MOre REsponse on Cardiac Resynchronization Therapy (CRT) With MultiPoint Pacing (MPP)
Phase: NA
Conditions: Heart Failure
Sponsor: Abbott Medical Devices

 
 
 
 
MORE-CRT MPP 
“MOre REsponse on Cardiac Resynchronization Therapy 
(CRT) with MultiPoint Pacing (MPP)” 
Clinical Investigation Plan (CIP) 
 
 
Version Number 
4 
Date 
April 9, 2018 
NCT Number 
NCT02006069 
Sponsor 
Abbott 
 

           
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CPRB Code 
: CR-13-006-ID-HF (Internal document number; SJM-CIP-10093D)
Project Acronym 
: MORE-CRT MPP
Project Version 
: 
 
Version Date 
: 
 
 
MORE-CRT MPP 
“MOre REsponse on Cardiac Resynchronization Therapy 
(CRT) with MultiPoint Pacing (MPP)” 
Clinical Investigation Plan (CIP) 
 
 
Sponsor 
St. Jude Medical 
 
 
  
 
 
VP Clinical Studies   
Signature 
 
 
 
Date 
 
 
Clinical Coordinating 
Investigator 
 
 
 
Signature 
 
Date 
 
 
 
 
 
 
 

           
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Table of Contents 
 
1 
Synopsis ................................................................................................................................ 7 
1.1 
Investigation Flow Chart ............................................................................................... 10 
Figure 1: Flow Chart ................................................................................................................ 10 
1.2 
Contacts ........................................................................................................................ 11 
1.2.1 
Sponsor ................................................................................................................. 11 
1.2.2 
Coordinating Clinical Investigator .......................................................................... 11 
2 
Background ......................................................................................................................... 12 
3 
Investigational Design ......................................................................................................... 14 
3.1 
Purpose ........................................................................................................................ 14 
3.2 
Objectives ..................................................................................................................... 14 
3.2.1 
Primary Objective .................................................................................................. 14 
3.3 
Endpoints ...................................................................................................................... 14 
3.3.1 
Primary Endpoint ................................................................................................... 14 
3.3.2 
Secondary Endpoint .............................................................................................. 14 
3.4 
Investigational Type ...................................................................................................... 14 
3.5 
Subject Population ........................................................................................................ 16 
3.6 
Inclusion and Exclusion Criteria .................................................................................... 16 
3.6.1 
Inclusion Criteria .................................................................................................... 16 
3.6.2 
Exclusion Criteria ................................................................................................... 16 
3.7 
Subject Enrollment Classification ................................................................................. 17 
3.8 
Randomization Procedure ............................................................................................ 17 
3.9 
Point of Enrollment ....................................................................................................... 18 
3.10 
Expected duration of the Investigation ...................................................................... 18 
3.10.1 
Expected duration of each subject’s participation ................................................. 18 
3.10.2 
Number of Subjects required to be included in the Investigation .......................... 18 
3.10.3 
Estimated time needed to select this subject population (Enrollment Time) ......... 18 
3.11 
Devices Used ............................................................................................................ 18 
3.11.1 
Control of Devices and Equipment ........................................................................ 20 
4 
Procedures .......................................................................................................................... 21 
4.1 
Investigation Flow Chart ............................................................................................... 21 
4.2 
Protocol Activities ......................................................................................................... 22 
4.2.1 
Enrollment Visit (In clinic) ...................................................................................... 27 
4.2.2 
Baseline Visit (In Clinic, between Enrollment and Implant) ................................... 28 
4.2.3 
Implant Procedure (In Clinic, within 30 days from Enrollment) .............................. 29 
4.2.4 
Patient Classification (In Clinic, within 7 days post Implant) .................................. 29 
4.2.5 
6 Months Follow-Up Visit (In Clinic, 183 days +/- 14 days from Implant) .............. 29 
4.2.6 
12 Months Follow-Up Visit (In Clinic, 365 days +/- 21 days from Implant, only for 
NON RESPONDERS) ......................................................................................................... 31 
4.2.7 
Unscheduled Visits (In Clinic or Remote) .............................................................. 32 
4.2.8 
Description of activities performed by Sponsor Representatives .......................... 32 
4.2.9 
Description of post investigational provision of medical care ................................ 32 
5 
Clinical Investigation Conduct ............................................................................................. 33 
5.1 
Statements of Compliance ............................................................................................ 33 
5.1.1 
Adherence to the Clinical Investigation Plan ......................................................... 33 
5.1.2 
Repeated non-compliance ..................................................................................... 34 
5.2 
Informed Consent Process ........................................................................................... 34 
5.2.1 
General Process .................................................................................................... 34 
5.2.2 
Special circumstances for informed consent ......................................................... 35 
5.3 
Adverse Event, Adverse Device Effect ......................................................................... 35 
5.3.1 
Definitions .............................................................................................................. 35 

           
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5.3.2 
Procedure for assessing, recording and reporting adverse events, adverse device 
effects, serious adverse events and serious adverse device effects: ................................. 36 
5.4 
Subject Death ............................................................................................................... 37 
5.4.1 
Procedure for recording and reporting Subject Death ........................................... 37 
5.5 
Criteria and procedures for subject withdrawal or discontinuation ............................... 37 
5.6 
Document and data control ........................................................................................... 38 
5.6.1 
Traceability of documents and data ....................................................................... 38 
5.6.2 
Recording of data .................................................................................................. 39 
5.6.3 
Review of data ....................................................................................................... 39 
5.7 
Monitoring ..................................................................................................................... 39 
5.7.1 
Designated Monitors .............................................................................................. 39 
5.7.2 
Monitoring Plan ...................................................................................................... 39 
5.7.3 
Competent Authority (CA) Inspections .................................................................. 39 
5.8 
Investigation Termination .............................................................................................. 40 
5.8.1 
Investigation Conclusion ........................................................................................ 40 
6 
Risks and Benefits of the clinical investigation .................................................................... 41 
6.1 
Risks ............................................................................................................................. 41 
6.2 
Anticipated Adverse Events and Adverse Device Effects ............................................. 41 
6.2.1 
Associated with device or leads ............................................................................ 41 
6.2.2 
Associated with device or leads implant procedure ............................................... 41 
6.2.3 
Associated with subject’s status/characteristics .................................................... 42 
6.3 
Benefits ......................................................................................................................... 43 
6.4 
Treatments in case of premature study termination ..................................................... 43 
7 
Statistical considerations ..................................................................................................... 44 
7.1 
Primary Endpoint Hypothesis and Sample size ............................................................ 44 
7.1.1 
First phase of the study ......................................................................................... 44 
7.1.2 
Second phase of the study .................................................................................... 44 
7.2 
Primary endpoint analysis ............................................................................................. 45 
7.2.1 
Timing of Analysis ................................................................................................. 45 
7.2.2 
Analysis methods .................................................................................................. 45 
7.3 
Secondary endpoints .................................................................................................... 45 
7.4 
Analyses will also be carried out to explore the effect of MPP programming parameters 
on responder status. Analysis population ............................................................................... 46 
7.5 
Procedures for reporting any deviation(s) from the original statistical plan .................. 46 
7.6 
The treatment of missing, unused or spurious data, including drop-outs and 
withdrawals ............................................................................................................................. 46 
7.7 
In multi-center investigations, the minimum and maximum number of subjects to be 
included for each center .......................................................................................................... 46 
8 
Data Management ............................................................................................................... 47 
8.1 
Data Management Plan ................................................................................................ 47 
9 
Document Retention ............................................................................................................ 48 
10 
Amendments to Clinical Investigation Plan ......................................................................... 49 
11 
Publication Policy ................................................................................................................ 50 
12 
Investigation Organization ................................................................................................... 51 
12.1 
Investigation Management / Sponsor ........................................................................ 51 
12.1.1 
Sponsor Responsibilities ....................................................................................... 51 
12.2 
Clinical Investigators ................................................................................................. 52 
12.2.1 
Investigator’s responsibilities ................................................................................. 52 
12.2.2 
Clinical Coordinating Investigator .......................................................................... 53 
12.2.3 
Source Data and Patient Files ............................................................................... 53 
12.3 
Boards ....................................................................................................................... 54 
12.3.1 
Steering Committee (SC) ...................................................................................... 54 

           
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12.4 
Outsourcing of duties and functions .......................................................................... 54 
12.4.1 
Echo CoreLab (EchoCL) ....................................................................................... 54 
12.4.2 
ECG Core Lab (ECG CL) ...................................................................................... 54 
12.4.3 
Fluoroscopy Images Core Lab (FCL) .................................................................... 54 
12.4.4 
EuroQoL (EQ-5D Questionnaire) .......................................................................... 54 
12.4.5 
MAPI Trust (MLWHF Questionnaire) ..................................................................... 55 
13 
Bibliography......................................................................................................................... 56 
Appendix A: Abbreviations .......................................................................................................... 59 
Appendix B: Declaration of Helsinki ............................................................................................ 61 
Appendix C: Device Manual ........................................................................................................ 66 
Appendix D: Data Collection Method .......................................................................................... 67 
Appendix E: Guidelines ............................................................................................................... 70 
 

           
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1 Synopsis 
Title: 
“MOre REsponse on Cardiac Resynchronization Therapy (CRT) with MultiPoint 
Pacing (MPP)” 
 
Acronym: 
MORE-CRT MPP 
 
Purpose: 
The purpose of this Clinical investigation is to assess the impact of the Multi 
Point Pacing (MPP) feature at 12 months in the treatment of patients not 
responding to standard Cardiac Resynchronization Therapy (CRT) after 6 
months. Due to a large number of combinations of parameters available for 
MPP programming, the MPP feature will be evaluated under two scenarios:  
(1) without mandating MPP programming parameters, and  
(2) with mandated MPP programming parameters. 
 
Objectives: 
Primary Objective 
To demonstrate that the activation of the MPP feature will increase the rate of 
CRT responders in patients that are classified as non-responders at 6 months 
of follow up.   
 
 
Secondary Objectives 
To assess the impact of the MPP feature on patients’ functional and clinical 
status, as well as complication free survival time. 
 
Endpoints: 
Primary Endpoint (assessed at 12 months) 
Percentage of non-responder patients converted to responders after 6 months 
of MPP feature turned ON compared to baseline, as measured by Left 
Ventricular End Systolic Volume (LVESV) reduction of at least 15%. 
 
 
Secondary Endpoints (assessed at 12 months) 
 
Reduction of LVESV between baseline and 6 month visit  
 
Packer’s Clinical Composite Score evaluation between the baseline and 
the 12 month visit; and between the 6 month and the 12 month visit  
 
Reverse LV remodelling, measured as changes in LVESV, LVEDD and 
LVEF 
 
NYHA Class changes 
 
6 minutes walking test changes 
 
Quality of Life (MLWHF and EQ-5D) changes 
 
Design: 
This study is designed as a Prospective, Randomized, Multi-center Trial.   
 
Data will be collected at Enrollment, Baseline, Implant Procedure, Patient 
Classification, 6 Months and 12 Months Follow-Up. 
 
During the Enrollment visit, the Informed Consent Procedure will be performed 
and the Inclusion/Exclusion criteria verified. 
 
During the Baseline visit the demographic data, medical history, clinical data 
and procedure details will be collected. 
  
After the Implant Procedure, the Patient Classification will be performed in 

           
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order to identify the Qualified Subjects that will constitute the Study Population. 
 
During the 6 Months visit, the subject’s response to CRT will be evaluated 
according to LVESV reduction:  
 
 
Subjects with a LVESV reduction of at least 15% will be classified as 
Responders: those subjects will terminate their participation to the study 
and return to the center’s standard practice. 
 
 
Subjects with a LVESV reduction less than 15% will be classified as 
Non Responders: for those subjects the MPP feature will be activated 
according to randomization result and they will be followed up until 12 
Months visit.  
 
During the 12 Months visit, the percentage of non-responder subjects 
converted to responders after 6 months of MPP feature turned ON will be 
assessed:  
 
 
Subjects with a LVESV reduction of at least 15% between Baseline and 
12 Months will be classified as Responders. 
 
 
Subjects with a LVESV reduction less than 15% between Baseline and 
12 Months will be classified as Non Responders.  
 
The investigation will be conducted in up to 250 centers worldwide. 
 
 
 
 
 
 
 
 
 
 
 
Devices used: 
All subjects will be implanted with a CE-approved St. Jude Medical CRT device 
(CRT-D or CRT-P) compatible with MultiPoint Pacing feature and St. Jude 
Medical quadripolar left ventricular lead.  
 
Any commercially available and CE marked right atrial and right ventricular 
leads can be used in this investigation for both treatment arms. 
During the follow ups, implanted devices will be checked with Merlin® Patient 
Care System (model 3650 or newer, software version 17.2.1 or newer) 
programmer. 
 
All of the devices used in this investigation, have received appropriate 
regulatory certification (and are market released). 
  
Subject 
Population:  
Patients with Heart Failure that meet current ESC or ACCF/AHA/HRS Class I 
or IIa indications for CRT implant. 

           
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Patients presenting at the investigational site can be screened by a member of 
the investigational team previously trained on the CIP and delegated to do so. 
Patients who do not meet the inclusion/exclusion criteria are not eligible to 
participate in this investigation. 
 
Patients meeting the inclusion/exclusion criteria will be fully informed about the 
investigation and will be asked to participate in the investigation. If the patient 
agrees, a duly signed and dated, EC and Sponsor approved, Patient Informed 
Consent form will be obtained. 
 
Inclusion Criteria: 
Eligible patients will meet ALL the following: 
 
Meets the current ESC or ACCF/AHA/HRS Class I or Class IIa 
indications for CRT implant (including upgrades from single or dual 
chamber ICDs) 
 
Must be willing and able to comply with study requirements 
 
Must indicate their understanding of the study and willingness to 
participate by signing an appropriate informed consent form 
 
Exclusion Criteria: 
Patients will be excluded if they meet ANY of the following criteria: 
 
Already had a CRT device implanted 
 
Myocardial Infarction, unstable angina within 40 days prior the 
enrollment  
 
Recent cardiac revascularization (PTCA, Stent or CABG) in the 4 
weeks prior the enrollment or planned for the 3 months following 
 
Cerebrovascular Accident (CVA) or Transient Ischemic Attack (TIA) in 
the 3 months prior the enrollment 
 
Primary valvular disease requiring surgical correction  
 
Atrial Fibrillation: 
o Persistent AF at the time of enrollment 
o Permanent AF not treated with AV node ablation within 2 weeks 
from the CRT implant 
o History or incidence of Paroxysmal or Persistent AF within 30 
days prior the enrollment  
 
Unable to comply with the follow up schedule 
 
Less than 18 years of age 
 
Pregnant or are planning to become pregnant during the duration of the 
investigation 
 
Classification of Status 1 for cardiac transplantation or consideration for 
transplantation over the next 12 months 
 
Undergone a cardiac transplantation   
 
Life expectancy < 12 months 
 
Currently participating in any other clinical investigation  
 
 
 

           
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1.1 Investigation Flow Chart 
 
 
Figure 1: Flow Chart 
 
 
 

           
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CR-13-006-ID-HF_CIP_V4.0_9APR2018 
 
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1.2  Contacts 
1.2.1 Sponsor 
 
 
 
 
 
 
 
 
 
 
1.2.2 Coordinating Clinical Investigator 
 
 
 
 
 
 
 
 
 

           
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2 Background 
 
Heart failure (HF) is an abnormality of cardiac structure or function leading to failure of the heart 
to deliver oxygen at the rate commensurate with the requirement of patient. European Society of 
Cardiology (ESC) 2012 guidelines defined HF as a syndrome in which patients have typical 
symptoms (e.g. breathlessness, swelling and fatigue) and signs (elevated jugular pressure, 
pulmonary crackles and displaced apex beat) resulting from an abnormality of cardiac structure 
or function1. 
 
HF is a varied clinical syndrome with complex pathophysiology, which continues to be defined, 
and often begins with a primary injury to the myocardium. Patients with HF experience 
decreased exercise capacity, inability to perform activities of daily living, diminished quality of life 
and an increased early mortality. 
 
It is estimated that in the Western world more than 20 million patients suffer from end-stage HF. 
This indicates that the prevalence of this syndrome is 2-2.5% overall, increasing up to 10% 
among persons 70 years of age or older2. 
HF is a major threat to public health affecting an estimated 14 million individuals in Europe and it 
is estimated that 50% of people diagnosed with HF will die within 5 years1-3. 
  
Cardiac resynchronization therapy (CRT) using biventricular (BiV) pacing has been developed to 
restore synchrony in HF patients with delayed ventricular activation, predominantly of the left 
ventricle (LV). Studies have demonstrated that simultaneous or sequential BiV pacing restores 
the synchrony of contraction, reduces mitral regurgitation, and improves cardiac output4, 5. 
Several landmark clinical trials published in the past few years have provided compelling 
evidence that CRT can produce significant clinical benefits, including improvements in patients’ 
HF symptoms, quality of life, reduced HF hospitalization, and echocardiographic measures 
which confer a mortality benefit.6-8  
 
Although a majority of treated patients show a benefit, up to 40% derive no improvement from 
CRT. In the MIRACLE study, 34% of patients did not demonstrate an improvement in a HF 
clinical composite score (CCS) that combined all-cause mortality, HF related hospitalization, 
NYHA class and patient global assessment into an outcome measure9. A summary of non-
responder rate from various clinical studies has been performed by Birnie and Tang10. Those 
rates of non-response to cardiac resynchronization therapy are often quoted as 20-30% in the 
listed studies, but the authors suggest that the true non-responder rate may be as high as 40-
50%. This inconsistent CRT effectiveness may be due to incomplete resynchronization and the 
presence of Intraventricular dyssynchrony.  
 
The cause for failed response to CRT is not completely understood; there is a general 
consensus, supported by growing evidence, that suboptimal LV lead placement accounts for a 
large percentage of patients who do not respond to CRT.  
 
Some studies have shown that lateral and postero-lateral lead placements have more favorable 
results than other locations, but the link between lead location and clinical benefit is not yet well 
understood11-16. Several methods have been used in attempts to optimize lead placement 
including using intracardiac electrograms to locate the site of most delayed activation, 
measuring acute hemodynamic response based on lead location; using scar burden and 
location to predict response; and using electrical mapping to optimize epicardial Left Ventricle 
(LV) lead placement17-22. However, unfavorable coronary venous anatomy with narrow and 
tortuous tributaries, phrenic nerve stimulation, high capture thresholds, or pacing lead instability 

           
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may limit the use of any of these approaches. Moreover, each of the methods used to optimize 
LV lead placement to date are time consuming and some are more invasive than the implant 
itself, imposing potentially higher implant risks. Standard LV lead placement criteria for a 
stimulation electrode typically focuses on the location of mechanical stability, freedom from 
phrenic nerve stimulation, reasonable pacing thresholds, or the site of latest electrical activation. 
However, ischemic cardiomyopathy can cause non-uniform propagation of electrical activity over 
the myocardium due to scarred myocardial segments and density near the LV stimulation 
electrode12. Thus, a site of latest electrical activation may not always yield the optimal response. 
In such cases, the ability to pace from more than one left ventricular site may provide benefit.  
 
All major medical devices companies offer bipolar LV leads that have one ring electrode and one 
tip electrode that can be positioned via the coronary sinus. This bipolar LV lead, when used in 
combination with right ventricular (RV) lead, may have up to six pacing vectors available to the 
physician for standard biventricular pacing.  
St. Jude Medical has developed a new family of quadripolar LV leads which increase the 
programmability by including one tip electrode and three ring electrodes. This quadripolar lead is 
called Quartet® LV lead (Model 1458Q, 1458QL, 1457Q, 1456Q and newer). If used with the 
Unify™ Quadra CRT-D device the system provides 10 different pacing vector options 
(VectSelect®) from the four pacing electrodes on the LV lead.  
Furthermore, this lead allows pacing from any two of the 10 available vectors at the same time in 
a multi-point fashion (MultiPoint™ pacing or MPP).  
 
MultiPoint™ pacing (MPP) is a new pacing feature in the Quadripolar CRT-D system that allows 
sequential pacing of the LV with two pacing vectors compared to one vector in a traditional CRT-
D system. A combination of any two of the 10 available vectors with inter-stimulus delays can be 
used. MPP via one LV lead may have the potential to act as an alternative to non-invasively 
optimize LV lead placement, and it may improve hemodynamics and the response to CRT. 
Studies showed that simultaneously exciting a larger mass or volume of cardiac tissue results in 
faster depolarization velocity and shorter left ventricular trans-ventricular conduction times23-24. In 
addition, by capturing a larger volume of cardiac muscle, the site of latest intrinsic activation 
within the left ventricle may be more likely to be depolarized early, resulting in better 
synchronization and maximizing cardiac output. 
 
Since MPP delivers two pulses at programmable delays (LV1 and LV2) to two LV sites, the initial 
volume of excited cardiac tissue is increased. By capturing more mass at the site of initial 
depolarization there is a greater likelihood of pacing the site of latest systolic delay. Both of 
these methods have been shown to improve LV function25-26 and it is believed that this additional 
improvement in LV function may benefit those patients who are otherwise identified as non-
responders to conventional BiV pacing. 
 
 

           
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3 Investigational Design 
3.1 Purpose 
The purpose of this clinical investigation is to assess the impact of the MultiPoint Pacing (MPP) 
feature at 12 months in the treatment of patients that are not responding to standard Cardiac 
Resynchronization Therapy (CRT). Due to a large number of combinations of parameters 
available for MPP programming, the MPP feature will be evaluated in two scenarios: 
(1) without mandating MPP programming parameters, and  
(2) with mandated MPP programming parameters. 
3.2 Objectives 
3.2.1 Primary Objective 
To demonstrate that the activation of the MPP feature will increase the rate of CRT responders 
in patients that were already classified as non-responders at 6 months follow up. 
 
3.2.2 Secondary Objectives 
To assess the impact of MPP feature on patients functional and clinical status  
3.3 Endpoints 
3.3.1 Primary Endpoint 
The primary endpoint of this study is evaluated at 12 months after enrollment and it is defined as 
the percentage of non-responder patients converted to responders after 6 months of MPP 
feature turned ON compared to baseline, as measured by Left Ventricular End Systolic Volume 
(LVESV) reduction of at least 15%. 
3.3.2 Secondary Endpoint 
The secondary endpoints of this study are evaluated at 12 months after enrollment and are 
defined as: 
 
Reduction of LVESV between baseline and 6 Months visit 
 
Packer’s Clinical Composite Score evaluation between baseline and 12 Months visit and 
between 6 Months and 12 Months visits 
 
Reverse LV remodeling, measured as changes in LVESV, LVEDD and LVEF 
 
NYHA Class changes 
 
6 minutes walking test changes 
 
Quality of Life (MLWHF and EQ-5D) changes 
3.4 Investigational Type 
This study is designed as a Prospective, Randomized, Multi-center Trial.   
 
Data will be collected at Enrollment, Baseline, Implant Procedure, Patient Classification, 6 
Months and 12 Months Follow-Up. 
 
During the Enrollment visit, the Informed Consent Procedure will be performed and the 
Inclusion/Exclusion criteria verified. 
 
During the Baseline visit the demographic data, medical history, clinical data and procedure 
details will be collected. 
  

           
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After the Implant Procedure, the Patient Classification will be performed in order to identify the 
Qualified Subjects that will constitute the Study Population. 
 
During the 6 Months visit, the subject’s response to CRT will be evaluated at the center level 
according to LVESV reduction. Before randomization in the second phase of the study, all 
subjects will undergo testing to determine if the mandated MPP settings can be programmed 
(see below for MPP programming requirements in Phase II). For those subjects in whom the 
mandated MPP settings cannot be programmed before randomization at 6 months, their 
participation in the study will end (an early termination form must be completed).  
 
 
Subjects with a LVESV reduction of at least 15% will be classified as RESPONDERS.  
For those subjects, their participation in the study will end (if confirmed by the Core Lab), 
and they will then return to the center’s routine follow up schedule/practice. 
 
o If the subject is evaluated as a Responder by the center and later as a Non 
Responder by the Core Lab, the center must randomize the subject and should 
call the subject back for an unscheduled visit (see 4.2.7) in case the 
randomization assignment is different from programmed. 
 
 
Subjects with an LVESV reduction of less than 15% will be classified as NON 
RESPONDERS.  These subjects should be randomized and the device programmed to 
either MPP OFF or MPP ON per the randomization assignment (Please refer to section 
3.8 “Randomization Procedure” for further details). 
 
o If the subject is evaluated as a Non Responder by the center and later as a 
Responder by the Core Lab, the subject continues to 12 Months visit but the data 
are excluded from the primary endpoint analysis. 
 
 
For those subjects randomized to MPP ON in the second phase of the study, the MPP 
feature should be programmed as follows: 
 
o MPP Vector combination: Two programmable vectors with widest spacing (≥30 
mm between two cathodes). The ‘Widest Spacing’ feature within the VectSelect 
Quartet™ MultiVector Tools in the Merlin Patient Care System should be used to 
program to widest spacing. 
o LV1-LV2 delay: 5 ms 
o LV2-RV delay: 5 ms 
 
During the 12 Months visit, the percentage of non-responder subjects converted to responders 
after 6 months of MPP feature turned ON and MPP feature turned OFF will be assessed:  
 
 
Subjects with a LVESV reduction of at least 15% between Baseline and 12 Months will 
be classified as Responders. 
 
 
Subjects with a LVESV reduction less than 15% between Baseline and 12 Months will be 
classified as Non Responders. Subjects who died due to cardiac cause post 
randomization will also be classified as Non Responders.  
 
The investigation will be conducted in up to 250 centers worldwide. 

           
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3.5 Subject Population 
The subject population enrolled in this investigation will be comprised of male and female 
patients. These subjects are patients who meet the specific eligibility criteria. 
 
The enrollment phase will continue until approximately 5638 Qualified Subjects will be identified. 
Please refer to section “3.7 Subject Enrollment Classification” for the definition of Qualified 
Subject. In order to achieve this number, approximately 6898 subjects should be enrolled in the 
Study. 
 
Patients meeting the Inclusion/Exclusion criteria will be fully informed about the investigation and 
asked to participate in the investigation. In case the patient agrees, a duly signed and dated 
Patient Informed Consent form will be obtained. 
3.6 Inclusion and Exclusion Criteria 
A patient who meets all of the inclusion criteria and none of the exclusion criteria is eligible to 
participate in this investigation.  
 
A patient is enrolled in this investigation only when he has provided a written signed / dated 
Patient Informed Consent form (refer to section 5.2 for the Informed Consent Process). 
 
Once enrolled, a subject is expected to comply with the scheduled visits and required activities 
according to the protocol. 
All subjects enrolled in the clinical investigation (including those withdrawn from the clinical 
investigation or lost to follow-up) shall be accounted for and documented in the Patient 
Identification Log, assigning an identification code linked to their names, alternative identification 
or contact information. 
This log shall be kept up to date throughout the clinical investigation by the principal investigator 
or his/her authorized designee. 
Since subject privacy and confidentiality of data must be maintained throughout the clinical 
investigation, this log will remain on site and the sponsor has no access to it. 
3.6.1 Inclusion Criteria 
Eligible patients will meet ALL the following criteria:  
 
Meets the current ESC Guidelines or ACCF/AHA/HRS Class I or Class IIa indications for 
CRT implant (including upgrades from single or dual chamber ICDs)  
 
Must be willing and able to comply with study requirements 
 
Must indicate their understanding of the study and willingness to participate by signing 
an appropriate informed consent form 
3.6.2 Exclusion Criteria 
Patients will be excluded if they meet ANY of the following criteria 
 
Already had a CRT device implanted 
 
Myocardial Infarction, unstable angina within 40 days prior the enrollment  
 
Recent cardiac revascularization (PTCA, Stent or CABG) in the 4 weeks prior to 
enrollment or planned for the 3 months following 
 
Cerebrovascular Accident (CVA) or Transient Ischemic Attack (TIA) in the 3 months prior 
the enrollment 
 
Primary valvular disease requiring surgical correction  
 
Atrial Fibrillation: 
o Persistent AF at the time of enrollment 

           
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o Permanent AF not treated with AV node ablation within 2 weeks from the CRT 
implant 
o History or incidence of Paroxysmal or Persistent AF within 30 days prior the 
enrollment  
 
Unable to comply with the follow up schedule 
 
Less than 18 years of age 
 
Pregnant or are planning to become pregnant during the duration of the investigation 
 
Classification of Status 1 for cardiac transplantation or consideration for transplantation 
over the next 12 months 
 
Undergone a cardiac transplantation   
 
Life expectancy < 12 months 
 
Currently participating in any other clinical investigation  
3.7 Subject Enrollment Classification 
Once the eligible subject has signed the Informed Consent and completed the Baseline visit, 
he/she will advance to the Implant Procedure and Patient Classification visit in which the CRT 
device implant and MPP activation tests will be performed. Depending on the result of the 
Patient Classification, the subjects will be classified as: 
 
 
Eligibility Failure:  
Patients who provided the Informed Consent but failed to meet the Inclusion/Exclusion 
Criteria. These subjects’ participation to the study will be terminated immediately. 
 
 
Implant Failure: 
Patients who provided the Informed Consent, meet the Inclusion/Exclusion criteria, but 
do not receive the CRT MPP compatible device because of implant failure or physician’s 
decision. These subjects’ participation to the study will be terminated immediately. 
 
 
MPP Activation Failure:  
Patients who provided the Informed Consent, meet the Inclusion/Exclusion Criteria, have 
been implanted with a CRT MPP compatible device but not enough MPP vector 
combinations are possible to allow the MPP activation. These subjects’ participation to 
the study will be terminated immediately. 
 
 
Qualified Subject: 
Patients who provided the Informed Consent, meet the Inclusion but not the Exclusion 
criteria, have been implanted with a CRT MPP compatible device, have MPP vector 
combinations to allow the MPP activation. These subjects will proceed in the study and 
constitute the Study Population. 
3.8 Randomization Procedure 
The Randomization procedure assigns subjects to the Treatment Group (MPP ON) or Control 
Group (MPP OFF) in a 1:1 ratio. Randomization should be based on the preliminary LVESV 
value measured at the center level at the 6 Months visit. However, this evaluation must be 
confirmed by the Echo Core Lab. In case of disagreement, the Core Lab evaluation will be 
considered the definitive one. The randomization will be stratified by center in order to obtain a 
homogeneous distribution.  For further information on randomization, refer to section 4.2.5. 

           
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3.9 Point of Enrollment 
Patients are considered enrolled in the clinical investigation from the moment the patient has 
provided written Patient Informed Consent form (refer to section 5.2 for the Informed Consent 
Process). 
3.10 Expected duration of the Investigation 
 
 
 
3.10.1 Expected duration of each subject’s participation 
The expected duration of each subject enrolled in the clinical investigation will be approximately: 
 
12 months for subjects classified as Non Responders at the 6 Months visit 
 
6 months for subjects classified as Responders at the 6 Months visit 
 
1 month for subjects that are not Qualified during the Patient Classification visit   
3.10.2 Number of Subjects required to be included in the Investigation 
Approximately 5914 Qualified Subjects in both first and second phases of the study should be 
included in the Study Population.  
Please refer to section “3.7 Subject Enrollment Classification” for Qualified Subject definition and 
section “7.1 Sample Size”). 
3.10.3 Estimated time needed to select this subject population (Enrollment Time) 
The estimated time needed to enroll the number of subjects is 72 months. 
3.11 Devices Used 
All subjects will be implanted with a regulatory approved St. Jude Medical CRT device 
compatible with MultiPoint Pacing feature and St. Jude Medical quadripolar LV lead.  
During the follow ups, implanted devices will be checked with Merlin® Patient Care System 
(model 3650 or newer, software version 17.2.1 or newer) programmer. 
Any commercially available and regulatory approved right atrial and right ventricular leads can 
be used in this investigation. 
 
All of the devices used in this investigation, have received appropriate regulatory certification 
and are market released. 
 
The CRT devices are equipped with an IS4-LLLL low voltage connector to facilitate implantation 
of an IS4 LV four electrode lead. Also, devices with a Q suffix have a high voltage DF4-LLHH 
bore that allows the use of Durata DF4 lead. 
 
The Quartet™ LV lead is a quadripolar, over–the-wire design that enables implantation using 
either a stylet or guidewire. The lead has an open lumen and an opening at the lead tip to allow 
the use of a guidewire. The body has Optim™ lead insulation and a maximum lead body 
diameter of 5.1 Fr. Like the QuickSite® and Quickflex® left heart lead families, the distal portion 
of the Quartet™ is pre-shaped in an “s-curve” shape to provide stabilization of the distal tip in 
the coronary veins of the left ventricle. The outer lead body is covered with Fast-Pass™ coating 
that increases lubricity during initial implant. 
 
The titanium nitride (TiN) coated platinum/iridium (PtIr) tip electrode on the lead contains a 
molded ring that elutes steroid. Additionally, the surface of the tip electrode is coated with a thin 
steroid film to provide immediate steroid release. 

           
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Three titanium nitride (TiN) coated platinum/iridium (PtIr) ring electrodes are located on the lead 
at a distance of 20 mm (Mid 2), 30 mm (Mid 3) and 47 mm (Proximal 4) from the tip of the lead. 
 
The lead provides pace/sense capability from 4 electrodes (tip and 3 rings): 

           
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Please note that Vector numbering is for protocol use only and is not reflected on the Merlin® 
Patient Care System (model 3650 or newer) programmer 
 
Please refer to Appendix C “Device Manuals” for further information.  
3.11.1 Control of Devices and Equipment  
Only regulatory approved and commercially available shelf-stock will be used within indications 
for the investigation. No specific device traceability is required. 

           
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4 Procedures 
4.1 Investigation Flow Chart 
 

           
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4.2 Protocol Activities 
 
The following table lists all electronic Case Report Forms (eCRFs) that are to be completed 
during the respective visits. Mandatory eCRFs are identified with an “X”. eCRFs that are optional 
or have to be completed only in case of a certain event (i.e. Adverse Event) are marked with an 
“(X)” 
 
 
(X): If applicable 
X§: Baseline Echocardiography can be performed at any time from 3 months prior CRT implant (by an echo qualified 
study center). 
 
Table 1: Data Collection: eCRF requested per visit 
 
 
 
All the mandatory activities/procedures are listed in the following table and detailed in the next 
pages: 
 
 
 
                   Visit 
 
 
CRFs  
Enroll 
Baseline 
Implant 
Proc. 
Patient 
Classification
6 
Months 
FU 
12 
Months 
FU 
Unsch 
FU 
Enrollment Form 
X 
 
 
 
 
 
 
Implant  Form 
 
 
X 
 
 
 
 
Patient 
Classification  
Form 
 
 
 
X 
 
 
 
Baseline Form 
 
X 
 
 
 
 
 
Echocardiography 
Form 
X§ 
 
 
X 
X 
(X) 
EQ-5D Form 
 
X 
 
 
X 
X 
(X) 
MLWHF Form 
 
X 
 
 
X 
X 
(X) 
Follow Up Form 
 
 
 
 
X 
X 
(X) 
System Revision 
Form 
 
 
(X) 
(X) 
(X) 
(X) 
(X) 
Deviation Form 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
Adverse Event 
Form 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
Termination Form 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
Death Form 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 

           
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Enroll 
Baseline 
Implant 
Proc. 
Patient 
Classification 
6 Month 
FU 
 12 Month 
FU 
Informed Consent 
procedure 
X 
 
 
 
 
 
Inclusion/Exclusion  
Criteria check 
X 
 
 
 
 
 
Implant Procedure Details 
 
 
X 
 
 
 
Fluoroscopy Images  
Collection (LAO and RAO 
– EDC upload) 
 
 
X 
 
 
 
Implant Procedure 
Success Confirmation 
 
 
 
X 
 
 
MPP Vector Test 
 
 
 
X 
X$ 
 
Patient Data and Medical 
History 
 
X 
 
 
 
 
Current Cardiac 
Medications 
 
X 
 
 
 
 
Changes in Cardiac 
Medications 
 
 
 
 
X 
X 
Patient Global Assessment 
 
 
 
 
X 
X 
NYHA Class Evaluation 
 
X 
 
 
X 
X 
Randomization procedure 
(only for Non Responders 
to CRT) 
 
 
 
 
X 
 
12-Lead ECG (EDC 
upload) 
 
X 
 
 
X 
X 
BNP/pro-BNP/  
NT-pro-BNP Test * 
 
(X*) 
 
 
(X*) 
(X*) 
6 Minutes Hall Walking 
Test 
 
X 
 
 
X 
X 
EQ-5D Questionnaire 
 
X 
 
 
X 
X 
MLWHF Questionnaire 
 
X 
 
 
X 
X 
Echocardiography 
X§ 
 
 
X 
X 
Preliminary LVESV  
Evaluation 
 
X 
 
 
X 
 
Conduction Delays Test 
 
 
X 
X 
X 
X 
Device Test and 
Programming (EDC 
upload) 
 
 
X 
X 
X 
X 
MPP Programming 
 
 
X 
X 
X 
 
(X*): If performed as Standard of care at the site 
X$: Testing of mandated MPP settings in Phase II before randomization (see section 4.2.5 for further details) 
X§: can be performed at any time from 3 months prior CRT implant (by an echo qualified study center) 
Table 2: List of all required activities/procedures 

           
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Informed Consent Procedure and Inclusion/Exclusion Criteria check:  
Patient’s eligibility criteria and Informed consent Procedure is performed before any study 
related activity. Please refer to section 4.2.1 “Enrollment visit” for further details. 
 
Implant Procedure Details: 
Implant Procedure details (standard CRT implant) will be collected at Implant visit. 
Indicate model n°, serial n° and date of implant of entire implanted system (CRT device, RA 
lead, RV lead and LV lead), even in case of implant failure.  
Final positions of all the implanted leads must be specified: right atrium, right ventricle and left 
ventricle lead positions. 
 
Fluoroscopy Images Collection (EDC upload):  
As the lead placement is important to understanding the subject’s response to CRT, two 
anonymized Fluoroscopy images are requested to be collected:  
 
LAO (Left Anterior Oblique, 45°±10°)  
 
RAO (Right Anterior Oblique, 45°±10°).  
The position of all leads must be clearly visible to allow matching with the venous anatomy. 
These anonymized images should be uploaded to the EDC system using the feature 
“Attachments to CRFs”, for further details on this topic please refer to Appendix E “Guidelines” 
part 1.1. 
 
Implant Procedure Success Confirmation: 
In the Patient Classification visit, the confirmation of a successful implant procedure will be 
asked in order to classify the subject as Qualified Subject or not. 
 
MPP Vector Test: 
In order to allow future activation of MPP, specific LV pacing capture thresholds and Phrenic 
Nerve Stimulation (PNS) tests must be performed for the 4 cathodes during the Patient 
Classification visit.  
The test is considered positive in case is possible to identify at least 2 vectors from different 
Groups (with different Cathodes) free from Phrenic Nerve Stimulation (PNS) and with a Pacing 
Threshold that do not exceed 4.5V at 0.5ms pulse duration in CRT-D devices and at 0.4ms 
pulse duration in CRT-P devices. 
Please refer to Appendix E “Guidelines” part 6 for the detailed testing procedure. 
 
Subject Data and Medical History:  
Subject’s Year of Birth and Gender will be collected at the Baseline visit together with 
cardiomyopathy etiology and co-morbidities. 
 
Current Cardiac Medications/Changes in Cardiac Medications:  
The current cardiac medications will be collected at Baseline, while during the Follow-up Visits 
only the changes will be documented.  
 
Patient Global Assessment:  
The Patient Global Assessment will be performed at 6 and 12 Months Follow Up visits and will 
be used to calculate the Packer’s Clinical Composite Score (CCS) together with NYHA Class 
evaluation, HF events and/or Cardiovascular death.  
For further information regarding CCS please refer to Appendix E “Guidelines” part 2. 
 
NYHA Class evaluation:  

           
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The subject’s New York Heart Association class will be assessed at Baseline and during all 
Follow-up Visits. 
 
Randomization procedure (only for Non Responders to CRT): 
The randomization procedure will be performed at 6 Months Follow Up only for subjects that are 
classified as NON RESPONDERS to CRT. The randomization will be stratified by center and will 
assign the subjects either to MPP ON or MPP OFF in a 1:1 fashion. 
 
12-Lead ECG (EDC upload):  
A 12-lead ECG must be performed at Baseline, 6 and 12 Months Follow-up Visit.  
The anonymized 12-Lead ECG (performed at paper speed 25mm/s or 50mm/s depending to 
center’s preference) should be uploaded to the Electronic data Capture (EDC) system using the 
feature “Attachments to CRFs”, for further details on this topic please refer to Appendix E 
“Guidelines” part 1.1. 
The following data will be retrieved:  
 
Date of ECG 
 
Heart rate 
 
Atrial and Ventricular rhythms  
 
QRS width 
 
PR Interval  
 
LBBB or RBBB occurrences 
 
B-Type natriuretic peptide (BNP), pro-BNP or NT-pro-BNP test (if performed per Standard 
of Care):  
The BNP/pro-BNP/NT-pro-BNP test is used to measure the amount of stress on the subject’s 
heart. If this test will be performed as per Standard of Care in the participating centers, the result 
will be collected at Baseline, 6 and 12 months follow-up. The test kit established at the 
investigational site will be used and intra-individual changes from Baseline to FU will be 
calculated. 
 
6 Minute Hall Walk test: 
The 6 Minute Hall Walk test is used to measure the subject’s health status and must be 
completed at Baseline, 6 Months and 12 Months Follow Ups. The 6 Minute Hall Walk test 
measures the distance an individual is able to walk over a total of six minutes on a hard, flat 
surface. The goal is for the individual to walk as far as possible in six minutes. The individual is 
allowed to self-pace, rest as needed or interrupt the test at any time.  
 
EQ-5D Questionnaire:  
In order to assess the subject’s health status, an EQ-5D questionnaire must be completed at 
Baseline, 6 Months and 12 Months Follow Ups. 
Please refer to Appendix E: “Guidelines” Part 4 for further details 
 
Minnesota Living With Heart Failure (MLWHF) Questionnaire:  
In order to assess the subject quality of life, a MLWHF questionnaire must be completed at 
Baseline, 6 Months and 12 Months Follow Ups. 
Please refer to Appendix E: “Guidelines” Part 5 for further details 
 
Echocardiography:  
Echocardiography must be performed, according to the MORE-CRT MPP study Echo Protocol, 
only by Trained Site Personnel, at Baseline, 6 Months and 12 Months Follow-ups. 

           
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Baseline Echo can be performed at any time from 3 Months prior CRT implant;  however, the 
center must be already Echo Qualified at the time echo is being performed and the echo should 
not be provided to the CoreLab until after the patient has signed the Informed Consent.  
The echocardiography must be recorded in DICOM format and sent/uploaded to the Echo Core 
Lab within 24 hours (1 working day). 
The Core Lab will analyze the Echocardiography received and provide the evaluation of the CRT 
response based on the LVESV reduction within 72 hours of reception of the echocardiography 
(3 working days).  
 
  
 
  
 
  
 
 
Centers can limit the number of non-evaluable echoes by choosing a wide scan angle and using 
contrast to enhance image quality of the endocardial borders. However, must note that contrast 
enhanced images will also require contrast enhanced images at other study time points 
(baseline, 6M and 12M follow-up) for the same subject in order to allow for comparison by the 
Core Lab. 
 
Preliminary LVESV Reduction Evaluation: 
At the Baseline and 6 Month FU visits, the center will be asked to provide, together with the 
recorded Echocardiography, a calculation/assessment of the LVESV value and (at 6 Months FU) 
reduction. 
This evaluation will preliminary help identify if the subject is a Responder or not and will be 
confirmed by the Echo Core Lab. In case of disagreement between the center and Core Lab 
evaluations, the Core Lab assessment will be considered as final. 
 
At the 6 Month FU, if the subject is identified as a Non Responder, the Randomization procedure 
will take place. In case of disagreement between the center and Core Lab evaluations during 
this visit, the Core Lab assessment will be considered as final and the following actions will need 
to be performed: 
 
 
If the subject is evaluated as Non Responder by the center and as a Responder by the 
Core Lab: continues to 12 Months visit but the data are excluded from the primary 
endpoint analysis. 
 
If the subject is evaluated as a Responder by the center and as a Non Responder by the 
Core Lab: the center should call back the subject for the randomization procedure (within 
a reasonable time window (e.g. 2 weeks) after the 6M visit). 
 
Conduction Delays Test: 
The conduction delays between right and left ventricle will be performed during implant and each 
in–clinic follow up. This is an automatic test that can be performed via Merlin PCS programmer 
and will end in about one minute. Please refer to Appendix E: “Guidelines” part 3 for further 
details regarding the Conduction Delay test. 
 
Device Test and Programming (EDC upload):  
Device will be interrogated and all the diagnostics retrieved; standard sensing, pacing and 
impedance measurements will be performed for all implanted leads at each in-clinic follow-up.  
Please refer to Appendix E “Guidelines” part 1.2 for further details on the “Upload Device Data” 
procedure. 

           
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The device programming will be left to Investigator’s discretion with the exception of the MPP 
feature. It is suggested that AV delay optimization is performed per centers’ preference. 
Please see below the MPP Programming activity. 
Follow-up session (including diagnostics) will be uploaded to the EDC system using the feature 
“Upload Device Data”. 
 
MPP Programming:  
Overall device programming will be left to the Investigator’s discretion with the exception of the 
MPP feature:  
 
 
MPP should NOT be programmed ON BEFORE the 6 Months FU 
 
At the 6 Months FU, the MPP feature will be programmed ON or OFF as per 
Randomization result (1:1) for subjects classified as NON RESPONDERS according to 
LVESV reduction less than 15%. Subjects randomized to MPP ON in the second phase 
of the study should be programmed as follows:   
o MPP Vector combination: Two programmable vectors with widest spacing (≥30 
mm between two cathodes).  The ‘Widest Spacing’ feature within the VectSelect 
Quartet™ MultiVector Tools in the Merlin Patient Care System should be used to 
program to widest spacing. 
o LV1-LV2 delay: 5 ms 
o LV2-RV delay: 5 ms 
 
Please refer to Appendix E: “Guidelines” Part 2 for further details regarding subject’s CRT 
response classification and Part 7 for further details about MPP Programming. 
 
Attachment to CRF and Upload Device Session 
Currently, two options are available to the centers to upload the requested documents: 
“Attachment to CRFs” and “Upload Device Data”. 
The “Attachment to CRFs” is designed to upload images, adobe acrobat files, and scanned 
documents. 
The “Upload Device Data” is reserved for the upload of Device Session records saved in the 
Merlin PCS programmer. These files are in a compressed format, and they should not be 
modified before the upload procedure. 
Please refer to Appendix E: “Guidelines” Part 1, 1.1 and 1.2 for further information regarding 
Attachment to CRFs and Upload Device session. 
4.2.1 Enrollment Visit (In clinic) 
The following enrollment activities are performed after the patient has been screened and must 
occur before any investigational procedure/visit. 
 
 
The principal or delegated investigator is responsible for screening all potential subjects 
to determine patient eligibility for the investigation. 
 
If a patient meets all inclusion criteria and does not meet any of the exclusion criteria, 
he/she is eligible for the investigation. 
 
Inform the eligible patient verbally about the investigation and provide the information 
sheet and consent form to the patient. 
 
Provide ample time to the patient to read and understand the information sheet and 
consent form and to consider participation in the clinical investigation. 
 
Obtain the signature and date from the eligible patient on the Ethics Committee (EC) 
approved informed consent form. 
 
If an eligible patient does not sign and date the informed consent form, he cannot 
participate in the investigation. No further protocol required activities are performed. 

           
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 
Obtain the signature and date from the principal or delegated investigator on the EC 
approved consent form. 
 
The subject is enrolled in the investigation when the patient signs the EC approved 
consent form. 
 
Provide one original signed version of the informed consent form to the subject (signed 
by both subject and investigator) 
 
File second original signed version of the informed consent form in the Investigator Site 
Binder (ISB).   
 
Record enrollment information (name of the investigation, date of consent and 
Inclusion/exclusion information) in the internal hospital records and complete the 
Enrollment form within 5 days of enrollment.  
 
Notification of enrollment to the sponsor will be completed only when the sponsor 
receives the enrollment form.  
 
NOTE: As soon as the patient signs the Patient Informed Consent form, adverse events need to 
be reported according to the guidelines mentioned in sections 5.3.2 and 5.4.1. 
 
If a patient does not meet all inclusion criteria or meets any of the exclusion criteria, the patient 
cannot participate in the investigation and cannot be enrolled.  
 
In case the subject was already consented to participate in the investigation, but does not meet 
inclusion/exclusion criteria, the following actions shall be taken: 
 
Document enrollment information (name of the investigation, date of consent and 
inclusion/exclusion) in the hospital records and complete the Enrollment and Withdrawal 
forms. The forms must be signed authorized / approved by the principal or delegated 
investigator. 
 
Refer to Tables 1 and 2 “Data Collection” and Appendix D “Data Collection Method”. 
 
Inform the subject about the Withdrawal.  
 
The EC/IRB and CA should be notified appropriately about any deviations with regards to 
obtaining the informed consent. 
4.2.2 Baseline Visit (In Clinic, between Enrollment and Implant) 
At Baseline the following information will be collected to describe subject’s clinical status: 
 
Demographics Data 
 
Cardiovascular History 
 
NYHA Class Evaluation 
 
Current Cardiac Medication 
 
Acknowledgement of any planned hospitalization for pre-existing condition, not study 
related (if applicable) 
 
Adverse Events and/or Protocol Deviation notification (if applicable) 
 
The following activities will be performed at the baseline visit: 
 
6 Minutes Hall Walk Test 
 
BNP/pro-BNP/NT-pro-BNP Test (if performed per Standard of Care) 
 
EQ-5D Questionnaire completion 
 
MLWHF Questionnaire completion 
 
Echocardiography 
 
Preliminary LVESV Evaluation 
 
12-Lead ECG and upload to EDC portal 
 

           
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The center should send/provide the Echocardiography to the Echo Core Lab within 24 hours (1 
working day). 
 
The Core Lab will analyze the Echocardiography received and provide the evaluation of the  
LVESV Baseline value within 72 hours of reception of the echocardiography (3 working days).  
4.2.3 Implant Procedure (In Clinic, within 30 days from Enrollment) 
The implant procedure must be performed within 30 days from the enrollment. SJM MPP 
compatible CRT system will be implanted with standard procedure. 
 
The following information will be collected at the Implant visit: 
 
Implant Procedure Details 
 
Adverse Events and/or Protocol Deviation notification (if applicable) 
 
The following activities will be performed at the Implant visit: 
 
Device Test and Programming  
 
Conduction Delay Test 
 
Fluoroscopy image Collection and upload to EDC portal 
 
MPP programming (OFF) 
 
Upload of device session (as .zip-file) to EDC portal 
4.2.4 Patient Classification (In Clinic, within 7 days post Implant) 
The purpose of this visit is to double check the implanted CRT system and to perform the MPP 
Vector test in order to identify the Qualified Subjects that will constitute the Study Population. 
 
The following information will be collected at the Patient Classification visit: 
 
CRT implant success confirmation 
 
Adverse Events and/or Protocol Deviation notification (if applicable) 
 
The following activities will be performed at the Patient Classification visit: 
 
Device Test and Programming 
 
Conduction Delay Test 
 
MPP Vector test 
 
MPP programming (OFF) 
 
Upload of device session (as .zip-file) to EDC portal 
 
Implant procedure and Classification visit are considered as two different visits. If both visits are 
performed on the same day, 2 different session records need to be uploaded to the EDC portal. 
 
As only Qualified subjects will proceed in the study and constitute the Study Population, subjects 
will be classified as explained in section “3.7 Subject Enrollment Classification” using the above 
mentioned information. 
4.2.5 6 Months Follow-Up Visit (In Clinic, 183 days +/- 14 days from Implant) 
The purpose of the 6 Months Follow-Up visit is to check the subject’s and CRT system’s status 
as well as identifying subjects responding or not to CRT according to LVESV reduction between 
Baseline and 6 Months FU. 
 
The following information will be collected at the 6 Months FU visit:  
 
Patient Global Assessment 
 
NYHA Class Evaluation 

           
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 
Changes in Cardiac Medication 
 
Adverse Events and/or Protocol Deviation notification (if applicable) 
 
The following activities will be performed at the 6 Months FU visit: 
 
Device Test and Programming  
 
Conduction Delay Test 
 
6 Minutes Hall Walk Test 
 
BNP/pro-BNP/NT-pro-BNP Test (if performed per Standard of Care) 
 
EQ-5D Questionnaire completion 
 
MLWHF Questionnaire completion 
 
Echocardiography 
 
Preliminary LVESV Evaluation 
 
Randomization Procedure 
 
MPP programming (according to Randomization result) 
 
12-Lead ECG and upload to EDC portal  
 
Upload of device session (as .zip-file) to EDC portal 
 
Subject’s response to CRT will be evaluated at the center level using the Preliminary LVESV 
Evaluation. Before randomization in the second phase of the study, all subjects will undergo 
testing to determine if the mandated MPP settings can be programmed (see below for MPP 
programming requirements in Phase II). For those subjects in whom the mandated MPP settings 
cannot be programmed before randomization at 6 months, the participation in the study will end 
(an early termination form must be completed). 
 
 
Subjects with a LVESV reduction of at least 15% will be classified as RESPONDERS.  
For those subjects, the participation in the study will end (if confirmed by the Core Lab), 
and they will then return to the center’s routine follow up schedule/practice. 
 
 
If the subject is evaluated as a Responder by the center and as a Non Responder by the 
Core Lab, the center must randomize the subject and should call the subject back for an 
unscheduled visit (see 4.2.7) in case the randomization assignment is different from 
programmed. 
 
 
Subjects with an LVESV reduction less than 15% will be classified as NON 
RESPONDERS.  These subjects should be randomized and the device programmed to 
either MPP OFF or MPP ON per the randomization assignment (Please refer to section 
3.8 “Randomization Procedure” for further details). 
 
 
If the subject is evaluated as Non Responder by the center and as a Responder by the 
Core Lab, the subject continues to 12 Months visit but the data are excluded from the 
primary endpoint analysis. 
 
Subjects randomized to the MPP ON group will undergo device programming before leaving the 
hospital: 
 
 
Device programming: MPP feature will be activated and programmed. Please refer to 
Appendix E: Part 6 and 7 for further details regarding MPP activation and required 
programming. No further device programming related to dyssynchrony is encouraged 
unless medically necessary. 
 

           
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 
For those subjects randomized to MPP ON in the second phase of the study, the MPP 
feature should be programmed as follows: 
 
o MPP Vector combination: Two programmable vectors with widest spacing (≥30 
mm between two cathodes). The ‘Widest Spacing’ feature within the VectSelect 
Quartet™ MultiVector Tools in the Merlin Patient Care System should be used to 
program to widest spacing. 
o LV1-LV2 delay: 5 ms 
o LV2-RV delay: 5 ms 
 
The center should send/provide the Echocardiography to the Echo Core Lab within 24 hours (1 
working day). The Core Lab will analyze the Echocardiography received and provide the 
evaluation of the CRT response based on the LVESV reduction within 72 hours of reception of 
the echocardiography (3 working days).  
 
4.2.6 12 Months Follow-Up Visit (In Clinic, 365 days +/- 21 days from Implant, only for 
NON RESPONDERS) 
The 12-Months Follow Up visit is the last protocol scheduled visit and will be performed only for 
those subjects classified as Non Responders by the center or Echo Core Lab during the 6 Month 
Follow Up visit.  
 
Once completed, the subject ends his participation to the study and returns to the Center’s 
routine follow up schedule. 
 
The purpose of the 12 Months Follow-Up visit is to check the subject’s and CRT system’s status 
as well as identifying the overall percentage of non-responders converted to responders 
(according to LVESV reduction of at least 15%). 
 
In this visit the primary and secondary endpoint of the study will be assessed. 
 
The following information will be collected at the 12 Months Follow Up visit: 
 
Patient Global Assessment 
 
NYHA Class Evaluation 
 
Changes in Cardiac Medication 
 
Adverse Events and/or Protocol Deviation notification (if applicable) 
 
The following activities will be performed at the 12 Months Follow Up visit: 
 
Device Test and Programming 
 
Conduction Delay Test  
 
6 Minutes Hall Walk Test 
 
BNP/pro-BNP/NT-pro-BNP Test (if performed per Standard of Care) 
 
EQ-5D Questionnaire completion 
 
MLWHF Questionnaire completion 
 
Echocardiography 
 
12-Lead ECG and upload to EDC portal 
 
Upload of device session (as .zip-file) to EDC portal 
 
The center should send/provide the Echocardiography to the Echo Core Lab within 24 hours (1 
working day). 
 

           
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The Core Lab will analyze the Echocardiography received and provide the evaluation of the CRT 
response based on the LVESV reduction to the sponsor.  
4.2.7 Unscheduled Visits (In Clinic or Remote) 
An Unscheduled Visit is defined as a follow up that is not explicitly requested by the protocol.  
An Unscheduled Visit should be documented by completing the appropriate forms as applicable, 
Adverse Event, System Revision, Death and/or Termination. 
 
No specific activity is forecasted for this visit, however the center must document all of the 
following whenever applicable: 
 
 
Any performed procedure or test 
 
Any changes in subject’s status (including NYHA Class and Medication) 
 
Any Adverse Event occurred 
 
Any changes made to the MPP programming 
 
Upload FU session (as .zip-file) to EDC system (if applicable) 
4.2.8 Description of activities performed by Sponsor Representatives 
Trained sponsor personnel may perform certain activities to ensure compliance to the 
investigational plan and provide technical expertise. 
 
Sponsor personnel may: 
 
Provide technical support to the Investigators during device tests and programming 
 
Provide the EQ-5D and the MLWHF Questionnaires to the Investigator 
Review medical charts to ensure accurate reporting of data in the eCRF 
Sponsor personnel will not: 
 
Perform the informed consent process 
 
Practice medicine 
 
Provide medical diagnosis or treatment to subjects 
 
Discuss a subject’s condition or treatment with a subject without the approval and 
presence of a health care practitioner 
 
Independently collect clinical investigational data 
 
Complete or sign study’s Case report Forms 
 
Assist the subject in the EQ-5D Questionnaire completion 
 
Assist the subject in the MLWHF Questionnaire completion 
4.2.9 Description of post investigational provision of medical care 
When the subject’s participation in the clinical investigation has been completed the subject will 
return to the medical care as per physician’s recommendation. 
 
 

           
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5 Clinical Investigation Conduct 
5.1 Statements of Compliance 
The investigation will be performed in accordance with the most current versions of the World 
Medical Association (WMA) Declaration of Helsinki and any regional and/or national regulations 
as appropriate. 
ISO14155 shall be used as a guideline with following exceptions: 
 
Limited AE reporting  refer to section “5.3.2 Procedure for assessing, recording and 
reporting adverse events, adverse device effects, serious adverse events and serious 
adverse device effects”  
 
Device Deficiencies as this is a post-market study 
 
Device Accountability  
 
The investigator shall not start enrolling patients or requesting informed consent prior to 
obtaining Ethics Committee approval and Competent Authority approval, if applicable, and 
authorization from the sponsor in writing for the investigation. 
 
In case additional requirements will be imposed by the Ethics Committee or Competent Authority 
they shall be followed, if appropriate. 
 
As sponsor, SJM has taken up general liability insurance in accordance with the requirements of 
the applicable local laws. 
If required, additional subject coverage or an investigation specific insurance shall be provided 
by the Sponsor as well. 
5.1.1 Adherence to the Clinical Investigation Plan 
The principal investigator and delegates are required to adhere to the CIP in order to prevent 
subjects being exposed to unreasonable risks. On top of that, the principal investigator and 
delegates are required to be compliant with the signed Study Agreement, applicable national or 
local laws and regulations, and any conditions required by the appropriate EC or applicable 
regulatory authorities are expected as well. 
Instances of failure, intentionally or unintentionally, to adhere to the requirements of the CIP are 
considered a deviation. 
 
In some cases failure to comply with the protocol may be considered failure to protect the rights, 
safety and well-being of subjects, since the non-compliance exposes subjects to unreasonable 
risks. For example, failure to adhere to the inclusion/exclusion criteria: these criteria are 
specifically defined by the Sponsor to exclude subjects for whom the investigational device is not 
beneficial and the use involves unreasonable risks. This may be considered failure to protect the 
rights, safety and well-being of the enrolled subject. Similarly, failure to perform safety 
assessments intended to detect adverse events may be considered failure to protect the rights, 
safety and well-being of the enrolled subject. Investigators should seek minimization of such 
risks by adhering to the protocol. 
 
Simultaneously, in the event that adhering to the protocol might expose the subject to 
unreasonable risks, the investigator is also required to protect the rights, safety and well-being of 
the patient by intentionally deviating from the requirements of the CIP, so that subjects are not 
exposed to unreasonable risks.  
It is the responsibility of the investigator to provide adequate medical care to a subject enrolled 
in an investigation. 

           
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The PI shall promptly report any deviations from the CIP to the Sponsor that affect the rights, 
safety or well-being of the subject or the scientific integrity of the clinical investigation, including 
those which occur under emergency circumstances. The reporting of these deviations should be 
done as soon as possible but no later than 72 hours after the investigator becomes aware. The 
investigator shall also notify promptly the EC, as per their requirements.  
 
Any corrective and preventive actions required by the EC must be complied with by the site. 
 
The sponsor will notify the Competent Authorities and EC as per their requirements. 
5.1.2 Repeated non-compliance 
In the event of repeated non-compliance, as determined by the Sponsor, a Clinical Research 
Associate or clinical representative will attempt to secure compliance by one or more of the 
following actions: 
 
Visiting the investigator 
 
Contacting the investigator by telephone 
 
Contacting the investigator in writing 
 
Retraining of the investigator (and local staff) 
 
If an investigator is found to be repeatedly non-compliant with the signed agreement, the CIP or 
any other conditions of the clinical investigation, the Sponsor will either secure compliance or, at 
its sole discretion, terminate the investigator’s participation in the clinical investigation. 
5.2 Informed Consent Process 
5.2.1 General Process 
Provision of the Informed Consent is mandatory. Informed Consent is required from all patients 
(or their legal representatives) prior to participation in the investigation. The process of obtaining 
Informed Consent shall comply with the most recent version of the declaration of Helsinki, ISO 
14155 and all applicable regulations.  
The principal investigator or his/her authorized designee will conduct the Informed Consent 
Process. This process will include a verbal discussion with the patient on all aspects of the 
clinical investigation that are relevant to the patient’s decision to participate in the clinical 
investigation. It is crucial that this discussion is documented in the source documents (read 
hospital records of the patient). 
The patient will be provided with the informed consent form that is written in a language that is 
understandable to the patient and has been approved by EC. The patient is given ample time to 
consider participation and ask questions if necessary. The patient’s legal rights will not be 
waived nor the appearance that these will be waived. Native nontechnical language, 
understandable for the patient, will be used.  
In order to avoid any possible coercion or undue improper influence on, or inducement of the 
patient to participate, the Sponsor requests the investigator to only sign the informed consent 
form once the patient has signed and dated the document and therefore decided to participate in 
the investigation. 
Informed Consent of a patient shall always be indicated by personally dated signature of the 
patient and by the investigator responsible for conducting the Informed Consent process. It is 
crucial that the signature of the informed consent form is documented in the source documents 
(read hospital records of the patient). 
One original signed consent document must be retained on file by the investigator and a second 
original signed consent document is provided to the subject (investigator’s responsibility). 

           
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Important new information that becomes available throughout the clinical investigation will have 
to be provided in writing to new and existing patients. If relevant, all affected patients shall be 
asked to confirm their continuing informed consent in writing. 
5.2.2 Special circumstances for informed consent 
5.2.2.1 Subject needing legally authorized representatives 
Informed consent may be given by the legal representative only if a subject is unable to make 
the decision to participate in a clinical investigation (e.g. infant, child and juvenile, seriously ill or 
unconscious subject, mentally ill person, mentally handicapped person). In such cases, the 
subject shall also be informed about the clinical investigation within his/her ability to understand. 
5.2.2.2 Subject unable to read or write 
Informed consent shall be obtained through a supervised oral process if a subject or legally 
authorized representative is unable to read or write. An independent witness shall be present 
throughout the process. The written informed consent form and any other information shall be 
read aloud and explained to the prospective subject or his/her legally authorized representative 
and, whenever possible, either shall sign and personally date the informed consent form. The 
witness also signs and personally dates the informed consent form attesting that the information 
was accurately explained and that informed consent was freely given. 
5.3 Adverse Event, Adverse Device Effect  
5.3.1 Definitions 
5.3.1.1 Medical device 
Any instrument, apparatus, implement, machine, appliance, implant, software, material or other 
similar or related article 
 
Intended by the manufacturer to be used, alone or in combination, for human beings for one 
or more of the specific purpose(s) of 
Diagnosis, prevention, monitoring, treatments or alleviation of disease, 
Diagnosis, monitoring, treatment, alleviation of, or compensation for, an injury, 
Investigation, replacement, modification, or support of the anatomy or of a physiological process, 
Supporting or sustaining life, 
Control of conception, 
Disinfection of medical devices and 
 
Which does not achieve its primary intended action in or on the human body by 
pharmacological, immunological or metabolic means, but which may be assisted in its 
intended function by such means 
5.3.1.2 Adverse Event (AE) 
Any untoward medical occurrence, unintended disease or injury, or untoward clinical signs 
(including abnormal laboratory findings) in subjects, users or other persons, whether or not 
related to the medical device. 
This definition includes events related to the medical device or the comparator. 
This definition includes events related to the procedures involved. 
5.3.1.3 Serious Adverse Event (SAE) 
An adverse event that led to: 
 
Death 
 
A serious deterioration in the health of the subject, that either resulted in: 

           
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o A life-threatening illness or injury OR 
o A permanent impairment to a body structure or a body function OR 
o An in-patient or prolonged hospitalization OR 
o A medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body OR 
o A malignant tumor 
 
Fetal distress, fetal death or a congenital abnormality or birth defect 
A planned hospitalization for a pre-existing condition, or a procedure required by the CIP is not 
considered a serious adverse event. 
5.3.1.4 Adverse Device Effect (ADE) 
An adverse event related to the use of a medical device 
This definition includes adverse events resulting from insufficient or inadequate instructions for 
use, deployment, implantation, installation, or operation, or any malfunction of the medical 
device. 
This definition includes any event resulting from the use error or from intentional misuse of the 
medical device. 
5.3.1.5 Serious Adverse Device Effect (SADE) 
Adverse device effect that has resulted in any of the consequences characteristic of a serious 
adverse event 
 
5.3.2 Procedure for assessing, recording and reporting adverse events, adverse device 
effects, serious adverse events and serious adverse device effects:  
 
Safety surveillance and reporting will be done for all subjects enrolled in this investigation. 
 
Safety surveillance within this investigation and the safety reporting both performed by the 
investigator, starts as soon as the subject is enrolled in this investigation (date of signature of 
the informed consent form). The safety surveillance and the safety reporting will continue until 
the last investigational visit has been performed or the subject is deceased or the 
subject/investigator concludes his participation into the investigation. 
 
Adverse Events Reporting 
 
The investigator must report all SAEs and SADEs to the Sponsor as soon as possible but no 
later than outlined below.  
 
Clinical Site 
Reporting timelines 
All Sites 
SAEs or SADEs must be reported no later than 3 calendar days 
from the day the site personnel became aware of the event or as 
per the investigative site’s local requirements, if the requirement 
is more stringent than those outlined.
 
The date the site staff became aware the event met the criteria of an SAE or SADE must be 
recorded in the source document.  
The Investigator will further report the SAE or SADE to the local EC according to the institution’s 
EC reporting requirements and in accordance with national and local laws and regulations. 
 
Adverse events (including Adverse Device Effects) that are not serious will be reported to the 
Sponsor, as soon as possible after the occurrence of the event. 

           
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Non-Serious Adverse Events documentation and reporting are limited to cardiovascular events. 
Within cardiovascular, all arrhythmias that require medical assessment and/or intervention 
should be documented as serious adverse event.  
 
All HF hospitalization ≥ 24 hours are to be documented and reported to the sponsor according to 
the reporting requirements for all SAEs and SADEs (Refer to Adverse Events Reporting 
section). 
 
All HF hospitalization < 24 hours requiring administration of IV inotropes or diuretics are to be 
documented and reported to the sponsor according to the reporting requirements for all SAEs 
and SADEs (Refer to Adverse Events Reporting section). 
 
Refer to table 1 ‘Data Collection’ and Appendix D ‘Data Collection Method’. 
 
In case of EDC failure, notify Sponsor via Fax (please refer to the Investigator Site Binder, 
section 0.3 “Sponsor Contact Details” for further details about Fax numbers). 
 
Additional information may be requested by the Sponsor in order to support the reporting of AEs 
to regulatory authorities. 
 
NOTE: If an adverse event is documented at the subject’s last follow up visit, both the 
notification and follow-up information on the AE CRF are to be provided to the sponsor. 
5.4 Subject Death 
5.4.1 Procedure for recording and reporting Subject Death 
All subject deaths are to be documented and reported to the sponsor according to the reporting 
requirements for all SAEs and SADEs (Refer to Adverse Events Reporting section). 
 
Should death occur, the investigator is requested to record death information in the hospital 
records and immediately document the information on the Death form. By completing the form 
the sponsor will be notified. 
Refer to table 1 ‘Data Collection’ and Appendix D ‘Data Collection Method’ 
In case of EDC failure, notify Sponsor via Fax (please refer to the Investigator Site Binder, 
section 0.1 “Sponsor Contact Details” for further details about Fax numbers). 
 
Subject Death can be an outcome of a serious adverse event (SAE) or serious adverse device 
effect (SADE). 
 
Death is therefore related to an SAE/SADE: all efforts to obtain the SAE/SADE details 
should be made and the Adverse Event form must be completed. 
 
The subject’s death is an Early Conclusion of the subject’s participation in the 
investigation. Therefore, the investigator is requested to complete the Termination form.  
 
The investigator must notify the EC / IRB, if appropriate, in accordance with national and 
local laws and regulations. 
5.5 Criteria and procedures for subject withdrawal or discontinuation 
Each subject should remain in the investigation until completion of the required follow up period; 
however, a subject’s participation in the investigation may be discontinued. Should this occur, 
the reason for discontinuation must be documented in the source documents. 
Subjects must be informed about their right to withdraw from the investigation at any time and 
for any reason without sanction, penalty or loss of benefits to which the subject is otherwise 

           
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entitled and withdrawal from the investigation will not jeopardize their future medical care or 
relationship with the investigator. Subjects will be asked to specify the reason for the 
termination, but have the right not to answer. 
The investigator may decide to withdraw a subject from the investigation at any time. 
The subject’s future care will not be influenced by a decision, voluntary or otherwise, to withdraw 
from the investigation. All reasonable efforts should be made to retain the subject in the clinical 
investigation until completion of the investigation. 
 
Reasons for subject’s withdrawal include, but are not limited to: 
 
 
Subject refuses to continue participating in the investigation (refuse all subsequent 
testing/follow up) 
 
Subject does not meet the inclusion/exclusion criteria 
 
Subject’s baseline Echo or 6 Month Echo is not analyzable or evaluable according to the 
Echo Core Lab. 
 
Subject had Permanent AF at the time of enrollment and no ablation has been performed 
within 2 weeks after the CRT implant 
 
Subject does not have a successful implant 
 
Subject does not meet criteria for turning MPP feature on 
 
Subject is deceased (cause must be documented) 
 
Subject’s non-compliance 
 
Subject’s participation is terminated by the PI or investigator, although the subject 
consented, since participation is no longer medically justified 
 
Subject is ‘lost to follow up’: Subject does not adhere to the scheduled follow up visits but 
has not explicitly requested to be withdrawn from the clinical investigation. (This does not 
apply to missed visits). Site personnel should at all times make all reasonable efforts to 
locate and communicate with the subject in order to achieve patient compliance to the 
scheduled follow up visits: 
1.  A subject will be considered ‘Lost to Follow Up’ after a minimum of 2 phone calls of a 
physician or delegate at the investigational site to the subject or contact. These 2 
phone calls need to be documented in the patient’s hospital records. 
2.  If these attempts are unsuccessful, a certified letter should be sent to the subject’s last 
known address or general practitioner (GP) and a copy of this letter should be 
maintained in the patient’s hospital records. 
 
If the subject misses two consecutive scheduled follow up visits and the above mentioned 
attempts to contact the subject/GP were unsuccessful, the subject will be considered ‘Lost to 
Follow Up’ and subject’s Withdrawal form should be completed. The investigator ensures that all 
attempts are documented in the patient’s hospital records. 
5.6 Document and data control 
5.6.1 Traceability of documents and data 
The investigator shall ensure accuracy, completeness, legibility and timeliness of the data 
reported to the sponsor on the CRFs and in all required reports. Where copies of the original 
source document as well as print outs of original electronic source documents are retained, 
these shall be signed and dated by a member of the investigation site team with a statement that 
it is a true reproduction of the original source document. 

           
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5.6.2 Recording of data 
Source documents shall be created and maintained by the investigation site team throughout the 
clinical investigation. 
The data reported on the eCRFs shall be derived from, and be consistent with, these source 
documents, and any discrepancies shall be explained in writing. 
 
The CRFs shall be validated by the principal investigator or delegated site personnel as 
specified on the Signature and Delegation Log. In case of modifications after the validation, the 
eCRFs should be re-approved. 
5.6.3 Review of data 
Data review can be done remotely as well as on-site by qualified sponsor personnel. At a 
minimum, eCRFs will be reviewed for completeness after data entry by the site and 
discrepancies will be created where needed. Additional needs for data review will be outlined in 
the Monitoring Plan (Refer to section 5.7.2).  
5.7 Monitoring  
The purpose of monitoring is to verify that the right and well-being of subjects are protected, that 
the reported data are accurate and complete and that the study is conducted in compliance with 
the approved CIP, subsequent amendments, GCPs and other applicable regulatory 
requirements. 
St. Jude Medical shall assess the extent and nature of monitoring appropriate for the clinical 
study, including the strategy for source data verification, based on considerations such as the 
objective, design, complexity, size, critical data points, and endpoints of the clinical 
study.  Results of this assessment shall be used to develop a monitoring plan. 
 
Monitoring will be performed according to the applicable SJM SOPs and the study-specific 
Monitoring Plan and can be done by conducting on-site monitoring visits as well as by remote 
data review. The specific monitoring approach will be outlined in the Monitoring Plan (Refer to 
section 5.7.2). 
5.7.1 Designated Monitors 
Qualified clinical representative(s) will be identified to monitor this clinical study.  A curriculum 
vitae and training records will be retained for any individual who has conducted monitoring 
activities during the course of the clinical study. 
A list of monitors is available upon request. 
5.7.2 Monitoring Plan 
A project specific Monitoring Plan (MP) will be developed explaining at the minimum the 
monitoring strategy for the study (including frequency of visits and SDV requirements). This 
Monitoring Plan will be available upon request. 
 
The Monitoring Plan may be updated and changed as needed.  All revisions will be tracked and 
the most recent released version will take precedent over any other version.  
5.7.3 Competent Authority (CA) Inspections 
The investigator and/or delegate should contact SJM immediately upon notification of a CA 
inspection at the site. A clinical representative will assist the investigator and/or delegate in 
preparing for the audit. 
 

           
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An investigator who has authority to grant access shall permit authorized CA employees, at 
reasonable times and in reasonable manner, to enter and inspect any establishment where 
devices are held (including any establishment where devices are used or where records or 
results are kept). 
 
An investigator, or any person acting on behalf of such a person with respect to the 
investigation, shall permit authorized CA employees, at reasonable times and in reasonable 
manner, to inspect and copy all records relating to the investigation. 
 
An investigator shall permit authorized CA employees to inspect and copy records that identify 
subjects, upon notice that CA has reason to suspect that adequate informed consent was not 
obtained, or that reports required to be submitted by the investigator, to the Sponsor or EC/IRB 
have not been submitted or are incomplete, inaccurate, false or misleading. 
5.8 Investigation Termination 
Suspension or premature termination of the investigation 
The Sponsor reserves the right to stop the investigation at any stage, with appropriate written 
notice to the investigator.  
Possible reasons for early termination of the investigation by the sponsor, either at local, 
national or international level, may include, but are not limited to: 
 
 
The therapy fails to perform as intended 
 
Occurrence of USADE which cannot be prevented in future cases 
 
Sponsor’s decision, e.g. based upon significant delays in enrollment 
 
Recommendation from Steering committee and Sponsor 
 
Request from Regulatory bodies 
 
Request of Ethics Committee(s) 
 
The investigation will be terminated according to applicable regulations. 
 
The investigator may also discontinue participation in the clinical investigation with appropriate 
written notice to the Sponsor. 
Should either of these events occur, the investigator shall return all documents to the sponsor; 
provide a written statement as to why the premature termination has taken place and notify the 
Ethics Committee and the Competent Authority (if applicable). Follow-up for all enrolled subjects 
will be as per center’s practice. 
The site shall be closed appropriately by the Sponsor. 
5.8.1 Investigation Conclusion 
The investigation will be concluded when: 
 
A Close Out has been performed AND 
 
The Final report has been provided 

           
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6  Risks and Benefits of the clinical investigation 
6.1 Risks 
The risks associated with the use of the Quadripolar CRT device system are anticipated to be 
comparable to those associated with the use of other currently available CRT devices, and 
leads.  Patients participating in this study are indicated for a CRT system as part of their 
standard medical management and are subject to the risks associated with these devices (refer 
to Section 6).  
 
Additional risks associated with MPP compared to conventional BiV pacing are considered to be 
minimal. There is a theoretical risk that addition of a second LV pacing pulse could have a pro-
arrhythmic effect.  However, among both preclinical and clinical experience, no arrhythmias 
have been reported that have been caused by MPP.  The risk of reentrant conduction pathways 
and induced VT is similar to that caused by standard BiV pacing.  
6.2 Anticipated Adverse Events and Adverse Device Effects 
6.2.1 Associated with device or leads 
Possible adverse events (in alphabetical order) associated with the pacing system (CRT and 
leads) include but are not limited to the following: 
 
 
Acceleration of arrhythmias (caused by device) 
 
Death 
 
Exacerbation of heart failure 
 
Inappropriate shocks 
 
Inability to defibrillate 
 
Inhibited therapy for a ventricular tachycardia 
 
Interruption of function due to electrical or magnetic interference 
 
Lead abrasion 
 
Lead fracture 
 
Mechanical malfunction of the pacing lead 
 
Multiple counting of cardiac events including T-waves, P-waves, or supplemental 
pacemaker stimuli  
 
Shunting of energy from defibrillation paddles 
 
System failure due to ionizing radiation 
These events are not unique to devices being used within this study and could occur during any 
device implant outside of the study 
6.2.2 Associated with device or leads implant procedure 
Possible adverse events (in alphabetical order) associated with the implantation of pacing 
system (CRT device and leads) include but are not limited to: 
 
 
Acute hemorrhage/bleeding 
 
Air emboli 
 
Allergic reaction to contrast media  
 
Arrhythmia acceleration 
 
Body rejection phenomena  
 
Cardiac or venous perforation 
 
Cardiac tamponade 

           
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 
Cardiogenic shock 
 
Chronic nerve damage 
 
Cardiac/coronary sinus dissection  
 
Cardiac/coronary sinus perforation  
 
Coronary sinus or cardiac vein thrombosis  
 
Death 
 
Excessive bleeding  
 
Extracardiac stimulation (phrenic nerve, diaphragm, chest wall) 
 
Fluid accumulation 
 
Hematoma/seroma formation 
 
Hemothorax  
 
Induced atrial or ventricular arrhythmias  
 
Infection 
 
Lead migration, dislodgment or poor lead placement 
 
Myocardial irritability  
 
Myocardial damage 
 
Myopotential sensing  
 
Pericardial effusion  
 
Pericardial rub  
 
Pneumothorax  
 
Prolonged exposure to fluoroscopic radiation  
 
Pulmonary edema 
 
Renal failure from contrast media used to visualize coronary veins  
 
Rise in threshold and exit block  
 
Thromboemboli 
 
Valve damage 
 
Venous occlusion 
These events are not unique to study procedures and could occur during any device implant 
outside of the study. 
6.2.3 Associated with subject’s status/characteristics 
Possible adverse events (in alphabetical order) associated with the subject’s unique response to 
a device or lead implantations includes but are not limited to: 
 
 
Allergic reaction to contrast media  
 
Body rejection phenomena  
 
Erosion 
 
Extrusion 
 
Endocarditis  
 
Excessive bleeding 
 
Histotoxic reactions  
 
Keloid formation 
 
Local tissue reaction; formation of fibrotic tissue; cyst formation 
 
Myocardial irritability  
 
Myocardial damage 
 
Myopotential sensing  

           
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6.3 Benefits 
Subjects enrolled in this investigation may benefit as it is expected that the Multi Point Pacing 
feature will increase the volume of excited cardiac tissue and by capturing more mass at the 
initial depolarization, there is a greater likelihood of pacing the site of latest systolic delay.  
Both of these methods have been shown to improve LV function24-25 and it is believed that this 
additional improvement in LV function may benefit those subjects who are otherwise identified 
as non-responders to conventional BiV pacing. 
6.4 Treatments in case of premature study termination 
In case the study will be prematurely terminated, subjects will return to the Center’s routine 
follow-up schedule. The device programming will be left at physician’s discretion and no study-
related activities will be performed. 
 
 
 

           
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7 Statistical considerations 
The following section describes the statistical methods for the clinical investigation. Additional 
details on statistical analyses, including study cohorts, subgroup analyses and analysis of 
secondary endpoints are maintained in a separate Statistical Analysis Plan (SAP). 
7.1 Primary Endpoint Hypothesis and Sample size 
7.1.1 First phase of the study 
 
The hypothesis and the sample size estimation in the first phase of the study are based on the 
purpose of this study, study design, and the primary endpoint. 
 
The hypothesis for this study is set up as 
 
H0: POFF  ≥  PON 
 
vs 
 
H1: POFF  <  PON 
  
With POFF: the proportion that the subjects are responders in the control group (MPP feature is OFF), with 
at least 15% reduction in LVESV at 12 months compared to baseline 
With PON: the proportion that the subjects are responders in the treatment group (MPP feature is ON), with 
at least 15% reduction in LVESV at 12 months compared to baseline 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
7.1.2 Second phase of the study 
 
The hypothesis and the sample size estimation in the second phase of the study are based on 
the purpose of this study, study design, and the primary endpoint.  
 
The hypothesis for this study is set up as  
H0: POFF ≥ PON vs H1: POFF < PON  
 
With POFF: the proportion of subjects that are responders in the control group (MPP feature is OFF), with 
at least 15% reduction in LVESV at 12 months compared to baseline  
 

           
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With PON: the proportion of subjects that are responders in the treatment group (MPP feature is ON), with 
at least 15% reduction in LVESV at 12 months compared to baseline  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
7.2 Primary endpoint analysis 
7.2.1 Timing of Analysis 
7.2.1.1 Data Analysis of Phase I Subjects 
The analysis will be performed when all randomized non-responder subjects (confirmed by the 
Echo Core Lab) from the Phase I study have either completed or crossed the 12 month visit 
window or discontinued before the 12 month visit. 
7.2.1.2 Data Analysis of Phase II Subjects 
The analysis will be will be performed when all randomized non-responder subjects (confirmed 
by the Echo Core Lab) from the Phase II study have either completed or crossed the 12 month 
visit window or discontinued before the 12 month visit. 
7.2.2 Analysis methods 
 
The number of responders and the percentage will be reported for each group. Chi-square test 
will be used for the comparison between the groups. In case the expected counts in each cell is 
less than 5, then Fisher’s exact test will be used instead.   
7.3 Secondary endpoints 
All secondary endpoints will be compared between baseline and 12 months, 6 months against 
12 months separately. As with the analysis of the primary endpoint, analysis of the secondary 
endpoints analysis will be conducted. 
 
All continuous secondary endpoints will be summarized with the number of non-missing data, 
mean ± standard deviation, median and range (minimum – maximum). Paired t test will be used 
for the comparison within the group, and the equivalent non-parametric test, such as signed rank 
test or sign test, will be used in case the assumption for paired t test is violated. Comparison 
between groups will be performed using t-test, or equivalent non-parametric test, such as 

           
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Wilcoxon rank sum test, Kolmogorov-Smirnov test, when the assumption for t-test is violated. 
The normality assumption will be tested by the normality test with the aid of QQ plot. 
 
All categorical secondary endpoints will be tabulated with number of occurrence and 
percentage. Chi-square test will be used for the comparison between the groups. In case the 
expected counts in each cell is less than 5, then Fisher’s exact test will be used instead. Ordinal 
data will be analyzed using Cochran-Mantel-Haenszel method. 
7.4 Analyses will also be carried out to explore the effect of MPP programming 
parameters on responder status. Analysis population 
The following subjects will be excluded from the analysis for the primary endpoint. 
 
 
Subjects who give consent to participate in the clinical investigation but fail to complete 
the study follow up, due to a reason other than cardiac death. 
 
 
Subjects who have completed the clinical investigation but fail to have valid LVESV data 
at baseline visit, 6 months visit and 12 months visit. 
7.5 Procedures for reporting any deviation(s) from the original statistical plan 
Any deviations from the statistical analysis plan will be documented. 
7.6 The treatment of missing, unused or spurious data, including drop-outs and 
withdrawals 
No imputation techniques will be used. 
7.7 In multi-center investigations, the minimum and maximum number of 
subjects to be included for each center 
A minimum of 1 subject and maximum of 600 subjects can be recruited for each center.  
 
 

           
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8 Data Management 
Overall, the Sponsor will be responsible for the data handling. 
The sponsor and/or its affiliates will be responsible for compiling and submitting all required 
reports to governmental agencies. 
Investigational data will be analyzed by the Sponsor and may be transferred to the Sponsor’s 
locations outside of Europe and/or any other worldwide regulatory authority in support of a 
market-approval application. 
  
St. Jude Medical respects and protects personally identifiable information collected or 
maintained for this clinical trial. The privacy of each subject and confidentiality of his/her 
information will be preserved in reports and when publishing any data. Confidentiality of data will 
be observed by all parties involved at all times throughout the clinical trial.  All data will be 
secured against unauthorized access. 
8.1 Data Management Plan 
CRF data will be entered in a validated electronic database using Oracle Clinical.  
 
The physician is required to enter the data through an electronic data capture system (EDC) 
system). 
 
The Data Validation Procedure (DVP), which is part of the Data Management Plan (DMP), 
describes all the computerized data cleaning checks (validation rules) as programmed at the 
time of database set-up. However, these validation rules may change and be updated 
throughout the course of the investigation. 
Manual review and Data Cleaning Convention (DCC) will be used in addition to computerized 
data cleaning checks, to check for discrepancies and to ensure consistency of the data. 
More information will be provided in the DMP which may be updated as appropriate. All 
revisions will be tracked and include an effective date. 
The DMP shall be available upon request. 
 
 

           
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9 Document Retention 
The principal investigator (PI) shall maintain all essential clinical investigation documents from 
prior, during and (as specified) after the clinical investigation on file at the site for a minimum of 
15 years (or longer if required by local legislation) after the termination of this investigation, or 
longer as per local laws, or when it is no longer needed to support a marketing application, 
whichever is later.   
The PI must contact the sponsor prior to destroying or archiving off-site any records and reports 
pertaining to this investigation to ensure that they no longer need to be retained on-site. 
All original patient files must be stored for the longest possible time permitted by the regulations 
at the hospital, research institute, or practice in question. If archiving can no longer be 
maintained at the site, the investigator will notify the sponsor.  
All data and documents shall be made available on request of the relevant authorities in case of 
an audit. 
 
The sponsor will archive and retain all essential clinical investigation documents from prior, 
during and (as specified) after the clinical investigation as per requirements.  
 
 
 

           
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10 Amendments to Clinical Investigation Plan  
The CIP, CRFs, Informed Consent form and other patient information, or other clinical 
investigation documents shall be amended as needed throughout the clinical investigation, and 
a justification statement shall be included with each amended section of a document. Proposed 
amendments to the CIP shall be agreed upon between the Sponsor and principal investigator, or 
the coordinating investigator.  
The amendments to the CIP and the subject’s Informed Consent shall be notified to, or 
approved by, the EC and regulatory authorities, if required. The version number and date of 
amendments shall be documented. 
 
The amendment will identify the changes made, the reason for the changes and if it is 
mandatory or optional to implement the amendment. 
Any amendment affecting the subject requires that the subject be informed of the changes and a 
new consent be signed and dated by the investigator and subject prior to the subject’s next 
follow up. 
Administrative changes to, or formal clarifications of, the CIP may be required. They will be 
documented separately in writing and provided to the investigators. These clarifications will be 
incorporated when an amendment occurs. 
 
 
 

           
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11 Publication Policy 
The results of the clinical investigation will be submitted, whether positive or negative for 
publication.  
 
A ‘Publication Agreement’ will be signed between the Principal Investigator and the Sponsor  
 
If such a Publication Agreement is not signed by both parties as a separate agreement but as 
part of an overall Clinical Trial Agreement, the publication policy should be part of such a Clinical 
Trial Agreement.   
 
For more information on publication guidelines, please refer to the International Committee of 
Medical Journal Editors (ICMJE) on www.icmje.org. 
 
 
 

           
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12 Investigation Organization 
12.1 Investigation Management / Sponsor 
The organization, which takes responsibility for the initiation and/or implementation and 
coordination for the investigation is St. Jude Medical, with offices located at: 
 
St. Jude Medical 
 
 
 
 
 
12.1.1 Sponsor Responsibilities 
Sponsor’s responsibilities are in accordance with applicable guidelines.  
This includes but is not limited to the following activities: 
 
Sign off the clinical investigational plan before the start of the investigation or after 
modifications to the protocol;  
 
Develop the database; 
 
Select the clinical investigators; 
 
Train the clinical investigational sites; 
 
Activate the sites after receipt of the required documentation; 
 
Monitor participating centers by reviewing collected data and investigation documentation 
for completeness and accuracy in line with the Monitoring Plan;  
 
Perform the analysis; 
 
Ensure that all adverse events and adverse device effects are reported and reviewed with 
the clinical investigator(s) and where appropriate that all serious adverse events and 
serious adverse device effects are reported to the relevant authorities and Ethics 
Committee(s) and/or safety monitoring committee(s); 
 
Maintain an updated list of principal investigators, investigational sites and institutions. 
This list shall be available upon request. 
 
SJM retains the right to terminate the participation of an investigator for any of, but not limited to, 
the following reasons: 
 
 
Concern for subject safety and welfare 
 
Failure to secure subject Informed Consent prior to any investigational activity 
 
Failure to report unanticipated adverse device effects within 72 hours to SJM and the EC 
 
Repeated non-compliance with this CIP or the Clinical Trial Agreement 
 
Inability to successfully implement this CIP 
 
Violation of the Declaration of Helsinki 2008 (refer to Appendix C) 
 
Violation of applicable national or local laws and regulations 
 
Falsification of data, or any other breach of ethics or scientific principles 
 
Loss of or unaccounted use of investigational device inventory 
 

           
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12.2 Clinical Investigators 
This clinical investigation will be conducted by qualified investigators who have experience with: 
 
Implant and Follow up of Cardiac Resynchronization Therapy (CRT) 
 
Conduct of clinical investigations 
12.2.1 Investigator’s responsibilities 
By agreeing to this Clinical Investigation Plan, the investigators accept to allow monitoring, 
audits, Ethics Committee and IRB review, and regulatory inspections that are related to the 
investigation. They also agree to provide authorized individuals with direct access to source data 
and documentation as well as the right to copy records, provided such activities do not violate 
subject consent and subject data confidentiality.  
A principal investigator should have experience in and/or will be responsible for: 
 
 
Providing signed Clinical Trial Agreement and appropriate appendices; 
 
Providing the Sponsor with copies of any clinical-investigation-related communications 
between the Principal Investigator and the EC; 
 
Screening and selecting appropriate patients; 
 
Providing appropriate Ethics Committees Approved Informed Consent; 
 
Collecting and archiving of source data obtained prior to implant, during implant, at follow-
up examinations and after the investigation has been completed; 
 
Strict adherence to the CIP testing requirements to provide for optimal safety and 
efficacious use of the device under clinical investigation; 
 
Adequate safety reporting; 
 
Supporting the monitor, and auditor, if applicable, in their activities to verify compliance 
with the CIP, to perform source data verification and to correct the case report forms 
where inconsistencies or missing values are identified. 
 
It is acceptable for the Principal Investigator to delegate one or more functions to an associate or 
co-investigator, however, the Principal Investigator remains responsible for the proper conduct 
of the clinical investigation, complying with the investigational plan and collecting all required 
data. This delegation of specific functions shall be documented on the Signature and Delegation 
List (provided by Sponsor). The investigation is not transferable to other implant centers 
attended by the investigator unless prior approval is obtained from SJM. 

           
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12.2.2 Clinical Coordinating Investigator 
 
In addition to the responsibilities of the investigators, the Clinical Coordinating Investigator will: 
 
Sign off the final version of the investigational protocol and after modifications to the 
protocol; 
 
Act as main contact for all investigators in case of medical questions related to the 
conduct of the investigation. 
 
The following investigator has been appointed by the Sponsor as the Clinical Coordinating 
Investigator: 
 
 
 
12.2.3 Source Data and Patient Files 
The investigator has to keep a written or electronic patient files for every subject participating in 
the clinical investigation. In this hospital file, the available demographic and medical information 
of a subject has to be documented, in particular the following:  
 
Name 
Year of Birth
Concomitant Medication
Gender 
Concomitant diseases
Scheduled follow ups
Subject History 
Date of PIC
Observed AEs
PIC process  
Clinical findings
CIP required examination 
 
It should be possible to verify the inclusion and exclusion criteria for the investigation from the 
available data in this file. It must be possible to identify each subject by using this patient file.  
Additionally, any other documents with source data have to bear at least the subject 
identification and the printing date printed by the recording device to indicate to which subject 
and to which investigational procedure the document belongs. The medical evaluation of such 
records should be documented as necessary and signed/dated by the investigator. All data 
recorded on the CRF must also be part of the subject’s source data. 
 
 
 

           
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12.3 Boards 
12.3.1 Steering Committee (SC) 
The SC is championed by the Clinical Coordination Investigator (CCI) Prof. Christophe Leclercq. 
This committee will be actively involved in the investigation, and review its progress at regular 
intervals. At any time, this committee may request that the investigation be put on hold or even 
terminated for safety, ethical or other reasons. Steering Committee’s components and specific 
activities are detailed in SC Charter document. 
12.4 Outsourcing of duties and functions 
The sponsor may transfer any or all of the duties and functions related to the clinical 
investigation, including monitoring, to an external organization (such as a CRO or individual 
contractor), but the ultimate responsibility for the quality and integrity of the clinical investigation 
shall reside with the sponsor. All requirements applying to the sponsor shall also apply to the 
external organization inasmuch as this organization assumes the clinical-investigation-related 
duties and functions of the sponsor. 
12.4.1 Echo CoreLab (EchoCL) 
The Echo CoreLab is entitled to bring specific echo expertise and scientific validation to the 
study by receiving and analyzing echo tests performed by all the centers participating in the 
study. 
The Echo tests will be recorded by all participating sites in DICOM format and sent/uploaded to 
the CoreLab. 
 
Centers will send/provide the Echocardiography tests to the Echo CoreLab within 24 hours (1 
working day). 
 
The CoreLab will analyze the Echocardiography received and provide the evaluation of the CRT 
response based on the LVESV value (at Baseline) or reduction (at 6-12 Months FU) within 72 
hours of reception of the echocardiography (3 working days).  
 
In case of disagreement between the center and CoreLab evaluations, CoreLab assessment will 
considered as final and the appropriate action will be performed. 
12.4.2 ECG Core Lab (ECG CL) 
The ECG Core Lab is entitled to bring specific ECG expertise and scientific validation to the 
study by receiving and analyzing ECG tests performed by all the centers participating in the 
study. 
12.4.3 Fluoroscopy Images Core Lab (FCL) 
The Fluoroscopy Images Core Lab is entitled to bring specific fluoroscopy images expertise and 
scientific validation to the study by receiving and analyzing fluoroscopy images recorded by all 
the centers participating in the study. 
12.4.4 EuroQoL (EQ-5D Questionnaire) 
EuroQoL Group comprises a network of international, multilingual, multidisciplinary researchers, 
originally from seven centers in England, Finland, the Netherlands, Norway and Sweden.  
 

           
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The process of shared development, local experimentation and lively discussion resulted in EQ-
5D, a measure generating a single index value for health status with considerable potential for 
use in health care evaluation.  
 
EQ-5D was initially developed simultaneously in Dutch, English, Finnish, Norwegian and 
Swedish. It is now widely used in many countries around the world and has been translated into 
most major languages with the Group closely monitoring the process. 
 
EuroQoL provides certified translations of the EQ-5D patient questionnaires. 
12.4.5 MAPI Trust (MLWHF Questionnaire) 
MAPI Research Trust is a non-profit organization facilitating access to information in the fields of 
Patient-Reported Outcomes (PRO) and Epidemiology, promoting the use of scientific 
approaches in these fields and encouraging exchanges between academics, pharmaceutical 
companies and international organizations around the world. 
 
MAPI Trust is the distributor of several different Quality of Life Questionnaires, including the 
Minnesota Living with Heart Failure QoL requested in this study.  
 
MAPI is also responsible for the certified translations in different languages required when 
performing a multi-centric study. 
  
 

           
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13 Bibliography  
 
1. Task Force for Diagnosis and Treatment of Acute and Chronic Heart Failure. ESC Guidelines 
for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012.  European Heart 
Journal doi:10.1093/eurheartj/ehs104 
 
2. Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, De Simone G, et al. Executive 
summary: Heart disease and stroke statistics--2010 update: A report from the American Heart 
Association. Circulation 2010;121:948-54. 
  
3. Roger VL, Go AS, Lloyd-Jones DM, Adams RJ, Berry JD, Brown TM, Carnethon MR, Dai S, 
de Simone G, Ford ES, Fox CS, Fullerton HJ, Gillespie C, Greenlund KJ, Hailpern SM, Heit JA, 
Ho PM, Howard VJ, Kissela BM, Kittner SJ, Lackland DT,Lichtman JH, Lisabeth LD, Makuc DM, 
Marcus GM, Marelli A, Matchar DB,McDermott MM, Meigs JB, Moy CS, Mozaffarian D, 
Mussolino ME, Nichol G,Paynter NP, Rosamond WD, Sorlie PD, Stafford RS, Turan TN, Turner 
MB, WongND, Wylie-Rosett J. Heart disease and stroke statistics--2011 update: A report from 
the american heart association. Circulation. 2011;123:e18-e209 
 
4. Macias A, Gavira JJ, Alegria E, Azcarate PM, Barba J, Garcia-Bolao I. [effect of the left 
ventricular pacing site on echocardiographic parameters of ventricular dyssynchrony in patients 
receiving cardiac resynchronization therapy]. Rev Esp Cardiol. 2004;57:138-145 
 
5. Rao RK, Kumar UN, Schafer J, Viloria E, De Lurgio D, Foster E. Reduced ventricular volumes 
and improved systolic function with cardiac resynchronization therapy: A randomized trial 
comparing simultaneous biventricular pacing, sequential biventricular pacing, and left ventricular 
pacing. Circulation. 2007;115:2136-2144 
 
6. Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, Kocovic DZ, Packer M, 
Clavell AL, Hayes DL, Ellestad M, Trupp RJ, Underwood J, Pickering F, Truex C, McAtee P, 
Messenger J. Cardiac resynchronization in chronic heart failure. N Engl J Med. 2002;346:1845-
1853 
 
7. Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, Tavazzi L. The 
effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med. 
2005;352:1539-1549 
 
8. Salukhe TV, Francis DP, Sutton R. Comparison of medical therapy, pacing and defibrillation 
in heart failure (companion) trial terminated early; combined biventricular pacemaker-
defibrillators reduce all-cause mortality and hospitalization. International journal of cardiology. 
2003;87:119-120 
 
9. Pires LA, Abraham WT, Young JB, Johnson KM. Clinical predictors and timing of new york 
heart association class improvement with cardiac resynchronization therapy in patients with 
advanced chronic heart failure: Results from the multicenter insync randomized clinical 
evaluation (miracle) and multicenter insync icd randomized clinical evaluation (miracle-icd) trials. 
Am Heart J. 2006;151:837-843 
 
10. Birnie DH, Tang AS. The problem of non-response to cardiac resynchronization therapy. 
Curr Opin Cardiol. 2006;21:20-26 
 

           
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11. Blanc JJ, Etienne Y, Gilard M, Mansourati J, Munier S, Boschat J, Benditt DG, Lurie KG. 
Evaluation of different ventricular pacing sites in patients with severe heart failure: Results of an 
acute hemodynamic study. Circulation. 1997;96:3273-3277 
 
12. Butter C, Auricchio A, Stellbrink C, Fleck E, Ding J, Yu Y, Huvelle E, Spinelli J. Effect of 
resynchronization therapy stimulation site on the systolic function of heart failure patients. 
Circulation. 2001;104:3026-3029 
 
13. D'Ivernois C, Lesage J, Blanc P. Resynchronization: What if the left ventricular lead cannot 
reach the lateral or posterolateral wall? Pacing and clinical electrophysiology: PACE. 
2008;31:1041-1045 
 
14. Gasparini M, Mantica M, Galimberti P, Bocciolone M, Genovese L, Mangiavacchi M, 
Marchesina UL, Faletra F, Klersy C, Coates R, Gronda E. Is the left ventricular lateral wall the 
best lead implantation site for cardiac resynchronization therapy? Pacing and clinical 
electrophysiology : PACE. 2003;26:162-168 
 
15. Macias A, Gavira JJ, Castano S, Alegria E, Garcia-Bolao I. Left ventricular pacing site in 
cardiac resynchronization therapy: Clinical follow-up and predictors of failed lateral implant. Eur 
J Heart Fail. 2008;10:421-427 
 
16. Rovner A, de Las Fuentes L, Faddis MN, Gleva MJ, Davila-Roman VG, Waggoner AD. 
Relation of left ventricular lead placement in cardiac resynchronization therapy to left ventricular 
reverse remodeling and to diastolic dyssynchrony. The American journal of cardiology. 
2007;99:239-241 
 
17. Ansalone G, Giannantoni P, Ricci R, Trambaiolo P, Fedele F, Santini M. Doppler myocardial 
imaging to evaluate the effectiveness of pacing sites in patients receiving biventricular pacing. 
Journal of the American College of Cardiology. 2002;39:489-499 
 
18. Chalil S, Stegemann B, Muhyaldeen SA, Khadjooi K, Foley PW, Smith RE, Leyva F. Effect 
of posterolateral left ventricular scar on mortality and morbidity following cardiac 
resynchronization therapy. Pacing and clinical electrophysiology : PACE. 2007;30:1201-1209 
 
19. Edgerton JR, Edgerton ZJ, Mack MJ, Hoffman S, Dewey TM, Herbert MA. Ventricular 
epicardial lead placement for resynchronization by determination of paced depolarization 
intervals: Technique and rationale. Ann Thorac Surg. 2007;83:89-92; discussion 92 
 
20. Gold MR, Auricchio A, Hummel JD, Giudici MC, Ding J, Tockman B, Spinelli J. Comparison 
of stimulation sites within left ventricular veins on the acute hemodynamic effects of cardiac 
resynchronization therapy. Heart Rhythm. 2005;2:376-381 
 
21. Singh JP, Fan D, Heist EK, Alabiad CR, Taub C, Reddy V, Mansour M, Picard MH, Ruskin 
JN, Mela T. Left ventricular lead electrical delay predicts response to cardiac resynchronization 
therapy. Heart Rhythm. 2006;3:1285-1292 
 
22. Ypenburg C, Schalij MJ, Bleeker GB, Steendijk P, Boersma E, Dibbets-Schneider P, Stokkel 
MP, van der Wall EE, Bax JJ. Impact of viability and scar tissue on response to cardiac 
resynchronization therapy in ischaemic heart failure patients. Eur Heart J.2007;28:33-41 
 

           
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23. Lloyd MS, Heeke S, Lerakis S, Langberg JJ. Reverse polarity pacing: The hemodynamic 
benefit of anodal currents at lead tips for cardiac resynchronization therapy. Journal of 
cardiovascular electrophysiology. 2007;18:1167-1171 
 
24. Theis C, Bavikati VV, Langberg JJ, Lloyd MS. The relationship of bipolar left ventricular 
pacing stimulus intensity to cardiac depolarization and repolarization in humans with cardiac 
resynchronization devices. Journal of cardiovascular electrophysiology. 2009;20:645-649 
 
25. Leclercq C, Gadler F, Kranig W, Ellery S, Gras D, Lazarus A, Clementy J, Boulogne E, 
Daubert JC. A randomized comparison of triple-site versus dual-site ventricular stimulation in 
patients with congestive heart failure. Journal of the American College of Cardiology. 
2008;51:1455-1462 
 
26. Lenarczyk R, Kowalski O, Kukulski T, Pruszkowska-Skrzep P, Sokal A, Szulik M, Zielinska 
T, Kowalczyk J, Pluta S, Sredniawa B, Musialik-Lydka A, Kalarus Z. Midterm outcomes of triple-
site vs. Conventional cardiac resynchronization therapy: A preliminary study. International 
journal of cardiology. 2009;133:87-94 
 
27. Packer M. Proposal for a new clinical end point to evaluate the efficacy of drugs and devices 
in the treatment of chronic heart failure. J. Card Fail. 2001;7:176-182 
 
28. Thibault B, Dubuc M, Kahiry P, Guerra P, Macle L, Rivard L, Roy D, Talajic M, Karst E, Ryu 
K, Paiement P, Farazi T. Acute haemodynamic comparison of multisite and biventricular pacing 
with a quadripolar left ventricular lead. Europace 10.1093/europace/eus435 
 
 
 
 

           
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Appendix A: Abbreviations 
 
Abbreviations used in this protocol: 
 
Abbreviation 
Term 
ADE 
AE 
ASADE 
BNP 
CA 
CABG 
CCS 
CCI 
CIP 
CRF 
CPRB 
CRT 
CVA 
DCC 
DMP 
DVP 
EC 
ECG 
eCRF 
EDC 
EQ-5D 
GP 
HF 
ICMJE 
IRB 
ISB 
ISO 
LAO 
LBBB 
LV 
LVEDD 
LVEDV 
LVEF 
LVESD 
LVESV 
MLWHF 
MP 
MPP 
NAP 
NYHA 
PCS 
PGA 
PI 
PNS 
POA 
PTCA 
RA 
Adverse Device Effect 
Adverse Event 
Anticipated Serious Adverse Device Effect 
B-Type Natriuretic Peptide 
Competent Authority 
Coronary Artery Bypass Graft 
Clinical Composite Score 
Clinical Coordination Investigator 
Clinical Investigational Plan 
Case Report Form 
Clinical Project Review Board 
Cardiac Resynchronization Therapy 
Cerebrovascular Accident 
Data Cleaning Convention 
Data Management Plan 
Data Validation Procedure 
Ethics Committee 
Electrocardiogram 
Electronic Case Report Form 
Electronic Data Capture 
EuroQol questionnaire 
General Practitioner 
Heart Failure 
International Committee of Medical Journal Editors 
Institutional Review Board 
Investigator Site Binder 
International Organization for Standardization 
Left Side Antero-Posterior 
Left Bundle Branch Block 
Left Ventricle 
Left Ventricle End Diastolic Diameter 
Left Ventricle End Diastolic Volume 
Left Ventricle Ejection Fraction 
Left Ventricle End Systolic Diameter 
Left Ventricle End Systolic Volume  
Minnesota Living With Heart Failure questionnaire 
Monitoring Plan 
Multi Point Pacing Feature 
Not Applicable 
New York Heart Association 
Patient Care System 
Patient’s Global Assessment 
Principal Investigator 
Phrenic Nerve Stimulation 
Power of Attorney 
Percutaneous Transluminal Coronary Angioplasty 
Right Atrium 

           
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RAO 
RBBB 
RDC 
RV 
SADE 
SAE 
SC  
SJM 
TIA 
USADE 
WMA 
Right Side Antero-Posterior 
Right Bundle Branch Block 
Remote Data Capture 
Right Ventricle 
Serious Adverse Device Effect 
Serious Adverse Event 
Steering Committee 
St. Jude Medical 
Transient Ischemic Attack 
Unanticipated Serious Adverse Device Effect 
World Medical Association
 

           
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Appendix B: Declaration of Helsinki 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 
and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000  
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of Clarification added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
 
Preamble 
 
The World Medical Association (WMA) has developed the Declaration of Helsinki as 
a statement of ethical principles for medical research involving human subjects, 
including research on identifiable human material and data. 
 
The Declaration is intended to be read as a whole and each of its constituent 
paragraphs should be applied with consideration of all other relevant paragraphs. 
 
Consistent with the mandate of the WMA, the Declaration is addressed primarily to 
physicians. The WMA encourages others who are involved in medical research 
involving human subjects to adopt these principles.  
 
General Principles 
 
The Declaration of Geneva of the WMA binds the physician with the words, “The 
health of my patient will be my first consideration,” and the International Code of 
Medical Ethics declares that, “A physician shall act in the patient's best interest when 
providing medical care.” 
 
It is the duty of the physician to promote and safeguard the health, well-being and 
rights of patients, including those who are involved in medical research. The 
physician's knowledge and conscience are dedicated to the fulfilment of this duty. 
 
Medical progress is based on research that ultimately must include studies involving 
human subjects. 
 
The primary purpose of medical research involving human subjects is to understand 
the causes, development and effects of diseases and improve preventive, diagnostic 
and therapeutic interventions (methods, procedures and treatments). Even the best 
proven interventions must be evaluated continually through research for their safety, 
effectiveness, efficiency, accessibility and quality. 
 
Medical research is subject to ethical standards that promote and ensure respect for 
all human subjects and protect their health and rights. 
 
While the primary purpose of medical research is to generate new knowledge, this 
goal can never take precedence over the rights and interests of individual research 
subjects. 
 
It is the duty of physicians who are involved in medical research to protect the life, 
health, dignity, integrity, right to self-determination, privacy, and confidentiality of 
personal information of research subjects. The responsibility for the protection of 
research subjects must always rest with the physician or other health care 
professionals and never with the research subjects, even though they have given 
consent. 

           
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 
Physicians must consider the ethical, legal and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable 
international norms and standards. No national or international ethical, legal or 
regulatory requirement should reduce or eliminate any of the protections for research 
subjects set forth in this Declaration. 
 
Medical research should be conducted in a manner that minimizes possible harm to 
the environment. 
 
Medical research involving human subjects must be conducted only by individuals 
with the appropriate ethics and scientific education, training and qualifications. 
Research on patients or healthy volunteers requires the supervision of a competent 
and appropriately qualified physician or other health care professional. 
 
Groups that are underrepresented in medical research should be provided 
appropriate access to participation in research. 
 
Physicians who combine medical research with medical care should involve their 
patients in research only to the extent that this is justified by its potential preventive, 
diagnostic or therapeutic value and if the physician has good reason to believe that 
participation in the research study will not adversely affect the health of the patients 
who serve as research subjects. 
 
Appropriate compensation and treatment for subjects who are harmed as a result of 
participating in research must be ensured. 
 
Risks, Burdens and Benefits  
 
In medical practice and in medical research, most interventions involve risks and 
burdens. 
 
Medical research involving human subjects may only be conducted if the importance 
of the objective outweighs the risks and burdens to the research subjects. 
 
All medical research involving human subjects must be preceded by careful 
assessment of predictable risks and burdens to the individuals and groups involved in 
the research in comparison with foreseeable benefits to them and to other individuals 
or groups affected by the condition under investigation. 
 
Measures to minimise the risks must be implemented. The risks must be 
continuously monitored, assessed and documented by the researcher.  
 
Physicians may not be involved in a research study involving human subjects unless 
they are confident that the risks have been adequately assessed and can be 
satisfactorily managed. 
 
When the risks are found to outweigh the potential benefits or when there is 
conclusive proof of definitive outcomes, physicians must assess whether to continue, 
modify or immediately stop the study.            
 
Vulnerable Groups and Individuals 
 
Some groups and individuals are particularly vulnerable and may have an increased 
likelihood of being wronged or of incurring additional harm. 
 
All vulnerable groups and individuals should receive specifically considered 
protection. 
 
Medical research with a vulnerable group is only justified if the research is responsive 
to the health needs or priorities of this group and the research cannot be carried out 
in a non-vulnerable group. In addition, this group should stand to benefit from the 
knowledge, practices or interventions that result from the research. 
 
Scientific Requirements and Research Protocols  
 
Medical research involving human subjects must conform to generally accepted 
scientific principles, be based on a thorough knowledge of the scientific literature, 

           
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other relevant sources of information, and adequate laboratory and, as appropriate, 
animal experimentation. The welfare of animals used for research must be respected. 
 
The design and performance of each research study involving human subjects must 
be clearly described and justified in a research protocol. 
 
The protocol should contain a statement of the ethical considerations involved and 
should indicate how the principles in this Declaration have been addressed. The 
protocol should include information regarding funding, sponsors, institutional 
affiliations, potential conflicts of interest, incentives for subjects and information 
regarding provisions for treating and/or compensating subjects who are harmed as a 
consequence of participation in the research study. 
 
In clinical trials, the protocol must also describe appropriate arrangements for post-
trial provisions. 
 
Research Ethics Committees 
 
The research protocol must be submitted for consideration, comment, guidance and 
approval to the concerned research ethics committee before the study begins. This 
committee must be transparent in its functioning, must be independent of the 
researcher, the sponsor and any other undue influence and must be duly qualified. It 
must take into consideration the laws and regulations of the country or countries in 
which the research is to be performed as well as applicable international norms and 
standards but these must not be allowed to reduce or eliminate any of the protections 
for research subjects set forth in this Declaration.  
 
The committee must have the right to monitor ongoing studies. The researcher must 
provide monitoring information to the committee, especially information about any 
serious adverse events. No amendment to the protocol may be made without 
consideration and approval by the committee. After the end of the study, the 
researchers must submit a final report to the committee containing a summary of the 
study’s findings and conclusions.  
 
Privacy and Confidentiality  
 
Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information. 
 
Informed Consent  
 
Participation by individuals capable of giving informed consent as subjects in medical 
research must be voluntary. Although it may be appropriate to consult family 
members or community leaders, no individual capable of giving informed consent 
may be enrolled in a research study unless he or she freely agrees. 
 
In medical research involving human subjects capable of giving informed consent, 
each potential subject must be adequately informed of the aims, methods, sources of 
funding, any possible conflicts of interest, institutional affiliations of the researcher, 
the anticipated benefits and potential risks of the study and the discomfort it may 
entail, post-study provisions and any other relevant aspects of the study. The 
potential subject must be informed of the right to refuse to participate in the study or 
to withdraw consent to participate at any time without reprisal. Special attention 
should be given to the specific information needs of individual potential subjects as 
well as to the methods used to deliver the information. 
 
After ensuring that the potential subject has understood the information, the physician 
or another appropriately qualified individual must then seek the potential subject’s 
freely-given informed consent, preferably in writing. If the consent cannot be 
expressed in writing, the non-written consent must be formally documented and 
witnessed.       

           
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 
All medical research subjects should be given the option of being informed about the 
general outcome and results of the study. 
 
When seeking informed consent for participation in a research study the physician 
must be particularly cautious if the potential subject is in a dependent relationship 
with the physician or may consent under duress. In such situations the informed 
consent must be sought by an appropriately qualified individual who is completely 
independent of this relationship. 
 
For a potential research subject who is incapable of giving informed consent, the 
physician must seek informed consent from the legally authorised representative. 
These individuals must not be included in a research study that has no likelihood of 
benefit for them unless it is intended to promote the health of the group represented 
by the potential subject, the research cannot instead be performed with persons 
capable of providing informed consent, and the research entails only minimal risk and 
minimal burden. 
 
When a potential research subject who is deemed incapable of giving informed 
consent is able to give assent to decisions about participation in research, the 
physician must seek that assent in addition to the consent of the legally authorised 
representative. The potential subject’s dissent should be respected. 
 
Research involving subjects who are physically or mentally incapable of giving 
consent, for example, unconscious patients, may be done only if the physical or 
mental condition that prevents giving informed consent is a necessary characteristic 
of the research  group. In such circumstances the physician must seek informed 
consent from the legally authorised representative. If no such representative is 
available and if the research cannot be delayed, the study may proceed without 
informed consent provided that the specific reasons for involving subjects with a 
condition that renders them unable to give informed consent have been stated in the 
research protocol and the study has been approved by a research ethics committee. 
Consent to remain in the research must be obtained as soon as possible from the 
subject or a legally authorised representative. 
 
The physician must fully inform the patient which aspects of their care are related to 
the research. The refusal of a patient to participate in a study or the patient’s decision 
to withdraw from the study must never adversely affect the patient-physician 
relationship. 
 
For medical research using identifiable human material or data, such as research on 
material or data contained in biobanks or similar repositories, physicians must seek 
informed consent for its collection, storage and/or reuse. There may be exceptional 
situations where consent would be impossible or impracticable to obtain for such 
research. In such situations the research may be done only after consideration and 
approval of a research ethics committee. 
 
Use of Placebo 
 
The benefits, risks, burdens and effectiveness of a new intervention must be tested 
against those of the best proven intervention(s), except in the following 
circumstances: 
 
Where no proven intervention exists, the use of placebo, or no intervention, is 
acceptable; or 
 
Where for compelling and scientifically sound methodological reasons the use of any 
intervention less effective than the best proven one, the use of placebo, or no 
intervention is necessary to determine the efficacy or safety of an intervention and 
the patients who receive any intervention less effective than the best proven one, 
placebo, or no intervention will not be subject to additional risks of serious or 
irreversible harm as a result of not receiving the best proven intervention.  

           
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 
Extreme care must be taken to avoid abuse of this option. 
 
Post-Trial Provisions 
 
In advance of a clinical trial, sponsors, researchers and host country governments 
should make provisions for post-trial access for all participants who still need an 
intervention identified as beneficial in the trial. This information must also be 
disclosed to participants during the informed consent process. 
 
Research Registration and Publication and Dissemination of Results 
 
Every research study involving human subjects must be registered in a publicly 
accessible database before recruitment of the first subject. 
 
Researchers, authors, sponsors, editors and publishers all have ethical obligations 
with regard to the publication and dissemination of the results of research. 
Researchers have a duty to make publicly available the results of their research on 
human subjects and are accountable for the completeness and accuracy of their 
reports. All parties should adhere to accepted guidelines for ethical reporting. 
Negative and inconclusive as well as positive results must be published or otherwise 
made publicly available. Sources of funding, institutional affiliations and conflicts of 
interest must be declared in the publication. Reports of research not in accordance 
with the principles of this Declaration should not be accepted for publication. 
 
Unproven Interventions in Clinical Practice 
 
In the treatment of an individual patient, where proven interventions do not exist or 
other known interventions have been ineffective, the physician, after seeking expert 
advice, with informed consent from the patient or a legally authorised representative, 
may use an unproven intervention if in the physician's judgement it offers hope of 
saving life, re-establishing health or alleviating suffering. This intervention should 
subsequently be made the object of research, designed to evaluate its safety and 
efficacy. In all cases, new information must be recorded and, where appropriate, 
made publicly available. 
 
 

           
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Appendix C: Device Manual 
 
The manuals for the programmer and devices used in this investigation can be found on-line at 
www.sjmprofessional.com and should be consulted. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

           
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Appendix D: Data Collection Method  
Sponsor/Investigators are required to prepare and maintain adequate an accurate case histories 
designed to record all observations and other data pertinent to the investigation on each subject 
1:1. Source documents include all original records from which CRFs derive their data. 
Worksheet can be provided. The purpose of these worksheets is to aid investigators in the 
capture of clinical investigational data and ensure all protocol required data, which is not 
captured in medical records, is recorded to support data for the investigation. These worksheets 
will not be a copy of the eCRFs, but will contain entry blanks for study required data not routinely 
collected by the investigators. 
 
All documentation pertaining to clinical assessments and medical evaluations should be signed 
and dated by the appropriate clinical personnel. 
 
Electronic Data Capture (EDC) will be used for this investigation, therefore, please find below 
instructions on how to access and use the eCRF application. 
 
Access to eCRF application 
The eCRF application is accessed through the internet and requires the use of a personal user 
account and password. 
The following documents and information are required prior to receipt of personnel user account 
and password: 
 
 
Current signed and dated CV 
 
Completed Signature and Delegation List 
 
Documented training 
 
Email address and telephone 
 
Personal user account and password are provided via email. User account and password are 
confidential and personal. They are not to be shared with other people. 
The first time the application is accessed, the password will need to be changed. 
If the password is forgotten and/or lost, a new password can be provided via email by following 
the instructions on the webpage. 
 
Each center must be authorized to start enrolling patients in the investigation before access 
privileges to the application is made available. 
 
Access privileges are based on the tasks assigned on the Signature and Delegation List and will 
be either: 
 
 
Data entry and review 
 
Data entry, review and sign off 
 
All eCRFs must be completed, saved (‘save complete’) and approved by an investigator in a 
timely manner. 
 
In order to ensure a timely event reporting to the authorities (as per local regulations), particular 
attention must be used with Adverse Events forms. The Site is required to always “save as 
complete” the Adverse Event eCRFs. 

           
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Part 2 - Packer’s Clinical Composite Score (CCS)  
 
The Packer’s Clinical Composite Score (CCS) will be assessed at 6 months and 12 months post 
implant.  
The CCS includes 4 components: NYHA class, Patient Global Assessment (PGA), HF events, 
and cardiovascular death27. 
 
The NYHA Class evaluation and PGA will be determined by an Investigator interviewing 
subjects about their symptoms. Specifically, the PGA will be a single interview question that 
asks the subject to categorize how they feel compared to their previous visits as either: 
 
 
Markedly better 
 
Better 
 
No change 
 
Worse 
 
Markedly worse 
 
At the 6 Months Follow Up visit, a PGA will be conducted to evaluate how the subject feels 
compared to the baseline visit before having the CRT system implanted. 
 
At the 12 Months Follow Up visit, two different PGAs will be conducted:  
 
 
The first one will evaluate how the subject feels compared to the baseline visit before 
having the CRT system implanted and  
 
The second one will evaluate how the subject feels compared to the 6-month visit. 
 
In this trial a HF event is defined as any one of the following when the subject has symptoms 
and/or signs consistent with congestive heart failure: 
 
 
Hospitalization or Emergency Department visit for HF ≥ 24 hours 
 
Hospitalization or Emergency Department visit for HF <24 hours requiring administration 
of IV inotropes or diuretics 
 
Finally, cardiovascular death is defined as sudden unexpected death; heart failure death; 
myocardial 
infarction 
related; 
or 
‘other’ 
such 
as 
pulmonary 
embolism, 
peripheral 
thromboembolism, stroke, deaths due to vascular procedure, or other major cardiovascular 
event. 
 
Using the CCS decision algorithm described below, subjects are categorized as Improved, 
Worsened or Unchanged based on the following rules: 
 
IMPROVED – subjects that demonstrate: 
 
At least a one-class improvement in NYHA Class OR improvement by PGA (“Better” or 
“Markedly better” 
AND 
 
No HF events as described above 
AND 
 
No Cardiovascular death 
 
WORSENED – subjects that demonstrate: 
 
Worsening in NYHA Class OR worsening by PGA (“Worse” or “Markedly worse” 

           
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OR 
 
Presence of HF events as described above 
OR 
 
Cardiovascular death 
 
UNCHANGED – subjects that are neither “Improved” nor “Worsened”. 
 
 
 
Clinical Composite Score Decision Algorhythm 
 

           
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Part 4 – EQ-5D Questionnaire 
Extract from “EQ-5D-3L User Guide – Basic on how to use the EQ-5D-3L instrument” 
Version 4.0 April 2011, © EuroQol group 2011  

           
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Part 5: Minnesota Living with Heart Failure Questionnaire 
Instructions for use: 
 
1. 
Patients should respond to the questionnaire prior to other assessments and interactions 
that may bias responses. You may tell the patient that you would like to get his or her 
opinion before performing other medical assessments. 
 
2. 
Ample, uninterrupted time should be provided for the patient to complete the questionnaire. 
 
3. 
The following instructions should be given to the patient each time the questionnaire is 
completed. 
 
 
a. 
Read the introductory paragraph at the top of the questionnaire to the patient. 
 
 
b. 
Read the first question to the patient - "Did your heart failure prevent you from living 
as you wanted during the last month by causing swelling, for example, in your 
ankles, legs"? Tell the patient, "If you did not have any ankle or leg swelling during 
the last month you should circle nought after this question to indicate that swelling 
was not a problem during the last month". Explain to the patient that if he or she did 
have swelling that was caused by a sprained ankle, or some other cause that was 
definitely not related to heart failure, he or she should also circle nought. Tell the 
patient, "If you are not sure why you had the swelling or think it was related to your 
heart condition, then rate how much the swelling prevented you from doing things 
you wanted to do and from feeling the way you would like to feel". In other words, 
how bothersome was the swelling? Show the patient how to use the 1 to 5 scale to 
indicate how much the swelling affected his or her life during the last month - from 
very little to very much. 
 
4. 
Let the patient read and respond to the other questions. The entire questionnaire may be 
read directly to the patient, being careful not to influence responses by verbal or physical 
cues. 
 
5. 
Check to make sure the patient has responded to each question and that there is only one 
answer clearly marked for each question. If a patient elects not to answer a specific 
question(s) indicate so on the questionnaire. 
 
6. 
Score the questionnaire by adding the responses to all 21 questions. In addition, physical 
(items 2, 3, 4, 5, 6, 7, 12 and 13) and emotional (items 17, 18, 19, 20, and 21) dimensions 
of the questionnaire have been identified by factor analysis, and may be examined to further 
characterize the effect of heart failure on a patient's life. 
 
 
 
 
 
 
 
 
 
 
 
LIVING WITH HEART FAILURE QUESTIONNAIRE 

           
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These questions concern how your heart failure (heart condition) has prevented you from living as 
you wanted during the last month. The items listed below describe different ways some people are 
affected. If you are sure an item does not apply to you or is not related to your heart failure, then 
circle 0 (No) and go on to the next item. If an item does apply to you, then circle the number relating 
to how much it prevented you from living as you wanted. 

           
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Part 6: MultiPoint Pacing Vectors Test  
 
This appendix describes the test procedure (Vector Test) that needs to be performed in order to 
establish if the MPP feature can be turned ON. The feature will be tested at the Classification 
visit. 
 
Vectors are divided in 4 groups depending on the Cathode. 
 
Group A: includes all the possible vectors using D1 as cathode 
Group B: includes all the possible vectors using M2 as cathode 
Group C: includes all the possible vectors using M3 as cathode 
Group D: includes all the possible vectors using P4 as cathode 
In order to allow the MPP feature to be turned ON, a patient will need to have at least 2 vectors 
from different groups (with different Cathodes) that fulfills the following conditions: 
 
 
 
 
 
 
 
 
Example: 
 
GROUP A: Test Vector D1-P4. 
Is the Capture Threshold is lower than 4.5V at 0.5ms pulse width AND there is no PNS at 1 
Volt above the Capture Threshold? 
 

           
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YES: First Vector found, please move to Group B. 
NO: Please Test Vector D1-M2 
 

           
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Study Document No: 
 
Study Name: MORE CRT MPP 
Statistical Analysis Plan 
 
 
 
 
1 
 
 
 
MORE-CRT MPP 
“MOre REsponse on Cardiac Resynchronization Therapy (CRT) with MultiPoint Pacing (MPP)” 
 
 
(
) 
 
Statistical Analysis Plan (SAP) 
 
 
 

  
 
Study Document No: 
 
Study Name: MORE CRT MPP 
Statistical Analysis Plan 
 
 
 
 
2 
 
 
 
Table of Contents 
1.0 
INTRODUCTION ......................................................................................................................................... 4 
2.0 
TRIAL OBJECTIVES ..................................................................................................................................... 4 
3.0 
TRIAL DESIGN ............................................................................................................................................ 4 
4.0 
TRIAL ENDPOINTS ..................................................................................................................................... 6 
4.1 
PRIMARY ENDPOINT .......................................................................................................................................... 6 
4.2 
SECONDARY ENDPOINTS ..................................................................................................................................... 6 
5.0 
STATISTICAL METHODS ............................................................................................................................. 6 
5.1 
PRIMARY ENDPOINT HYPOTHESIS ......................................................................................................................... 6 
5.1.1 
Analysis Methods ..................................................................................................................................... 7 
5.1.2 
Analysis Population .................................................................................................................................. 7 
5.1.3 
Sample Size .............................................................................................................................................. 8 
5.1.4 
Sensitivity Analyses .................................................................................................................................. 9 
5.1.5 
Timing of Analysis .................................................................................................................................... 9 
5.1.6 
Poolability Analysis ................................................................................................................................ 10 
5.1.7 
Supplemental Analysis ........................................................................................................................... 11 
5.1.8 
Subgroup Analyses ................................................................................................................................. 11 
5.2 
SECONDARY ENDPOINTS ................................................................................................................................... 12 
5.2.1 
Percent reduction (%) in LVESV from baseline to 6 months ................................................................... 12 
5.2.2 
Packer’s Clinical Composite Score evaluation between baseline and 12 Months visit and between 6 
months and 12 months visits. ............................................................................................................................. 12 
5.2.3 
Reverse LV remodeling, measured as % changes in LVESV, LVEDD and LVEF ........................................ 15 
5.2.4 
NYHA Class changes ............................................................................................................................... 15 
5.2.5 
6-minute walk test changes ................................................................................................................... 15 
5.2.6 
Quality of Life (MLWHF and EQ-5D) changes ........................................................................................ 16 
5.3 
OVERALL SAMPLE SIZE ..................................................................................................................................... 16 
5.4 
TRIAL SUCCESS ............................................................................................................................................... 16 
5.5 
MULTIPLICITY ADJUSTMENT .............................................................................................................................. 16 
6.0 
ADDITIONAL DATA .................................................................................................................................. 17 

  
 
Study Document No: 
 
Study Name: MORE CRT MPP 
Statistical Analysis Plan 
 
 
 
 
3 
 
 
 
6.1 
BASELINE AND DEMOGRAPHIC CHARACTERISTICS................................................................................................... 17 
6.2 
MORTALITY .................................................................................................................................................... 17 
6.3 
ADVERSE EVENTS ............................................................................................................................................ 17 
6.4 
WITHDRAWALS ............................................................................................................................................... 17 
6.5 
PROTOCOL DEVIATIONS .................................................................................................................................... 17 
7.0 
DOCUMENTATION AND OHER CONSIDERATIONS .................................................................................... 17 
7.1 
SOFTWARE ..................................................................................................................................................... 17 
7.2 
RATIONALE OF SAP REVISION ............................................................................................................................ 18 
 
 

  
 
Study Document No: 
 
Study Name: MORE CRT MPP 
Statistical Analysis Plan 
 
 
 
 
4 
 
 
 
1.0 INTRODUCTION 
This document is a statistical analysis plan for the MORE-CRT MPP trial (
).  
2.0 TRIAL OBJECTIVES 
 
The objective of this clinical trial is to assess the impact of the MultiPoint Pacing (MPP) feature at 12 
months in the treatment of patients that are not responding to standard Cardiac Resynchronization 
Therapy (CRT) after 6 months. Due to the many combinations of parameters available for MPP 
programming, the MPP feature will be evaluated in two scenarios: 
(1) without mandated MPP programming parameters, and  
(2) with mandated MPP programming parameters. 
 
The primary objective is 
• 
To demonstrate that the activation of the MPP feature will increase the rate of CRT responders in 
patients who are classified as non-responders at 6 months of follow-up.   
The secondary objective is  
• 
To assess the impact of the MPP feature on patients’ functional and clinical status 
3.0 TRIAL DESIGN 
 
This study is designed as a prospective, randomized, multi-center trial.  Data will be collected at 
Enrollment, Baseline, Implant Procedure, Patient Classification, and at 6-month and 12-month follow-up 
visits.  
At the 6-month visit, the subject’s response to CRT will be evaluated according to left ventricular end 
systolic volume (LVESV) reduction as follows:  

  
 
Study Document No: 
 
Study Name: MORE CRT MPP 
Statistical Analysis Plan 
 
 
 
 
5 
 
 
 
• 
Subjects with a LVESV reduction of at least 15% relative to baseline will be classified as 
responders: these subjects will terminate their participation in the study and return to the 
center’s standard practice. 
 
• 
Subjects with a LVESV reduction of less than 15% relative to baseline will be classified as non-
responders: for these subjects, the MPP feature will be activated according to randomization 
result (MPP ON versus MPP OFF) and they will be followed until the 12-month visit.   
 
In the first phase of the study (Phase I), for those subjects who are randomized to MPP ON, the MPP 
feature is programmed at the physician’s discretion.  
 
 
  
 
In the second phase of the study (Phase II), for those subjects who are randomized to MPP ON, the 
MPP feature will be programmed with mandated parameters as follows: 
• 
MPP vector combination: Two programmable vectors with the widest spacing 
 
) between the two cathodes.   The ‘Widest Spacing’ feature within the 
VectSelect Quartet™ MultiVector Tools in the Merlin Patient Care System should be 
used to program to widest spacing. 
• 
LV1-LV2 delay: 
 
• 
LV2-RV delay: 
 
 
At 12 months, responder status will be assessed as follows:  
• 
Subjects with LVESV reduction of at least 15% between Baseline and 12 months will be classified 
as responders. 
• 
Subjects with LVESV reduction of less than 15% between Baseline and 12 months, or who died 
due to cardiac cause prior to the 12-month visit, will be classified as non-responders.  
 
The percentage of non-responder subjects converted to responders after 6 months of MPP ON versus OFF 
will be assessed. 
 

  
 
Study Document No: CL1003419 Ver. C 
Study Name: MORE CRT MPP 
Statistical Analysis Plan 
 
 
 
 
6 
 
 
 
4.0 TRIAL ENDPOINTS 
4.1 
Primary Endpoint 
The primary endpoint of this study is evaluated at 12 months after implant (6 months after randomization) 
and is defined as the percentage of non-responder subjects converted to responders compared to 
baseline, as measured by LVESV reduction of at least 15%. 
4.2 
Secondary Endpoints 
 
Reduction of LVESV between baseline and 6 Months visit 
 
Packer’s Clinical Composite Score evaluation between baseline and 12 Months visit and 
between 6 Months and 12 Months visits 
 
Reverse LV remodeling, measured as changes in LVESV, 
 and LVEF 
 
NYHA Class changes 
 
6 minutes walking test changes 
 
Quality of Life (MLWHF and EQ-5D) changes 
5.0 STATISTICAL METHODS  
This trial has one primary endpoint and 6 secondary endpoints.  
5.1 
Primary Endpoint Hypothesis 
  
  
  
 
 
 
 
 
 

  
 
Study Document No: 
 
Study Name: MORE CRT MPP 
Statistical Analysis Plan 
 
 
 
 
7 
 
 
 
5.1.1 
Analysis Methods 
The hypothesis will be tested at the one-sided 2.5% significance level.  The null hypothesis will be rejected 
if the 97.5% lower confidence bound (LCB) for the difference between the proportion of subjects who are 
responders in the treatment group (MPP ON) and the proportion of subjects who are responders in the 
control group (MPP OFF),  (PON-POFF), is greater than 0. The 97.5% LCB will be calculated using the Wald 
asymptotic confidence limits for difference of binomial proportions. 
 
 
 
5.1.2 
Analysis Population 
The primary endpoint analysis will be carried out on three subject cohorts:  
• 
The first subject cohort (Cohort #1) 
 
 
 
 
 
 
 
 
• 
The second subject cohort (Cohort #2) 
 
 
 
 
 
• 
The third subject cohort (Cohort #3) 
 
 
 
 
 
 
 

  
 
Study Document No: 
 
Study Name: MORE CRT MPP 
Statistical Analysis Plan 
 
 
 
 
8 
 
 
 
5.1.3 
Sample Size 
Phase I Sample Size 
 
 
 
 
 
  
 
 
 
  
Phase II Sample Size 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 

  
 
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5.1.4 
Sensitivity Analyses 
  
 
 
 
5.1.5 
Timing of Analysis 
Data Analysis of Phase I Subjects 
The analysis will be performed when all randomized non-responder subjects (confirmed by the Echo 
Core Lab) from Phase I study have either completed or crossed the 12-month visit window or 
discontinued before the 12-month visit. This analysis will be carried out on Cohort #1. 
Data Analysis of Phase II Subjects 
One interim analysis and a final analysis will be conducted. 
• 
Interim Analysis  
 
 
 
 
 
 
 
 
  
 
• 
The final analysis will be performed when all randomized non-responder Phase II subjects have 
either completed or crossed the 12-month visit window or discontinued before the 12-month 
visit.  

  
 
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o 
 
  
o 
 
  
5.1.6 
Poolability Analysis 
The poolability analysis between Cohort #2 and Cohort #3 subjects is planned at the interim and final 
analysis as follows: 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
   
 
  

  
 
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5.1.7 
Supplemental Analysis  
 
 
 
 
 
  
  
  
 
 
 
  
 
5.1.8 
Subgroup Analyses 
The following analyses of the primary endpoint may be performed for the following subgroups 
using the same datasets as those included in the primary endpoint analysis for publication 
purpose:  
• 
 
 
 
 
 
 
 
 
 
 
 
 
  
 

  
 
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5.2 
Secondary Endpoints 
5.2.1 
Percent reduction (%) in LVESV from baseline to 6 months 
Percent reduction (%) in LVESV from baseline to 6 months will be summarized as sample size, 
mean, standard deviations, median and range. Subjects with missing LVESV at either Baseline or 
6 months visit will be excluded from this analysis. 
5.2.2 
Packer’s Clinical Composite Score evaluation between baseline and 12 Months visit and 
between 6 months and 12 months visits.  
Using the Packer’s clinical composite score (CCS), subjects are categorized as Improved, 
Worsened or Unchanged based on the following rules:  
• 
“Worsened” – subjects that demonstrate: 
o 
Worsening in NYHA Class at last observation carried forward (LOCF) OR worsening 
by PGA (“worse” or “markedly worse”) at LOCF 
OR 
o 
Presence of HF events as described in CIP 
OR 
o 
Cardiac death 
 
• 
“Improved” – subjects that demonstrate: 

  
 
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o 
At least a one-class improvement in NYHA Class at LOCF OR improvement by PGA 
(“better” or “markedly better”) at LOCF 
AND 
o 
No HF events as described in CIP 
AND 
o 
No cardiac death 
 
• 
“Unchanged” – subjects who have non-missing NYHA at LOCF or non-missing PGA at LOCF 
and are neither “Improved” nor “Worsened”. 
 
 
If both NYHA and PGA are missing based on LOCF and doesn’t have HF event and cardiac death, they will 
be excluded from the analysis. 
 

  
 
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Has the NYHA functional class at LOCF 
worsened or the subject’s global assessment 
worsened (“moderately worse” or “markedly 
worse”) at LOCF? 
WORSENED 
YES 
Has the subject experienced a heart failure 
event? 
WORSENED 
YES 
Did the subject have a cardiac death? 
WORSENED 
YES 
NO 
NO 
NO 
Has the NYHA functional class at LOCF 
improved or the subject’s global assessment 
improved (“moderately better” or “markedly 
better”) at LOCF? 
NO 
 YES 
UNCHANGED 
IMPROVED 

  
 
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5.2.3 
Reverse LV remodeling, measured as % changes in LVESV, 
 and LVEF 
• 
 
  
 
 
 
 
 
 
  
 
 
 
 
5.2.4 
NYHA Class changes 
• 
 
 
 
 
 
 
5.2.5 
6-minute walk test changes 
• 
 
 
 
 

  
 
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• 
 
 
 
5.2.6 
Quality of Life (MLWHF and EQ-5D) changes 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.3 
Overall Sample Size 
A total number of up to 6896 subjects will be enrolled (see section 5.1.1.4). 
5.4 
Trial Success 
 
 
 
   
5.5 
Multiplicity Adjustment  
No multiplicity adjustment is planned in this study. 

  
 
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6.0 ADDITIONAL DATA 
6.1 
Baseline and Demographic Characteristics 
 
Descriptive statistics of continuous variables will be presented by treatment group and include sample 
size, mean median, standard deviation, minimum and maximum. For categorical variables, the number 
and percentage of subjects in each category will be presented by treatment group. Baseline characteristics 
will be tabulated and compared between the two treatment groups. Categorical variables will be tested 
using Fisher’s exact test and continuous variables will be tested using two sample t-test.  
6.2 
Mortality 
Kaplan-Meier survival curves will be used to summarize freedom from all-cause mortality and freedom 
from cardiovascular mortality by treatment groups.  Randomization will be considered day 0. 
6.3 
Adverse Events 
Adverse events, serious adverse events and unanticipated adverse device effects (UADE) will be 
summarized in terms of number of events, the percentage of subjects with events, and event rate 
estimated as # event/patient-years.   
6.4 
Withdrawals 
Withdrawals will be summarized for subjects who have withdrawn from the trial. 
6.5 
Protocol Deviations 
Protocol deviations will be summarized for subjects in whom a protocol deviation was reported.  
 
7.0 
DOCUMENTATION AND OHER CONSIDERATIONS 
7.1 
Software  
All analyses will be performed using SAS for Windows, version 9.3 or higher.  

  
 
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7.2 
Rationale of SAP Revision 
The following table provide the rationale of changes from SAP 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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. 

  
 
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) 

  
 
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.  

  
 
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. 
 

  
 
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