JenaValve Trilogy for Patients With Pure Native Aortic Valve Rigurgitation: the ARTEMIS Data Collection Study
Conditions: Aortic Regurgitation Disease
Sponsor: IRCCS Policlinico S. Donato

                                                                                                                                              
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JenaValve Trilogy for patients with pure native Aortic valve Regurgitation:  
The ARTEMIS Data Collection Study 
Short Title: ARTEMIS  
 
 
 
 
 
Artemis Protocol Version 1.0 
 
 
                                                                       Date: 15th April 2025 
 
 
 
 
 
 Promoter: IRCCS Policlinico San Donato 
                    NCT 07075861 
 
 
 
 
 
 

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 STATEMENT OF COMPLIANCE AND INVESTIGATOR SIGNATURE PAGE 
 
Investigator Signature  
I have read and understand the contents of this protocol. I agree to adhere to its requirements. I will ensure 
that the Study is conducted in compliance with the protocol, the EU Medical Device Regulation (EU) 2017/745 
(“MDR”), the ISO 14155 for Good Clinical Practice in Clinical investigations of medical devices for human 
subjects; the EU General Data Protection Regulation (EU) 2016/679 (“, GDPR”), Good Clinical Practice, 
Declaration of Helsinki, and all applicable regulatory requirements.  
 
 
 
 
 
 
 
 
 
 
 
Investigator Name (print) 
 
 
 
 
 
 
 
 
 
 
 
 
____________________ 
Investigator Signature  
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents 
 
STATEMENT OF COMPLIANCE AND INVESTIGATOR SIGNATURE PAGE ................................................. 2 
SYNOPSIS .......................................................................................................................................... 5 
1.0  INTRODUCTION.......................................................................................................................... 8 
1.1 Aortic Regurgitation (AR) and Current Treatment Options .............................................................................. 8 
1.4 
Mortality in AR Patients Treated Conservatively ......................................................................................... 9 
1.5  
JenaValve Device Concept ......................................................................................................................... 10 
1.6  
JenaValve Device Preclinical Testing .......................................................................................................... 10 
1.7 
Prior Clinical Experience with JenaValve Device ........................................................................................ 11 
2.0 DEVICE DESCRIPTION ............................................................................................................... 11 
2.1  
JenaValve Trilogy™ Heart Valve (THV) ....................................................................................................... 12 
2.2 
JenaValve Trilogy™ Heart Valve System .................................................................................................... 13 
2.2.1 JenaValve Trilogy™ Delivery Catheter & Introducer Sheath ........................................................................ 13 
2.2.2 JenaValve Trilogy™ Loading Tools ............................................................................................................... 14 
3.0 DATA COLLECTION STUDY OBJECTIVE ......................................................................................... 14 
4.0 DATA COLLECTION STUDY ENDPOINTS/OTHER DATA COLLECTION .............................................. 15 
4.1 
Data Collection DATA COLLECTION STUDY Objective ................................................................................ 15 
Primary Efficacy Objective .................................................................................................................................... 15 
5.0  DATA COLLECTION STUDY DESIGN ............................................................................................ 15 
6.0 ELIGIBILITY CRITERIA .................................................................................................................. 16 
6.1 
Inclusion Criteria ........................................................................................................................................ 16 
6.2 
Exclusion Criteria ....................................................................................................................................... 17 
7.0 SUBJECT POPULATION .............................................................................................................. 17 
7.1 
Subject Population ..................................................................................................................................... 17 
7.2      Informed Consent Procedures ................................................................................................................... 17 
7.3 
Subject Discontinuation/Withdrawal Criteria ............................................................................................ 18 
7.4 Data collection and Follow-Up for Discontinued/Withdrawn Subjects ....................................................... 18 
7.5 
Subjects Lost to Follow-Up ........................................................................................................................ 18 
8.0  PRE-INDEX PROCEDURE METHODOLOGY .................................................................................. 19 
9.0 INDEX PROCEDURE- GENERAL DESCRIPTION ............................................................................. 19 
10.0 INDEX PROCEDURE THROUGH DISCHARGE ............................................................................... 20 
10.1 Antithrombotic Therapy ............................................................................................................................ 20 
As per local routine practice: IV unfractionated heparin with a target ACT ≥ 250 seconds ................................. 20 
10.1.2 
Post-Index TAVR Procedure ................................................................................................................. 20 
10.2 Implantation Procedure ............................................................................................................................. 20 
10.2.1 
THV Prosthesis Assessment ................................................................................................................. 20 
10.3  Post-Index Procedure/ Prior to Leaving Hospital ....................................................................................... 20 
11.0 FOLLOW-UP EVALUATIONS ...................................................................................................... 20 
11.1 1-Month Post-Index Procedure Follow-Up Evaluation .............................................................................. 21 
11.4  12 Month (1 Year) Post-Index Procedure Follow-Up Evaluation ............................................................... 21 
11.5  Data collection study Exit ........................................................................................................................... 22 
12.0  SCHEDULE OF ASSESSMENTS & SUBJECT EVALUATIONS ............................................................ 22 

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13.0  ADVERSE EVENTS ..................................................................................................................... 22 
13.1  General Adverse Event Definitions ............................................................................................................ 22 
13.2  Adverse Event Classification ...................................................................................................................... 23 
13.3  Events Expected to Occur with Index-Procedure ...................................................................................... 24 
13.4  Adverse Event Reporting Requirements .................................................................................................... 25 
13.4.1  
General Reporting Requirements (Non-Serious Adverse Events) ........................................................ 25 
13.4.2  
Reporting Requirements (Serious & Unanticipated Adverse Events) .................................................. 25 
13.5  Patient Death ............................................................................................................................................. 25 
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Treatment Failures & Device Malfunctions ............................................................................................... 25 
15.0  ADMINISTRATIVE RESPONSIBILITIES ......................................................................................... 26 
15.1  Ethics Committee (EC) Approval ................................................................................................................ 26 
15.2  Informed Consent ...................................................................................................................................... 26 
15.3  Confidentiality ............................................................................................................................................ 26 
15.4.1 Electronic Case Report Forms .................................................................................................................... 27 
15.4.3 
 Data Reporting .................................................................................................................................... 28 
15.5  Record Maintenance ................................................................................................................................. 28 
15.5.1  
Records ................................................................................................................................................ 28 
16.  Publication Policy ........................................................................................................................................... 29 
APPENDIX 1: CLINICAL RISK / BENEFIT ANALYSIS .............................................................................. 30 
1.0 SUMMARY ................................................................................................................................. 30 
2.0 POTENTIAL BENEFITS OF TAVR ................................................................................................... 30 
3.0 POTENTIAL RISKS OF TAVR ......................................................................................................... 30 
3.1 
Alternatives to participation ....................................................................................................................... 32 
4.0 CONCLUSION ............................................................................................................................. 32 
APPENDIX 2: ADVERSE EVENT DEFINITIONS ...................................................................................... 33 
BIBLIOGRAPHY ................................................................................................................................ 54 
 
 
 
 

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                                                                   Synopsis 
 
Title 
JenaValve Trilogy for patients with pure native Aortic valve Regurgitation:  
The ARTEMIS Data Collection Study 
Trial Name 
ARTEMIS Data Collection Study 
Investigational 
Device 
JenaValve Trilogy™ Heart Valve System 
Data collection 
study Objective 
To observe the safety and effectiveness of the JenaValve Trilogy™ Heart Valve System for 
transcatheter aortic valve replacement (TAVR) in subjects with severe native aortic 
regurgitation (AR) who are indicated for TAVR 
Data collection 
study Design 
A retrospective/prospective, single-arm, post-market study in patients with 
symptomatic, severe native aortic regurgitation to monitor the outcomes of Jena Valve 
Trilogy in a real-world clinical setting 
Estimated 
Timeline 
After enrollment is completed, patients are followed to 1 year (an amendment to 
extend the follow up to 5 years will be evaluated).  Thereafter, the patient exits the 
data collection study and is to be followed per institutional standard of care for TAVR 
patients. 
Data collection 
study Devices  
The JenaValve Trilogy™ Heart Valve System contains the following sub-components: a 
prosthetic transcatheter porcine pericardial aortic valve, 20Fr Introducer Sheath System, 
transfemoral Delivery Catheter, and Loading Tool.   
Indications for 
Use 
The JenaValve Trilogy™ Heart Valve System is indicated for use in patients with 
clinically significant aortic regurgitation (AR) who are considered high risk candidates 
for surgical aortic valve replacement as deemed by the local multi-disciplinary heart 
team.   
Principal 
Investigators 
Luca Testa, MD, PhD 
Number of 
Subjects 
This is an investigator initiated study that will include 75 suitable patients according 
to the inclusion/exclusion criteria as per IFU. 
Inclusion 
criteria 
Patient with severe symptomatic aortic valve regurgitation in a native valve and: 
• 
Considered at high or prohibitive risk for surgical aortic valve replacement 
by the Heart Team  
• 
18 years of age or older 
• 
Suitable anatomy according to the IFU 
• 
Absence of significant disease of the ascending aorta, including ascending 
aortic aneurysm (defined as maximal luminal diameter of 50mm or greater) 
or atheroma (especially if thick [>5mm], protruding or ulcerated) 
 
Exclusion 
criteria 
The JenaValve Trilogy Heart Valve System is contraindicated for use in patients who 
have known hypersensitivity or contraindication to Nitinol (titanium and/or nickel), 
an anti-coagulation/anti-platelet regimen or contrast medium that cannot be 
managed with premedication, or who have active bacterial endocarditis or other 
active infections. 
The JenaValve Trilogy Heart Valve System is contraindicated in those patients whose 
anatomy does not accommodate the System due to anatomical considerations 
outlined in the inclusion criteria. 
Data collection 
study Duration 
Expected data collection study duration: 36 months 
Enrolment completion: Approx. 24 months 
Follow-up Visits as per routine clinical practice: 30 days, and 12 Months  
Population 
The data collection study population will consist of subjects with pure native Aortic Valve 
Regurgitation  
 

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Schedule of Assessments:  
 
For subjects included in the study, scheduled visits will be performed in the following 
order: Baseline, Index Procedure, Discharge, 30 days, 12 months (and annually thereafter, 
if required). 
The study-required activities and standard of care data collection in the ARTEMIS Data 
Collection Data collection study are summarized in Table 1: Schedule of Assessments. 
 
 

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Table 1: Schedule of Assessments 
Schedule of assessment 
Screening/baseline 
Procedure 
Discharge 
30d [-
7/+21  
days] 
12 
months 
[+45 
days] 
Demographics 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
Physical Examination 
X 
 
x 
x 
x 
Surgical Risk Assessment (STS & 
EuroSCORE II) 
X 
 
 
 
 
NYHA Classification 
X 
 
 
x 
x 
Frailty Index 
X 
 
 
 
 
Cardiovascular Medications 
Documentation 
X 
 
x 
x 
x 
CT Angiography 
X 
 
 
 
 
Modified Rankin Scale (mRS) 
X 
 
(x) 
(x) 
(x) 
12 lead Electrocardiogram (ECG) A,B 
X 
   x B 
     x A, B 
  x A 
  x A 
2D Transthoracic Echocardiogram (TTE) 
X 
x  
x 
x 
x 
Angiogram 
 
x 
 
 
 
CT Scan with Angiography of chest, 
abdomen and pelvis 
X  
 
 
 
 
KCCQ (23 question questionnaire) 
X 
 
 
x 
x 
CBC and Platelet Count 
X 
 
 
 
 
Creatinine 
x  
x  
x 
 
 
INR (if subject is on Warfarin) 
X 
 
 
x 
x 
Troponin or CK-MB 
 
x  
x 
 
 
Adverse Event Assessment  
X 
x 
x 
x 
x 
Deviation 
(x) 
(x) 
(x) 
(x) 
(x) 
Device Deficiency 
 
(x) 
(x) 
(x) 
(x) 
Withdrawal 
 
(x) 
(x) 
(x) 
(x) 
Survival Status 
 
 
(x) 
(x) 
(x) 
A For subjects receiving a new permanent pacemaker, ECG should be completed showing the underlying rhythm 
B Record a 12-lead ECG following the implant of the valve and daily until day of discharge.  
(X) indicates if applicable 
 
 
 
 
 
 
 
 
 
 

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1.0  
INTRODUCTION 
 
The objective of this data collection study is to observe the ability of the JenaValve Trilogy™ 
Heart Valve System device to treat patients with pure native aortic regurgitation (AR) safely 
and effectively through the collection of data from the regular use of the CE-marked device 
in accordance with the medical standard of care and clinical practice. 
The JenaValve Trilogy™ Heart Valve System device is used to treat symptomatic severe AR 
commercially in the EU under CE mark and is being evaluated in the ALIGN-AR IDE study and 
ALIGN-AR CAP protocol for patients at high-risk for surgery (1).   
The data collection study is not being conducted to assess a new indication or to otherwise 
assess the JenaValve Trilogy Heart Valve System outside the scope of its intended purpose. 
 
1.1 Aortic Regurgitation (AR) and Current Treatment Options  
Aortic regurgitation (AR) occurs in approximately 0.4% of all adults, in 1% of individuals aged 
65-74 years and 2% of individuals over 70 years of age.(2)  Symptomatic patients with chronic 
severe AR have a poor prognosis and should therefore undergo open heart surgery per 
current guidelines. However, an increasing number of patients with symptomatic severe AR 
have excessive comorbidities or a clinical condition that contraindicates open heart surgery.  
Patients where open-heart surgery is not an option are often treated conservatively with 
medical management (3). 
 
There are a host of factors involved in the Heart Team’s assessment of eligibility for SAVR; the 
process involves evaluation of surgical risk using not only Society of Thoracic Surgeons (STS) 
scores, but also taking into account other technical and clinical factors.  The AHA/ACC 
Guidelines for the Management of Patients with Valvular Heart Disease (4) details that 
surgical risk assessment should include consideration of STS risk estimate, frailty, major organ 
system dysfunction, and procedure-specific impediments. Evaluation of surgical risk includes 
but is not limited to: 
 
Any combination of the above health factors may influence the categorization of a patient as 
high surgical risk and preclude referral for a SAVR procedure.  The ALIGN-AR IDE trial was 
conducted to evaluate the safety and efficacy of the JenaValve Trilogy™ Heart Valve 
System for transcatheter aortic valve replacement (TAVR) in subjects clinically significant 
aortic regurgitation (AR) who are indicated for TAVR.  Reported data from the study met 
the 30-day performance goal for safety outcomes (26.7%, p for noninferiority<0.0001), as 
− 
Advanced age 
− 
Peripheral vascular disease 
− 
Low body mass index (BMI) 
− 
Lung disease 
− 
Low ejection fraction 
− 
Multiple pulmonary emboli 
− 
Cerebrovascular disease 
− 
Obesity 
− 
Porcelain aorta 
− 
Severely impaired mobility 
− 
Immunosuppressive therapy 
− 
Reconstructed sternum 
− 
Prior CABG 
− 
Hematologic disorder 
− 
Chest wall radiation 
− 
Renal failure 
− 
Liver disease 
− 
Chest wall deformity 
− 
Severe pulmonary 
hypertension 
− 
GI bleeding 
− 
Other neurologic disease 

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well as the 12-month performance goal for the efficacy outcome of all-cause mortality 
(7.8%, p for noninferiority <0.0001).   
 
1.4 Mortality in AR Patients Treated Conservatively 
 
The presence of NYHA functional class III/IV and congestive heart failure (CHF) are strong 
predictors of survival in AR.  Dujardin et al. (2) found that in patients with moderate to 
severe AR, NYHA functional classification was the most powerful predictor of survival 
(Figure 1). When comparing symptomatic moderate to severe AR with asymptomatic 
moderate to severe AR, the yearly mortality rate was 9.4% vs. 2.4%. This association is 
observed also in patients with severe AR in whom symptoms seem to be major 
determinants of outcomes. In patients with LVEF>55%, but severe pure AR with CHF, 
reported a 2-year mortality rate of 88%.    
 
 
Figure 1: NYHA Functional Classification and Survival in Patients with Moderate-Severe Aortic 
Regurgitation. (Dujardin et al. 1999)4 
Similarly, Dujardin et.al reported CHF as an important predictor of mortality in patients 
with AR. The yearly mortality rate was 24.5% in patients with NYHA functional class III/IV, 
but 5.8% in those with LVEF<55 compared to 2.0% in those with LVEF > 55.  Patients with 
symptoms present  higher CHF event rates compared to those with LVEF <50 (Figure 2). 
Furthermore, in severe AR with LVEF>50%, LVEDD less than 70 mm, and LVESD less than 
50 mm (for whom aortic valve replacement is not recommended according to ACC/AHA 
guidelines), mortality rates at 6 months was still as high as 21%(4).  Thus, the presence of 
NYHA Functional Class III/IV symptoms and CHF are associated with higher mortality rates 
than LVEF<50.  
 

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Figure 2: Event rates of congestive heart failure (CHF) in patients with or without symptoms 
and in patients with left ventricular ejection fraction (LVEF) <50% or LVEF>55 (Detaint D et al. 
2008)12. 
1.5  JenaValve Device Concept 
The JenaValve Trilogy Heart Valve System is designed to allow a controlled valve release 
and deployment during the entire implantation procedure under beating heart 
conditions. The JenaValve Pericardial Transcatheter Heart Valve (THV) prosthesis includes 
three positioning Locators which are released in the first step during implantation. These 
Locators are intended to enable a correct positioning and re-positioning of the prosthesis 
into the cusps of the native aortic valve. After introducing the system via transfemoral 
access, the positioning Locators are released under fluoroscopic control. By gently 
advancing the delivery catheter towards the aortic root, the Locators are positioned in 
native aortic valve cusps. These three Locators are designed to precisely define the 
implantation plane of the valve stent in the aortic root below the coronary ostia. After 
correct anatomical positioning, the prosthesis is released and deployed. Once the valve is 
unfolded by the self-expanding mechanism of the nitinol stent, the native aortic valve 
leaflets are fixed in between the Locators and the rail (see Figure 5), thus defining correct 
height and position of the valve prosthesis. 
 
1.6  JenaValve Device Preclinical Testing 
 
JenaValve conducted acute and chronic preclinical animal studies using the ovine model. 
Acute animal studies have demonstrated the feasibility of successful delivery and 
implantation of the JenaValve Trilogy Heart Valve System with very good hemodynamic 
valve performance post procedure. Results of chronic animal implant studies revealed 
excellent long-term macroscopic/microscopic outcomes with no signs of valve 
degeneration or dislocation. Valve performance was evaluated by echocardiography at 
predefined time points throughout the studies and demonstrated durable long-term 
effectiveness of the valve.  

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1.7 Prior Clinical Experience with JenaValve Device 
 
JenaValve has developed a lower profile system with transcatheter heart valve (THV) 
prosthesis that consists of porcine pericardial tissue mounted on a nitinol support frame. 
The tissue is sewn in place to secure the material to the frame and construct the valve 
leaflets. A transfemoral (TF) introducer-based delivery system has been developed to 
provide this alternative access approach. The first version of the TF delivery system was 
studied with the pericardial tissue valve prosthesis in a First-in-Man (FIM) clinical study in 
Europe (study number JV04FIM) which enrolled seven patients, with encouraging overall 
results. The delivery system has been modified since the conduct of JV04FIM; however, 
the results are relevant to the implant because that is the identical THV under 
investigation in this data collection study.   
The JenaValve Trilogy Heart Valve system clinical program was conducted at sites in the 
US, Europe (Germany, The Netherlands) and New Zealand for two cohorts: 
• Patients with symptomatic aortic regurgitation (AR) at high surgical risk 
• Patients symptomatic, severe aortic stenosis (AS) at high surgical risk  
In May 2021, the JenaValve Trilogy Heart Valve System received CE Mark approval for use 
in patients with symptomatic severe aortic stenosis (AS) or symptomatic severe aortic 
regurgitation (AR) who are considered by a Heart Team, including a cardiac surgeon, to 
be at increased risk for open surgery (STS-PROM ≥ 8% at 30 days, or if less than 8%, 
significant comorbidities are present that are not captured by STS-PROM), and eligible for 
the TAVR procedure.  
The clinical program for AR is ongoing in the US under another protocol (IDE G150035). 
IDE G150035 was initially approved on October 22, 2015, and the pivotal HDE study was 
approved under G150035/S034 on May 22, 2020. 
 
 
 
2.0 
DEVICE DESCRIPTION  
 
This data collection study is investigating the JenaValve Trilogy™ Heart Valve System 
when used to perform transcatheter aortic valve replacement (TAVR) for treatment of 
symptomatic, severe aortic regurgitation.  The JenaValve TrilogyTM Heart Valve System 
consists of the following major components: 
• JenaValve Trilogy™ Heart Valve (THV) 
• JenaValve Trilogy™ Delivery System (comprising the 20Fr Introducer Sheath 
System, Delivery Catheter, and Loading Tool) 
 
Intended Use/Indication or Use: The JenaValve Trilogy™ Heart Valve System is intended 
for use in patients with symptomatic, severe tri-leaflet aortic valve regurgitation (AR, not 

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due to acute endocarditis, rheumatic heart disease, or acute aortic dissection) who are 
assessed by a Heart Team, including a cardiac surgeon, to be at high or greater risk for 
open surgical therapy.   
The JenaValve Trilogy™ Heart Valve System is not intended for use in patients with 
congenital aortic valve disease (i.e., unicuspid, bicuspid, or quadricuspid valves), with 
acute conditions requiring surgical aortic valve replacement (i.e., acute endocarditis, 
acute aortic dissection), or patients who require concomitant cardiac surgery (e.g., 
ascending aortic aneurysm repair; aortic root replacement, coronary artery bypass 
grafting). 
 
2.1  JenaValve Trilogy™ Heart Valve (THV)  
 
The JenaValve Trilogy™ Heart Valve (Figure 3) is constructed from porcine pericardium 
that is attached to a self-expanding nitinol frame with polyester suture. The frame has a 
crown design that can collapse with the valve to be implanted using the JenaValve 
Trilogy™ Heart Valve System.  
 
 
Figure 3: JenaValve Trilogy™ Heart Valve System 
At the upper part the JenaValve Trilogy™ Heart Valve contains three eyelets designed to 
gear into the corresponding recesses at the crown of the delivery system enabling a firm 
attachment.  The THV prosthesis has three positioning covered Locators that spread apart 
after the first step of the deployment process. The covers allow for safe positioning of the 
Locators within the native aortic valve cusps without perforating the cusps. At the base 
of THV is a nitinol sealing (‘rhombi’) ring that is covered by a pericardium skirt to seal with 
the native annulus and prevent paravalvular regurgitation.  When placed into the native 
valve cusps, the Locators capture the native valve leaflets. This unique valve design 
anatomically aligns with the native commissures and fixes the transcatheter heart valve 
in place.   
 

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2.2 JenaValve Trilogy™ Heart Valve System 
 
The JenaValve Trilogy™ Heart Valve System is designed to allow for a transfemoral 
approach using the JenaValve Introducer Sheath System and its compatible Delivery 
Catheter and Loading Tool.  The delivery system is designed to implant the JenaValve THV 
using percutaneous access.   
 
2.2.1 JenaValve Trilogy™ Delivery Catheter & Introducer Sheath  
 
The JenaValve Trilogy™ Delivery Catheter (Figure 4 and Figure 5) delivers the THV 
transfemorally through the JenaValve Pre-Shaped 20Fr Introducer Sheath System (Figure 
8). The Delivery Catheter features a tapered tip for crossing the valve, and a Catheter 
shaft which is controlled by three mechanisms: a Deflector (to centrally align the THV and 
its Locators above the native aortic cusps prior to alignment), a Controller (to rotate the 
THV above the native aortic cusps for alignment), and (3) a Deployer (to release the THV 
from the Catheter after the Locators are placed into the native cusps).  
 
 
Figure 4: JenaValve Trilogy™ Delivery Catheter THV Dock 
 
  
 
 
Figure 5: JenaValve Trilogy™ Delivery Catheter Handle 
The JenaValve Trilogy™ Introducer Sheath System (Figure 6) is comprised of a polymeric 
shaft Dilator and a 20Fr Introducer Sheath (22Fr outer profile), with a pre-shaped distal 
end and a proximal housing with a hemostatic seal.  
 

14 
 
              
 
Figure 6: JenaValve Trilogy™ Introducer Sheath System: Dilator (bottom); Pre-Shaped Introducer 
Sheath (top) 
 
The JenaValve Trilogy™ Heart Valve is crimped/loaded into the main Delivery Catheter at 
the time of the procedure using a dedicated Loading Tool.  
 
2.2.2 JenaValve Trilogy™ Loading Tools 
 
The Trilogy™ Loading Tool enables crimping and loading the THV into the same size 
Delivery Catheter (Figure 7).  
 
 
Figure 7: JenaValve Trilogy™ Loading Tool Configurations 
 
 
 
3.0 DATA COLLECTION STUDY OBJECTIVE 
 
This data collection study will observe the use of TAVR (Transcatheter Aortic Valve 
Replacement), using the JenaValve Trilogy™ Heart Valve System, in patients with 
clinically significant aortic regurgitation, deemed at high or prohibitive risk for surgery 
by the Heart Team. 
 
 

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4.0 DATA COLLECTION STUDY ENDPOINTS/OTHER DATA COLLECTION 
 
4.1 Data Collection DATA COLLECTION STUDY Objective 
 
Primary Efficacy Objective 
 
Device Success at 12 Months according to Valve Academic Research Consortium (VARC)-3 
definition (5) consisting of: 
• Freedom from all-cause mortality 
• Freedom from unsuccessful delivery of the device, and retrieval of the delivery 
system 
• Freedom from incorrect positioning of a single prosthetic heart valve into the 
proper anatomical location 
• Freedom from surgery or intervention related to the device or to a major 
vascular or access-related or cardiac structural complication 
• Intended performance of the valve (i.e., no moderate or severe prosthetic valve 
regurgitation) 
 
 
Rationale for primary efficacy objective 
 
Ongoing Safety and Efficacy data collection to be assessed at 1yr. Assessed according to 
VARC 3 criteria. 
 
 
5.0  
DATA COLLECTION STUDY DESIGN 
 
This is a retrospective and prospective, single-arm, data collection study in patients with 
severe native aortic regurgitation who are at high or prohibitive surgical  risk according 
to the Heart Team, in a real-world clinical setting. 
 
Subjects will provide informed consent for the collection of their clinical data. 
 
Subjects participating in the Data collection study will initially be followed for 1 year (an 
amendment to extend the follow up to 5 years will be evaluated). Data collected will 
include the following visits: at screening/baseline, procedure, hospital discharge, and 
follow-up at 30 days, 12 months (annually thereafter if the follow up will be extended to 
5 years).  
 
5.1 Statistical analysis 
Categorical variables will be shown as count and percentage, normal variables as 
mean±SD, non-normal variables as median and interquartile range. Normality assumption 
will be tested in continuous variable by visual inspection of qq-plot. Correlations between 

16 
 
continuous variables will be evaluated according to Pearson R or Spearman Rho, 
depending on the distribution. Paired T tests will be used to compare continuous 
variables. T test or Wilcoxon rank sum test will be used to compare unpaired means in 
normally or non-normally distributed variable, respectively. Fisher’s exact test will be 
used to compare categorical data between groups. The null hypothesis will be refused 
with p <0.05.  
Device success on the study end points will be evaluated by Kaplan–Meier estimates of 
survival curves and their 95% confidence intervals. 
 
According to the local experience in TAVR, the number of patients with severe AR deemed 
at prohibitive surgical risk is around 2/month. Considering a prospective enrollment of 2 
years and historical patients collected data for 1 year, the final number of expected 
patients will be about 75. In fact, according to reference [1], a composite of all-cause 
mortality and heart failure rehospitalization at 1 year had cumulative incidence of about 
17%. Therefore, considering an exponential distribution with event rate 0.17 (17 events 
per 100 person years), 75 patients amount to a total of 75-13*.5=68 person years. The 
resulting 95% confidence interval of the cumulative incidence will be 0.06; 0.24 [2].  
 
 
[1] Poletti E, De Backer O, Scotti A, Costa G, Bruno F, Fiorina C, Buzzatti N, Latini A, Rudolph 
TK, van den Dorpel MMP, Brinkmann C, Patel KP, Panoulas V, Schofer J, Giordano A, 
Barbanti M, Regazzoli D, Taramasso M, Saia F, Baumbach A, Maisano F, Van Mieghem 
NM, Søndergaard L, Latib A, Amat Santos IJ, Bedogni F, Testa L. Transcatheter Aortic Valve 
Replacement for Pure Native Aortic Valve Regurgitation: The PANTHEON International 
Project. 
JACC 
Cardiovasc 
Interv. 
2023 
Aug 
28;16(16):1974-1985. 
doi: 
10.1016/j.jcin.2023.07.026. PMID: 37648345. 
 
[2] Riley RD, Ensor J, Snell KIE, Harrell FE, Martin GP, Reitsma JB, et al. Calculating the 
sample size required for developing a clinical prediction model. BMJ (Clinical research ed). 
2020 
 
 
 
6.0 ELIGIBILITY CRITERIA 
 
 
6.1 Inclusion Criteria 
 
Patient with severe symptomatic aortic valve regurgitation in a native valve and: 
• Considered at high or prohibitive risk for surgical aortic valve replacement by the 
Heart Team  
• 18 years of age or older 
• Suitable anatomy according to the IFU 

17 
 
• Absence of significant disease of the ascending aorta, including ascending aortic 
aneurysm (defined as maximal luminal diameter of 50mm or greater) or 
atheroma (especially if thick [>5mm], protruding or ulcerated) 
 
6.2 Exclusion Criteria 
 
The JenaValve Trilogy Heart Valve System is contraindicated for use in patients who 
have known hypersensitivity or contraindication to Nitinol (titanium and/or nickel), an 
anti-coagulation/anti-platelet regimen or contrast medium that cannot be managed 
with premedication, or who have active bacterial endocarditis or other active infections. 
The JenaValve Trilogy Heart Valve System is contraindicated in those patients whose 
anatomy does not accommodate the System due to anatomical considerations outlined 
in the inclusion criteria. 
 
 
 
7.0 
SUBJECT POPULATION  
 
7.1 Subject Population 
 
Adult subjects with pure native aortic regurgitation, as assessed by heart team, will be 
considered for inclusion if ineligible to surgical treatment.  
 
 
7.2      Informed Consent Procedures 
 
The study investigator(s) and support staff will approach patients being considered for 
TAVI with the JenaValve Trilogy Heart Valve System to assess their interest in participating 
in the data collection study. If patients are interested in participating, the subject will sign 
the Ethics Committee (EC)-approved informed consent form (ICF).  
The general process for obtaining informed consent is as follows: 
• Ensure that the principal investigator or his/her authorised designee conducts the 
informed consent process; 
• Include all aspects of the data collection that are relevant to the subject's decision 
to participate throughout the clinical investigation; 
• Avoid any coercion or undue improper influence on, or inducement of, the subject 
to participate; 
• Not waive or appear to waive the subject's legal rights; 
• Use native non-technical language that is understandable to the subject; 
• Provide ample time for the subject to read and understand the informed consent 
form and to consider participation in the data collection study; 

18 
 
• Include personally dated signatures of the subject/subject’s legal representative 
and the principal investigator/authorised designee responsible for conducting the 
informed consent process; 
• Provide the subject with a copy of the informed consent form and any other 
written information; and, 
• Ensure important new information is provided to new and existing subjects 
throughout the data collection process. 
 
7.3 Subject Discontinuation/Withdrawal Criteria 
 
Once the subject has been enrolled in the data collection study she/he may withdraw 
her/his consent to participate in the data collection study at any time without prejudice.  
Participation in this clinical investigation is entirely voluntary.  Likewise, the Investigator 
may identify a reason that deems the subject no longer suitable for the data collection 
study. Reasons for discontinuation or withdrawal may include, but are not limited to, the 
following:   
• Subject is uncooperative; 
• Investigator determines that subject has developed a condition in which 
continued participation in the data collection study is considered potentially 
harmful to the subject; 
• Subject withdraws their consent; 
• Subject is lost to follow-up (missing scheduled consecutive follow-up visits); 
• Subject incorrectly enrolled in the data collection study. 
 
7.4 
Data collection and Follow-Up for Discontinued/Withdrawn Subjects 
 
All subjects in the data collection study are considered eligible for follow-up and will be 
followed per the assessment schedule outlined in Table 1.  Subjects may withdraw at any 
time from the clinical trial without jeopardy or prejudice.  If a subject terminates from the 
data collection study, the reason for data collection study termination will be recorded.  
If termination is a result of adverse event or death, an Adverse Event Form will also be 
completed.  Every attempt will be made to conduct an exit/final visit prior to a subject 
terminating from the data collection study.  The reason for early discontinuation will be 
documented in the source documents and electronic case report forms (eCRF). 
 
7.5 Subjects Lost to Follow-Up 
 
All reasonable efforts will be made to obtain complete data for all subjects, before they 
are considered lost to follow-up.   
 
 

19 
 
8.0  
PRE-INDEX PROCEDURE METHODOLOGY 
 
The following baseline data must be collected prior to the index procedure for all subjects 
meeting the inclusion / exclusion criteria: 
• Subject Interview 
• Signed Informed Consent  
• Medical History 
• Targeted Physical Exam (including vital signs) 
• Surgical Risk Assessment (STS & EuroScore II) 
• Cardiovascular Medications Documentation 
• 12 lead Electrocardiogram (ECG) 
• Laboratory Tests (Complete blood count (CBC): WBC with differential, RBC with 
HCT and Hb, platelet count, coagulation panel (PT, PTT and an INR for subjects on 
vitamin-K antagonist), serum creatinine, serum albumin, C-reactive protein, 
plasma-free Hb, serum LDH, haptoglobin and cardiac biomarkers (troponin I or T 
or CK/CK-MB) 
• Pregnancy test for women of childbearing age within 72 hours of Index procedure 
• 2D Transthoracic Echocardiogram (TTE) 
• Multi-detector CT Scan Imaging 
• NYHA Functional Class 
• Modified Rankin Scale (mRS) 
• Kansas City Cardiomyopathy Questionnaire (KCCQ) 
 
The procedures required for screening/baseline may be conducted during more than one 
visit.  
 
9.0 
INDEX PROCEDURE- GENERAL DESCRIPTION 
 
The TAVR procedure will be performed according to the IFU. Additionally, the physician 
will follow standard of care regarding administration of concomitant medication, 
antibiotics and anticoagulation therapy before and during the procedure. 
 
The following data should be collected during the index procedure assessment period: 
• Procedural details   
• Adverse Event Assessment 
• Anticoagulation/antiplatelet therapy administered intra-procedure 
 
 
 
 
 
 

20 
 
10.0 
INDEX PROCEDURE THROUGH DISCHARGE 
 
10.1 Antithrombotic Therapy 
 
As per local routine practice: IV unfractionated heparin with a target ACT ≥ 250 seconds 
 
10.1.2 Post-Index TAVR Procedure 
As per local routine practice: Aspirin, clopidogrel, anticoagulant, based on 
presence/absence of any concomitant disease 
10.2 Implantation Procedure  
 
According to the IFU 
 
10.2.1 THV Prosthesis Assessment 
 
After deployment the valve function is assessed by angiography and echocardiography.   
 
10.3  Post-Index Procedure/ Prior to Leaving Hospital 
 
The following items will be recorded once (except as specified) post–index procedure or 
prior to discharge. 
• Cardiovascular medications 
• Targeted Physical Exam (including vital signs)  
• 12 lead ECG / rhythm strip 
• Laboratory Tests  
o (coagulation panel (PT, PTT and an INR for subjects on vitamin-K 
antagonist),  
o serum creatinine, Hb, and platelet count (daily during index 
hospitalisation - up to 7 days post-index procedure or discharge) 
and  
o cardiac biomarkers (troponin I or T or CK/CK-MB) 
• Echocardiographic assessment of THV function 
• NYHA Functional ClassAdverse Events 
• Modified Rankin Scale (mRS)  
 
11.0 
FOLLOW-UP EVALUATIONS 
 
Follow-up evaluations will be scheduled for 1 month and 12 Months after the index 
procedure.  Thereafter, the patient exits the data collection study and is to be 
followed per institutional requirements for patients with transcatheter aortic valves. 
 
 

21 
 
11.1 1-Month Post-Index Procedure Follow-Up Evaluation 
 
A follow-up evaluation will be scheduled for 30 days post-index procedure (-7 /+21 days).  
The following assessments will be performed: 
• Targeted Physical Exam (including vital signs) 
• NYHA Functional Class 
• Cardiovascular Medications 
• Adverse Events 
• 12 lead ECG  
• Modified Rankin Scale (mRS) 
• Echocardiography (TTE or TEE) including assessment of THV function 
• Kansas City Cardiomyopathy Questionnaire (KCCQ) 
• INR (if subject is on Warfarin) 
• Adverse Events Assessment 
• IF Applicable: 
o 
Deviation 
o 
Device Deficiency 
o 
Withdrawal 
o 
Survival Status 
 
 
If the subject reports any adverse events that are potentially serious during the follow-up 
evaluation period, the subject should return to the investigator’s facility for further 
evaluation of the event.   
 
11.4  12 Month (1 Year) Post-Index Procedure Follow-Up Evaluation 
 
A follow-up evaluation will be scheduled for 12 Month post-index procedure ( 45 days).  
The following assessments will be performed: 
• Targeted Physical Exam (including vital signs) 
• NYHA Functional Class 
• Cardiovascular Medications 
• Modified Rankin Scale (mRS) in the event of a stroke 
• 12 lead ECG (per schedule of tests) 
• Echocardiography (TTE or TEE) including assessment of THV function 
• INR (if subject is on Warfarin) 
• Adverse Events 
• Kansas City Cardiomyopathy Questionnaire (KCCQ) 
 
If the subject reports any adverse events that are potentially serious during the follow-up 
evaluation period, the subject should return to the investigator’s facility for further 
evaluation of the event.   
 

22 
 
11.5  Data collection study Exit 
 
If the patient exits the study prior to completing the required assessments, the data 
collection study exit CRF must be completed.  
 
12.0  SCHEDULE OF ASSESSMENTS & SUBJECT EVALUATIONS 
Evaluation of subjects enrolled in this data collection study will include all tests and 
procedures listed in the Schedule of Assessments as outlined in Table 1.  
 
Pre-procedural echocardiography (TEE or TTE) and a baseline multi-detector CT scan are 
used to determine anatomical suitability for TAVR. Following ethics committee approval 
and patient written informed consent, the patient will be screened for eligibility by heart 
teams. After the procedure, enrolled patients are to be followed immediately post- 
procedure, at hospital discharge, and then at 1 month and 1 year as in Schedule of 
Assessments Table 1. 
 
13.0  ADVERSE EVENTS 
 
TAVR procedures to treat aortic regurgitation are well described in the literature.  Risks 
to the subjects will be clearly explained in the Clinical Risk/Benefit Analysis Section (see 
Appendix 1- Clinical Risk/Benefit Analysis). 
 
13.1  General Adverse Event Definitions 
 
Adverse Event: is defined as any untoward medical occurrence, unintended disease or 
injury or any untoward clinical signs (including an abnormal laboratory finding) in 
subjects, users or other persons, whether or not related to the investigational medical 
device (See Appendix 2 – Adverse Event Definitions). 
 
Adverse Event Identification: a condition that is one of the following: 
a) A unique symptom or event that is a change from the patient’s baseline status 
b) A series of symptoms or events that can be categorized as a single entity based on 
definitions found herein 
c) A specific diagnosis responsible for a clinical change  
d) A worsening or exacerbation of a pre-existing condition 
 
Serious Adverse Event: A serious adverse event (SAE) is any untoward medical 
occurrence that: 
• Results in death 
• Led to serious deterioration in the health of the subject, that either resulted in: 
o a life-threatening illness or injury, or 
o a permanent impairment of a body structure or a body function, or 
o in-patient or prolonged hospitalisation, or 

23 
 
o medical or surgical intervention to prevent life-threatening illness or 
injury or permanent impairment to a body structure or a body function, 
• Led to fetal distress, fetal death or a congenital abnormality or birth defect 
 
 
Serious Adverse Device Effect (SADE) 
An adverse device effect that has resulted in any of the consequences characteristics of a 
serious adverse event. 
 
Unanticipated Serious Adverse Device Effect (USADE) 1F 
A 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.   
 
13.2  Adverse Event Classification 
 
Adverse events will be assigned an attribution according to the Investigator’s believed 
primary cause.  Events will be categorized as follows: 
 
Device Related Adverse Event: An adverse event, which in the judgment of the Investigator, 
results from use of the JenaValve Trilogy™ Heart Valve System. 
 
Procedure Related Adverse Event: An adverse event which, in the judgment of the 
Investigator, results as a consequence of the procedure. 
 
Concomitant Medication-Related Adverse Event: an adverse event is considered to be 
concomitant medication related when, in the judgment of the Investigator, it is reasonable 
to believe that the event is associated with concomitant medications used in conjunction 
with the investigational device and is not otherwise specific to the investigational device 
(e.g. bleeding associated with anticoagulation medication). 
 
Pre-Existing Condition-Related Adverse Event: an adverse event is considered to be related 
to a pre-existing condition when, in the judgment of the Investigator, it is reasonable to 
believe that the event is associated with the patient’s pre-existing condition and is not 
specific to the investigational device or index procedure.  Pre-existing conditions that are 
aggravated or become more severe during or after the index procedure should be 
evaluated on a case-by-case basis to determine if the event may be more appropriately 
classified as device or index procedure-related. 
 
Intercurrent Condition: It is reasonable to believe that the event is directly associated with 
an intercurrent condition/co-morbidity.   
 

24 
 
Intercurrent Intervention: It is reasonable to believe that the event is directly associated 
with an intercurrent intervention which was performed for reasons other than to address 
a device- or index procedure-related complication.  
Unknown: The adverse reaction cannot be judged because information is insufficient or 
contradictory and cannot be supplemented or verified. 
 
The Investigator, will assess all serious adverse events considered device-related for 
potential reportability as an Unanticipated Adverse Device Effect (UADE).  
 
The Investigator should follow all unresolved serious adverse events until the events are 
resolved, the subject is lost to follow-up, the subject has withdrawn consent, or the 
adverse event is otherwise explained.   
 
13.3  Events Expected to Occur with Index-Procedure 
 
 
For purposes of this data collection study, the following events are not considered 
reportable adverse events because they are normally expected to occur in conjunction 
with treatment of Aortic Regurgitation or structural heart interventional procedures, or 
are associated with customary, standard care of subjects undergoing minimally invasive 
cardiovascular intervention: 
• Chest pain without associated enzyme/ECG changes.  
• Post-operative pain.  
• Post-anesthesia emesis, nausea, or headache (within 48 hours of procedure). 
• Electrolyte imbalance without clinical sequelae following procedure, even if 
requiring correction. 
• Low grade temperature increase (38.5C). 
• Dizziness: Imprecise term commonly used to describe various symptoms such as 
faintness, giddiness, imbalance, lightheadedness, unsteadiness or vertigo.  
• Elevated White Blood Count, outside the standard laboratory normal value, without 
signs and symptoms of infection.   
• Minor, localized tenderness, swelling, induration, oozing, etc. at surgical site. 
• Sinus bradycardia/tachycardia that does not require treatment or intervention. 
• Systolic or diastolic blood pressure changes that do not require treatment or 
intervention. 
• Any blood transfusions during preplanned operative procedure and unrelated to an 
adverse event. 
• Thrombocytopenia: does not become an AE until treatment is administered.     
• Hyperglycemia: The use of insulin in the post op period does not constitute 
hyperglycemia if during the same hospitalisation.  An elevated blood sugar of less 
than 250 mg/dl during the first 48 hours post op does not constitute hyperglycemia.  
• Expected, non-clinically significant events such as non-significant lab variances. 
 

25 
 
 
13.4  Adverse Event Reporting Requirements  
 
13.4.1  General Reporting Requirements (Non-Serious Adverse Events) 
 
All adverse events must be recorded on the Adverse Event Electronic Case Report Form 
(eCRF) by the Investigator (or designee).  The report should include: severity, duration, 
action taken, treatment outcome and relationship of the adverse experience to the data 
collection study device, procedure, concomitant medications, pre-existing condition, etc. 
(i.e., unrelated, related or relationship unknown).   
 
The Investigator must also adhere to the following criteria: 
• Use separate Adverse Event Form(s) to document each series of events. 
• The Adverse Event Form(s) causality must be assessed by the Investigator or co-
Investigator or sub-investigator. 
• It is the responsibility of the Investigator to inform their IRB/EC of serious adverse 
events as required by their IRB/EC procedures. 
 
13.4.2  Reporting Requirements (Serious & Unanticipated Adverse Events)  
 
All serious and any unanticipated adverse device effects must be reported by the 
Investigator (or designee) by submitting the Adverse Event Electronic Case Report Form  
within 24 hours of learning of the adverse event.   
The Investigator (or designee) shall send a written report including a narrative description 
of the serious and/or unanticipated adverse event to the EC or its designee within ten 
(10) working days of the initial report.   
13.5  Patient Death 
 
Patient death during the data collection must be reported via written documentation 
within 24 hours of Investigator’s knowledge of the death. Notification can be made by 
entering the CRF in the database. Patient death must be reported to the EC in accordance 
with EC requirements. 
 
14  Treatment Failures & Device Malfunctions 
 
All reported device observations, malfunctions or failures for the JenaValve TrilogyTM 
Heart Valve System are required to be documented on the Procedure / Device 
Observation Case Report Form and reported to the EC. In the event of a suspected 
observation or device problem, the device shall be returned to the manufacturing 
company for analysis.  Instructions for returning the investigational device are included in 
the Instructions for use (IFU). 

26 
 
  
 
15.0  ADMINISTRATIVE RESPONSIBILITIES 
 
The ARTEMIS data collection study will be performed in accordance with Good Clinical 
Practice Guidelines, the MDR 2017/745, and ISO 14155.     
 
15.1  Ethics Committee (EC) Approval 
 
The Clinical Investigational Plan shall be reviewed and approved by the Ethics Committee 
prior to patient enrollment.   
 
15.2  Informed Consent 
 
The Heart Team will determine whether the patient should be treated with the JenaValve 
device as being at high/prohibitive surgical risk. After that determination, if the patient 
meets all clinical eligibility criteria, the patient (and/or their authorised legal 
representative) will be approached to obtain written informed consent.  The background 
of the proposed data collection study and the benefits and risks of the procedures and 
data collection study should be explained to the patient or the patient’s legally authorised 
representative.  The patient or patient’s legally authorised representative must sign the 
consent form prior to enrollment. Failure to obtain signed informed consent renders the 
patient ineligible for the data collection study. All enrolled subjects will complete the 
appropriate consent form that has been approved by ethics committee (EC). Copies of 
the signed informed consent shall be kept in the patient’s medical records and data 
collection study files.  A copy of the informed consent form must be given to each patient 
(or their authorised legal representative) enrolled in the data collection study. 
 
Modifications to the data collection study Informed Consent must have approval from the 
EC. 
 
Retrospective arm 
The information relating to the processing of personal data will be made available to 
participants through the publication of the Information form on the Promoter's website. 
 
15.3  Confidentiality 
 
All data used in the analysis and reporting of this observational data collection study will 
be used in a manner without identifiable reference to the patient. 
 
The investigator must assure that the subject’s anonymity will be maintained and that the 
confidentiality of records and documents that could identify subjects will be protected, 

27 
 
respecting the privacy of and confidentiality rules in accordance with applicable 
regulatory requirements, including all applicable provisions of the GDPR and its current 
regulations. 
 
• Subjects must be identified only by their assigned data collection study number and 
initials on all CRFs and other records and documents submitted to the EC, and other 
authorised parties. 
• The investigator will keep a Patient Identification List with complete identification 
information (name, address, contact number, informed consent version number) on 
each subject. 
• Documents such as subject written informed consent forms should be maintained by 
the investigator in strict confidence. 
 
The subject should also be informed about the use of his/ her health information collected 
during the data collection study(data collection study data). 
 
 
15.4.1 Electronic Case Report Forms 
 
Electronic Case Report Forms (eCRF) will be used to collect all patient data during the 
course of the data collection study. The eCRF must be fully completed for each subject 
and electronically signed by the Investigator when complete.  
 
MDR Regulations and Good Clinical Practice Guidelines require that Investigators 
maintain information in the data collection study patient's medical records that 
corroborate data collected on the eCRF. To comply with these regulatory requirements, 
the following information should be maintained: 
• Medical history/physical condition of the data collection study patient before 
involvement in the data collection study sufficient to verify protocol entry 
criteria 
• Dated and signed notes on the day of entry into the data collection study 
including the data collection study investigator, data collection study 
•  name, patient number assigned and a statement that consent was obtained 
• Dated and signed notes from each data collection study patient visit with 
reference to the CRFs for further information, if appropriate (for specific results 
of procedures and exams) 
• Information related to adverse events 
• Data collection study patient's condition upon completion of or withdrawal 
from the data collection study 
• Discharge summaries/procedure reports 
 
 
 
 

28 
 
15.4.3  Data Reporting 
 
The Investigator or designated individual shall be responsible for recording all data 
collection study data on the electronic case report forms (eCRF).   
 
The Investigator is required to electronically sign the eCRF to verify that he/she has 
reviewed and agrees with the recorded data. All protocol deviations shall be documented 
and a justification for any missed assessments shall be provided on the Protocol Deviation 
Case Report Form. 
 
 The Investigator will allow any regulatory body to review and inspect the data collection 
study files, patient eCRF, patient medical records and other related data collection study 
documents as required. 
 
15.5  Record Maintenance 
 
15.5.1  Records 
 
The following records must be maintained in designated ARTEMIS Data collection study 
administrative files: 
• 
Clinical data collection protocol and all amendments 
• 
Ethics Committee Approval Letter(s) including EC-approved informed consent(s) 
(including any revisions)  
• 
CV for all investigators  
• 
Correspondence with the EC 
• 
EC membership list and/or assurance number  
• 
Investigational site authorised data collection study personnel signature list 
• 
Device Instructions for Use 
• 
Printed copy of blank set of CRFs  
• 
Patent Screening & Enrollment Log 
• 
Adverse Event Log 
• 
Reports (includes Adverse Event reports and final reports from Investigator) 
 
The following records must be maintained for each patient enrolled in the data 
collection study: 
• 
Signed patient consent forms 
• 
Copy of final completed CRFs  
• 
All lab and testing results 
• 
Record of any complications, adverse events, device problems and/or 
malfunctions, with supporting documentation 
• 
Procedure reports, progress notes, physician and/or nursing notes, and patient 
office files 

29 
 
• 
Records pertaining to patient deaths throughout the course of the data 
collection study (including death records, death certificate and autopsy report, if 
performed) 
 
 
 
 
16.  Publication Policy 
 
The result of the study will be published in peer-reviewed publications and other different 
forms such as abstracts, oral communications or posters.  
All data and results are property of the Promoter. 
 
 
 
 
 
 
 

30 
 
APPENDIX 1: CLINICAL RISK / BENEFIT ANALYSIS 
 
1.0 SUMMARY 
 
The objective of this data collection study is to evaluate the “real world” safety and effectiveness of the 
JenaValve TrilogyTM Heart Valve System for transcatheter aortic valve replacement (TAVR) in subjects 
with pure native aortic regurgitation (AR) who are indicated for TAVR as being at high/prohibitive 
risk for surgery. There is no specific risk of participation as the indication to proceed to TAVR using 
the JenaValve Trilogy device is taken independently from and prior to the participation to the study.  
General risks to subjects undergoing the TAVR procedure are listed below. 
 
2.0 POTENTIAL BENEFITS of TAVR 
 
The potential benefit to data collection study subjects outweighs the risks of participation in this 
data collection study. The benefits may include but are not limited to, the following:  
 
• 
Clinical Improvement (e.g. fewer heart failure hospitalisations, reduction in need for or high 
doses of cardiac medications including diuretics)  
• 
Functional improvement (e.g. NYHA Functional Class, KCCQ) 
• 
Unique device design features that may enhance safety of valve deployment/implantation as 
compared to other available non-dedicated TAVR devices 
• 
Overall advancement of medical and scientific knowledge that may benefit future patients 
with similar conditions may be gained through this clinical data collection study. 
• 
Subjects may also benefit indirectly from increased medical attention from participating in an 
data collection study. 
 
There may also be other benefits that are unforeseen at this time. 
 
3.0 POTENTIAL RISKS of TAVR 
 
Adverse events that may be anticipated in this clinical data collection study are believed to be 
consistent with those associated with other minimally invasive surgical and catheter-based 
procedures, including TAVR procedures.  Complications may occur at any time during the procedure, 
post-procedure or follow-up period.   
 
Potential adverse events (AE) which may be associated with the ancillary procedures including 
cardiac catheterization, aortic balloon valvuloplasty and local and/or general anaesthesia include 
but are not limited to the following: 
• 
Vascular damage (e.g. perforation, dissection, contrast media extravasation) 
• 
Vascular access (femoral entry site) complications (e.g. bleeding, hematoma, 
arteriovenous fistula, arterial occlusion, pseudo aneurysm, wound healing disorder, 
pain) 
• 
Peripheral nerve injury and/or ischemia 

31 
 
• 
Cardiovascular injury (e.g. damage of ventricle, ventricular septal perforation, 
myocardium or valvular structures including annulus rupture) 
• 
Hypotension, Hypertension 
• 
Cardiogenic tamponade or pericardial effusion 
• 
Arrhythmias and conduction system disorders (e.g. ventricular tachycardia or 
fibrillation; AV block) which may require permanent pacemaker implantation 
• 
Heart murmur 
• 
Hemodynamic compromise or cardiogenic shock 
• 
Heart failure or low cardiac output 
• 
Cardiac arrest 
• 
Angina pectoris 
• 
Myocardial infarction 
• 
Thrombus formation 
• 
Embolization (e.g. air, calcific material, thrombus) 
• 
Cerebrovascular event (e.g. TIA, Stroke, neurologic changes) 
• 
Pulmonary embolism 
• 
Pulmonary edema 
• 
Pleural effusion 
• 
Respiratory compromise or respiratory failure 
• 
Renal compromise or renal failure 
• 
Allergic reaction/hypersensitivity to contrast media, medication, or device materials 
• 
Inflammation 
• 
Infection (e.g. endocarditis, access site infection) and sepsis 
• 
Fever 
• 
Pneumonia 
• 
Hemorrhage or bleeding, possibly requiring intervention or transfusion 
• 
Retroperitoneal bleeding 
• 
Restenosis 
• 
Syncope 
• 
Anemia 
• 
Abnormal laboratory values (e.g. electrolyte imbalance) 
• 
Exercise intolerance or weakness 
• 
Paralysis, permanent disability, or other comorbid condition (new onset or worsening)  
• 
Death 
 
Potential adverse events (AE) that may be specifically associated with the TAVR procedure and the 
use of the investigational device include but are not limited to the following: 
• Anemia including hemolytic anemia 
• Coronary obstruction/transvalvular flow disturbance 
• Mitral valve injury 
• Device thrombosis 
• Device embolization, malposition, or deployment in unintended location 
• Device endocarditis 
• Valve explantation 
• Mechanical failure of delivery system and/or accessories 
• Structural valve deterioration (intrinsic damage of valve integrity e. g. cusps tear, 
suture line disruption, stent breakage, wear, calcification) or device degeneration 

32 
 
• Non-structural valve dysfunction (e.g., regurgitation- paravalvular or transvalvular) 
• Conversion into an open cardiac surgery including an extracorporeal circulation 
• Implantation of second TAVR device 
• Re-operation or emergency cardiac surgery 
• Aortic valve stenosis 
 
The above risks may require intervention to address the condition.  There may also be other 
risks that are unforeseen at this time. 
 
3.1 Alternatives to participation 
Patients with severe AR who are candidates for TAVR because at high/prohibitive surgical risk have 
no good treatment alternatives. If patients cannot be treated by means of TAVR, the medical 
therapy has poor results and is the last and least effective treatment. 
 
4.0 CONCLUSION 
 
Patients with severe aortic regurgitation who cannot be treated surgically, can nowadays be 
succesfully treated by means of TAVR with the JVT device.  
This study could objectively add useful “real world” information to the current evidence from the 
literature. 

33 
 
APPENDIX 2: ADVERSE EVENT DEFINITIONS 
 
Definitions in table below are adapted from VARC-3: 
 
ACUTE KIDNEY INJURY (VARC-3 Definition)  
Stage 1: AKI that fulfills at least one of the following criteria: 
• Increase in serum creatinine to 150–200% (1.5–2.0× increase) within 7 
days compared with baseline 
• Increase of ≥0.3 mg/dL (≥26.4 mmol/L) within 48 h of the index procedure 
Stage 2: AKI that fulfills the following criterion:  
• Increase in serum creatinine to 200–300% (2.0–3.0× increase) within 7 
days compared with baseline  
Stage 3: AKI that fulfills at least one of the following criteria:  
• Increase in serum creatinine to ≥300% (>3× increase) within 7 days 
compared with baseline 
• Serum creatinine of ≥4.0 mg/dL (≥354 mmol/L) with an acute increase of 
≥0.5 mg/dL (44 mmol/L)  
Stage 4: AKI requiring new temporary or permanent renal replacement therapy 
 
ACUTE VESSEL OCCLUSION 
State of complete luminal obstruction with no antegrade blood flow. 
 
ADVERSE EVENT DEFINITIONS 
• Adverse Event (AE) An adverse event is any undesirable 
experience (sign, symptom, illness, or other medical event) 
occurring to the patient, and that appears or worsens during the 
clinical data collection study, whether or not associated with the 
investigational product or related procedures.  
• Serious Adverse Event (SAE) Adverse event that: a) led to a 
death, b) led to a serious deterioration in health that either: 1) 
resulted in a life-threatening illness or injury, or 2) resulted in a 
permanent impairment of a body structure or a body function, 
or 3) required in-patient hospitalisation or prolongation of 
existing hospitalisation, or 4) resulted 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 fetal distress, fetal death or a congenital abnormality or 
birth defect.  
This definition includes device deficiencies that might have led to a serious adverse event 
if a) suitable action had not been taken or b) intervention had not been made or c) if 

34 
 
circumstances had been less fortunate. These are handled under the SAE reporting 
system.  
A planned hospitalisation for pre-existing condition, or a procedure required by the data 
collection study protocol without a serious deterioration in health, is not considered to be 
a serious adverse event.  
• Adverse Device Effect (ADE) Adverse event related to the use of an 
investigational medical device. 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: This includes any 
event that is a result of a use error or intentional misuse. 
• Serious Adverse Device Effect (SADE) Adverse device effect that has 
resulted in any of the consequences characteristic of a serious adverse 
event.  
• Unanticipated Adverse Device Effect (UADE) Any serious adverse effect 
on health or safety or any life-threatening problem or death caused by, or 
associated with, a device, if that effect, problem, or death was not 
previously identified in nature, severity, or degree if incidence in the 
investigational plan or application (including a supplementary plan or 
application), or any other unanticipated serious problem associated with 
a device that relates to the rights, safety or welfare of subjects.  
• Unanticipated Serious Adverse Device Effect (USADE) Serious adverse 
device effect which by its nature, incidence, severity, or outcome has 
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. NOTE: 
Anticipated: an effect which by its nature, incidence, severity, or outcome 
has been previously identified in the risk analysis report. 
 
ALL-CAUSE MORTALITY (VARC-3 Defined) 
• Cardiovascular mortality  
Death meeting one of the following criteria: 
▪ 
Related to heart failure, cardiogenic shock, bioprosthetic 
valve dysfunction, myocardial infarction, stroke, 
thromboembolism, bleeding, tamponade, vascular 
complication, arrhythmia or conduction system 
disturbances, cardiovascular infection (e.g. mediastinitis, 
endocarditis), or other clear cardiovascular cause 
▪ 
Intraprocedural death 
▪ 
Sudden death 
▪ 
Death of unknown cause 

35 
 
 
• Valve Related Mortality 
Cardiovascular mortality adjudicated to be associated with bioprosthetic valve 
dysfunction (BVD). 
 
• Non-cardiovascular mortality  
Death clearly related to a non-cardiovascular cause: such as respiratory failure 
not related to heart failure (e.g. pneumonia), renal failure, liver failure, 
infection (e.g. urosepsis), cancer, trauma, and suicide. 
 
BLEEDING (VARC-3 Defined)  
Overt bleeding that fulfils one of the following criteria: 
Type 1 
• 
Overt bleeding that does not require surgical or percutaneous 
intervention, but does require medical intervention by a health care 
professional, leading to hospitalisation, an increased level of care or 
medical evaluation (BARC 2) 
• 
Overt bleeding that requires a transfusion of 1 unit of whole 
blood/red blood cells (BARC 3a)  
Type 2 
• 
Overt bleeding that requires a transfusion of 2-4 units of whole 
blood/red blood cells (BARC 3a) 
• 
Overt bleeding associated with a hemoglobin drop of >3 g/dL (>1.86 
mmol/L) but <5 g/d (<3.1 mmol/L) (BARC 3a) 
Type 3 
• 
Overt bleeding in a critical organ, such as intracranial, intraspinal, 
intraocular, pericardial (associated with hemodynamic 
compromise/tamponade and necessitating intervention), or 
intramuscular with compartment syndrome (BARC 3b, BARC 3c) 
• 
Overt bleeding causing hypovolemic shock or severe hypotension 
(systolic blood pressure <90 mmHg lasting >30 min and not 
responding to volume resuscitation) or requiring vasopressors or 
surgery (BARC 3b) 
• 
Overt bleeding requiring reoperation, surgical exploration, or re-
intervention for the purpose of controlling bleeding (BARC 3b, BARC 
4) 
• 
Post-thoracotomy chest tube output ≥2 L within a 24 h period 
(BARC 4) 
• 
Overt bleeding requiring a transfusion of ≥5 units of whole 
blood/red blood cells (BARC 3a) 

36 
 
• 
Overt bleeding associated with a hemoglobin drop ≥5 g/dL (≥3.1 
mmol/L) (BARC 3b) 
Type 4 
• 
Overt bleeding leading to death. Should be classified as: 
▪ Probable: Clinical suspicion (BARC 5a) 
▪ Definite: Confirmed by autopsy or imaging (BARC 5b) 
 
CARDIAC STRUCTURAL COMPLICATIONS (VARC-3 Defined)  
Major - One of the following: 
▪ 
Cardiac structure perforation, injury, or compromise resulting in 
death, VARC type ≥2 bleeding, hemodynamic compromise or 
tamponade, or requiring unplanned surgical or percutaneous 
intervention 
▪ 
New pericardial effusion resulting in death, VARC type ≥2 
bleeding, hemodynamic compromise or tamponade, or requiring 
unplanned surgical or percutaneous intervention 
▪ 
Coronary obstruction resulting in death, hemodynamic 
compromise, myocardial infarction, or unplanned surgical or 
percutaneous intervention. Coronary obstruction may be acute 
(during the procedure) or delayed (after completion of the 
procedure). 
▪ 
Coronary artery access difficulties for needed coronary 
angiography or intervention, resulting in death, hemodynamic 
compromise, myocardial infarction, coronary or aortic root 
injury, compromise in aortic valve prosthesis integrity, 
unplanned surgical or percutaneous intervention, or the inability 
to perform the intended procedure. 
• Minor - One of the following: 
▪ 
Cardiac structure perforation, injury, or compromise not 
resulting in death, VARC type ≥2 bleeding, hemodynamic 
compromise or tamponade, or requiring unplanned surgical or 
percutaneous intervention 
▪ 
New pericardial effusion not resulting in death, VARC type ≥2 
bleeding, hemodynamic compromise or tamponade, or requiring 
unplanned surgical or percutaneous intervention 
▪ 
Coronary obstruction not resulting in death, hemodynamic 
compromise, myocardial infarction, or unplanned surgical or 
percutaneous intervention 
▪ 
Coronary artery access difficulties for needed coronary 
angiography or intervention, not resulting in death, 
hemodynamic compromise, myocardial infarction, coronary or 

37 
 
aortic root injury, compromise in aortic valve prosthesis 
integrity, unplanned surgical or percutaneous intervention, or 
the inability to perform the intended procedure. 
 
CARDIOGENIC SHOCK 
Acute decreased pumping ability of the heart and/or LVAD that causes a 
shock-like state. 
 
CONDUCTION DISTURBANCES AND ARRHYTHMIAS (VARC-3 Defined)  
New-onset conduction disturbance: defined as a new conduction disturbance 
relative to baseline. 
• Timing of occurrence: 
▪ 
Procedural: ≤24 h after the index procedure 
▪ 
Delayed: > 24 h after the index procedure 
• Conduction disturbances 
▪ 1st-, 2nd-, 3rd-degree AV block 
▪ Left bundle branch block 
▪ IVCD with QRS ≥120 ms 
• Duration: 
▪ Transient: resolved before discharge or ≤7 days after the 
index procedure in case of prolonged hospitalisation 
▪ Persistent: present at hospital discharge or >7 days after the 
index procedure in case of prolonged hospitalisation 
▪ Permanent: present >30 days after the index procedure 
• Permanent pacemaker 
▪ Type: single, dual, biventricular, defibrillator, leadless 
▪ Timing: No. of days after the index procedure 
▪ Indication: including AV Block, SSS 
• Atrial fibrillation (or flutter) 
 
New-onset arrhythmia: defined as any arrhythmia that was not present at baseline that 
has the ECG characteristics of atrial fibrillation (or flutter) and lasts sufficiently long to be 
recorded on a 12-lead ECG or at least 30 s on a rhythm strip. 
Timing of occurrence: 
▪ Periprocedural: ≤30 days after the index procedure 
▪ Late/spontaneous: >30 days after the index procedure 
▪ Paroxysmal: atrial fibrillation that terminates 
spontaneously or with intervention ≤7 days of onset. 
▪ Persistent: Continuous atrial fibrillation that is sustained 
>7 days. 

38 
 
▪ Long-standing persistent: Continuous atrial fibrillation 
>12 months in duration. 
▪ Permanent: Used when the patient and clinician make a 
joint decision to stop further attempts to restore and/or 
maintain sinus rhythm. 
 
CONGESTIVE HEART FAILURE 
Re-hospitalisation for signs or symptoms of right or left sided volume 
overload. Diagnosis must be confirmed by at least one of the following: 
• Chest x-ray report confirming pulmonary vascular congestion, 
• Unplanned treatment of diagnosed new or worsening HF requiring the 
use of intravenous diuretics, inotropes, or vasodilators during any 
hospital admission or overnight stay in a healthcare facility. 
• Hemodynamic assessment showing elevated right or left sided 
increased pressures. 
 
CONVERSION TO OPEN SURGERY (VARC-3 Defined)  
Conversion to open sternotomy or thoracotomy using cardiopulmonary 
bypass secondary to any procedure-related complication or failed intended 
transcatheter approach. Should be classified as: 
• Intraprocedural conversion: during the index procedure 
• Periprocedural conversion: ≤30 days after the index procedure 
• Delayed conversion: >30 days after the index procedure 
 
ENDOCARDITIS (VARC-3 Defined) 
  
Meeting at least one of the following criteria: (i) Fulfillment of the Duke 
endocarditis criteria (ii) Evidence of abscess, pus, or vegetation confirmed as 
secondary to infection by histological or microbiological studies during re-
operation; and (iii) Evidence of abscess, pus, or vegetation confirmed on 
autopsy. 

39 
 
MITRAL REGURGITATION 
Echocardiographic and Doppler parameters used in grading mitral regurgitation (MR) severity, according to the current 
American Society of Echocardiography Guidelines for Non-invasive Evaluation of Native Valve Regurgitation21. 
Mitral regurgitation grading according to the American Society of Echocardiography (4) 
 
MR Severity* 
 
Mild MR 
Moderate MR 
Severe MR 
Structural  
MV morphology 
None or mild leaflet abnormality 
(e.g., mild thickening, 
calcifications or prolapse, mild 
tenting) 
Moderate leaflet 
abnormality or moderate 
tenting 
Severe valve lesions (primary: flail 
leaflet, ruptured papillary muscle, 
severe retraction, large perforation; 
secondary: severe tenting, poor leaflet 
coaptation) 
LV and LA size† 
Usually normal 
Normal or mild dilated 
Dilated‡ 
Qualitative Doppler 
Color flow jet area§ 
Small, central, narrow, often brief 
Variable 
Large central jet (>50% of LA) or eccentric 
wall-impinging jet of variable size 
Flow convergence‖ 
Not visible, transient or small 
Intermediate in size and 
duration 
Large throughout systole 
CWD jet 
Faint/partial/parabolic 
Dense but partial or parabolic 
Holosystolic/dense/triangular 
Semiquantitative 

40 
 
Mitral regurgitation grading according to the American Society of Echocardiography (4) 
 
MR Severity* 
 
Mild MR 
Moderate MR 
Severe MR 
VCW (cm) 
<0.3 
Intermediate 
≥0.7 (>0.8 for biplane)¶ 
Pulmonary vein flow# 
Systolic dominance (may be blunted 
in LV dysfunction or AF) 
Normal or systolic blunting# 
Minimal to no systolic flow /  systolic flow 
reversal 
Mitral inflow∗∗ 
A-wave dominant 
Variable 
E-wave dominant (>1.2 m/sec) 
Quantitative††,‡‡ 
 EROA, 2D PISA (cm2) 
<0.20 
0.20-0.29 
0.30-0.39 
Bolded qualitative and semiquantitative signs are considered specific for their MR grade. 
∗ All parameters have limitations, and an integrated approach must be used that weighs the strength of each echocardiographic measurement. All signs and measures 
should be interpreted in an individualized manner that accounts for body size, sex, and all other patient characteristics;† This pertains mostly to patients with primary MR; 
‡ LV and LA can be within the “normal” range for patients with acute severe MR or with chronic severe MR who have small body size, particularly women, or with small LV 
size preceding the occurrence of MR; § With Nyquist limit 50-70 cm/sec. 
‖ Small flow convergence is usually <0.3 cm, and large is ≥ 1 cm at a Nyquist limit of 30-40 cm/sec; ¶ For average between apical two- and four-chamber views; # Influenced 
by many other factors (LV diastolic function, atrial fibrillation, LA pressure); ∗∗ Most valid in patients >50 years old and is influenced by other causes of elevated LA pressure; 
†† Discrepancies among EROA, RF, and RVol may arise in the setting of low or high flow states; ‡‡ Quantitative parameters can help subclassify the moderate regurgitation 
group. 

41 
 
 
MYOCARDIAL INFARCTION (VARC-3 and 4th Universal Definition(6) Defined 
Type 1 (Spontaneous MI) (>48 h after the index procedure) 
• Detection of a rise and/or fall of cTn values with at least one value above the 99th percentile URL with at 
least one of the following: 
▪ Symptoms of acute ischemia 
▪ New ischemic ECG changes (new ST-segment or T-wave changes or new LBBB) 
▪ New pathologic Q-waves in ≥2 contiguous leads 
▪ Imaging evidence of a new loss of viable myocardium or new wall motion abnormality in a pattern 
consistent with an ischemic etiology 
▪ Identification of a coronary thrombus by angiography or autopsy 
• Post-mortem demonstration of an atherothrombus in the artery supplying the infarcted myocardium, or 
a macroscopically large, circumscribed area of necrosis with or without intramyocardial hemorrhage, 
meets the type 1 MI criteria regardless of cTn values 
Type 2 (Imbalance between myocardial oxygen supply and demand) 
• Detection of a rise and/or fall of cTn values with at least one value above the 99th percentile URL, and 
evidence of an imbalance between myocardial oxygen supply and demand unrelated to coronary 
thrombosis, requiring at least one of the following: 
▪ Symptoms of ischemia 
▪ ECG changes indicative of new ischemia (new ST-segment or T-wave changes or new LBBB) 
▪ New pathologic Q-waves in ≥2 contiguous leads 
▪ Imaging evidence of a new loss of viable myocardium or new wall motion abnormality 
Type 3 (MI associated with sudden cardiac death) 
• Patients who suffer cardiac death, with symptoms suggestive of myocardial ischemia accompanied by 
presumed new ischemic ECG changes or ventricular fibrillation but die before blood samples for 
biomarkers can be obtained, or before increases in cardiac biomarkers can be identified, or MI is 
detected by autopsy examination. 
Type 4A (Criteria for PCI-related MI ≤48 h after the index procedure) 
• In patients with normal baseline CK-MB: The peak CK-MB measured within 48 h of the procedure ≥10 x 

42 
 
the local laboratory ULN or CKMB≥5 x ULN with one or more of the following: 
▪ New pathologic Q-waves in ≥2 contiguous leads 
▪ New persistent LBBB 
▪ Flow-limiting angiographic complications in a major epicardial vessel or >1.5 mm diameter branch 
▪ Substantial new loss of viable myocardium on imaging related to the procedure 
• In the absence of CK-MB measurements and a normal baseline cTn, a cTn (I or T) level measured within 
48 h of the procedure rises to ≥70 x the local laboratory ULN or ≥35 x ULN with one or more of the 
following: 
▪ New pathologic Q-waves in ≥2 contiguous leads 
▪ New persistent LBBB 
▪ Flow-limiting angiographic complications in a major epicardial vessel or >1.5 mm diameter branch 
▪ Substantial new loss of viable myocardium on imaging related to the procedure 
• 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. 
Type 4B (Stent thrombosis) 
• Stent thrombosis as documented by angiography or autopsy using the same criteria utilized for type 1 
MI. 
• Acute: 0 to 24 h 
• Subacute: >24 h to 30 days 
• Late: >30 days to 1 year 
• Very late: >1 year after stent implantation 
Type 5 Periprocedural (post-SAVR, TAVR or CABG) MI (≤48 h after the index procedure) 
• In patients with normal baseline CK-MB: The peak CK-MB measured within 48 h of the procedure ≥10 x the local 
laboratory ULN or CKMB ≥5 x ULN with one or more of the following: 
▪ New pathologic Q-waves in ≥2 contiguous leads 
▪ New persistent LBBB 
▪ Flow-limiting angiographic complications in a major epicardial vessel or >1.5 mm diameter branch 
▪ Substantial new loss of viable myocardium on imaging related to the procedure 

43 
 
• In the absence of CK-MB measurements and a normal baseline cTn, a cTn (I or T) level measured within 48 h of the 
procedure rises to ≥70x the local laboratory ULN or ≥35x ULN with one or more of the following: 
▪ New pathologic Q-waves in ≥2 contiguous leads 
▪ New persistent LBBB 
▪ Flow-limiting angiographic complications in a major epicardial vessel or >1.5 mm diameter branch 
▪ Substantial new loss of viable myocardium on imaging related to the procedure 
• 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. 
 
NEW YORK HEART ASSOCIATION CLASSIFICATION (NYHA) 
Classification system for defining cardiac disease and related functional limitations into four categories: 
Class 
Symptoms 
I 
Cardiac disease, but no symptoms and no limitation in ordinary physical 
activity, e.g. no shortness of breath when walking, climbing stairs etc. 
II 
Mild symptoms (mild shortness of breath and/or angina) and slight 
limitation during ordinary activity. 
III 
Marked limitation in activity due to symptoms, even during less-than-
ordinary activity, e.g., walking short distances (20–100 m). 
Comfortable only at rest. 
IV 
Severe limitations. Experiences symptoms even while at rest. Mostly 
bedbound patients. 
 
PULMONARY INSUFFICIENCY 
Post-bronchodilator forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) ratio [FEV1/FVC] 
less than 70% Post-bronchodilator FEV1 less than 80% predicted, with or without chronic symptoms (i.e., cough 
or sputum production) 
 
STROKE (VARC-3 Defined)  
Stroke classiﬁcation 

44 
 
• Ischemic: Acute onset of focal neurological signs or symptoms conforming to a focal or multifocal 
vascular territory within the brain, spinal cord, or retina (NeuroARC23 Type 1a or 1aH) and fulfilling 
one of the following criteria: 
▪ Signs or symptoms lasting ≥24 h or until death, with pathology or neuroimaging evidence of 
CNS infarction, or absence of other apparent causes 
▪ Symptoms lasting <24 h, with pathology or neuroimaging confirmation of CNS infarction in the 
corresponding vascular territory 
• Hemorrhagic: Acute onset of neurological signs or symptoms due to intracranial bleeding from 
intracerebral or subarachnoid hemorrhage not due to trauma (NeuroARC23 Types 1b or 1c) 
• Stroke, not otherwise specified: Acute onset of neurological signs or symptoms persisting ≥24 h or 
until death but without sufficient neuroimaging or pathology evidence to be classified (NeuroARC23 
Type 1d). 
 
Stroke Grading 
• Acute stroke severity 
▪ Mild neurological dysfunction: NIHSS 0-5 
▪ Moderate neurological dysfunction: NIHSS 6-14 
▪ Severe neurological dysfunction: NIHSS ≥15 
 
Stroke Disability 
• 
Fatal stroke: death resulting from a stroke 
• 
Stroke with disability: mRS score of ≥2 at 90 days and increase of ≥1 from pre-stroke baseline 
• 
Stroke without disability: mRS score of 0 (no symptoms) or 1 (able to carry out all usual duties and 
activities) at 90 days or no increase in mRS category from pre-stroke baseline 
 
SURGERY OR INTERVENTION RELATED TO THE DEVICE OR A MAJOR VASCULAR OR ACCESS RELATED OR CARDIAC 
STRUCTURAL COMPLICATION 
 

45 
 
Surgery or intervention related to the device involves dysfunction of the valve requiring AVR (e.g. implantation of another 
THV or SAVR) or intervention that does not require replacement (e.g. BAV or paravalvular leak closure) will be collected 
and reported as separate secondary endpoints.  Both surgery or interventions that require AVR or non replacement 
intervention on the device are considered events resulting in technical and device failure, and are components of the 
primary safety endpoint at 30 days.    
 
Surgery or intervention will be adjudicated by the CEC as related to device, implant procedure, both.  Surgery or 
intervention adjudicated by the CEC as related to the device or implant procedure will be reported as surgery or 
intervention related to the device but unrelated procedures unrelated will not.   Cardiac structural complications and 
vascular or access related complications, as defined by VARC-3, fulfill the criteria as well as device failure.  
 
TRANSPLANTATION 
 
• Planned Transplantation:  Patient undergoes the transplantation procedure as an event unrelated to the THV or 
THV procedure 
• Unplanned Transplantation:  Patient undergoes the cardiac transplantation procedure on an urgent basis within 
30 days of THV implant as a consequence of THV implantation or the THV implant procedure.  
 
 
TRICUSPID REGURGITATION  
Echocardiographic and Doppler parameters used in grading tricuspid regurgitation (TR) severity, according to the current 
American Society of Echocardiography Guidelines for Non-invasive Evaluation of Native Valve Regurgitation 21. 
Tricuspid regurgitation grading according to the American Society of Echocardiography (4)   
Parameters 
Mild TR 
Moderate TR 
Severe TR 
Structural 
TV morphology 
Normal or mildly abnormal leaflets 
Moderately 
abnormal leaflets 
Severe valve lesions (e.g., 
flail leaflet, severe 

46 
 
Tricuspid regurgitation grading according to the American Society of Echocardiography (4)   
Parameters 
Mild TR 
Moderate TR 
Severe TR 
retraction, large 
perforation) 
RV and RA size 
Usually normal 
Normal or mild 
dilatation 
Usually dilated∗ 
Inferior vena cava 
diameter 
Normal < 2 cm 
Normal or mildly 
dilated 2.1- 2.5 cm 
Dilated > 2.5 cm 
Qualitative Doppler 
Color flow jet area† 
Small, narrow, central 
Moderate central 
Large central jet or eccentric 
wall-impinging jet of variable 
size 
Flow convergence zone 
Not visible, transient or small 
Intermediate in 
size and duration 
Large throughout systole 
CWD jet 
Faint/partial/parabolic 
Dense, parabolic or 
triangular 
Dense, often triangular 
Semiquantitative 
Color flow jet area (cm2)† 
Not defined 
Not defined 
>10 
VCW (cm)† 
<0.3 
0.3-0.69 
≥0.7 
PISA radius (cm)‡ 
≤0.5 
0.6-0.9 
>0.9 
Hepatic vein flow§ 
Systolic dominance 
Systolic blunting 
Systolic flow reversal 
Tricuspid inflow§ 
A-wave dominant 
Variable 
E-wave >1.0 m/sec 
Quantitative 
EROA (cm2) 
<0.20 
0.20-0.39 
≥0.40 
RVol (2D PISA) (mL) 
<30 
30-44 
≥45 
∗ RV and RA size can be within the “normal” range in patients with acute severe TR;† With Nyquist limit >50-70 cm/sec; ‡ With baseline Nyquist limit shift of 28 cm/sec; 
§ Signs are nonspecific and are influenced by many other factors (RV diastolic function, atrial fibrillation, RA pressure); ‖ There are little data to support further 
separation of these values. 

47 
 
 
 
 
VALVE DYSFUNCTION - Aortic Bioprosthetic Valve Dysfunction (BVD) (VARC-3 Defined)  
 
Unintended Performance of the Valve 
 
Standard VARC-3 criteria are mean gradient <20 mmHg, peak velocity <3 m/s, 
Doppler velocity index >_0.25, and less than moderate aortic regurgitation. 
hemodynamic criteria.  The intended use of the THV is to avoid aortic regurgitation, 
As such this definition is modified to the presence of moderate or greater aortic 
regurgitation. 
 
Clinical Presentation 
Subclinical: Any bioprosthetic valve dysfunction associated with absent or mild 
hemodynamic changes, AND absent symptoms or sequelae 
 
Structural valve deterioration (SVD) 
Intrinsic permanent changes to the prosthetic valve, including wear and tear, leaflet 
disruption, flail leaflet, leaflet fibrosis and/or calcification, or strut fracture or 
deformation. 
 
Non-structural valve dysfunction (NSVD) 
Any abnormality, not intrinsic to the prosthetic valve, resulting in valve dysfunction. 
Examples include residual intra- or paraprosthetic aortic regurgitation; leaflet 
entrapment by pannus, tissue, or suture; inappropriate positioning or sizing; 
dilatation of the aortic root after stentless prostheses or aortic valve sparing 
operations; prosthesis-patient mismatch; and embolization. 
 
Hemodynamic Changes 
   Stage 1: Morphological valve deterioration 
• Evidence of structural valve deterioration, non-structural valve 
dysfunction (other than paravalvular regurgitation or prosthesis- 
patient mismatch), thrombosis, or endocarditis without significant 
hemodynamic changes. 
 
Stage 2: Moderate hemodynamic valve deterioration 
• Increase in mean transvalvular gradient ≥10 mmHg resulting in 
mean gradient ≥20 mmHg with concomitant decrease in EOA ≥0.3 
cm2 or ≥25% and/or decrease in Doppler velocity index ≥0.1 or 

48 
 
≥20% compared with echocardiographic assessment performed 
1–3 months post-procedure, OR new occurrence or increase of ≥1 
grade of intraprosthetic AR resulting in ≥moderate AR. 
 
Stage 3: Severe hemodynamic valve deterioration 
• Increase in mean transvalvular gradient ≥20 mmHg resulting in 
mean gradient ≥30 mmHg with concomitant decrease in EOA ≥0.6 
cm2 or ≥50% and/or decrease in Doppler velocity index ≥0.2 or 
≥40% compared with echocardiographic assessment performed 
1–3 months post-procedure, OR new occurrence, or increase of 
≥2 grades, of intraprosthetic AR resulting in severe AR. 
 
Bioprosthetic valve failure (BVF) 
• Stage 1: Any bioprosthetic valve dysfunction associated with 
clinically expressive criteria (new-onset or worsening symptoms, LV 
dilation/ hypertrophy/dysfunction, or pulmonary hypertension) or 
irreversible Stage 3 hemodynamic valve deterioration (HVD) 
• Stage 2: Aortic valve reoperation or re-intervention 
• Stage 3: Valve-related death 

49 
 
 
Prosthetic Aortic Valve Regurgitation (VARC-3 Defined)  
Prosthetic aortic valve regurgitation 
Three-class grading 
None/ Trace 
Mild 
Moderate 
Severe 
Five-class grading 
None/ Trace 
Mild 
Mild-moderate Moderate 
Moderate-
severe 
Severe 
Doppler parameters (qualitative or semi-quantitative) 
Jet features 
Extensive/ wide jet 
origin 
Absent 
Absent 
Absent 
Present 
Present 
Present 
Multiple jets 
Possible 
Possible 
Often present 
Often present 
Usually 
present 
Usually 
present 
Jet path visible along 
the stent 
Absent 
Absent 
Possible 
Often present 
Usually 
present 
Present 
Proximal flow 
convergence 
Absent 
Absent 
Absent 
Possible 
Often present 
Often present 
E/A ratio 
<1.0 
<1.0 
<1.0 
≥1.5 
≥1.5 
≥1.5 
Vena contracta width 
(mm) 
N.Q. 
<2 
2 to <4 
4 to <5 
5 to <6 
≥6 
Vena contracta area 
(mm2) 
N.Q. 
<5 
5 to <10 
10 to <20 
20 to <30 
≥30 
Jet width at its origin 
Narrow (<5) 
Narrow (5 
to <15)  
Intermediate 
(15 to <30) 
Intermediate 
(30 to <45) 
Large (45 to 
<60) 
Large (≥60) 
Jet density 
Faint 
Faint 
Variable 
Dense 
Dense 
Dense 
Jet deceleration rate 
Slow 
Slow 
Variable (200 
to <500) 
Variable (200 to 
<500) 
Variable (200 
to <500) 
Steep (<200) 

50 
 
 
Prosthetic aortic valve regurgitation 
Three-class grading 
None/ Trace 
Mild 
Moderate 
Severe 
Five-class grading 
None/ Trace 
Mild 
Mild-moderate Moderate 
Moderate-
severe 
Severe 
Diastolic flow reversal in 
descending aorta 
Absent 
Absent or 
brief 
Intermediate 
Intermediate 
Holodiastolic 
Holodiastolic 
Circumferential extent 
of PVR 
N.Q. 
<5 
5 to <10 
10 to <20 
20 to <30 
≥30 
Doppler parameters (quantitative) 
Regurgitant volume 
<15 
<15 
15 to <30 
30 to <45 
45 to <60 
≥60 
Regurgitant orifice area 
<5 
<5 
5 to <10 
10 to <20 
20 to <30 
≥30 
Regurgitant fraction 
<15 
<15 
15 to <30 
30 to <40 
40 to <50 
≥50 
CMR regurgitant 
fraction 
<15 
<15 
15 to <30 
30 to <40 
40 to <50 
≥50 

51 
 
VALVE MALPOSITIONING (VARC-3 Defined)  
Should be classified as: 
• 
Valve migration: After initial correct positioning, the valve prosthesis 
moves upward or downward, within the aortic annulus from its 
initial position, without valve embolization 
• 
Valve embolization: The valve prosthesis moves either upward or 
downward after final deployment such that it loses contact with the 
aortic annulus 
• 
Ectopic valve deployment: Irretrievable deployment of a valve 
prosthesis at a site other than the intended position because of 
valve embolization or inability to deliver the prosthesis to the 
desired location 
 
VALVE THROMBOSIS (VARC-3 Defined)  
Clinical sequelae of a thromboembolic event (e.g., stroke, TIA, retinal 
occlusion, other evidence of systemic thromboembolism) or worsening 
valve stenosis/regurgitation (e.g., signs of heart failure, syncope) and: 
• 
Hemodynamic valve deterioration Stage 2 or 3a or 
• 
Confirmatory imaging (CT evidence of HALT or TEE findings) 
 
In the absence of clinical sequelae, both: 
 
• 
Hemodynamic valve deterioration Stage 3a and 
• 
Confirmatory imaging (CT evidence of HALT or TEE findings) 
 
• Timing 
▪ 
Acute: Within 0–24 h of the index procedure 
▪ 
Subacute: >24 h and ≤30 days after the index procedure 
▪ 
Late: >30 days and ≤1 year after the index procedure 
▪ 
Very late: >1 year after the index procedure 
 
Response to anticoagulant therapy (≥3 months) 
 
• 
Resolved: Partial or complete resolution of symptoms, 
imaging findings, and HVD 
• 
Persistent: No improvement in symptoms, imaging findings, 
or HVD 
• 
Recurrent: Recurrence of symptoms, imaging findings, or 
HVD 

52 
 
 
• Certainty of diagnosis 
▪ 
Definite: Histopathological confirmation 
▪ 
Probable: Hemodynamic changes and imaging findings 
compatible with valve thrombosis, with resolution of 
hemodynamic changes and imaging findings following 
anticoagulation therapy 
▪ 
Possible: Imaging demonstrated findings compatible with 
leaflet thrombosis formation, but either hemodynamic 
changes or imaging findings persist following anticoagulation 
therapy or anticoagulation therapy is not (yet) administered. 
 
VASCULAR AND ACCESS-RELATED COMPLICATIONS (VARC-3 Defined)  
• Vascular complications 
▪ Major - One of the following: 
o 
Aortic dissection or aortic rupture 
o 
Vascular (arterial or venous) injury (perforation, 
rupture, dissection, stenosis, ischemia, arterial or 
venous thrombosis including pulmonary embolism, 
arteriovenous fistula, pseudoaneurysm, hematoma, 
retroperitoneal hematoma, infection) or compartment 
syndrome resulting in death, VARC type ≥2 bleeding, 
limb or visceral ischemia, or irreversible neurologic 
impairment.   
o 
Distal embolization (non-cerebral) from a vascular 
source resulting in death, amputation, limb or visceral 
ischemia, or irreversible end-organ damage 
o 
Unplanned endovascular or surgical intervention 
resulting in death, VARC type ≥2 bleeding, limb or 
visceral ischemia, or irreversible neurologic 
impairment.  Planned initial vascular access via 
surgical cutdown is not considered a vascular 
complication, while complications of this form of 
access are. 
o 
Closure device failure resulting in death, VARC type ≥2 
bleeding, limb or visceral ischemia, or irreversible 
neurologic impairment 
▪ Minor – One of the following: 
o 
Vascular (arterial or venous) injury (perforation, rupture, 
dissection, stenosis, ischemia, arterial or venous thrombosis 

53 
 
including pulmonary embolism, arteriovenous fistula, 
pseudoaneurysm, hematoma, retroperitoneal hematoma, 
infection) not resulting in death, VARC type ≥2 bleeding, limb or 
visceral ischemia, or irreversible neurologic impairment 
o 
Distal embolization treated with embolectomy and/or 
thrombectomy, not resulting in death, amputation, limb or 
visceral ischemia, or irreversible end-organ damage 
o 
Any unplanned endovascular or surgical intervention, ultra-
sound guided compression, or thrombin injection, not resulting 
in death, VARC type ≥2 bleeding, limb or visceral ischemia, or 
irreversible neurologic impairment 
o 
Closure device failure not resulting in death, VARC type ≥2 
bleeding, limb or visceral ischemia, or irreversible neurologic 
impairment  
• Access-related non-vascular complications 
▪ Major – One of the following: 
o 
Non-vascular structure, non-cardiac structured perforation, 
injury, or infection resulting in death, VARC type ≥2 bleeding, 
irreversible nerve injury or requiring unplanned surgery or 
percutaneous intervention. 
o 
Non-vascular access site (e.g., trans-apical left ventricular) 
perforation, injury, or infection resulting in death, VARC type ≥2 
bleeding, irreversible nerve injury or requiring unplanned surgery 
or percutaneous intervention. 
 
▪ Minor – One of the following: 
o 
Non-vascular structure, non-cardiac structure perforation, 
injury, or infection not resulting in death, VARC type 2, 
irreversible nerve injury, or requiring unplanned surgery or 
percutaneous intervention 
o 
Non-vascular access site (e.g. trans-apical left ventricular) 
perforation, injury, or infection not resulting in death, VARC type 
2 bleeding, irreversible nerve injury or requiring unplanned 
surgery or percutaneous intervention.  
 

54 
 
BIBLIOGRAPHY 
 
 
1.  Vahl, Torsten P et al. Transcatheter aortic valve implantation in 
patients with high-risk symptomatic native aortic regurgitation (ALIGN-
AR): a prospective, multicentre, single-arm study. The Lancet, Volume 
403, Issue 10435, 1451 – 1459. 
2. Nkomo VT, Gardin JM, Skelton TN, Gottdiener JS, Scott CG, Enriquez-
Sarano M. Burden of valvular heart diseases: a population-based  . 
Lancet 2006; 368(9540): 1005-11. 
3. Dujardin KS, Enriquez-Sarano M, Schaff HV, Bailey KR, Seward JB, Tajik 
AJ. Mortality and morbidity of aortic regurgitation in clinical practice. A 
long-term follow-up study. Circulation 1999; 99(14): 1851-7. 
4. Otto CM, Nishimura RA, Bonow RO, et al. 2020 ACC/AHA Guideline for 
the Management of Patients With Valvular Heart Disease: A Report of 
the American College of Cardiology/American Heart Association Joint 
Committee on Clinical Practice Guidelines. Circulation 2021; 143(5): 
e72-e227. 
5. Généreux P, Piazza N, Alu MC, et al. Valve Academic Research 
Consortium 3: Updated Endpoint Definitions for Aortic Valve Clinical 
Research. Journal of the American College of Cardiology 2021; 77(21): 
2717-46. 
6. Thygesen K, Alpert JS, Jaffe AS, et al. Fourth Universal Definition of 
Myocardial Infarction (2018). Circulation 2018; 138(20): e618-e51. 
 
 
 
 
 
 
 
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