HeartMate 3 CE Mark Study Long Term Follow-up Clinical Investigation Plan
Conditions: Advanced Refractory Left Ventricular Heart Failure
Sponsor: Abbott Medical Devices

 
HeartMateTM 3 
CE Mark Study Long Term Follow-up  
Clinical Investigation Plan 
 
CONFIDENTIAL 
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Version 1:  11/Mar/2016 
 
 
 
 
 
 
 
 
 
 
 
 
HeartMateTM 3 
CE Mark Study Long Term Follow-up  
Clinical Investigation Plan 
 
 
 
 
 
 
 
Sponsor: 
St. Jude Medical  
6035 Stoneridge Drive 
Pleasanton, CA 94588 
(925) 847-8600 
(925) 847-8574 
 
 
 
 
 
Proprietary information: This document and the information contained herein may not be reproduced, 
used or disclosed without the permission of St. Jude Medical. 
 
 
 
 

 
HeartMateTM 3 
CE Mark Study Long Term Follow-up  
Clinical Investigation Plan 
 
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REVISION HISTORY 
 
Version 
Date 
Revision Summary 
Originator 
Release Date 
1 
11/Mar/2016 
Original Protocol 
Laura Damme 
11/Mar/2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Clinical Investigation Plan 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .........................................................................................................5 
TABLE OF APPENDICES ...........................................................................................................7 
STUDY SYNOPSIS.....................................................................................................................8 
1 
Introduction ........................................................................................................................10 
2 
Indications for Use .............................................................................................................10 
3 
Device Description and Theory of Operation ......................................................................10 
4 
Device Testing ...................................................................................................................12 
5 
Study Design .....................................................................................................................12 
6 
Study Duration ...................................................................................................................12 
7 
Number of Clinical Sites and Patients ................................................................................12 
8 
Study Population ................................................................................................................12 
9 
Clinical Study Objectives....................................................................................................13 
9.1 
Study Objective .........................................................................................................13 
9.2 
Study Endpoints ........................................................................................................13 
9.2.1 Survival ..........................................................................................................13 
9.2.2 Quality of Life .................................................................................................13 
9.2.3 Functional Status ...........................................................................................13 
9.2.4 Adverse Events ..............................................................................................13 
9.2.5 Device Malfunctions .......................................................................................13 
9.2.6 Reoperations..................................................................................................13 
9.2.7 Rehospitalizations ..........................................................................................13 
9.2.8 Survival Free of Debilitating Stroke (Modified Rankin Score >3) ....................13 
10 Inclusion Criteria ................................................................................................................13 
11 Exclusion Criteria ...............................................................................................................13 
12 Data Analysis and Statistical Issues/Justification for Study design .....................................13 
12.1 Sample Size ..............................................................................................................13 
12.2 Statistical Analysis ....................................................................................................14 
12.2.1 Analysis Population ........................................................................................14 
12.2.2 Study Hypothesis ...........................................................................................14 
12.2.3 Analyses of Study Endpoints ..........................................................................14 
12.2.3.1 Survival ..........................................................................................14 
12.2.3.2 Adverse Events .............................................................................14 
12.2.3.3 Device Malfunctions .......................................................................14 
12.2.3.4 Rehospitalization ...........................................................................15 
12.2.3.5 Reoperations/Operative Procedures ..............................................15 
12.2.3.6 Functional Status ...........................................................................15 
12.2.3.7 Quality of Life .................................................................................15 
12.2.4 Collection of Pump Log Files ..........................................................................15 
12.2.5 Long Term Follow-up .....................................................................................15 
12.3 Withdrawals ..............................................................................................................16 
13 Adverse Events (AE) and Adverse Device Effect (ADE).....................................................16 
13.1 Adverse Events/Adverse Device Effect .....................................................................16 
13.2 Serious Adverse Event/Serious Adverse Device Effect .............................................16 

 
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TABLE OF CONTENTS 
13.3 Early Study Termination for Safety Concerns ............................................................16 
14 Unanticipated Serious Adverse Device Effects (USADE) ...................................................17 
15 Study Procedures and Assessments .................................................................................17 
15.1 Enrollment .................................................................................................................17 
15.2 Patient Follow-up Assessments ................................................................................17 
15.2.1 Clinic Follow-up: Month 36, 48 and 60 (+/- 2 month) Post-implant..................17 
16 Anticoagulation ..................................................................................................................18 
17 Infection Control Guidelines ...............................................................................................18 
18 Post-mortem Examination ..................................................................................................18 
19 Device Retrieval .................................................................................................................18 
20 Patient Withdrawal .............................................................................................................18 
21 Risks ..................................................................................................................................18 
22 Mitigations .........................................................................................................................19 
23 Benefits..............................................................................................................................19 
24 Ethical Requirements .........................................................................................................19 
24.1 Informed Consent ......................................................................................................19 
24.2 Vulnerable Populations .............................................................................................19 
24.3 Ethics Committee Review .........................................................................................19 
24.4 Confidentiality ...........................................................................................................20 
25 Protocol Deviations ............................................................................................................20 
26 Protocol Amendments ........................................................................................................20 
27 Data Collection, Case Report Forms and Record Keeping Requirements ..........................20 
27.1 Database and Electronic Case Report Forms (eCRFs) .............................................20 
27.2 Device Accountability Records ..................................................................................21 
27.3 Source Documentation ..............................................................................................21 
27.4 Maintenance of Study Documentation .......................................................................21 
27.5 Retention of Records.................................................................................................22 
27.6 Laboratory Accreditation and Normal Values ............................................................22 
28 Insurance ...........................................................................................................................22 
29 Quality Control ...................................................................................................................22 
29.1 Investigator & Site Selection......................................................................................22 
29.2 Hospital Staff Training ...............................................................................................22 
29.3 Monitoring .................................................................................................................23 
29.3.1 Study Close-out Activities...............................................................................23 
29.4 Investigator and/or Study Site Termination/Suspension ............................................23 
29.5 Early Study Termination ............................................................................................23 
30 Emergency Contacts ..........................................................................................................23 
31 Publication Policy ...............................................................................................................24 
32 HeartMate 3 CE Mark long Term Follow-up Study Visit Schedule ......................................24 
33 References ........................................................................................................................25 
 
 

 
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Clinical Investigation Plan 
 
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LIST OF ABBREVIATIONS 
6MWT ............... Six-Minute Walk Test 
ACC .................. American College of Cardiology 
ACE .................. Angiotensin Converting Enzyme 
ADE .................. Adverse Device Effect 
AE ..................... Adverse Event 
AHA .................. American Heart Association 
AI ...................... Aortic Insufficiency 
AICD ................. Automatic Internal Cardiac Defibrillator 
AIMDD .............. Active Implantable Medical Device Directive 
ALT ................... Alanine Aminotransferase 
ARB .................. Angiotensin Receptor Blocker 
AST ................... Aspartate Aminotransferase 
AV ..................... Aortic Valve 
BNP .................. B-type Natriuretic Peptide 
BSA .................. Body Surface Area 
BUN .................. Blood Urea Nitrogen (Urea, blood) 
CE..................... Conformité Européenne  
CFR .................. Code of Federal Regulations 
CI ...................... Cardiac Index 
CIP .................... Clinical Investigation Plan 
CK..................... Creatine Kinase 
CNS .................. Central Nervous System 
COPD ............... Chronic Obstructive Pulmonary Disease 
CPB .................. Cardiopulmonary Bypass 
CRF .................. Case Report Form 
CRP .................. C-reactive Protein 
CRT .................. Cardiac Resynchronization Therapy 
CSA .................. Clinical Study Agreement 
CV..................... Cardiovascular 
CVP .................. Central Venous Pressure 
DT ..................... Destination Therapy 
EC..................... Ethics Committee 
ECG .................. Electrocardiogram 
eCRF ................ Electronic Case Report Form 
EDC .................. Electronic Data Capture 
EEG .................. Electroencephalogram 
eGFR ................ Glomerular Filtration Rate  
EQ-5D-5L .......... EuroQol Health Utility Index 
EU..................... European Union 
FEV1……………………Forced Expiratory Volume in one second 
FVC…………….Forced Vital Capacity 
FDA .................. U.S. Food and Drug Administration 
GCP .................. Good Clinical Practices 
H0 ...................... Null Hypothesis 
HA ..................... Alternative Hypothesis 
HF ..................... Heart Failure  

 
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LIST OF ABBREVIATIONS 
HM II ................. HeartMate II 
HM 3 ................. HeartMate 3 
HR .................... Heart Rate 
Hs-CRP............. High Sensitivity C-reactive Protein 
IABP ................. Intra Aortic Balloon Pump 
IB ...................... Investigator Brochure 
ICD ................... Internal Cardiac Defibrillator 
ICH ................... International Conference On Harmonization 
ICF .................... Informed Consent Form 
IFU .................... Instructions For Use 
INTERMACS ..... Interagency Registry for Mechanically Assisted Circulatory Support 
INR ................... International Ratio 
LDH .................. Lactic Acid Dehydrogenase 
LOS .................. Length of Stay 
LV ..................... Left Ventricle 
LVAD ................ Left Ventricular Assist Device 
LVAS ................ Left Ventricular Assist System 
LVEDD .............. Left Ventricular End Diastolic Diameter 
LVEF ................. Left Ventricular Ejection Fraction 
LVESD .............. Left Ventricular End Systolic Diameter 
MB .................... Myocardial Band 
MCS .................. Mechanical Circulatory Support 
MR .................... Mitral Regurgitation 
NB..................... Notified Body 
NT-ProBNP ....... N terminal B-type natriuretic peptide  
NYHA ................ New York Heart Association 
OMM ................. Optimal Medical Management 
PHgb ................. Plasma Free Hemoglobin 
PI ...................... Principal Investigator 
PRBC ................ Packed Red Blood Cells 
PT ..................... Prothrombin Time 
PTT ................... Partial Thromboplastin Time 
PVD .................. Peripheral Vascular Disease 
PVR .................. Pulmonary Vascular Resistance 
RV..................... Right Ventricle 
RVAD ................ Right Ventricular Assist Device 
SAE .................. Serious Adverse Event 
SBP .................. Systolic Blood Pressure 
SHFM ............... Seattle Heart Failure Model 
TR ..................... Tricuspid Regurgitation 
USADE ............. Unanticipated Serious Adverse Device Effect 
VAD .................. Ventricular Assist Device 
WBC ................. White Blood Cells 
WMA ................. World Medical Association 
 

 
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Clinical Investigation Plan 
 
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TABLE OF APPENDICES 
Appendix 
Contents 
1 
Anticipated Adverse Event Definitions 
2 
NYHA Classification 
3 
6MWT Protocol 
4 
Modified Rankin Score 

 
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STUDY SYNOPSIS  
Device 
HeartMate 3 Left Ventricular Assist System (LVAS); The HeartMate 3 LVAS is 
commercially approved in the European Union (CE Mark approval received October 8, 
2015) and in Kazakhstan. 
Indications for 
Use 
The HeartMate 3 LVAS(HM3) is intended to provide long term hemodynamic support 
in Patients with advanced, refractory left ventricular heart failure.  It is intendedeither 
for temporary support, such as a bridge to cardiac transplantation (BTT) or  as 
permanent destination therapy (DT).  The HeartMate 3 LVAS is intended for use inside 
or outside the hospital. 
Study Design 
The study will be a single arm, prospective, multi-center, non-blinded and non-
randomized study, intended to report on the long term use of the HeartMate 3 LVAS in 
those patients that completed the 2-year follow-up in the HeartMate 3 CE Mark study. 
Study 
Population 
Patients with advanced refractory left ventricular heart failure who were implanted with 
HeartMate 3 in the CE Mark Study and continue to be ongoing with the HeartMate 3 
LVAS after the CE Mark Study 2 year follow-up will be enrolled in this study.   
Study 
Objective 
The study objective is to report the long term survival and incidence of adverse events 
in the patients who were implanted with HM3 in the CE Mark Study and continue to be 
ongoing with the HeartMate 3 LVAS after the CE Mark Study 2 year follow-up.  
Study 
Endpoints 
The following will be evaluated:   
1. Survival: Patient outcomes and survival over time will be reported 
2. Quality of Life as measured by the EuroQoL (EQ-5D-5L) 
3. Functional status as measured by the Six Minute Walk Test (6MWT) and New York 
Heart Association (NYHA) classification 
4. Frequency and incidence of pre-defined anticipated Adverse event rates 
5. Frequency and incidence of device malfunction rates 
6. Frequency and incidence of reoperations 
7. Frequency and incidence of rehospitalizations 
8. Survival free of debilitating stroke (Modified Rankin Score > 3). 
Sample Size 
The study will include the ongoing CE Mark study patients that have consented to 
continue the long term follow-up data collection. 
Study Duration 
Patients will be followed for 3 years in this study; from the time of completing the 2 
year follow-up in the HeartMate 3 CE Mark study to 5 years post-implant or outcome 
(transplant, explant or death), whichever occurs first. 
Inclusion 
Criteria 
 
1) Patient or legal representative has signed Informed Consent Form (ICF) 
2) Patient was enrolled in the HeartMate 3 CE Mark Study and continues to be 
supported with the HeartMate 3 LVAS  
Exclusion 
Criteria 
1) Patient does not consent to continued data collection.   
Study Follow-
up Intervals  
Months 36, 48 and 60 post-implant. 
Anticipated 
Adverse 
Events 
Adverse events will be reported using INTERMACS Definitions : Major bleeding, 
Cardiac Arrhythmias, Pericardial fluid collection, Device malfunctions, Hemolysis, 
Hepatic dysfunction, Major Infection (Localized non-device infection, percutaneous site 
and/or pocket infection, internal pump component, inflow or outflow tract infection, 
sepsis), Myocardial infarction, Neurologic dysfunction, psychiatric episode, renal 
dysfunction, Arterial Non-CNS thromboembolism, Venous thromboembolism event, 
Wound dehiscence, Other adverse event. 
 

 
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Clinical Investigation Plan 
 
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STUDY SYNOPSIS  
Statistical 
Analysis 
Long term data analyses including survival, adverse events, functional status and 
quality of life will be performed when all patients have been followed for 3, 4 and 5 
years post HeartMate 3 CE Mark study implant. The 5 year survival of the HeartMate 3 
patients will be compared against the INTERMACS data cohort which was used for the 
HeartMate 3 CE Mark study 6-month data analysis.     
 
In general, continuous data will be presented as the number of patients, mean with 
standard deviation, median and minimum and maximum values.  Categorical data will 
be reported as frequencies and percentages.  Survival data will be presented using the 
Kaplan-Meier product limit method, as well as the percentage of patients who 
successfully reach the pre-defined study endpoint.  
 
Every effort will be made to collect all required data.  Missing secondary endpoints will 
not be imputed. 
 
Statistical analysis will be performed using SAS version 9.1 or higher 
  
Number of 
Sites 
Up to 10 centers 

 
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1 
INTRODUCTION 
The HeartMate 3 CE Mark study was conducted to evaluate the performance and safety 
of the HeartMate 3 Left Ventricular Assist System (HM 3 LVAS) in patients with 
advanced refractory left heart failure. A total of 50 patients were enrolled at 10 clinical 
centers in 6 countries between June 25, 2014 and November 27, 2014.  The study met 
its 6-month primary study endpoint on May 26, 2015 after which time the data was 
submitted for CE Mark approval.  The CE Mark for the HeartMate 3 LVAS was obtained 
October 8, 2015.  The HM3 LVAS is approved for commercial use in the European 
Union and Kazakhstan, but remains investigational in Canada and Australia. The 6-
month study results werepublished in the Journal of American College of Cardiology on 
December 15, 2015.12 
 
On October 8, 2015, Thoratec Corporation, the sponsor of the HeartMate 3 CE Mark 
Study, was acquired by St. Jude Medical.  
 
This purpose of this study is to continue the long term follow-up of the HeartMate 3 CE 
Mark Study patients.  Those patients that are still ongoing after completing the 2-year 
follow-up in the CE Mark study will be enrolled into this study and followed for an 
additional 3 years (a total of 5 years of follow-up for the CE Mark study patients). This 
will allow for the evaluation of late adverse events, long-term quality of life, functional 
status and provide more information on the in vivo reliability of the device. The long term 
follow-up will be reported in the post-market clinical surveillance report in compliance 
with MedDev 2.12-2:201210 and GHT/SG5/N48.   
2 
INDICATIONS FOR USE 
The indication for use in the HeartMate 3 LVAS CE Mark labelling is:  The HeartMate 3 
LVAS is intended to provide long term hemodynamic support in patients with advanced 
refractory left ventricular heart failure. It is intended either for temporary support, such as 
a bridge to cardiac transplantation (BTT), or as permanent destination therapy (DT).  
The HeartMate 3 LVAS is intended for use inside or outside the hospital. 
3 
DEVICE DESCRIPTION AND THEORY OF OPERATION  
The HeartMate 3 Left Ventricular Assist System (LVAS) is a set of equipment and 
materials that together comprise a medical device designed to provide therapeutic 
benefit to those afflicted with advanced heart failure.  In service, the LVAS assumes 
some or all of the workload of the left ventricle, thereby restoring the patient's systemic 
perfusion while palliating the underlying pathology.  The LVAS features a Left Ventricular 
Assist Device (LVAD), a centrifugal magnetically levitated pump intended for long-term 
implantation in such patients, an extracorporeal Controller, plus all of the features, 
controls, attachments, interfaces, power sources, supporting equipment, labeling, and 
tools required to achieve the desired therapeutic benefit. 
 
The LVAS may be used in either of two configurations.  First, line power may be utilized 
through the Power Module or Mobile Power Unit to run the LVAD indefinitely, convenient 
for sedentary or sleeping periods.  Second, portable Battery power may be utilized for 
limited periods, convenient for active periods.  Due to the bifurcation of the Patient 

 
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Cable, switching among these configurations or from one set of Batteries to another (as 
when one set has been depleted and a fully charged set is available) may be 
accomplished without interrupting LVAS function.  Whenever the Power Module is used 
a System Monitor may also be used as a means of viewing operating conditions, 
changing operating parameters, and manipulating stored data. 
 
The HeartMate 3 LVAD is part of the LVAS.  See Figure 1.  The LVAD is a blood pump 
intended for long-term implantation in the thorax of patients afflicted with advanced heart 
failure.  The LVAD is surgically connected to the patient's circulatory system via an 
Inflow Cannula placed into the left ventricular apex, and an Outflow Graft anastomosed 
to the ascending aorta.  Detailed surgical, patient management and storage and 
handling instructions can be found in the HeartMate 3 Instructions For Use (IFU).  
 
 
 
Figure 1 – HeartMate 3 System during Battery-powered Operation 
 
 
 
 
The HeartMate 3 LVAD contains an Inflow Cannula, a Pump Cover, a Lower Housing, a 
Screw Ring to attach the Pump Cover to the Lower Housing, a Motor, the Outflow Graft, 
and a Pump Cable. 
 
The HeartMate 3 Controller is also part of the Left Ventricular Assist System (LVAS).  
The Controller is an extracorporeal interface device that receives power from the Power 

 
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Module, Mobile Power Unit, or portable Batteries, and appropriately delivers that power 
to the LVAD.  It is the primary user interface and has several important functions: 
 Operating condition display, 
 Source of audible and visible alarms, 
 Communication link for transferring event/period log and alarm information, and 
 Battery backup in the case of full power disconnection. 
 
The HeartMate 3 LVAD is assembled in St. Jude Medical’s manufacturing facility in 
Zurich, Switzerland.  All other HeartMate 3 components and accessories are 
manufactured at St. Jude Medical’s manufacturing facility in Pleasanton, California, 
U.S.A.  A complete list of HeartMate 3 LVAS components and accessories, including 
model and/or serial/lot numbers is included in the HeartMate 3 IFU. 
4 
DEVICE TESTING 
The HeartMate 3 LVAD/LVAS is an implantable long-term support device/system.  As 
such, it has been designed in compliance with all applicable EU and international 
standards5,6,7,9.  The device/system has been subjected to a comprehensive verification 
and validation effort to ensure its safety including evaluation of biocompatibility, sterility 
and long term reliability and this was performed prior to the HeartMate 3 CE Mark clinical 
study.  The device testing data was submitted to the Notified Body for the purpose of 
obtaining the CE Mark.     
5 
STUDY DESIGN 
The study will be a single arm, prospective, multi-center, non-blinded and non-
randomized study, intended to report on the long term use of the HeartMate 3 LVAS in 
those patients that completed the 2-year follow-up in the HeartMate 3 CE Mark study.  
6 
STUDY DURATION 
Patients will be followed for 3 years in this study; from the time of completing the 2 year 
follow-up in the HeartMate 3 CE Mark study to 5 years post-implant or outcome 
(transplant, explant or death), whichever occurs first.   
7 
NUMBER OF CLINICAL SITES AND PATIENTS 
A total of 50 patients at 10 centers were enrolled in the HeartMate 3 CE Mark Study.  
The patients that continue to be ongoing with the HeartMate 3 LVAS after the CE Mark 
Study 2 year follow-up will be enrolled in this study.   
8 
STUDY POPULATION 
Patients with advanced refractory left ventricular heart failure who were implanted with 
HeartMate 3 in the CE Mark Study and continue to be ongoing with the HeartMate 3 
LVAS after the CE Mark Study 2 year follow-up will be enrolled in this study.   

 
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9 
CLINICAL STUDY OBJECTIVES 
9.1 
STUDY OBJECTIVE 
The study objective is to report the long term survival and incidence of adverse events in 
the patients who were implanted with HeartMate 3 in the CE Mark Study and continue to 
be ongoing with the HeartMate 3 LVAS after the CE Mark Study 2 year follow-up.   
9.2 
STUDY ENDPOINTS 
9.2.1 
Survival  
Patient outcomes and survival over time will be reported. 
9.2.2 
Quality of Life 
Quality of Life as measured by the EuroQoL-5D-5L  
9.2.3 
Functional Status 
Functional status as measured by the Six Minute Walk Test (6MWT). 
Functional status as measured by New York Heart Association (NYHA) 
Classification. 
9.2.4 
Adverse Events 
Frequency and incidence of pre-defined anticipated adverse event rates 
9.2.5 
Device Malfunctions 
Frequency and incidence of device malfunction rates 
9.2.6 
Reoperations 
Frequency and incidence of reoperations   
9.2.7 
Rehospitalizations 
Frequency and incidence of rehospitalizations 
9.2.8 
Survival Free of Debilitating Stroke (Modified Rankin Score >3)  
10 
INCLUSION CRITERIA 
1) Patient or legal representative has signed Informed Consent Form (ICF). 
2) Patient was enrolled in the HeartMate 3 CE Mark Study and continues to be 
supported with the HeartMate 3 LVAS after the 2 year CE Mark study follow-up.    
11 
EXCLUSION CRITERIA 
1) Patient does not consent to the continued data collection.   
12 
DATA ANALYSIS AND STATISTICAL ISSUES/JUSTIFICATION FOR STUDY 
DESIGN 
12.1 
SAMPLE SIZE 
The study will include the ongoing CE Mark study patients that have consented to 
continue the long term follow-up data collection.   

 
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12.2 
STATISTICAL ANALYSIS 
Long term data analyses including survival, adverse events, functional status and quality 
of life will be performed when all patients have been followed for 3, 4 and 5 years post 
HeartMate 3 CE Mark study implant. The 5 year survival of the HeartMate 3 patients will 
be compared against the INTERMACS data cohort which was used for the HM3 CE 
Mark study 6-month data analysis.     
 
In general, continuous data will be presented as the number of patients, mean with 
standard deviation, median and minimum and maximum values.  Categorical data will be 
reported as frequencies and percentages.  Survival data will be presented using the 
Kaplan-Meier product limit method, as well as the percentage of patients who 
successfully reach the pre-defined study endpoint.  
 
Every effort will be made to collect all required data.  Missing secondary endpoints will 
not be imputed. 
 
Statistical analysis will be performed using SAS version 9.1 or higher. 
12.2.1 
Analysis Population 
The ongoing CE Mark study patients that have consented to continue the long 
term follow-up data collection will be included in the analysis.   
12.2.2 
Study Hypothesis 
This is an long-term observational study of the ongoing CE Mark study 
patients.  Long term data analyses including survival, adverse events, 
functional status and quality of life will be performed when all patients have 
been followed for 3, 4 and 5 years post HeartMate 3 CE Mark study implant. 
The 5 year survival of the HeartMate 3 patients will be compared against the 
INTERMACS data cohort which was used for the HM3 CE Mark study 6-month 
data analysis.   
12.2.3 
Analyses of Study Endpoints 
12.2.3.1 
Survival 
Overall survival will be analyzed using the product-limit method of 
Kaplan and Meier. A competing outcome analysis will also be 
performed. 
12.2.3.2 
Adverse Events 
All pre-defined adverse events will be collected and reviewed to 
ensure accurate reporting.  Tables will be created that show the 
relation to device, frequency and incidence of all adverse events, 
time to event, and the event rate per patient year of support.  Tables 
will be created that show the incidence and event rates per patient 
year of support for all serious adverse events.  
12.2.3.3 
Device Malfunctions 
All suspected device malfunctions of the HeartMate 3 LVAS will be 
reported.  St. Jude Medical will ask that all explanted devices 
including their components be returned for analysis.  Data on device 

 
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malfunctions will be analyzed and tables will be created that report 
the following: 
 
• If the event is confirmed by analysis of the device by St Jude 
Medical engineers 
• The component of the device involved (internal or external) 
• Days to the malfunction 
• Action(s) taken in response to the malfunction 
12.2.3.4 
Rehospitalization 
Time to rehospitalization, frequency and the reason for 
rehospitalization will be reported.  Time in and out of the hospital will 
also be reported. 
12.2.3.5 
Reoperations/Operative Procedures 
Time to reoperation, frequency of reoperation, and the reason for 
the surgery will be reported.  
12.2.3.6 
Functional Status 
Functional status will be measured using the New York Heart 
Association Functional Class (NYHA) and the Six Minute Walk Test 
(6MWT).   
 
NYHA 
Results will will be compared to baseline scores using Fisher’s 
Exact Test.  
 
Six Minute Walk Test 
Patients may not be able to walk due to illness, especially at 
baseline.  Patients unable to walk due to illness will receive a score 
of 0 meters.  For all other reasons for missing data the score will 
remain missing and not included in the analysis.  The distance 
walked will be compared to baseline distances using a paired t-test.  
All data will also be graphically presented. 
12.2.3.7 
Quality of Life 
Quality of Life will be measured using the EQ-5D-5L.  The EQ-5D-
5L VAS and total score post-implant will be compared to baseline 
scores using a paired t-test.  In addition, the percentage of each 
component of the EQ-5D-5L will be graphically presented over time. 
12.2.4 
Collection of Pump Log Files 
Pump log files should be submitted to St. Jude Medical in association with a 
suspected device malfunction to assist in characterization of pump operation 
and system diagnostic purposes.  No specific pre-defined analysis will be 
performed on this data. 
12.2.5 
Long Term Follow-up 
Patients who complete the 5 year follow-up in this study will continue to be 
followed by their health care providers in accordance with the standard of care 
established by their healthcare provider. 

 
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12.3 
WITHDRAWALS 
Patients will be considered withdrawn from the study if: 
 The patient withdraws their consent to participate in the study, or 
 The patient has their HeartMate 3 permanently explanted or deactivated for reasons 
other than myocardial recovery, or 
 The patient has their HeartMate 3 replaced with a LVAD other than a HeartMate 3 
 
In all cases, the reason for withdrawal will be determined and an adverse event or 
device malfunction reported, if applicable.  Patients who are withdrawn from the study 
will not be replaced.  Patients who are withdrawn will be censored at the time of 
withdrawal in all survival analysis  
13 
ADVERSE EVENTS (AE) AND ADVERSE DEVICE EFFECT (ADE) 
13.1 
ADVERSE EVENTS/ADVERSE DEVICE EFFECT 
Adverse Events are any unfavorable and unintended sign (including abnormal labs), or 
symptom or disease temporally associated with the device and whether or not related to 
the use of the device.  Investigators are responsible for reporting required pre-defined 
AEs to the study sponsor in a timely manner by submitting AEs through the electronic 
data capture system (EDC), and for reporting AEs to their Ethics Committee (EC) as 
required. 
 
All pre-defined AEs, including those occurring after discharge, will be reported and will 
be categorized as related to the device (Adverse Device Effect) or not. 
 
INTERMACS definitions will be used for all anticipated adverse events.  Anticipated 
adverse event definitions can be found in Appendix 1. 
13.2 
SERIOUS ADVERSE EVENT/SERIOUS ADVERSE DEVICE EFFECT 
Serious adverse events (SAEs) are defined as those causing death, fetal distress, fetal 
death or congenital abnormality or birth defect, or a life-threatening illness or injury that 
results in permanent disability, requires hospitalization, or prolongs a hospitalization, 
and/or requires intervention to prevent permanent injury or damage.  Investigators are 
responsible for reporting SAEs to the study sponsor in a timely manner (but no later than 
24 hours after becoming aware of an SAE) by submitting SAEs through the electronic 
data capture system (EDC), and for reporting SAEs to their EC as required. 
 
All SAEs will be reported and will be categorized as related to the device (Serious 
Adverse Device Effect) or not. 
13.3 
EARLY STUDY TERMINATION FOR SAFETY CONCERNS 
St. Jude Medical will monitor all adverse events and device malfunctions throughout the 
trial.  As this is a long term follow-up study, early study termination does not apply to this 
study.   

 
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14 
UNANTICIPATED SERIOUS ADVERSE DEVICE EFFECTS (USADE) 
An unanticipated serious adverse device effect includes any serious adverse effect on 
health or safety or any life-threatening problem or death caused by, or associated with, a 
device, if that effect, problem, or death was not previously identified in nature, severity, 
or degree of incidence.  Investigators are responsible for reporting any USADEs to St 
Jude Medical by telephone or email and through the electronic data capture system 
(EDC) as soon as the study site personnel are made aware of an event, but no later than 
24 hours of becoming aware. Telephone reports concerning USADEs must be followed 
by a written report to St. Jude Medical within five (5) working days of the event.  St. Jude 
Medical will review all malfunctions and determine if they are USADEs.  St. Jude Medical 
will report all such effects to the appropriate regulatory bodies, in accordance with 
regulatory requirements.  
 
In addition to reporting USADEs to the Study Sponsor, Investigators must report 
USADEs to their EC in accordance with local EC requirements. 
15 
STUDY PROCEDURES AND ASSESSMENTS 
Special equipment is not required to conduct study procedures or assessments.  
Participating centers will utilize their own local laboratories for protocol required 
laboratory assessments, and will be instructed to follow their institutions requirements for 
maintenance and/or calibration of laboratory equipment.  For EDC, a computer with 
256Mb RAM, Intel II processor or higher, current version Internet Explorer Firefox or 
Chrome, and an available internet connection is required.  
15.1 
ENROLLMENT 
Patients will be enrolled after the 2 year CE Mark study follow-up visit.  Any events (e.g. 
adverse events, rehospitalizations, reoperations) that occur after the 2 year CE Mark 
study visit are intended to be captured in this long term follow-up study.  Patients are 
considered enrolled upon signing of the informed consent for this follow-up study.    
 
15.2 
PATIENT FOLLOW-UP ASSESSMENTS 
15.2.1 
Clinic Follow-up: Month 36, 48 and 60 (+/- 2 month) Post-implant  
The Patients must be seen for a clinic visit to assess the following:  
 
1. Current patient status: whether the patient is ongoing on HeartMate 3 
support 
2. Patient outcome: whether or not the patient has been transplanted,  
explanted or expired 
3. EQ-5D-5L 
4. 6MWT  
5. Pump Replacements/Explants/ Device Exchanges  
6. Occurrence of AEs (date of the adverse event, determination of 
seriousness and/or relation to device, resolution of the adverse event) 
7. Device Malfunctions 
8. Laboratory assessments per standard of care 
9. Driveline management assessment 

 
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10. Reoperations/Operative procedures 
11. Rehospitalizations  
12. NYHA Classification 
13. Log files (pump period log, pump event log, controller period log, and 
controller event log) if a device malfunction is suspected should be 
submitted to St. Jude Medical. 
 
For a detailed list of assessments and timelines, refer to the Study Visit 
Schedule in Section 32. 
16 
ANTICOAGULATION 
Patients supported with the HeartMate 3 must be properly anticoagulated to decrease 
the possibility of thromboembolism.  Anticoagulation guidelines are provided in the 
HeartMate 3 Instructions for Use (IFU).  
17 
INFECTION CONTROL GUIDELINES 
It is recommended that the Patient Care and Management Guidelines developed for the 
HeartMate 3 LVAS are followed.  Guidelines for infection control and driveline 
management are provided in the HeartMate 3 Instructions for Use (IFU). 
18 
POST-MORTEM EXAMINATION 
All attempts to obtain permission for a full body autopsy should be made for patients that 
experience a death that is possiblydevice related.  Performance of an autopsy is to be 
noted on the eCRF and a copy of the final autopsy is to be provided to St. Jude Medical.  
The primary objective of the autopsy is to determine the cause of death, complications 
and other relevant findings.  In addition, special attention should be directed toward 
documentation of patient-prosthesis interaction and any HeartMate 3 LVAD associated 
complications. 
19 
DEVICE RETRIEVAL 
Upon patient death or device explantation, all HeartMate 3 LVAS System Components 
(pump, system controller and modular cable/driveline) must be retrieved and returned to 
St. Jude Medical for analysis within 48 hours of explant.  Devices must be returned using 
the Explant Kit and instructions.  
20 
PATIENT WITHDRAWAL 
The patient retains the right to withdraw from the study at any time.  Should the patient 
elect to withdraw from the study, the reason for withdrawal must be documented.  
21 
RISKS  
The HeartMate 3 LVAS is a commercially available device in Kazakhstan and also the 
European Union (as of October 8, 2015 after receiving CE Mark approval).  
 
The potential risks including anticipated adverse eventsare expected to be similar to 
those seen with other commercially available mechanical circulatory support devices.1-4  
 

 
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The patients enrolled in the HeartMate 3 CE Mark study that continue on HeartMate 3 
support will be included in the CE Mark Long Term Follow-Up study. These patients will 
continue to be followed beyond the 2 years specified in the CE Mark study. No new 
patients will be exposed to risk and the patients in the study will not experience any new 
risk by being followed in the long term study. 
22 
MITIGATIONS 
Mitigations and treatment for all adverse events should be per the current practice 
standards/standards of care as determined by the investigator.  The long term follow-up 
care will continue with experienced and trained LVAS personnel.   
23 
BENEFITS 
Commercially available mechanical circulatory support devices have been previously 
shown to provide safe and effective long term hemodynamic support in advanced heart 
failure patients with clinical meaningful improvement in survival, quality of life and 
functional capacity when compared to optimal medical management.  It is therefore 
expected that similar benefits may be observed with the HeartMate 3 LVAS.   
24 
ETHICAL REQUIREMENTS 
24.1 
INFORMED CONSENT 
Written informed consent must be obtained by the principal investigator or designee, 
before any study-related procedures or tests are performed that would otherwise not be 
performed according to the standard of care.  If the patient is unable to participate in the 
informed consent process, consent must be obtained from a legally authorized 
representative prior to administering any study-related test or procedure.  The use of a 
legally authorized representative is only permissible if allowed by the local EC. 
 
If new information becomes available by the Sponsor that may affect a patient’s 
participation in the trial, Investigators will be required to update/revise the informed 
consent as necessary, and all patients will be re-consented by the site. 
 
Revisions to the informed consent will be approved by the Sponsor and the EC prior to 
re-consenting patients. 
 
Each clinical site is responsible for keeping the original signed informed consent forms, 
and any updated signed informed consent forms for each patients on file, and available 
for inspection by St. Jude Medical.  
 
The process of obtaining Informed consent must be documented in each patient’s 
medical record. 
24.2 
VULNERABLE POPULATIONS 
Vulnerable populations will not be recruited for this study. 
24.3 
ETHICS COMMITTEE REVIEW 
Investigators will conduct the study in compliance with the Declaration of Helsinki11 and 
local and national regulatory requirements.  

 
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St. Jude Medical will comply with all Ethics Committee and all national regulatory 
requirements. 
 
Before initiation of the study, EC approval of the protocol and the informed consent form 
must be obtained.  Modifications made to the ICF should be sent to St. Jude Medical for 
approval, prior to submitting to the EC.  Copies of the EC submission and approval, 
including the approved informed consent form, must be forwarded to St. Jude Medical 
prior to the enrollment of patient into the study.  A Final Report must be submitted by the 
investigator to the Ethics Committee and St. Jude Medical Corporation upon study 
termination or termination of site participation.  Copies of all submissions to and 
correspondence from the Ethics Committee (approvals and disapprovals) must be sent 
to St. Jude Medical and maintained on file at the study site.  
24.4 
CONFIDENTIALITY 
No individually identifiable/confidential patient data collected as part of this study will be 
released beyond St. Jude Medical.  The patient will continue to be identified by the 
unique patient study identification code that was assigned during the CE Mark study.    
Patient identifiable data should be de-identified by the site prior to submission to St. 
Jude Medical. 
25 
PROTOCOL DEVIATIONS 
This study should be conducted as described in this protocol.  All deviations from the 
protocol will be flagged and evaluated through the Electronic Data Capture system 
(EDC). 
 
For sites who demonstrate repeated deviations that may affect the safety of patients, 
and/or the integrity of the data, corrective measures will be instituted such as re-training. 
 
Sites must notify their EC of protocol deviations in accordance with local EC 
requirements. 
 
Refer to Section 29.5 for additional information on Sponsor management of Investigator 
compliance. 
26 
PROTOCOL AMENDMENTS 
Significant changes to the protocol will be handled by a formal protocol amendment.  
Protocol amendments will be submitted to Investigators with instructions to submit their 
local ECs for approval.   
27 
DATA COLLECTION, CASE REPORT FORMS AND RECORD KEEPING 
REQUIREMENTS 
27.1 
DATABASE AND ELECTRONIC CASE REPORT FORMS (ECRFS) 
An EDC system that complies with United States regulations on electronic records and 
signatures (21 CFR Part 11) will be utilized for this study.  Users will have unique 
usernames and passwords, and the user list will be maintained by a St. Jude Medical 
administrator for all study personnel.  The Investigator must ensure that the observations 

 
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and study findings are recorded correctly and completely in the eCRFs.  Each eCRF 
requiring a signature must be signed and dated by the authorized personnel.  
 
Data being submitted through the course of the clinical trial will be reviewed by the 
Sponsor for accuracy and completion.  Database cleaning and the process for issuing 
and/or resolving queries will be documented in the Sponsors study specific data 
management plan. 
27.2 
DEVICE ACCOUNTABILITY RECORDS 
The HeartMate 3 LVAS is not an investigational device in the European Union and 
Kazakhstan and therefore device accountability records will not be required. In Canada 
and Australia the HeartMate 3 LVAS has not yet received commercial approval and the 
devices will continue to be tracked via device accountability records. 
 
Traceability of the LVAS is maintained by the Sponsor through the use of unique serial 
and/or lot numbers.  
27.3 
SOURCE DOCUMENTATION 
Original Documentation supporting the data recorded on the eCRFs must be maintained, 
and include: clinical charts, medical records, laboratory reports, physician referral or 
consultation letters, X-ray reports, etc.  Adverse events which are managed at a health 
care facility other than the study site must be reported on an eCRF and every attempt 
must be made to obtain source documentation from that facility. 
 
Source documents may be be reviewed to ensure accuracy and validity of data recorded 
on the eCRFs.  Source document verification will be performed by St. Jude Medical, or 
its designee, with due regard to patient confidentiality.  
27.4 
MAINTENANCE OF STUDY DOCUMENTATION 
The following documents should be maintained by the study site, and copies of site 
specific documents sent to St. Jude Medical:  
 Copy of the Study Protocol 
 Ethics Committee Approval(s)  
 Pertinent Ethics Committee Correspondence 
 Ethics Committee approved Informed Consent Form(s), including translation 
certification if applicable 
 Ethics Committee Membership Roster(s)  
 Financial Disclosure(s) 
 Investigator’s Agreement(s) 
 Curriculum Vitae(s) 
 Study Staff Signature and Delegation of Responsibilities Log 
 Laboratory Certification(s) and Normals 
 Source documentation (such as patient clinic charts, medical records, laboratory 
records) 
 Clinical Study Agreement (CSA) 
 St. Jude Medical Correspondence  
 Documentation of Training  

 
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 Monitoring Visit Log 
 Instructions for Use (IFU) 
 Patient Manual 
27.5 
RETENTION OF RECORDS 
The investigator is responsible for retaining the necessary records in accordance with 
local country requirements.  This includes a copy of the protocol, the device labeling, 
case report forms, medical records, original test result reports, all study-related 
correspondence, a record of written informed consent, and any other documents 
pertaining to the conduct of this study.   
 
The investigator must not dispose of any records relevant to this study without either (1) 
written permission from St. Jude Medical or (2) providing an opportunity for St. Jude 
Medical to collect such records.  The investigator shall take responsibility for maintaining 
adequate and accurate electronic or hard copy source documents of all observations 
and data generated during this study.  Such documentation is patients to inspection by 
St. Jude Medical and regulatory bodies. 
27.6 
LABORATORY ACCREDITATION AND NORMAL VALUES 
Only standard of care laboratory assessments will be collected during the study.  
Laboratories used should be accredited and the documentation provided to St. Jude 
Medical.  Throughout the study, the Investigator should provide St. Jude Medical 
documentation of all renewals of accreditation.   
28 
INSURANCE 
St. Jude Medical will obtain insurance to cover potential injury to patients in accordance 
with national requirements. 
29 
QUALITY CONTROL 
29.1 
INVESTIGATOR & SITE SELECTION 
Prior to the initiation of the CE Mark study, investigators and sites were selected based 
on their qualifications and experience (qualified by education and training) to ensure 
patient safety and adherence to the protocol. 
 
The Sponsor will maintain an updated list of principal investigators, investigation sites 
and/or institutions separately from the protocol.  The list will be included in clinical 
investigation reports as required by EN ISO 14155:2011. 
29.2 
HOSPITAL STAFF TRAINING 
Only trained personnel will perform study-related procedures.  All clinical personnel 
(principal investigators, co-investigators, study coordinators) must be thoroughly familiar 
with the function, care and maintenance of the HeartMate 3 LVAS.  These individuals 
underwent  training by St. Jude Medical or designee prior to the CE Mark study initiation, 
and documentation of that training is maintained.  The St. Jude Medical HeartMate 3 
LVAS Instructions for Use will be provided to assist the healthcare team on the proper 
care and operation of the device. 

 
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29.3 
MONITORING 
St. Jude Medical is responsible for monitoring the study.  St. Jude Medical or its 
designee will perform study monitoring remotely to ensure study progress and that the 
data is submitted in a timely manner.  Ongoing communication with investigators and 
study staff will be performed through written correspondence and telephone 
conversations.   
 
Details related to site monitoring will be documented in the Sponsor’s study-specific 
monitoring plan. 
 
The Investigator or designee upon request must provide to the sponsor the necessary 
study records for a thorough review of the study’s progress.  These records include, but 
are not limited to, case report forms and original source documents and records such as 
hospital and clinic charts, consent forms, and operative reports.  
29.3.1 
Study Close-out Activities  
The following study close out activities will be performed prior to completion of 
the study:  
 Ensure that all required eCRFs have been completed/submitted 
 Remind the investigator of the obligation to retain the records in accordance 
with local country requirements, and prepare a final report for the sponsor 
and Ethics Committee. 
29.4 
INVESTIGATOR AND/OR STUDY SITE TERMINATION/SUSPENSION 
If a serious compliance problem or deviation from the protocol is noted, St. Jude Medical 
will recommend corrective action 
 
St. Jude Medical may consider terminating or suspending an investigator and/or study 
site in the following cases: 
 Confirmed serious or repeated deviations and general non-compliance to the protocol 
 Unacceptable critical changes in personnel, administrative, or scientific standards 
 Unacceptable risk to patient safety is confirmed 
In such cases, St. Jude Medical will notify the appropriate regulatory authority, and/or 
other participating centers as required by local and national regulations. 
29.5 
EARLY STUDY TERMINATION 
St. Jude Medical reserves the right to discontinue the study.  St. Jude Medical intends to 
exercise this right only for valid scientific or administrative reasons.  After such a 
decision, all collected data must be entered into EDC. 
30 
EMERGENCY CONTACTS 
Sponsor Contact:  
Laura Damme, BSN, MPH 
Director Clinical Studies, EMEA 
St. Jude Medical  
Burnett House  
Ermine Business Park 

 
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Huntingdon, PE29 6UA, UK 
Office phone:  +44-1480-455200 
 
All participating centers will be provided with country specific (Sponsor) emergency 
contact information for device related emergencies and/or safety reporting. 
31 
PUBLICATION POLICY 
All publications will be reviewed by the study investigators and the Sponsor, and in 
accordance with the center specific Clinical Study Agreement (CSA). 
32 
HEARTMATE 3 CE MARK LONG TERM FOLLOW-UP STUDY VISIT SCHEDULE 
 
 
 
 
Enrollment Month 36-60 
(+/- 2 month) 
As occurs 
Inclusion/ Exclusion 
X 
 
 
Enrollment 
X 
 
 
EQ-5D-5L 
 
X 
 
Modified Rankin Score1 
 
X 
X 
NYHA Classification2 
 
X 
 
Laboratory Assessments3 
 
X 
 
Six Minute Walk Test 
 
X 
 
Pump Parameters4 
 
X 
 
Current Patient Status 
 
X 
 
Patient Outcome 
 
 
X 
Rehospitalizations 
 
X 
X 
Driveline Management 
 
X 
X 
Pump Log Files5 
 
 
X 
Adverse Events  
 
X 
X 
Device Malfunctions  
 
X 
X 
Reoperations/Operative Procedures 
 
 
X 
Pump Replacements/ Exchanges  
 
 
X 
Autopsy6 
 
 
X 
1 Required only if a neurological event occurred. 
2 Must be performed by an independent assessor. 
3 Standard of Care laboratory assessments to be recorded 
4 Pump Parameters include: Pump Flow, Pump Speed, Pulsatility Index and 
Pump Power  
5 Pump Log Files include: Pump Period Log, Pump Event Log, Controller Period 
Log and Controller Event Log. These should be provided in cases of 
suspected device malfunction 
6Required only if device related death occurred 
 

 
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33 
REFERENCES 
1. Miller LW, Pagani FD, Russell SD, et al. Use of a continuous-flow device in patients 
awaiting heart transplantation. N Engl J Med 2007; 357: 885-896 
 
2. Slaughter, MS, Rogers JG, Milano CA et al.  Advanced Heart Failure Treated with 
Continuous-Flow Left Ventricular Assist Device N Engl J Med 2009; 361: 2241-2251 
 
3. Starling RC, Naka Y, Boyle AJ et al. Results of the Post U.S. Food and Drug 
Administration-Approval Study with a Continuous Flow Left Ventricular Assist Device 
as a Bridge to Heart Transplantation, J Am Coll Cardiol 2011; 57:1890-1898. 
 
4. Strueber, M. et al. Multicenter Evaluation of an Intrapericardial Left Ventricular Assist 
System .J Am Coll Cardiol. 2011; 57:1375-1382. 
 
5. Active Implantable Medical Device Directive (AIMDD) 90/385/EEC. (June 20, 1990) 
 
6. EN ISO 14155: 2011 - Clinical investigation of medical devices for human subjects – 
Part 1: General requirements   
 
7. FDA. United States Code of Federal Regulations, Electronic Records: Electronic 
Signatures; Final Rule. Source: 21 CFR Part 11 (April 1, 2003). 
 
8. GHT/SG5/N4: 2009 - Post Market Clinical Follow up Studies 
 
9. Guidelines on Clinical Investigation: a Guide for Manufacturers and Notified Bodies, 
MEDDEV 2.7/4 
 
10. Med Dev 2.12-2:2012 - Post Market Clinical Follow up Studies 
 
11. World Medical Association Declaration of Helsinki: Ethical Principles for Medical 
Research Involving Human Subject. 2013 
 
12. Netuka I, Sood P, Pya Y, Zimpfer D, Krabatsch T, Garbade J, Rao V, Morshuis M, 
Marasco S, Beyersdorf F, Damme L, Schmitto JD. Fully Magnetically Levitated Left 
Ventricular Assist System for Treating Advanced HF: A Multicenter Study.  J Am Coll 
Cardiol. 2015 Dec 15;66(23):2579-89.  
 

 
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APPENDIX 1: ANTICIPATED ADVERSE EVENT DEFINITIONS 
(INTERMACS DEFINITIONS) 
 

 
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Major Bleeding 
An episode of SUSPECTED INTERNAL OR EXTERNAL BLEEDING that results in one or more 
of the following: 
a. Death, 
b. Reoperation, 
c. Hospitalization, 
d. Transfusion of red blood cells as follows: 
 If transfusion is selected, then apply the following rules:  
During first 7 days Post-implant 
 
Adults (≥ 50 kg): ≥ 4U packed red blood cells (PRBC) within any 24 hour period 
during first 7 days post-implant. 
After 7 days Post-implant 
 
Any transfusion of packed red blood cells (PRBC) after 7 days following implant with 
the investigator recording the number of units given.  (Record number of units given 
per 24 hour period). 
Note:  Hemorrhagic stroke is considered a neurological event and not as a separate bleeding 
event. 
 
Cardiac Arrhythmias 
Any documented arrhythmia that results in clinical compromise (e.g., diminished VAD flow, 
oliguria, pre-syncope or syncope) that requires hospitalization or occurs during a hospital stay.  
Cardiac arrhythmias are classified as 1 of 2 types: 
1) Sustained ventricular arrhythmia requiring defibrillation or cardioversion. 
2) Sustained supraventricular arrhythmia requiring drug treatment or cardioversion. 
 
Pericardial Fluid Collection 
Accumulation of fluid or clot in the pericardial space that requires surgical intervention or 
percutaneous catheter drainage.  This event will be subdivided into those with clinical signs of 
tamponade (e.g. increased central venous pressure and decreased cardiac/VAD output) and 
those without signs of tamponade. 
 
Device Malfunctions 
Device malfunction denotes a failure of one or more of the components of the MCSD system 
which either directly causes or could potentially induce a state of inadequate circulatory support 
(low cardiac output state) or death.  A failure that was iatrogenic or recipient-induced will be 
classified as an Iatrogenic/Recipient-Induced Failure.  
 
Device failure should be classified according to which components fails as follows: 
1) Pump failure (blood contacting components of pump and any motor or other pump actuating 
mechanism that is housed with the blood contacting components).  In the special situation of 
pump thrombosis, thrombus is documented to be present within the device or its conduits 
that result in or could potentially induce circulatory failure. 
2) Non-pump failure (e.g., external pneumatic drive unit, electric power supply unit, batteries, 
controller, interconnect cable,) 
 
 

 
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Hemolysis 
A plasma-free hemoglobin value that is greater than 40 mg/dl, in association with clinical signs 
associated with hemolysis (e.g., anemia, low hematocrit, hyperbilirubinemia) occurring after the 
first 72 hours post-implant.  Hemolysis related to documented non-device-related causes (e.g. 
transfusion or drug) is excluded from this definition. 
 
Hepatic Dysfunction 
An increase in any two of the following hepatic laboratory values (total bilirubin, aspartate 
aminotransferase/AST and alanine aminotransferease/ALT) to a level greater than three times 
the upper limit of normal for the hospital, beyond 14 days post-implant (or if hepatic dysfunction 
is the primary cause of death).   
 
Hypertension 
New onset blood pressure elevation greater than or equal to 140 mm Hg systolic or 90 mm Hg 
diastolic (pulsatile pump) or 110 mm Hg mean pressure (rotary pump).    
 
Major Infection 
A clinical infection accompanied by pain, fever, drainage and/or leukocytosis that is treated by 
anti-microbial agents (non-prophylactic).  A positive culture from the infected site or organ 
should be present unless strong clinical evidence indicates the need for treatment despite 
negative cultures.  The general categories of infection are listed below: 
Localized Non-Device Infection 
Infection localized to any organ system or region (e.g. mediastinitis) without evidence of 
systemic involvement (see sepsis definition), ascertained by standard clinical methods and 
either associated with evidence of bacterial, viral, fungal or protozoal infection, and/or requiring 
empirical treatment.  
Percutaneous Site and/or Pocket Infection 
A positive culture from the skin and/or tissue surrounding the drive line or from the tissue 
surrounding the external housing of a pump implanted within the body, coupled with the need to 
treat with antimicrobial therapy, when there is clinical evidence of infection such as pain, fever, 
drainage, or leukocytosis. 
Internal Pump Component, Inflow or Outflow Tract Infection 
Infection of blood-contacting surfaces of the LVAD documented by positive site culture.   
Sepsis 
Evidence of systemic involvement by infection, manifested by positive blood cultures and/or 
hypotension.

 
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Myocardial Infarction 
Two categories of myocardial infarction will be identified: 
 
Peri-Operative Myocardial Infarction 
The clinical suspicion of myocardial infarction together with CK-MB or Troponin > 10 times the 
local hospital upper limits of normal, found within 7 days following VAD implant together with 
ECG findings consistent with acute myocardial infarction.  (This definition uses the higher 
suggested limit for serum markers due to apical coring at the time of VAD placement, and does 
not use wall motion changes because the apical sewing ring inherently creates new wall motion 
abnormalities.)  
 
Non-Perioperative Myocardial Infarction 
The presence at > 7 days post-implant of two of the following three criteria:   
 
a) Chest pain which is characteristic of myocardial ischemia,  
b) ECG with a pattern or changes consistent with a myocardial infarction, and  
c) Troponin or CK (measured by standard clinical pathology/laboratory medicine methods) 
greater than the normal range for the local hospital with positive MB fraction (≥ 3% total CK).  
This should be accompanied by a new regional LV or RV wall motion abnormality on a 
myocardial imaging study. 
 
Neurologic Dysfunction 
Any new, temporary or permanent, focal or global neurological deficit ascertained by a standard 
neurological examination (administered by a neurologist or other qualified physician and 
documented with appropriate diagnostic tests and consultation note).  The examining physician 
will distinguish between a transient ischemic attack (TIA), which is fully reversible within 24 
hours (and without evidence of infarction), and a stroke, which lasts longer than 24 hours (or 
less than 24 hours if there is evidence of infarction).  Each neurological event must be 
subcategorized as:  
 
1) Transient Ischemic Attack (acute event that resolves completely within 24 hours with no 
evidence of infarction)  
2) Ischemic or Hemorrhagic Cerebral Accident/CVA (event that persists beyond 24 hours or 
less than 24 hours associated with infarction on an imaging study.  
 
 
Psychiatric Episode 
Disturbance in thinking, emotion or behavior that causes substantial impairment in functioning or 
marked subjective distress requiring intervention.  Intervention is the addition of new psychiatric 
medication, hospitalization, or referral to a mental health professional for treatment.  Suicide is 
included in this definition. 
 
Renal Dysfunction 
Two categories of renal dysfunction will be identified: 

 
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Acute Renal Dysfunction 
Abnormal kidney function requiring dialysis (including hemofiltration) in patients who did not 
require this procedure prior to implant, or a rise in serum creatinine of greater than 3 times 
baseline or greater than 5 mg/dL sustained for over 48 hours. 
 
Chronic Renal Dysfunction 
An increase in serum creatinine of 2 mg/dl or greater above baseline, or requirement for 
hemodialysis sustained for at least 90 days. 
 
Respiratory Failure 
Impairment of respiratory function requiring reintubation, tracheostomy or  the inability to 
discontinue ventilatory support within six days (144 hours) post-VAD implant.  This excludes 
intubation for reoperation or temporary intubation for diagnostic or therapeutic procedures. 
 
Right Heart Failure 
Symptoms and signs of persistent right ventricular dysfunction [central venous pressure (CVP) 
> 18 mmHg with a cardiac index <2.3 L/min/m2 in the absence of elevated left atrial/pulmonary 
capillary wedge pressure (greater than 18 mmHg), tamponade, ventricular arrhythmias or 
pneumothorax] requiring RVAD implantation; or requiring inhaled nitric oxide or inotropic 
therapy for a duration of more than 1 week at any time after LVAD implantation. 
 
Arterial Non-CNS Thromboembolism 
An acute systemic arterial perfusion deficit in any non-cerebrovascular organ system due to 
thromboembolism confirmed by one or more of the following:  
 
1) Standard clinical and laboratory testing 
2) Operative findings 
3) Autopsy findings 
 
This definition excludes neurological events. 
 
Venous Thromboembolism Event 
Evidence of venous thromboembolic event (e.g. deep vein thrombosis, pulmonary embolism) by 
standard clinical and laboratory testing.  
 
Wound Dehiscence 
Disruption of the exposed surfaces of a surgical incision, excluding infectious etiology, and 
requiring surgical repair. 
 
Other 
An event that causes clinically relevant changes in the patient’s health (e.g. cancer). 
 
 

 
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APPENDIX 2: NYHA CLASSIFICATION 
 

 
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Classification 
Definition 
I 
Cardiac disease without resulting limitations of physical activity. Ordinary 
physical activity does not cause undue fatigue, palpitations, dyspnea or 
anginal pain. 
II 
Cardiac disease resulting in slight limitation of physical activity. Patients 
are comfortable at rest. Ordinary physical activity results in fatigue, 
palpitation, dyspnea or anginal pain. 
IIIA 
Cardiac disease resulting in marked limitations of physical activity. 
Patients are comfortable at rest. Less than ordinary physical activity 
causes fatigue, palpitation, dyspnea, or anginal pain. 
IIIB 
Cardiac disease resulting in marked limitations of physical activity. 
Patients are comfortable at rest. Mild physical activity causes fatigue, 
palpitation, dyspnea, or anginal pain. 
IV 
Cardiac disease resulting in inability to carry on any physical activity 
without discomfort. Symptoms of cardiac insufficiency or of the anginal 
syndrome may be present even at rest. If any physical activity is 
undertaken, discomfort is increased. 

 
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Clinical Investigation Plan 
 
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APPENDIX 3: 6MWT PROTOCOL 
 
 
 

 
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Clinical Investigation Plan 
 
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SIX-MINUTE HALLWAY WALK TEST INSTRUCTIONS  
 
Purpose 
The purpose of the 6-Minute Hallway Walk test (6MWT) is to walk as far as possible for 6-
minutes, without running or jogging, as a way of measuring functional status. 
 
Preparing for the test 
1. Establish a 30-meter walking course in an enclosed corridor, preferably free of distractions 
and close to a wall so that if needed, the patient may rest against it during the test (note: a 
treadmill is not an acceptable alternate method for this study).   
2. Mark the course at 3-meter intervals using a method unnoticeable to the patient.   
3. Place noticeable markers at either end of the 30-meter course to indicate the turnaround 
points.  
4. The distance covered during the preceding walk test will not be revealed to the patient 
during the study.  
5. A warm up prior to the test should not be performed. 
 
Explaining the test procedure to the patient 
1. Clearly explain to the patient what is required of him/her using the following instructions 
verbatim: 
THE PURPOSE OF THIS TEST IS TO WALK AS FAR AS POSSIBLE FOR SIX-MINUTES.  
YOU WILL START FROM THIS POINT AND FOLLOW THE HALLWAY TO THE MARKER 
AT THE END, THEN TURN AROUND AND WALK BACK.  WHEN YOU ARRIVE BACK AT 
THE STARTING POINT, YOU WILL GO BACK AND FORTH AGAIN.  YOU WILL GO BACK 
AND FORTH AS MANY TIMES AS YOU CAN IN THE SIX-MINUTE PERIOD.  IF YOU 
NEED TO, YOU ARE PERMITTED TO SLOW DOWN, TO STOP, AND TO REST AS 
NECESSARY.  YOU MAY LEAN AGAINST THE WALL WHILE RESTING, BUT RESUME 
WALKING AS SOON AS YOU ARE ABLE.  HOWEVER, THE MOST IMPORTANT THING 
ABOUT THE TEST IS THAT YOU COVER AS MUCH GROUND AS YOU POSSIBLY CAN 
DURING THE SIX MINUTES.  I WILL KEEP TRACK OF THE NUMBER OF LAPS YOU 
COMPLETE AND I WILL LET YOU KNOW WHEN THE SIX MINUTES ARE UP.  WHEN I 
SAY STOP, PLEASE STAND RIGHT WHERE YOU ARE. 
DO YOU HAVE ANY QUESTIONS ABOUT THE TEST? 
PLEASE EXPLAIN TO ME WHAT YOU ARE GOING TO DO. 
 
2. The patient will re-state the instructions.  If the patient does not seem to understand, repeat 
the entire instructions. 
 
Conducting the test 
1. Position the patient at the starting line.   
2. Repeat the sentence: 
THE MOST IMPORTANT THING ABOUT THE TEST IS THAT YOU COVER AS MUCH 
GROUND AS YOU POSSIBLY CAN DURING THE SIX MINUTES. 
ARE YOU READY? 
START NOW, OR WHENEVER YOU ARE READY.

 
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3. Start the timer as soon as the patient takes the first step.   
4. During the test, the walking pace of the patient should not be influenced.  The test 
supervisor must walk behind the patient – do not walk with, rush up behind, or rush past 
the patient. 
5. Each time the patient returns to the starting line, record the lap. 
6. While walking, encourage the patient at one minute intervals with the following phrases: 
 
1 minute: 
YOU ARE DOING WELL.  YOU HAVE 5 MINUTES TO GO.  
2 minutes: 
KEEP UP THE GOOD WORK.  YOU HAVE 4 MINUTES TO GO. 
3 minutes: 
YOU ARE DOING WELL.  YOU ARE HALFWAY DONE. 
4 minutes: 
KEEP UP THE GOOD WORK.  YOU HAVE ONLY 2 MINUTES LEFT. 
5 minutes: 
YOU ARE DOING WELL.  YOU HAVE ONLY ONE MINUTE TO GO. 
 
7. The patient should be spoken to only during the 1-minute encouragements; no response 
should be made to the patient’s questions about the time and distance elapsed.   
a. If the patient is not concentrating on the walking, the patient can be reminded at a 1-
minute mark: 
THIS IS A WALKING TEST, TALKING WILL UTILIZE YOUR ENERGY RESERVE 
AND INTERFERE WITH YOUR PERFORMANCE. 
 
9. When only 15 seconds remain, state: 
IN A MOMENT I AM GOING TO TELL YOU TO STOP.  WHEN I DO, STOP RIGHT 
WHERE YOU ARE AND I WILL COME TO YOU.   
 
9. When the timer reads 6-minutes, instruct the patient to STOP and walk over to him/her. 
Consider bringing a chair if the patient appears exhausted.  Mark the spot where the 
patient stopped.   
  
If the patient wishes to stop walking during the test 
If the patient is slowing down and expresses that he/she wants to pause, keep the timer 
running and state: 
REMEMBER, IF YOU NEED TO, YOU MAY LEAN AGAINST THE WALL UNTIL YOU 
CAN CONTINUE WALKING AGAIN. 
 
If the patient wishes to stop before the 6-minutes are complete and refuses to continue 
(or you decide that he/she should not continue), provide a chair for the patient to sit on 
and discontinue the test.  Record the distance completed, the time the test was stopped 
and the reason for pre-maturely stopping.   
 
Immediately after the test 
1. Total the number of completed laps and add the additional distance covered in the 
final partial lap.  Record the distance walked to the nearest meter. 
2. Observe the patient sitting in a chair for at least 10 minutes after the test is 
completed.  

 
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CE Mark Study Long Term Follow-up  
Clinical Investigation Plan 
 
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APPENDIX 4: MODIFIED RANKIN SCORE 
 

 
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Clinical Investigation Plan 
 
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Score 
Definition1  
0 
No observed neurological symptoms 
1 
No significant neurological disability despite symptoms; able to 
carry out all usual duties and activities 
2 
Slight neurological disability; unable to carry out all previous 
activities, but able to look after own affairs without assistance 
3 
Moderate neurological disability; requiring some help, but able to 
walk without assistance 
4 
Moderate severe neurological disability; unable to walk without 
assistance and unable to attend to own bodily needs without 
assistance 
5 
Severe neurological disability; bedridden, incontinent and 
requiring constant nursing care and attention as a result of a 
neurological deficit 
6 
Dead 
 
                                               
 
 
 
 
 
1 van Swieten J, Koudstaal P, Visser M, Schouten H, et al (1988). “Interobserver agreement for the 
assessment of handicap in stroke Subject”. Stroke 19 (5): 604-607