Assessment of the Safety and Performance of the HARPOON™ Beating Heart Mitral Valve Repair System; a Multi-center Post-market Study (ASCEND)
Phase: NA
Conditions: Mitral Regurgitation
Sponsor: Edwards Lifesciences

PMCF for the Harpoon Medical Device 
 Assessment of the safety and performanCe of thE HARPOON™ BeaƟng Heart  
Mitral Valve Repair System; a mulƟ-center post-market stuDy (ASCEND #2018-22) 
NCT04382612 
November 25, 2019 

 
 
 
 
CONFIDENTIAL AND PROPRIETARY DATA: This document and the information contained herein may not be reproduced, used, or disclosed 
without written permission from Edwards Lifesciences LLC 
Version B:  25 November 2019 
 
 
Page 1 of 61 
 
                     
                                                     
Assessment of the safety and performanCe of thE 
HARPOON™ Beating Heart Mitral Valve Repair 
System; a multi-center post-market stuDy 
(ASCEND)  
CLINICAL STUDY PROTOCOL 
 
 
Protocol Number: 2018-22 
 
Version: B  
25 November 2019 
 
 
Study Sponsor: 
HARPOON Medical, an indirect wholly-owned subsidiary of Edwards Lifesciences Corporation  
Edwards Lifesciences  
One Edwards Way 
Irvine, CA 92614  
USA 
 
 
 

EDWARDS LIFESCIENCES LLC 
 
 
ASCEND CLINICAL INVESTIGATIONAL PLAN  
PROTOCOL NUMBER: 2018-22 
 
CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B: 25 NOVEMBER 2019 
 
 
PAGE 2 OF 61 
 
 
 
1.0 PROTOCOL REVISION HISTORY 
Protocol Revision Number 
Protocol Revision Date 
A 
13 September 2019 
B 
25 November 2019 
 
 
 

EDWARDS LIFESCIENCES LLC 
 
 
ASCEND CLINICAL INVESTIGATIONAL PLAN  
PROTOCOL NUMBER: 2018-22 
 
CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B: 25 NOVEMBER 2019 
 
 
PAGE 3 OF 61 
 
 
2.0 PROTOCOL SIGNATURE PAGE 
Study Title: 
ASsessment of the safety and performanCe of thE HARPOON™ 
Beating Heart Mitral Valve Repair System; a multi-center post- 
market stuDy (ASCEND) 
Protocol Number: 
2018-22 
Version: 
Rev. B 
Date: 
 25 November 2019 
 
I have read this protocol and agree to participate in the clinical investigation sponsored by HARPOON 
Medical, an indirect wholly-owned subsidiary of Edwards Lifesciences Corporation.  I agree to conduct 
this investigation according to the requirements of the study protocol and in accordance with the 
International Standard ISO 14155, ethical principles that have their origins in the Declaration of Helsinki, 
applicable European or regional laws and regulations, and conditions imposed by the reviewing Ethics 
Committee.   
 
I agree to supervise all sub-investigators at my site as well and to ensure appropriate informed consent 
is obtained from all subjects prior to inclusion in this study. This protocol contains confidential 
proprietary information with respect to Edwards Lifesciences’ products and clinical studies. I agree to 
hold this information in confidence and not to disclose it to any third parties as outlined in the clinical 
trial 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. 
STATEMENT OF COMPLIANCE 
 
The Study Protocol will be conducted in accordance with 
• 
Declaration of Helsinki (Rev. 2013)  
• 
ISO 14155: 2011 
 
In addition, the Study Protocol will comply with any applicable regional regulations. The clinical 
investigation shall not begin until the required approval/favourable opinion from the EC is obtained. 
 
 
 
INVESTIGATOR SIGNATURE 
 
DATE 
INVESTIGATOR NAME (PRINTED) 
 
 

EDWARDS LIFESCIENCES LLC 
 
 
ASCEND CLINICAL INVESTIGATIONAL PLAN  
PROTOCOL NUMBER: 2018-22 
 
CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B: 25 NOVEMBER 2019 
 
 
PAGE 5 OF 61 
 
 
3.3 
CLINICAL SITES 
The study will be conducted in the following European countries: Austria, Germany, Italy, Poland, 
Switzerland and United Kingdom. The Sponsor will maintain a list of principal investigators and 
investigational sites for the duration of the study; the definitive list of sites will be provided with the 
final clinical investigation report of the study.  
 
 

EDWARDS LIFESCIENCES LLC 
 
 
ASCEND CLINICAL INVESTIGATIONAL PLAN  
PROTOCOL NUMBER: 2018-22 
 
CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B: 25 NOVEMBER 2019 
 
 
PAGE 6 OF 61 
 
 
4.0 PROTOCOL SYNOPSIS 
Title: 
ASsessment of the safety and performanCe of thE HARPOONTM 
Beating Heart Mitral Valve Repair System; a multicenter post-market 
stuDy (ASCEND) 
Protocol Number: 
2018-22 
Sponsor 
HARPOON Medical, an indirect wholly-owned subsidiary of Edwards 
Lifesciences Corporation 
Design: 
A single arm, prospective, multicentre, non-randomised and open-label 
post-market study 
Device: 
HARPOONTM Beating Heart Mitral Valve Repair System (MVRS) 
Population: 
Patients with severe degenerative mitral regurgitation as a result of mid- 
segment posterior leaflet prolapse undergoing treatment with HARPOONTM 
Beating Heart Mitral Valve Repair System 
Enrolment: 
250 implanted subjects in up to 25 centers in Europe 
Duration: 
Initial enrolment: 
Q4 2019 
Last enrolment: 
Q4 2021 
Last follow-up visit: Q1 2027  
Follow-up: 
Follow-up at 7 days or discharge from hospital post-index procedure 
(whichever occurs first), at 30 days, and at 6, 12, 18, 24, 36, 48, and 60 
months post-treatment 
Objectives: 
To evaluate the long-term safety and performance of the HARPOONTM 
MVRS for use in patients presenting with severe degenerative mitral 
regurgitation due to posterior leaflet prolapse in the post-market phase. 
Endpoints: 
Primary Safety Endpoint: 
 Freedom from all-cause mortality, disabling stroke and life- threatening 
bleeding at 30 days post-implant. 
 
Primary Performance Endpoint: 
 Procedure success at 30 days post-treatment, as measured by: 
Technical success with reduction of MR to less than or equal to mild 
and the absence of major device or procedure-related SAEs. 
Other Planned Analyses:  
 Technical success defined as survival and exit from the operating room (OR) 
with successful implantation of 3 or more expanded 
polytetrafluoroethylene (ePTFE) chords. 
 Freedom from major device or procedure-related serious adverse 
event (SAE) at 30 days, 1 year and 2 years post-implant 
 Quality of Life (change from baseline to 1 and 6 months) 

EDWARDS LIFESCIENCES LLC 
 
 
ASCEND CLINICAL INVESTIGATIONAL PLAN  
PROTOCOL NUMBER: 2018-22 
 
CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B: 25 NOVEMBER 2019 
 
 
PAGE 7 OF 61 
 
 
 6-minute walk test (change from baseline to 1 and 6 months) 
 Freedom from ePTFE chord rupture as reported by echo core lab at 1 
year and 2 years post-implant 
 Freedom from reoperation or re-intervention due to ePTFE chord 
rupture at 1 year and 2 years post-implant 
 Functional improvement from baseline NYHA Functional 
Classification at 1 year and 2 years post-implant 
 Freedom from reoperation or reintervention on the mitral valve annually 
through 5 years post-implant 
 Freedom from ≥ moderate MR annually through 5 years post-implant  
Subject Enrolment: 
 
 
 
Inclusion Criteria: 
 
 
 
Each subject is required to meet all of the following inclusion criteria: 
1. Subject is > 18 years old 
2. Presence of severe MR as read on a transthoracic echocardiographic study  
3. Mitral leaflet coaptation surface is sufficient to reduce mitral regurgitation 
without undue leaflet tension (approximate leaflet to gap ratio of 2:1) based 
on the judgment of the patient eligibility committee and the operating 
surgeon  
4. Degenerative mitral valve disease with mid-segment P2 prolapse  
5. Patient is able to sign informed consent and able to return for follow-up and 
is capable of participating in all testing associated with this clinical 
investigation 
 
Exclusion Criteria: 
 
 
 
A subject meeting any of the following criteria shall be excluded: 
1. Patient is of the age where further growth is expected  
2. Active endocarditis 
3. Left ventricular or left atrial appendage thrombus 
4. Severe mitral annular and/or leaflet calcification 
5. Cannot tolerate procedural anticoagulation or post-procedure antiplatelet 
regimen 
6. Mitral stenosis 
7. Functional Mitral Valve disease 
8. Previous mitral valve replacement surgery 
9. Fragile or thinning apex 
10. Contraindications to transoesophageal echocardiography (atlantoaxial 
disease, severe generalized cervical arthritis, upper gastrointestinal 
bleeding, significant dysphagia and odynophagia, has received extensive 
radiation to the mediastinum) 
11. Patient is pregnant or lactating 
 
Statistical Analysis: The primary safety and performance endpoints will be summarized by counts, 
percentages and corresponding 95% confidence intervals. Other categorical 
variables will be summarized by counts and percentages. Continuous variables 

EDWARDS LIFESCIENCES LLC 
 
 
ASCEND CLINICAL INVESTIGATIONAL PLAN  
PROTOCOL NUMBER: 2018-22 
 
CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B: 25 NOVEMBER 2019 
 
 
PAGE 8 OF 61 
 
 
will be summarized using means, medians, ranges and standard deviations. 
 
Statistical calculations will be based on all available data. No missing value 
imputations are planned for primary safety and effectiveness endpoints. Missing 
month and days for adverse events will be imputed. An initial analysis of 
apparent product failure will be conducted once 50 patients achieve 12 months 
of follow-up. Thereafter, a failure analysis will be repeated for each subsequent 
10 patients achieving 12 months of follow-up. The rates of apparent product 
failure will be deemed unacceptable if the lower limit of any 95% confidence 
interval at 12 months is above 6%. 
Study Oversight: 
 
Echo Core Lab will evaluate all echocardiograms performed per protocol. 
(Echocardiograms will be obtained at Baseline, Discharge, 30 days, 6, 12, 18, 
24, 36, 48 and 60 months).   
Clinical Events Committee will adjudicate all potential safety endpoints (death, 
stroke, bleeding) and reintervention post-index procedure through the 2-year 
follow up. 
Safety Review will be conducted for all adverse events reported during the 
course of the study. 
Routine Monitoring will be conducted for reported data per the monitoring 
plan. 
 
 
 

EDWARDS LIFESCIENCES LLC 
 
 
ASCEND CLINICAL INVESTIGATIONAL PLAN  
PROTOCOL NUMBER: 2018-22 
 
CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B: 25 NOVEMBER 2019 
 
 
PAGE 9 OF 61 
 
 
5.0 ABBREVIATIONS 
AE 
Adverse event 
CA 
Competent authority 
CE 
Conformité Européene 
CEC 
Clinical events committee 
CKD 
Chronic kidney disease 
CRF 
Case report form 
EC 
Ethics Committee 
ECL 
Echo Core Laboratory 
EDC 
Electronic data capture 
eCRF 
Electronic case report form 
ePTFE 
Expanded polytetrafluoroethylene 
GCP 
Good clinical practice 
ID 
Identity Number 
ISO 
International Organization for Standardization 
LTFU 
Lost to follow-up 
MDD 
Medical Device Directive 
MR 
Mitral Regurgitation 
MVRS 
Beating Heart Mitral Valve Repair System 
NYHA 
New York Heart Association 
OR 
Operating Room 
PA 
Pulmonary Artery 
PEC 
Patient Eligibility Committee 
SAE 
Serious Adverse Event 
SOC 
Standard of Care 
TOE 
Transoesophageal Echocardiogram 
TTE 
Transthoracic Echocardiogram 
USADE 
Unanticipated Serious Adverse Device Effect 
 
 
 
 
 

EDWARDS LIFESCIENCES LLC 
 
 
ASCEND CLINICAL INVESTIGATIONAL PLAN  
PROTOCOL NUMBER: 2018-22 
 
CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B: 25 NOVEMBER 2019 
 
 
PAGE 10 OF 61 
 
 
Table of Contents 
 
Section 
Page 
1.0 
PROTOCOL REVISION HISTORY ............................................................................................... 2 
2.0 
PROTOCOL SIGNATURE PAGE ................................................................................................. 3 
3.0 
STUDY CONTACTS .................................................................................................................. 4 
3.1 SPONSOR AND STUDY CONTACTS .................................................................................................... 4 
3.2 STUDY OVERSIGHT ........................................................................................................................... 4 
3.3 CLINICAL SITES ................................................................................................................................. 5 
4.0 
PROTOCOL SYNOPSIS ............................................................................................................. 6 
5.0 
ABBREVIATIONS ..................................................................................................................... 9 
6.0 
INTRODUCTION AND BACKGROUND ..................................................................................... 13 
6.1 MITRAL REGURGITATION, TRANS-APICAL VALVE REPAIR, AND THE HARPOON™ MVRS ................ 13 
6.2 DEVICE DESCRIPTION ..................................................................................................................... 14 
6.3 PRIOR CLINICAL EXPERIENCE WITH THE HARPOON SYSTEM: EFS AND CE MARK TRIALS ................ 15 
7.0 
STUDY DESIGN ..................................................................................................................... 19 
7.1 OBJECTIVE ...................................................................................................................................... 19 
7.2 DESIGN .......................................................................................................................................... 19 
7.3 ENDPOINTS .................................................................................................................................... 19 
7.4 NUMBER OF SUBJECTS ................................................................................................................... 22 
8.0 
STUDY POPULATION ............................................................................................................ 23 
8.1 SUBJECT INCLUSION CRITERIA ........................................................................................................ 23 
8.2 SUBJECT EXCLUSION CRITERIA ....................................................................................................... 23 
8.3 SCREENING AND ENROLMENT ....................................................................................................... 23 
8.4 SUBJECT AND STUDY DURATION .................................................................................................... 23 
9.0 
STUDY PROCEDURES AND SCHEDULE OF ASSESSMENTS ........................................................ 24 
9.1 SUBJECT SCREENING AND INFORMED CONSENT ............................................................................ 24 
9.2 SCHEDULE OF ASSESSMENTS ......................................................................................................... 25 
9.3 SCREENING EVALUATIONS AND PATIENT ELIGIBILITY COMMITTEE ................................................ 26 
9.4 BASELINE/PRE-PROCEDURE EVALUATIONS .................................................................................... 26 
9.5 TREATMENT/PROCEDURE ASSESSMENTS ...................................................................................... 26 
9.6 MISSED FOLLOW-UP ...................................................................................................................... 27 
9.7 STUDY EXIT CRITERIA AND PROCEDURES ....................................................................................... 28 

EDWARDS LIFESCIENCES LLC 
 
 
ASCEND CLINICAL INVESTIGATIONAL PLAN  
PROTOCOL NUMBER: 2018-22 
 
CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B: 25 NOVEMBER 2019 
 
 
PAGE 11 OF 61 
 
 
9.8 DEATH AND SURGICAL VALVE INTERVENTION ............................................................................... 29 
10.0 
ENDPOINT ANALYSIS AND STATISTICAL METHODS ................................................................ 30 
10.1 ANALYSIS POPULATION ................................................................................................................. 30 
10.2 SAMPLE SIZE RATIONALE ............................................................................................................... 30 
10.3 STUDY ENDPOINT TESTING ............................................................................................................ 31 
10.4 ADDITIONAL PLANNED ANALYSES .................................................................................................. 31 
10.5 STATISTICAL ANALYSIS METHODOLOGY ......................................................................................... 32 
10.6 METHODS USED TO MINIMISE BIAS ............................................................................................... 32 
11.0 
SAFETY REPORTING .............................................................................................................. 33 
11.1 DEFINITIONS OF ADVERSE EVENTS AND DEVICE DEFICIENCIES ....................................................... 33 
11.2 CAUSALITY RELATIONSHIP ............................................................................................................. 34 
11.3 REPORTING ADVERSE EVENTS ........................................................................................................ 36 
11.4 CLINICAL EVENTS COMMITTEE ADJUDICATION .............................................................................. 38 
12.0 
DEVICE DISTRIBUTION, ACCOUNTABILITY, AND REPORTING .................................................. 39 
12.1 DEVICE TRACEABILITY .................................................................................................................... 39 
12.2 DEVICE MALFUNCTIONS AND FAILURE – VIGILANCE REPORTING ................................................... 39 
13.0 
BENEFITS AND RISKS ............................................................................................................ 40 
13.1 BENEFITS ........................................................................................................................................ 40 
13.2 RISKS .............................................................................................................................................. 41 
13.3 MINIMISING SUBJECT RISK ............................................................................................................ 43 
13.4 JUSTIFICATION OF CLINICAL STUDY ................................................................................................ 44 
14.0 
STUDY AND DATA MANAGEMENT ........................................................................................ 45 
14.1 ECHOCARDIOGRAPHY CORE LAB .................................................................................................... 45 
14.2 CLINICAL EVENTS COMMITTEE ....................................................................................................... 45 
14.3 PROTOCOL DEVIATIONS ................................................................................................................. 45 
14.4 STUDY CONDUCT, TRAINING, MONITORING RESPONSIBILITIES AND CONFIDENTIALITY ................ 46 
14.5 DOCUMENTATION REQUIREMENTS ............................................................................................... 47 
14.6 DATA COLLECTION ......................................................................................................................... 48 
14.7 DATA AND DOCUMENT RETENTION ............................................................................................... 48 
14.8 STUDY PROTOCOL AMENDMENTS ................................................................................................. 48 
14.9 STUDY COMPLETION ...................................................................................................................... 48 
14.10 
FUTURE PLANS ....................................................................................................................... 49 
15.0 
STATEMENTS OF COMPLIANCE, CONFIDENTIALITY AND RESPONSIBILITIES ............................ 50 

EDWARDS LIFESCIENCES LLC 
 
 
ASCEND CLINICAL INVESTIGATIONAL PLAN  
PROTOCOL NUMBER: 2018-22 
 
CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B: 25 NOVEMBER 2019 
 
 
PAGE 12 OF 61 
 
 
15.1 APPLICABLE REGULATIONS AND GUIDELINES ................................................................................ 50 
15.2 DATA PROTECTION AND PATIENT CONFIDENTIALITY ..................................................................... 50 
15.3 INVESTIGATOR RESPONSIBILITIES .................................................................................................. 51 
15.4 SPONSOR RESPONSIBILITIES .......................................................................................................... 51 
16.0 
PUBLICATIONS ..................................................................................................................... 53 
17.0 
REFERENCES ........................................................................................................................ 54 
 
List of Tables 
TABLE 1: PRIOR CLINICAL EXPERIENCE: SAFETY ENDPOINTS FOR THE IMPLANTED COHORT ................................ 16 
TABLE 2: PRIOR CLINICAL EXPERIENCE: MITRAL REGURGITATION RESULTS ......................................................... 17 
TABLE 3: SCHEDULE OF ASSESSMENTS ................................................................................................................. 25 
TABLE 4: ADVERSE EVENT DEFINITIONS ............................................................................................................... 33 
TABLE 5: REGULATIONS AND GUIDELINES ............................................................................................................ 50 
 
Attachments 
ATTACHMENT A – DEFINITIONS ........................................................................................................ 55 
 
 
 

EDWARDS LIFESCIENCES LLC 
 
 
ASCEND CLINICAL INVESTIGATIONAL PLAN  
PROTOCOL NUMBER: 2018-22 
 
CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B: 25 NOVEMBER 2019 
 
 
PAGE 13 OF 61 
 
 
6.0 INTRODUCTION AND BACKGROUND 
6.1 
MITRAL REGURGITATION, TRANS-APICAL VALVE REPAIR, AND THE HARPOON™ MVRS 
Mitral valve disease is the second most common valvular heart disorder requiring surgery in Europe, 
with nearly 8 million Europeans estimated to have severe mitral valve regurgitation (MR) (AGENAS, 
2015).  MR results in a volume overload on the left ventricle which in turn leads to ventricular dilation, 
decreased ejection performance, pulmonary hypertension, symptomatic congestive heart failure, atrial 
fibrillation, right ventricular dysfunction and death. Successful surgical mitral valve repair restores mitral 
valve function, eliminates volume overload on the left ventricle, improves symptom status and prevents 
adverse left ventricular remodelling. 
 
The large majority of MR results from either degenerative disease (caused by elongated or ruptured 
native chords that fail to support the mitral valve leaflets) or functional ischemic or idiopathic MR (the 
motion of the normal mitral valve leaflets is restricted by the enlarged ventricle) both of which lead to 
ineffective valve closure and regurgitation. Other less common causes of chronic primary MR include 
infective endocarditis, connective tissue disorders, rheumatic heart disease, cleft mitral valve, and 
radiation heart disease. If the subsequent volume overload of chronic primary MR is prolonged and 
severe, it causes myocardial damage, heart failure (HF), and eventual death. Correction of the MR is 
curative (Nishimura et al., 2014). 
 
There is no effective medical treatment for degenerative MR (DMR). Medical treatment, e.g. diuretics, 
vasodilators, might relieve HF symptoms but does not alter the course of DMR and ultimately surgery 
will be required (Nishimura et al., 2016).  Two-thirds of all mitral valve surgical procedures in North 
America are performed on patients with degenerative MR and that percentage is estimated to be similar 
in Europe.  Open cardiac surgery is a common method of treating DMR which involves replacing and/or 
supplementing elongated or ruptured chords with artificial chords made of ePTFE, a commercially 
available material which has a 20+ year history of safety in conventional mitral valve repair procedures. 
 
Current ESC/EACTS Guidelines state that surgery is indicated in: 
• asymptomatic patients with LVEF ≤60% or LVESD ≥45mm, new onset AF or SPAP >50mmHg 
and who are at low surgical risk; 
• symptomatic MR patients with LVEF >30% or those who are refractory to medical treatment 
and in whom a durable valve repair is likely with low comorbidity. 
 
In all patients, valve repair rather than valve replacement is advocated whenever possible and is now 
the standard of care (Vahanian et al. 2012). A systematic review found that mortality is particularly 
high in patients >80 years old: 10% for MV replacement (N=3,105) compared with 7% for MV repair 
(N=2,642), with 5-year survival rates of 23% for MV replacement (N=335) and 29% for MV repair 
(N=250). It was concluded that many patients are unfit for major heart surgery (Andalib et al. 2014). 
 
Although open-heart surgery is the gold-standard approach for the treatment of severe MR, it is not 
performed in up to 50% of patients due to the increased risk associated with co-morbidities. Excellent 
outcomes can be achieved in most patients with minimally invasive approaches and transcatheter 
mitral interventions might be an alternative therapeutic option (Maisano et al. 2015; Lam et al. 2011). 

EDWARDS LIFESCIENCES LLC 
 
 
ASCEND CLINICAL INVESTIGATIONAL PLAN  
PROTOCOL NUMBER: 2018-22 
 
CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B: 25 NOVEMBER 2019 
 
 
PAGE 14 OF 61 
 
 
Mitral valve repair technologies, including the HARPOON™ Beating Heart MVRS (Chordal repair), can be 
used in cases of DMR. The following available treatments to replace ruptured or elongated chordae 
tendinae can reduce MR.  However, other than the HARPOON™ Beating Heart Mitral Valve Repair 
System, there is no currently effective medical therapy that treats or cures MR. 
 
• Edge-to-edge leaflet repair: MitraClip (Abbott Vascular); Cardica Mitral Repair (Cardica); 
MitraFlex (TransCardiac); PASCAL (Edwards Lifesciences) 
• Chordal repair: ePTFE sutures, HARPOON™ MVRS (HARPOON Medical), NeoChord DS1000 
(NeoChord); V-Chordal-Off Pump (Valtech); V-Chordal-Transfemoral (Valtech); MISTRAL 
(Mitralix) 
• Indirect annuloplasty: CARILLON (Cardiac Dimensions) (Lam et al. 2011). 
• Direct annuloplasty: GDS Accucinch (GDS); Mitralign Bident (Mitralign); Cardioband TF 
(Valtech); Millipede Ring (Millipede); Kardium MR (Kardium); ValCare MV Repair (ValCare), 
QuantumCor (QuantumCor) 
• Enhanced coaptation: Mitra-Spacer-Transapical (Cardiosolutions) (Maisano et al. 2015), 
Middle Peak Medical, US 
 
6.2 
DEVICE DESCRIPTION 
The HARPOON™ Beating Heart Mitral Valve Repair System, known hereafter as HARPOON System, is 
described in detail in the Instructions For Use (IFU).  The IFU will be provided to the sites and Ethics 
Committees (ECs), and a copy is part of the Trial Master File and Investigator Site File. 
 
6.2.1 
REGULATORY STATUS 
The HARPOON System is CE-marked. Its use in this study is consistent with the product’s labelling. 
 
6.2.2 
INDICATION FOR USE  
The HARPOON System is indicated to reduce the degree of mitral regurgitation in patients with severe 
MR caused by mid-segment posterior leaflet prolapse as a result of degenerative mitral valve disease by 
delivering and anchoring ePTFE chords to the prolapsed mitral valve leaflet in a beating heart.   
 
6.2.3 
TECHNICAL DESCRIPTION OF THE DEVICE 
The HARPOON System consists of two parts: 1) HARPOON Introducer and 2) HARPOON Delivery System. 
Both items are essential for proper delivery of ePTFE implants in the mitral valve leaflet to eliminate or 
reduce mitral valve regurgitation (MR).  The HARPOON System is a Class III product following rule 8 of 
the Annex IX of the MDD 93/42/EEC (intended to be used to deliver an implant in direct contact with the 
heart).  For a detailed description of the HARPOON System, please refer to the HARPOON™ Beating 
Heart Mitral Valve Repair System Instructions for Use. 
 
6.2.4 
MANUFACTURE OF HARPOON INTRODUCER AND DELIVERY SYSTEM 
The HARPOON System (Introducer and Delivery System) are manufactured by HARPOON Medical, an 
indirect wholly-owned subsidiary of Edwards Lifesciences Corporation.  
 

EDWARDS LIFESCIENCES LLC 
 
 
ASCEND CLINICAL INVESTIGATIONAL PLAN  
PROTOCOL NUMBER: 2018-22 
 
CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B: 25 NOVEMBER 2019 
 
 
PAGE 18 OF 61 
 
 
6.3.6.2 
NYHA FUNCTIONAL CLASS 
Performance was also assessed using NYHA functional classification change.  At 1 year of follow-up, 
92.3% of subjects were in NYHA class I, 5.8% were in NYHA class II, and 1.9% were in NYHA class III, 
corresponding to an improvement (50%) or maintenance (48%) of NYHA class for 98% (51/52) of 
subjects. 
 
6.3.7 
SUMMARY 
The results of the EFS and CE Marking trials support the safety and performance of the HARPOON 
System. 
 
 

EDWARDS LIFESCIENCES LLC 
 
 
ASCEND CLINICAL INVESTIGATIONAL PLAN  
PROTOCOL NUMBER: 2018-22 
 
CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B: 25 NOVEMBER 2019 
 
 
PAGE 19 OF 61 
 
 
7.0 STUDY DESIGN 
7.1 
OBJECTIVE 
The objective of this study is to evaluate the long-term safety and performance of the HARPOON System 
for use in patients presenting with severe degenerative mitral regurgitation due to posterior leaflet 
prolapse in the post-market phase. 
 
7.2 
DESIGN 
A single arm, prospective, multicentre, non-randomised and open-label, post-market study. 
7.3 
ENDPOINTS 
The following are the planned endpoints for the study: 
7.3.1 
PRIMARY SAFETY ENDPOINT: 
 
Freedom from all-cause mortality, disabling stroke and life-threatening bleeding at 
30 days post-implant. 
 
7.3.2 
PRIMARY PERFORMANCE ENDPOINT: 
 Procedure success at 30 days post-treatment, as measured by: technical success 
with reduction of MR to less than or equal to mild and the absence of major device 
or procedure-related SAEs. 
 
7.3.3 
OTHER PLANNED ANALYSES:  
 Technical success defined as survival and exit from the operating room (OR) with 
successful implantation of 3 or more expanded polytetrafluoroethylene (ePTFE) chords 
 Freedom from major device or procedure-related serious adverse event (SAE) at 30 days, 1 
year and 2 years post-implant 
 Quality of Life (change from baseline to 1 and 6 months) 
 6-minute walk test (change from baseline to 1 and 6 months) 
 Freedom from ePTFE chord rupture as reported by echo core lab at 1 year and 2 years 
post-implant 
 Freedom from reoperation or re-intervention due to ePTFE chord rupture at 1 year and 2 
years post-implant 
 Functional improvement from baseline NYHA Functional Classification at 1 year and 2 
years post-implant 
 Freedom from reoperation or reintervention on the mitral valve annually through 5 years 
post-implant 
 Freedom from ≥ moderate MR annually through 5 years post-implant  

EDWARDS LIFESCIENCES LLC 
 
 
ASCEND CLINICAL INVESTIGATIONAL PLAN  
PROTOCOL NUMBER: 2018-22 
 
CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B: 25 NOVEMBER 2019 
 
 
PAGE 20 OF 61 
 
 
 
7.3.4 
KEY ENDPOINT DEFINITIONS:  
A complete list of definitions can be found in Attachment A. Key endpoint definitions include: 
 
All-cause mortality: 
Mortality for any cause will be reported with a further stratification by Cardiovascular and Non-
Cardiovascular.  All Deaths will be adjudicated for a cause of death and relationship to the 
investigational device and the index/implant procedure. 
 
Cardiovascular mortality  
Expirations for any of the contributing conditions such as Heart failure, Myocardial 
infarction, Major bleeding, Thromboembolism, Stroke, Arrhythmia and conduction 
system disturbance, Cardiovascular infection and sepsis (e.g., mediastinitis and 
endocarditis), Tamponade, Sudden, unexpected death Other cardiovascular, Device 
failure, Death of unknown cause (adjudicated as cardiovascular) 
 
Noncardiovascular mortality 
Any death in which the primary cause of death is clearly related to another 
condition such as Non-cardiovascular infection and sepsis (e.g., pneumonia,) 
Renal failure, Liver failure, Cancer, Trauma, Homicide, Suicide, Other non-
cardiovascular causes. 
 
 
Disabling Stroke 
Stroke is defined as a focal or global neurological deﬁcit lasting more than 24 h OR less 
than 24 h if available neuroimaging documents a new intracranial or subarachnoid 
hemorrhage (hemorrhagic stroke) or central nervous system infarction (ischemic stroke) 
OR the neurological deﬁcit results in death. 
 
A disabling stroke includes any neurological deficit (for example partial visual field cut) 
with a modified Rankin scale score equal or more than 2 with an increase in equal 1 or 
more modified Rankin scale score category from individual’s pre-stroke baseline at 90 days 
after stroke onset. 
 
 
Life-threatening Bleeding 
Bleeding in a critical organ, such as intracranial, intraspinal, intraocular, intrathoracic, or 
pericardial necessitating surgery or intervention, or intra- muscular with compartment 
syndrome OR bleeding causing hypovolemic shock or hypotension (systolic blood pressure 
<90 mm Hg lasting >30 min and not responding to volume resuscitation) or requiring 
signiﬁcant doses of vasopressors or surgery. 
 
Fatal Bleeding:   Bleeding adjudicated as being a proximate cause of death. Severe 
bleeding adjudicated as being a major contributing cause of a subsequent fatal 
complication, such as MI or cardiac arrest, is also considered fatal bleeding. 
 
 

EDWARDS LIFESCIENCES LLC 
 
 
ASCEND CLINICAL INVESTIGATIONAL PLAN  
PROTOCOL NUMBER: 2018-22 
 
CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B: 25 NOVEMBER 2019 
 
 
PAGE 21 OF 61 
 
 
 
Major device or procedure related serious adverse event 
All Major Serious Adverse Events adjudicated as device or procedure related, as defined by 
modified MVARC (Stone, et al.) including: 
 
• 
Procedure or Device related Death 
• 
Procedure or Device related Stroke 
• 
Procedure or Device related Life-threatening bleeding (MVARC scale) 
• 
Major vascular or access (index procedure) complications 
• 
Major cardiac structural complications related or cause by device or procedure 
• 
Procedure related Stage 2 or 3 acute kidney injury (includes new dialysis) 
• 
Procedure related Myocardial infarction or coronary ischemia requiring PCI or CABG 
• 
Procedure or device related severe hypotension, heart failure, or respiratory failure 
requiring intravenous pressors or invasive or mechanical heart failure, treatments 
such as ultrafiltration or hemodynamic assist devices, including intra-aortic balloon 
pumps or left ventricular or biventricular assist devices, or prolonged intubation for 
more than 48 h. 
• 
Any device-related dysfunction, migration, thrombosis, or other complication 
requiring surgery or repeat intervention including: 
o Structural or Functional failure of the HARPOON device, introducer or 
artificial chords (ePTFE) requiring an intervention. 
o Conversion to the Open Mitral Valve Surgery secondary to mitral valve 
apparatus damage or dysfunction, requiring surgical valve repair or 
replacement, or Secondary to procedural complications (such as cardiac 
perforation, removal of an embolized artificial chords, injury to Aortic valve 
and so on) 
o Device malpositioning (Artificial chords malpositioning) requiring 
intervention. Permanent deployment of artificial chord(s) in a location 
other than intended or movement of the artificial chords during or post 
deployment which requires an intervention. 
o Artificial Chord detachment (used with HARPOON device) which requires an 
intervention 
o Device fracture: a break, tear, perforation, or other structural defect in the 
artificial chords (housing, leaflet, and so on) resulting in device failure, 
resulting in recurrent MR symptoms, or requiring reintervention. 
o Damage to the native mitral valve apparatus (damage to native chordae 
tendinae, Leaflets, Papillary muscles or Mitral annulus) requiring an 
intervention or conversion to Open Mitral Valve Surgery. 
o Symptomatic or requiring intervention Device Thrombosis (any thrombus 
attached or near the artificial HARPOON implanted chords) 
o Interaction with non-mitral valve intracardiac structures which requires 
intervention and 
o Endocarditis (as diagnosed by modified Duke endocarditis criteria or 
evidence of abscess, pus, or vegetation confirmed as secondary to infection 

EDWARDS LIFESCIENCES LLC 
 
 
ASCEND CLINICAL INVESTIGATIONAL PLAN  
PROTOCOL NUMBER: 2018-22 
 
CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B: 25 NOVEMBER 2019 
 
 
PAGE 22 OF 61 
 
 
by histological or bacteriological studies during an operation or autopsy) 
which required a surgical intervention. 
o Hemolysis (a presence of a leaflet perforation on transesophageal or 
transthoracic echocardiography plus anemia requiring transfusion plus 
increased haptoglobin and/or LDH levels; which lead to a surgical 
intervention. 
o Other major device or procedure related SAEs 
7.4 
NUMBER OF SUBJECTS 
Two-hundred and fifty (250) subjects will be implanted at up to twenty-five (25) centers in Europe. The 
enrolment period completion is anticipated to be two (2) years.   
 
 

EDWARDS LIFESCIENCES LLC 
 
 
ASCEND CLINICAL INVESTIGATIONAL PLAN  
PROTOCOL NUMBER: 2018-22 
 
CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B: 25 NOVEMBER 2019 
 
 
PAGE 23 OF 61 
 
 
8.0 STUDY POPULATION 
8.1 
SUBJECT INCLUSION CRITERIA 
A subject who meets all of the following criteria potentially may be included in the study: 
1. Subject is > 18 years old 
2. Presence of severe MR as read on a transthoracic echocardiographic study  
3. Mitral leaflet coaptation surface is sufficient to reduce mitral regurgitation without undue 
leaflet tension (approximate leaflet to gap ratio of 2:1) based on the judgment of the patient 
eligibility committee and the operating surgeon  
4. Degenerative mitral valve disease with mid-segment P2 prolapse  
5. Patient is able to sign informed consent and able to return for follow-up and is capable of 
participating in all testing associated with this clinical investigation 
 
8.2 
SUBJECT EXCLUSION CRITERIA 
A subject who meets any of the following criteria will not be included in the study: 
 
1. Patient is of the age where further growth is expected  
2. Active endocarditis 
3. Left ventricular or left atrial appendage thrombus 
4. Severe mitral annular and/or leaflet calcification 
5. Cannot tolerate procedural anticoagulation or post-procedure antiplatelet regimen 
6. Mitral stenosis 
7. Functional Mitral Valve disease 
8. Previous mitral valve replacement surgery 
9. Fragile or thinning apex 
10. Contraindications to transesophageal echocardiography (atlantoaxial disease, severe 
generalized cervical arthritis, upper gastrointestinal bleeding, significant dysphagia and 
odynophagia, has received extensive radiation to the mediastinum). 
11. Patient is pregnant or lactating 
 
8.3 
SCREENING AND ENROLMENT 
All subjects who are clinically suitable for treatment with the HARPOON System, and who meet the 
study inclusion/exclusion criteria will be approached for inclusion in the study.  (Subjects who do not 
wish to participate in the study may be treated with the HARPOON System outside of the study.)   
Subjects who agree to participate will sign an Ethics Committee (EC)-approved study informed consent 
and will be considered part of the enrolled population.    
 
8.4 
SUBJECT AND STUDY DURATION 
The total enrolment period for this study is estimated to be two years, with an estimated start date in 
Q4 2019 and estimated completion in Q4 2021.  Follow-up for implanted subjects is five years, therefore 
the entire study duration is seven years, with an estimated completion in Q1 2027. 
 

EDWARDS LIFESCIENCES LLC 
 
 
ASCEND CLINICAL INVESTIGATIONAL PLAN  
PROTOCOL NUMBER: 2018-22 
 
CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B: 25 NOVEMBER 2019 
 
 
PAGE 24 OF 61 
 
 
9.0 STUDY PROCEDURES AND SCHEDULE OF ASSESSMENTS 
9.1 
SUBJECT SCREENING AND INFORMED CONSENT 
 
All subjects who are clinically suitable for treatment with the HARPOON System and meet study 
eligibility requirements will be asked to participate in further screening and will sign a study-specific 
Ethics Committee (EC) approved study informed consent form.  
 
A “Screening Log” is provided to the investigational sites to maintain a cumulative log of all screened 
subjects. For subjects who are ineligible for participation in the clinical investigation or choose not to 
participate, a reason supporting the disqualification of the subject shall be entered on the Screening Log.  
Sites are not required to enter any data into the EDC system for screen failures.   
 
 

EDWARDS LIFESCIENCES LLC 
 
 
ASCEND CLINICAL INVESTIGATIONAL PLAN  
PROTOCOL NUMBER: 2018-22 
 
CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B: 25 NOVEMBER 2019 
 
 
PAGE 26 OF 61 
 
 
9.3 
SCREENING EVALUATIONS AND PATIENT ELIGIBILITY COMMITTEE 
All screening testing and assessment to determine if a patient is suitable for treatment with the 
HARPOON System is conducted within the standard-of care at the hospital outside of the study.  This 
assessment includes the review of the patient’s 3D TOE by a Patient Eligibility Committee (PEC) who will 
independently assess the eligibility of the patient for general treatment with the device.   
 
Only once a patient is confirmed to be eligible (Pass) for treatment with the HARPOON System, is the 
patient approached for inclusion in the post-market study.  Once consented and enrolled, the results of 
the previously-conducted HARPOON System suitability screening will be recorded as historical data.   
 
 
9.4 
BASELINE/PRE-PROCEDURE EVALUATIONS 
Once the subject has signed a study informed consent, data from the following assessments which 
would have already been conducted as part of the standard of care, will be recorded: 
• 
Routine laboratory assessment (recording any of the following that are done as part of the 
standard of care: WBC count; haemoglobin haematocrit, platelet count, creatinine, INR, total 
albumin, total bilirubin, BNP, NTproBNP) 
• 
Routine electrocardiogram (ECG) 
• 
Routine physical examination 
• 
Assessment of NYHA Heart Failure Class 
• 
Transthoracic echocardiogram (TTE)  
• 
3D Transoesophageal echocardiogram (TOE)  
• 
Patient Eligibility Committee report of the TOE 
• 
Assessment of Medical History 
 
The following baseline assessments will be conducted as part of the study following informed consent. 
• 
Assessment of STS score risk 
• 
Assessment of EURO score risk 
• 
6 Minute Walk Test 
• 
Quality of Life Assessment - SF-36  
• 
Quality of Life Assessment - KCCQ 
• 
Assessment of cardiac medications  
• 
Pregnancy test (if applicable) 
 
 
9.5 
TREATMENT/PROCEDURE ASSESSMENTS 
 
9.5.1 
PROCEDURE OVERVIEW: 
The HARPOON System procedure will be conducted in accordance to the HARPOON System CE-Mark 
Instructions for Use.   
 

EDWARDS LIFESCIENCES LLC 
 
 
ASCEND CLINICAL INVESTIGATIONAL PLAN  
PROTOCOL NUMBER: 2018-22 
 
CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B: 25 NOVEMBER 2019 
 
 
PAGE 27 OF 61 
 
 
The study investigator will be trained in device use through didactic, practicum training, and proctoring. 
Complete details on the preparation and use of the HARPOON System can be found in the device’s 
Instructions for Use. 
 
 
9.5.2 
CONVERSION TO MITRAL VALVE SURGERY 
If in the judgment of the operating surgeon, adequate MR reduction has not been achieved, or if for any 
other clinical reason, conversion to standard-of-care mitral valve surgery shall be performed.  Subjects 
who undergo a conversion to standard-of-care mitral valve surgery shall continue safety assessments (all 
tests identified in this protocol at each follow-up visit) through 30 days or until resolution of any adverse 
events related to the procedure, and then exited from the study. 
 
9.5.3 
PRIMARY FOLLOW-UP ASSESSMENTS 
Post-procedure management: Standard hospital protocols for the management of subjects after mitral 
valve surgery shall be followed.   
 
7-Day/Discharge assessment: All subjects shall be discharged from the hospital at the discretion of the 
attending cardiac surgeon.  Prior to discharge, all subjects shall undergo a comprehensive pre-discharge 
TTE as well as a physical exam on either day 7 or at the time of discharge, whichever occurs first. 
 
Primary subject follow-up: Subjects shall be seen at 30 days (+20/-0 days) after the HARPOON System 
procedure.  A TTE and specific clinical assessments, in accordance with the Schedule of Assessments, 
shall be performed at that time. 
 
Additional clinical and TTE follow-up shall occur for all active subjects in accordance with the Schedule of 
Assessments at the following intervals: 
• 
6-months (+/- 30 days) 
• 
12-months (+/- 30 days) 
• 
18-months (+/- 30 days) 
• 
24-months (+/- 60 days) 
• 
36-months (+/- 60 days) 
• 
48-months (+/- 60 days) 
• 
60 months (+/- 60 days) 
 
9.6 
MISSED FOLLOW-UP 
The Investigator(s) will make every attempt to follow the subjects. All subjects will be encouraged by the 
Investigator(s) to report any address or telephone number changes to the study site personnel. Subjects 
should be informed of the importance of returning for scheduled follow-up visits even if they are not 
having any medical issues. 
 
If a subject cannot be reached for a follow-up visit, or misses a scheduled visit, and is not willing to go to 
a local hospital/clinic for protocol-required assessments, the visit will be recorded as a missed visit on 
the date of last attempted contact. The procedure for attempts at contact should be two phone calls 
made and recorded in the study medical record.  Subjects who miss a visit will not be considered 

EDWARDS LIFESCIENCES LLC 
 
 
ASCEND CLINICAL INVESTIGATIONAL PLAN  
PROTOCOL NUMBER: 2018-22 
 
CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B: 25 NOVEMBER 2019 
 
 
PAGE 28 OF 61 
 
 
withdrawn. Subjects who miss two (2) sequential follow-up visits may be considered lost to follow-up at 
the second missed visit, and exited from the study.  
 
9.7 
STUDY EXIT CRITERIA AND PROCEDURES 
The reason for study exit will be documented on the appropriate case report forms and in the medical 
records for each subject who exits the study. 
Subjects may exit the study for any of the following reasons: 
• 
Screen Failure 
• 
Device Attempted but Not Implanted 
o Enrolled subjects for whom the implant procedure was prematurely aborted (e.g., 
entered operating room and anesthesia induced, but study procedure not 
attempted) or the HARPOON procedure was attempted but device not implanted, 
will be followed for 30 days or until resolution of any adverse events related to the 
implant procedure, and then exited from the study. 
• 
Device Reintervention or Explant 
o Subjects who have a surgical reintervention where the device is explanted will be 
followed for 30 days post-reintervention or until resolution of any adverse events 
related to the procedure, and then exited from the study.  
• 
Completion per Protocol 
• 
Withdrawal 
o Subject Withdrawal: The subject may voluntarily withdraw from the clinical 
study at any time, without penalty or loss of benefits to which they are 
otherwise entitled. 
o Physician Withdrawal: The Investigator also has the right to withdraw a subject if 
s/he feels it is in the best interest of the subject. 
o Sponsor Withdrawal: The Sponsor may prematurely terminate the study. 
Circumstances under which the Sponsor can suspend or stop this trial include, but 
are not limited to, low study enrolment or new information regarding safety or 
efficacy. 
• 
Death 
• 
Lost to Follow-up 
o If a subject cannot be reached for a follow-up visit, the Investigator will document 
the contact efforts made to the subject and/or effort to obtain hospital records in 
the appropriate electronic case report form.  
 
For subjects who are lost-to-follow-up or withdraw early, Edwards may request the site to search 

EDWARDS LIFESCIENCES LLC 
 
 
ASCEND CLINICAL INVESTIGATIONAL PLAN  
PROTOCOL NUMBER: 2018-22 
 
CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B: 25 NOVEMBER 2019 
 
 
PAGE 29 OF 61 
 
 
death registries as available or applicable per GDPR requirements and may request the site to obtain 
the death certificate, if applicable. 
In all cases of withdrawal (as described above), withdrawn subjects will not undergo further study follow-
up procedures after the time of study exit. A study subject who has been withdrawn from the study will 
not be replaced. 
 
9.8 
DEATH AND SURGICAL VALVE INTERVENTION 
9.8.1 
DEATH 
 
In the event of subject death, every effort should be made to obtain a copy of a death summary/death 
certificate. Information on the cause of death will be determined by the investigator(s) and reported in 
the study EDC system.   
 
9.8.2 
SURGICAL VALVE INTERVENTION 
 
In the event of explant/subject surgical valve intervention, every effort should be made to obtain a copy 
of the procedure notes as well as any accompanying imaging data (CT, echo). Information on the cause 
of explant/surgical intervention will be determined by the investigator(s) and reported in the study EDC 
system.  Subjects who have a surgical reintervention or whose device is explanted will be followed for 30 
days or until resolution of any adverse events related to the procedure, and then exited from the study. 
Effort should also be made to return any explanted study devices to the Sponsor for analysis by the 
Edwards Complaint Handling team.  Return kits for explanted devices will be provided, upon request, by 
the Edwards Surgical Complaint Handling Department.  
 
 

EDWARDS LIFESCIENCES LLC 
 
 
ASCEND CLINICAL INVESTIGATIONAL PLAN  
PROTOCOL NUMBER: 2018-22 
 
CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B: 25 NOVEMBER 2019 
 
 
PAGE 30 OF 61 
 
 
10.0 ENDPOINT ANALYSIS AND STATISTICAL METHODS 
10.1 ANALYSIS POPULATION 
The analysis population is the 250 subjects who were implanted and entered the HARPOON System 
procedure, regardless of procedure outcome.  The analysis population excludes any subjects who signed 
the study consent (were enrolled) but were exited from the study prior to the procedure. 
 
10.2 SAMPLE SIZE RATIONALE 
Edwards has established a minimum sample size of 250 participants for this study. The rationale for this 
sample size can be viewed from two different perspectives: precision of estimation and statistical 
monitoring for product failure. 
 
10.2.1 PRECISION OF ESTIMATION 
Regarding precision of estimation, the relevant statistical properties for n=250 are 
straightforward. As with any descriptive study, the principal impact of sample size is on precision 
of estimation, typically expressed in terms of a confidence interval. Increasing sample size 
always improves precision; however, the corresponding gain in precision eventually is small 
when weighed against the increase in study cost, time and complexity. An ideal sample size 
represents a balance between resources, time and precision of estimation. 
 
Simple rates and proportions, and their corresponding 95% confidence intervals are the most 
easily understood method of analysis for the primary outcomes (MR grade and major serious 
device- or procedure-related adverse events) as well as the various safety parameters, 
performance measures and subject outcomes measured in this study. 
 
Observed rates from 2% (0.02) to 17% (0.17) represent the full range of event rates (or their 
compliments) likely to be observed in this study. Adopting a precision goal of 5% or better for 
the full range (2% to 17%) of rates that are likely to be observed, a sample size of 250 is 
reasonable. Regardless of the rate considered, there is a substantial improvement in precision as 
sample size is increased from 50 to 100. However, the amount of improvement is much smaller 
as the sample size is increased further. 
 
10.2.2 STATISTICAL MONITORING FOR PRODUCT FAILURE 
Chord failures, detected by echo, will be monitored in a semi-continuous manner to detect a 
suspicious failure rate as early as possible. Detailed echo screenings will be performed at 
discharge, 30 days, 6 months, 12 months, and beyond, including unscheduled echos as deemed 
appropriate due to clinical symptoms. An adaptive algorithm will be used to analyse the 12-
month failure rate for the device. The sample size of 250 subjects provides greater than 80% 
power to detect an underlying failure rate of 10% or greater.  
 
10.2.3 SAMPLE SIZE RATIONALE CONCLUSION 
The sample size for this study (n=250) provides adequate support for statistical estimation of the 
safety parameters, performance measures and subject outcomes measured in this study 

EDWARDS LIFESCIENCES LLC 
 
 
ASCEND CLINICAL INVESTIGATIONAL PLAN  
PROTOCOL NUMBER: 2018-22 
 
CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B: 25 NOVEMBER 2019 
 
 
PAGE 31 OF 61 
 
 
including the primary outcomes of MR grade and major serious device- or procedure-related 
adverse events. In addition, this sample size provides acceptable power for statistical monitoring 
of apparent product failure. 
 
10.3 STUDY ENDPOINT TESTING 
The following outlines the test outcomes for success/failure of each of the stated endpoints: 
 
10.3.1 PRIMARY SAFETY ENDPOINT TEST:  
Freedom from all-cause mortality, disabling stroke and life- threatening bleeding at 30 days post-
implant.  
 
10.3.2 PRIMARY PERFORMANCE ENDPOINT TEST:  
Procedure success at 30 days post-treatment, as measured by: technical success with reduction of 
MR to less than or equal to mild and the absence of major device or procedure-related SAEs.   
 
 
10.4 ADDITIONAL PLANNED ANALYSES  
The following analyses are planned:  
• 
Technical success defined as survival and exit from the operating room (OR) with successful 
implantation of 3 or more ePTFE chords 
• 
Freedom from major device or procedure-related serious adverse event (SAE) at 30 days, 1 
year and 2 years post-implant 
• 
Quality of Life (change from baseline to 1 and 6 months)  
• 
6 minute walk test (change from baseline to 1 and 6 months) 
• 
Freedom from ePTFE chord rupture as reported by echo core lab at 1 year and 2 years 
post-implant 
• 
Freedom from reoperation or re-intervention due to ePTFE chord rupture at 1 year and 2 
years post-implant 
• 
Functional improvement from baseline NYHA Functional Classification at 1 year and 
2 years post-implant 
• 
Freedom from reoperation or reintervention on the mitral valve annually through 5 
years post-implant 
• 
Freedom from ≥ moderate MR annually through 5 years post-implant 
 
To address the uncertainty around ePTFE chord rupture, an initial analysis of apparent product failure 
will be conducted once 50 patients achieve 12 months of follow-up. Thereafter, a failure analysis will be 
repeated for each subsequent 10 patients achieving 12 months of follow-up. The rates of apparent 
product failure will be deemed unacceptable if the lower limit of any 95% confidence interval at 12 
months is above 6% (inclusive of 95% CI). It should be noted that “Failure” is defined conservatively as 
suspected ePTFE chord rupture based only on echo. Confirmation of a rupture, which requires 
reoperation, is not required. 

EDWARDS LIFESCIENCES LLC 
 
 
ASCEND CLINICAL INVESTIGATIONAL PLAN  
PROTOCOL NUMBER: 2018-22 
 
CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B: 25 NOVEMBER 2019 
 
 
PAGE 32 OF 61 
 
 
 
10.5 STATISTICAL ANALYSIS METHODOLOGY 
The primary safety and performance endpoints will be summarized by counts, percentages and 
corresponding 95% confidence intervals. Other categorical variables will be summarized by counts and 
percentages. Continuous variables will be summarized using means, medians, ranges and standard 
deviations. Time to event analysis, including survival probabilities and standard errors, will be estimated 
using the Kaplan Meier method. Time to event will be calculated in days and standard errors will use the 
greenwood algorithm. 
 
Statistical calculations will be based on all available data. No missing value imputations are planned for 
the primary and secondary analyses will be performed. Missing month and days for adverse events will 
be imputed. Regarding the secondary endpoint, an initial analysis of apparent product failure will be 
conducted once 50 subjects achieve 12 months of follow-up. Thereafter, a failure analysis will be 
repeated for each subsequent 10 subjects achieving 12 months of follow-up. The rates of apparent 
product failure will be deemed unacceptable if the lower limit of any 95% confidence interval at 12 
months is above 6%. 
 
10.6 METHODS USED TO MINIMISE BIAS  
The following methods are employed to minimise bias in the study: 
 
10.6.1 INCLUSION BIAS 
All patients clinically eligible for treatment with the HARPOON System device and who meet the study 
criteria will be offered inclusion in the study. 
 
10.6.2 ENDPOINT EVALUATION 
An independent Echo Core Lab will evaluate all echocardiograms performed as part of the protocol (and 
in particular in relationship to the Primary Performance Endpoint and the Secondary chord rupture 
monitoring endpoint), and an independent Clinical Events Committee will adjudicate all potential safety 
endpoints and reinterventions through 2-year follow-up. 
 
10.6.3 REPORTED DATA VERACITY 
Routine monitoring will be conducted for all reported data according to the study monitoring plan. 
 
10.6.4 AVOIDING ANALYSIS BIAS 
Statistical analysis will be conducted according to a pre-specified Statistical Analysis Plan (SAP).  
 
10.6.5 PUBLICATION BIAS  
The study will be registered at clinicaltrials.gov to ensure that publication of results will occur whether 
results are favourable or unfavourable to the sponsor.   
 
 

EDWARDS LIFESCIENCES LLC 
 
 
ASCEND CLINICAL INVESTIGATIONAL PLAN  
PROTOCOL NUMBER: 2018-22 
 
CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B: 25 NOVEMBER 2019 
 
 
PAGE 35 OF 61 
 
 
• 
the serious event does not follow a known response pattern to the medical device (if 
the response pattern is previously known) and is biologically implausible; 
• 
the discontinuation of medical device application or the reduction of the level of 
activation/exposure - when clinically feasible – and reintroduction of its use (or increase 
of the level of activation/exposure), do not impact on the serious event; 
• 
the event involves a body-site or an organ not expected to be affected by the device or 
procedure; 
• 
the serious event can be attributed to another cause (e.g. an underlying or concurrent 
illness/ clinical condition, an effect of another device, drug, treatment or other risk 
factors); 
• 
harms to the subject are not clearly due to use error; 
• 
In order to establish the non-relatedness, not all the criteria listed above might be met 
at the same time, depending on the type of device/procedures and the serious event. 
2) Unlikely: the relationship with the use of the device seems not relevant and/or the event can 
be reasonably explained by another cause, but additional information may be obtained. 
3) Possible: the relationship with the use of the investigational device is weak but cannot be 
ruled out completely. Alternative causes are also possible (e.g. an underlying or concurrent 
illness/ clinical condition or/and an effect of another device, drug or treatment). Cases were 
relatedness cannot be assessed or no information has been obtained should also be classified as 
possible. 
4) Probable: the relationship with the use of the investigational device seems relevant and/or 
the event cannot reasonably have explained by another cause, but additional information may 
be obtained. 
5) Causal relationship: the serious event is associated with the investigational device or with 
procedures beyond reasonable doubt when: 
• 
the event is a known side effect of the product category the device belongs to or of 
similar devices and procedures; 
• 
the event has a temporal relationship with investigational device use/application or 
procedures; 
• 
the event involves a body-site or organ that 
• 
the investigational device or procedures are applied to; 
• 
the investigational device or procedures have an effect on; 
• 
the serious event follows a known response pattern to the medical device (if the 
response pattern is previously known); 
• 
the discontinuation of medical device application (or reduction of the level of 
activation/exposure) and reintroduction of its use (or increase of the level of 
activation/exposure), impact on the serious event (when clinically feasible); 

EDWARDS LIFESCIENCES LLC 
 
 
ASCEND CLINICAL INVESTIGATIONAL PLAN  
PROTOCOL NUMBER: 2018-22 
 
CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B: 25 NOVEMBER 2019 
 
 
PAGE 36 OF 61 
 
 
• 
other possible causes (e.g. an underlying or concurrent illness/ clinical condition or/and 
an effect of another device, drug or treatment) have been adequately ruled out; 
• 
harm to the subject is due to error in use. 
 
In order to establish the relatedness, not all the criteria listed above might be met at the same time, 
depending on the type of device/procedures and the serious event. 
 
11.3 REPORTING ADVERSE EVENTS 
 
11.3.1 REPORTING BY THE INVESTIGATOR  
 
Adverse Event reporting to the sponsor is the Investigator’s responsibility and will start at time of 
enrolment and will continue until a closure of the study follow-up or until a subject exits the study. 
Adverse events will be recorded on the Electronic Case Report Form by the Clinical Study Coordinator (or 
any designated site personnel). If the system is not accessible, the event can be reported to sponsor by 
using the following e-mail address: ASCEND-Safety@edwards.com 
AE information (start and stop date, description of event, severity, and relatedness to the HARPOON 
System procedure and the HARPOON System) will be assessed and recorded in the EDC system in a 
timely manner by the site. Whether an AE meets the definition for serious adverse event will be 
determined by the study investigator using the ISO 14155 definition (see Table 4).  Relatedness of the AE 
to the index procedure or the HARPOON System device itself will be judged by the investigator by using 
the causality categories listed in Section 11.2.  
 
The investigator shall notify the sponsor immediately and not later than 3 calendar days after the 
investigator has become aware of a SAE or device deficiency that might have led to a SAE by completing 
the Adverse Event electronic Case Report Form. 
 
All reported events will be followed until resolution, stabilization or 30 days after the last subject 
implanted has completed the study, whichever occurs first. 
 
11.3.2 SAFETY ASSESSMENT AND REPORTING BY THE SPONSOR 
 
The Safety Overview and Process (Adverse Event Handling) in the ASCEND Study has been established as 
an independent two-level review of reported Adverse Events (AE) and Device Deficiencies conducted by 
the Sponsor’s Safety Department and an independent clinical adjudication of potential safety endpoints 
(Death, stroke, bleeding) and reintervention post index procedure by the Clinical Events Committee 
(CEC). The process includes: 
 
Adverse Event Review   Upon receipt of Adverse Event (AE) notification (electronic EDC , email ASCEND-
Safety@edwards.com), reported by the Investigator and/or Research Coordinator, Safety conducts a 
Sponsor Assessment of each AE on the AE Review form as per Regulatory requirements specific to the 

EDWARDS LIFESCIENCES LLC 
 
 
ASCEND CLINICAL INVESTIGATIONAL PLAN  
PROTOCOL NUMBER: 2018-22 
 
CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B: 25 NOVEMBER 2019 
 
 
PAGE 37 OF 61 
 
 
study/region where the study is conducted, per MEDDEV 2.7/3 (Clinical Investigations: Serious Adverse 
Event Reporting), MEDDEV 2.12-1 rev 8 (Vigilance Reporting), ISO 14155-2011 (Clinical investigation of 
Medical Devices for Human Subjects) where applicable and internal EW standard operating procedures, 
including USADE decision and complaint reporting.   
  
AEs are assessed as serious or non-serious, assessed for causality, and if anticipated or unanticipated.  
Any updated AE is re-assessed for seriousness, causality and if anticipated or unanticipated.  In any 
urgent situation concerning patient’s safety or to report an unanticipated adverse device effect (USADE), 
the sites can contact Edwards Surgical Safety, Safety Officer directly. 
  
• 
USADE Reporting   During Safety’s AE review, any AE assessed as a USADE will be reported as soon 
as possible to EW Regulatory Affairs (RA) and by RA to the EU Regulatory Authorities within local 
regulatory requirements and timelines.  Safety will notify all ethics committees and Investigators as 
required. 
• 
CRO Responsibilities   This study is monitored by an external CRO to ensure complete AEs and SAEs 
reporting through a monitoring process as identified/described in the monitoring plan, and to verify 
that all reported data are consistent and queries answered.   
• 
Complaint Reporting   In addition, as required in post market investigation, each AE will be assessed 
in regards to a device causality, and will be reported to the Edwards EU Complaint Handling group. 
EU Complaint Group will assess and report appropriately all device complaints to EU Authorities as 
per MEDDEV 2.12-1. 
Clinical Events Committee (CEC) Adjudication   During the Sponsor’s Safety review potential safety 
endpoints and reinterventions are identified for adjudication.  If an event meets the safety endpoint 
definition as specified in the protocol and CEC Charter (or can possibly be related to any safety endpoint, 
although reported as “Other”), the source documents are requested from the site to support CEC 
adjudication.  
 
The CEC reviews forwarded events and their source documents to verify if additional records are 
required, and to determine if the event meets the safety endpoint definition (as in the CEC Charter).   
During this process non-reported events can be identified by the CEC and queried to Edwards Safety 
Team for additional information.  CEC activities are outlined in the CEC Charter. 
 
11.3.3 SAFETY REPORTING TO AUTHORITIES  
 
Depending on the local requirements or following agreement between both parties, the sponsor or the 
principal investigator will be responsible for performing safety reporting to the Ethics Committees 
according to the relevant local regulatory requirements.  
The sponsor or sponsor designee will report all reportable Events to the National Competent 
Authority in accordance with the Medical Device Directive and all applicable official guidelines and 
national regulations. 
 

EDWARDS LIFESCIENCES LLC 
 
 
ASCEND CLINICAL INVESTIGATIONAL PLAN  
PROTOCOL NUMBER: 2018-22 
 
CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B: 25 NOVEMBER 2019 
 
 
PAGE 38 OF 61 
 
 
11.4 CLINICAL EVENTS COMMITTEE ADJUDICATION 
The study will have an independent Clinical Events Committee (CEC) whose role it will be to review all 
potential safety endpoints and reinterventions through 24-month follow-up for final safety endpoint 
evaluation as well as device and procedure relatedness. All CEC activities and the detailed adjudication 
process is regulated by the CEC Charter. 
 
 
 

EDWARDS LIFESCIENCES LLC 
 
 
ASCEND CLINICAL INVESTIGATIONAL PLAN  
PROTOCOL NUMBER: 2018-22 
 
CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B: 25 NOVEMBER 2019 
 
 
PAGE 39 OF 61 
 
 
12.0 DEVICE DISTRIBUTION, ACCOUNTABILITY, AND REPORTING 
12.1 DEVICE TRACEABILITY 
Each component of the HARPOON System will be traceable via a lot number. Lot numbers are assigned 
according to date of manufacture and/or sterilization. 
Records of device shipments will be maintained at Edwards Lifesciences in accordance with Quality 
System and internal procedures. As the HARPOON System to be used in this study has CE mark, device 
accountability records will not be required as the device is non-investigational. Lot numbers of devices 
used in/implanted in study subjects will be recorded within the study to provide traceability. 
 
12.2 DEVICE MALFUNCTIONS AND FAILURE – VIGILANCE REPORTING 
Should any device defect or malfunction be noticed at any point, whether prior to, during, or after a 
procedure, this defect or malfunction will be reported through the Edwards Lifesciences standard 
vigilance reporting process. 
 
 

EDWARDS LIFESCIENCES LLC 
 
 
ASCEND CLINICAL INVESTIGATIONAL PLAN  
PROTOCOL NUMBER: 2018-22 
 
CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B: 25 NOVEMBER 2019 
 
 
PAGE 40 OF 61 
 
 
13.0 BENEFITS AND RISKS 
13.1 BENEFITS 
13.1.1 BENEFITS OF THE HARPOON SYSTEM AS COMPARED TO ALTERNATIVE TREATMENTS 
Mitral valve regurgitation (MR) results in volume overload on the left ventricle, which in turn leads to 
ventricular dilation, decreased ejection performance, pulmonary hypertension, symptomatic congestive 
heart failure, atrial fibrillation, right ventricular dysfunction and death. Successful mitral valve repair 
restores mitral valve competence, eliminates volume overload on the left ventricle, improves symptom 
status and prevents adverse left ventricular remodelling. MR is corrected either by surgical open repair 
or replacement with a surgical mitral valve. Conventional mitral valve repair is performed with the 
support of cardio-pulmonary bypass (CPB). The key clinical benefit of the HARPOON System is the 
elimination of need for CPB to perform mitral valve repair for reduction of MR which in turn provides 
relief from the symptoms of severe degenerative mitral valve disease.  HARPOON System facilitates 
mitral valve repair on a beating heart through a small incision without the need for CPB, thereby 
potentially reducing the perioperative complications such as wound infection, sternal dehiscence, 
bleeding, blood transfusions, cerebrovascular events, and renal failure. 
 
Compared with surgical valve replacement, mitral valve repair has the following advantages: 
 
• 
Lower operative mortality  
• 
Improved left ventricular function  
• 
Lower risk of stroke  
• 
Lower risk of infection  
• 
Freedom from anticoagulation and reoperation  
• 
Superior long-term survival  
 
While surgical mitral valve repair remains the gold standard, transcatheter techniques have the 
potential to decrease invasiveness and surgical morbidity, with shorter procedure and recovery times, 
while maintaining comparable performance.  
 
The HARPOON System facilitates echo image-guided placement and anchoring of ePTFE chords on the 
mitral valve leaflets, offers a simplified technique for off-pump repair of degenerative MR, image-guided 
placement and anchoring of the chords, and real-time beating heart titration of the artificial chordae 
length to maximise leaflet coaptation and minimise mitral regurgitation. The technology provides:  
 
• 
a low profile 9 Fr delivery system;  
• 
secure anchoring of the artificial chordae to the mitral leaflet with a proprietary “bulky knot” 
anchor;  
• 
easy to use delivery system that can implant an artificial ePTFE chord anywhere on the leaflet 
without the need to “catch” a moving leaflet;  
• 
ability to implant multiple artificial chords via a haemostatic valve to minimise blood loss; and  

EDWARDS LIFESCIENCES LLC 
 
 
ASCEND CLINICAL INVESTIGATIONAL PLAN  
PROTOCOL NUMBER: 2018-22 
 
CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B: 25 NOVEMBER 2019 
 
 
PAGE 41 OF 61 
 
 
• 
real-time, image guided adjustment of artificial chord length to maximise leaflet coaptation and 
minimise residual MR.  
 
The HARPOON System provides a treatment method for degenerative mitral valve disease without the 
need for a sternotomy, cardio-pulmonary bypass, aortic cross-clamping and cardiac arrest.  
 
It is therefore expected that the risks and the long-term discomfort associated with open heart surgery 
will be reduced because the HARPOON System is implanted using a less invasive procedure compared to 
classical open-heart surgery. These innovations result in a simpler procedure and may reduce trauma to 
the heart and blood loss. 
 
13.1.2 BENEFITS OF PARTICIPATING IN THE ASCEND STUDY 
As this study is a post-market study, the patient will receive treatment with the HARPOON System 
whether or not s/he takes part in this study.  As part of the study, subjects would receive a higher level 
of echo imaging and clinical follow-up than they would outside of the study environment. They also have 
a dedicated clinical research team following their progress.   Finally, an additional benefit in participating 
in the study is that it furthers knowledge of this treatment.  The study may also allow the subject to 
receive therapy with this device and procedure with potentially lower complications than conventional 
method which in turn may benefit other patients in the future. 
 
 
13.2 RISKS 
13.2.1 HARPOON SYSTEM PROCEDURE RISKS 
Prior evaluation in early feasibility and CE mark studies demonstrated reduced blood loss, reduced blood 
transfusions and no episodes of acute renal failure on comparison with conventional approaches to 
mitral valve repair. However, the HARPOON System implantation procedure may result in failures such 
as recurrence of MR or complications similar to commercially available devices with similar indications 
for use. Like any other new device, failures are related to factors such as learning curve, technical 
problems, procedural changes, and limited expertise with an investigational device. Risks are related to 
recurrence of MR secondary to rupture of ePTFE chords as previously described. Root cause analysis of 
chordal ruptures led to implementation of specific changes to case selection, pre-procedural screening, 
selection of appropriate echo-imaging technology to support the procedure, and procedural steps.  
 
Physicians routinely discuss the risks associated with the use of general anaesthetic and the procedure 
itself during the process of acquiring informed consent from a patient. Anticipated adverse events are 
discussed in section 13.2.2. 
 
13.2.2 ANTICIPATED ADVERSE DEVICE EFFECTS 
The Potential Adverse Events that may be associated with the use of the HARPOON System include but 
are not limited to the following conditions and their symptoms: 
 
• 
Abnormal lab values 
• 
Allergic reaction/Hypersensitivity to contrast media, medication or device materials 
• 
Anaemia 

EDWARDS LIFESCIENCES LLC 
 
 
ASCEND CLINICAL INVESTIGATIONAL PLAN  
PROTOCOL NUMBER: 2018-22 
 
CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B: 25 NOVEMBER 2019 
 
 
PAGE 42 OF 61 
 
 
• 
Angina 
• 
Arrhythmia or Conduction Disorders 
• 
Artificial Chord(s) (ePTFE) Detachment 
• 
Artificial Chord(s) embolization, migration, malposition or deployment in unintended location 
• 
Artificial Chord(s) (ePTFE) Rupture or Breakage 
• 
Bleeding 
• 
Cardiac Arrest/Cardiogenic Shock 
• 
Conversion to standard valve repair surgery or valve replacement 
• 
Damage to cardiovascular tissue/Cardiovascular injury 
• 
Damage to native chords (chordae tendinea) 
• 
Damage to native mitral valve apparatus 
• 
Device (artificial chord(s)) migration - etopic 
• 
Device (artificial chords) thrombosis 
• 
Dyspnoea 
• 
Embolization (air, calcific, material, thrombus, etc.) 
• 
Endocarditis 
• 
Exercise intolerance or weakness 
• 
Failure to deliver ePTFE artificial chord to the intended leaflet site 
• 
Fever 
• 
Heart Failure 
• 
Hematoma 
• 
Hemodynamic compromise 
• 
Haemolysis 
• 
Haemothorax 
• 
Hypertension 
• 
Hypotension 
• 
Infection   
• 
Inflammation 
• 
Injury to Left Atrium 
• 
Injury to Left Ventricle   
• 
Injury, perforation or damage of mitral valve or leaflets 
• 
Interaction with non-mitral valve intracardiac structures 
• 
Left Ventricular outflow tract obstruction 
• 
Mitral Regurgitation 
• 
Mitral Stenosis 
• 
Multiorgan failure 
• 
Myocardial Infarction 
• 
Nerve injury 
• 
Oedema 
• 
Other device functional malfunction with recurrent MR more than mild 
• 
Other structural deterioration of the device with recurrent MR more than mild 
• 
Pain at the incision site 
• 
Pericardial damage 

EDWARDS LIFESCIENCES LLC 
 
 
ASCEND CLINICAL INVESTIGATIONAL PLAN  
PROTOCOL NUMBER: 2018-22 
 
CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B: 25 NOVEMBER 2019 
 
 
PAGE 43 OF 61 
 
 
• 
Pericardial tamponade 
• 
Pericarditis 
• 
Pleural Effusion 
• 
Pulmonary embolism 
• 
Reaction to anaesthesia 
• 
Recurrent Mitral Regurgitation 
• 
Renal failure/insufficiency 
• 
Reoperation or emergency cardiac surgery 
• 
Respiratory event 
• 
Stroke/TIA 
• 
Sudden Death 
• 
Syncope 
• 
Thrombosis 
• 
Transvalvular flow disturbance 
 
Anticipated conditions may require medical treatment, intervention including surgery, or resolve in 
death or serious deterioration in the health of the subject.   
 
 
13.2.3 RESIDUAL DEVICE AND PROCEDURE RISKS  
On the basis of the risk analysis following the implementation of risk control measures, Edwards 
Lifesciences has identified a number of residual risks. Most of these are typical of the potentially severe 
consequences associated with any cardiac procedure, but the likelihood of occurrence was considered 
to be remote. These included damage to cardiac tissues or the introduction of air into the circulation, 
due to procedural error. Similarly, the possibility of sterility being compromised is a remote risk with any 
surgical device. 
 
13.2.4 RISKS ASSOCIATED WITH PARTICIPATION IN THE STUDY 
Participation in the ASCEND study carries additional assessments and imaging above the standard-of-
care.  Specifically, study subjects will be assessed via transthoracic echocardiogram (TTE) more often 
than they would outside of a clinical study.  The risk of TTE, however, as it is based on ultrasound 
technology, is minimal.  Other than the TTE, all other study-specific assessments are simply clinic and 
physical assessments that would be within the range of standard follow-up of patients with a MR 
history. 
 
An additional risk of participating in a clinical study is the risk of a lapse of confidentiality or exposure of 
personal identifying information.  Mitigation of this risk is noted in section 13.3. 
 
13.3 MINIMISING SUBJECT RISK 
Several safeguards are incorporated into the study to minimize subject risk.   
 
The HARPOON System has been studied in two pre-market studies and the device is being used in this 
study within the CE-marked indication for use. 

EDWARDS LIFESCIENCES LLC 
 
 
ASCEND CLINICAL INVESTIGATIONAL PLAN  
PROTOCOL NUMBER: 2018-22 
 
CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B: 25 NOVEMBER 2019 
 
 
PAGE 44 OF 61 
 
 
 
Prior to subject screening and within the standard of care, patients are assessed for clinical suitability for 
treatment with the HARPOON System by an independent Patient Eligibility Committee (PEC) to minimise 
the risk of known adverse device effects.  Only once eligibility for treatment has been confirmed are 
patients approached for inclusion in this post-market study.  Within the study, routine 
echocardiographic monitoring of subjects also mitigates the risk of adverse device effects.  An 
independent Clinical Events Committee will review all potential safety endpoint events and 
reinterventions, which allows a higher degree of monitoring of such risks throughout the study. 
 
Subject risk specific to the functioning of the device has been mitigated through a documented didactic 
and hands-on training programme for surgeons on the device and surgical technique, in alignment with 
the IFU as provided by Edwards Lifesciences. In addition to other device use specifics, the training 
includes the requirement of the implantation of 3 chords, the use of trans-oesophageal 
echocardiography (TOE) prior to and during the procedure, and direction on the appropriate tensioning 
of the chords to minimise the risk of device malfunction. 
 
The risk of lapse of patient confidentiality is mitigated by use of anonymised patient identification 
numbers (IDs) so that no personal-identifying information is entered into the electronic data capture 
(EDC) system, which is only accessible by trained study personnel.  Study records including personal 
identifying information will only be accessible to the site study team and monitors during routine 
monitoring of the data.  The transmission of study imaging utilises a software that ensures that images 
are appropriately anonymised prior to transmission.  Any publication of the study data will include 
aggregate results only and will not include any identifying information. 
 
13.4 JUSTIFICATION OF CLINICAL STUDY 
The risk involved in the clinical study is minimised due to the fact the device being used is CE-marked 
and the study design falls within the intended use population.  Subjects can still receive the same device 
treatment outside of the study.  The risk of participating in the study is only minimally increased as 
compared to receiving the device outside the study, as there is a higher degree of imaging (TTE) and 
clinical assessment than would be present otherwise.  Additionally, there are the risks involved in data 
collection.  These risks, though, have been mitigated by the benefit of additional clinical follow-up and 
closer care, as well as procedures which have been put in place to protect subjects’ personal 
information. 
 
 

EDWARDS LIFESCIENCES LLC 
 
 
ASCEND CLINICAL INVESTIGATIONAL PLAN  
PROTOCOL NUMBER: 2018-22 
 
CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B: 25 NOVEMBER 2019 
 
 
PAGE 45 OF 61 
 
 
14.0 STUDY AND DATA MANAGEMENT 
14.1 ECHOCARDIOGRAPHY CORE LAB 
The Echocardiography Core Lab is responsible for independently evaluating all baseline, procedural and 
follow-up echocardiograms submitted by study sites. The purpose of the Core Lab is to ensure unbiased, 
timely and consistent analysis of the diagnostic data, and for evaluating changes in subject status over 
the course of the study.  
 
Echocardiograms will be sent directly from the investigational sites to the Core Lab via an image transfer 
software. The Core Lab will enter the data into the electronic case report form (eCRF).  
 
14.2 CLINICAL EVENTS COMMITTEE 
The ASCEND Clinical Events Committee (CEC) is an independent institutionalized adjudicator who 
conducts real-time ongoing review of all potential safety endpoints and reinterventions. The review is 
done by independent reviewers, physicians ranging in speciality from interventional cardiology, 
structural heart radiology, and cardiac surgery.  The activities of the CEC along with the definitions and 
detailed process are described in the CEC Charter.  
 
14.3 PROTOCOL DEVIATIONS 
A protocol deviation is defined as an instance of failure to follow, intentionally or unintentionally, the 
requirements of the protocol.  The Investigator is not allowed to deviate from the study protocol except 
as specified in 5.6.4 c ISO 14155, to protect the rights, safety and well-being of human subjects under 
emergency circumstances. 
 
Deviations shall be reported to the study Sponsor regardless of whether medically justifiable or taken to 
protect the subject in an emergency. Investigators will adhere to procedures for reporting study 
deviations to the EC in accordance with their specific reporting policies and procedures. 
 
For reporting purposes, deviations are classified as major or minor: 
 
14.3.1 MAJOR DEVIATIONS 
A major protocol deviation (PD) or noncompliance is one that may have a significant impact on subject 
safety, well-being, the subjects’ willingness to participate in the study, or that may compromise the 
integrity of the study data and analysis. Examples include: 
•         Subject implanted/treated with study device not having met eligibility criteria at the time of 
implant/treatment. 
•         Informed Consent not signed or signed after the initiation of non-standard of care, research 
related assessments. 
•         USADE not reported to EC/Sponsor within the required timeframe  
•         Unauthorized use/implant of an investigational device  
  

EDWARDS LIFESCIENCES LLC 
 
 
ASCEND CLINICAL INVESTIGATIONAL PLAN  
PROTOCOL NUMBER: 2018-22 
 
CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B: 25 NOVEMBER 2019 
 
 
PAGE 46 OF 61 
 
 
14.3.2 MINOR DEVIATIONS 
A minor protocol deviation or noncompliance is unlikely to have a significant impact on subject safety, 
well-being, or is unlikely to compromise the integrity of the study data and analysis. 
 
   
14.4 STUDY CONDUCT, TRAINING, MONITORING RESPONSIBILITIES AND CONFIDENTIALITY 
 
The study will be conducted in accordance with the applicable regulations and guidelines as set forth in 
Section 15 and this protocol. The study investigators are responsible for obtaining the appropriate 
regulatory approvals (ethics committee and where applicable to Competent Authority) prior to initiation 
of the study. The Investigator provides current copies of the study protocol to all sub-Investigators or 
other staff responsible for study conduct. 
 
14.4.1 SITE INITIATION AND TRAINING 
Site staff will be trained and experienced to perform their delegated tasks. Training may be in person, 
webinar, read and review, or other methods as deemed appropriate.  
 
Training is documented on an “Individual Training Log.” An “Individual Delegation of Authority Form” is 
completed at each site for each study staff individual designating which specific clinical study related 
tasks may be performed. The delegated tasks will determine what the training requirements are for 
each member of the study support staff.  Technicians performing the echocardiograms do not require 
any additional training to perform the study tests, as the requested procedures are standard clinical 
exams used in standard practice. 
 
New research staff members may be trained by previously trained personnel on the study protocol and 
procedures. 
 
Site Initiation will not be complete until the surgeons who will be operating the HARPOON System 
device are confirmed as trained.  The training may occur outside of the study training, but 
documentation of that training must be present in the study regulatory binder file prior to site initiation 
being completed. 
 
14.4.2 MONITORING 
Edwards Lifesciences personnel (or designee) will conduct site monitoring in accordance with the 
ASCEND Monitoring Plan to ensure that all investigators are in compliance with the protocol. Monitoring 
visits to the study site will be made periodically during the study. The monitor will ensure that the study 
sites adhere to ISO 14155 and all aspects of the protocol, including the accurate recording of results, the 
reporting of adverse events and device traceability.   
The investigator agrees that representatives of the sponsor and appropriate regulatory agencies will be 
given direct access to source documents. The study site may also be subject to an audit by or on order of 
the sponsor as well as inspection by regulatory agencies. It is important that the investigators and their 
study personnel are available during the monitoring visits and possible audits and that sufficient time is 
devoted to the process. 

EDWARDS LIFESCIENCES LLC 
 
 
ASCEND CLINICAL INVESTIGATIONAL PLAN  
PROTOCOL NUMBER: 2018-22 
 
CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B: 25 NOVEMBER 2019 
 
 
PAGE 47 OF 61 
 
 
 
14.4.3 SUBJECT AUTHORIZATION AND CONFIDENTIALITY 
Subject authorization and written informed consent must be obtained prior to the subject’s enrolment 
into the study and in accordance with GCP, ISO 14155, the Medical Devices Directive and all other 
applicable standards, regulations (local and national), guidelines and institutional policies. Subject 
confidentiality must be maintained in accordance with ISO 14155, GCP, GDPR, the Medical Devices 
Directive and all other applicable standards, regulations (local and national), guidelines and institutional 
policies. 
 
14.4.4 INVESTIGATOR CONFIDENTIALITY 
Study investigators must comply with the applicable provisions of the study agreement with regard to 
non-disclosure and confidentiality. 
 
14.5 DOCUMENTATION REQUIREMENTS 
14.5.1 SOURCE DOCUMENTS 
Clinical regulations require that Investigators maintain information in the clinical study subject’s medical 
records that corroborate data collected on the eCRF. Some examples of critical information to be 
maintained for possible review by regulatory inspectors are: 
 
• 
Medical history and physical condition of the clinical study subject before involvement in the 
clinical study, sufficient to verify protocol entry criteria  
• 
Dated and signed notes in the subject’s medical record on the day of entry into the clinical study 
• 
Dated and signed notes, test reports, procedure and intervention reports, from each clinical 
subject visit with reference to the eCRF for further information, if appropriate (for specific 
results of procedures and exams) 
• 
Notes regarding concomitant anticoagulant/antithrombotic medications taken during the 
clinical study 
• 
Subject’s condition upon completion of or withdrawal from the clinical study 
• 
Visit report and admission and discharge summaries for any reported SAE or potential endpoint 
• 
All relevant documentation from Index admission including Harpoon index/implant procedure. 
Any additional intervention/procedure reports, if applicable, and index/implant discharge 
summary.  
 
To protect subject confidentiality, the subject’s name must not appear anywhere on the imaging media 
sent to study Sponsor e.g. prepared for evaluation by the core lab. All other subject identifiers (i.e. 
medical record number, personal number) are to be obscured. Original copies of all data must be kept at 
the site. 
 
14.5.2 STUDY DOCUMENTS 
The study Sponsor will provide pre-printed or electronic forms to each study site for documentation of: 
 
• 
Investigator and site training to the protocol (Individual/Group Training Log) 
• 
Authorized study site personnel (Individual/Group Delegation of Authority) 

EDWARDS LIFESCIENCES LLC 
 
 
ASCEND CLINICAL INVESTIGATIONAL PLAN  
PROTOCOL NUMBER: 2018-22 
 
CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B: 25 NOVEMBER 2019 
 
 
PAGE 48 OF 61 
 
 
• 
Subject consent and screening (Screening and Enrolment Log) 
• 
Visit tracking (Site Visit Log) 
 
The site visit is recorded on the appropriate site visit log, a copy of which is sent to the Sponsor. During 
the course of the study, all correspondence regarding the study must be maintained in the regulatory 
binder provided by the study Sponsor. Emails may be archived electronically on CD/DVD. This regulatory 
binder must be made available for possible audits. 
 
14.6 DATA COLLECTION 
All required data for this study are to be collected with standardized Case Report Forms (CRF) for 
individual subjects.  Electronic CRF (eCRF) will be utilised for this study. If for any reason an eCRF is 
unavailable and/or inaccessible, a paper CRF will be provided by the study Sponsor to be completed, 
signed by the Principal Investigator or designee, and submitted to the Sponsor.  
 
The Edwards Lifesciences data management group is responsible for database development, edit check 
programming, validation, database maintenance, and statistical support.  The application provides the 
capability of data collection remotely through the Internet so the participating site personnel may log on 
to the system securely with digital signature and audit trail, enter data, and answer/resolve data 
discrepancies/queries online.  Other programming and/or data analyses will be done in the database 
system through the study Sponsor’s internal network. 
 
14.7 DATA AND DOCUMENT RETENTION 
Study-related correspondence, subject records, consent forms, and source documents are to be 
maintained on file by the study site. The study Sponsor requires that it be notified in writing if the 
Principal Investigator wishes to relinquish ownership of the data and information so that mutually 
agreed upon arrangements can be made for transfer of ownership to a qualified entity.  Records of each 
subject’s participation in the study must be maintained for no less than a period of two (2) years after 
study closure and submission of the final report to the EC, or longer, as dictated by local regulations. 
 
14.8 STUDY PROTOCOL AMENDMENTS 
Changes in the protocol affecting the study outcome are made only by written amendment agreed upon 
by the study Sponsor, the applicable regulatory agency, and if pertinent, the EC. As appropriate, the 
study Sponsor will submit changes in the protocol and investigators will obtain EC re-approval. A report 
of withdrawal of EC approval must be submitted to the study Sponsor within five (5) business days. Any 
major revisions to the protocol, must be approved by the Sponsor and the EC. 
 
14.9  STUDY COMPLETION 
A final clinical report shall be compiled once data collection is complete. Such reports include all 
information required and outlined in this protocol. The final report will be provided to the ethics 
committees and other regulatory agencies as per applicable laws. The final clinical report will be filed in 
the clinical study master file. 
 

EDWARDS LIFESCIENCES LLC 
 
 
ASCEND CLINICAL INVESTIGATIONAL PLAN  
PROTOCOL NUMBER: 2018-22 
 
CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B: 25 NOVEMBER 2019 
 
 
PAGE 49 OF 61 
 
 
14.10 FUTURE PLANS 
No changes are planned at this time. 
 
 

EDWARDS LIFESCIENCES LLC 
 
 
ASCEND CLINICAL INVESTIGATIONAL PLAN  
PROTOCOL NUMBER: 2018-22 
 
CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B: 25 NOVEMBER 2019 
 
 
PAGE 51 OF 61 
 
 
access to the confidential files and will have the right to inspect and copy all records pertinent to this 
study.  
 
With respect to data protection and patient confidentiality, Sponsor, Institution and all Study Personnel 
will comply with applicable requirements (for example, the General Data Protection Regulation 
2016/679 (“GDPR”) for EU patients), including providing notice and obtaining patient consent regarding 
the processing of their personal data. 
 
15.3 INVESTIGATOR RESPONSIBILITIES 
The study Investigator(s) shall ensure that all work and services herein, or incidental to those described 
herein, shall be conducted in accordance with the highest standards of medical and clinical research 
practice and the applicable regulations. The Investigator will adhere to the study protocol, ISO 14155, 
GDPR, and compliance with applicable government and institutional regulations. The study 
Investigator(s) is responsible for obtaining appropriate regulatory approvals and reporting to regulatory 
authorities per all applicable regulations.  
 
The Investigator is responsible for ensuring that this clinical study is conducted according to the Clinical 
Trial Agreement, Protocol, all conditions of regulatory and EC/IRB approval and applicable regulations. 
Written EC approval of the protocol and consent forms must be provided to the Sponsor prior to the 
enrolment of any subject in the clinical study at each site. The Investigator is responsible for ensuring 
that informed consent is obtained from all subjects prior to any diagnostic tests or treatments that are 
outside the standard course of treatment that would be followed if this subject was not being 
considered for enrolment in this clinical study.  Periodic reports should be provided to reviewing boards 
and deviations reported per institution’s EC policy. 
 
Subjects must be informed that their medical records will be subject to review by the Sponsor, its 
authorized designee or regulatory agencies.  Subjects will be informed that they are free to refuse 
participation in this clinical study without loss of benefits to which they are otherwise entitled, and that 
if they choose to participate, they may withdraw at any time without prejudice to future care.  The 
informed consent will be provided by each site’s EC and consent must be obtained by the subject.  The 
original signed informed consent for each subject must be retained by the Investigator and is subject to 
review by the Sponsor.  A copy of the informed consent will be provided to the subject. 
 
The Principal Investigator (or designee)/Institution should maintain the study documents as specified in 
ISO 14155 or as required by applicable regulatory requirement(s). The Principal Investigator (or 
designee)/Institution should take measures to prevent accidental or premature destruction of these 
documents. 
 
 
15.4 SPONSOR RESPONSIBILITIES 
The study Sponsor will adhere to the study protocol, ISO 14155, GDPR, and compliance with applicable 
government and institutional regulations. The study Sponsor is responsible for obtaining appropriate 
regulatory approvals and reporting to regulatory authorities per all applicable regulations. The Sponsor 
is responsible for ensuring that this study will be conducted in compliance with all applicable local and 

EDWARDS LIFESCIENCES LLC 
 
 
ASCEND CLINICAL INVESTIGATIONAL PLAN  
PROTOCOL NUMBER: 2018-22 
 
CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B: 25 NOVEMBER 2019 
 
 
PAGE 52 OF 61 
 
 
European regulations including but not limited to those listed in Table 5.  The Sponsor will submit 
progress and final reports to EC’s and Regulatory Authorities as required, if applicable.  
 
The Sponsor will provide Investigators with the information and training required to conduct the clinical 
study properly and in accordance with the Clinical Investigational Plan (protocol) and any amendments, 
if applicable.  The Sponsor must ensure that EC approval is obtained and remains current, and that the 
reviewing boards are informed of significant new information about the clinical study.   
 
The Sponsor clinical study manager is responsible for the conduct and administration of this clinical 
study. These responsibilities include maintaining regular contact with each study site to ensure 
compliance with this Clinical Investigational Plan and verify that data are reported in a timely manner. 
 
This study does collect safety/adverse event information which will be reviewed by the Sponsor’s Safety 
Department along with relevant source documents provided by the sites. However, in addition to 
protocol-specified reporting, any complaint associated with an Edwards product will be forwarded to 
the Edwards Lifesciences complaint handling group.  The complaint handling procedure should be 
followed.   
 
 

EDWARDS LIFESCIENCES LLC 
 
 
ASCEND CLINICAL INVESTIGATIONAL PLAN  
PROTOCOL NUMBER: 2018-22 
 
CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B: 25 NOVEMBER 2019 
 
 
PAGE 53 OF 61 
 
 
16.0 PUBLICATIONS 
HARPOON Medical, an indirect wholly-owned subsidiary of Edwards Lifesciences Corporation, as the 
study Sponsor on record, has a proprietary interest in this study. Authorship and manuscript 
composition will reflect cooperation between multiple investigators and sites, core laboratories, and 
Edwards Lifesciences. Authorship will be established prior to the writing of the manuscript.  
 
All information related to the study is considered confidential and remains the sole property of Edwards. 
This includes but is not limited to the patent applications and the manufacturing process of HARPOON 
System. The investigator agrees to use this information only for purposes of this study. Publication or 
presentation of the overall clinical study results and/or site-specific results requires prior written 
approval of Edwards. If Edwards approves the publication or presentation of the overall clinical study 
results and/or study specific results, then Institutions and Investigators will comply with the Publication 
and Public Disclosure Section of the Clinical Trial Agreement. Edwards may provide statistical support for 
the publication process. 
 
 

EDWARDS LIFESCIENCES LLC 
 
 
ASCEND CLINICAL INVESTIGATIONAL PLAN  
PROTOCOL NUMBER: 2018-22 
 
CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B: 25 NOVEMBER 2019 
 
 
PAGE 54 OF 61 
 
 
17.0 REFERENCES 
AGENAS, Agenzia Nazionale per i Servizi Sanitari Regionali Italy. 2015. Transcatheter implantable 
devices for mitral valve repair in adults with chronic mitral valve regurgitation. European 
Network for Health Technology Assessment. 
 
Andalib, A, S Mamane, I Schiller, A Zakem, D Mylotte, et al. 2014. A systematic review and metaanalysis 
of surgical outcomes following mitral valve surgery in octogenarians: implications for 
transcatheter mitral valve interventions., EuroIntervention : journal of EuroPCR in 
collaboration with the Working Group on Interventional Cardiology of the European Society of 
Cardiology, 9: 1225-34. 
 
Gammie, J. S., P. Wilson, K. Bartus, A. Gackowski, J. Hung, et al. 2016. Transapical Beating-Heart Mitral 
Valve Repair With an Expanded Polytetrafluoroethylene Cordal Implantation Device: Initial 
Clinical Experience, Circulation, 134: 189-97. 
 
Lam, Y-Y, P-W Lee, G Yong, and B P Yan. 2011. Investigational devices for mitral regurgitation: state of 
the art., Expert Review of Medical Devices, 8: 105-14. 
 
Maisano, F, O Franzen, S Baldus, U Schafer, J Hausleiter, et al. 2013. Percutaneous mitral valve 
interventions in the real world: early and 1-year results from the ACCESS-EU, a prospective, 
multicenter, nonrandomized post-approval study of the MitraClip therapy in Europe., Journal 
of the American College of Cardiology, 62: 1052-61. 
 
Nishimura, R. A., A. Vahanian, M. F. Eleid, and M. J. Mack. 2016. Mitral valve disease--current 
management and future challenges, Lancet, 387: 1324-34. 
 
Nishimura, Rick A., Catherine M. Otto, Robert O. Bonow, Blase A. Carabello, I. I. I. John P. Erwin, et al. 
2014. 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart DiseaseA 
Report of the American College of Cardiology/American Heart Association Task Force on 
Practice Guidelines, Journal of the American College of Cardiology, 63: e57-e185. 
 
Stone, Gregg W. M.D., Adams David H. M.D., et al. 2015. Clinical Trial Design Principles and Endpoint 
Definitions for Transcatheter Mitral Valve Repair and Replacement: Part 2; Endpoint Definitions A 
Consensus Document from the Mitral Valve Academic Research Consortium. Journal of American 
College of Cardiology Vol 66, NO, 3. ISSN 0735-1097. 
 
Vahanian, Alec, Ottavio Alfieri, Felicita Andreotti, Manuel J. Antunes, Gonzalo Baron-Esquivias, et al. 
2012. Guidelines on the management of valvular heart disease (version 2012), The Joint Task 
Force on the Management of Valvular Heart Disease of the European Society of Cardiology 
(ESC) and the European Association for Cardio-Thoracic Surgery (EACTS), 33: 2451-96. 
 
Zoghbi WA, Adams D, Bonow RO, et al. Recommendations for Noninvasive Evaluation of Native Valvular 
Regurgitation: A Report from the American Society of Echocardiography Developed in Collaboration 
with the Society for Cardiovascular Magnetic Resonance. J Am Soc Echocardiogr. 2017;30(4):303-371. 

EDWARDS LIFESCIENCES LLC 
CLINICAL INVESTIGATIONAL PLAN 
PROTOCOL NUMBER: 2018-06 
 
ATTACHMENTS 
 
CONFIDENTIAL AND PROPRIETATARY DATA: This document and the information contained herein may not be reproduced, used, or disclosed 
without written permission from Edwards Lifesciences LLC 
VERSION B:25 NOVEMBER 2019                                      
 
 
 
 
ATTACHMENT A – DEFINITIONS 
 
ACCESS SITE AND VASCULAR COMPLICATIONS 
I. Vascular complications 
A. Major access site vascular complications, including: 
• 
Aortic dissection or aortic rupture, or 
• 
Access site-related arterial or venous injury (dissection, stenosis, ischemia, arterial, or venous 
thrombosis including pulmonary emboli, perforation, rupture, arteriovenous fistula, 
pseudoaneurysm, hematoma, retroperitoneal hematoma, atrial septal defect), irreversible 
nerve injury, or compartment syndrome resulting in death; hemodynamic compromise; life-
threatening, extensive, or major bleeding (MVARC bleeding scale); visceral ischemia; or 
neurological impairment, or 
• 
Distal embolization (noncerebral) from a vascular source requiring surgery or resulting in 
amputation or irreversible end-organ damage, or 
• 
Unplanned endovascular or surgical interventions resulting in death; life-threatening, extensive, 
or major bleeding (MVARC bleeding scale); visceral ischemia; or neurological impairment 
 
B. Minor access site vascular complications, including: 
• 
Access site arterial or venous injury (dissection, stenosis, arterial, or venous thrombosis 
including pulmonary emboli, ischemia, perforation, rupture, arteriovenous fistula, 
pseudoaneurysm, hematoma, retroperitoneal hematoma, atrial septal defect) not resulting in 
death; life-threatening, extensive, or major bleeding (MVARC scale); visceral ischemia; or 
neurological impairment, or 
• 
Distal embolization treated with embolectomy and/or thrombectomy not resulting in 
amputation or irreversible end-organ damage, or 
• 
Any unplanned endovascular stenting or unplanned surgical intervention not meeting the 
criteria for a major vascular complication, or 
• 
Vascular repair (via surgery, ultrasound-guided compression, transcatheter embolization, or 
stent-graft) 
 
II. Cardiac structural complications due to access-related issues 
A. Major cardiac structural complications, including cardiac perforation (including the left ventricle, left 
atrium, coronary sinus, right atrium, and right ventricle) or pseudoaneurysm resulting in death, life-
threatening bleeding, hemodynamic compromise, or tamponade, or requiring unplanned surgical or 
percutaneous intervention 
 
B. Minor cardiac structural complications, including cardiac perforation (including the left ventricle, left 
atrium, coronary sinus, right atrium, and right ventricle) or pseudoaneurysm not meeting major criteria 
 
ACUTE KIDNEY INJURY 
Maximal change in sCr from baseline to 7 days post-procedure: 
 
• 
Stage 1: Increase in sCr to 150%–199% (1.50–1.99 x increase vs. baseline), increase of ≥0.3 
mg/dl (≥26.4 mmol/l) within 48 h, or urine output <0.5 ml/kg/h for ≥6 h but <12 h 

EDWARDS LIFESCIENCES LLC 
 
ATTACHMENTS 
CLINICAL INVESTIGATIONAL PLAN 
PROTOCOL NUMBER: 2018-06 
CONFIDENTIAL AND PROPRIETATARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED 
WITHOUT WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B:25 NOVEMBER 2019 
 
 
 
• 
Stage 2: Increase in sCr to 200%–299% (2.00–2.99 x increase vs. baseline) or urine output 
<0.5 ml/kg/h for ≥12 h but <24 h 
• 
Stage 3:  Increase in sCr to ≥300% (>3.0 x increase vs. baseline), sCr of ≥4.0 mg/dl (≥354 
mmol/l) with an acute increase of ≥0.5 mg/dl (44 mmol/l), urine output <0.3 ml/kg/h for ≥24 
h, or anuria for ≥12 h; patients receiving renal replacement therapy are considered stage 3 
irrespective of other criteria 
 
ARRHYTHMIAS AND CONDUCTION SYSTEM DISTURBANCES 
For emerging mitral valve procedures in which the frequency of major arrhythmias and conduction 
system disturbances is unknown, continuous rhythm monitoring for at least 48 h in the post-procedural 
period is recommended to maximize the detection of arrhythmias and conduction system disturbances. 
Data elements to be collected for all patients should include: 
• 
Baseline conduction abnormalities, paroxysmal or permanent atrial fibrillation (or flutter), 
ventricular arrhythmias, and the presence of permanent pacemaker and implantable 
defibrillators. The type of permanent pacemaker should be recorded (e.g., single vs. dual 
chamber, biventricular). 
• 
Procedure-related new or worsened cardiac conduction disturbance (including first-, second- 
[Mobitz I or Mobitz II], or third-degree AV block; incomplete and complete right bundle branch 
block; intraventricular conduction delay; left bundle branch block; left anterior fascicular block; 
or left posterior fascicular block, including heart block) requiring a permanent pacemaker 
implant; each subclassified as persistent or transient 
• 
New-onset atrial fibrillation (or flutter) which lasts sufficiently long to be recorded on a 12-lead 
electrocardiogram, or at least 30 s on a rhythm strip. 
• 
New-onset ventricular tachycardia or fibrillation 
• 
Pacemaker or defibrillator lead dislodgement 
 
Arrhythmias and conduction system disturbances are subclassified according to: 
• 
The occurrence of hemodynamic instability 
• 
Need for therapy including electrical/pharmacological cardioversion or initiation of a new 
medication (oral anticoagulation, rhythm, or rate control therapy) 
• 
Need for new permanent pacemaker and/or defibrillator implantation, including the 
indication(s) and the number of days post-implant. For patients with defibrillators, the number 
of appropriate and inappropriate shocks should be recorded. 
 
ATRIAL FIBRILLATION (AF) – Heart Rhythm Society Guidelines 
• 
Paroxysmal: Recurrent (≥ 2) atrial fibrillation episodes that terminate spontaneously within 7 
days. 
• 
Persistent: Atrial fibrillation that is sustained beyond 7 days, or lasting less than 7 days but 
necessitating pharmacologic or electrical cardioversion. 
• 
Longstanding Persistent AF: Continuous atrial fibrillation of greater than 1 year 
duration. 
• 
Permanent: Atrial fibrillation in which cardioversion has failed or not been attempted. 

EDWARDS LIFESCIENCES LLC 
 
ATTACHMENTS 
CLINICAL INVESTIGATIONAL PLAN 
PROTOCOL NUMBER: 2018-06 
CONFIDENTIAL AND PROPRIETATARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED 
WITHOUT WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B:25 NOVEMBER 2019 
 
 
 
 
BLEEDING 
• 
Minor 
Any overt*, actionable sign of hemorrhage (e.g., more bleeding than would be expected for a 
clinical circumstance, including bleeding found by imaging alone) that meets ≥1 of the following: 
requiring nonsurgical medical intervention by a health care professional; leading to 
hospitalization or increased level of care; prompting evaluation; or requires 1 or 2 U of whole 
blood or packed RBC transfusion and otherwise does not meet criteria for major, extensive, or 
life-threatening bleeding. 
 
• 
Major 
Overt bleeding either associated with a drop in the hemoglobin of ≥3.0 g/dl** or requiring 
transfusion of ≥3U of whole blood or packed RBCs AND does not meet criteria of life-threatening 
or extensive bleeding. 
 
• 
Extensive 
Overt source of bleeding with drop in hemoglobin of  ≥ 4 g/dl or whole blood or packed RBC 
transfusion  ≥ 4U within any 24-h period, or bleeding with drop in hemoglobin of  ≥ 6 g/dl or 
whole blood or packed RBC transfusion  ≥ 4 U (Overt bleeding plus hemoglobin drop ≥ 5 g/dl, 
cardiac tamponade, Bleeding requiring surgical intervention for control) excluding 
dental/nasal/skin/hemorrhoid)), OR Bleeding requiring IV vasoactive agents 
 within 30 days of the procedure. 
 
• 
Life-threatening 
Bleeding in a critical organ, such as intracranial, intraspinal, intraocular, or pericardial 
necessitating surgery or intervention, or intra- muscular with compartment syndrome OR 
bleeding causing hypovolemic shock or hypotension (systolic blood pressure <90 mm Hg lasting 
>30 min and not responding to volume resuscitation) or requiring signiﬁcant doses of 
vasopressors or surgery. 
 
• 
Fatal 
Bleeding adjudicated as being a proximate cause of death. Severe bleeding adjudicated as being 
a major contributing cause of a subsequent fatal complication, such as MI or cardiac arrest, is 
also considered fatal bleeding. 
*”Overt” bleeding is defined by any of the following criteria being met: Reoperation after closure of 
sternotomy for the purpose of controlling bleeding; chest tube output >2 l within any 24-h period, >350 
ml within the first post-operative hour, ≥250 ml within the second post-operative hour, or >150 ml 
within the third post-operative hour; or visible bleeding from the vascular system either at or remote 
from the access/surgical site. 
**Adjusted for the number of units of blood transfused (1 U packed red blood cells or whole blood is 
equivalent to 1 g/dl hemoglobin). 
DEATH (ALL-CAUSE MORTALITY) 
A. Cardiovascular mortality 

EDWARDS LIFESCIENCES LLC 
 
ATTACHMENTS 
CLINICAL INVESTIGATIONAL PLAN 
PROTOCOL NUMBER: 2018-06 
CONFIDENTIAL AND PROPRIETATARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED 
WITHOUT WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B:25 NOVEMBER 2019 
 
 
 
Any of the following contributing conditions: 
• 
Heart failure (subclassified into left ventricular vs. right ventricular dysfunction) 
• 
Myocardial infarction 
• 
Major bleeding 
• 
Thromboembolism 
• 
Stroke 
• 
Arrhythmia and conduction system disturbance 
• 
Cardiovascular infection and sepsis (e.g., mediastinitis and endocarditis) 
• 
Tamponade 
• 
Sudden, unexpected death 
• 
Other cardiovascular 
• 
Device failure 
• 
Death of unknown cause (adjudicated as cardiovascular) 
 
B. Noncardiovascular mortality 
Any death in which the primary cause of death is clearly related to another condition: 
• 
Noncardiovascular infection and sepsis (e.g., pneumonia) 
• 
Renal failure 
• 
Liver failure 
• 
Cancer 
• 
Trauma 
• 
Homicide 
• 
Suicide 
• 
Other noncardiovascular 
 
 
MAJOR DEVICE OR PROCEDURE RELATED SERIOUS ADVERSE EVENT 
All Major Serious Adverse Events adjudicated as device or procedure related, as defined by modified 
MVARC including: 
 
• 
Procedure or Device related Death 
• 
Procedure or Device related Stroke 
• 
Procedure or Device related Life-threatening bleeding (MVARC scale) 
• 
Major vascular or access (index procedure) complications 
• 
Major cardiac structural complications related or cause by device or procedure 
• 
Procedure related Stage 2 or 3 acute kidney injury (includes new dialysis) 
• 
Procedure related Myocardial infarction or coronary ischemia requiring PCI or CABG 
• 
Procedure or device related severe hypotension, heart failure, or respiratory failure requiring 
intravenous pressors or invasive or mechanical heart failure, treatments such as ultrafiltration or 
hemodynamic assist devices, including intra-aortic balloon pumps or left ventricular or 
biventricular assist devices, or prolonged intubation for more than 48 h. 
• 
Any device-related dysfunction, migration, thrombosis, or other complication requiring surgery 
or repeat intervention including: 

EDWARDS LIFESCIENCES LLC 
 
ATTACHMENTS 
CLINICAL INVESTIGATIONAL PLAN 
PROTOCOL NUMBER: 2018-06 
CONFIDENTIAL AND PROPRIETATARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED 
WITHOUT WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B:25 NOVEMBER 2019 
 
 
 
 
Structural or Functional failure of the HARPOON device, introducer or artificial chords 
(ePTFE) requiring an intervention. 
 
Conversion to the Open Mitral Valve Surgery secondary to mitral valve apparatus 
damage or dysfunction, requiring surgical valve repair or replacement, or Secondary to 
procedural complications (such as cardiac perforation, removal of an embolized artificial 
chords, injury to Aortic valve and so on) 
 
Device malpositioning (Artificial chords malpositioning) requiring intervention. 
Permanent deployment of artificial chord(s) in a location other than intended or 
movement of the artificial chords during or post deployment which requires an 
intervention. 
 
Artificial Chord detachment (used with HARPOON device) which requires an 
intervention 
 
Device fracture: a break, tear, perforation, or other structural defect in the artificial 
chords (housing, leaflet, and so on) resulting in device failure, resulting in recurrent MR 
symptoms, or requiring reintervention. 
 
Damage to the native mitral valve apparatus (damage to native chordae tendinae, 
Leaflets, Papillary muscles or Mitral annulus) requiring an intervention or conversion to 
Open Mitral Valve Surgery. 
 
Symptomatic or requiring intervention Device Thrombosis (any thrombos attached or 
near the artificial HARPOON implanted chords) 
 
Interaction with non-mitral valve intracardiac structures which requires intervention 
and 
 
Endocarditis (as diagnosed by modified Duke endocarditis criteria or evidence of 
abscess, pus, or vegetation confirmed as secondary to infection by histological or 
bacteriological studies during an operation or autopsy) which required a surgical 
intervention. 
 
Hemolysis (a presence of a leaflet perforation on transesophageal or transthoracic 
echocardiography plus anemia requiring transfusion plus increased haptoglobin and/or 
LDH levels; which lead to a surgical intervention. 
 
Other major device or procedure related SAEs. 
 
 
MYOCARDIAL INFARCTION 
MI After Transcatheter and Surgical Mitral Valve Replacement 
 
Periprocedural MI (≤48 h after the index procedure) 
• 
In patients with normal baseline CK-MB (or cTn): The peak CK-MB measured within 48 h of the 
procedure rises to ≥10 x of the local laboratory ULN plus new ST-segment elevation or 
depression of ≥1 mm in ≥2 contiguous leads (measured 80 ms after the J-point), or to ≥5 x ULN 
with new pathological Q waves in ≥2 contiguous leads or new persistent LBBB, OR in the 
absence of CK-MB measurements and a normal baseline cTn, a cTn (I or T) level measured 
within 48 h of the PCI rises to ≥70 x the local laboratory ULN plus new ST-segment elevation or 
depression of ≥1 mm in ≥2 contiguous leads (measured 80 ms after the J-point), or ≥35 x ULN 
with new pathological Q waves in ≥2 contiguous leads or new persistent LBBB. 
 

EDWARDS LIFESCIENCES LLC 
 
ATTACHMENTS 
CLINICAL INVESTIGATIONAL PLAN 
PROTOCOL NUMBER: 2018-06 
CONFIDENTIAL AND PROPRIETATARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED 
WITHOUT WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B:25 NOVEMBER 2019 
 
 
 
• 
In patients with elevated baseline CK-MB (or cTn): The CK-MB (or cTn) rises by an absolute 
increment equal to those levels recommended above from the most recent pre-procedure level 
plus, new ECG changes as described. 
 
Spontaneous MI (>48 h after the index procedure) 
Detection of rise and/or fall of cardiac biomarkers (preferably cTn) with at least 1 value above the 99th 
percentile URL (or ULN in the absence of URL) together with at least 1 of the following: 
• 
Symptoms of ischemia 
• 
ECG changes indicative of new ischemia (new ST-segment or T-wave changes or new LBBB) or 
new pathological Q waves in ≥2 contiguous leads 
• 
Imaging evidence of a new loss of viable myocardium or new wall motion abnormality 
 
MI associated with sudden, unexpected cardiac death 
Sudden cardiac death or cardiac arrest, often with symptoms suggestive of myocardial ischemia, and 
accompanied by presumably new ST-segment elevation or new LBBB and/or evidence of fresh thrombus 
by coronary angiography and/or at autopsy, but death occurs before blood samples could be obtained 
or at a time before the appearance of cardiac biomarkers in the blood 
 
Pathological findings of an acute myocardial infarction 
 
STROKE AND TIA 
Stroke is defined as a focal or global neurological deﬁcit lasting more than 24 h OR less than 24 h if 
available neuroimaging documents a new intracranial or subarachnoid hemorrhage (hemorrhagic 
stroke) or central nervous system infarction (ischemic stroke) OR the neurological deﬁcit results in 
death. 
A disabling stroke includes any neurological deficit (for example partial visual field cut) with a modified 
Rankin scale score equal or more than 2 with an increase in equal 1 or more modified Rankin scale score 
category from individual’s pre-stroke baseline at 90 days after stroke onset. 
Stroke and Transient Ischemic Attack: Diagnosis and Classiﬁcation 
 
Diagnostic criteria 
• 
Acute episode of a focal or global neurological deﬁcit with at least 1 of the following: 
a. Change in the level of consciousness 
b. Hemiplegia, hemiparesis, numbness, or sensory loss affecting 1 side of the body 
c. Dysphasia or aphasia, hemianopia, amaurosis fugax, or other neurological signs or 
symptoms consistent with stroke 
 
• 
In addition, there is no other readily identiﬁable nonstroke cause for the clinical presentation 
(e.g., brain tumor, trauma, infection, hypoglycemia, peripheral lesion, pharmacological 
inﬂuences) as determined by or in conjunction with the designated neurologist.  
Patients with nonfocal global encephalopathy will not be reported as having had a stroke 
without unequivocal evidence of cerebral infarction based upon neuroimaging studies (CT scan 
or cerebral MRI). 
 

EDWARDS LIFESCIENCES LLC 
 
ATTACHMENTS 
CLINICAL INVESTIGATIONAL PLAN 
PROTOCOL NUMBER: 2018-06 
CONFIDENTIAL AND PROPRIETATARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED 
WITHOUT WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
VERSION B:25 NOVEMBER 2019 
 
 
 
The neurological event type classiﬁcation 
• 
Stroke: duration of a focal or global neurological deﬁcit ≥24 h OR <24 h if available neuroimaging 
documents a new intracranial or subarachnoid hemorrhage (hemorrhagic stroke) or central 
nervous system infarction (ischemic stroke) OR the neurological deﬁcit results in death 
• 
TIA: duration of a focal or global neurological deﬁcit <24 h and neuroimaging does not 
demonstrate a new hemorrhage or infarct 
 
Conﬁrmation of the diagnosis of stroke or TIA requires at least 1 of the following 
 
Neurologist or neurosurgical specialist, or 
 
Neuroimaging procedure (CT scan or brain MRI) 
 
Stroke/TIA etiology classiﬁcation 
• 
Ischemic: an acute episode of focal cerebral, spinal, or retinal dysfunction caused by 
infarction of the central nervous system tissue 
• 
Hemorrhagic: an acute episode of focal or global cerebral or spinal dysfunction caused by 
intraparenchymal, intraventricular, or subarachnoid hemorrhage 
• 
Undetermined: if there is insufﬁcient information to  allow categorization as ischemic or 
hemorrhagic 
 
Stroke severity is further classiﬁed as 
- 
Disabling stroke: an mRS score ≥2 at 90 days plus an increase in ≥1 mRS category from the pre-
stroke baseline 
- 
Nondisabling stroke: an mRS score <2 at 90 days or without an increase ≥1 mRS category from 
the pre-stroke baseline 
 
Reference:  
Clinical Trial Design Principles and Endpoint Definitions for Transcatheter Mitral Valve Repair and 
Replacement: Part 2; Endpoint Definitions A Consensus Document from the Mitral Valve Academic 
Research Consortium. 
Stone, Gregg W. M.D., Adams David H. M.D., et al. 
Journal of American College of Cardiology Vol 66, NO, 3, 2015 
ISSN 0735-1097