Safety and Performance Study of the Harpoon Medical Device in Patients With Degenerative Mitral Regurgitation
Phase: NA
Conditions: Mitral Valve Regurgitation, Mitral Valve Prolapse, Mitral Valve Insufficiency
Sponsor: Edwards Lifesciences

Edwards Lifesciences LLC 
One Edwards Way  Irvine, CA USA  92614 
Phone: 949.250.2500  Fax: 949.250.2525  www.edwards.com 
Safety and Performance Study of the Harpoon 
Mitral Valve Repair System
NCT03285724  
October 12, 2016

 
 
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Protocol Title: 
Safety and Performance study of the Harpoon Medical Device 
in patients with degenerative mitral regurgitation 
 
 
Protocol Number: 
 
HMEFS -2000 
Version: 
00a dated 12Oct2016 
 
 
Sponsor: 
 
Monitor: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
European Authorized Representative: 
 
 
 
 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
 
This study is confidential in nature.  All information related to this study is considered proprietary and should not be 
made available to those not directly involved in this study.  Authorized recipients of this information include investigators 
and co-investigators, other health care personnel necessary to conduct the study and Ethical Committees  
 
The above personnel provided with data from this study are hereby informed of its confidential and proprietary nature.  
Release of this data to individuals other than those listed above requires the prior written permission of Sponsor. 
 
 

 
 
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Contents 
I. 
PRIMARY CONTACTS ......................................................................................................... 3 
II. STUDY SUMMARY ............................................................................................................... 4 
III. BACKGROUND AND RATIONALE ....................................................................................... 7 
DEVICE DESCRIPTION ..................................................................................................... 8 
SUMMARY OF PRECLINICAL STUDIES ........................................................................... 9 
POTENTIAL BENEFITS .....................................................................................................10 
POTENTIAL RISKS ...........................................................................................................10 
MINIMIZATION OF RISKS .................................................................................................12 
OPERATOR TRAINING AND EXPERIENCE .....................................................................12 
IV. STUDY OBJECTIVES ......................................................................................................... 13 
Endpoints ...........................................................................................................................13 
V. STUDY DESIGN ................................................................................................................. 13 
VI. STUDY POPULATION ........................................................................................................ 13 
NUMBER OF PATIENTS ...................................................................................................13 
INTENDED USE ................................................................................................................14 
INCLUSION CRITERIA ......................................................................................................14 
EXCLUSION CRITERIA .....................................................................................................14 
VII. PATIENT ENROLLMENT .................................................................................................... 15 
PRE SCREENING .............................................................................................................15 
TREATMENT PROCEDURE/ASSESSMENTS ..................................................................16 
FOLLOW-UP PROCEDURES/ASSESSMENTS ................................................................17 
UNSCHEDULED FOLLOW UP VISITS ..............................................................................20 
PATIENT WITHDRAWAL FROM THE STUDY ..................................................................20 
END OF PARTICIPATION .................................................................................................20 
DURATION OF INVESTIGATION ......................................................................................20 
VIII. 
SAFETY MANAGEMENT ............................................................................................... 21 
DEFINITIONS ........................................................................................................................... 21 
EVENT SEVERITY ............................................................................................................22 
CAUSALITY RELATIONSHIP ................................................................................................... 22 
INVESTIGATOR REPORTING RESPONSIBILITIES ................................................................ 23 
REPORTING TO EC/CA ....................................................................................................24 
IX. INVESTIGATIONAL DEVICEDISTRIBUTION AND ACCOUNTABILITY ............................. 24 
X. STATISTICAL ANALYSIS ................................................................................................... 25 
XI. STUDY ORGANISATION .................................................................................................... 25 
INVESTIGATIONAL SITE PERSONNEL ...........................................................................25 
CLINICAL MONITORING ...................................................................................................26 
CLINCAL EVENTS COMMITTEE ......................................................................................27 
STUDY ADMINISTRATION ...............................................................................................27 
REGULATORY CONSIDERATIONS: RECORDS RETENTION POLICY ...........................29 
DATA QUALITY ASSURANCE ..........................................................................................29 
STATEMENT OF INSURANCE POLICY ............................................................................30 
XII. ETHICAL CONSIDERATIONS ............................................................................................ 30 
DECLARATION OF HELSINKI...........................................................................................30 
PATIENT INFORMATION AND INFORMED CONSENT....................................................30 
PATIENT CONFIDENTIALITY ...........................................................................................30 
ETHICS COMMITTEE .......................................................................................................31 
REGULATORY APPROVAL ..............................................................................................31 
XIII. 
QUALIFICATIONS OF STUDY CENTERS AND INVESTIGATORS ............................... 31 
XIV. 
PUBLICATION POLICY ................................................................................................. 31 

 
 
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XV. REFERENCES .................................................................................................................... 33 
 
I. 
PRIMARY CONTACTS 
 
Sponsor: 
 
Monitor: 
 
 
 
 
 
 
 
 
 
 
European Authorized Representative: 
 
 
 
 
 
 
 
 
Principal Investigator(s) 
 
 
(Protocol Signature pages are provided separate 
to this protocol) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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II. 
STUDY SUMMARY 
 
Title: 
Safety and Performance study of the Harpoon Medical Device in 
patients with degenerative mitral regurgitation 
Protocol Number: 
HMEFS-2000 Ver 00a 
Design: 
This is a prospective, single arm, nonrandomized, early feasibility 
study to evaluate the safety and performance of the Harpoon 
Medical Device. 
Study Duration: 
Projected enrollment of first patient December 2016 
Projected exit of final patient: December 2019 
Primary Objective: 
The primary objective of this study is to evaluate the safety and 
performance of the Harpoon Medical Device. 
Patient Population: 
Patients with “Severe” mitral regurgitation as a result of posterior, bi-
leaflet or anterior prolapse. 
Sample Size: 
Up to twenty (20) patients in PL will be enrolled. 
Number of Sites: 
Krakow will be the only center participating in this study. 
Treatments: 
Up to eight (8) pairs of ePTFE cords may be placed in the anterior 
and/or posterior mitral valve using the Harpoon Medical Device in 
order to establish effective coaptation of the mitral leaflets. 
Endpoints: 
Primary Performance Endpoints: To demonstrate that the Harpoon 
Medical Device performs as designed and can successfully implant 
one or more ePTFE artificial cords on either the anterior, posterior, 
or both leaflets of the mitral valve via a small left thoracotomy on the 
beating heart and reduce mitral regurgitation from “severe” to less 
than or equal to “moderate” at the conclusion of the procedure and 
at 30 days post-procedure. 
 
Secondary Performance Endpoints: Severity of mitral 
regurgitation at 6 months, 12 months and 24 months follow-up shall 
be tracked and recorded 
 
Primary Safety Endpoints: Procedure freedom from Serious 
Adverse Events (SAEs) during the procedure, at discharge, and at 
30 days follow-up shall be tracked and recorded.  Rates are 
expected to be not significantly worse than conventional mitral valve 
surgery. 
 
Secondary Safety Endpoints Freedom from Serious Adverse 
Events (SAEs) at 6 months, 12 months and 24 months follow-up 
shall be tracked and recorded 
 
 

 
 
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Inclusion Criteria: 
• 
Age > 18 years  
• 
Patient referred for mitral valve surgery 
• 
Presence of severe MR as read on an echocardiographic study 
performed within 60 days prior to procedure.   
• 
Estimated post-ePTFE cordal implantation coaptation surface 
is adequate in the judgment of the operating surgeon and the 
patient eligibility committee 
• 
Degenerative mitral valve disease associated with anterior, 
bileaflet, or posterior leaflet prolapse 
• 
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 
• 
Women of child-bearing potential have a negative pregnancy 
test 
 
Exclusion Criteria: 
• 
Age < 18 years 
• 
Infective endocarditis 
• 
History of Mediastinal Radiation 
• 
Inflammatory (rheumatic) valve disease 
• 
Requirement for concomitant cardiac surgery (e.g., coronary 
artery bypass grafting (CABG), aortic valve surgery, etc.) 
• 
Symptomatic coronary artery disease 
• 
Cardiogenic shock at the time of enrollment 
• 
ST segment elevation myocardial infarction requiring 
intervention within 30 days prior to enrollment 
• 
Evidence of cirrhosis or hepatic synthetic failure 
• 
Pregnancy at the time of enrollment (women of child bearing 
age should have negative pregnancy within 14 days of surgery) 
• 
Severe pulmonary hypertension (PA systolic pressure > 70 
mmHg) 
• 
Previous cardiac surgery, or surgery on the left pleural space 
• 
Left ventricular, atrial or appendage thrombus 
• 
Severely calcified mitral leaflets 
• 
Recent stroke (<  6 months) with permanent impairment 
• 
EuroScore (for mitral valve repair) > 8% 
• 
Patients with contraindications to Transesophageal 
echocardiography 
• 
Severe left or right ventricular dysfunction 
• 
NYHA Class IV 
• 
Renal insufficiency CKD stage 3b or worse (GFR < 45 
ml/min/1.73 m2) 
• 
Patient is participating in another clinical study for which follow-
up is currently ongoing. (Co-enrollment in an investigational 
device or interventional study) 
• 
Patient with non-cardiac co-morbidities and life expectancy < 1 
year 

 
 
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• 
Patient has a condition or conditions that, in the opinion of the 
Investigator, preclude participation, including willingness to 
comply with all follow-up procedures 
Follow-up: 
The estimated enrollment period is 24 months, and all patients will 
have follow-up visits at 30 days, 6 months, 12 months and 24 
months after implantation. 
 
 

 
 
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III. 
BACKGROUND AND RATIONALE  
 
Mitral Regurgitation, Transapical mitral valve repair, and the Harpoon Medical Device 
 
Patients with Mitral Regurgitation may benefit from treatment with this device.  Mitral valve 
disease is the most common valvular heart disorderi. Nearly 4 million Americans are thought to 
have severe mitral valve regurgitation (“MR”).  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 surgical mitral valve repair restores mitral valve competence, abolishes 
volume overload on the left ventricle, improves symptom status and prevents adverse left 
ventricular remodeling. 
 
 
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 patients with ischemic or 
idiopathic MR (the motion of the normal mitral valve leaflets is restricted by the enlarged ventricle, 
both of which lead to ineffective apposition of the anterior and posterior mitral valve leaflets and 
failed valve closure and regurgitation. 
 
Two-thirds of all mitral valve repair procedures in North America are performed on patients with 
degenerative MR. The case mix is estimated to be similar in the European Union (EU).  Mitral 
valve repair that requires open cardiac surgery, aortic manipulation and cardio-pulmonary bypass 
is the most common method to treat MR. There are also other less invasive devices currently on 
the market in the US and the EU that are considered alternative treatment options for MR. The 
follow is a summary of the current treatment options available to replace ruptured or elongated 
cords and reduce MR: 
 
There are alternate treatments available to replace ruptured or elongated chordae tendineae and 
reduce MR. However, there is no currently effective medical therapy that cures MR, and the 
alternate procedures to repair the mitral valve are generally more invasive and associated with 
greater morbidity and/or less effective repair of the mitral valve. The current technologies available 
to address the structural defects of MR include: 
 
• 
Open heart operations to repair or replace the mitral valve.  Open cardiac mitral valve 
operations require a large chest incision (either sternotomy or thoracotomy), cardiopulmonary 
bypass, aortic manipulation and cardioplegic cardiac arrest. Mitral valve repair often requires 
a mitral annuloplasty ring and is performed with leaflet resectional techniques (Carpentier) or 
nonresectional techniques using ePTFE cords placed under direct vision. Mitral valve 
replacement is performed by replacing the native diseased valve with a mechanical prosthesis 
or a bioprosthesis. In either event, a large incision, cardio-pulmonary bypass and extensive 
surgery are required. Moreover, lifelong anticoagulation is required post-operatively.  
 
• 
In 2008, Evalve received a CE mark for the MitraClip Transcatheter Mitral Valve Repair in the 
European Union.  Shortly thereafter, the company was acquired by Abbott Labs. In 2013, 
Implantation of MitraClip does not involve open-heart surgery, but mimics a surgical method 
of edge-to-edge valve repair (the Alfieri technique) where the mitral valve leaflets are clipped 
together with the device instead of being sutured together. The MitraClip Transcathether Mitral 
Valve Repair Clip delivery system (MitraClip CDS) consists of implant catheters and the 
MitraClip device. The device is a permanent implant that attaches to the mitral valve leaflets.  
The MitraClip CDS is intended to treat patients with significant symptomatic degenerative 
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does improve apposition of the mitral leaflets, the apposition does not mimic the natural 
pattern of valve movement, and the device has not been widely adopted. 
 
• 
In 2013, Neochord released a CE marked, Class III medical device to the European Union as 
a minimally invasive procedure that is performed on a beating heart to replace cords that have 
become elongated or ruptured.  Neochord does not involve open-heart surgery. It mimics the 
surgical method of suturing replacement cords to the free-edge of the mitral valve leaflet.  The 
NeoChord procedure is performed transapically on the beating heart via a thorocotomy 
between the ribs. Using echocardiographic guidance, the NeoChord DS1000 places individual 
cords on the prolapsed leaflet using an expandable jaw to grasp the leaflet and insert the 
chord. When a sensor on the DS100 jaws confirms that the leaflet has been adequately 
captured the surgeon deploys the ePTFE suture into the leaflet. The device is then removed 
and the distal end of the suture is secured to the epicardium with pledgets. Correct length of 
the suture is determined by using real time echocardiographic guidance to observe 
improvement in mitral valve regurgitation in the beating heart. Data from the TACT study 
(NCT01777815) used to support the CE mark showed a high procedural success and 
demonstrated that off-pump transapical implantation of artificial chordae to correct MR is 
technically safe and feasible.  NeoChord is currently conducting a TACT Post-Market 
Surveillance Registry (NCT01784055) to evaluate patients who had at least one cord placed 
using the DS1000 System AND reduction in mitral regurgitation ≤ 2+ at the time of the 
procedure.  NeoChord is not currently available in the US.  The NeoChord system is currently 
being used to treat patients in 18 hospitals in 8 country’s which include TACT registry and 
non-registry centres in Europe.  Over 250 patients have been treated to date. Mid-term 
outcomes in treating severe MR are very promising. 
 
Although these procedures are available to cardiac surgeons in the US and/or EU, there is still a 
need for additional minimally invasive treatment options for patients suffering from MR. Ideally, 
these treatments should avoid cardio-pulmonary bypass and open heart surgery. They should be 
minimally invasive, technically simple. 
 
DEVICE DESCRIPTION 
 
The Harpoon Medical Transapical device is intended to be used to reduce the degree of 
degenerative mitral regurgitation by delivering and anchoring ePTFE cords to the affected mitral 
valve leaflet(s) in a beating heart in patients with anterior, bi-leaflet or posterior prolapse.  The 
device is intended to be a Single Use Device, used in a surgical operating suite or equivalent 
setting.  Harpoon Medical has developed a novel small-diameter (< 3 mm) rigid linear delivery 
system (TSD-5) using a needle wrapped with ePTFE in a pre-formed knot configuration. The 
device delivers replacement ePTFE cords using a valved introducer (TAV-5) and 
Transesophageal echocardiography (TEE). To deploy the pre-formed knot on the atrial side, the 
TSD-5 is actuated to advance the needle and pre-formed knot through the leaflet.  The TSD-5 
then retracts the needle, leaving the pre-formed knot on the atrial side of the leaflet.  After 
deployment, the TSD-5 is withdrawn from the TAV-5, exposing the replacement cords.  The 
replacement cords are adjusted under real-time TEE to optimize the surface of coaptation 
between leaflets before they are secured to an ePTFE pledget on the epicardium.   
 
The Harpoon Medical Device consists of two parts: 1) the delivery system (TSD-5) – Figure 1 and 
2) the valved introducer (TAV-5) – Figure 2.  Both items are essential for the proper delivery of 
the suture(s) in the mitral valve leaflet to eliminate or reduce Mitral Valve Regurgitation (MR). 
 

 
 
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Figure 1 - Delivery System (TSD-5) 
Figure 2 - Valved Introducer (TAV-5) 
 
The manufacturer of the study device is Harpoon Medical, Inc. having an address of 351 West 
Camden Street Suite 801 Baltimore, MD 21201 USA. 
 
The purpose of this study is to evaluate the safety and performance of this Harpoon Medical 
Device.   
 
Devices used in the clinical investigation will be traced according to their lot number. The Lot 
numbers are coded YY-WWW, where the YY is “16” for those devices sterilized in 2016 and DDD 
signifies the Julian calendar day of the associated year. 
 
A detailed device description is provided in the Investigator’s Brochure in section 1.2 and the 
Instructions for Use for the system. 
 
SUMMARY OF PRECLINICAL STUDIES 
 
Harpoon has completed enrollment (n = 13) in an Early Feasibility Study across two locations in 
Poland and has begun enrolling patients in a larger randomized study across multiple countries 
in Europe to support CE Mark. All thirteen patients enrolled in the EFS had severe degenerative 
MR and will be evaluated for two years with follow-up visits at 30 days, 6 months, 1 year and 2 
years. All echocardiographic studies are graded by an independent core laboratory based on 
the American Society of Echocardiographer (ASE) Guidelines. An interim report of the Early 
Feasibility Study based on data available as of December 31, 2015 was published by Gammie 
et al. in Circulation on July 19, 2016. There was 100% procedural success in the thirteen 
patients enrolled in the EFS and zero procedural and perioperative mortality. Between 3 and 5 
chords were implanted in each patient. The average introducer time (the time TAV-5 is inserted 
into the left ventricle) was 38 minutes and the average skin-to-skin procedure time was 110 
minutes. After the ePTFE suture pairs were implanted and secured at the epicardial site; 
anterior-posterior mitral leaflet coaptation was restored and the severity of MR was significantly 
reduced. Ten of the EFS patients had None/Trace MR and the balance had Mild MR at the 
conclusion of the procedure. 
 
As of August 31, 2016, all of the eligible patients in the EFS have completed their thirty day and 
six month follow-up visits, and 6 patients have completed one-year follow-up. 9 of the 13 
patients in the EFS had none/trace or mild MR at six months and 2 were graded as moderate 
MR and were asymptomatic. The result observed at six months has been stable in each of the 
six patients who have completed their one-year follow-up visit.  Among 6 patients with one-year 
follow-up, 3 had none/trace MR, 1 had mild, and 2 had moderate MR and were asymptomatic. 
There has been no mortality, no procedural conversion to open-heart surgery, no stroke, no 

 
 
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renal failure, no myocardial infarctions, no blood transfusions and no new onset atrial fibrillation 
in patients enrolled in the EFS. There were two reoperations for delayed tamponade on post-
operative day 5 and 13. Both patients recovered rapidly and were discharged in excellent 
condition. Two patients required re-operation for recurrent MR. In one patient an ePTFE cord 
came untied at the apical pledget. The other patient had recurrent MR as a result of a ruptured 
native anterior leaflet cord. Both patients underwent a successful on-pump mitral valve 
operation (post-operative day 72 and 231 respectively) and recovered without incident. To date 
the EFS has generated 4,651 total “patient days” (patients implanted * days implanted) equal to 
12.7 years and 16,843 “cord implant days” (total number of cords implanted * days implanted).  
 
Harpoon Medical has begun enrollment in the CE Mark Study, and while the data is not 
complete yet, the preliminary results appear to be consistent with the Early Feasibility Study. As 
of August 31, 2016, a total of 92 ePFTE cords have been implanted in 24 patients across the 
EFS and CE Mark studies. Harpoon has a total of 5,465 patient implant days equal to 15.0 
years and 19,964 cord implant days which is equal to 54.7 years of experience with Harpoon 
chords implanted in a human heart. The Harpoon ePTFE bulky knot anchoring mechanism has 
proven durable to date with no cords pulling out of a leaflet after implantation in the operating 
room. In summary, the data collected to date supports the conclusion that the Harpoon Medical 
Delivery System (TSD-5) and the Valved Introducer (TAV-5) can be used safely on 
degenerative MR patients.  
 
Since this study will use the same device, as was studied in the first Early Feasibility Study and 
the CE Mark study to investigate the feasibility of the use of the device for anterior, bi-leaflet and 
posterior degenerative mitral regurgitation, and since there has been no mortality, no stroke, no 
renal failure, no myocardial infarctions, no blood transfusions and no new onset atrial fibrillation 
for the enrolled patients, the expected outcomes for this study should be similar. 
 
POTENTIAL BENEFITS 
 
It is anticipated, that the Harpoon Medical Device will provide advantages over current surgical 
interventions including:  
1) a small minimally invasive incision  
2) no sternotomy,  
3) no cardiopulmonary bypass,  
4) no aortic manipulation,  
5) a direct path to the valve plane,  
6) performed on a beating heart,  
7) real-time TEE-guided ePTFE cordal length adjustment and  
8) less complicated procedure that is teachable and adoptable.  
The only intracardiac implant associated with the Harpoon Medical Device is an ePTFE suture, 
which has a 25+ year history of safety in conventional mitral valve repair procedures. Moreover, 
the Harpoon approach is unlikely to compromise subsequent traditional open-heart mitral valve 
repair or replacement procedures.  
 
POTENTIAL RISKS 
 
There are risks associated with our protocol. The Harpoon Medical Device is an “Investigational 
Device” that does not bear a CE Mark.  It is not available for market into the EU. The study uses 
minimally invasive surgical techniques to repair/replace the native chordae in a human heart.  The 
discomforts and risks that are equivalent to what is expected from similar cardiac procedures 

 
 
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performed through the chest wall on a beating heart to repair the mitral valve (i.e., localized pain, 
discomfort at the incision site(s) and the risks of bleeding, injury to the myocardium and injury to 
the mitral valve).    
 
A detailed risk analysis has been completed in accordance with ISO 14971:2012.  The 
conclusions from the risk assessment is that when the Harpoon Medical Investigational device 
is used in accordance with the Indications for Use of the device, it will not present risks to the 
patient that are not able to be mitigated either through the device design controls, the 
contraindications, warnings and operator training.  All risks that were evaluated, analyzed or 
reviewed assured that the risk of the TRACER procedure using the Harpoon Medical Device is 
as low as possible to for the user or the patient.  The following categories of procedure and 
device related functional risk were analyzed as part of the risk analysis: 
 
A) Ability to Access – the risks assessed are associated with the patient type, the access to the 
heart using a left thoracotomy and the ability to complete the procedure without a 
conversion to open repair.  The key risks evaluated are: 
• 
Conversion to open repair of the mitral neochodae post-procedure 
• 
Excessive Blood loss through the valved introducer 
• 
Assembled components joints fail resulting in excessive blood loss 
• 
Ability to Access the Mitral Leaflet using a thoracotomy and the valved introducer to 
complete the procedure 
B) Implant Integrity – the risks assessed are associated with the device performance and 
function and intended use to be able to implant one or more ePTFE cords to reduce mitral 
regurgitation.  The key risks evaluated are:  
• 
The knot pulls through the leaflet after implant at the time of implant or post-implant 
• 
Damage occurs to previously deployed knots with the passage of subsequent devices 
through the valved introducer 
• 
The knot fails for form correctly resulting in reduced anchoring force on the mitral leaflet 
• 
The suture does not un-thread from the device resulting in catching and the knot pulls 
out during device withdrawal 
• 
The Mitral valve cordal repair construct fails due to fatigue 
• 
The Manufacturing joints fail causing the knot to form incorrectly resulting in low anchor 
forces or detached components 
• 
Post-Implant, the body fails to endothealise the ePTFE suture 
C) Lack of Sterility - the risks assessed are associated with the device being marked as sterile 
and the device not delivered as sterile and results in cross-contamination or infection to the 
patient. The key risks evaluated are: 
• 
Breach of the sterile barrier on the packaging and contamination to the patient 
• 
Use of the device with an expired shelf life 
• 
Use of contaminated or unclean product, results in infection and/or contamination to the 
patient 
D) Lack of Biocompatibility – the risks assessed are associated with the device or the ePTFE 
implant not being physiologically compatible with the patient.  The key risks evaluated were: 
• 
Use of materials that are not physiologically compatible with the human body and 
tissues, results in the human body rejecting the ePTFE implant 
 
All risk management was performed in accordance with BS EN ISO 14971: 2012 which primarily 
affects the Essential Requirements of the Medical Device Directive in accordance with 
2007/47/EC and 93/42/EEC to assure that the risk is mitigated to the lowest possible risk.  
Contraindications and Warnings were placed in the labeling to exclude patients that are 

 
 
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identified in the Exclusion criteria of the Clinical Protocol.  Cautions, Pre-Cautions and Important 
Notes are added to the Instructions for Use and the Surgeons Technical Guide as a means to 
reinforce risks that the surgeon should be aware of when performing the TRACER procedure. 
 
All risks analyzed as part of the risk management process were able to be mitigated to a level as 
low as reasonable either through a design control, contraindication or warning in the Surgeon’s 
Technical Guide or the Instructions for Use. Although not credited directly for any mitigation of 
risk, the Investigator Training program provides qualification of the investigators to perform the 
TRACER procedure.  The pre-clinical testing and the Risk Analysis completed in accordance with 
ISO-14971 provides good confidence that the device when used in accordance with the intended 
use is a safe device for Patients who meet the inclusion criteria 
MINIMIZATION OF RISKS 
 
Measures which have been taken to minimize risks which include testing of materials and 
device configurations. 
Measures which will be taken to minimize risks related to the study include: 
• 
Selection of investigator(s) trained in performing this type of implant 
• 
Investigator training by Harpoon Medical personnel or representative 
• 
Well defined clinical investigation plan, including specific inclusion/exclusion criteria to enroll 
appropriate patients in the study 
• 
Close patient monitoring during the device implant procedure and follow-up period by the 
investigator(s) and their associates 
• 
Ongoing monitoring of study data and results by the study sponsor and sponsor’s 
representatives   
• 
Selection of patients in rigorous compliance with the clinical investigational plan  
 
OPERATOR TRAINING AND EXPERIENCE 
 
Each of the Principal Investigators AND any physician having an integral part in the procedure 
are required to complete an extensive training program in order to qualify them as Harpoon trained 
study doctors.  The training program is focused on hands-on practical experience and an 
understanding of the philosophy of the Harpoon device and use in the clinical setting.  The 
following is an overview of the Harpoon Clinical Therapy Training program that the on-site surgical 
team shall: 
 
• 
Establish an understanding on how to identify patient’s that are eligible for the Harpoon 
mitral valve repair procedure 
• 
Establish an understanding of the intra-operative surgical and echo guidance techniques 
employed in the Harpoon procedure 
• 
Be able to properly insert the Harpoon valved introducer (TAV-5) and deploy the Harpoon 
delivery system (TSD-5) 
• 
Demonstrate suture titration techniques 
• 
Understand post-operative care  
 
Additionally, each of the PIs must also complete the several training exercises, prior to using the 
Harpoon device on any of the patient enrolled from their study sites.  Once the surgical team has 
completed these training elements, they are considered to be a certified Harpoon center  

 
 
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IV. 
STUDY OBJECTIVES 
 
The primary objective of this study is to evaluate the safety and performance of the Harpoon 
Medical Device.   
 
Study Hypothesis 
 
Reduction in Mitral Regurgitation from “severe” to less than or equal to “moderate” at the 
conclusion of the procedure and at 30 days post-procedure. 
 
Endpoints 
 
Primary Performance Endpoints: To demonstrate that the Harpoon Medical Device performs 
as designed and can successfully implant one or more ePTFE artificial cords on either the 
anterior, posterior, or both leaflets of the mitral valve via a small left thoracotomy on the beating 
heart and reduce mitral regurgitation from “severe” to less than or equal to “moderate” at the 
conclusion of the procedure and at 30 days post-procedure. 
 
Secondary Performance Endpoints: Severity of mitral regurgitation at 6 months, 12 months 
and 24 months follow-up shall be tracked and recorded 
 
Primary Safety Endpoints: Procedure freedom from Serious Adverse Events (SAEs) during 
the procedure, at discharge, and at 30 days follow-up shall be tracked and recorded.  Rates are 
expected to be not significantly worse than conventional mitral valve surgery. 
 
Secondary Safety Endpoints Freedom from Serious Adverse Events (SAEs) at 6 months, 12 
months and 24 months follow-up shall be tracked and recorded 
 
Rationale for Endpoint selection 
 
The primary and secondary performance and safety endpoints are the same endpoints as what 
was currently tested in the first Early Feasibility Study in PL and what is currently being tested in 
the CE mark study design.  Our intent of this study and using these endpoints, if to further 
understand if the treatment of using the Harpoon Medical device for anterior, posterior and bi-
leaflet prolapse can meet these endpoints.  
 
V. 
STUDY DESIGN 
 
This is a prospective, single arm, nonrandomized, early feasibility study to evaluate the safety 
and performance of the Harpoon Medical Device. 
 
VI. 
STUDY POPULATION 
 
NUMBER OF PATIENTS 
 
Up to 20 patients in PL may be enrolled.  The estimated enrollment period is 24 months, and all 
patients shall be followed for 30 days, 6 months, 12 months and 24 months after implantation in 
accordance with the Clinical Investigations schedule provided in Section VIII. 
 

 
 
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INTENDED USE 
 
The Harpoon Medical Device is intended to be used by a trained medical professional.  The device 
is designed to reduce the degree of mitral regurgitation by delivering and anchoring artificial 
chordae tendineae to the affected mitral valve leaflet(s) in a beating heart.  The device is intended 
to be a Single Use Device, used in a surgical operating suite or equivalent setting. 
 
INCLUSION CRITERIA 
 
• 
Age > 18 years  
• 
Patient referred for mitral valve surgery 
• 
Presence of severe MR as read on an echocardiographic study performed within 60 days 
prior to procedure.   
• 
Estimated post-ePTFE chordae tendineae implantation coaptation surface is adequate in 
the judgment of the operating surgeon and the patient eligibility committee 
• 
Degenerative mitral valve disease associated with anterior, bileaflet, or posterior leaflet 
prolapse 
• 
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 
• 
Women of child-bearing potential have a negative pregnancy test 
 
EXCLUSION CRITERIA 
 
• 
Age < 18 years 
• 
Infective endocarditis 
• 
History of Mediastinal Radiation 
• 
Inflammatory (rheumatic) valve disease 
• 
Requirement for concomitant cardiac surgery (e.g., coronary artery bypass grafting (CABG), 
aortic valve surgery, etc.) 
• 
Symptomatic coronary artery disease 
• 
Cardiogenic shock at the time of enrollment 
• 
ST segment elevation myocardial infarction requiring intervention within 30 days prior to 
enrollment 
• 
Evidence of cirrhosis or hepatic synthetic failure 
• 
Pregnancy at the time of enrollment (women of child bearing age should have negative 
pregnancy within 14 days of surgery) 
• 
Severe pulmonary hypertension (PA systolic pressure > 70 mmHg) 
• 
Previous cardiac surgery, or surgery on the left pleural space 
• 
Left ventricular, atrial or appendage thrombus 
• 
Severely calcified mitral leaflets 
• 
Recent stroke (<  6 months) with permanent impairment 
• 
EuroScore (for mitral valve repair) > 8% 
• 
Patients with contraindications to Transesophageal echocardiography 
• 
Severe left or right ventricular dysfunction 
• 
NYHA Class IV 
• 
Renal insufficiency CKD stage 3b or worse (GFR < 45 ml/min/1.73 m2) 
• 
Patient is participating in another clinical study for which follow-up is currently ongoing. (Co-
enrollment in an investigational device or interventional study) 

 
 
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• 
Patient with non-cardiac co-morbidities and life expectancy < 1 year 
Patient has a condition or conditions that, in the opinion of the Investigator, preclude 
participation, including willingness to comply with all follow-up procedures 
 
VII. 
PATIENT ENROLLMENT 
 
PRE SCREENING 
 
Screening evaluations: All patients that are identified as potential candidates for the study shall 
undergo transthoracic echocardiography (TTE).  This echo should have been performed within 
the two months preceding the patient’s inclusion in the study. 
 
A TEE will be performed at the referring doctor’s request. Both the TTE and TEE are routinely 
performed in patients undergoing heart valve surgery. 
 
If the patient is deemed to be a good candidate for the study, the investigator will ask him to sign 
the Echo PIC to release existing medical records to the Harpoon Patient Eligibility Committee 
(PEC) for review and evaluation for enrollment.    These records include the   screening 
evaluations (anonymized echocardiogram along with the limited medical information (age, vital 
signs)). 
 
The PEC will provide the study site with a Pass or Fail for the patient being screened.   
 
If the PEC determines a PASS for the patient under consideration, Harpoon Medical will validate 
the participation and the patient will be asked to sign the study informed consent and, once 
officially enrolled, will proceed to the pre-procedure/baseline evaluations.   
 
If the PEC determines a FAIL for the patient, the patient will be referred back to the standard of 
care. If the patient data is not satisfactory for the PEC, the PI may request a new echo be 
completed if this falls under standard practice.  This new echo will then be submitted to the PEC 
for re-evaluation. All data received by the PEC for this patient will be destroyed. Only data 
compiled in screening enrollment log will remain. 
  
In any case, the PEC will provide the site with an MDDX number for each patient reviewed. The 
site will be asked to maintain a list of these numbers and the related patients. This information 
will be reported on a Screening and Enrollment log maintained in the study file on site. The 
MDDX number is composed of two digits for site number and two digits for patient number. Only 
one number will be given per patient and will remains the same if the patient is further enrolled.   
 
INFORMED CONSENT 
 
Patients who have been pre-screened and for whom the principal investigator feels would be a 
good candidate for inclusion in the Trial, will be asked to sign the study specific Ethics Committee 
(EC) approved Patient Information Sheet before any study-specific tests or procedures are 
performed.  Enough time will be given to the patient (at least 24h) to read and understand the 
informed consent form and to consider participation in the clinical investigation.   
 
The PI (or one of his co investigators specifically identified on the delegation log and authorized 
to do so) will answer all patients’ questions and will clearly explain to the patients that even if they 
agree to participate in the study and sign the Patient Information Sheet, they can withdraw their 

 
 
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consent to participate at any time. They will continue to be followed and treated by the site as 
normal. The site personal will make sure also that the patients have understood what their 
participation means (visits and tests scheduled) and that even if they sign the consent they may 
not be eligible to participate if he/she fails additional eligibility criteria.  
 
The Screening/Enrollment Log is maintained in the on-site clinical records located at the study 
site to document select information about candidates who pass or fail to meet the entry criteria. 
In the case a patient does not want to participate to the study, the PEC will destroy the data 
transferred. 
 
ENROLLMENT 
 
Point of enrollment: a patient will be officially considered as enrolled after consent has been 
signed and dated by him/her. The patient will be followed until his/her study exit (study completed, 
withdrawal, lost to follow up, death). All the events will be registered from that date and until the 
patient leaves the study for one of the reason previously mentioned. 
 
One original form will be kept on site (in patient’s medical records) and one will be provided to the 
patient. The version kept on site will be reviewed by the clinical monitor during the monitoring visit 
to ensure that the correct version has been signed and that the consenting process has been 
respected.  
 
The site staff will also make sure that the patient study participation is clearly indicated in patient’s 
files. 
 
PRE-PROCEDURE/BASELINE EVALUATIONS 
 
Once the patient is officially enrolled for the Harpoon Medical study, a Physical Assessment will 
be performed.  This includes: 
• 
Vital signs 
• 
12-lead ECG 
• 
Routine Laboratory assessment (including WBC count; Hemoglobin; hematocrit; platelet 
count; creatinine Level, INR) 
• 
Additional Laboratory assessment (including Total Albumin, Total Bilirubin, BNP, NTproBNP)  
• 
A chest radiograph (X-Ray) 
• 
A serum pregnancy test for females with childbearing potential (age < 50 years) shall be 
completed within 14 days prior to the procedure 
• 
In accordance with the hospital’s clinical Standard of Care, a left heart catheterization (LHC) 
may be required for all patients >/= 45 years of age without risk factors and for any patient 
with symptoms of coronary artery disease 
• 
Pulmonary Function Tests, when clinically indicated 
• 
6 Minute Walk test 
• 
Quality of Life Assessment 
• 
EUROscore assessment 
 
The data from this physical assessment shall be recorded on a Case Report Form (CRF). 
 
TREATMENT PROCEDURE/ASSESSMENTS 
 

 
 
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The procedural approach requires that the patient be administered a general (single lumen) 
endotracheal anesthesia with appropriate monitoring lines (e.g. arterial line) and heparinized 
saline to achieve an activated clotting time of ≥ 350 seconds.  The patient should be placed in the 
supine position with elevation of the left hemithorax to 30o.  Briefly, the procedure consists of 
performing a small left lateral thoracotomy incision overlying the left ventricular apex, opening the 
pericardium and selecting an insertion site on the epicardium for the Harpoon Medical  device 
where a monofilament purse-string suture is placed to hold the Harpoon device introducer in place 
and reduce bleeding. Once the introducer is in place, the device is inserted and positioned 
adjacent to the mitral leaflet under TEE guidance and bulky suture knot is deployed to secure 
paired sutures in the leaflet. The paired sutures are brought outside the ventricle. Up to four (4) 
suture pairs may be placed, using a single valved introducer (TAV-5), to secure and align 
apposition between the anterior and posterior mitral leaflets. If more than four (4) suture pairs are 
required, the TAV-5 must be removed and reinserted for reuse, and then an additional four (4) 
suture pairs may be inserted.  Once an adequate number of suture pairs are placed, the device 
and introducer are removed, and the suture pairs are tightened and secured to the exterior 
myocardium using pledgets for each suture pair. The thoracotomy should be closed, and chest 
tube(s) should be inserted, per hospital standard of care.  
 
The details of the procedure a described thoroughly in the Harpoon Medical Device Instructions 
for Use. 
 
If in the judgment of the operating surgeon, adequate MR reduction has not been achieved, or if 
for any other clinical reason, conversion to SOC mitral valve surgery via a median sternotomy 
shall be performed. This procedure may be performed at the time of the Harpoon Medical 
procedure or at a later date/time at the discretion of the operating surgeon. 
 
FOLLOW-UP PROCEDURES/ASSESSMENTS 
 
Post-procedure management: Standard hospital protocols for the management of patients after 
mitral valve surgery shall be followed.  Unless other indications for anticoagulation are present, 
all patients shall receive only 325 mg/day low dose aspirin, beginning on arrival to the intensive 
care unit). 
 
Discharge:  All patients shall be discharged from the hospital at the discretion of the attending 
cardiac surgeon.   
 
For the patients where a procedure was finally not started (i.e. echo results) or started but finally 
interrupted with no use of the study device, the discharge date will be registered as the study 
termination date and no more data will be collected for these patients. 
 
For the patients where a procedure attempt has been made, Harpoon device used, but procedure 
was finally not completed and patients were converted to another treatment a safety period of 30 
days post procedure will be required. Clinical data will be collected and CRF completed until that 
date. The 30 days Follow up date will be registered as the study termination date for these 
patients. 
 
For the patients successfully treated, the expected follow period is 24 months. Patients will be 
followed until that date except under certain circumstances (withdrawal, death, lost to follow up). 
 
Prior to dismissal all patients shall undergo a comprehensive pre-dismissal TTE, as well as a 
physical assessment (vide supra) in accordance with the schedule of Clinical Investigations. 

 
 
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Patient follow-up: The expected follow up period after the Harpoon procedure is from 24 months.  
Assessments will be completed at 30days, Discharge, 6 months, 12 months and 24 months. 
 
30 days follow up (+10/0 days post procedure) - Patients will be seen in the outpatient clinic and 
the following exams will be performed: 
• 
Physical exam, including NHYA evaluation if needed 
• 
ECG 
• 
TTE AE evaluation 
• 
Concomitant medication changes 
 
6 months follow up (+/- 30 days) - Patients will be seen in the outpatient clinic and the following 
exams will be performed: 
• 
Physical exam, including NHYA evaluation if needed 
• 
TTE 
• 
AE evaluation 
• 
Concomitant medication changes 
 
12 months follow up (+/- 30 days) - Patients will be seen in the outpatient clinic and the following 
exams will be performed: 
• 
Physical exam, including NHYA evaluation if needed 
• 
6 minute walk test (6MWT) 
• 
SF36 questionnaire 
• 
TTE 
• 
AE evaluation 
• 
Concomitant medication changes 
 
24 months follow up (+/- 30 days) - Patients will be seen in the outpatient clinic and the following 
exams will be performed: 
• 
Physical exam, including NHYA evaluation if needed 
• 
TTE 
• 
AE evaluation 
• 
Concomitant medication changes 
 
The table below summarizes the general and cardiac assessments and expected follow up. 

 
 
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General Assessment 
PL study site 
Responsibility  
Harpoon Medical 
Responsibility 
Screening and pre-
operative evaluation 
Surgery Date 
Discharge 
30 Days  
(+ 10/-0 d) 
6 Months 
(+/- 30 d) 
12 Months 
(+/- 30 d) 
24 Months 
(+/- 30 d) 
Invitation to enroll in the study 
X 
 
X 
 
 
 
 
 
 
Screening worksheet 
completed 
X 
 
X 
 
 
 
 
 
 
Patient Eligibility Committee 
Assessment 
 
X 
X 
 
 
 
 
 
 
Patient Information Sheet 
Signed  
X 
 
X 
 
 
 
 
 
 
Pre-Procedure worksheet 
completed 
X 
 
X 
 
 
 
 
 
 
Release of Medical Information 
** 
X 
 
X 
 
 
 
 
 
 
Medical History ** 
X 
 
X 
 
 
X 
X 
X 
X 
Medications & Dosage ** 
X 
 
X 
X 
X 
X 
X 
X 
X 
Physical Exam ** 
X 
 
X 
 
X 
X 
X 
X 
X 
Laboratory Assessment (blood work) 
X 
 
X 
 
 
 
 
 
 
 
** - included as part of the baseline/pre-procedure worksheet 
 
Cardiac Assessment 
PL study site 
Responsibility  
Harpoon Medical 
Responsibility 
Screening and pre-
operative evaluation 
Surgery Date 
Discharge 
30 Days  
(+ 10/-0 d) 
6 Months 
(+/- 30 d) 
12 Months 
(+/- 30 d) 
24 Months 
(+/- 30 d) 
Chest Radiograph (X-Ray) 
X 
 
X 
 
 
 
 
 
 
Diagnostic Left Heart 
Catheterization or Clinical 
Standard of Care 
X 
 
X 
 
 
 
 
 
 
NYHA Heart Failure Class 
X 
 
X 
 
 
X 
X 
X 
X 
Electrocardiogram (ECG) 
X 
 
X 
 
 
X 
 
 
 
Transthoracic Echocardiogram 
(TTE) *** 
X 
 
X 
 
X 
X 
X 
X 
X 
Transesophageal 
Echocardiogram (TEE)  
X 
 
X 
X 
 
 
 
 
 
SF-36 Quality of Life 
Assessment 
X 
 
X 
 
 
 
 
X 
 
6 Minute Walk Test 
X 
 
X 
 
 
 
 
X 
 
EUROscore risk assessment 
X 
 
X 
 
 
 
 
 
 
Pulmonary Function Test (if 
clinically indicated) 
X 
 
X 
 
  
  
  
  
  
 
*** TEE: may be required if the TTE images are not readable 
 

 
 
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UNSCHEDULED FOLLOW UP VISITS 
 
If the patient is seen by the investigator or center outside planned study follow-up, an unscheduled 
follow-up visits eCRF should be completed.  In the case of adverse event occurrence the 
corresponding eCRF, documentation, and notification should be completed. In the case of a 
serious adverse event the corresponding eCRF and documentation should be complete in 
addition to notifying the Sponsor/Monitor in case the SAE is the cause of the unscheduled visit.   
 
PATIENT WITHDRAWAL FROM THE STUDY   
 
A withdrawal refers to a patient who is determined to be inactive in the study due to physician 
discretion, patient or family choice (if the patient becomes incapacitated and is unable to continue 
with the study due to a family choice), and loss to follow-up or patient death.  Final status shall be 
reported on all patients as per the informed consent.  Three documented phone calls and a 
registered/certified letter shall be used to assure that there is minimal loss to follow-up. 
 
In the event that patients are not reachable after repeated contact attempts, investigators must 
quickly clarify their whereabouts and health status with the family doctor or the contact person 
stated in the patient consent form (e.g., family doctor) as per the applicable regulation in each 
country. Patients will agree in the data exchange in the informed consent form. 
 
If these efforts to contact the patient and his family doctor/contact person are unsuccessful, the 
patient shall be considered lost to follow-up. Attempts made to contact the patients and host family 
doctor/contact person must be recorded by the study center and monitored by the monitor. 
 
END OF PARTICIPATION 
 
Subjects who have finished the required follow-up visits will be considered to have completed 
the study. 
 
Withdrawal: all patients have the right to withdraw themselves from participation at any point 
during the study. In addition, PIs also have the authorization to terminate a patient’s 
participation in the study. A description of the reason for the patient’s termination will be 
documented. Reasons for termination include: completion of study, patient’s voluntary 
withdrawal, physician-directed patient withdrawal, and death. 
 
Upon study exit the patient will be followed per standard of care by the investigator and/or 
another physician.   
 
DURATION OF INVESTIGATION 
 
The estimated duration for the main investigational plan (e.g. from start of screening to last 
participant processed and finishing the study) is approximately 36 months. 
 
Each patient will be followed for 24 months and then exit the investigation. It is anticipated that 
all clinical investigation patients will be enrolled within a 24 month time period.  

 
 
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VIII. 
SAFETY MANAGEMENT 
 
Subjects will be carefully monitored during the study for possible Adverse Events (AEs) from the 
time the Subject signs the Patient Informed Consent form to the completion of their participation 
in the study. Any AE observed will be fully investigated by the Investigator and classified in line 
with the definitions of the ISO14155:2011 below. 
DEFINITIONS 
 
Adverse Event (AE): 
Any untoward medical occurrence, unintended disease or injury, or untoward clinical signs 
(including abnormal laboratory findings) in patients, users or other persons, whether or not 
related to the investigational medical device 
 
This definition includes events related to the investigational medical device. 
This definition includes events related to the procedures involved. 
For users or other persons, this definition is restricted to events related to investigational 
medical devices. 
 
Serious Adverse Event (SAE): 
Adverse event that: 
a) led to death, 
b) led to a serious deterioration in the health of the patient, that either resulted in 
a life-threatening illness or injury, or 
a permanent impairment of a body structure or a body function, or 
in-patient hospitalization or prolongation of existing hospitalization, or 
in medical or surgical intervention to prevent life-threatening illness or injury or permanent 
impairment to a body structure or a body function, 
c) led to foetal distress, foetal death or a congenital abnormality or birth defect 
 
NOTE: Planned hospitalization for a pre-existing condition, or a procedure required by the 
Clinical Investigation Plan, without serious deterioration in health, is not considered a serious 
adverse event. 
 
Device Deficiency 
Inadequacy of an investigational medical device related to its identity, quality, durability, 
reliability, safety or performance. This may include malfunctions, use error, or inadequacy in the 
information supplied by the manufacturer. 
 
Adverse Device Effect (ADE): 
Adverse event related to the use of an investigational medical device 
 
NOTE 1: This includes any adverse event resulting from insufficiencies or inadequacies in the 
instructions for use, the deployment, the implantation, the installation, the operation, or any 
malfunction of the investigational medical device. 
NOTE 2: This includes any event that is a result of a use error or intentional abnormal use of the 
investigational medical device. 
 
Serious Adverse Device Effect (SADE): 
Adverse device effect that has resulted in any of the consequences characteristic of a serious 
adverse event 

 
 
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Unanticipated Serious Adverse Device Effect (USADE) 
 
Serious adverse device effect which by its nature, incidence, severity or outcome has not been 
identified in the current version of the risk analysis report. 
 
Anticipated Serious Adverse Device Effect (ASADE) 
 
Anticipated serious adverse device effect (ASADE) is an effect which by its nature, incidence, 
severity or outcome has been identified in the risk analysis report. 
EVENT SEVERITY  
Event severity is classified as follows: 
• 
Mild: awareness of a sign or symptom that does not interfere with the patient’s usual 
activity or is transient, resolved without treatment and with no sequelae. 
• 
Moderate: interferes with the patient’s usual activity and/or requires symptomatic 
treatment 
• 
Severe: symptom(s) causing severe discomfort and significant impact on the patient’s 
usual activity and requires treatment. 
 
CAUSALITY RELATIONSHIP 
The investigator will assess the causality of all adverse events in relation to the research, i.e., 
the relationship between the AE / SAE and the investigational treatment or any other study-
related procedures. 
 
Each SAE will be classified according to five different levels of causality: 
1) Not related: relationship to the device or procedures can be excluded when: 
• 
the event is not a known side effect of the product category the device belongs to or of 
similar devices and procedures; 
• 
the event has no temporal relationship with the use of the investigational device or the 
procedures; 
• 
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 patient 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 

 
 
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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 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); 
• 
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 patient 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.  
 
INVESTIGATOR REPORTING RESPONSIBILITIES 
 
Notification of events to the sponsor 
The investigator should report to the sponsor the following events, whether expected or not, in 
the corresponding sheet of the eCRF, with the exception of AEs / SAEs detected before the 
patients has signed the patient consent form.   
• 
AE 
• 
SAE 
• 
Device Deficiencies that did not but might have led to a SAE if: 
i. 
Suitable action had not been taken or 
ii. 
Intervention had not been made or 
iii. 
If circumstances had been less fortunate 
• 
New findings/updated in relation to already reported events 
 
If an AE / SAE is present at the beginning of study prior to the patient providing signed consent 
to participate in the study, only its worsening should be reported. 
 
The investigator shall notify the sponsor immediately and not later than 24 hours after the 
investigator has become aware of a SAE or device deficiency that might have led to a SAE. 
The investigator must ensure that all additional relevant information that becomes available is 
also forwarded to the sponsor immediately after the initial notification. 
 

 
 
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The investigator shall transmit to the sponsor all relevant supporting documents related to the 
SAE (i.e., copy of laboratory exams, hospitalization reports indicating the SAE) ensuring 
anonymization of the documents and indicating the identification number of the patient in the 
study. 
 
How to report 
The investigator will report “to the sponsor, without unjustified delay, all serious adverse events 
and device deficiencies that could have led to a serious adverse device effect; this information 
shall be promptly followed by detailed written reports” [ISO 14155:2011 § 9.8 b]. Device 
malfunctions and use errors should also be reported without unjustified delay.  
All Serious Adverse Events (SA(D)Es), including all device deficiencies should be reported to 
the Sponsor within 24 hours of awareness of an event via the Adverse Event electronic Case 
Report Form in the study’s electronic database, as that will trigger an immediate e-notification to 
the Sponsor and MedPass. Additional information can be provided to the Sponsor or MedPass 
via email, telephone, or fax using the information below.  
 
Sponsor: 
 
Monitor: 
Harpoon Medical Inc. 
351 West Camden Street 
Suite 801 
Baltimore, MD 21201, U.S.A. 
+1 410-346-5687 
rvillanueva@harpoonmedical.com                         
 
MedPass International 
95 Bis Boulevard Pereire 
75017 Paris, France 
Tel. +33 1 42 12 83 30 
Fax: +33 1 40 53 81 11 
fredericbillaut@medpass.org  
 
The investigator will document all AEs on the Adverse Event Form, including (at a minimum) a 
description of the event, date of onset, severity, relationship to the investigational device and/or 
procedure, required interventions, duration, and outcome. The investigator will monitor all AEs 
until they are resolved, determined to be a chronic condition or the patient is lost to follow-up. 
The investigator will report all AEs regardless of whether it is anticipated or unanticipated and 
regardless of classification, seriousness, intensity, outcome or causality. 
REPORTING TO EC/CA 
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 
Committee according to the relevant local regulatory requirements. 
 
The sponsor will be responsible for reporting to the National Competent Authority according to 
national requirements and in line with MEDDEV 2.7/4 and/or MEDDEV 2.12-1, as applicable. 
 
IX. 
INVESTIGATIONAL DEVICEDISTRIBUTION AND ACCOUNTABILITY 
 
The PI is responsible for ensuring that the investigational devices are used only under the PI’s 
supervision and are only used according to this protocol and any approved amendments. At the 
time of each study, Harpoon will provide the proper quantity of investigational devices the 
persons authorized to participate in the study. Harpoon will maintain adequate records of the 
receipt and disposition of all investigational devices. Harpoon and/or MedPass shall document 
in CRFs the lot numbers of the devices used during a case. Unused devices will be taken back 
by Harpoon Medical upon completion of a patient.  No devices will be left at the study site. 

 
 
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X. 
 STATISTICAL ANALYSIS 
 
This is an early feasibility study.  The sample size for this study was determined from the first 
early feasibility study for this device for the treatment of mitral regurgitation at the conclusion of 
the procedure and at the time of the hospital dismissal and at one year.  Specifically the 
percentage of patients that demonstrate MR reduction from severe to </+ moderate at the 
conclusion of the procedure and at 30 days.  These data will be used to assess the safety and 
performance of the device when used on a human patient.  These data will be used to assess 
initial safety and performance of the Harpoon Medical Device, and are not designed to test a 
statistical hypothesis, therefore a formal sample size has not been calculated.  All data will be 
captured on an intent-to-treat basis.  Data will be reported as descriptive statistics. 
 
XI. 
STUDY ORGANISATION 
 
INVESTIGATIONAL SITE PERSONNEL 
 
Investigator and co-investigators 
 
The Investigator is responsible for ensuring that this study is conducted according to this protocol 
and that signed Informed Consent is obtained from each patient prior to their inclusion in this 
study. 
 
It is the Investigator’s responsibility to ensure that all staff assisting with this study have the 
appropriate qualifications and are fully instructed on the study procedures and respect patient 
confidentiality, as specified in the Investigator Agreement with the Sponsor. 
 
The Investigator is responsible for ensuring that the conduct of the study conforms to the EC and 
Competent Authority (CA) requirements and provides all necessary communication with the EC, 
but not limited to, annual study reports and required adverse event notifications. 
Specific responsibilities: 
 
• 
An Investigator shall conduct an investigation in accordance with the ethical principles that 
have their origin in the Declaration of Helsinki, the ISO14155:2011, the signed Investigator 
Agreement with the Sponsor, the Protocol, applicable national regulations, and any conditions 
of approval imposed by a local regulatory body, Ethical Committee (EC), or Competent 
Authority. 
• 
The standardized Case Report Forms (CRFs) will be used to collect complete and accurate 
records of the clinical data from the study. The Investigator is responsible for collecting and 
accurately recording the data generated for this study. 
• 
Investigators will maintain a screening log that will record the date of informed consent, the 
date of screening, the enrollment status (enrolled/excluded) and the reason for exclusion for 
all screen failures. 
• 
A participating Investigator shall maintain accurate, complete, and current records (listed in 
detail in the Investigator Agreement) relating to the Investigator’s participation in the study for 
a period of 10 years or longer, as may be required by applicable laws, rules and regulations.  
 
• 
An Investigator shall prepare and submit complete, accurate, and timely reports on adverse 
events, withdrawal of EC approval, progress, deviations from the protocol, informed consent, 

 
 
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termination or completion of the study, and other study-related aspects requested by the EC. 
(These are described in more detail in the Investigator Agreement.) 
 
Study Coordinator 
 
Each site in this study is required to identify a Study Coordinator who will be responsible for, but not 
limited to, the following: 
• 
Scheduling diagnostic and assessment procedures. 
• 
Informing all study team members of scheduled treatments. 
• 
Paging study team members on the morning of scheduled treatments to ensure that all 
necessary personnel will be present. 
• 
Entering all study data into the Case Report Forms. 
• 
Maintaining a list of all patients screened for the study and those who have entered the study 
and their patient numbers.  
• 
Maintaining the Device Accountability Log. 
• 
Scheduling all follow-up visits within the appropriate follow-up windows and ensuring that all 
follow-up data is collected in accordance with the protocol. 
 
CLINICAL MONITORING 
 
The clinical study site(s) shall be monitored in accordance with policies at Harpoon Medical, Inc. 
and those federal regulations that pertain to clinical research; namely ISO14155:2011. 
 
A monitoring plan will be developed prior to the initiation of the investigation which outlines the 
extent and nature of monitoring appropriate for the clinical investigation, including the frequency 
of visits, the strategy for source data verification, based on considerations such as the objective, 
design, complexity, size, critical data points and endpoints of the clinical investigation.   
 
The Sponsor or its designated representative, qualified by training and experience, will be 
responsible for monitoring and overseeing the conduct of the study. These responsibilities include 
maintaining regular contact with each Investigational site and conducting on-site monitoring visits 
at the Investigational site to ensure compliance with this Protocol, to verify that accurate and 
complete data are being submitted in a timely manner, and to verify that the Investigational site 
facilities continue to be adequate.  
 
Monitors are responsible for assuring that each Investigator and his/her staff clearly understand 
and accept their obligations under the clinical investigation through site visits, written 
communications and phone calls between the Monitor and the PI and staff.   
 
During the course of the investigation, the Monitor shall assure that the PI and his/her staff: 
 
• 
Understand and agree to the requirements of the protocol; 
• 
Agree to their obligations to conduct the study; 
• 
Accept the obligation to obtain informed consent using the approved Patient Information 
Sheet; 
• 
Have access to an adequate number of suitable patients to conduct the investigation; 

 
 
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• 
Have facilities adequate to conduct the clinical investigation; and  
• 
Have sufficient time to fulfill his/her obligations under the study; 
 
During the course of a clinical investigation, the Monitor shall periodically visit the clinical 
investigation site to assure that:  
 
• 
Changes to the protocol have been submitted and approved by ethics committees; 
• 
Adverse events (anticipated and unanticipated) are recorded and reported in accordance with 
the spirit of Good Clinical Practices (GCPs), ISO-14155-2011, Declaration of Helsinki, and as 
per the Investigator Agreement; 
• 
Accurate, complete, and current records are being maintained;  
• 
Patient confidentiality of records and study participation are being maintained; and  
• 
Accurate, complete and timely reports are being made to Sponsor and to the EC.  
 
Patient information shall remain confidential. Should any new knowledge about the patients’ 
medical condition become known, it will be kept confidential. Any data that may be published in 
scientific journals will not reveal the identity of the patients. Data retrieved (case report forms, 
surgery reports, discharge summaries, laboratory and test reports, etc.) from the site will identify 
patients by their patient number / patient name code only.   
 
CLINCAL EVENTS COMMITTEE 
 
The purpose of the Clinical Events Committee (CEC) will be to review specific information 
obtained from research patients who are participating in the study. The CEC will have the authority 
to undertake a critical examination of this information and to draw conclusions regarding pre-
specified events that may or may not correspond with the conclusions of the investigator or 
Harpoon Medical for a specific site. Should a discrepancy arise the CEC’s conclusion will serve 
as the final decision for publication. 
 
The CEC will draw its own conclusions as to whether or not certain clinical events occurred as a 
result of the patient’s study participation. Definitions of clinical endpoints are previously 
established and are recorded in the Clinical Investigation Plan for use by the committee members. 
The CEC has the authority to request all available data for a given patient and to use state-of-the-
art scientific, technical and clinical information in order to reach its conclusions. These conclusions 
are required to be drawn independently from those of the treating physician, investigator and 
Harpoon Medical. 
 
The CEC is composed of 3 physicians: 2 Interventional Cardiologists and a Cardiac Surgeon in 
clinical practice.  These physicians should: 
• 
Not participate in the clinical study 
• 
Have no conflict of interest regarding the device under evaluation  
• 
Be independent from the clinical sites  
 
STUDY ADMINISTRATION 
 
Harpoon Medical, Inc. will make necessary efforts to ensure that this study is conducted in 
compliance with Good Clinical Practices (GCPs), with the ISO14155:2011 and all applicable 
regulatory requirements. 
 

 
 
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The clinical investigation shall not begin until the required approval / favorable opinion from the 
EC or regulatory authority have been obtained. As appropriate, the Sponsor will submit changes 
to the protocol to the appropriate regulatory authorities for approval and investigators (to obtain 
Ethics Committee approval) prior to implementing any changes. 
 
Additional requirements imposed by the EC or regulatory authority shall be followed, as 
appropriate. 
 
Source Documentation 
 
The Investigator must maintain detailed source documents on all study patients who are enrolled. 
Source documents include patient medical records, hospital charts, clinic charts, Investigator’s 
patient study files, as well as the results of diagnostic tests (e.g., laboratory tests).  These records 
will be kept in an individual patient binder and stored in a secured and locked location and must 
be made available to the Monitor during site visits. 
 
Criteria for Terminating a Study 
 
Harpoon Medical, Inc. reserves the right to terminate the study at any time.  The reasons for 
exercising the right would be for valid scientific or administrative reasons related to protection of 
the safety, rights or welfare of patients. Investigators and associated EC and CA will be notified 
in writing in the event of termination. 
 
Possible reasons for study termination include but are not limited to: 
• 
The discovery of an unexpected, significant, or unacceptable risk to the patients enrolled in 
the study 
• 
A decision on the part of Harpoon Medical, Inc. to suspend or discontinue development of the 
device 
 
Criteria for Suspending/Terminating a Study Center 
 
Possible reasons for suspending/terminating a study center include, but are not limited to: 
• 
Repeated failure to complete case report forms prior to scheduled monitoring visits 
• 
Failure to obtain written Informed Consent 
• 
Failure to report SAEs/UADEs to Harpoon Medical within 24 hours of knowledge 
 
Protocol Deviations 
 
The Investigator is not allowed to deviate from the protocol.  
 
Under emergency circumstances, deviations from the protocol to protect the rights, safety and 
well-being of human patients may proceed without prior approval of the sponsor and the Ethics 
Committee including these under emergency circumstances. Such deviations shall be reported 
to the Sponsor as soon as possible and no later than 24hours and to the Ethics Committee, if 
required, or national regulations 
 
Any deviations should be documented on the appropriate Protocol Deviation Case Report Form. 
If a Clinical Monitor becomes aware that an Investigator is not complying with the signed 
Investigator’s Agreement, the Investigational Plan, the requirements of ISO 14155 or other 
applicable regulations, or any conditions of approval imposed by the reviewing Ethics Committee, 

 
 
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Harpoon Medical, Inc. will immediately either secure compliance or discontinue shipments of the 
device to the Investigator and terminate the Investigator’s participation in the investigation.  
 
Protocol deviations will be analyzed by Harpoon Medical, Inc. for the impact to the overall integrity 
of the study.  Disqualification is warranted when an investigator has repeatedly or deliberately 
violated governing regulations or has repeatedly or deliberately submitted false information in any 
report.  Where protocol deviations occur which do not warrant disqualification from a study, 
Harpoon Medical, Inc. will implement appropriate corrective and preventive actions, including 
repeat training as deemed necessary. 
 
Any deviations from the protocol must be documented in detail by the Investigator including date 
and reasons for each deviation and reported to the study monitor as soon as possible. 
 
REGULATORY CONSIDERATIONS: RECORDS RETENTION POLICY 
 
Sponsor  
 
The Sponsor will maintain copies of correspondence, data, shipment of devices, serious adverse 
device effects and other records related to the clinical study.   
 
Site  
 
The Sponsor and clinical sites will maintain all records pertaining to this study for a period of at 
least 15 years following the date on which the investigation is terminated or completed as per 
national requirements, or the date that the records are no longer required for purposes of 
supporting a regulatory submission.  
 
Ethics Committee (EC) and Competent Authority (CA) Approval 
 
A center my initiate enrollment in this study only after the Sponsor has received written approval 
from the appropriate Ethics Committee. Amendments to the protocol should be submitted to the 
Ethics Committee for either notification or approval. Regulatory and local approvals must be 
obtained prior to enrolment of the first patient. The Sponsor will arrange regulatory and local 
approvals for the study. 
 
The Sponsor or its Monitor (MedPass International) will require a copy of any EC and CA 
correspondence, as well as the final approval letter from the EC and CA, where applicable.  These 
communication will be kept in the regulatory communication binder at each participating site.  
 
DATA QUALITY ASSURANCE 
 
Electronic Case Report Forms (eCRF) specific to this study will be used for the collection and 
recording of data at the Investigational site. Investigators are responsible for the timely completion 
and submission of these forms to the Clinical Monitor, but in any event submission must be made 
before payment to the Investigational site is required. All data collected will be entered by 
MedPass into a database. All case report forms received will be reviewed, tracked and filed. Prior 
to data entry, a pre-entry review will be conducted to ensure that mandatory fields have been 
completed. Incoming data will be reviewed to identify inconsistent or missing data and adverse 
events. Data problems will be addressed through written communication with the investigational 
site and/or during site visits. The Investigator will be queried on errors concerning data 

 
 
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completeness and consistency. All hard copy forms and data files will be secured to ensure 
confidentiality. 
 
Investigators are to maintain all source documents, including diagnostic test reports, laboratory 
results, completed case report forms, supporting medical records and informed consent. The 
source documents will be referenced during monitoring visits to verify the information documented 
on the case report forms.   
 
STATEMENT OF INSURANCE POLICY 
 
Harpoon Medical, Inc. shall, at its own expense, carry and maintain professional and general 
liability insurance or clinical investigation from a carrier in amounts sufficient to cover the covering 
the cost of treatment of patients in the event of clinical-investigation-related 
Injuries, in accordance with the national regulation.  
 
XII. 
ETHICAL CONSIDERATIONS 
 
DECLARATION OF HELSINKI 
 
This study will be conducted in accordance with the Declaration of Helsinki (see Appendix A). 
 
PATIENT INFORMATION AND INFORMED CONSENT 
 
Patient Information and Informed Consent documents (including the Patient Information sheet) 
will be submitted to the local site’s Ethical Committee for approval prior to initiation of the study. 
A copy of the consent form approved by the local clinical site’s Ethics Committee will be 
maintained in the official clinical files. All signed consent forms will be reviewed by the Monitor to 
ensure that only the approved version is being used. 
 
Patients eligible for the study will receive detailed written information on the study, after which 
they will be asked to give written informed consent in accordance with the local clinical site’s 
Ethics Committee. Oral consent is not an acceptable substitute. The patient should be asked to 
sign a consent form prior to undergoing any study-required procedures or assessments. A copy 
of the Patient Informed Consent document and the Patient Information Sheet will be given to the 
patient. 
 
The date that consent is obtained must be documented on the consent form and in the 
patient’s medical record. 
 
PATIENT CONFIDENTIALITY 
 
All information concerning patients or their participation in this study will be considered 
confidential. Only authorized Harpoon Medical personnel and designated consultants and 
regulatory agencies will have access to these confidential files. Enrolled patients will be assigned 
a unique identifier that will be used to maintain confidentiality of each patient’s medical 
information. Patient names and other protected health information will not be captured on the 
case report forms. In addition, angiographic and ultrasonic images submitted from the 

 
 
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participating site to the Sponsor or angiographic reviewers for analysis should be redacted from 
all patient identifiers. 
 
ETHICS COMMITTEE 
 
A center will initiate enrollment in this study only after the Sponsor has received copies of the 
written approval of the protocol and Patient Informed Consent from the appropriate Ethics 
Committee. Any subsequent amendment to the protocol should be submitted to the Ethics 
Committee for either notification or approval. 
 
REGULATORY APPROVAL 
 
Regulatory and local approvals must be obtained prior to enrollment of the first patient. The 
Sponsor will arrange regulatory and local approvals for the study. 
 
XIII. 
QUALIFICATIONS OF STUDY CENTERS AND INVESTIGATORS 
 
Each investigator must fulfill the following requirements prior to participation in this study: 
• 
Be appropriately trained on the use of the Harpoon Medical Device and procedure. 
• 
Be willing to change their clinical / surgical routine if required by the protocol. 
• 
Have an adequate medical Ethics Committee and be willing to comply with Good Clinical 
Practice, and the European standard ISO14155:2011 for the conduct of clinical investigations 
of medical devices. 
• 
Be willing to fill out all relevant documentation (e.g. Case Report Form) in a suitable, legible 
and timely manner, not to exceed 30 days, to allow analysis.  
• 
Be willing to allow clinical monitors to enter at reasonable times for inspection of all records 
pertaining to the study. 
 
XIV. 
PUBLICATION POLICY 
 
Sponsor follows local regulatory requirements relating to clinical trial registration and disclosure 
of results. In the United States, Harpoon Medical Inc. complies with requirements of the FDA 
Amendments Act of 2007 (FDAAA) to register this study on www.clinicaltrials.gov. 
 
Sponsor commits to seek publication of results of its clinical studies in the peer-reviewed scientific 
literature, regardless of study outcome. Sponsor supports recognized standards concerning 
authorship and publication, including those of the ICMJE (International Committee of Medical 
Journal Editors) and CONSORT (Consolidated Standards of Reporting Trials).  In the event that 
the Sponsor decides not to CE Mark the Investigational Medical Device for the intended purpose 
being investigated, the Sponsor shall publish the analysis of the results within twenty four (24) 
months of the completion of this study. In the case of Clinical Investigations closed on safety 
grounds, the Sponsor shall publish the analysis of the results within twelve (12) months of the 
date of closure.  
 
The Sponsor and the Investigators are committed to the publication and widespread 
dissemination of the results of the study. This study represents a joint effort between Sponsor and 
Investigators, and as such, the parties agree that the recommendation of any party concerning 
manuscripts or text shall be taken into consideration in the preparation of final scientific 
documents for publication or presentation. Patient to the terms of Confidentiality but not before 

 
 
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publication of the multi-center study results, Institution and the Investigator shall be free to publish, 
present or use any results arising out of the performance of the study at their centers for their own 
instructional, study or publication objectives, provided that such Publication does not disclose any 
Confidential Information other than the results of the Study performed. At least one hundred and 
eighty (180) days prior to submission for publication, presentation or use, Institution and the PI 
shall submit to Sponsor for review and comment any proposed oral or written Publication, which 
period may be extended for an additional thirty (30) days if requested in writing by Sponsor in the 
event that Sponsor provides reasonable need for such extension. Expedited reviews for abstracts 
or poster presentations may be arranged if mutually agreeable to Sponsor, Institution and the PI.  
 
Upon written notice to Institution that Sponsor reasonably believes that one or more patent 
applications relating to an Invention (as defined above) should be filed prior to any Publication, 
then such Publication will be delayed until such patent application(s) have been filed, provided 
that Institution, PI and Sponsor shall cooperate in expeditiously filing any such patent 
application(s), and provided further that any such delay of a Publication shall not exceed ninety 
(90) days from the date of such Sponsor notice to Institution and PI. Sponsor shall have the right 
to request modification of any Publication if in Sponsor's reasonable opinion such Publication will 
jeopardize a patent application or patent.  Harpoon Medical Inc. has the right to review all 
proposed publications and presentation materials for scientific integrity, effect on clinical activities, 
and relevance to patent protection and partnership agreements. Harpoon Medical Inc. will not 
suppress publications or presentations, but reserves the right to delay publications to avoid 
compromising intellectual property. Additionally, Harpoon Medical Inc. reserves to right to delay 
publications of sub-analyses until after the publication of the main study results. 
 
Sponsor will provide final reports of protocol-derived outcomes to external authors. Sponsor 
reserves the right to review and comment on draft abstracts, manuscripts, presentations and other 
communications by external investigators related to this study or a subset analysis of any patients 
enrolled in this study, prior to submission or public disclosure, in order to protect intellectual 
property and confidential information.  As study sponsor, Harpoon Medical, Inc. does not approve 
or veto such publications provided they are made after the publication of the main publication 
disclosing the multi-center study results.   
 
Authorship and accountability: Per ICMJE recommendations, an author is generally 
considered to be anyone who provides substantive intellectual contributions to a published study. 
Specifically, authorship credit should be based on 1. Substantial contributions to study conception 
and design, or acquisition, analysis and interpretation of data, and 2. Drafting the article or revising 
it critically for important intellectual content, and 3. Final approval of the version to be published, 
and 4. Agreement to be accountable for all aspects of the work to ensure its accuracy and 
integrity. All four conditions should be met. Conversely, individuals who do not contribute in this 
manner do not warrant named authorship. Individuals who do not meet criteria for authorship but 
who contributed materially to the manuscript will be recognized in acknowledgments when the 
manuscript is published. In some cases, journals recognize contributors rather than authors. 
Patient to journal policy, we will list the names of all investigators at the end of a manuscript. Final 
authorship determination will be made the sponsor in accordance with ICMJE recommendations.  
Determination of meeting (for an abstract presentation) or journal (for a manuscript submission) 
will be mutually agreeable to Sponsor, Institution and the investigators. 
 
 

 
 
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XV. 
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