 
notified to Regulatory Authority, if required.  
With regard to individual subjects, no dedicated closure visit will occur in association with 
overall study closure, and no medical care as defined by the study will be provided to the 
subject following overall study closure.   
H DATA ANALYSIS AND REPORTING 
A detailed description of the statistical methods will be contained in the Statistical Analysis 
Plan. Any changes to the data analysis methods will be described and justified in the Final 
Report or publication.  
H.1 
Analysis of clinical data 
Descriptive statistics will be used to summarize the patient demographic and clinical 
characteristics at baseline.  Data for qualitative variables will be presented as incidence 
rates (total number of patients, number of events, and percent). Data for continuous 
variables will be summarized using measures of central tendency and dispersion.    
 
P-values for hypothesis testing will be evaluated based on a two-sided significance level of 
0.05 except for the secondary objective 1 which is evaluated using a one-sided significance 

 
 
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level of 0.025. No adjustments will be made for multiple testing because of the exploratory 
nature of this study. No imputation of missing data is planned. No interim reports are 
planned for this study. 
 
Any change to the data analysis methods described in the Clinical Investigational Plan will 
require an amendment only if it changes an objective of the Clinical Investigational Plan. 
Any other change to the data analysis methods described in the Clinical Investigational 
Plan, and the justification for making the change, will be described in the clinical study 
report. Additional exploratory analyses of the data will be conducted as deemed 
appropriate. 
 
All patients who signed the informed consent document will be defined as the enrolled 
population. The Analysis Population is defined as patients who are enrolled, have no 
inclusion or exclusion criteria violation regarding the most important criteria, i.e., inclusion 
criteria 1 and 2 and exclusion criterion 3, and for whom the EP procedure could be 
completed successfully. Patients, who are not part of the Analysis Population, will not be 
included in the primary analysis of the primary objectives, but will be reported in the patient 
disposition table. A secondary analysis might be performed including patients who have 
eligibility violations.  Safety will be reported on the All Enrolled Population and the primary 
objectives will be reported on the Analysis Population. 
 
Endpoint for the primary objective 1, primary objective 2 and secondary objective 1 will be 
% change LV dP/dt max from baseline. This percentage change is calculated as ([median 
dP/dt max during pacing On] – 
[median baseline dP/dt max during pacing Off])/[median dP/dt max during pacing Off]. This 
endpoint will be used primarily to evaluate the hypothesis of objective 1, primary objective 2 
and secondary objective 1. Other endpoints, e.g., blood pressures, might be included in an 
exploratory secondary analysis for these objectives. 
 
Primary objective 1 
H.1.1
Compare the hemodynamic response of a MultiSpot-SYN Left Ventricular pacing 
configuration (simultaneous LV pacing) to a single spot LV pacing configuration in patients 
undergoing a research study, an EP exploratory procedure or CRT implant using the 
contractility parameter positive LV dP/dt max. 
It is hypothesized that MultiSpot SYN (pacing on all 3 LV electrodes simultaneously) is 
superior to conventional BiV pacing (i.e. using only the basal LV electrode). 
 
The null and alternative hypotheses are: 
 
H0: MultiSpot SYN-  BiV= 0% 
 H1: MultiSpot SYN-  BiV  0%, 
where  indicates percentage change from baseline for the respective pacing configuration. 
 
For each patient, a regression analysis will be performed to model % change LV dP/dt max 
dependent on configuration and AV delay. Based on the fitted model for each patient, the 
best AV delay for each configuration will be determined together with the predicted % 
change at this best AV delay. This best AV delay may differ from the optimal AV delay 
determined by the CardioSync formula. Paired two-sided t–tests will be used to evaluate 
whether there is a statistical significantly difference between MultiSpot-SYN and standard 
BiV pacing. Instead of paired t-tests, a Wilcoxon signed rank test might be performed if 
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Primary objective 2 
H.1.2
Compare the hemodynamic response of a MultiSpot-SEQ Left Ventricular pacing 
configuration (sequential LV pacing) to a single spot LV pacing configuration in patients 
undergoing a research study, an EP exploratory procedure or CRT implant using the 
contractility parameter positive LV dP/dt max. 
It is hypothesized that MultiSpot SEQ (pacing on 3 LV electrodes activated sequentially 
from apex to mid and then to base) is superior to conventional BiV pacing (i.e. using only 
the basal LV electrode). 
 
The null and alternative hypotheses are thus: 
 
H0: MultiSpot SEQ-  BiV = 0% 
 H1: MultiSpot SEQ-  BiV  0%, 
where  indicates percentage change from baseline for the respective pacing configuration. 
Statistical analysis will use the methods described for the primary objective 1, with 
MultiSpot-SYN LV pacing replaced by MultiSpot-SEQ LV pacing configuration. 
 
Secondary objective 1 
H.1.3
Compare the positive LV dP/dt max from a MultiSpot-SEQ LV pacing configuration to a 
MultiSpot-SYN LV pacing configuration in patients undergoing a research study, an EP 
exploratory procedure or CRT-implant using the contractility parameter positive LV dP/dt 
max. 
 
It is hypothesized that that MultiSpot SEQ (pacing using 3 LV electrodes activated 
sequentially from apex to mid and then to base) is non-inferior to MultiSpot SYN (pacing on 
all 3 LV electrodes simultaneously). 
 
The null and alternative hypotheses are thus: 
H0: MultiSpot SEQ -  MultiSpot SYN < - 3% (inferiority) 
 
H1: MultiSpot SEQ -  MultiSpot SYN > - 3% (non-inferiority) 
 
Statistical analysis will use the methods described for the primary objective 1, with single 
spot LV pacing configuration (standard BiV) replaced by MultiSpot-SEQ LV pacing. 
 
Based on previous research (iSPOT study,19), we assume that the lower-border of the 95 % 
confidence interval for % change MultiSpot SYN to baseline (AAI mode) in the targeted 
patient population is 12.6. In this study we consider MultiSpot SEQ non-inferior to MultiSpot 
SYN if the difference in their means is less than a quarter of the difference between 
MultiSpot SYN pacing and baseline. 
 
Secondary objective 2  
H.1.4
Correlate the (non)invasive measures (blood pressure, electrocardiographic mapping and 
RV/LV EGM timings) obtained during the up to 6 different pacing configuration’s to the 
positive LV dP/dt max measures obtained. 
 
Regression analysis will be used to determine pairwise Pearson’s correlation between the 
(non)invasive measures and LV dP/dt max. There are no hypotheses specified. 
 
Secondary objective 3  
H.1.5
Evaluate the (non)invasive measures ability to identify the pacing configuration with the 
highest positive LV dP/dt max. 

 
 
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A categorical variable of the best pacing configuration per patient will be calculated (the 
configuration that achieves the largest dP/dt value) and the agreement with each 
(non)invasive evaluation of best pacing configuration (also derived into a categorical 
variable) will be evaluated and tested with an unweighted Kappa statistic. There are no 
hypotheses specified. 
H.2 
Publication Policy 
There are no plans to form a publication committee. Publication activities will be assessed 
during the study or after the study is completed and any collaboration with the investigators 
will be determined at that time. In case a Publication committee will be installed, all the 
roles and responsibilities will be defined in the Publication Plan. 
Publications and presentations referring to this clinical study will be coordinated by 
Medtronic to allow the use of all available data. The following publication policy will have to 
be adhered to by all participating investigation sites: 
Medtronic intends to publish the results of the clinical study in a scientific journal.  
Authorship on any publication(s) resulting from this clinical study might be assigned 
according to: 
• 
Substantial contributions to the conception or design of the work; or the acquisition, 
analysis, or interpretation of data for the work 
• 
Drafting the work or revising it critically for important intellectual content 
• 
Final approval of the version to be published 
• 
Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved. 
This is in accordance with the Vancouver principles (The Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical 
Publication, ICMJE), as agreed upon by the editors of all major medical journals.  
The number of authors will be dependent on the regulations of the concerning journal. 
Based on the principle that Medtronic owns the data of this clinical study, a single 
investigation site may access and use the data provided by itself for scientific publications 
following prior approval by Medtronic. 
Pooling data from several investigation sites for publication purposes, national projects and 
international projects all require prior approval from Medtronic. 
Medtronic as the owner of the data can use the data and/or any results derived from the 
data or publications based on that data for marketing purposes, further research and 
development of devices or educational use. 
The study sponsor will collect data in such way that no subject can be identified, and 
monitor study records. 
Participating subjects will not be identified by name in any published reports about the 
clinical study.  
Each investigator must agree that no publications will be submitted that will jeopardize a 
multi-center publication.  
The study results will also be published on http:/clinicaltrials.gov. 
 
 
 
 

 
 
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I 
STUDY MANAGEMENT 
I.1 
Study staff  
The sponsor of this study is Medtronic Bakken Research Center BV, Endepolsdomein 5, 
6229 GW, Maastricht, the Netherlands. Table 4 lists the sponsor contact information. This 
information is subject to change during the course of the clinical study and a list will be kept 
separate from the CIP. Periodic updates to study contact information will be sent to the 
centers. The Lead Monitor contact details are not yet known. As soon as the Lead Monitor 
is assigned to the study, an update will be sent to the sites. 
Table 4: Sponsor Contact Information 
Role / Name
Email
Scientist/ 
Richard 
Cornelussen 
 
Scientist/        
Berthold 
Stegemann 
 
 
 
 
 
 
richard.cornelussen@medtronic.com 
 
 
 
berthold.stegemann@medtronic.com 
 
Clinical 
Research 
Specialist/ 
Laurence 
Hogge 
 
 
laurence.hogge@medtronic.com 
 
I.2 
Advisory committees 
 
Data Monitoring Committee 
I.2.1
No Data Monitoring Committee will be installed for this clinical study considering: 
• 
As a result of risk analysis and mitigation efforts as outlined in Section J, any residual 
risk associated with this study is considered low and acceptable. 
• 
All products used in the study (leads and pacing devices) are commercially released 
(and CE-marked) and used within their intended purpose, except for the Connection 
Box which is investigational. 
 
Publication Committee 
I.2.2
There are no plans to form a publication committee. Publication activities will be assessed 
during the study or after the study is completed and any collaboration with the investigators 
will be determined at that time. In case a Publication committee will be installed, all the 
roles and responsibilities will be defined in the Publication Plan. 
I.3 
Records and reports 
 
Investigator records 
I.3.1
At a minimum, the following records must be kept by the investigator:  
• 
Clinical Investigation Plan and, if applicable, any amendments 
• 
Investigator’s Brochure and Instructions for Use 
• 
Medtronic and EC approved Patient Informed Consent 

 
 
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• 
Competent authority approval or notification, if required 
• 
EC approval documents and documentation that the investigator did not participate 
in the approval process 
• 
Fully signed clinical investigation agreement and confidentiality agreement (if not 
included in the clinical investigation agreement) 
• 
Financial disclosures, if local requirements 
• 
Insurance certificates 
• 
Completed Delegated Task List and Curriculum Vitae of all investigation site 
personnel  
• 
Training documentation of all investigation site personnel 
• 
Relevant communications 
• 
Subject screening log and/or subject identification log  
• 
Signed, dated and fully executed informed consent forms 
• 
Fully executed eCRFs and corrections 
• 
Reports of Adverse Events and Device Deficiencies 
• 
Connection box disposition log containing serial numbers of connection boxes 
brought to the site by Medtronic personnel for the EP study visit, received dates of 
the connection boxes, subject IDs of the subjects paced with the connection box 
and dates the connection boxes are taken back to Medtronic after the EP study 
visit.  
• 
Final report 
• 
Any other records that local regulatory agencies require to be maintained 
 
 
Investigator reporting responsibilities 
I.3.2
Each investigator must submit the final report to their EC (each investigator for their own 
EC). The final report contains a summary of the clinical study’s findings and conclusions. 
The investigator is responsible for the preparation (review and signature) and submission to 
Medtronic of all case report forms. If any action is taken by an EC with respect to the 
investigation, the information must be forwarded to Medtronic. The investigator shall 
prepare and submit in a complete, accurate and timely manner the reports listed in Table 
Table 5. 

 
 
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Table 5: Investigator Reports 
Report
Submit To
Description / Constraints
Withdrawal of EC 
approval 
 
Medtronic 
report required by local law 
Study Deviations 
Medtronic, EC or 
competent 
authorities or 
other regulatory 
bodies 
Any deviation from the CIP shall be 
recorded together with an explanation 
for the deviation. Deviations shall be 
reported to the sponsor who is 
responsible for analyzing them and 
assessing their significance. 
Note: When relevant, Ethics Boards, 
competent authorities or the 
appropriate regulatory bodies should 
be informed.  
 
Failure to obtain informed 
consent 
 
Medtronic, EC 
Notification within five working days.   
Progress Reports (if 
required) 
Medtronic, EC 
Provide if required by local law or 
Ethics Board 
 
 
Sponsor records 
I.3.3
At a minimum, the sponsor will keep the following records: 
• 
All essential study documents and correspondence that pertains to the clinical 
study 
• 
CIP and, if applicable, any amendments 
• 
Investigator Brochure and Instructions for Use 
• 
Sample of labeling attached to the investigational device 
• 
Curriculum vitae of investigators and site staff 
• 
Delegated Task Lists and training records of investigators and site staff 
• 
Study training records of Medtronic personnel involved in the study 
• 
EC approvals/notifications and regulatory approvals/notifications 
• 
Signed Clinical Investigation Agreements and signed agreements with third parties 
• 
Insurance certificates, 
• 
Medtronic and EC approved Patient Informed Consents/Data Release Forms 
• 
Monitoring visit reports  
• 
Adverse event and Device Deficiency reports 
• 
Financial disclosure information, if local requirements 
• 
Fully executed eCRFs and corrections 
• 
Connection box traceability record containing serial numbers of connection boxes, 
shipping date and name and address of person that received shipped connection 
box, location (if different than person shipped to), transfer and receipt by Medtronic 
dates 
• 
Names of the institutions in which the clinical investigation will be conducted 
• 
Correspondence with authorities as required by national legislation 

 
 
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• 
Final report of the clinical investigation 
• 
Any other records that local regulatory agencies require to be maintained 
 
 
Sponsor reporting responsibilities 
I.3.4
Medtronic shall prepare and submit the following complete, accurate, and timely reports 
listed in the Table 6 below. In addition to the reports listed below, Medtronic shall, upon 
request of reviewing MEC or regulatory agency, provide accurate, complete and current 
information about any aspect of the investigation. 
Table 6: Sponsor Reports 
Report 
Submit To 
Description/Constraints 
Premature termination 
or suspension of the 
clinical investigation 
Investigators, EC, 
Relevant Authority 
 
Provide prompt notification of termination 
or suspension and reason(s). (ISO 
14155:2011)  
Withdrawal of EC 
approval 
Investigators, EC, 
Relevant Authority 
 
All applicable investigators will be notified 
only if required by local laws or by the EC. 
Withdrawal of CA 
approval 
Investigators, EC, 
Relevant Authority 
All applicable investigators and ECs will 
be notified only if required by local laws or 
by the EC. 
Progress Reports 
EC and/or CA 
This will be submitted to the EC/CA only if 
required by the EC/CA. 
Final Report 
Investigators, EC, 
and Regulatory 
Authority  
The investigator shall have the 
opportunity to review and comment on the 
final report.  If a clinical investigator does 
not agree with the final report, his/her 
comments shall be communicated to the 
other investigator(s).  The principal 
clinical investigator in each center shall 
sign the report.  (ISO 14155:2011) 
 
Study deviation  
Investigators 
Ensure that all deviations from the Clinical 
Investigation Plan are reviewed with the 
appropriate clinical investigator(s), are 
reported on the case report forms and the 
final report of the clinical investigation.   
Site specific study deviations will be 
submitted to investigators quarterly. (ISO 
14155:2011) 
Vigilance Reporting 
Competent 
Authorities 
 
Report incidents and near-incidents within 
10 (incidents) or 30 (near-incidents) days. 
(Meddev.2.12-1 rev.5) 
Significant New 
Evidence 
EC, Regulatory 
Authorities 
 
Ensure that EC and Regulatory 
Authorities are informed of significant new 
information about the clinical 
investigation. (ISO 14155:-2011) 
Incident 
Regulatory 
Authorities 
Any malfunction or deterioration in the 
characteristics and/or performance of a 
device, as well as any inadequacy in the 
labeling or instructions for use which led 

 
 
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or might have led to the death or serious 
deterioration in the state of health of a 
patient, user, or other person. Any 
technical or medical reason resulting in 
withdrawal of a device from the market by 
the manufacturer. (Meddev.2.12-1 rev.5, 
AIMD 90/385/EEC) 
 
Electronic versions of Medtronic records and reports will be kept on a password-protected 
document management system during the course of the study. After closure of the study, 
all records and reports will be archived indefinitely. 
 
Record retention  
I.3.5
The investigator must retain the Investigator Site File, patient medical files and CRFs in 
accordance with local law and regulations for a minimum period of 2 year (or longer if local 
laws require).   
The investigator should take measures to prevent accidental or early destruction of the 
clinical study related materials. 
I.4 
Miscellaneous 
 
Insurance and warranty 
I.4.1
 
The Medtronic Bakken Research Center B.V. is a wholly owned subsidiary of Medtronic 
Inc., which as the parent company of such entity maintains appropriate clinical study liability 
insurance coverage as required under applicable laws and regulations and will comply with 
applicable law and custom concerning specific insurance coverage. If required, a Clinical 
Trial Insurance statement/certificate will be provided to the EC. 
Warranty information is provided in the product packaging for the connection box and 
additional copies are available upon request. 
 
Subject confidentiality 
I.4.2
All records and other information about subjects participating in this study will be treated as 
confidential. Participating subjects will not be identified by name in any published 
reports/publication about the study. 
 
Subject compensation 
I.4.3
The subject will not receive any compensation for the participation in this clinical 
investigation. Only the travel expenses related to the participation in the study (for visits 
which are not part of standard care) may be reimbursed depending on country regulations 
(all information are available in the Patient Informed Consent). A copy of the Patient 
Informed Consent is provided under separate cover. 
 
 
 
 
 

 
 
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J 
RISKS AND BENEFITS 
J.1 
Anticipated Clinical Benefits 
There are no immediate direct patient benefits to participating in this study. 
One potential benefit is that the response to CRT therapy in a given patient may be 
predicted on basis of the knowledge obtained in the experimental study. In addition, 
patients which are non-responders to conventional CRT, but displaying an improved acute 
hemodynamic response (i.e., LV dP/dt max) with the alternative CRT strategy are being 
recognized for potential future benefit. An indirect benefit is the knowledge that the subject 
may be helping doctors and scientists understand the best method for determining LV lead 
placement so that outcomes to CRT are optimized.  
J.2 
Risks 
The potential risks to a subject participating in this study are believed to be somewhat 
higher to those encountered during standard CRT (CRT-P and/or CRT-D) implantation. 
This is due to the prolonged duration of the complete procedure, the addition of the 
temporary second LV-lead and the pacing from more than one position on the LV. The risks 
include, but are not limited to the following: increased arrhythmogenity, valve damage; 
puncture of the heart muscle, vein, artery or lung; infection; a blood or air embolism in the 
heart, lung, brain, arteries or veins; bleeding; hematoma; seroma; hemothorax; 
pneumothorax; swelling/bruising; stimulating muscles or nerves outside the heart; damage 
to a central vein including dissection and perforation; arteriovenous fistula; pseudo-
aneurysm; or localized pain where the incision is made to insert the catheters and CRT 
device.  
There may be additional risks related to study participation that are unknown at this time. 
The risks associated with the use of the pressure catheter include, but are not limited to the 
following: infection, bleeding, hematoma, lack of blood flow to the tissue supplied by the 
artery, injury to blood vessel, valve or heart and localized pain where the incision is made 
to insert the catheter. The introducer used to insert the left ventricular pressure wire will 
also be used to measure invasively the blood pressure, adding no risk to the patient. 
Kidney dysfunction could be another risk because of increased use of contrast fluid used 
during the total study protocol.  
Bleeding and bruising may be more likely to occur with the administration of blood-thinning 
medications (heparin) to minimize the risk of blood clot formation during the procedure. 
Procedure prolongation will not only increase duration of the anesthesia but also the risk of 
infection. The protocol procedures will result in an additional 30 to 45 minutes to the 
standard procedure time and an addition of about 10 minutes of fluoroscopy exposure. In 
case of the research study, all times are of course experimental time and no additional time 
on top of another procedure. 
There is a very low risk of box malfunction, due to either failure of one of the components of 
the box (connectors, switches, cabling), potentially withholding pacing stimuli, causing 
unintended cardiac pacing, or leading to asynchronous pacing of the hand-held pacers, 
potentially causing arrhythmia. 
Improper use of the connection box may lead to the false connection of cardiac leads 
and/or false delivery of stimulation to the heart, potentially causing cardiac arrhythmia.
For all the other CE marked devices used in this study: 
Medtronic is not aware of any significant problems with the products. In the clinical study, 
the products will be used in accordance with their labeling, therefore no risks other than the 
risks typically associated with a routine device use are anticipated.  
Standard risks associated with the medical device used in this clinical study, an analysis of 
Adverse Device Effects and a history of modification or recall of device under investigation 
or equivalent devices/products are listed in the Investigator’s Brochure.  

 
 
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J.3 
Risk-to-benefit rationale 
Medtronic has minimized the occurrence of applicable risks by: providing guidelines for 
patient selection and evaluation, selecting an investigator who has demonstrated previous 
experience with CRT implantation and left heart catheterization, and clinical research (i.e. 
trained electrophysiologists). Investigators will be thoroughly trained on the study 
procedures and during the study Medtronic personnel will be present to provide technical 
support. 
Investigators are also required to monitor continuously the study risks. They should assess 
what the risks are and document them. 
Risks will be minimized through the use of strict aseptic technique and by close monitoring 
of the patient’s physiologic status during the implant and follow-up procedures. The 
availability of the connection box in this study mitigates the risks of improper study 
conduction and/or data collection. 
Data collection will be minimized to the essential data. Women who are pregnant should 
not participate in this study due to the radiation exposure. If a patient becomes pregnant 
during the duration of this study, they should notify the study physician immediately, as 
there may be potential risks to the patient and/or the embryo or fetus.  
Subjects will be closely observed throughout the duration of the study to identify any 
adverse events.  
The risks involved with the investigational device (i.e. connection box) are considered 
minor. It is a passive device designed to mitigate the risks of using alligator clips or other 
loose connections. Personnel using the connection box will be restricted.  All personnel 
intended to use the connection box will be trained on how to use the box and how to 
mitigate human errors. Mitigation of connection box malfunction damage entails electrical 
pre-testing of the electrical connections before every study (100% inspection). The possible 
pro-arrhythmic effect will be mitigated by the proper instructions for use of the box and by 
the study protocol design. 
The results of risk analysis, balancing benefits against risks associated with both the device 
system itself and procedures involved in its use, is included in the Investigator’s Brochure. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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K REFERENCES 
 
1. 
Bristow, MR, Saxon, LA, Boehmer, J, et al. Cardiac-resynchronization therapy with or 
without an implantable defibrillator in advanced chronic heart failure. N Engl J Med, 
2004;350:2140-50. 
2. 
Cleland, JG, Daubert, JC, Erdmann, E, Freemantle, N, Gras, D, Kappenberger, L, 
Tavazzi, L, and Cardiac Resynchronization-Heart Failure Study, I. The effect of cardiac 
resynchronization on morbidity and mortality in heart failure. N Engl J Med, 
2005;352:1539-49. 
3. 
European Heart Rhythm, A, European Society of, C, Heart Rhythm, S, et al. 2012 
EHRA/HRS expert consensus statement on cardiac resynchronization therapy in heart 
failure: implant and follow-up recommendations and management. Europace, 
2012;14:1236-86. 
4. 
Daubert, C, Cazeau, S, Ritter, P, and Leclercq, C. Past, present and future of cardiac 
resynchronization. Arch Cardiovasc Dis, 2012;105:291-9. 
5. 
Pappone, C, Calovic, Z, Vicedomini, G, et al. Multipoint left ventricular pacing in a single 
coronary sinus branch improves mid-term echocardiographic and clinical response to 
cardiac resynchronization therapy. J Cardiovasc Electrophysiol, 2015;26:58-63. 
6. 
Pappone, C, Calovic, Z, Vicedomini, G, et al. Multipoint left ventricular pacing improves 
acute hemodynamic response assessed with pressure-volume loops in cardiac 
resynchronization therapy patients. Heart Rhythm, 2014;11:394-401. 
7. 
Rinaldi, CA, Leclercq, C, Kranig, W, et al. Improvement in acute contractility and 
hemodynamics with multipoint pacing via a left ventricular quadripolar pacing lead. J 
Interv Card Electrophysiol, 2014;40:75-80. 
8. 
van Gelder, BM and Bracke, FA. Acute hemodynamic effects of single- and dual-site left 
ventricular pacing employing a dual cathodal coronary sinus lead. Pacing Clin 
Electrophysiol, 2015;38:558-64. 
9. 
Thibault, B, Dubuc, M, Khairy, P, et al. Acute haemodynamic comparison of multisite and 
biventricular pacing with a quadripolar left ventricular lead. Europace, 2013;15:984-91. 
10. 
Zanon, F, Baracca, E, Pastore, G, et al. Multipoint pacing by a left ventricular quadripolar 
lead improves the acute hemodynamic response to CRT compared with conventional 
biventricular pacing at any site. Heart Rhythm, 2015;12:975-81. 
11. 
van Geldorp, IE, Vanagt, WY, Prinzen, FW, and Delhaas, T. Chronic ventricular pacing in 
children: toward prevention of pacing-induced heart disease. Heart Fail Rev, 
2011;16:305-14. 
12. 
Peschar, M, de Swart, H, Michels, KJ, Reneman, RS, and Prinzen, FW. Left ventricular 
septal and apex pacing for optimal pump function in canine hearts. J Am Coll Cardiol, 
2003;41:1218-26. 
13. 
Vanagt, WY, Prinzen, FW, and Delhaas, T. Reversal of pacing-induced heart failure by 
left ventricular apical pacing. N Engl J Med, 2007;357:2637-8. 
14. 
Merchant, FM, Heist, EK, McCarty, D, Kumar, P, Das, S, Blendea, D, Ellinor, PT, Mela, T, 
Picard, MH, Ruskin, JN, and Singh, JP. Impact of segmental left ventricle lead position on 
cardiac resynchronization therapy outcomes. Heart Rhythm, 2010;7:639-44. 
15. 
Russel, IK, Gotte, MJ, Bronzwaer, JG, Knaapen, P, Paulus, WJ, and van Rossum, AC. 
Left ventricular torsion: an expanding role in the analysis of myocardial dysfunction. JACC 
Cardiovasc Imaging, 2009;2:648-55. 
16. 
Pedrizzetti, G, La Canna, G, Alfieri, O, and Tonti, G. The vortex--an early predictor of 
cardiovascular outcome? Nat Rev Cardiol, 2014;11:545-53. 
17. 
Shetty, AK, Sohal, M, Chen, Z, et al. A comparison of left ventricular endocardial, 
multisite, and multipolar epicardial cardiac resynchronization: an acute haemodynamic 
and electroanatomical study. Europace, 2014;16:873-9. 

 
 
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18. 
Ginks, MR, Duckett, SG, Kapetanakis, S, Bostock, J, Hamid, S, Shetty, A, Ma, Y, Rhode, 
KS, Carr-White, GS, Razavi, RS, and Rinaldi, CA. Multi-site left ventricular pacing as a 
potential treatment for patients with postero-lateral scar: insights from cardiac magnetic 
resonance imaging and invasive haemodynamic assessment. Europace, 2012;14:373-9. 
19. 
Sohal, M, Shetty, A, Niederer, S, et al. Mechanistic insights into the benefits of multisite 
pacing in cardiac resynchronization therapy: The importance of electrical substrate and 
rate of left ventricular activation. Heart Rhythm, 2015. 
20. 
Whinnett, ZI, Davies, JE, Willson, K, Manisty, CH, Chow, AW, Foale, RA, Davies, DW, 
Hughes, AD, Mayet, J, and Francis, DP. Haemodynamic effects of changes in 
atrioventricular and interventricular delay in cardiac resynchronisation therapy show a 
consistent pattern: analysis of shape, magnitude and relative importance of 
atrioventricular and interventricular delay. Heart, 2006;92:1628-34. 
21. 
Horowitz, LN, Kay, HR, Kutalek, SP, Discigil, KF, Webb, CR, Greenspan, AM, and 
Spielman, SR. Risks and complications of clinical cardiac electrophysiologic studies: a 
prospective analysis of 1,000 consecutive patients. J Am Coll Cardiol, 1987;9:1261-8. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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L APPENDICES 
L.1 
Case Report Forms 
A copy of the Case Report Form will be provided under a separate cover. 
L.2 
Foreseeable adverse event and anticipated adverse 
device effects 
The information provided in this section pertains to foreseeable adverse events that may be 
observed in study subjects and may collectively assist in identifying those events for a 
given device or therapy that are unexpected in nature. The foreseeable adverse events 
information consists of two parts, events related to cardiac catheterization and events 
related to LV lead placement. An evaluation of potentially anticipated events, adverse 
device effects observed in previous clinical studies, and reported events in literature may 
be used in combination with device labeling, current event reporting information, and other 
published data to assess for an unexpected occurrence.  
 
The EP study for the study involves surgery, therefore, standard adverse events associated 
with a surgical procedure may be experienced (e.g. anesthesia complications, injury, 
infections, bleeding, exacerbation of pre-existing conditions, healing complications, etc.). 
However, the focus of this section is to address in more detail, those events that are 
foreseeable due to the procedures under investigation.  
 
Potential risks associated with the study procedures, as well as risk minimization are 
discussed within Section J.  
 
Events related to cardiac catheterization  
 
Potential adverse events and patient complications associated with the cardiac 
catherization procedure have been documented in the literature21. These events include, 
but are not limited to, the following: 
• 
stimulation of more severe rhythm problems  
• 
bleeding from the catheter insertion site(s)  
• 
damage to the vessel at the catheter insertion site(s)  
• 
infection of the catheter site(s)  
• 
perforation of the heart (rare)  
• 
Allergic reactions to medications or latex21 
 
Additional adverse events associated with the use of the left ventricular pressure catheter 
are infection, bleeding, hematoma, lack of blood flow to the tissue supplied by the artery, 
injury to blood vessel, valve or heart and localized pain where the incision is made to 
insert the pressure catheter.  
 
Events related to LV lead placement 
 
The listings below provide examples of adverse events associated with the use of 
transvenous leads, pacing and defibrillation systems reported in previous Medtronic 
studies that included predicate LV leads, including Concerto AT, InSync III US study, 
Model 4194, 4195, 4196 and 4396 pre-market clinical studies. Table 7 displays adverse 
events classified as LV lead related. The incidence rate and 2-sided 95% Confidence 
Interval, for each event type are displayed to provide an estimate of percent of patients 
experienced such event in the historical dataset.  

 
 
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All events were collected and reviewed during the study phase and have been 
reclassified utilizing MedDRA, the Medical Dictionary for Regulatory Activities, to allow 
coding to a standard set of medical terms. The MedDRA Lowest Level Term (LLT) and 
the Preferred Terms (PT) are provided.  The LLT is the specific granular term or verbatim 
term, and the PT is the linked parent term for the LLT that is the single medical concept.  
 
Table 7: Observed LV Lead Related Adverse Events  
Preferred Term 
Lower Level 
Term 
Number of 
Incidence
Number 
of 
Patients 
Event 
Rate 
95% Confidence 
Interval 
Atrioventricular 
block 
 
2 
2 
0.12% 
(0.01% ,    0.45%)
Heart block 
2 
2 
0.12% 
(0.01%,    0.45%) 
Cardiac 
perforation 
 
1 
1 
0.06% 
(0.00% ,    0.34%)
Cardiac 
perforation 
1 
1 
0.06% 
(0.00% ,    0.34%)
Cardiac vein 
dissection 
 
4 
4 
0.25% 
(0.07% ,    0.63%)
Coronary sinus 
dissection 
4 
4 
0.25% 
(0.07% ,    0.63%)
Cardiac vein 
perforation 
 
1 
1 
0.06% 
(0.00%,    0.34%) 
Coronary sinus 
perforation 
1 
1 
0.06% 
(0.00% ,    0.34%)
Complication of 
device removal 
 
4 
4 
0.25% 
(0.07% ,    0.63%)
Complication of 
device removal 
4 
4 
0.25% 
(0.07% ,    0.63%)
Decompensated 
heart failure 
 
1 
1 
0.06% 
(0.00% ,    0.34%)
Cardiac failure 
1 
1 
0.06% 
(0.00% ,    0.34%)
Deep vein 
thrombosis 
 
2 
2 
0.12% 
(0.01% ,    0.45%)
Deep vein 
thrombosis 
1 
1 
0.06% 
(0.00% ,    0.34%)
Deep venous 
thrombosis arm 
1 
1 
0.06% 
(0.00% ,    0.34%)
Device capturing 
issue 
 
14 
13 
0.80% 
(0.43% ,    1.37%)
Loss of capture 
14 
13 
0.80% 
(0.43% ,    1.37%)
Device 
dislocation 
 
58 
55 
3.40% 
(2.57% ,    4.41%)
Lead 
dislodgement 
58 
55 
3.40% 
(2.57% ,    4.41%)
Device electrical 
 
1 
1 
0.06% 
(0.00% ,    0.34%)

 
 
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Preferred Term 
Lower Level 
Term 
Number of 
Incidence
Number 
of 
Patients 
Event 
Rate 
95% Confidence 
Interval 
impedance issue 
Impedance 
increased 
1 
1 
0.06% 
(0.00% ,    0.34%)
Device lead 
damage 
 
2 
2 
0.12% 
(0.01% ,    0.45%)
Lead conductor 
fracture 
2 
2 
0.12% 
(0.01% ,    0.45%)
Device lead issue
 
1 
1 
0.06% 
(0.00% ,    0.34%)
Device lead 
issue 
1 
1 
0.06% 
(0.00% ,    0.34%)
Device pacing 
issue 
 
37 
36 
2.23% 
(1.57% ,    3.07%)
Elevated pacing 
threshold 
37 
36 
2.23% 
(1.57% ,    3.07%)
Device 
stimulation issue 
 
260 
200 
12.38%
(10.81% ,   
14.08%) 
Inappropriate 
device 
stimulation of 
tissue 
9 
8 
0.50% 
(0.21% ,    0.97%)
Inappropriate 
pectoral muscle 
stimulation 
8 
7 
0.43% 
(0.17% ,    0.89%)
Inappropriate 
phrenic nerve 
stimulation 
17 
13 
0.80% 
(0.43% ,    1.37%)
Inappropriate 
stimulation of 
diaphragm 
226 
176 
10.89%
(9.41% ,   12.51%)
Implant site 
infection 
 
1 
1 
0.06% 
(0.00% ,    0.34%)
Implant site 
infection 
1 
1 
0.06% 
(0.00% ,    0.34%)
Implant site pain 
 
1 
1 
0.06% 
(0.00% ,    0.34%)
Implant site pain
1 
1 
0.06% 
(0.00% ,    0.34%)
Palpitations 
 
3 
3 
0.19% 
(0.04% ,    0.54%)
Palpitations 
3 
3 
0.19% 
(0.04% ,    0.54%)
Pericardial 
effusion 
 
1 
1 
0.06% 
(0.00% ,    0.34%)
Pericardial 
effusion 
1 
1 
0.06% 
(0.00% ,    0.34%)
Pneumothorax 
 
1 
1 
0.06% 
(0.00% ,    0.34%)

 
 
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Preferred Term 
Lower Level 
Term 
Number of 
Incidence
Number 
of 
Patients 
Event 
Rate 
95% Confidence 
Interval 
Pneumothorax 
1 
1 
0.06% 
(0.00% ,    0.34%)
Septic shock 
 
1 
1 
0.06% 
(0.00% ,    0.34%)
Septic shock 
1 
1 
0.06% 
(0.00% ,    0.34%)
Thrombosis 
 
1 
1 
0.06% 
(0.00% ,    0.34%)
Thrombosis 
1 
1 
0.06% 
(0.00% ,    0.34%)
 
The above incidences of each adverse event were reported from the collection of similar 
Medtronic studies. Other events that have been experienced in other studies or have the 
potential to be experienced by subjects, but were not recorded in the few Medtronic 
studies (or may have been reported with different terminology) also include: 
 
Cardiac rupture, cardiac tamponade, depression, dysplasia, electrical conduction 
disorders, emotional distress, implant tool delivery problem, tissue fibrosis, tissue 
necrosis, implant site seroma, inappropriate device therapy, inappropriate shocks, keloid 
scar, lead abrasion and discontinuity, insulation or conductor failure, mortality due to 
inability to deliver therapy, myocardial irritability or damage, nerve damage, pacemaker 
syndrome, pericardial rub, transient ischemic attack, valve damage, or venous stenosis.  
 
L.3 
Abbreviations 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
AEAC 
Adverse Event Advisory Committee 
AV 
Atrioventricular 
BiV 
Biventricular 
CIP 
Clinical Investigation Plan 
CRF 
Case Report Form 
CRT 
Cardiac Resynchronization Therapy 
DD 
Device Deficiency 
EC 
Ethical Committee  
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EGM 
Electrogram 
EP  
Electrophysiology 
HF 
Heart Failure 
LBBB 
Left Bundle Branch Block 
LV 
Left Ventricle 
(M)EC 
(Main)Ethical Committee  
MRI 
Magnetic Resonance Imaging 
MSP 
Multi Spot Pacing 
RA 
Right Atrium 
RBBB 
Right Bundle Branch Block 

 
 
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RV 
Right Ventricle 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
SOP 
Standard Operating Procedure