C-Pulse System eurOPean mulTicenter Study, Implantable cOuNterpulsation System in patIents With Moderate to Severe Heart Failure
Conditions: Heart Failure
Sponsor: Nuwellis, Inc.

 
 
 
 
C-Pulse® System 
European Multicenter Study 
 
 
CLINICAL PROTOCOL 
(Clinical Investigation Plan) 
Clinical Investigation Number: 2012-01 
 
 
 
 
 
Protocol Change Status 
Protocol Revision # 
Effective Date 
PRO-04654 
Revision C 
13 Jan 2014 
 
 
 
Sponsor 
Sunshine Heart, Inc. 
12988 Valley View Road 
Eden Prairie, MN 55344 
USA 
 
 
 
CONFIDENTIAL AND PROPRIETARY DATA: This document and the information contained herein may not 
be reproduced, used or disclosed without written permission from Sunshine Heart, Inc. 

 
 
 
 
 
 
 
STATEMENT OF COMPLIANCE 
 
The C-Pulse®  System Study will be conducted in accordance with the Declaration of Helsinki 
and EN ISO 14155:2011 (Clinical investigation of medical devices for human subjects - Good 
Clinical Practices.) and any additional provisions outlined in the Study Agreement. In addition, 
the Study will comply with any applicable European or regional regulations. 
 
The clinical investigation shall not begin until the required approval/favorable opinion from the 
local Ethics Committee (EC) or regulatory authority has been obtained, as appropriate. 
 
 
 
SIGNATURES 
 
Site Principal Investigator 
 
I have read and understand the contents of the C-Pulse® System European Multicenter Study 
protocol. I agree to conduct this study according to the requirements of the study protocol and 
in accordance with Good Clinical Practice and applicable regulations. I agree to supervise all 
Co-investigators at my site as well as the use of all devices and study materials at my 
institution and to ensure appropriate informed consent is obtained from all subjects prior to 
inclusion in this study. I agree to hold all information related to the study in confidence and not 
to disclose it to any third parties for a period of five years from the date of this agreement, or 
until this information becomes a matter of public knowledge or until a formal agreement for 
that purpose is entered into by the parties. 
 
 
Name 
Signature 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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SUNSHINE HEART C-PULSE SYSTEM 
European Multicenter Study Protocol 
 
 
 
STUDY SYNOPSIS 
 
 
Title 
C-Pulse® System European Multicenter Study 
 
Study design 
Multi-center, prospective, open label study. 
 
Study 
objective 
The study is designed to observe the clinical outcomes of heart failure 
patients treated with C-Pulse® System in the usual manner and according to 
the approved indications and contraindications. 
 
Enrollment 
Up to 50 patients with moderate to severe heart failure who receive the C- 
Pulse® System will be followed up for 5 years to collect performance and 
safety data. 
 
Locations 
A maximum of 15 European sites will participate. Study data from additional 
geographies may be included. 
 
Estimated 
Time Course 
First Patient In: May 2013 
Last Patient In:  Dec 2014 
Last Patient Out:    Dec 2019 
Introduction 
Pharmacological and device-based therapies for heart failure continue to be 
refined though still pose challenges. Now Sunshine Heart introduces the C- 
Pulse® System, designed to provide the well-known clinical benefits of 
counter-pulsation heart pumping support while allowing the patient to move 
and go back home, having a quite normal day-life style. 
 
Technology Sunshine Heart’s C-Pulse® System is a new approach for patients with 
moderate to severe heart failure that can be used in combination with other 
heart failure therapies. The device is designed to assist the heart’s function, 
not replace it and may be implanted using a minimally invasive approach. 
The C–Pulse® system is designed to provide an effective, low risk and low 
cost wearable mechanical heart assist device for use in patients in NYHA 
Class III–IV ambulatory. It is intended for use in hospital and at home. 
 
Implantable C-Pulse Cuff. 
External wearable components. 
 
 
 
 
 
 
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How does C- 
Pulse® 
System 
work? 
The C-Pulse® implanted cuff is wrapped around the ascending aorta and is 
pneumatically driven, via a percutaneous line, by an external driver. Inflation 
and deflation are timed from the ECG, sensed via an epicardial lead that is 
connected to the percutaneous interface lead. 
The C-Pulse® System is simple to implant and accommodates aortic anatomic 
variability. C-Pulse® System allows patient mobility and can be turned off or 
used intermittently if recovery occurs or for day-life exigencies. In addition, 
the C-Pulse cuff sits outside the bloodstream, therefore eliminating the need 
for anti-clotting medications. 
 
Regulatory 
status 
Study 
objective 
CE marked 
 
Evaluation of the post-market clinical performance and safety of the C-Pulse® 
System for the treatment of Heart Failure in the population of patients who 
meet the approved clinical conditions provided in the indications and 
contraindications. 
 
Patient 
population 
A patient population of up to 50 patients with moderate to severe heart 
failure refractory to optimal medical therapy, who are implanted with the C- 
Pulse System as clinically appropriate, will be enrolled into the Study. 
 
Inclusion 
Criteria 
 
 
 
 
 
 
 
 
 
 
Exclusion 
Criteria 
According to the CE mark authorization, patients with the following conditions 
can be included: 
• 
Patient is 18 years or older 
• 
Patients with moderate to severe ambulatory heart failure [American 
College of Cardiology/American Heart Association (ACC/AHA) Stage C; 
NYHA Class III/IV ambulatory], who are refractory to optimal medical 
therapy. 
• 
Patients who are non-responders to CRT pacemaker therapy 
• 
Patient has signed and dated the investigation informed consent form. 
According  to  the 
CE  mark  authorization,  patients  with  the  following 
conditions (contraindications) have to be excluded: 
• 
Evidence of significant ascending aortic calcification on postero-anterior 
chest X-ray or CT scan 
• 
Moderate or severe atherosclerotic aortic disease 
• 
Ascending aorto-coronary artery bypass grafts 
• 
Any history of aortic dissection 
• 
Connective tissue disorder such as Marfans disease 
• 
Previous aortic root replacement 
• 
Aorta not conforming to specified dimensional constraints 
• 
Patient has severe mitral valve incompetence, grade 4+ 
• 
Patient has moderate to severe aortic valve incompetence, grade 2 - 4+ 
• 
Patient has systolic blood pressure less than 90 or greater than 140mmHg 
• 
Presence of active systemic infection 
• 
Presence of bleeding or coagulation disorder (relative) 
 
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SUNSHINE HEART C-PULSE SYSTEM 
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Screening 
process 
Patients diagnosed with moderate to severe heart failure and who are 
treated at the participating centers are eligible for screening evaluation. 
The investigator(s) will obtain informed consent for study participation 
from each patient prior to implementation of screening procedures. 
Patients eligible for device implantation must meet all the inclusion and not 
meet the exclusion criteria (indications and contraindications based on 
device CE mark authorization and Instructions for Use). In addition, a 
screening process will be carried out with the objective of selecting ideal 
candidates for the C-Pulse System. Patients’ suitability will be evaluated in 
agreement between the Investigator and Sponsor, based on the 
assessment of heart failure severity, concomitant cardiac disease, need for 
concomitant cardiac surgery, co-morbidity, life expectancy < 2 years, 
pregnancy and other conditions potentially interfering with the ability to 
manage the C-Pulse therapy. 
 
 
 
 
 
 
Implantation 
As the C-pulse implantation procedure is clinically indicated patients may be 
enrolled prospectively with informed consent obtained prior to the procedure 
or retrospectively with informed consent for the collection of the patient’s 
data obtained after the procedure as appropriate for an observational study. 
procedure 
The C-Pulse Cuff and the Sense Lead are implanted through a chest 
incision and without the use of cardiopulmonary bypass. Only a small 
pericardiotomy is required, limiting the potential for bleeding and for post- 
operative adhesions. The ascending aorta is isolated and its circumference 
measured. The circumferential length is noted on the pre-marked wrap. 
The Cuff is passed around the aorta such that the inflating aspect of the 
Cuff is positioned on the outside curvature. The Cuff is then checked to fit 
the aorta conformably and that the circumferential marks are appropriate 
prior to securing of the wrap with sutures. Pre-loaded interrupted 
‘mattress’ sutures are placed through the tail of the Cuff at the appropriate 
circumferential marks with the Cuff ‘open’, and such that the inflation 
chamber of the Cuff is always visualized. The sutures are then tied down 
and the wrap checked to be conformal to the aorta. The excess wrap fabric 
is trimmed off. A bipolar ECG Sense Lead is placed on the heart, most 
preferably the left ventricular free wall. The gas line of the Cuff is trimmed 
to length and it and the ECG Sense Lead are attached to the intra- 
corporeal “Y- connector” end of the Percutaneous Lead. The Percutaneous 
Lead is then tunneled beneath the rectus sheath, the extra-corporeal end 
of the Lead having a Patient Connector permanently attached. 
Alternatively, the lines may be tunneled to an intermediary incision for 
connection, particularly if a less invasive surgical technique (sternal- 
sparing) is used. The Percutaneous Lead is designed to be exchanged or 
removed if required, the latter eliminating the exit site. If removal occurs, 
the Cuff and Sense Lead can remain within the thorax with the gas line of 
the Cuff and the connector of the Sense Lead capped off and accessible 
with minimal surgery in the subcutaneous tissue of the abdominal area. If 
the Cuff is infected, it should be removed. 
 
 
 
 
 
 
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Performance 
Endpoints 
The following performance endpoints will be assessed during follow-up visits: 
• 
Improvement in INTERMACS™ and/or NYHA functional class 
• 
Freedom from worsening heart failure resulting in hospitalization, LVAD 
implantation, or death 
• 
Explant for recovery of ventricular function or cardiac transplantation 
Secondary endpoints assessed at 6 and 12 months post implant include: 
• 
Improvement in LVEF 
• 
Improvement in Quality of Life scores 
• 
Improvement in 6MWT 
 
Safety 
Endpoints 
The following primary safety endpoints will be assessed throughout each 
subject’s participation in the investigation: 
• 
All cause and device-related mortality 
• 
Aortic disruption 
• 
Exit Site infection 
• 
Internal PIL/Cuff infection 
• 
Thromboembolism 
• 
Device malfunction 
• 
All protocol-defined adverse events 
 
 
Data 
collection 
The study will aim to collect patient data while supported with C-Pulse 
therapy (i.e. the subjects will be censored from analysis if the device is 
permanently “off” unless due to signs of recovery). Data will be captured at 
the following time points: Baseline, procedure, discharge assessment, clinical 
follow-up at 6 weeks, 6 months, 12 months, 18 months, 2 years and yearly 
thereafter. Data from any other additional time points may be collected and 
analyzed if available. 
Data from baseline and up to 5 years of follow-up will be captured in an 
electronic database. Hemodynamic performance and functional testing will be 
determined according to procedures based on standard center practices. Any 
protocol-defined adverse events, including adverse device effects and 
outcomes will be reported by the Investigator. 
 
 
Sponsor 
 
 
 
Sponsor 
Contacts 
Sunshine Heart Inc. 
12988 Valley View Rd 
Eden Prairie MN 55344 
USA 
Naomi Tatarek, Director of Clinical Studies 
Tel +1 952 388 6047 
Email naomi.tatarek@sunshineheart.com 
Peter Goettel, MD, European Medical Director 
Tel +49 176 63696484 
email: peter.goettel@sunshineheart.com 
 
 
 
 
 
 
 
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ABBREVIATIONS 
 
ACC 
American College of Cardiology 
AE 
Adverse Event 
AHA 
American Heart Association 
CABG 
Coronary artery bypass grafting 
CCS 
Canadian Cardiovascular Society 
CEC 
Clinical Events Committee 
CHF 
Congestive Heart Failure 
CI 
Cardiac Index 
CIP 
Clinical Investigation Plan 
CO 
Cardiac output 
CPB 
Cardiopulmonary Bypass 
CRF 
Case Report Form 
CRT 
Cardiac Resynchronization Therapy 
CTS 
Cardiothoracic Surgeon 
DMC 
Data Monitoring Committee 
EAB 
Extra Aortic Balloon 
EC 
Ethics Committee 
EF 
Ejection fraction 
ECG 
Electrocardiogram 
HF 
Heart Failure 
HFC 
Heart Failure Cardiologist 
ICD 
Implantable Cardiac Defibrillator 
IFU 
Instructions for Use 
LV 
Left Ventricle 
LVAD 
Left Ventricular Assist Device 
LVEF 
Left Ventricular Ejection Fraction 
LVMI 
Left Ventricular Mass Index 
LVOT 
Left Ventricular Outflow Tract 
MDD 
Medical Devices Directive 93/42/EEC 
MRI 
Magnetic Resonance Imaging 
NLM 
National Library of Medicine 
Non-CNS 
Non-Central Nervous System 
PICC 
Peripherally Inserted Central Catheter 
PIL 
Percutaneous Interface Lead 
 
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NCBI 
National Center for Biotechnology 
NIH 
National Institute of Health 
NYHA 
New York Heart Association 
RV 
Right Ventricle 
SAE 
Serious Adverse Event 
VAD 
Ventricular Assist Device 
6MHW or 
6MWT 
Six Minute Hall Walk or Six Minute Walk Test 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table of Contents 
 
1. 
INTRODUCTION .................................................................................12 
1.1. 
Study Sponsor ............................................................................................... 12 
1.2. 
Heart Failure Prevalence ............................................................................... 12 
1.3. 
Morbidity and Mortality ................................................................................. 12 
1.4. 
Limitations of Existing Treatment ................................................................... 12 
1.5. 
C-PULSE SYSTEM Innovation ......................................................................... 13 
2. 
IDENTIFICATION OF THE DEVICE ..................................................... 14 
2.1. 
C-Pulse System Description ........................................................................... 14 
2.2. 
Intended Purpose and Indications .................................................................. 15 
2.3. 
Mechanism of Action .................................................................................... 15 
2.3.1. 
C-Pulse Cuff Design and Operation ............................................................... 15 
2.3.2. 
C-Pulse Cuff Gas-line .................................................................................. 16 
2.3.3. 
C-Pulse Cuff Wrap Materials ........................................................................ 16 
2.3.4. 
C-Pulse Cuff Sizes and Volumes ................................................................... 16 
2.3.5. 
C-Pulse Cuff Safety Features ....................................................................... 16 
2.3.6. 
Intended Duration of Use ............................................................................ 17 
2.4. 
Components and Materials ............................................................................ 18 
3. 
PROCEDURES.....................................................................................19 
3.1. 
Pre-implant Considerations ........................................................................... 19 
3.2. 
Implant Procedure ....................................................................................... 19 
3.3. 
Postoperative Patient Care ............................................................................ 19 
4. 
C-PULSE SYSTEM STUDY RATIONALE ................................................ 20 
4.1. 
Study Classification ..................................................................................... 20 
4.2. 
C-Pulse Clinical Results ................................................................................. 20 
4.3. 
C-PULSE SYSTEM Benefits ............................................................................. 24 
4.4. 
C-PULSE SYSTEM Risks ................................................................................. 24 
4.5. 
Clinical Risk/Benefit Assessment .................................................................... 26 
5. 
STUDY DESIGN ..................................................................................28 
5.1. 
Overview .................................................................................................... 28 
5.2. 
Inclusion Criteria ......................................................................................... 28 
5.3. 
Exclusion Criteria ........................................................................................ 28 
5.4. 
Patient Recruitment ..................................................................................... 29 
5.5. 
Patient Screening and Suitability for C-Pulse Therapy ........................................ 29 
5.6. 
Schedule of Assessments .............................................................................. 31 
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6. 
STUDY DESIGN AND OBJECTIVES ..................................................... 33 
6.1. 
Study Objective .......................................................................................... 33 
6.2. 
Enrollment .................................................................................................. 33 
6.3. 
Performance Endpoints ................................................................................. 33 
6.4. 
Safety Endpoints ......................................................................................... 33 
6.5. 
Statistical Methodology ................................................................................. 34 
6.6. 
Sample Size Analysis .................................................................................... 34 
7. 
DATA COLLECTION AND MANAGEMENT ............................................. 36 
7.1. 
Data Management Activities .......................................................................... 36 
7.2. 
Information Collected in the Electronic Case Report Forms (e-CRFs) .................... 36 
7.3. 
Patients Lost to Follow-up ............................................................................. 36 
7.4. 
Source Documents ....................................................................................... 36 
7.5. 
Site Documentation ..................................................................................... 37 
7.6. 
Quality Assurance and Access ........................................................................ 38 
7.7. 
Monitoring Plan ........................................................................................... 38 
7.8. 
Data Retention ............................................................................................ 38 
7.9. 
Study Closeout ............................................................................................ 38 
7.10. 
Final Report ................................................................................................ 38 
8. 
PROCEDURE FOR ADVERSE EVENT MANAGEMENT ............................. 39 
8.1. 
Reporting Procedure .................................................................................... 39 
8.2. 
Definitions .................................................................................................. 39 
8.2.1. 
Adverse Event ........................................................................................... 39 
8.2.2. 
Adverse Device Effect ................................................................................. 39 
8.2.3. 
Serious Adverse Event ................................................................................ 39 
8.2.4. 
Adverse Event Definitions ........................................................................... 40 
8.2.5. 
Serious Adverse Device Effect (SADE) ........................................................... 44 
8.3. 
Deaths and Explants .................................................................................... 44 
8.3.1. 
Subject Deaths .......................................................................................... 44 
8.3.2. 
Device Explants ......................................................................................... 44 
9. 
STUDY CONDUCT, RESPONSIBILITIES AND CONFIDENTIALITY ........ 46 
9.1. 
Patient Authorization .................................................................................... 46 
9.2. 
Patient Confidentiality .................................................................................. 46 
9.3. 
Physician Confidentiality ............................................................................... 46 
9.4. 
Device Accountability ................................................................................... 46 
9.5. 
Protocol Changes/Amendments ..................................................................... 46 
9.6. 
Patient Termination or Withdrawal .................................................................. 46 
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10. 
PUBLICATION POLICY .......................................................................47 
11. 
REFERENCES ......................................................................................48 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1. INTRODUCTION 
 
 
 
1.1. . Study Sponsor 
 
 
The Sponsor of this study is Sunshine Heart Inc. 
 
Sponsor 
Sunshine Heart Inc. 
12988 Valley View Rd 
Eden Prairie MN 55344 
USA 
 
Contacts 
Naomi Tatarek, Director of Clinical Studies 
Tel +1 952 388 6047 
Email 
Naomi.Tatarek@sunshineheart.com 
Peter Goettel, MD, European Medical Director 
Tel +49 176 63696484 Email: peter.goettel@sunshineheart.com 
 
1.2. . Heart Failure Prevalence 
There are over 1.4M people in the USA in Class III and IV heart failure. Biventricular 
pacemakers are indicated in patients with a wide QRS – approximately 30% of this 
population. Approximately 2200 heart transplants are done per year. A similar number 
might receive an LVAD as either a bridge to transplant or as destination therapy. 
There remains a very large number of people that may benefit from an improvement in 
their clinical status from NYHA Class III/IV to Class I/II. 
 
1.3. . Morbidity  and Mortality 
 
As the severity of heart failure disease increases, there is greater certainty regarding imminent 
death, and less certainty is required regarding the performance of a device and patient 
outcome after implantation. However, generally, increasing disease severity also increases the 
risk of adverse outcomes that are attributable more to the patient’s co-morbidities than the 
device used. At lesser grades of disease severity, when death is not imminent, details 
regarding the expected function and quality of life with mechanical circulatory support become 
more critical. 
 
Patient preference for quality of life versus survival shows remarkable variation at every level 
of disease severity. From a practical standpoint, apart from those with high predicted in– 
hospital mortality, many patients exhibit a dynamic state that fluctuates over months, with 
exacerbations related to dietary indiscretion, seasonal viral infections, and other exogenous 
factors. Ambulatory heart failure patients on oral therapy are generally not as sick, but 
experience discomfort during any physical activity and may have discomfort while at rest. 
 
1.4. . Limitations of Existing Treatment 
Chronic HF is conventionally treated with drugs. However there are many circumstances 
where drug therapy is insufficient or where the heart has become refractory to drug 
therapy. Cardiac Resynchronization Therapy (CRT) is suitable for approximately 30% of 
moderate HF (New York Heart Association - NYHA Class III) patients, and has been shown 
to provide significant clinical improvement. However, as many as 30% of patients who have 
CRT implants do not have a satisfactory response (“non–responders”). Further, many 
patients initially have a good response but then develop more advanced symptoms. 
Heart transplantation is an effective therapy for end stage NYHA Class IV patients. However, 
the number of donor hearts falls short of meeting the needs of patients and many patients 
are excluded because of age (the upper limit for transplant being approximately 65 years) 
 
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Left Ventricular Assist Devices (LVADs) have been shown to offer the potential for the 
treatment of end stage NYHA Class IV HF patients. However, because of the blood– 
contacting nature, these devices have high associated risks such as bleeding, stroke, 
infection and device failure. Furthermore patients spend time in hospital due to these 
associated complications. 
There is growing evidence that the unloading actions of LVADs can facilitate significant 
recovery and reverse remodeling of the heart. However, LVADs tend to be implanted late in 
the clinical course of heart failure, due to the risk profile versus the expected benefits. 
Earlier implant may improve the chance of recovery of the heart. Therefore, there is a need 
for lower risk, lower cost devices that allow for long–term implant in less sick patients. 
Such a device could provide for partial unloading of the heart such that the patient can be 
weaned and for the device to not necessarily be removed. 
 
1.5. 
. 
C- PULSE SYSTEM Innovation 
 
Sunshine Heart’s C-Pulse® System is a new approach for patients with moderate to severe 
heart failure that can be used in combination with other heart failure therapies. The device is 
designed to assist the heart’s function, not replace it and may be implanted using a minimally 
invasive approach. The objective of the C–Pulse® system is to provide an effective, low risk 
and low cost mechanical heart assist device for use in patients in NYHA Class III–IV 
ambulatory. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2. IDENTIFICATION OF THE DEVICE 
 
 
2.1. 
. 
C- Pulse System Description 
 
The C-Pulse® System (C-Pulse or C-Pulse System) has been proposed as a non-blood 
contacting wearable heart assist device to perform long-term aortic counterpulsation in 
patients suffering moderate to severe heart failure. The device is designed: 
 
• 
to be simple to implant, 
• 
to accommodate aortic anatomic variability, 
• 
to be safe for the aorta and have a high cycle-life, 
• 
to provide measurable improvement in hemodynamic variables, 
• 
to allow mobility, 
• 
to be able to be turned off or used intermittently if left ventricular recovery occurs, and 
• 
to be able to be disconnected. 
 
Figure 1 below provides a graphic representation of the C-Pulse® System. The system 
provides cardiac assistance through an extra-aortic balloon Cuff and ECG sense lead connected 
by means of a Percutaneous Interface Lead (PIL) to an external pneumatic Driver. The PIL and 
external driveline are held securely externally with 2-3 simple adhesive clips for immobilization 
of the Driver lead and external part of the PIL at the exit site. The Driver is adjusted using a 
dedicated notebook computer (the Programmer) with specialized software. The Driver inflates 
and deflates the Cuff in counter-synchrony to the cardiac cycle. The C-Pulse® System has been 
designed to have simple, effective and safe implantable components (the Cuff and PIL) and an 
external wearable component (the Driver). The C-Pulse System sits outside the bloodstream, 
reducing the risk of stroke and blood clots and therefore eliminating the need for anti-clotting 
medications directly related to the C-Pulse System. 
 
 
 
Cuff 
 
 
 
 
Percutaneous 
Interface Lead 
(PIL) 
 
 
 
External Driver 
 
 
 
 
 
 
 
 
 
Figure 1. Sunshine Heart C-PULSE SYSTEM 
 
 
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2.2. . Intended  Purpose and Indications 
 
The C–Pulse® System is indicated for use in patients with moderate to severe heart failure 
[American College of Cardiology/American Heart Association (ACC/AHA) Stage C; NYHA Class 
III/IV ambulatory], who are refractory to optimal medical therapy. The C–Pulse® System is 
intended to relieve the symptoms of heart failure, improve quality of life and cardiac function. 
 
The C–Pulse® System is also indicated for use in patients who are non-responders to CRT 
pacemaker therapy. It is intended for use in hospital and at home. It is not intended as a 
replacement for heart function; it is not life sustaining or life–supporting therapy. It does not 
preclude the use of other heart failure therapies, such as valve surgery, heart transplantation 
or LVAD. 
 
2.3. . Mechanism  of Action 
 
 
2.3.1. 
1.      C-Pulse Cuff Design and Operation 
 
The C-Pulse® Cuff is designed to displace blood from the ascending aorta during diastole when 
inflated and to restore normal anatomic structure deflating before systole. The volume 
displacement of the extra-aortic cuff, by virtue of the short ascending aorta, is limited 
compared to the descending Intra-aortic Balloon (IAB) capacity, but the proximity of the C- 
Pulse to the aortic valve is expected to allow equivalent or better counterpulsation compared to 
methods of descending aortic counterpulsation. 
 
The balloon is intended to inflate and deflate in a manner that causes the least possible strain 
to both the balloon material and to the aorta while maximizing blood volume displacement 
within the ascending aorta. The balloon is inflated to a volume typically 15-20% less than its 
 
 
 
natural volume. Inflating the balloon further does not achieve significantly greater volume 
displacement but does lead to a higher intra-balloon pressure. Thus, the optimal balloon 
inflation point results in a small (approximately 5-10 mmHg) transmural pressure between the 
inflated cuff and the aorta whilst displacing close to optimal volume per beat. 
 
The balloon is designed to not occlude the aorta when fully inflated. A dipping process is 
utilized to manufacture the balloon from DSM Biomedical’s (DSM)  proprietary BioSpan® 
segmented polyurethane (an FDA master file material). The balloon is manufactured in its 
inflated shape and is stored and supplied in this stress free state. This material exhibits high 
strength, flexibility, and fatigue resistance together with biological compatibility and 
biostability. Furthermore, the material has a long history of use in permanent cardiovascular 
implants. 
 
The bushing provides a structural whilst flexible interface between the balloon and gas-line. It 
is shaped to correspond with the internal surface of the three sizes of balloon and the outer 
diameter of the gas-line.  The three components are permanently bonded using a solution 
bonding process.  The bonding solution is manufactured from urethanes and DMAC from a 
 
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registered manufacturer of biomaterials. The bushing is injection molded from DSM’s Bionate® 
polycarbonate-urethane, also FDA master file material. 
 
2.3.2. 
 C-Pulse Cuff Gas- 
line 
 
The cuff gas-line is connected to the Percutaneous Interface Lead (PIL) via a barbed fitting on 
the pneumatic arm of the PIL Y-junction. The Cuff is inflated using filtered air. 
 
The gas-line is a flexible tube which provides the pneumatic interface between the balloon and 
PIL. It is extruded from Bionate material and formed into a ‘Shepard’s hook’ shape adjacent to 
the bushing to promote routing through the thoracic cavity. The gas-line has a 4mm inner 
diameter and 6mm outer diameter and is provided with a length of velour fabric, known as 
‘flocking’, bonded with master file silicone RTV adhesive, to promote anchoring of the gas-line 
by tissue in-growth and mitigate infection transmission. The flocking material is implant-grade 
loosely knitted polyester velour with complete biocompatibility testing and an established 
implant history. The placement of the flocking allows for trimming of the gas-line in the event 
of a PIL replacement. 
 
2.3.3. 
 C-Pulse Cuff Wrap  Materials 
 
The wrap is contoured and comes in three sizes to correspond to the outer surface of the 
balloon as well as conform to the typical range of aorta curvatures and diameters. It converts 
balloon inflation into aortic depression and blood flow. The wrap material is implant-grade 
woven polyester with complete biocompatibility testing and an established implant history. 
The wrap material is cut on the bias and the edges of the wrap have strain-relief design 
features. The wrap is bonded to the balloon with the same silicone RTV adhesive used to 
attach the flocking. The wrap is sutured to itself to secure the device around the ascending 
aorta using pre-loaded sutures and pre-printed alignment markings. The excess wrap is 
trimmed before completion of surgery. 
 
2.3.4. 
 C-Pulse Cuff Sizes and Volumes 
 
The Cuff is pre-shaped to conform to the ascending aorta and comes in three sizes: small, 
medium and large. The external diameter of the ascending aorta (AA) determines the 
appropriate cuff size. Refer to Table 1 below for cuff sizing specifications. 
 
Table 1. Cuff Size and Aortic Dimension Relationship 
 
Cat # 
 
Cuff size 
AA external 
diameter (mm) 
AA circumference 
(mm) 
Max Inflation 
Volume 
(Note 1) 
(cc) 
93120 
Small (S) 
28—33 
91—106 
20 
94120 
Medium (M) 
33—38 
106—121 
25 
95120 
Large (L) 
37—42 
118—133 
26 
 
Note 1: Maximum inflation volume when used with C-Pulse® Driver Cat# 97200. 
The Cuff is packaged with a 60 cc syringe and an evacuation adapter consisting of a luer 
connector, a one-way valve and luer barb connector, which is used for manual deflation of the 
balloon prior to implantation to aid with correct placement of the Cuff on the aorta. 
 
2.3.5. 
C- 
Pulse Cuff Safety Features 
 
The balloon was designed to optimize volume displacement versus aortic and balloon wall 
strain. This was achieved by conducting finite element analyses on both deflection of the aortic 
wall, and on a proposed balloon mechanism of action. The inflation and deflation mechanism 
 
 
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employs a low strain rolling action to reduce or eliminate fatigue stresses resulting from long 
term use. 
 
The Balloon is designed with a shape such that maximum inflation will not occlude the aorta 
and avoids aortic inner wall surface contact. 
 
The Cuff is designed to be conformal to a defined range of aortic dimensions and to minimize 
pressure points during inflation, deflation, and non-operational states. This minimizes risk of 
cuff migration as well. 
 
The Cuff is sutured in place using an “open” technique that allows the balloon to be clearly 
visualized throughout suture placement. This technique minimizes the risk of needle puncture 
of the balloon. 
 
The wrap design allows some radial expansion of the aorta during systole; however 
containment of the balloon ensures the proper inward inflation profile for counter-pulsation 
displacement. 
 
The Gas-line is designed for high flow rates, thus ensuring rapid balloon inflation and deflation 
(if the gas-line is disconnected from the driver or if driver power is lost). Natural blood 
pathways are maintained if balloon inflation is lost (e.g. due to hole in balloon). 
 
The Gas-line is a small diameter and thick-walled to enhance kink resistance. The gas-line 
includes a velour polyester fabric portion (the flocking) to promote tissue in-growth. 
 
The Implant procedure minimizes risk to the patient by avoiding the need for cardiopulmonary 
bypass. 
 
2.3.6. 
  Intended Duration of Use 
 
The C-Pulse cuff and sense lead are implanted. The cuff has a minimum intended use period of 
5 years. It is intended these are replaceable if there is a failure. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2.4. 
Components and Materials  
 
The following components are available for the C-Pulse System: 
Table 2. C-Pulse System Components and Accessories 
Part/Cat 
Num. 
Name 
Description 
93120 
94120 
95120 
C-Pulse Cuff 
(Small, Medium, Large) 
Implanted extra-aortic balloon Cuff. Available in 3 sizes. 
Provided sterile. 
96500 
96510 
Percutaneous Interface 
Lead (PIL) 
Percutaneous catheter that interfaces between the implanted 
Cuff and ECG sense lead and the Driver. Provided sterile. 
96400 
Test Lead 
Used for intra-operative System testing. Bridges from the 
sterile field to the non-sterile Driver Lead. Provided sterile. 
96340 
Tunnelling Tool 
Surgical tool used during implant of the PIL. Reusable, 
provided non-sterile. Must be cleaned and sterilized before 
use. 
96330 
Gas-Line Cap 
Cap used for sealing the gas-line where the implanted 
components need to be partially explanted. Provided sterile. 
97200 
C-Pulse Driver 
Control unit that pneumatically operates the Cuff. 
Communicates with the Programmer via an infrared link. It is 
intended to be operated in a Carry Bag. 
97220 
Driver Carry Bag 
Carry Bag allows the user to carry the Driver and two spare 
battery packs. 
97600 
C-Pulse Programmer 
Consists of a notebook computer together with software, 
communication module, and power pack. It is used to adjust 
Driver parameters and to obtain real-time and logged data. 
02141 
End Cap, PIL 
Allows capping of PIL at Patient Connector for showering / 
bathing and whenever the Driver Lead is not connected. 
02140 
End Cap, Driver Lead 
Allows capping of Driver Lead when the Driver is not in use. 
91031 
Battery Pack 
A rechargeable Battery Pack for use with the Driver. 
91021 
Power Adapter, Driver 
Power Pack with cable to plug directly into the Battery Carrier 
for running the Driver off mains power and slow charge the 
Battery Pack in the Battery Carrier. Includes power cord. 
91011 
Battery Charger 
A fast charger for the spare Battery Packs. Includes power 
supply and power cord. 
 
Various components are also available as spare and/or replacement parts.  Contact Sunshine 
Heart for details. 
 
 
 
 
 
 
 
 
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3. PROCEDURES 
 
 
3.1. . Pre-implant Considerations 
 
 
In advance of surgery, have the patient carry the Driver to determine the most appropriate 
location of the percutaneous exit site. The goal is to minimize trauma to the exit site and to 
maximize patient comfort – pay particular attention to the costal margins, belt line, and 
impact of sitting and standing and lying on the exit site when wearing the Driver. The 
distance of the exit site from the costal margin should be considered in relation to the 
thickness of subcutaneous tissue, in order to prevent the PIL from rubbing against the 
costal margin. Also consider patients who inject insulin into the abdominal area. 
 
After deciding on the exit site, plan the orientation of the PIL, and subsequently the path of 
the Cuff, Gas-line and ECG lead. The implanted PIL location should allow adequate access 
to the implanted end for future replacement if necessary. 
 
Reference the System, Driver and Programmer IFUs for details on System start-up. 
 
3.2. . Implant  Procedure 
 
The surgical procedure involves the implant of the C-Pulse Cuff, Epicardial ECG lead 
(IS-1 compatible, bipolar) and the C-Pulse PIL. 
 
Note: The following is a summary of the recommended surgical procedure. 
The procedure may be modified subject to medical advice. 
 
For more detail, consult the Instructions for Use provided with the Cuff, PIL, and 
Tunnelling Tool. 
1. Prepare the patient for surgery. Establish physiological monitors, including invasive 
pressure monitoring. 
2. Incise chest and implant Cuff as described in the Cuff IFU. 
3. Implant the ECG sense lead as per the lead manufacturer’s Instructions for Use and 
in conjunction with the Cuff IFU. 
4. Implant the PIL as per the PIL and Tunnelling Tool IFUs. 
5. Perform initial Driver adjustments and verify system function. 
6. Inflate lungs fully to check PIL location and lay of Cuff gas line. 
7. Check for hemostasis and irrigate with an antibiotic solution. 
8. Insert mediastinal and any other drains as required, and close all wounds. 
9. Apply occlusive surgical dressings to all wounds. 
10. Immobilize the external portion of the PIL, removing the Test Lead if used. 
 
3.3.  
Postoperative  Patient Care 
 
1. Educate patient and caregiver on how to operate the Driver, as per the Patient Manual. 
 
2. Exit-site management by patient/care-giver demonstrated. Strict stabilization for the 
first 6 weeks to allow good ingrowth and anchoring of PIL. 
 
3. Reconfirm Driver settings once patient is stable and re-established on oral heart failure 
medications. Ensure the backup Driver settings match the settings of the Driver in use. 
 
 
 
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4. C-PULSE SYSTEM STUDY RATIONALE 
 
 
4.1 Study Classification 
The Sunshine Heart’s C-Pulse® System is CE marked under Active Implantable Medical Devices 
Directive 90/385/CEE. 
 
Based on European legislation
, this post-market Study is considered to be an observational 
study. The following rationale supports this consideration: 
 
- This study is collecting the data of subjects treated with the study product - C-Pulse® System 
in the usual manner and in accordance with the CE mark authorization. 
 
- The assignment of the patient to this study is not decided by this study plan but falls within 
the current practice, and the treatment decision is separated from the decision to include the 
patient in this study. 
 
- As the C-Pulse implantation procedure is clinically indicated patients may be enrolled 
prospectively with informed consent obtained prior to the procedure or retrospectively with 
informed consent for the collection of the patient’s data obtained after the procedure as 
appropriate for an observational study. Standard diagnostic or monitoring procedures are 
applied to the treated patients. Available data will be collected in a central database. 
 
The purpose of this observational surveillance study is to monitor the safety and performance 
of the C-Pulse System in the intended use population and confirm the favorable results 
obtained in premarket clinical investigations, which are summarized below. 
 
 
 
 

 
SUNSHINE HEART C-PULSE SYSTEM 
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     4.2 C- 
PULSE SYSTEM Benefits 
 
The progressive design and mechanism of action incorporated into the C-Pulse® System has 
provided treated patients with opportunities that are different than most heart failure devices. 
The C-Pulse® System broadens the treatment options for heart failure patients by providing a 
therapy that improves quality of life for patients who have failed optimal medications and CRT 
therapy. Many patients have no other alternatives or do not want an LVAD or heart 
transplant. For these patients with no alternatives, progression of heart failure symptoms 
continues and they are frequently re-hospitalized for worsening heart failure. 
 
The C-Pulse® is not intended to support patients in a manner similar to a VAD or transplant. 
The C-Pulse® is intended to allow patients’ relief of symptoms of heart failure, improved quality 
of life, improved cardiac function and the opportunity to receive other therapies in the future. 
The clinical study results demonstrated that these intended outcomes were met. When faced 
with the option of a VAD or the C-Pulse® for treatment of heart failure, the risk profile is 
markedly reduced for the patients who received the C-Pulse® based on the fact the C-Pulse® is 
non-blood contacting and the patient has the ability to disconnect from the system. 
 
The surgery to implant the device is relatively straightforward and with low risk. There is no 
need to place the patient on cardiopulmonary bypass during the procedure so the patient’s 
heart remains continuously beating. No anticoagulation is required. The C-Pulse® may be 
implanted via a minimally invasive procedure, which can reduce procedural time, hospital 
stays, overall cost and patient risk as compared to a traditional sternotomy procedure. As 
such, C-Pulse® System is a leading innovation in the surgeon’s portfolio for heart failure 
therapy. 
 
In addition, the quality of life is markedly enhanced by being treated with a device like the C- 
Pulse® which is non-obligatory  and non-life sustaining and allows safe disconnection as 
necessary for daily activities or any intervention (as the PIL substitution in case of exit site 
infection). The clinical study data at one year demonstrated continued improvement in quality 
of life, NYHA and 6MWT. 
 
The C-Pulse provides the patient with a treatment option avoiding or delaying the need for 
VAD and/or transplant procedure. The average time on the C-Pulse® device for patients is 335 
days (to date) and two patients were successfully weaned from C-Pulse® within one year. 
Therefore, treatment with the C-Pulse® may extend the time before a patient may require a 
VAD or transplant, if at all. 
 
4.3 
C- 
PULSE SYSTEM Risks 
Implantation is an invasive procedure requiring a sternotomy or thoracotomy and the use of 
general anesthesia and mechanical respiratory support. The potential risks associated with the 
implant procedure also include those associated with any cardiothoracic surgery, including 
implantation of devices and include the following: 
• Bleeding 
• Infection 
• Neurological Dysfunction 
• Renal Dysfunction 
• Cardiac Arrhythmias 
• Pericardial Fluid Collection 
• Aortic Disruption 
• Device Malfunction 
 
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• 
Hemolysis 
• 
Hepatic Dysfunction 
• 
Hypertension 
• 
Myocardial Infarction 
• 
Psychiatric Episode 
• 
Respiratory Failure 
• 
Right Heart Failure 
• 
Arterial Non–CNS Thromboembolism 
• 
Wound Dehiscence 
• 
Death 
 
Potential Adverse Effects may include Damage to the C-Pulse Cuff on implantation or 
misplacement of the ECG lead – not able to sense ‘R’ wave appropriately. There have been no 
unanticipated adverse events during the premarket clinical study. Percutaneous Interface Lead 
(PIL) failures and infections were the two areas of risk identified by Risk Analysis and 
confirmed during the C-Pulse clinical study. 
 
PIL Failures 
 
The risk associated with the PIL failures are related to the PIL replacement procedure. The 
only risks would involve re-hospitalization and minor superficial surgery. There have been no 
observed complications with PIL removal and replacement during the C-Pulse® study. 
Therefore, based upon current clinical experience, the risk is low. 
 
Sunshine Heart has addressed the cause of the device failures. The risk of PIL failure 
occurrence has been mitigated by design changes which address 1) the wire breakages related 
to cyclic fatigue, 2) kinking and 3) IS1 insertion. Implementation of these design changes will 
mitigate the risk of occurrence of the PIL failures to an acceptable low level. The changes will 
reduce the observed PIL failures to 5% (1/20). 
 
The clinical benefit of the PIL and its design features, e.g. ease of accessibility, ability for the 
patient to temporarily disconnect, and modular design for ease of replacement outweigh the 
residual risk. The PIL is essential in order to reduce exit site infection clinical consequences. 
 
Infections 
 
The infections and associated risk levels observed during the clinical study may be subdivided 
into different levels based upon risk to the patient and clinical management: 
 
1) Exit site related infection 
 
Observed rate of exit site infections in the C-Pulse® clinical study was 40%. However the risks 
associated with this type of infection are low. Normally the resolution of this type of infection is 
managed through use of antibiotics, antiseptics, exit site management and PIL stabilization. 
Since C-Pulse® is not blood contacting, the risk of sequelae, particularly sepsis, is significantly 
less than observed with LVADs, thus exit site infections with the C-Pulse® device are not as 
high a risk as in LVADs. There remains a risk of ascending infection – exit-site pain, tenderness 
or swelling over the subcutaneous flocking, etc., should be investigated and treated 
aggressively. The PIL is specifically designed as a modular component of the C-Pulse® System, 
such that if an infection is chronic the PIL can be removed and the infection easily treated with 
antibiotics. 
 
Adoption of the requirement for a stabilization device and new infection management 
techniques and protocol will require the sites to treat the C-Pulse® PIL as critically as the VAD 
drivelines to facilitate minimizing infection. The anticipated rate of residual risk in the post- 
market experience following implementation of the mitigations is expected to be no greater 
 
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than 30%. This rate is acceptable since it is consistent with what is currently  being 
experienced with other devices having a drive-line exit site. 
 
The clinical benefit of the PIL and its design features (e.g. ease of accessibility, ability for the 
patient to temporarily disconnect, removability) continue to support that the benefit outweighs 
the residual risk. 
 
2) Sternal wound infection 
 
During the C-Pulse® clinical study, one patient experienced a sternal wound infection resulting 
from the surgical procedure. The outcome of the management of the sternal wound after 
several attempts for debridement and a sternal flap was an aortic disruption. The rate of this 
incident is low, observed at 5% (1/20). 
 
The risks associated with this type of infection are high if not properly managed. Resolution of 
this type of infection is normally managed through use of antibiotics and sternal wound 
debridement and drainage. If the sternal wound infection progresses to include the sternal 
bone the Cuff should be explanted to avoid infection of the Device. 
 
3) Pneumo-mediastinum Infection 
 
Another infection observed during the C-Pulse® clinical study was a pneumo-mediastinum 
infection that resulted from a breach in the PIL due to a patient fall. The rate of this incident is 
low, observed at 5%. 
 
The risks associated with this type of infection are high if not properly managed. Resolution of 
this type of infection is normally managed through use of antibiotics and removal of the C- 
Pulse® System. Device related infections should be continuously monitored and treated 
accordingly to mitigate this risk (this statement is included in the C-Pulse System IFU). In 
addition, the revised exit site guidelines include lead stabilization techniques that will minimize 
trauma from falls or pulling on the exit site. 
 
4.2. 
Clinical Risk/Benefit Assessment 
 
The C-Pulse® uses proven balloon counter-pulsation technology to increase left ventricular 
coronary artery blood flow and cardiac output and to reduce the workload on the heart. The 
C-Pulse® System is an earlier intervention than other mechanical circulatory support therapies, 
such as LVADs, meeting a clinical need for relief of symptoms in heart failure patients that are 
refractory to optimal medical therapy and CRT therapy. 
 
The C-Pulse® System is designed to treat clinical symptoms associated with Class III and 
ambulatory Class IV heart failure (INTERMACS™ category 4-7). These symptoms normally 
include shortness of breath, dizziness, low blood pressure and fluid retention. Patients 
associated with Class III and ambulatory Class IV heart failure are typically unable to engage 
in normal activities, compromising their quality of life. 
 
C–Pulse® system has demonstrated patient benefits during the clinical studies to date which 
include the following: 
 
• 
Reduction in NYHA classification by at least 1 class. 
• 
Improvement in Quality of Life as demonstrated by MLWHF and KCCQ. 
• 
Improvement in Ejection Fraction. 
• 
Positive trend in 6 Minute Hall Walk capacity. 
• 
Reductions of symptoms and the ability to be discharged and remain at home with 
their heart failure. 
 
 
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Other benefits characterize the device concept: 
 
• C-Pulse® is designed to be implanted without the need for cardiopulmonary bypass 
or extensive dissection 
• Device does not come in contact with blood, thus an anticoagulant therapy is not 
required. 
• The C-Pulse® is not life-sustaining and can be disconnected as needed for personal 
hygiene. 
• C-Pulse may be permanently stopped for patients who experience sustained left 
ventricular recovery. 
• The device does not preclude future use of an LVAD or heart transplantation if 
required (bridge function). 
• The C-Pulse®  is provided with features that facilitate the management of adverse 
events. 
 
C-Pulse® does not directly contact the patient’s blood and it may be turned on or off at any 
time allowing the patient intervals of freedom to perform certain activities. Because the C- 
Pulse® remains outside the  circulatory system,  there is negligible risk of device-related 
bleeding, blood clots and stroke in comparison to other mechanical devices that reside or 
function in the bloodstream. The risk associated with device failure is also significantly less. 
C-Pulse® allows for weaning of the device if is there is sustained cardiac recovery. Heart 
function replacement therapies such as LVAD or heart transplantation remain therapeutic 
options if heart failure progresses. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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5. STUDY DESIGN 
 
 
 
5.1. Overview 
 
 
The study is designed to observe the clinical outcomes of heart failure patients treated with the 
C-Pulse® System in the usual manner and according to the approved indications and 
contraindications. 
 
A maximum of 15 European sites will participate. Study data from additional geographies may 
be included 
 
The study will include a cohort of up to 50 patients with moderate to severe heart failure 
refractory to optimal medical therapy, who receive the C-Pulse® System at the study sites. 
Patients must have provided written consent that their data can be used in the study. The 
patients will be followed for up to 5 years to collect performance and safety data. All available 
follow-up data of patients treated with the study device at the participating sites will be 
recorded via electronic CRFs. 
 
The study will have the following estimated time course: 
First Patient In: 
May 2013 
Last Patient In: 
Dec 2014 
Last Patient Out: 
Dec 2019 
5.2. Inclusion Criteria 
 
The inclusion criteria are consistent with the indications section of the C-Pulse® System 
Instruction For Use (IFU). According to the CE mark authorization, patients with the following 
conditions can be included: 
 
1. Patient is 18 years or older 
2. Patients with moderate to severe heart failure [American College of Cardiology/American 
Heart Association (ACC/AHA) Stage C; NYHA Class III/IV ambulatory], who are refractory 
to optimal medical therapy. 
3. Patients who are non-responders to CRT pacemaker therapy. When clinically indicated, CRT 
should be implanted ≥90 days prior to enrollment. 
In addition: 
4. Patient has signed and dated the investigation informed consent form. 
 
As the C-pulse implantation procedure is clinically indicated patients may be enrolled 
prospectively with informed consent obtained prior to the procedure or retrospectively with 
informed consent for the collection of the patient’s data obtained after the procedure as 
appropriate for an observational study. 
 
 
5.3. Exclusion Criteria 
Patients with the following conditions (contraindications in the IFU), as assessed within 90 
days prior to enrollment, have to be excluded: 
1. Evidence of significant ascending aortic calcification on postero-anterior chest X-ray or CT 
scan 
 
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2. Moderate or severe atherosclerotic aortic disease 
3. Ascending aorto-coronary artery bypass grafts 
4. Any history of aortic dissection 
5. Connective tissue disorder such as Marfans disease 
6. Previous aortic root replacement 
7. Aorta not conforming to specified dimensional constraints 
8. Patient has severe mitral valve incompetence, grade 4+ 
9. Patient has moderate to severe aortic valve incompetence, grade 2 - 4+ 
10. Patient has systolic blood pressure less than 90 or greater than 140mmHg 
 
11. Presence of active systemic infection 
 
12. Presence of bleeding or coagulation disorder (relative) 
 
5.4. Patient Recruitment 
 
Patient authorization and written informed consent must be obtained prior to the patient’s 
enrollment into the study and in accordance with GCPs, the Medical Devices Directive and all 
other applicable standards, regulations (local and national), guidelines and institutional 
policies. 
 
The investigator(s) will verify each patient’s inclusion/exclusion criteria before inclusion in 
the study. Selection criteria and completion of informed consent will be indicated on the 
Case Report Form. 
 
All patients who sign a consent form will be assigned a study identification number. The 
identification number will be formatted using the abbreviation for the country, site 
identification number – sequential site recruited patient number (i.e. DE-005-004). Any patient 
meeting the study inclusion criteria, for whom this device is clinically indicated, can be 
recruited for the study after receiving and documenting informed consent. 
 
5.5. Patient Screening and Suitability for C- 
Pulse Therapy 
Patients diagnosed with moderate to severe heart failure and who are treated at the 
participating centers are eligible for screening evaluation. 
Patients eligible for device implantation must meet all the inclusion and not meet the 
exclusion criteria (indications and contraindications based on device CE mark authorization 
and Instructions for Use). In addition, a screening process will be carried out for the 
objective of selecting ideal candidates for the C-Pulse System. Patient suitability will be 
evaluated in agreement between the Investigator and Sponsor. 
Patients with one more of the following conditions may be considered unsuitable for 
implantation of the C-Pulse system. 
With regards to the severity of heart failure, patients with the following conditions may be 
unsuitable for implantation: 
1. Inotrope dependence – inability to wean from inotropic therapy 
2. ACC/AHA Stage D heart failure or non-ambulatory NYHA Class IV subject 
3. Need for biventricular support 
4. Functional limitation due to heart failure as defined by a 6 Minute Walk test of ≤ 175 
meters, measured within 30 days prior to implantation 
 
 
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5. Need for concomitant cardiac surgery 
 
Patients with the following cardiac conditions may also be excluded based on clinical judgment: 
1. Hypertrophic obstructive cardiomyopathy, restrictive cardiomyopathy, pericardial 
disease, amyloidosis, active myocarditis, diastolic heart failure or technically challenging 
congenital heart disease 
2. Reversible cause of heart failure that may be remedied by conventional surgery or 
other intervention 
3. Cardiac surgery within 90 days prior to implantation 
4. Prior cardiac transplantation, left ventricular reduction surgery, passive restraint device 
or surgically implanted left ventricular assist device 
 
In addition, patients with severe co-morbidity may be excluded according to the judgment of 
the investigator. Condition of exclusion may include the following: 
1. Body Mass Index (BMI) < 18 or > 45 kg/m2 
 
2. Serum creatinine ≥ 2.5mg/dL or any form of dialysis within 30 days prior to the 
planned implantation 
 
3. Evidence of intrinsic hepatic disease as defined as biopsy proven liver cirrhosis; or liver 
enzyme values (AST, ALT or total bilirubin) that are > 3 times the upper limit of normal 
within 30 days prior to enrollment 
 
4. Patient has severe intrinsic pulmonary disease in judgment of the investigator 
 
5. Stroke or transient ischemic attack (TIA) within 30 days prior to the planned 
implantation; or > 80% carotid stenosis as determined by carotid Doppler ultrasound 
 
6. ST elevation myocardial infarction (STEMI) within 30 days 
 
7. Uncontrolled atrial fibrillation or other tachycardias 
 
8. Patient has a condition, other than heart failure, which would limit survival to less than 
2 years 
 
9. Patient demonstrates compliance issues that in the opinion of the investigator could 
interfere with the ability to manage the therapy (i.e. uncontrolled diabetes, mental 
health issues, etc.) 
10. Positive serum pregnancy test, for women of childbearing potential 
 
 
 
 
 
 
 
 
 
 
 
 
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5.6. 
Schedule of Assessments 
 
The study will aim to collect patient data while supported with C-Pulse therapy (i.e. the 
subjects will be censored from analysis if the device is permanently “off”). Data will be 
captured at the following time points: Baseline, procedure, discharge assessment, clinical 
follow-up at 6 weeks, 6 months, 12 months, 18 months, 2 years and yearly thereafter. Data 
from any other additional time points may be collected and analyzed if available. 
 
The treatment procedure will be performed according to the instructions outlined in the current 
approved IFU. The data will be recorded from baseline and during a 5 year follow-up period 
following the enrollment. Treatments will be performed according to standard hospital 
practices. The clinical assessments will be done as per routine practice at the participating 
institutions. 
 
The clinical variables of interest are presented in Table 8 below. Hemodynamic performance 
and functional testing will be determined according to procedures based on standard center 
practices. Any protocol-defined adverse events, including adverse device effects and outcomes 
will be reported by the Investigator. All available variables of interest, that will be collected by 
the investigators, will also be recorded in the Study electronic CRFs. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 3 .Data Collection Summary. 
 
Pre- 
Implant 
(Baseline) 
Implant 
Pre- 
Discharge2 
6 
week 
6, 18 
month 
Annually1 
Yr 1-5 
PATIENT ELIGIBILITY 
X 
GENERAL 
Demographic Data 
X 
Medical History 
X 
General Physical Exam 
X 
X 
X 
X 
X 
X 
Concurrent Cardiac Meds 
X 
X 
X 
X 
X 
X 
Weight (Height at enrollment) 
X 
X 
X 
X 
X 
Pregnancy test (if applicable) 
X 
VITAL PARAMETERS 
Heart rate/rhythm 
X 
X 
X 
X 
X 
Blood pressure 
X 
X 
X 
X 
X 
Respiration rate 
X 
X 
X 
X 
X 
CARDIOPULMONARY3 
ECHO 
X 
X 
X 
6MWT 
X 
X 
X 
X 
QUALITY OF LIFE 
INTERMACS™/NYHA 
Classification 
X 
X 
X 
X 
KCCQ 
X 
X 
X 
HEMATOLOGY 
Hemoglobin 
X 
X 
X 
X 
Hematocrit 
X 
X 
X 
X 
Platelet count 
X 
X 
X 
X 
White cell count 
X 
X 
X 
X 
C-reactive Protein 
X 
X 
X 
X 
BIOCHEMISTRY 
Serum sodium 
X 
X 
X 
X 
Serum potassium 
X 
X 
X 
X 
Serum creatinine 
X 
X 
X 
X 
BUN 
X 
X 
X 
X 
NTProBNP or BNP4 
X 
X 
X 
Serum bilirubin 
X 
X 
X 
X 
Serum ALT 
X 
X 
X 
X 
Serum AST/GGT 
X 
X 
X 
X 
IMPLANT DETAILS 
X 
DEVICE LOG 
X 
X 
X 
DISCHARGE CHECKLIST 
X 
ADVERSE EVENTS 
X 
X 
X 
X 
X 
X 
DATA FROM THE FOLLOWING ITEMS WILL BE COLLECTED IF COMPLETED UPON PHYSICIAN 
REQUEST: 
MVO2 
X 
X 
Right Heart Catheterization 
X 
X 
1 Annually post-implant for years 2-5 
2 At Discharge - within 36 hours prior and as close to discharge as possible 
3 Imaging within 90 days prior to implant may be included as Baseline data collection 
4 Complete NTProBNP or BNP consistently to the institution’s standard practice (i.e. if BNP collected at baseline, continue BNP in scheduled follow-up) 
 
 
 
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6. STUDY DESIGN AND OBJECTIVES 
 
 
6.1. 
Study Objective 
 
This is a multi-center, prospective, open label observational study, designed to observe the 
clinical outcomes of heart failure patients treated with the C-Pulse® System in the usual 
manner and according to the approved indications and contraindications. 
 
6.2. 
Enrollment 
 
A patient population of up to 50 patients with moderate to severe heart failure refractory to 
optimal medical therapy, who are implanted with the C-Pulse System as clinically appropriate, 
will be enrolled into the Study. A maximum of 15 European centers will participate. Study data 
from additional geographies may be included. 
 
Patients diagnosed with moderate to severe heart failure and who are treated at the 
participating centers are eligible for screening evaluation. The investigator(s) will obtain 
informed consent for study participation from each patient. 
 
Patients eligible for the study must meet all the inclusion criteria and not meet the exclusion 
criteria (indications and contraindications based on device CE mark authorization and 
Instructions for Use). In addition, a screening process will be carried out the objective of 
selecting ideal candidates for the C-Pulse System (see Section 5.5). Patients suitability will be 
evaluated in agreement between the Investigator and Sponsor, based on the assessment of 
heart failure severity, concomitant cardiac disease, need for concomitant cardiac surgery, co- 
morbidity, life expectancy < 2 years, pregnancy and other conditions potentially interfering 
with the ability to manage the C-Pulse therapy. 
 
After implantation of the C-Pulse System, patients will be followed up for 5 years to collect 
performance and safety data. 
 
The estimated time course of the study is as follows: 
First Patient In: 
May 2013 
Last Patient In: 
Dec 2014 
Last Patient Out: 
Dec 2019 
6.3. 
Performance Endpoints 
The following performance endpoints will be assessed during follow-up visits: 
• 
Improvement in INTERMACS™ and/or NYHA functional class 
• 
Freedom from worsening heart failure resulting in hospitalization, LVAD implantation, or 
death 
• 
Explant for recovery of ventricular function or cardiac transplantation 
Secondary endpoints assessed at 6 and 12 months post implant include: 
• 
Improvement in LVEF 
• 
Improvement in Quality of Life scores 
• 
Improvement in 6MWT 
 
6.4. 
Safety Endpoints 
The following primary safety endpoints will be assessed throughout each subject’s participation 
in the investigation: 
 
 
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• 
All cause and device-related mortality 
• 
Aortic disruption 
• 
Exit Site infection 
• 
Internal PIL/Cuff infection 
• 
Thromboembolism 
• 
Device malfunction 
• 
All protocol-defined adverse events 
 
 
6.5. 
Statistical Methodology 
 
The sample size for the European protocol (N= 50 patients) was calculated on the basis of 
preliminary discussions with the Scientific Advisors of Sunshine Heart, and predicted success 
and safety rates observed in the literature data. Consistent design, procedures and endpoints 
of this study, as compared with the US trial, may allow pooling of data and comparative 
analyses. Demographic and baseline data will be summarized using descriptive statistics, 
including %, mean, median, standard deviation, and 1st-3rd quartile, as appropriate. The 
performance and safety endpoints of the C-Pulse® System will be assessed by monitoring the 
patient clinical status, assessing the standard quality-of-life scores, and evaluating vital, 
cardiopulmonary, hematology, biochemistry and neurological parameters, cardiopulmonary 
test data during the visits within the follow-up period, as detailed in the Data Collection 
Summary shown in Table 8. Follow-up analysis will include both safety and performance 
analyses, at each of the defined intervals. Adverse event data will be summarized using 
descriptive statistics. These will include information concerning nature, severity and duration of 
all adverse events and their relationship to the different treatments. In addition, tables will be 
presented for the number of patients potentially available for follow-up and those actually 
followed. Reference rates for anticipated complications (adverse events), based on historical 
data on morbidity and mortality from previous device clinical experience, in similar populations 
and for analogous surgical procedures, are listed in the Literature Review. Overall mortality 
rate will be determined at the end of the study. 
 
6.6. 
Sample Size Analysis 
 
The sample size chosen in the post-market trial is 50 patients. The adequacy of this sample 
size was verified, see table below. The width of the confidence interval provide information 
about precision of the estimates about the unknown parameter. Confidence intervals are more 
informative than the simple results of hypothesis tests (namely, conclusion to "reject H0" or 
"don't reject H0") since they provide a range of plausible values for the unknown parameter. 
 
Reference safety rates are based on published literature, and assume a 2-tailed alpha of 5% in 
order to build 95% confidence intervals for the outcome of interest. According to the 
computations, a sample size of 50 patients provides adequate precision for statistical inference 
concerning endpoints, even those with low incidence. 
 
 
 
 
 
 
 
 
 
 
 
 
 
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7. DATA COLLECTION AND MANAGEMENT 
 
 
7.1. Data Management  Activities 
 
Data Management activities include, but are not limited to, collecting and tracking data and 
instituting quality control measures for data entry verification and trial compliance. The 
Sponsor and the Data Management Center will review significant new information, including 
adverse events and deviations from the clinical protocol, and ensure that such information is 
provided to relevant parties including Regulatory Authorities, Investigators, ECs as required by 
local and national regulations and this Clinical Investigational Plan. 
 
Study data will be reviewed during regular Investigator meetings. 
The Data Management Center for the study is: 
Sunshine Heart Inc. 
12988 Valley View Road 
Eden Prairie, MN  55344 
USA 
 
7.2. Information Collected in the Electronic Case Report Forms (e- 
CRFs) 
 
The study physician or his designee at each clinical site will perform primary data collection. 
Only the study physician or other pre-designated study personnel will be authorized to enter 
data (from source documents) via internet-based e-CRFs. Study personnel will each be 
assigned a unique user name and pass code to access the e-CRFs. Representatives, agents or 
consultants of the Data Management Center, the Sponsor or other designee will provide 
training, clinical monitoring, including review of e-CRFs with verification to the source 
documentation. 
 
Study patients will be enrolled based on the current approved labeling (as outlined in the 
Instructions for Use). Eligibility for each patient enrolled will be based on the current CE mark 
labeling and will be documented appropriately in the medical records (source documents) and 
entered in the e-CRFs. 
 
Only anonymous data will be collected after the patient has consented that personal data can 
be used. Patients treated with the study device are asked to consent in writing that their data 
can be entered into a central database. 
 
7.3. Patients Lost to Follow- 
up 
 
Patients that refuse to make their data available at a certain time point will be considered ”lost 
to follow-up”. The data that has been obtained from a patient that was subsequently lost to 
follow-up may still be used in any subsequent analysis. 
 
7.4. Source Docu ments 
 
The study physician or his designee at each clinical site will perform primary data collection. 
Only the study physician or other pre-designated study personnel will be authorized to enter 
data (from source documents) via internet-based e-CRFs. Study personnel will each be 
assigned a unique user name and pass code to access the e-CRFs. Representatives, agents or 
consultants of Data Management Center, the Sponsor or other designee will provide training, 
clinical monitoring, including review of e-CRFs with verification to the source documentation. 
 
Source documentation may include any of the following: 
 
1. Medical history/physical condition of the study subject before involvement in the study. 
 
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2. Dated and signed notes in the subject’s medical record on the day of entry into the 
study that identify: 
a. the subject’s date of entry into the study, the study Sponsor, the clinical site, the 
subject number 
b. A signed statement that informed consent was obtained. 
c. Dated and signed notes from each study subject visit with reference to the e-CRFs 
for further information, if appropriate (for specific results of procedures and exams). 
d. Description of device implantation procedure (material used, drugs administered 
during the procedure, date, time duration, echocardiographic and clinical findings, 
etc.). 
3. Notations on abnormal lab results and their resolution. 
4. Dated printouts or reports of special assessments, i.e., ECG reports. 
5. Adverse event reporting and follow-up of the adverse events (event description, 
severity, onset date, duration, relation to study device, outcome and treatment for 
adverse event). 
6. Notes regarding concomitant medications taken during the study (including start and 
stop dates). 
7. Study subject’s condition upon completion of or withdrawal from the study. 
 
Periodic teleconference calls between Sponsor or CRO and each clinical site may be performed 
to resolve any issues concerning the e-CRF and data collection methods. 
 
7.5. 
Site Documentation 
 
Each clinical site will maintain a Regulatory Binder in which the following documents will be 
maintained: 
 
1. Signed Investigator and Institutional Agreement 
 
2. Signed Study Protocol and Amendments including: 
 
a. Device Instructions for Use 
 
b. Electronic Case Report Forms and completion guidelines 
 
3. All Investigator and Co-Investigator CVs and Medical Licenses 
 
4. If applicable for the participating site: 
 
a. EC documents, including member list and number 
 
b. EC approval letter and updates 
 
5. Master copy of EC approved informed consent, advertising and recruitment materials 
 
6. General Correspondence 
 
7. Delegation of Responsibilities/Duties 
 
8. Patient Enrollment Logs 
 
9. Site Visit Log & Reports 
 
 
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10. Study communications including: 
 
a. Documentation of written and verbal communications with Sponsor 
 
b. Documentation of written and verbal communications with other Investigators 
 
7.6. 
Quality Assurance and Access  
 
The Sponsor or designee will create and maintain the database as per its internal procedures 
and policies and in accordance with applicable regulations on personal data protection. The 
Sponsor or designee will also be responsible for verification and validation of the database 
(including applicable security methods). 
 
Data entered into the e-CRF database are the sole property of the Sponsor and the frequency 
for review and use of the data will be at its discretion. Only designated Sponsor personnel are 
authorized to access the database. 
 
7.7. 
Monitoring Plan  
 
The Sponsor or designee will perform site monitoring during the Clinical Trial to ensure 
compliance with the Clinical Investigation Plan and applicable regulations, that data is collected 
in a timely, accurate and complete manner and that the Investigator continues to have 
appropriate staff and facilities to conduct the Clinical Trial safely and effectively. Monitoring will 
performed in accordance with a pre-specified monitoring plan that is in compliance with 
applicable Standard Operating Procedures. 
 
7.8. 
Data Retention 
 
All study records and reports must remain on file for a minimum of ten (10) years after the 
completion or termination of the study. Study records are to be discarded only upon 
notification by the Sponsor. 
 
The study physicians should contact the Sponsor before the destruction of any records and 
reports pertaining to the study to ensure they no longer need to be retained. In addition, the 
Sponsor should be notified if the study physician plans to leave the institution. 
 
7.9. 
Study Closeout  
 
Upon completion of the study (when all subjects enrolled have been followed at 5 years and 
the e-CRFs and queries have been completed), a close-out visit will be performed. All unused 
study materials and equipment will be collected and returned to the Sponsor or designee. 
Items that will be reviewed at this visit include: discussing retention of study files, publication 
policy, and to ensure that the study physician will notify the local ethics committee and/or 
competent authority regarding study closure, if needed. 
 
7.10. Final Report  
 
The Sponsor will generate a final report at the close of the study. The final report will include a 
descriptive analysis of the clinical data for all study cohorts.  
 
 
 
 
 
 
 
 
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8. PROCEDURE FOR ADVERSE EVENT MANAGEMENT 
 
 
8.1. Reporting Procedure 
 
Adverse event information will be reported throughout the clinical investigation as they occur. 
Adverse events will be followed until they are adequately resolved or explained. A list of 
potential AEs, which may result from the study procedure, is included as part of the IFU. 
 
The investigator(s) will report any serious adverse event to the Sponsor’s Clinical Research 
department no later than three calendar days after the Investigator first learns of the event, 
followed by a written report within ten working days. This reporting will be done via data entry 
in the electronic CRF: the sponsor will receive an email alert for each serious adverse event 
that is entered. 
 
In addition, investigational centers will report all serious adverse events to their local EC and 
National Competent Authority in accordance with the review committee’s and national 
requirements. 
 
The Sponsor or its designee will determine requirements of reporting adverse events according 
to its responsibilities for medical device vigilance. 
 
8.2. Definitions 
 
For purposes of this protocol adverse event definitions are taken from the guidance ISO 
document; please refer to EN ISO 14155:2011. 
 
8.2.1. 
.      Adverse Event 
 
An adverse event (AE) is defined as any untoward medical  occurrence,  unintended 
disease or injury, or untoward clinical signs (including abnormal laboratory findings) in 
subjects, users  or other persons, whether or not related to the investigational medical 
device. 
 
NOTE 1: This definition includes events related to the investigational medical device or 
the comparator. 
 
NOTE 2: This definition includes events related to the procedures involved. 
 
NOTE 3: For users or other persons, this definition is restricted to events related to 
investigational medical devices. 
 
8.2.2. 
.      Adverse Device Effect 
 
 
An adverse device effect (ADE) is defined as any adverse event related to the use of an 
investigational medical device. 
 
NOTE 1: This definition includes adverse events resulting from insufficient or inadequate 
Instructions for  Use, deployment, implantation, installation, or operation, or any malfunction 
of the investigational medical device. 
 
NOTE 2: This definition includes any event resulting from use error or from intentional 
misuse of the investigational medical device. 
 
8.2.3. 
.      Serious Adverse Event 
 
 
A serious adverse event (SAE) is defined an adverse event that: 
 
a. led to death, 
 
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b. led to a serious deterioration in the health of the subject, that either resulted in: 
 
1. a life threatening illness or injury, or 
 
2. a permanent impairment of a body structure or a body function, or 
 
3. in patient or prolonged hospitalization, or 
 
4. 
medical or surgical intervention to prevent life threatening illness or injury or 
permanent impairment to body structure or a body function, 
 
c. 
led to fetal distress, fetal death or a congenital abnormality or birth defect. 
 
NOTE:  Planned hospitalization for a preexisting condition, or a procedure required by the CIP, 
without serious deterioration in health, is not considered a serious adverse event. 
 
The serious adverse events will be reported into the following categories: 
 
8.2.4. 
. 
Adverse  Event Definitions 
Definitions are listed below for anticipated adverse events. The definitions are 
consistent with Version 2.2 adverse event definitions for the INTERMACS™ registry with 
the exception of Major Bleeding which does not have a minimum standard of 
transfusion. Aortic Disruption has been added in addition to the INTERMACS™ registry 
definitions as an additional screening for safety with respect to the C-Pulse unique 
application. Worsening Heart Failure has been added due to C-Pulse System not being 
a heart function replacement rather a heart assist device and based on the definition 
used by the CEC in the US Feasibility study. 
 
 
Major Bleeding  
 
An episode of suspected internal or external bleeding that results in one or more of the 
following: 
1. death 
2. re-operation 
3. hospitalization 
4. transfusion of red blood cells 
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. 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 
 
 
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signs of tamponade (e.g. increased central venous pressure and decreased cardiac 
output) and those without signs of tamponade. 
 
Aortic Disruption 
 
Disruption to the intima of the ascending aorta. Disruption may be partial or complete 
(i.e. transmural), and the latter may result in contained or free rupture. Typically this 
would be documented initially by CT scan with or without contrast or by trans- 
esophageal echocardiography. 
 
Device Malfunction  
 
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. The manufacturer must confirm 
device failure. 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 (implanted components of pump and any motor or other pump 
actuating mechanism that is housed with the implanted 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. 
Note:  For C-Pulse system – this includes the Cuff and Gas line and/or ECG 
lead. 
2) Non-pump failure (e.g., external pneumatic drive unit, electric power supply 
unit, batteries, controller, interconnect cable, compliance chamber). 
Note: For C-Pulse system – this includes the Percutaneous Interface Lead 
and the Driver. 
 
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 aminotransferase/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 
90mmHg diastolic (pulsatile pump) or 110mmHg 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 
 
 
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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 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 (PIL Only) 
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 (Cuff, ECG 
Lead and Gas line not including the PIL) 
Infection of the implanted C-Pulse Cuff or surrounding tissue (e.g. aorta) 
documented by positive site culture. 
Sepsis 
Evidence of systemic involvement by infection, manifested by positive blood 
cultures and/or hypotension. 
 
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 
implant together with ECG findings consistent with acute myocardial infarction. 
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. 
 
Neurological 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). The NIH Stroke Scale (for patients > 5 years old) must be re-administered 
at 30 and 60 days following the event to document the presence and severity of 
neurological deficits. Each neurological event must be subcategorized as: 
 
1) Transient Ischemic Attack (acute event that resolves completely within 24 
hours with no evidence of infarction) 
 
 
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2) Ischemic or Hemorrhagic Cerebrovascular 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: 
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 (in children, 
creatinine greater than 3 times upper limit of normal for age) 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 (for patients 
older than age 5 years) the inability to discontinue ventilatory support within six days 
(144 hours) post-implant. This excludes intubation for re-operation 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 <2.0 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 implantation. 
 
Worsening Heart Failure  
 
A heart failure event requiring hospitalization including the following: 
 
• 
Signs and symptoms of worsening heart failure; and 
• 
Treatment with intravenous heart failure therapy (including but not limited to 
diuretic or inotropic therapy); and 
• 
A minimum of one date change in the hospital or emergency room 
 
 
 
 
 
 
 
 
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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 apposed 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). 
 
8.2.5. 
.      Serious Adverse Device Effect (SADE) 
 
 
A serious adverse device effect (SADE) is defined as an adverse device effect that results in 
any of the consequences characteristics of a serious adverse event. 
 
8.3. Deaths and Explants 
 
8.3.1. 
.      Subject Deaths 
 
 
In the event of subject death, every effort should be made to obtain a copy of the autopsy 
report and/or death summary. Information on the cause of death and its relationship to the 
device used in this clinical investigation will be determined by the principal investigator. Copies 
of an autopsy report, if available, and/or a death summary are to be sent to the Investigation 
Sponsor. 
 
If a device is explanted during autopsy, the device should be returned to the 
Investigation Sponsor for analysis. Return kits for devices will be provided upon request by the 
clinical monitor. 
 
8.3.2. 
.      Device Explants 
 
In the event a device component is explanted in the intra-operative or early post-operative 
period (i.e., while the patient is hospitalized at the investigational center), a copy of the 
procedure report must be provided to the Investigation Sponsor. Information on the cause of 
explant and its relationship to the device component will be determined by the principal 
investigator. Explanted device components during this period must be returned to the 
Investigation Sponsor for analysis. Return kits for devices will be provided upon request by the 
clinical monitor. 
 
In the event a device component is explanted in the late post-operative period, every effort 
should be made to obtain a copy of the explant procedure report, as applicable. 
Information on the cause of explant and its relationship to the device component will be 
 
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determined by the principal investigator. Copies of an explant report, if available, are to be 
sent to the Investigation Sponsor. Explanted device components during this period should be 
returned to the Investigation Sponsor for analysis. Return kits for devices will be provided 
upon request by the clinical monitor. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9. STUDY CONDUCT, RESPONSIBILITIES AND CONFIDENTIALITY 
 
 
The study will be conducted in accordance with Good Clinical Practice (GCPs) and the 
Declaration of Helsinki and any additional provisions outlined in the Study Agreement. 
 
The study physicians are responsible for obtaining the appropriate regulatory approvals (ethics 
committee and/or competent authority) prior to initiation of the study. The Investigator will 
provide current copies of the study protocol to all Co-Investigators or other staff responsible 
for study conduct. 
 
9.1. Patient Authorization 
 
Patient authorization and written informed consent must be obtained prior to the patient’s 
enrollment into the study and in accordance with GCPs, the Medical Devices Directive and all 
other applicable standards, regulations (local and national), guidelines and institutional 
policies. 
 
9.2. Patient Confidentiality 
 
Patient confidentiality must be maintained in accordance with GCPs, the Medical Devices 
Directive and all other applicable standards, regulations (local and national), guidelines and 
institutional policies. 
 
9.3. Physician Confidentiality 
 
Study physicians will comply with the applicable provisions of the study agreement with regard 
to nondisclosure and confidentiality. 
 
9.4. Device Accountability 
 
The Investigator shall document in the surgery reports and e-CRFs the serial/lot number of all 
devices used during procedures. 
 
9.5. Protocol Changes/ 
A mendments 
 
Protocol changes or amendments cannot be made by the study physician without prior written 
approval by the Sponsor and EC. 
 
9.6. Patient Termination or Withdrawal  
 
 
Once enrolled, patients may discontinue participation at any time by withdrawing informed 
consent or meeting the requirement for termination. Participation in the study is entirely 
voluntary. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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10. 
PUBLICATION POLICY  
 
 
All information related to the study device is considered confidential and remains the sole 
property of the Sponsor. This includes, but is not limited to the patent applications and the 
manufacturing process. The investigator agrees to use this information only to accomplish this 
study and will not use it for other purposes without the Sponsor’s written consent. The 
investigator understands that the information developed in the clinical study will be used by 
the Sponsor and may be disclosed as required to other investigators or competent authorities. 
To permit the information derived from the clinical studies to be used, the investigator is 
obliged to provide Sponsor (or designated representative) all data obtained in the study. 
 
Sponsor and investigators are committed to the publication and widespread dissemination of 
the Study results. This study represents a joint effort between sponsor and investigators, and 
as such, the parties agree that the recommendation of any party concerning manuscripts or 
text shall be taken into consideration in the preparation of final scientific documents for 
publication or presentation. 
 
At various milestones in the C-Pulse System study, including the conclusion, it is intended that 
multicenter papers will be published, in peer reviewed scientific journals and scientific 
meetings. These publications/presentations will be coordinated by Sunshine Heart via the 
Investigator Meeting. Publication (abstracts and manuscripts) or presentation of the study 
results are subject to review by Sunshine Heart prior to submission or presentation. Sunshine 
Heart will review the manuscript within sixty (60) days after receipt with the purpose to ensure 
technical accuracy of the information presented. If any such proposed publication or 
presentation contains patentable subject matter which in Sponsor's sole discretion, warrants 
intellectual proprietary protection, the sponsor may delay any publication or presentation for 
up to 1 month after sponsor approval for the purpose of pursuing such protection. 
 
Authors of publications will include the participating physicians who have enrolled significant 
numbers of patients. Final author lists will be based on direct involvement in hypothesis 
generation, data analysis, patient recruitment, and composition of abstracts and manuscripts. 
The final decision about author lists will be the prerogative of the sponsor and the participating 
Investigators in accordance with guidelines to authors for each journal. 
 
If a multicenter publication is not issued after 1 year from the conclusion of the C-Pulse 
System Study (final database closure), single center results may be published with review by 
Sunshine Heart within 30 days of submission. Exceptions to this rule require prior approval 
from Sunshine Heart. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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11. 
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