JENAVALVE ALIGN-AS TRIAL: Safety and Effectiveness/Performance of the Transfemoral JenaValve Pericardial TAVR System in the Treatment of Patients With Symptomatic Severe Aortic Stenosis (AS)
Phase: NA
Conditions: Aortic Valve Stenosis, Heart Valve Diseases, Heart Diseases, Cardiovascular Diseases, Ventricular Outflow Obstruction
Sponsor: JenaValve Technology, Inc.

 
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A Feasibility Study to Assess Safety and Effectiveness of the 
Transfemoral JenaValve Pericardial TAVR System in the Treatment 
of Patients with Symptomatic Severe Aortic Stenosis (AS) 
 
 
 
 
 
THE ALIGN-AS EFS TRIAL: JenaValve Pericardial TAVR Aortic 
Stenosis Study 
 
NCT02732691 
 
 
 
 
Rev. J 
 
 15 July 2019 
 
 
 
 
 
CONFIDENTIAL 
 
This investigational protocol contains confidential information for use by the principal investigators and 
their designated representatives participating in this clinical investigation. It should be held confidential 
and maintained in a secure location. It should not be copied, distributed, or made available for review by 
any unauthorized 
 person or firm. 

 
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 Table of Contents 
TABLE OF CONTENTS ........................................................................................................... 2 
PROTOCOL SYNOPSIS .......................................................................................................... 5 
1.0  INTRODUCTION ........................................................................................................ 10 
1.1  Background on Aortic Stenosis and TAVR ............................................................................ 10 
1.2 
Background on Transcatheter Aortic Valve Replacement (TAVR) ............................................ 10 
1.3  JenaValve Device Concept .................................................................................................... 12 
1.4 
JenaValve Device Preclinical Testing .................................................................................... 12 
1.5 
Prior Clinical Experience with JenaValve Device .................................................................. 12 
1.6 
Conclusion ............................................................................................................................ 13 
2.0 DEVICE DESCRIPTION ................................................................................................ 13 
2.1  JenaValve Pericardial Transcatheter Heart Valve (THV) ....................................................... 13 
2.2 
JenaValve Pericardial Transfemoral (TF) Delivery System .................................................... 14 
2.2.1 
JenaValve Coronatix™ Transfemoral (TF) Delivery Catheter & Introducer 
Sheath ............................................................................................................ 14 
2.3 
JenaValve Pericardial Transfemoral (TF) Loading Tools ....................................................... 15 
2.4 
Product Identification ........................................................................................................... 15 
3.0  STUDY OBJECTIVE ..................................................................................................... 15 
4.0  STUDY ENDPOINTS/OTHER DATA COLLECTION .......................................................... 16 
4.1 
Primary Endpoint .................................................................................................................. 16 
4.2 
Performance Endpoints ........................................................................................................ 16 
4.3 
Additional Analyses .............................................................................................................. 17 
4.3.1 
Safety ............................................................................................................. 17 
4.3.2 
Other Data ..................................................................................................... 17 
5.0  STUDY DESIGN .......................................................................................................... 17 
6.1  General ................................................................................................................................. 19 
6.1.1 
Analysis of Endpoints ..................................................................................... 19 
6.1.2 
Other .............................................................................................................. 19 
6.2  Sample Size Justification ....................................................................................................... 20 
6.3  Analysis Populations ............................................................................................................. 20 
6.3.1 
Screening Population ..................................................................................... 20 
6.3.3 
Implanted Population .................................................................................... 20 
6.4 
Final Analyses ....................................................................................................................... 20 
6.5 
Reports for Safety ................................................................................................................. 20 
7.0 SUBJECT POPULATION AND SELECTION ..................................................................... 21 
7.1 
Subject Population ................................................................................................................ 21 
7.2  Inclusion Criteria ................................................................................................................... 21 
7.3  Exclusion Criteria .................................................................................................................. 22 
7.4 
Subject Screening ................................................................................................................. 23 
7.5 
Informed Consent Procedures .............................................................................................. 23 
7.6 
Subject Discontinuation/Withdrawal Criteria ...................................................................... 23 
7.6.1 
Data collection and Follow-Up for Discontinued/Withdrawn Subjects ......... 24 

 
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7.7 
Subjects Lost to Follow-Up ................................................................................................... 24 
8.0  PRE-INDEX PROCEDURE METHODOLOGY .................................................................. 24 
9.0 INDEX PROCEDURE- GENERAL DESCRIPTION ............................................................. 25 
10.0 INDEX PROCEDURE THROUGH DISCHARGE ................................................................ 25 
10.1 Antithrombotic Therapy ....................................................................................................... 25 
10.1.1 During Index TAVR Procedure ........................................................................ 26 
10.1.2 Post-Index TAVR Procedure ........................................................................... 26 
10.2  Patient Preparation in Procedure Room .............................................................................. 26 
10.3 Implantation Procedure ........................................................................................................ 26 
10.3.1 THV Prosthesis Assessment ............................................................................ 27 
10.4  Index Procedure Completion and Tissue Closure ................................................................. 27 
10.5  Post-Index Procedure/ Prior to Leaving Hospital ................................................................. 27 
11.0 FOLLOW-UP EVALUATIONS .................................................................................................. 27 
11.1  
Thirty (30) Days Post-Index Procedure Follow-Up Evaluation ....................... 28 
11.2  
One hundred eighty (180) Days Post-Index Procedure Follow-Up Evaluation
 ....................................................................................................................... 28 
11.3  
One (1) to Five (5) Year Post-Index Procedure Follow-Up Evaluation ........... 28 
11.4 Study Exit ............................................................................................................ 29 
12.0 SCHEDULE OF ASSESSMENTS & SUBJECT EVALUATIONS ............................................. 29 
13.0  ADVERSE EVENTS...................................................................................................... 30 
13.1  General Adverse Event Definitions ....................................................................................... 30 
Serious Adverse Device Effect (SADE) ......................................................................... 31 
Unanticipated Serious Adverse Device Effect (USADE) .............................................. 31 
13.2  Adverse Event Classification ................................................................................................. 31 
13.3  Events Expected to Occur with Index-Procedure ................................................................. 32 
13.4  Adverse Event Reporting Requirements .............................................................................. 33 
13.4.1  General Reporting Requirements (Non-Serious Adverse Events)................... 33 
13.4.2  Reporting Requirements (Serious & Unanticipated Adverse Events) ............. 33 
13.5  Patient Death ........................................................................................................................ 34 
13.6  Treatment Failures & Device Malfunctions .......................................................................... 34 
14.0  STUDY OVERSIGHT ................................................................................................... 34 
14.1  Independent Subject Screening Committee ......................................................................... 34 
14.2  Clinical Events Committee/Data Monitoring Committee (CEC/DMC) .................................. 35 
14.3  Core Laboratory .................................................................................................................... 35 
15.0  ADMINISTRATIVE RESPONSIBILITIES ......................................................................... 35 
15.1  Institutional Review Board (IRB)/ Ethics Committee (EC) Approval ..................................... 35 
15.2  Informed Consent ................................................................................................................. 36 
15.3  Confidentiality ...................................................................................................................... 36 
15.4  Data Monitoring and Quality Control ................................................................................... 37 
15.4.1  Training .......................................................................................................... 38 
15.4.2  Electronic Case Report Forms ........................................................................ 38 
15.4.3  Data Reporting ............................................................................................... 38 
15.4.4  Data Review ................................................................................................... 39 

 
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15.5  Record Maintenance ............................................................................................................ 39 
15.5.1  Records ........................................................................................................... 39 
15.5.2  Investigator Reports ....................................................................................... 40 
15.6  Investigator’s and Sponsor’s Annual and Final Reports ....................................................... 40 
15.7  Investigational Site Monitoring ............................................................................................ 40 
15.8  Deviations from Clinical Protocol and Medical Emergencies ............................................... 41 
15.9  Investigational Site Termination ........................................................................................... 41 
15.9.1   Monitoring Methods ...................................................................................... 41 
15.9.2 Monitoring Plan ............................................................................................... 41 
15.10 Medicare Coverage Related to Investigational Device Exemption (IDE) Studies ................. 42 
15.10.1 Release of Results .......................................................................................... 42 
15.11 Protocol Amendments ......................................................................................................... 42 
15.12 Quality Assurance and Auditing ........................................................................................... 42 
APPENDIX 1: ADVERSE EVENT DEFINITIONS ....................................................................... 43 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Protocol Synopsis 
Title 
An early feasibility study to assess safety and effectiveness of the transfemoral 
JenaValve Pericardial TAVR System in the treatment of patients with 
symptomatic severe aortic stenosis (AS) 
Study Objective 
The objective of this study is to evaluate the safety and effectiveness of the 
transfemoral JenaValve Pericardial TAVR System in a patient population with 
symptomatic severe AS requiring replacement of their native aortic valve that 
are at high risk for open surgical aortic valve replacement (SAVR). 
Study Design 
Prospective, multicenter, single arm feasibility study 
Study Devices  
The JenaValve Pericardial TAVR System contains the following 
subcomponents: a prosthetic transcatheter porcine pericardial aortic valve, 
19Fr introducer sheath system, transfemoral delivery catheter, and loading 
tool.   
Indications for 
Use 
The JenaValve Pericardial TAVR System is intended for use in patients with 
symptomatic, severe aortic stenosis (AS) who are at high risk for surgical 
aortic valve replacement (SAVR) and who meet all of the inclusion criteria 
outlined in this clinical protocol.   
The JenaValve Pericardial TAVR System is contraindicated for use in 
patients who have any of the exclusion criteria outlined in this clinical 
protocol. 
Number of 
Sites 
A maximum of 10 centers located in the United States; maximum of 8 centers 
in Germany for a total of  maximum of 12 centers in Europe, maximum of 3 
centers in NZ 
Number of 
Subjects 
A maximum of 40 subjects will be enrolled in the US, A maximum of 30 
subjects in the Netherlands, A maximum of 30 subjects in Germany, and a 
maximum of 30 subjects in New Zealand  
Population 
The study population will consist of subjects with severe symptomatic AS 
who are at high risk for SAVR and have a predicted risk of operative 
mortality ≥8%  at 30 days as assessed by the local heart team consisting of a 
minimum of 2 physicians (at least one interventional cardiologist and one 
cardiac surgeon). 
Inclusion 
Criteria 
1. Adult patients with severe degenerative native AS; as assessed by 
either resting or stress echocardiography: 
-  mean pressure gradient > 40 mmHg or peak jet velocity > 4.0 m/s; 
    AND 
 -  aortic valve area < 1.0 cm2;  OR 
 -  indexed aortic valve area < 0.6 cm2/m2 
2. Patient symptomatic according to NYHA functional class II or higher 
3. Patient at high risk for SAVR (STS ≥ 8% or if STS < 8%, a documented 
heart team agreement determines that significant co-morbidities are 

 
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not captured on STS), and heart team agrees that patient can undergo 
SAVR for “bail out”/to address unfavorable circumstances if necessary 
4. Patient has suitable anatomy to accommodate the insertion and 
delivery of the JenaValve delivery system 
5. Patient or the patient’s legal representative has provided written 
informed consent 
6. Patient or the patient’s legal representative agrees to comply with all 
required post-procedure follow-up visits 
Exclusion 
Criteria 
1. Congenital uni- or bicuspid aortic valve morphology 
2. Previous prosthetic aortic valve (bioprosthesis or mechanical) implant 
3. Mitral regurgitation > moderate 
4. Clinically significant coronary artery disease (CAD) requiring 
revascularization within 30 days prior to index procedure, or planned 
CAD revascularization procedure within 12 months after index 
procedure 
5. Echocardiographic evidence of left cardiac thrombus  
6. Endocarditis or other active infection 
7. Hypertrophic cardiomyopathy with or without obstruction 
8. Severe pulmonary hypertension (systolic PA pressure > 80 mmHg) or 
severe RV dysfunction (RV fractional area change <35%, or TAPSE < 16 
mm, or tissue Doppler S‘ <10) 
9. Very severely reduced left ventricular ejection fraction (LVEF <20%)  
10. Aortic annular diameter of  < 21 mm or > 27 mm (assessed by Multi-
detector CT measurement) 
11. Aortic annulus angulation > 60° (assessed by Multi-detector CT 
measurement) 
12. Straight length of ascending aorta of < 55 mm 
13. Significant disease of ascending aorta, including ascending aortic 
aneurysm (defined as maximal luminal diameter of 50 mm or greater) 
or atheroma (including if thick [>5 mm], protruding or ulcerated)  
14. Need for urgent or emergent TAVR procedure for any reason 
15. Cardiogenic shock or hemodynamic instability requiring inotropic 
support or ventricular assist device 
16. Myocardial infarction < 30 days prior to index procedure 
17. Cerebrovascular event (TIA, stroke) < 180 days prior to index 
procedure 
18. Severe renal insufficiency (GFR < 30 ml/min), OR renal disease 
requiring renal replacement therapy 
19. Blood dyscrasias as defined: leukopenia (WBC < 3000/mm³), or 
thrombocytopenia (platelets < 90,000/µl) or anemia (Men: Hgb < 8.1 
g/dl; Women: Hgb < 7.4 g/dl) 
20. Active peptic ulcer or upper gastrointestinal bleeding < 90 days prior to 
index procedure 

 
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21. Known hypersensitivity or contraindication to aspirin, heparin, 
ticlopidine or clopidogrel, nitinol, tantalum or allergy to contrast 
agents that cannot be premedicated 
22. Contraindication to intraoperative transesophageal echocardiography 
and/ or Multi-Detector CT (MDCT) scan 
23. Estimated life-expectancy of < 24 months  
24. Patient is enrolled in another investigational medical device or drug 
study, which has not completed the required primary endpoint follow-
up. (Note: Patients involved in a long-term surveillance phase of 
another study are eligible for enrollment in this study)  
25. Other medical, social, or psychological conditions that in the opinion of an 
Investigator precludes the patient from providing appropriate informed 
consent 
26. Severe dementia (resulting in either inability to provide informed consent 
for the trial/procedure, prevents independent lifestyle outside of a chronic 
care facility, or will fundamentally complicate rehabilitation from the 
procedure or compliance with follow-up assessments). 
27. Unable to comply with follow-up requirements 
Study 
Endpoints and 
Analyses  
Study endpoints are defined according to the standardized endpoint 
definitions for transcatheter aortic valve implantation as outlined in The 
Valve Academic Research Consortium-2 consensus document (i.e., VARC-
2). 
 
Primary Safety Endpoint 
All-cause Mortality at 30 days 
 
 
Performance Endpoints 
• 
Technical Success at exit from OR, hybrid room or cath lab post-index 
procedure (VARC-2) 
• 
Procedural Success at 1-month (VARC-2), consisting of: 
• 
Device Success at 1-month, 6-months, 1-year and annually thereafter for 
up to 5 years 
• 
Individual Patient Success at 1-year and annually thereafter up to 5 years 
• 
NYHA functional classification at discharge, 1-month, 6-months, 1-year, 
and annually thereafter for 5 years 
• 
6-minute walk test at 6 months, 1 year and annually thereafter for 5 years 
• 
Kansas City Cardiomyopathy Questionnaire at 1 year and annually 
thereafter for 5 years 
• 
Clinically acceptable hemodynamic performance and function as 
confirmed by Core Lab evaluation of echocardiography for the following 
parameters at discharge, 1-month, 6-months, 1-year, and annually 
thereafter for 5 years:  
  
 
 

 
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Schedule of Tests: 
 
 
Pre-procedural echocardiography (TEE or TTE) and a baseline multi-detector CT scan with Core 
Lab assessment are used to determine anatomical eligibility for enrollment. Following ethics 
committee/IRB approval and patient written informed consent, the patient will be screened for 
eligibility by heart teams. Final eligibility determination is made by an Independent Screening 
Committee evaluation of site screening records and Core Lab measurements/assessments. After 
the procedure, enrolled patients are to be followed immediately post- procedure, at hospital 
discharge, and then at 1 month, 6 months, 1 year; and annually thereafter for 5 years, listed in 
Schedule of Assessments Table below: 
 
Schedule of Assessments: 
Screen
ing/ 
Baseli
ne  
Proced
ure 
(Day 0) 
Pre-
Discha
rge 
1 
Mon
th 
6 
Mon
ths 
1- to 
5-
years  
Medical History including consent 
x 
 
 
 
 
 
STS Score 
x 
 
 
 
 
 
Targeted Physical Exam†  
x 
 
x 
x 
x 
x 
Laboratory Tests‡ 
x 
 
x 
x 
x 
x 
Pregnancy Testα 
x 
 
 
 
 
 

 
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Multi-detector CT Imaging ¥ 
x 
 
 
 
 
 
12 lead ECG / Rhythm Strip 
x 
 
x 
x 
x 
x 
Echocardiography (TTE or TEE) ¥ 
x 
x 
x 
x 
x 
x 
NYHA Classification 
x 
 
x 
x 
x 
x 
6 minute walk test (6MWT) 
x 
 
 
 
x 
x 
KCCQ 
x 
 
 
 
 
x 
Modified Rankin Scale & Mini Mental State 
Exam (MMSE) § 
x 
 
x 
x 
x 
x 
Cardiovascular Medications 
x 
x 
x 
x 
x 
x 
Adverse Events 
 
x 
x 
x 
x 
x 
† Physical exam includes overall health and physical assessment and vital signs.  
‡ Labs include a 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), creatinine, urine or serum albumin, C-reactive protein, 
plasma-free Hb, serum LDH or haptoglobin and cardiac biomarkers (troponin I or T or CK/CK-MB) will be assessed at 
baseline, discharge, 1 month, 6 months, 1 year and annually thereafter for 5 years.  
α Only for females of child bearing potential and performed within 72 hours prior to index procedure. 
¥ Imaging procedures performed within 1 year prior to index procedure may be used for baseline, unless otherwise 
indicated.  
§ Modified Rankin Scale is performed for each patient at baseline and at each follow-up interval thereafter until study 
completion. MMSE is performed at Screening/Baseline only unless subject experiences a stroke. 
Follow-up windows: ±7 days (1-month visit); ±30 days (6-month visit); ±2 months (1- to 5-Year visits). Screening tests 
with the exception of imaging procedures should be performed within 60 days of index procedure.  
 
 
 

 
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1.0  
INTRODUCTION 
 
The objective of this study is to evaluate the safety and effectiveness of the transfemoral JenaValve 
Pericardial TAVR System in treating subjects with symptomatic severe aortic stenosis requiring 
replacement of their native aortic valve; who are at high risk for open surgical aortic valve replacement 
(SAVR), by using a minimally invasive transcatheter aortic valve replacement (TAVR) procedure. 
The study protocol will ensure consistency in performing the procedure, patient management, 
and results of the procedure.  The results of this feasibility study shall be used to design a pivotal 
trial to support a PMA application for approval of the JenaValve Pericardial TAVR System for 
treatment of aortic stenosis. 
 
1.1  
Background on Aortic Stenosis and TAVR 
 
Degenerative aortic valve stenosis is the most common heart valve problem in adults in western 
industrialised nations (Iung, et al., 2003). Prevalence grows continuously as age increases such 
that, in view of growing life expectancy and demographic development, patients in their eighth 
and ninth decades of life are also particularly affected – representing a challenge for therapeutic 
management (Lindroos, Kupari, Heikkila, & Tilvis, 1993). Patients with aortic valve stenosis are 
asymptomatic until late in the course of disease. However, as soon as the first symptoms such as 
angina pectoris, syncope and dyspnoea occur, the prognosis is poor (Vahanian, et al., 2002). 
Clinical studies report a mortality rate of 25% in the first year and 50% in the second year after 
the onset of symptoms, despite drug-based therapy (Frank, Johnson, & Ross, 1973). 
 
Open surgical aortic valve replacement (SAVR) is the treatment of choice. Patients treated benefit 
from relief of symptoms and significant improvement in long-term survival (Schwarz, et al., 1982). 
The procedure is carried out under general anaesthesia via sternotomy and the use of 
extracorporeal circulation. Despite improved operating techniques and intensive care support 
afterwards, the operation represents a high-risk procedure in patients over the age of 75 with 
multiple co-morbidities (Bernard, et al., 1992). Concomitant diseases such as renal failure, 
pulmonary hypertension, heart failure or previous cardiac surgery can lead to a significant 
increase in peri-operative morbidity and mortality (Iung, et al., 2003) (Roques, et al., 1999) 
(Vaquette, et al., 2005). In view of the growing proportion of this patient group in the overall 
population, there is a growing demand for alternative methods for lesser invasive and potentially 
safer aortic heart valve replacement. 
 
1.2 
Background on Transcatheter Aortic Valve Replacement (TAVR) 
In this context, transcatheter aortic valve replacement (TAVR) was developed as a treatment 
option that enables implantation of a biological valve in a minimally invasive procedure without 
the need for sternotomy and extracorporeal circulatory support. Since the first percutaneous 
transluminal implantation of an aortic valve was carried out in humans in 2002, the procedure has 
been performed on more than 50 000 patients worldwide. (Piazza, et al., 2008) There are 
essentially two key access pathways via which the aortic valve prosthesis can be implanted: via 
antegrade access, a left lateral mini-thoracotomy is performed and the apex of the left ventricle 
is punctured with a cannula through which a stiff guidewire is inserted. A delivery catheter which 
encloses the valve prosthesis is inserted in over the wire technique and advanced through the left 
ventricle into the ascending aorta (transapical TAVR). Alternatively, the retrograde technique 
allows the implantation of the aortic valve prosthesis via transarterial access following puncture 

 
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of the iliofemoral artery. The delivery catheter which encloses the aortic valve prosthesis is 
advanced retrograde through the aorta into the aortic root (transfemoral TAVR). Patients with 
contraindications for transapical or transfemoral access can potentially be treated via subclavian 
or direct aortic access (Bauernschmitt, et al., 2009). 
 
Since the first implantation in 2002 a remarkable number of case studies, clinical trials and 
registries in TAVR were performed. To date, results from multiple randomized clinical trials 
comparing TAVR and SAVR are available in various risk levels. In the PARTNER trial, safety and 
effectiveness of the Edwards SAPIEN transcatheter aortic valve was evaluated. Cohort A 
compared TAVR with SAVR in patients with high operative risk. Cohort B compared TAVR to 
medical treatment in inoperable patients. Results for Cohort A were published in 2011 showing 
that TAVR is non-inferior to SAVR with respect to all-cause mortality at one year. (Smith, et al., 
2011) Results for Cohort B were published in 2010 already showing that TAVR significantly 
reduced all-cause mortality by nearly 50%, thus being superior to medical treatment in inoperable 
patients. (Leon, et al., 2010) In the CoreValve extreme risk trial, patients with symptomatic AS at 
extreme operative risk were randomized to either SAVR or TAVR using the CoreValve® 
(Medtronic, MN, USA). The rate of all-cause mortality at 12 months was significantly lower in the 
TAVR group when compared to the SAVR group. Current guidelines state that TAVR is an 
acceptable alternative to surgical AVR in selected operable high-risk patients, and that the benefit 
from TAVR greatly exceeds the risk in inoperable patients (Holmes, et al., 2012). Based on these 
convincing results TAVR has emerged as an accepted treatment option for high-risk patients with 
severe aortic stenosis. The SAPIEN (P100041/P110021), SAPIEN XT (P130009), SAPIEN 3 
(P140031), CoreValve and CoreValve Evolut R (P130021), and Lotus Edge (P180029) TAVR devices 
have obtained US FDA approval for treatment of patients with severe aortic stenosis who are at 
extreme or high risk for SAVR. Extended approvals for intermediate risk patients are available for 
some devices. 
 
According to a recent European registry including more than 4500 patients, 16.4% of all TAVR 
procedures were performed via the TA access route (Di Mario, Eltchaninoff, Moat, Goicolea, & et 
al., 2013). Besides the JenaValve TA TAVR system, which consists of a porcine aortic root mounted 
on a self-expandable Nitinol stent and the CathleteTM delivery system, four TA TAVR devices 
received CE mark: the SAPIEN XT/SAPIEN 3 (Edwards Lifesciences, CA, USA), Engager (Medtronic, 
MN, USA) and ACURATE TA (Symetis SA, Switzerland). In contrast to the JenaValve System, which 
can be deployed without rapid pacing, all four other TA systems rely on rapid pacing during 
deployment to minimize left ventricular output and stabilize the position of the valve prosthesis 
during deployment.  Of all devices mentioned above, the SAPIEN XT and SAPIEN 3 are the only 
balloon-expandable valve prostheses.  
 
The SAPIEN™/SAPIEN 3 as well as the ACURATE TA bioprosthesis anchor within the aortic root 
through active or passive expansion of the stent by transferring the force onto the wall of the 
aortic annulus or the ascending aorta. The prostheses are inserted, positioned and deployed 
under fluoroscopic control in order to avoid malpositioning with the risk of antegrade (into the 
aorta) or retrograde (into the left ventricle) embolization of the valve or obstructing the coronary 
ostia. The precise positioning and correct placement of the valve prosthesis is a demanding and 
crucial element in all catheter-based valve implantation techniques.  
 

 
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1.3  
JenaValve Device Concept 
JenaValve has developed a new system for transcatheter aortic valve replacement that differs 
from other available systems.  The JenaValve Pericardial TAVR 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 a 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 transapical or transfemoral access, the 
positioning locators are released under fluoroscopic control. By gently advancing (TF approach) 
or retracting (TA approach) the respective delivery system 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 
true anatomical positioning, the prosthesis is released and deployed stepwise.  Once the valve is 
unfolded by the self-expanding mechanism of the Nitinol stent, the native aortic valve cusps are 
fixed in between the locators and the rail (see Figure 1), thus defining correct height and position 
of the valve prosthesis. 
1.4 
JenaValve Device Preclinical Testing 
Preclinical animal testing of TAVR devices is challenging as there is no suitable animal model 
replicating the human anatomy of a diseased aortic valve. Thus, frequently used large animal 
models such as ovine or swine model have limitations to fully evaluate TAVR devices but 
nevertheless can provide valuable information about device performance, deliverability and valve 
functionality.  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 Pericardial TAVR System with very good hemodynamic valve 
performance post procedure. Results of chronic GLP 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.  
 
The positive in-vitro and in-vivo results with the JenaValve Pericardial TAVR System are a 
substantial base to justify the conduct of a clinical feasibility study with the JenaValve Pericardial 
TAVR System in patients who suffer from severe aortic stenosis and who are not considered 
suitable candidates to undergo surgical aortic valve replacement. 
 
1.5 
Prior Clinical Experience with JenaValve Device 
The JenaValve system was CE-Marked for treatment of aortic stenosis (AS) on September 30, 
2011, based on a multicenter, prospective, single arm trial conducted at seven (7) centers in 
Germany that enrolled 73 patients. This trial showed the JenaValve system was safe and effective 
in the treatment of severe AS in patients at high risk for surgery [Treede, et al., 2012].  A 
subsequent indication for treatment of aortic regurgitation (AR) in high surgical risk patients was 
granted CE Mark on September 16, 2013. [Seiffert, et al, 2014] A post-approval clinical registry, 
(the JUPITER Registry, NCT01598844) was conducted in Europe to continue the assessment of 
product performance in 180 patients with severe AS.  The interim results of the JUPITER study 

 
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were presented by Wendler at EuroPCR, Paris, France on May 20-23, 2014.  One-year results have 
been published (Silaschi et al. 2017). This study is now completed. 
JenaValve discontinued marketing the porcine aortic root valve in Europe in mid-2016 to focus 
development efforts on the pericardial valve and transfemoral delivery system.   
 
 
1.6 
Conclusion  
 
The positive in-vitro and in-vivo results with the JenaValve Pericardial TAVR System are a 
substantial base to justify the conduct of an early feasibility clinical study with the JenaValve 
Pericardial TAVR System in patients who suffer from severe aortic stenosis and who are not 
considered suitable candidates to undergo surgical aortic valve replacement. Based on the 
encouraging initial experiences, the Sponsor believes that a multi-center, prospective, feasibility 
study of a TAVR transfemoral approach for treatment of aortic stenosis is warranted. 
 
2.0 
DEVICE DESCRIPTION  
 
This study is investigating the JenaValve Pericardial TAVR System when used to perform 
transcatheter aortic valve repair (TAVR) for treatment of severe aortic stenosis.  The JenaValve 
Pericardial TAVR System consists of three (3) major components: 
• 
JenaValve Pericardial Transcatheter Heart Valve (THV) 
• 
JenaValve Pericardial Transfemoral (TF) Delivery Systems 
• 
JenaValve Pericardial Transfemoral (TF) Loading Tools 
 
Intended Use: The JenaValve Pericardial TAVR System is intended for use in patients with 
symptomatic, severe aortic stenosis (AS) who are at high risk for surgical aortic valve replacement 
(SAVR) and who meet all of the inclusion criteria outlined in this clinical protocol.   
The JenaValve Pericardial TAVR System is contraindicated for use in patients who have any of the 
exclusion criteria outlined in this clinical protocol. 
 
 
2.1  
JenaValve Pericardial Transcatheter Heart Valve (THV)  
 
The JenaValve Pericardial Transcatheter Heart Valve (Figure 1) 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 
Transfemoral (TF) Delivery System. 
 

 
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Figure 1: JenaValve Pericardial THV 
 
 
2.2 
JenaValve Pericardial Transfemoral (TF) Delivery System 
 
The JenaValve Pericardial Delivery Systems is designed to allow for a transfemoral approach using 
the JenaValve Pericardial Transfemoral (TF) introducer Sheath and its compatible Delivery 
Catheter.  The delivery system is designed to implant the JenaValve THV using percutaneous 
access.   
 
2.2.1 
JenaValve Coronatix™ Transfemoral (TF) Delivery Catheter & Introducer Sheath 
 
The JenaValve Coronatix™ Delivery Catheter delivers the THV transfemorally through the 
JenaValve Pre-Shaped 19Fr Introducer Sheath. 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 deployment), a 
Controller (to rotate the THV into the native aortic cusps), and (3) a Deployer (to release the THV 
from the catheter). The Transition Tube located on top of the Catheter protects the body of the 
THV during insertion into the Introducer Sheath hemostasis valve. After Delivery Catheter 
introduction and THV/Locator positioning, a safety clip placed on the catheter handle is removed 
to permit push-activated deployment of the THV inflow segment (Sealing Ring), followed by 
secondary push-activated deployment of the THV outflow segment (Eyelets). After deployment, 
the Delivery Catheter is retracted into the Introducer Sheath and removed. The Delivery Catheter 
is sterilized by ethylene oxide gas and is for single use only. 
 
The JenaValve Introducer Sheath System is comprised of a polymeric shaft Dilator and a 19Fr 
Introducer Sheath (22Fr outer profile), with a Pre-Shaped distal end and a proximal housing with 
a hemostatic seal. The Dilator accommodates guidewire diameters of 0.035”. The Introducer 
Sheath and Dilator are sterilized by ethylene oxide gas and are for single use only. 
 
The JenaValve Pericardial THV is crimped/loaded into the main delivery system at the time of the 
procedure using a dedicated loading tool. The delivery system has a steerable catheter handle 

 
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located at its proximal end which the physician can use to articulate the distal end of the catheter 
to properly “centralize” and position the locators of the THV as needed and is advanced through 
the pre-shaped introducer sheath until its tip exits the distal tip of the sheath. Once position is 
confirmed the pre-shaped sheath is retracted proximally to expose the JenaValve Pericardial THV 
in the ascending aorta. At this point, the locators are exposed and “open” for cusp/positioning 
placement. 
 
The JenaValve Pericardial THV is deployed via the main delivery system.  Upon confirmation of 
the correct locator position, the most proximal delivery handle is used to deploy the THV. 
Following THV deployment, the catheter is slowly withdrawn from the THV and brought into the 
pre-shaped sheath, and the entire assembly is removed from the patient as a unit. 
 
2.3 
JenaValve Pericardial Transfemoral (TF) Loading Tools 
 
JenaValve loading tools are available for the Transfemoral (TF) delivery system. The TF loading 
tool enables crimping and loading the THV into the delivery system. This is accomplished prior to 
insertion of the JenaValve Pericardial TAVR System into the body.  
 
The Loading Tool consists of a Core which comes in 3 different sizes to accompany each valve size 
(23, 25 and 27), and a Loading Tube, Cone and Wheel which are not size-dependent. The tool is 
ethylene oxide-sterilized and for single use only.  
 
2.4 
Product Identification 
Product identification is ensured for both the JenaValve Pericardial Transcatheter Heart Valve and 
the Delivery System. The THV can be identified by means of a model number and serial number. 
The delivery system components (introducer system, delivery catheter, and loading tool) are 
identified by lot numbers.  See Table 1 below for a list of Model numbers: 
 
Table 1: JenaValve Transfemoral Pericardial TAVR System Model Numbers 
Product Name 
Size 23 System 
Size 25 System 
Size 27 System 
JenaValve Everdur™ Pericardial Transcatheter 
Heart Valve 
JV-2000-PY23 
JV-2000-PY25 
JV-2000-PY27 
JenaValve Introducer Sheath System 
INTR000001 
JenaValve Coronatix™ Transfemoral Delivery 
Catheter 
CATH23TF01 
CATH25TF01 
CATH27TF01 
JenaValve Transfemoral Loading Tools 
LOAD23TF01 
LOAD25TF01 
LOAD27TF01 
*One complete system includes one (1) of each of system components listed in Table 1. 
 
3.0  
STUDY OBJECTIVE 
 
The objective of this study is to evaluate the safety and effectiveness of the transfemoral JenaValve 
Pericardial TAVR System in treating subjects with symptomatic severe aortic stenosis requiring 
replacement of their native aortic valve who are at high risk for open surgical aortic valve replacement 
(SAVR), using a minimally invasive transcatheter aortic valve replacement (TAVR) procedure. The 

 
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study protocol will ensure consistency in patient enrollment, procedural conduct, patient follow-
up, data management, and results reporting. Results obtained in this feasibility study and 
investigational plan are intended to support the design and initiation of a pivotal trial to support 
a future PMA application for approval of the JenaValve Pericardial TAVR System for treatment of 
aortic stenosis. 
 
4.0  
STUDY ENDPOINTS/OTHER DATA COLLECTION 
 
4.1 
Primary Endpoint 
The primary endpoint of the study is defined as All-Cause Mortality within the first 30 days post 
index procedure as adjudicated by the Clinical Events Committee/Data Monitoring Committee 
(CEC/DMC).  
Study endpoints are defined according to the standardized endpoint definitions for 
transcatheter aortic valve implantation as outlined in The Valve Academic Research Consortium-
2 consensus document (i.e., VARC-2). 
 
4.2 
Performance Endpoints 
Performance endpoints are defined as below and measured at time points specific to each 
endpoint: 
1. Technical Success at exit from OR, hybrid room or cath lab post-index procedure: 
• 
Absence of procedure mortality; and 
• 
Successful access, delivery and retrieval of transcatheter delivery system; and 
• 
Deployment and correct positioning of a single intended THV; and 
• 
Freedom from re-intervention related to the device or access  
 
2. Procedural Success at 1-month (VARC-2), consisting of: 
o Device success at 30 days; and 
o No device- or procedure-related serious adverse events  
 
3. Device Success at 1-month, 6-months, 1-year and annually thereafter for up to 5 years, 
consisting of: 
• 
Absence of procedure mortality; and 
• 
Correct position of a single prosthetic heart valve in the proper anatomic location 
• 
Intended performance of the prosthetic heart valve:  
• 
mean aortic valve gradient <20 mmHg or peak velocity <3 m/s; and  
• 
no moderate or severe prosthetic valve regurgitation 
4. Individual Patient Success at 1-year and annually thereafter for up to 5 years, consisting of: 
o Device and Procedural Success (as defined above); and, 
o No re-hospitalizations or re-interventions for the underlying condition (e.g., aortic 
stenosis) 
o Improvement vs. baseline in symptoms (e.g., NYHA Class improvement >1 from 
baseline, or NYHA Class < III or IV) 
o Improvement vs. baseline in functional status (e.g., 6MWT improvement > 50 feet from 
baseline) 

 
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o Improvement vs. baseline in Quality of Life (QoL) (e.g., KCCQ improvement > 10 from 
baseline)   
5. NYHA functional classification at discharge, 1-month, 6-months, 1-year, and annually thereafter 
for 5 years 
6. 6-minute walk test at 6-months, 1 year and annually thereafter for 5 years 
7. Kansas City Cardiomyopathy Questionnaire at 1 year and annually thereafter for 5 years 
8. Clinically acceptable hemodynamic performance and function as confirmed by Core Lab 
evaluation of echocardiography for the following parameters at discharge, 1-month, 6-months, 
1-year, and annually thereafter for 5 years:  
 
4.3 
Additional Analyses  
 
4.3.1 
Safety  
 
The incidence of the following as determined by the Clinical Events Committee will be assessed 
at 1-month, 6-months, 1-year, and annually thereafter for 5 years: 
A. Mortality 
B. Myocardial Infarction 
C. Neurological Complications 
D. Bleeding Complications 
• Life-threatening or disabling (including fatal) 
• Major bleeding 
• Minor bleeding 
E. Acute Kidney Injury (AKIN classification as Stage 1, Stage 2, or Stage 3, ≤7 days post-index 
procedure) 
F. Vascular Complications  
• Minor 
• Major 
• Percutaneous device closure failure 
G. Conduction Disturbances and Arrhythmias 
H. Other TAVR-Related Complications 
 
4.3.2 
Other Data 
Blood laboratory data includes 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), creatinine, urine or serum albumin, C-reactive protein, plasma-free Hb, serum LDH 
or haptoglobin and cardiac biomarkers (troponin I or T or CK/CK-MB) will be assessed at baseline, 
discharge, 1 month, 6 months, 1 year and annually thereafter for 5 years.  
 
5.0  
STUDY DESIGN 
 
This is a prospective, multicenter, single-arm, feasibility study evaluating the safety and 
effectiveness of transcatheter aortic valve replacement utilizing the JenaValve Pericardial TAVR 
System for the treatment of aortic stenosis.   
 

 
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A maximum of 40 subjects will be enrolled in the US, a maximum of 30 subjects in the Netherlands, 
a maximum of 30 subjects in Germany, and a maximum of 30 subjects in New Zealand. A maximum 
of 10 centers in the United States,  8 centers in Germany for a maximum of 12 centers in Europe, 
and a maximum of 3 centers in New Zealand will participate in the study. The duration of the study 
is estimated at approximately 72 months total, for the period spanning enrollment (estimated at 
approximately 12 months) through completion of 2 year follow up in Germany, The Netherlands, 
and New Zealand and through 5 year follow-up in the United States. 
 
The data from this study shall be utilized to design a future pivotal clinical trial. Other data 
collected from this study will also be considered in the development of the TAVR treatment for 
aortic stenosis. 

 
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6.0  
STATISTICAL METHODS 
 
6.1  
General 
 
Descriptive summaries will be the basis of study reports to generate an overall summary of the 
safety and effectiveness of the transcatheter aortic valve replacement utilizing the JenaValve 
Pericardial TAVR System for the treatment of aortic stenosis. Continuous outcome variables will 
be analyzed as means and standard deviations with 95% confidence intervals, as well as medians 
and ranges. For categorical outcome variables, relative frequencies will be determined.  
Descriptive tables will be produced for baseline characteristics including demographics, medical 
history, operative characteristics, and procedural outcomes, adverse events, physical exams, 
laboratory assessments, and hemodynamic variables.  
 
6.1.1 
Analysis of Endpoints 
 
Exact binomial confidence interval will be provided for all endpoints measured within the first 30 
days. Supplemental Kaplan-Meier event rates (95% CI) will be presented for time-to event 
outcomes at 30 days, 180 days, 1 year, and annually thereafter for 5 years. Time is calculated from 
index procedure to first event. Subjects who did not experience an event will be censored to the 
most recent follow up visit or withdrawal date.    
 
The clinical outcomes measured by the NYHA, 6MWT, and KCCQ, are treated as continuous 
outcomes. The raw value and change from baseline at each time point will be analysed by 
repeated measures methodology. Only actual data will be used in this analysis. Note that for 
patients who are unable to perform the 6MWT, due to a medical reason will be considered to 
have walked an actual distance of zero. 
 
6.1.2 
Other 
 
Reasonable efforts will be made to obtain complete data for all subjects; however, missing 
observations may occur due to subjects lost to follow-up or noncompliance with required 
assessments. Any missing data on study endpoints will be described. Adjustments for missing 
endpoint data will be performed only if deemed necessary and will be described completely.  In 
the case of evidence showing systematic patterns of missing data (“informative” missing data), 
alternative strategies for analyzing the data, depending on the pattern of the missing, will be 
investigated.  Secondary sensitivity analyses will be considered if necessary, and may include an 
analysis using multiple imputations for missing observations and an analysis in which all missing 
observations are considered failures. 
 
Statistical analyses will be performed using SAS/STAT software, Version 9.2 or higher of the SAS 
System for Windows.   
 
Patient confidentiality will be protected at all times, and patient identifiers will not be included in 
study summaries.  
 
 
 

 
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6.2  
Sample Size Justification 
 
This study is a single-arm, multicenter, prospective early feasibility study that is exploratory in 
nature. A maximum of 40 subjects will be included in the US, a maximum of 30 subjects in the 
Netherlands, a maximum of 30 subjects in Germany, and a maximum of 30 subjects in New Zealand 
 
 
6.3  
Analysis Populations 
 
6.3.1 
Screening Population  
 
Subjects who sign the consent form but are not deemed as eligible are considered screen failures. 
Should a subject be a screen failure, the reason for failure will be documented, and the subject 
will be exited from the study.    
 
Eligible, consenting subjects will be considered to be “Enrolled” in the study upon entering the 
procedure room. Intent-to-Treat (ITT) subjects are those who enter the study procedure room, 
regardless of whether they receive the study device or not. See section 6.3.2. Implanted subjects 
are those who receive the study device. See section 6.3.3. 
 
Serious adverse events will be reported for all enrolled (Intent-to-Treat and Implanted) subjects 
from enrollment through the time of study exit.  
 
6.3.2 
Intent-to-Treat (ITT) Population 
 
The Intent-to-Treat (ITT) population will consist of all subjects who have signed the ICF and 
entered the interventional suite, regardless of whether the study THV implantation was 
attempted or not attempted for whatever reason. Subjects in this population in whom the THV 
deployment is not attempted will be followed for safety purposes through 30 days or until all 
serious adverse events experienced by subject are resolved. Endpoint analyses will not be 
performed on the entire ITT population.  Safety reporting will include a report on this population. 
 
6.3.3 
Implanted Population 
 
The Implanted population will consist of any subjects that receive treatment with the JenaValve 
Pericardial TAVR System, where treatment is defined as successful THV implantation. The 
implanted population represents the Primary Analysis population for this study. 
 
 
6.4 
Final Analyses 
 
All final study analyses will be performed when all implanted subjects have completed the 5 year 
follow-up visit. 
 
6.5 
Reports for Safety 
 

 
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The Independent Clinical Events Committee/Data Monitoring Committee (CEC/DMC) will conduct 
interim safety reviews per the Charter.  Information will be provided to the CEC/DMC for review, 
but no formal analyses will be completed. 
 
7.0 
SUBJECT POPULATION AND SELECTION 
 
7.1 
Subject Population 
 
Adult subjects who have been diagnosed with aortic stenosis who are at high risk for SAVR as 
assessed by the local heart team will be considered for enrollment. A maximum of 40 subjects will 
be included in the study who will receive the JenaValve THV. Eligible, consenting subjects will be 
considered to be “Enrolled” in the study upon entering the procedure room. Subjects enrolled 
and receive treatment with the JenaValve Pericardial TAVR System, where treatment is defined 
as successful THV implantion is considered the implantation cohort. This implanted cohort t) 
represents the Primary Analysis population for this study.   
 
Subjects that sign the ICF, but are found ineligible during the screening process will be considered 
screen failures and will be exited from the study at that time. Subjects in the “enrolled” population 
(Intent-to-Treat and Implanted) will have a subject ID number assigned in the electronic data 
capture (EDC) system. Those subjects that sign the ICF, enter the interventional suite, including 
those in whom the THV implantation is not attempted for whatever reason will be followed 
through the 30 day follow-up visit to assess safety, until serious adverse events experienced by 
subject are resolved, whereupon their participation in the study is complete. Protocol-specified 
tests are not required on subjects who did not receive the study device (i.e. implanted with 
commercial Transcatheter valve or surgical aortic valve replacement), however, baseline and 
operative data will need to be entered in the EDC for these subjects.   
 
Subjects that sign the ICF, enter the interventional suite and receive treatment with the JenaValve 
Pericardial TAVR System, where Treatment is defined as successful attempt with JenaValve THV 
will be followed through to the 5-year follow-up visit, whereupon their participation in the study 
is complete.   
 
 
7.2  
Inclusion Criteria 
 
1. Adult patients with severe degenerative native AS as assessed by either resting or stress 
echocardiography: 
      -  mean pressure gradient > 40 mmHg or peak jet velocity > 4.0 m/s; 
    AND 
       -  aortic valve area < 1.0 cm2;  OR 
       -  indexed aortic valve area < 0.6 cm2/m2 
2. Patient symptomatic according to NYHA functional class II or higher 
3. Patient with high risk for SAVR (STS ≥ 8% or if STS < 8%, a documented heart team 
agreement determines that significant co-morbidities are not captured on STS), and heart 
team agrees that patient can undergo SAVR for “bail out”/to address unfavorable 
circumstances if necessary 

 
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4. Patient has suitable anatomy to accommodate the insertion and delivery of the JenaValve 
delivery system 
5. Patient or the patient’s legal representative has provided written informed consent 
6. Patient or the patient’s legal representative agrees to comply with all required post-
procedure follow-up visits 
 
7.3  
Exclusion Criteria 
 
1. Congenital uni- or bicuspid aortic valve morphology 
2. Previous prosthetic aortic valve (bioprosthesis or mechanical) implant 
3. Mitral regurgitation > moderate 
4. Clinically significant coronary artery disease (CAD) requiring revascularization within 30 days 
prior to index procedure, or planned CAD revascularization procedure within 12 months 
after index procedure 
5. Echocardiographic evidence of left cardiac thrombus 
6. Endocarditis or other active infection 
7. Hypertrophic cardiomyopathy with or without obstruction 
8. Severe pulmonary hypertension (systolic PA pressure >80 mmHg) or severe RV dysfunction 
(RV fractional area change <35%, or TAPSE < 16 mm, or tissue Doppler S‘ <10) 
9. Very severely reduced left ventricular ejection fraction (LVEF <20%)  
10. Aortic annular diameter of less than 21 mm or more than 27 mm (assessed by Multi-
detector CT (MDCT) measurement) 
11. Aortic annulus angulation >60° (assessed by Multi-detector CT measurement) 
12. Straight length of ascending aorta of < 55 mm 
13. Significant disease of ascending aorta, including ascending aortic aneurysm (defined as 
maximal luminal diameter of 50 mm or greater) or atheroma (including if thick [>5 mm], 
protruding or ulcerated)  
14. Need for urgent or emergent TAVR procedure for any reason 
15. Cardiogenic shock or hemodynamic instability requiring inotropic support or ventricular 
assist device 
16. Myocardial infarction < 30 days prior to index procedure 
17. Cerebrovascular event (TIA, stroke) < 180 days prior to index procedure 
18. Severe renal insufficiency (GFR < 30 ml/min), OR renal disease requiring renal replacement 
therapy 
19. Blood dyscrasias as defined: leukopenia (WBC < 3000/mm³), thrombocytopenia (platelets < 
90,000/µl) or anemia (Men: Hgb < 8.1 g/dl; Women: Hgb < 7.4 g/dl)  
20. Active peptic ulcer or upper gastrointestinal bleeding < 90 days prior to index procedure 
21. Known hypersensitivity or contraindication to aspirin, heparin, ticlopidine or clopidogrel, 
nitinol, tantalum or allergy to contrast agents that cannot be premedicated 
22. Contraindication to intraoperative transesophageal echocardiography and/ or MDCT 
23. Estimated life-expectancy of < 24 months  
24. Patient is enrolled in another investigational medical device or drug study, which has not 
completed the required primary endpoint follow-up. (Note: Patients involved in a long-term 
surveillance phase of another study are eligible for enrollment in this study)  

 
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25. Other medical, social, or psychological conditions that in the opinion of an Investigator precludes 
the patient from providing appropriate informed consent 
26. Severe dementia (resulting in either inability to provide informed consent for the 
trial/procedure, prevents independent lifestyle outside of a chronic care facility, or will 
fundamentally complicate rehabilitation from the procedure or compliance with follow-up 
assessments). 
27. Unable to comply with follow-up requirements 
 
7.4 
Subject Screening 
 
Adult subjects who have been diagnosed with aortic stenosis and who are at high risk for SAVR 
will be screened for eligibility. All subjects screened for the study will be listed on the site’s 
Screening Log.  The log will capture the subject’s gender, age, date of screening and the reason(s) 
for study exclusion. 
 
7.5 
Informed Consent Procedures 
 
Written Informed Consent must be obtained for all subjects who are potential study candidates 
before any study specific tests or procedures are performed.  
 
The general process for obtaining informed consent is as follows: 
• 
Ensure that the principal investigator or his/her authorized designee conducts the 
informed consent process; 
• 
Include all aspects of the clinical investigation 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 clinical investigation; 
• 
Include personally dated signatures of the subject/subject’s legal representative and the 
principal investigator/authorized 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 clinical investigation. 
 
7.6 
Subject Discontinuation/Withdrawal Criteria 
 
Once the subject has been enrolled in the study, she/he may withdraw her/his consent to 
participate in the study at any time without prejudice.  Participation in this clinical investigation is 
entirely voluntary. Likewise, there may be a reason identified by the Investigator that deems the 
subject no longer suitable for the study. In either case, the Investigator should contact the Sponsor 
to discuss the circumstances for discontinuation/withdrawal. Reasons for discontinuation or 
withdrawal may include, but are not limited to the following:   

 
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• 
Subject is uncooperative with compliance of required study tests, medical management 
and/or procedures for two (2) or more consecutive follow-up visits; 
• 
Investigator determines that subject has developed a condition in which continued 
participation in the study is considered potentially harmful to the subject; 
• 
Subject withdraws their consent; 
• 
Subject is lost to follow-up; 
• 
Subject incorrectly enrolled in the study; or 
• 
The Sponsor terminates the study 
 
7.6.1 
Data collection and Follow-Up for Discontinued/Withdrawn Subjects 
 
All “implanted” subjects in the study are considered eligible for follow-up and will be followed per 
the assessment schedule outlined in Table 2 (Section 12.0).  Subjects may withdraw at any time 
from the clinical trial without jeopardy or prejudice. If a subject terminates from the study, the 
reason for study termination will be recorded.  If termination is a result of adverse event or death, 
an Adverse Event Form will also be completed. Subjects who withdraw consent after treatment 
will not be required to undergo follow-up after withdrawal, but will still be considered part of the 
study cohort.   
 
Every attempt will be made to conduct an exit/final visit prior to a subject terminating from the 
study. The reason for early discontinuation will be documented in the source documents and 
electronic case report forms (eCRF). 
 
 
 
7.7 
Subjects Lost to Follow-Up 
 
All reasonable efforts (at least 3 contact attempts via phone/email or 2 registered letters) will be 
made to obtain complete data for all subjects, before they are considered lost to follow-up.  
Missing observations may occur due to subjects who are lost to follow-up, or demonstrate 
noncompliance with the required assessments.   
 
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: 
• 
Signed Informed Consent  
• 
Medical History 
• 
Cardiovascular Medications 
• 
STS Score 
• 
Targeted Physical Exam (including vital signs) 
• 
12 lead ECG / rhythm strip 
• 
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), creatinine, urine or serum albumin, C-reactive protein, plasma-free Hb, 
serum LDH or haptoglobin and cardiac biomarkers (troponin I or T or CK/CK-MB) 
• 
Echocardiography (TTE or TEE) 

 
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• 
Multidetector CT Scan Imaging 
• 
NYHA Class 
• 
MMSE (Mini Mental State Exam) 
• 
Modified Rankin Scale (mRS) 
• 
INR for subjects on vitamin-K antagonist anticoagulation therapy 
• 
6-minute walk test (6MWT) 
• 
Kansas City Cardiac Questionnaire (KCCQ) 
 
The procedures required for screening and baseline may be conducted during more than one visit, 
provided that procedures are conducted within 60 days prior to index procedure, unless 
otherwise noted. Appropriately acquired imaging studies (baseline multidetector CT scans and 
Echocardiograms) performed within 1 year of the index procedure may be used. 
 
9.0 
INDEX PROCEDURE- GENERAL DESCRIPTION 
 
The TAVR procedure will be performed in a minimally invasive manner, using a transfemoral 
approach to deliver and deploy the THV. 
 
Note: Refer to the Instructions for Use (IFU) for the device for complete details on device 
preparation and use. 
 
The following data must be collected during the index procedure assessment period: 
• 
Transesophageal Echo (TEE) 
• 
Procedural details   
• 
Adverse Event Assessment 
• 
Anticoagulation/antiplatelet therapy administered intra-procedure 
 
The index TAVR procedure may be performed in a standard operating room, hybrid operating 
room, or cardiac catheterization lab. In any of these settings emergency equipment and resources 
including adequate blood products, external defibrillator paddles, proper anesthesia 
administration, and monitoring capabilities must be available.   
 
Note: A recommended technique is presented in the following sections. It is recognized that 
individual patient anatomic variation or surgical/interventional conditions may necessitate 
modifications to the outlined procedures. However, to the extent possible, physicians should 
adhere to the procedure steps. Unless a modification to the procedures outlined below is required 
for anatomic or surgical/interventional reasons, it will be considered a protocol deviation. 
 
 
10.0 
INDEX PROCEDURE THROUGH DISCHARGE 
 
10.1 
Antithrombotic Therapy 
To protect subjects from bleeding or thromboembolic events, a recommended process for 
antithrombotic therapy based on AHA/ACC 2014 guidelines [Nishimura, et al., 2014] is provided 
below.  Investigators may utilize their institutional procedures for anticoagulation/antiplatelet 

 
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therapy, in recognition of various agents available as well as individual patient factors such as 
CHA2DS2-VASC score. 
 
10.1.1 During Index TAVR Procedure  
• 
Time of Heparin administration must be recorded 
• 
IV unfractionated heparin with a target minimum ACT ≥ 250-300 seconds 
• 
ACT of >250 should be documented prior to guidewire placement  
• 
The ACT should be measured at least every 30 minutes, starting 5 minutes after 
heparin administration. Additional heparin should be administered if the ACT is <250.  
The additional ACT should also be measured starting 5 minutes after every heparin 
administration. The most recent ACT should be measured and documented every 30 
minutes. 
 
The JenaValve Introducer System should be inserted only after the ACT is verified to be >250-300 
seconds, and the delivery catheter is loaded and ready for use. 
 
10.1.2 Post-Index TAVR Procedure 
• 
Aspirin 75 – 100 mg daily by mouth, indefinitely 
• 
Clopidogrel 75 mg daily by mouth, for 6 months  
• 
If oral anticoagulation is indicated, no clopidogrel should be given 
 
To monitor anticoagulation for patients on vitamin-K antagonists, International Normalized Ratio 
(INR) should be measured at each follow up visit. Additional INR testing may be performed 
according to institutional practice or the physician’s discretion. 
 
10.2  
Patient Preparation in Procedure Room 
 
The patient is prepped and draped so that the interventionalist/cardiac surgeon has access to the 
entire left lateral thorax, the sternum, and both groin areas.   
 
Non-sterile, external defibrillator pads are placed behind the right shoulder and on the left flank, 
away from femoral insertion sites.  Alternatively, if sterile external defibrillator pads are available, 
one can be placed over the sternum and one directly posterior on the back of the patient.  
 
General anesthesia or conscious sedation is induced and the patient ventilated according to 
institutional practices.   
 
10.3 
Implantation Procedure  
 
A femoral access for diagnostic intervention is performed in standard technique. Via a 
percutaneous vascular sheath a pigtail catheter is advanced into the left ventricle which is used 
for hemodynamic measurements and angiographic control.  Aortography of the aortic root using 
different planes is performed at the beginning of the procedure to determine the aortic valve 
plane, the plane of alignment of the aortic cusps, and to identify the course of the coronary 
arteries.Transesophageal echocardiography (TEE) will also be used during the implantation 
procedure. 
 

 
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Through venous femoral access, a temporary pacemaker lead is inserted into the right ventricular 
cavity, to allow reliable rapid pacing during balloon valvuloplasty (BAV). Pre-BAV is performed 
through a separate sheath; see Instructions for Use (IFU) for detailed procedural 
information. Balloon valvuloplasty is performed as applicable per IFU, then the JenaValve 
Pericardial TAVR System prepared, delivered, and deployed per the transfemoral IFU. 
 
Note: After implant of the JenaValve THV, the serial number associated with the THV should be 
recorded on the supplied Implant Card. The completed Implant Card is to be provided to the patient 
prior to discharge. 
 
10.3.1 THV Prosthesis Assessment 
 
After deployment the valve function is assessed by angiography and echocardiography.   
 
10.4  
Index Procedure Completion and Tissue Closure  
 
Once all maneuvers are complete, catheters and sheaths are withdrawn.  Catheter insertion site 
hemostasis and dressings should be performed according to institutional techniques.   
 
The patient is awakened and extubated, at the discretion of the interventionalist(s) in consultation 
with the anesthesiologist, if general anesthesia was used. The patient is transferred to the 
recovery area.   
 
10.5  
Post-Index Procedure/ Prior to Leaving Hospital 
 
The following items will be recorded post–index procedure, or anytime prior to discharge but no 
more than 10 days post-procedure (i.e. in case of prolonged hospitalization). 
• 
Cardiovascular Medications 
• 
Targeted Physical Exam (including vital signs)  
• 
12 lead ECG / rhythm strip 
• 
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), creatinine, urine or serum albumin, C-reactive protein, plasma-free Hb, 
serum LDH or haptoglobin and cardiac biomarkers (troponin I or T or CK/CK-MB) 
• 
Echocardiography (TTE or TEE) including assessment of THV function 
• 
NYHA Class 
• 
Adverse Events 
• 
Modified Rankin Scale (mRS) 
 
 
 
11.0 
FOLLOW-UP EVALUATIONS 
 
Follow-up evaluations will be scheduled for 1 month, 6 months, 1 year, and annually thereafter 
for 5 years after the index procedure. Thereafter, the patient exits the study and is to be followed 
per institutional requirements for patients with transcatheter aortic valves.  
 

 
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11.1  
Thirty (30) Days Post-Index Procedure Follow-Up Evaluation 
 
A follow-up evaluation will be scheduled for 30 days post-index procedure (± 7 days).  The 
following assessments will be performed: 
• 
Cardiovascular Medications 
• 
Targeted Physical Exam (including vital signs) 
• 
12 lead ECG / rhythm strip 
• 
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), creatinine, urine or serum albumin, C-reactive protein, plasma-free Hb, 
serum LDH or haptoglobin and cardiac biomarkers (troponin I or T or CK/CK-MB) 
• 
Echocardiography (TTE or TEE) including assessment of THV function 
• 
NYHA Class 
• 
Adverse Events 
• 
Modified Rankin Scale (mRS) 
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.   
 
11.2  
One hundred eighty (180) Days Post-Index Procedure Follow-Up Evaluation 
 
A follow-up evaluation will be scheduled for 180 days post-index procedure (± 30 days).  The 
following assessments will be performed: 
• 
Cardiovascular Medications 
• 
Targeted Physical Exam (including vital signs) 
• 
12 lead ECG / rhythm strip 
• 
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), creatinine, urine or serum albumin, C-reactive protein, plasma-free Hb, 
serum LDH or haptoglobin and cardiac biomarkers (troponin I or T or CK/CK-MB) 
• 
Echocardiography (TTE or TEE) including assessment of THV function 
• 
NYHA Class 
• 
Adverse Events 
• 
6 minute walk test 
• 
Modified Rankin Scale (mRS) 
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.   
 
11.3  
One (1) to Five (5) Year Post-Index Procedure Follow-Up Evaluation 
 
A follow-up evaluation will be scheduled for 1 year post-index procedure (± 60 days).  The 
following assessments will be performed: 
• 
Cardiovascular Medications 
• 
Targeted Physical Exam (including vital signs) 
• 
12 lead ECG / rhythm strip 

 
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• 
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), creatinine, urine or serum albumin, C-reactive protein, plasma-free Hb, 
serum LDH or haptoglobin and cardiac biomarkers (troponin I or T or CK/CK-MB) 
• 
Echocardiography (TTE or TEE) including assessment of THV function 
• 
NYHA Class 
• 
Adverse Events 
• 
6 minute walk test 
• 
Kansas City Cardiomyopathy Questionnaire (KCCQ) 
• 
Modified Rankin Scale (mRS) 
 
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 Study Exit 
 
If the patient exits the study prior to completing the required assessments, the Study Exit CRF 
must be completed.  
 
12.0 SCHEDULE OF ASSESSMENTS & SUBJECT EVALUATIONS 
 
Evaluation of subjects enrolled in this study will include all tests and procedures listed in the 
Schedule of Assessments as outlined in Table 2 below.   
 
Table 2: Schedule of Assessments 
Pre-procedural echocardiography (TEE or TTE) and a baseline multi-detector CT scan with Core Lab 
assessment are used to determine anatomical eligibility for enrollment. Following ethics committee/IRB 
approval and patient written informed consent, the patient will be screened for eligibility by heart teams. 
Final eligibility determination is made by an Independent Screening Committee evaluation of site 
screening records and Core Lab measurements/assessments. After the procedure, enrolled patients are to 
be followed immediately post- procedure, at hospital discharge, and then at 1 month, 6 months, 1 year; 
and annually thereafter for 5 years listed in Schedule of Assessments Table below: 
 
Schedule of Assessments: 
Screening/ 
Baseline  
Procedure 
(Day 0) 
Pre-
Discharge 
1 
Month 
6 
Months 
1- to 5-
years 
annually 
Medical History including 
consent 
x 
 
 
 
 
 
STS Score 
x 
 
 
 
 
 
Targeted Physical Exam†  
x 
 
x 
x 
x 
x 
Laboratory Tests‡ 
x 
 
x 
x 
x 
x 
Pregnancy Testα 
x 
 
 
 
 
 

 
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Multi-detector CT Imaging ¥ 
x 
 
 
 
 
 
12 lead ECG / Rhythm Strip 
x 
 
x 
x 
x 
x 
Echocardiography (TTE or 
TEE) ¥ 
x 
x 
x 
x 
x 
x 
NYHA Classification 
x 
 
x 
x 
x 
x 
6 minute walk test (6MWT) 
x 
 
 
 
x 
x 
KCCQ 
x 
 
 
 
 
x 
Modified Rankin Scale & 
Mini Mental State Exam 
(MMSE) § 
x 
 
x 
x 
x 
x 
Cardiovascular Medications 
x 
x 
x 
x 
x 
x 
Adverse Events 
 
x 
x 
x 
x 
x 
† Physical exam includes overall health and physical assessment and vital signs.  
‡ Labs include a 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), creatinine, urine or serum albumin, C-reactive protein, 
plasma-free Hb, serum LDH or haptoglobin and cardiac biomarkers (troponin I or T or CK/CK-MB) will be assessed at 
baseline, discharge, 1 month, 6 months, 1 year and annually thereafter for 5 years.  
α Only for females of child bearing potential and performed within 72 hours prior to index procedure. 
¥ Imaging procedures performed within 1 year prior to index procedure may be used for baseline, unless otherwise 
indicated.  
§ Modified Rankin Scale is performed for each patient at baseline and at each follow-up interval thereafter until study 
completion. The MMSE is performed at Screening/Baseline only unless the subject experiences a stroke 
Follow-up windows: ±7 days (1-month visit); ±30 days (6-month visit); ±2 months (1- to 5-Year visits) 
Note: Screening tests with the exception of imaging procedures should be performed within 60 days of index procedure.  
 
 
All testing should be conducted at the investigational site. Follow-up testing may be performed at 
another site only if it is not possible for the patient (or the patient refuses) to return to the 
investigational site.  In such cases, the Investigator may arrange for the study-required testing to 
be completed by the patient’s local physician.  However, it remains the responsibility of the study 
Investigator to ensure collection of appropriate information.  Copies of source documents from 
the local physician must be obtained and kept in the patient’s study file. 
 
13.0  
ADVERSE EVENTS 
 
TAVR procedures to treat aortic stenosis 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 

 
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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 hospitalization, or 
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)1 
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 by relationship to the investigational device, index procedure, 
concomitant medications, pre-existing condition, intercurrent condition, intercurrent intervention, 
or other. 
 
Investigational Device Related Adverse Event: An adverse event, which in the judgment of the 
Investigator, results from use of the JenaValve Pericardial TAVR System. 
 
Procedure Related Adverse Event: An adverse event which, in the judgment of the Investigator, 
results as a consequence of the index 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 
 
 
1 Equivalent to unanticipated adverse device effect (UADE).  Refer to Section 13.4.2 of this document for 
further details.   

 
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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.   
 
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 Sponsor, or its designee, in cooperation with the Investigator, will assess all serious adverse 
events considered device-related for potential reportability to the FDA 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 study, the following events are not considered reportable adverse events 
because they are normally expected to occur in conjunction with treatment of Aortic Stenosis 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 
• 
Pre - Planned future Surgical Procedures 
• 
Low grade temperature increase (101F or 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   
• 
Post-operative hematocrit decrease from baseline, not associated with hemodynamic 
changes, remaining above 25% and requiring < 2 units PRBC’s 

 
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• 
Minor, localized tenderness, swelling, induration, oozing, etc. at surgical site 
• 
Sinus bradycardia/tachycardia that does not require treatment or intervention 
• 
Trace/trivial or mild paravalvular or transvalvular leak not requiring 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     
• 
Atelectasis: collapse of lung tissue affecting part or all of one lung; the alveoli are deflated 
(not considered to be an AE unless treatment other than Chest PT is required or it prolongs 
hospitalization) 
• 
Hyperglycemia: The use of insulin in the post op period does not constitute hyperglycemia if 
during the same hospitalization. An elevated blood sugar of less than 250 mg/dl during the 
first 48 hours post op does not constitute hyperglycemia  
• 
Pleural effusion unless treatment with thoracentesis or chest tube insertion is required  
• 
Pericardial effusion without hemodynamic compromise or treatment  
• 
Atrial Fibrillation / Atrial Flutter / Atrial Tachycardia with or without cardioversion 
 
This listing of events is intended to provide guidance to the investigational sites for the purpose 
of adverse event reporting. The Investigator at the investigational site should utilize his/her own 
clinical judgment in evaluating adverse experiences, and may decide that the above events should 
be reported as adverse events.   
 
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 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/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 and in conformance with FDA requirements 
 
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 or via email to the 
sponsor, 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 Sponsor or its designee within three (3) 
working days of the initial report.    

 
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The Sponsor will evaluate all serious adverse events for reportability as an unanticipated adverse 
device effect in accordance with 21 CFR part 812.46(b)
2. The investigator and sponsor will comply 
with reporting requirements per 21 CFR part 812.150.  A sponsor who conducts an evaluation of 
an unanticipated adverse device effect under 812.46(b) shall report the results of such evaluation 
to FDA and to all reviewing IRB's and participating investigators within 10 working days after the 
sponsor first receives notice of the effect. Thereafter the sponsor shall submit such additional 
reports concerning the effect as FDA requests. 
Any unanticipated adverse events: (including all deaths and/or serious adverse device effects) 
must also be reported to the FDA, all reviewing IRB’s/EC’s and participating investigators within 
ten (10) days of receiving notice of the serious adverse event or death, (or per local IRB/EC 
requirements), and documentation of the report sent to the Sponsor or its designee. 
 
13.5  
Patient Death 
 
Patient death during the investigation must be reported via telephone or with written 
documentation to the Sponsor or designee within 24 hours of Investigator’s knowledge of the 
death. Notification can be made by entering the CRF in the database or providing an email 
notification to a representative of the Study Team (i.e. site monitor, study manager) and include 
a brief description of the relevant details of the death. The electronic Adverse Event Form must 
be electronically signed by the Investigator once finalized. A copy of the death records, death 
certificate and an autopsy report (if performed) are required to be sent to the Sponsor or designee 
following the death. In addition, patient death must be reported to the IRB/EC in accordance with 
IRB/EC requirements. 
 
13.6  
Treatment Failures & Device Malfunctions 
 
All reported device observations, malfunctions or failures for the JenaValve Pericardial TAVR 
System are required to be documented on the Procedure / Device Observation Case Report Form. 
In the event of a suspected observation or device problem, the device shall be returned to the 
Sponsor for analysis.  Instructions for returning the investigational device are included in the Study 
Reference Manual.  
14.0  
STUDY OVERSIGHT 
 
14.1  
Independent Subject Screening Committee 
 
An Independent Subject Screening Committee (ISSC) will be established under the direction of the 
Sponsor. The role of the ISSC is to review key information on subjects and establish their final 
eligibility for participation in the study. ISSC review shall occur after the investigational site heart 
team has established initial eligibility of a subject.  Screening Committee members shall not 
participate in ISSC review of their own site’s patients. 
 
 
2 Unanticipated adverse device effect is any serious adverse effect on health or safety, any life-threatening 
problem or death caused by, or associated with a device, if that effect, problem, or death was not 
previously identified in nature, severity, or degree of incidence in the application; or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects. 

 
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14.2  
Clinical Events Committee/Data Monitoring Committee (CEC/DMC) 
 
A Clinical Events Committee/Data Monitoring Committee (CEC/DMC) will be assembled prior to 
patient enrollment and will be comprised of leading physician practitioners and a biostatistician 
who are not investigators in the trial and who are not affiliated with the investigation sites.  
Membership of the committee shall remain anonymous to the investigational sites to reduce any 
potential bias. 
 
The CEC/DMC will establish a charter that includes a mission statement, operating procedures, 
safety event adjudication definitions and guidelines, and proposed safety monitoring criteria for 
the study, including any required interim analysis time points for assessing safety and proposed 
study stopping rules. The specific stopping rules shall remain confidential to the site and Sponsor 
to minimize bias.  
 
This CEC/DMC will be responsible for the review and validation of reported adverse events that 
occur over the course of the study per the charter and shall classify the adverse events based on 
severity and association to the device and/or procedure. The charter shall include consistent 
adjudication definitions for each type of event and shall outline the review process. During the 
review of the events, the physicians shall be blinded to the clinical site as much as possible. 
 
Written minutes of all meetings shall be developed after each CEC/DMC meeting and major 
conclusions (i.e. the assessment for study enrollment continuation, protocol modification or 
enrollment stop) shall be documented. Meeting summaries shall be included in reports to the 
IRB’s and EC’s as appropriate.  
 
14.3  
Core Laboratory 
 
An independent CT scan imaging core laboratory will be utilized for assessment of baseline 
multidetector CT scans. All CT scan image acquisition shall be performed in accordance to the core 
laboratory’s recommended protocol which is provided to the sites in the Study Reference Manual. 
 
An independent echocardiographic imaging core laboratory will be utilized for assessment of 
echocardiograms. All echocardiogram image acquisition shall be performed in accordance to the 
core laboratory’s recommended protocol which is provided to the sites in the Study Reference 
Manual. 
 
15.0  
ADMINISTRATIVE RESPONSIBILITIES 
 
The JenaValve AS EFS study will be performed in accordance with Good Clinical Practice 
Guidelines, the Code of Federal Regulations Title 21 CFR Parts 812, 50, 54, 56, 45 CFR Part 46, the 
MDD 93/42/EC, and ISO 14155, as applicable.     
 
15.1  
Institutional Review Board (IRB)/ Ethics Committee (EC) Approval 
 
The Clinical Investigational Plan shall be reviewed and approved by the US FDA and the 
Investigator’s Institutional Review Board/ Ethics Committee prior to patient enrollment.  All 
proposed changes to the investigational plan must be reviewed by the Sponsor, and /or their 

 
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authorized agent, prior to implementation. Significant changes to the investigational plan must 
be approved in writing by the Sponsor, the IRB/EC and FDA, prior to implementation. A significant 
change is one which may increase the risk or present a new risk to a patient, or which may 
adversely affect the scientific validity of the study. 
 
Prior to shipment of the investigational study devices, a signed copy of the IRB/EC approval letter 
identifying the clinical study and investigational site is required to be submitted to the sponsor 
signifying study approval. Investigators are responsible for obtaining and maintaining annual 
renewal of the study by their IRB/EC (or according to renewal schedule imposed by the IRB/EC). 
Evidence of renewal and continued IRB/EC approval must be provided to the Sponsor or its 
designee accordingly. 
 
15.2  
Informed Consent 
 
If the patient meets all clinical eligibility criteria, the patient (and/or their authorized legal 
representative) should be approached to obtain written informed consent. The background of the 
proposed study and the benefits and risks of the procedures and study should be explained to the 
patient or the patient’s legally authorized representative.  The patient or patient’s legally 
authorized representative must sign the consent form prior to enrollment. Failure to obtain 
signed informed consent renders the patient ineligible for the study. All enrolled subjects will 
complete the appropriate consent form that has been approved by the FDA, the institutional 
review board (IRB)/ ethics committee (EC) and the Sponsor (see sample in the Study Reference 
Manual).  Copies of the signed informed consent shall be kept in the patient’s medical records 
and study files.  A copy of the informed consent form must be given to each patient (or their 
authorized legal representative) enrolled in the study. 
 
Modifications to the Study Informed Consent must have approval from the Sponsor, the IRB/EC, 
and FDA as required. 
 
15.3  
Confidentiality 
 
All information and data sent to the Sponsor or their authorized designees, concerning subjects 
or their participation in this study will be considered confidential.  All data used in the analysis 
and reporting of this evaluation 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, respecting 
the privacy of and confidentiality rules in accordance with applicable regulatory requirements, 
including all applicable provisions of the Health Insurance Portability and Accountability Act 
(HIPAA) and its current regulations. 
• 
Subjects must be identified only by their assigned study number and initials on all CRFs and 
other records and documents submitted to the Sponsor, the monitor, 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 

 
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• 
Documents not for submission to the Sponsor 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 study (study data). 
 
15.4  
Data Monitoring and Quality Control 
 
Data Monitoring 
All required data for this study will be collected on standardized Case Report Forms (CRFs). The 
Investigator (or designated hospital staff) will assure primary data collection based on source-
documented hospital chart reviews. Independent monitoring will be performed to ensure that 
the investigator and his/her study team conduct the clinical investigation in accordance with 
contract specifications, protocol, Declaration of Helsinki, Good Clinical Practice according to ICH 
E6 and applicable regulations, to ensure adequate protection of the rights and safety of subjects 
and the quality and integrity of the resulting data. 
 
If a clinical monitor becomes aware that an Investigator is not complying with the requirements 
mentioned above, the Sponsor will be notified by the monitor. The Sponsor will evaluate the non-
compliance and if necessary, immediately either secure compliance or discontinue shipments of 
the investigational device to the Investigator and terminate the Investigator’s participation in 
continued enrollment in the investigation. The Investigator will be required to return all unused 
devices to the Sponsor. 
 
Source Documentation 
Auditors, monitors, Institutional Review Boards (IRBs), the Sponsor, and regulatory authorities 
may have access to the medical records related to this study. Original or certified copies of all 
relevant clinical findings, observations, and other activities throughout the clinical investigation 
must be recorded and maintained in the medical file of each enrolled Subject. At a minimum, the 
following must be included in each Subject’s file: 
• 
Sufficient medical history and current physical condition, including any medication(s) the 
Subject is taking at the time of the procedure to assess the Subject’s eligibility; 
• 
The medical file should reveal the Subject’s participation in this study, including 
documentation of written informed consent; 
• 
Dated report of the investigational procedure including medication, material usage, and 
complications, if applicable; 
• 
Dated reports of the discharge and follow-up assessments; 
• 
Dated results of required laboratory tests; 
• 
Any adverse event(s), the resultant action or treatment, and outcome, if applicable; and 
In the case of withdrawal of subject consent, reason and subject status at time of withdrawal. 
 
The Investigator will permit study-related monitoring, audits, IRB review and authority inspections 
by allowing direct access to the source data. In case of electronic source data, access will be 
granted to the Sponsor.  JenaValve Technology, Inc. in collowill monitor and manage the data for 
the investigational study.  
 

 
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15.4.1  Training 
 
The training of clinical site personnel will be the responsibility of the Sponsor. Sponsor is 
responsible for housing the database and providing training on the Electronic Data Capture (EDC) 
System and data entry functions. . This procedure may only be performed by qualified 
investigators, familiar with TAVR procedures and techniques. A formal training program consisting 
of didactic and interactive sessions will be performed with participating investigators and study 
personnel identified at each site prior to patient treatment. The Sponsor or affiliated personnel 
shall be available to assist with the technical aspects of the device/procedure.  The JenaValve 
Clinical Study Team or designee shall be available for protocol related training.  Training will be 
documented. It is ultimately the responsibility of the Investigator to ensure all clinical site 
personnel participating in this trial are trained. 
 
To ensure uniform data collection and protocol compliance, appointed monitors will perform 
study initiation visits to review the clinical protocol, techniques for the identification of eligible 
subjects, instructions on in-hospital data collection, methods for soliciting data from alternative 
sources, and schedules for follow-up with study site personnel.  This initiation/ training is aimed 
to take place at the same time as device training.  
 
15.4.2  Electronic Case Report Forms 
 
Electronic Case Report Forms (eCRFs) will be used to collect all patient data during the course of 
the study. The eCRFs must be fully completed for each subject and electronically signed by the 
Investigator when complete.  
 
Federal Regulations and Good Clinical Practice Guidelines require that Investigators maintain 
information in the study patient's medical records that corroborate data collected on the eCRFs. 
In order to comply with these regulatory requirements, the following information should be 
maintained: 
• Medical history/physical condition of the study patient before involvement in the study 
sufficient to verify protocol entry criteria 
• Dated and signed notes on the day of entry into the study including the study 
investigator, study name, patient number assigned and a statement that consent was 
obtained 
• Dated and signed notes from each 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. 
• Study patient's condition upon completion of or withdrawal from the study 
• Discharge summaries/procedure reports 
 
 
15.4.3  Data Reporting 
 
The Investigator or designated individual shall be responsible for recording all study data on the 
electronic case report forms (eCRFs) supplied by the Sponsor or its authorized representatives.   
 

 
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The Investigator is required to electronically sign the eCRFs 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. 
 
Completed eCRFs will be verified by the monitor at the investigational sites at regular intervals 
throughout the study. The Investigator will allow the monitor and/or representative of the 
Sponsor, and any regulatory body to review and inspect the study files, patient eCRFs, patient 
medical records and other related study documents as required. 
 
15.4.4  Data Review 
 
CRFs will be reviewed for completeness and clarity. Missing or unclear data will be investigated 
by the monitor and will be retrieved, clarified and entered by study personnel as necessary 
throughout the study. The Sponsor or their authorized representatives, may request additional 
documentation from the investigator such as physician procedure notes or physician written 
summaries when adverse events are observed and reported.  Adverse events reported during the 
study shall be adjudicated by the Clinical Events Committee/Data Monitoring Committee 
(CEC/DMC) per the Charter. 
 
Development of the primary database for the study will be performed by the Sponsor or designee.  
The Sponsor or designee will also be responsible for the quality control of the database and 
confirming the overall integrity of the data. 
 
15.5  
Record Maintenance 
 
15.5.1  Records 
 
The following records must be maintained in designated JenaValve AS EFS study administrative 
files: 
• 
Clinical protocol and all amendments 
• 
Signed Investigator Agreement 
• 
Institutional Review Board/Ethics Committee Approval Letter(s) including IRB/EC-
approved informed consent(s) (including any revisions)  
• 
CV for all investigators  
• 
Correspondence relating to this study 
• 
Correspondence with the IRB/EC 
• 
IRB/EC membership list and/or assurance number  
• 
Investigational site authorized study personnel signature list 
• 
Device Instructions for Use 
• 
Lab certification, including a set of the lab’s normal range for tests performed  
• 
Printed copy of blank set of CRFs and instructions for completion 
• 
Patent Screening & Enrollment Log 
• 
Site Visit Log (e.g. for Monitor sign-in) 
• 
Investigational Device Accountability Log with invoices, including: date, quantity, lot 
numbers of all devices, device returns and identification of all persons the device was 
used on  
• 
Adverse Event Log 

 
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• 
Reports (includes Adverse Event reports and final reports from Investigator and 
Sponsor) 
 
The following records must be maintained for each patient enrolled in the 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 
• 
Records pertaining to patient deaths throughout the course of the study (including 
death records, death certificate and autopsy report, if performed) 
 
15.5.2  Investigator Reports 
 
Investigators are required to prepare and submit the following complete, accurate and timely 
reports on this clinical investigation when necessary. Investigator files containing all records and 
reports of the investigation should be retained by the sites for a minimum of two (2) years after 
the completion/ termination of the investigational study.  They may be discarded upon written 
notification by the Sponsor.  To avoid error, the Principal Investigator should contact the Sponsor, 
before the destruction of any records and reports pertaining to the study to ensure they no longer 
need to be retained. 
 
In addition, in accordance with the Clinical Study Agreement, the Sponsor should be contacted if 
the Principal Investigator plans to leave the investigational site so that appropriate arrangements 
for file custodianship can be made. 
 
15.6  
Investigator’s and Sponsor’s Annual and Final Reports 
 
Each year, at a minimum, an annual summary report shall be prepared by the Investigator to 
provide a summary of the number of subjects treated to date as well as other pertinent clinical 
information associated with the investigational procedure.  The annual report is required to be 
provided to the IRB/EC and the Sponsor or their authorized agent.   
 
The Sponsor or its designee will be responsible for preparing a compilation of all of the 
participating site results for submittal as an annual progress report to the US FDA.  
 
Upon completion and/or termination of the study a final report shall be prepared. This report will 
contain a critical evaluation of all data collected during the course of the investigation at each 
institution. The Sponsor or its designee is responsible for preparing this compilation to 
Investigators for submittal as a final report to their reviewing IRB/EC.  The Sponsor or its designee 
will also provide this final report to the US FDA. 
 
15.7  
Investigational Site Monitoring 
 

 
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The Sponsor is responsible for monitoring the safety and effectiveness of this study.  The Sponsor 
may utilize the services of a CRO or independent contractors to facilitate the monitoring process. 
The study will be monitored according to applicable provisions of JenaValve Technology, Inc. or 
designees clinical monitoring procedures and in compliance with Title 21 CFR Part 812. 
 
15.8  
Deviations from Clinical Protocol and Medical Emergencies 
 
The investigator will not deviate from the clinical protocol without the prior written approval of 
the Sponsor except in medical emergencies or in unforeseen, isolated instances where minor 
changes are made that will not increase the patient’s risk or affect the validity of the study. In 
medical emergencies, prior written approval for protocol deviations will not be required, but the 
Sponsor or its designee must be notified via telephone or email within 24 hours of occurrence. 
 
15.9  
Investigational Site Termination 
 
The Sponsor reserves the right to terminate an investigational site from the study for any of the 
following reasons including, but not limited to: 
• 
Failure to obtain Informed Consent 
• 
Failure to report Serious Adverse Events within 24 hours of knowledge 
• 
Repeated protocol violations 
• 
Repeated failure to complete Case Report Forms 
• 
Failure to enroll an adequate number of subjects 
 
15.9.1   Monitoring Methods 
Sponsor will assign a monitor to clinical sites.  The monitor will be responsible to monitor the 
study progress and to provide assistance throughout the duration of the study.  The monitor will 
be responsible to train all new study staff, perform device accountability, monitor the study files 
to make sure all the regulatory approvals are in place, and source verify the clinical data.  The 
monitor will also provide the study staff with any needed documentation for the study and answer 
questions as needed.  The monitor will visit the sites according to the subject enrollment and as 
needed to make sure the study is being followed according to the study protocol.   
15.9.2 Monitoring Plan 
Prior to subject enrollment, an initiation visit will be completed at the study center to ensure the 
following:   
• 
All approvals have been obtained and filed in the study regulatory binder 
• 
The site has the infrastructure to perform the study according to the protocol 
• 
Delegation of authority is complete 
 
Routine monitoring will be performed according to the number of subjects enrolled in the study 
and/or as needed based on the study requirements.  
Upon termination or conclusion of the study, the study monitor will perform a close-out visit. 
 

 
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15.10 Medicare Coverage Related to Investigational Device Exemption (IDE) Studies 
 
Consistent with CMS coverage of IDE studies effective January 1, 2015 the following information 
is provided as part of this clinical protocol. 
 
15.10.1 Release of Results 
 
This clinical study will utilize a Publications Committee which will oversee the analysis of the study 
and author a publications policy strategy consistent with JenaValve policies and procedures. In 
particular, this committee will ensure that the pre-specified primary endpoint results and 
outcomes and information important to the scientific community are disseminated in a timely 
fashion (i.e., within 24 months of the end of the study) at scientific meetings and within the 
scientific literature. Full details of the presentation and publication strategy will be outlined in the 
Steering Committee Charter that will be issued before study enrollment is completed. 
 
15.11 Protocol Amendments 
 
Protocol amendments will be approved by the Sponsor, the Principal Investigators, the 
Institutional Review Boards and any necessary regulatory body before it can be implemented.  
 
15.12 Quality Assurance and Auditing 
 
As a quality assurance measure, the site may be audited during the course of the ongoing clinical 
trial as well as following completion of the trial. The audit will be conducted by sponsor personnel 
(or designee). The purpose of an audit is to provide an independent evaluation separate from 
routine monitoring or quality control functions of trial conduct, protocol and GCP compliance. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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APPENDIX 1: ADVERSE EVENT DEFINITIONS 
 
Definitions in table below are adapted from VARC-2; European Heart Journal (2012) and Journal 
of Thoracic and Cardiovascular Surgery (2013). 
 
Term 
Definition 
Acute Kidney 
Injury 
• 
Stage 1 
Increase in serum creatinine to 150–199% (1.5–1.99 × increase compared 
with baseline) OR increase of ≥ 0.3 mg/dl (≥ 26.4 mmol/l) OR urine output 
< 0.5 ml/kg/h for > 6 but < 12 h  
• 
Stage 2 
Increase in serum creatinine to 200–299% (2.0–2.99 × increase compared 
with baseline) OR urine output < 0.5 ml/kg/h for > 12 but < 24 h  
• 
Stage 3 
Increase in serum creatinine to ≥ 300% (> 3 × increase compared with 
baseline) OR serum creatinine of ≥ 4.0 mg/dl (≥ 354 mmol/l) with an 
acute increase of at least 0.5 mg/dl (44 mmol/l) OR urine output 
< 0.3 ml/kg/h for ≥ 24 h OR anuria for ≥ 12 h 
NOTE: Patients receiving renal replacement therapy are considered to 
meet Stage 3 criteria irrespective of other criteria. 
Bleeding  
Life-threatening or Disabling Bleeding 
• 
Fatal bleeding  
OR 
• 
Bleeding in a critical area or organ, such as intracranial, intraspinal, 
intraocular, or pericardial necessitating pericardiocentesis, or 
intramuscular with compartment syndrome  
OR  
• 
Bleeding causing hypovolemic shock or severe hypotension requiring 
vasopressors or surgery  
OR 
• 
Overt source of bleeding with drop in hemoglobin of ≥ 5 g/dl or 
whole blood or packed red blood cells (RBC) transfusion ≥ 4 units* 
Major Bleeding 
• 
Overt bleeding either associated with a drop in the hemoglobin level 
of at least 3.0 g/dl or requiring transfusion of 2–3 units of whole 
blood/RBC, or causing hospitalization or permanent injury, or 
requiring surgery  
AND  
• 
Does not meet criteria of life-threatening or disabling bleeding 
Minor Bleeding 
Any bleeding worthy of clinical mention (e.g., access site hematoma) that 
does not qualify as life-threatening, disabling or major 
* Given that one unit of packed RBC typically will raise blood hemoglobin 
concentration by 1 g/dl, an estimated decrease in hemoglobin will be 
calculated. 
Death/Mortality 
• 
All-Cause Mortality 

 
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Term 
Definition 
• 
Cardiovascular Mortality: any of the following criteria: 
• 
Death due to proximate cardiac cause (e.g., myocardial infarction, 
cardiac tamponade, worsening heart failure)  
• 
Death caused by non-coronary vascular conditions such as 
neurological events, pulmonary embolism, ruptured aortic 
aneurysm, dissecting aneurysm, or other vascular disease  
• 
All procedure-related deaths, including those related to a 
complication of the procedure or treatment for a complication of 
the procedure  
• 
All valve-related deaths including structural or non-structural 
valve dysfunction or other valve-related adverse events  
• 
Sudden or unwitnessed death 
• 
Death of unknown cause 
• 
Non-cardiovascular Mortality:  Any death in which the primary cause 
of death is clearly related to another condition (e.g., trauma, cancer, 
suicide) 
Myocardial 
Infarction 
Peri-Procedural MI (≤ 72 h after the index procedure) 
• 
New ischemic symptoms (e.g., chest pain or shortness of breath), or 
new ischemic signs (e.g., ventricular arrhythmias, new or worsening 
heart failure, new ST-segment changes, hemodynamic instability, 
new pathological Q-waves in at least two contiguous leads, imaging 
evidence of new loss of viable myocardium or new wall motion 
abnormality)  
AND 
• 
Elevated cardiac biomarkers (preferable CK-MB) within 72 h after the 
index procedure, consisting of at least one sample post-procedure 
with a peak value exceeding 15× as the upper reference limit for 
troponin or 5× for CK-MB. If cardiac biomarkers are increased at 
baseline (> 99th percentile), a further increase in at least 50% post-
procedure is required AND the peak value must exceed the previously 
stated limit 
Spontaneous MI (> 72 h after the index procedure) Any one of the 
following criteria: 
• 
Detection of rise and/or fall of cardiac biomarkers (preferably 
troponin) with at least one value above the 99th percentile URL, 
together with the evidence of myocardial ischemia with at least one 
of the following: 
• 
Symptoms of ischemia 
• 
ECG changes indicative of new ischemia (new ST-T changes or 
new left bundle branch block [LBBB]) 
• 
New pathological Q-waves in two or more contiguous leads  
• 
Imaging evidence of a new loss of viable myocardium or new wall 
motion abnormality 
• 
Sudden, unexpected cardiac death, involving cardiac arrest, often 
with symptoms suggestive of myocardial ischemia, and 

 
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Term 
Definition 
accompanied by presumably new ST elevation, or new LBBB, and/ 
or evidence of fresh thrombus by coronary angiography and/or at 
autopsy, but death occurring before blood samples could be 
obtained, or at a time before the appearance of cardiac 
biomarkers in the blood 
• 
Pathological findings of an acute myocardial infarction 
Stroke and TIA 
Diagnostic Criteria 
• 
Acute episode of a focal or global neurological deficit with at least 
one of the following: change in the level of consciousness, 
hemiplegia, hemiparesis, numbness, or sensory loss affecting one 
side of the body, dysphasia or aphasia, hemianopia, amaurosis fugax 
or other neurological signs or symptoms consistent with stroke 
• 
Stroke: duration of a focal or global neurological deficit ≥ 24 h; OR 
< 24 h if available neuroimaging documents a new hemorrhage or 
infarct; OR the neurological deficit results in death 
• 
TIA: duration of a focal or global neurological deficit < 24 h, any 
variable neuroimaging does not demonstrate a new hemorrhage or 
infarct 
• 
No other readily identifiable non-stroke cause for the clinical 
presentation (e.g., brain tumor, trauma, infection, hypoglycemia, 
peripheral lesion, pharmacological influences), to be determined by 
or in conjunction with the designated neurologist 
• 
Confirmation of the diagnosis by at least one of the following: 
• 
Neurologist or neurosurgical specialist 
• 
Neuroimaging procedure (CT scan or brain MRI), but stroke may 
be diagnosed on clinical grounds alone 
Stroke Classification 
• 
Ischemic: an acute episode of focal cerebral, spinal, or retinal 
dysfunction caused by infarction of the central nervous system tissue 
• 
Hemorrhagic: an acute episode of focal or global cerebral or spinal 
dysfunction caused by intra-parenchymal, intraventricular, or 
subarachnoid hemorrhage. 
• 
A stroke may be classified as undetermined if there is insufficient 
information to allow categorization as ischemic or hemorrhagic. 
Stroke Definitions 
• 
Disabling stroke: an mRS score of 2 or more at 90 days and an 
increase in at least one mRS category from an individual’s pre-stroke 
baseline 
• 
Non-disabling stroke: an mRS score of <2 at 90 days or one that does 
not result in an increase in at least one mRS category from an 
individual’s pre-stroke baseline. 
 
Vascular Access 
Site and Access-
Related 
Complications  
Major Vascular Complications 
• 
Any aortic dissection, aortic rupture, annulus rupture, left ventricle 
perforation, or new apical aneurysm/pseudoaneurysm OR 

 
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Term 
Definition 
• 
Access site or access-related vascular injury (dissection, stenosis, 
perforation, rupture, arterio-venous fistula, pseudoaneurysm, 
hematoma, irreversible nerve injury, compartment syndrome, 
percutaneous closure device failure, infection) leading to death, life-
threatening or major bleeding, visceral ischemia, or neurological 
impairment  
OR 
• 
Distal embolization (non-cerebral) from a vascular source requiring 
surgery or resulting in amputation or irreversible end-organ damage  
OR 
• 
The use of unplanned endovascular or surgical intervention 
associated with death, major bleeding, visceral ischemia or 
neurological impairment OR 
• 
Any new ipsilateral lower extremity ischemia documented by patient 
symptoms, physical exam, and/or decreased or absent blood flow on 
lower extremity angiogram OR 
• 
Surgery for access site-related nerve injury OR  
• 
Permanent access site-related nerve injury  
Minor Vascular Complications 
• 
Access site or access-related vascular injury (dissection, stenosis, 
perforation, rupture, arterio-venous fistula, pseudoaneurysms, 
hematomas, percutaneous closure device failure) not leading to 
death, life-threatening or major bleeding, visceral ischemia, or 
neurological impairment  
OR 
• 
Distal embolization treated with embolectomy and/or thrombectomy 
and not resulting in amputation or irreversible end-organ damage  
OR 
• 
Any unplanned endovascular stenting or unplanned surgical 
intervention not meeting the criteria for a major vascular 
complication  
OR 
• 
Vascular repair or the need for vascular repair (via surgery, 
ultrasound-guided compression, transcatheter embolization, or stent-
graft) OR 
Percutaneous Closure Device Failure 
Failure of a closure device to achieve hemostasis at the arteriotomy site 
leading to alternative treatment (other than manual compression or 
adjunctive endovascular ballooning)  
 
 
Conduction 
disturbances and 
arrhythmias 
• 
Baseline conduction abnormalities, paroxysmal or permanent atrial 
fibrillation (or flutter), and the presence of permanent 
pacemaker 
• 
Implant-related new or worsened cardiac conduction disturbance 

 
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Term 
Definition 
(new or worsened first-degree atrioventricular (AV) block, 
second-degree AV block (Mobitz I or Mobitz II), third-degree AV 
block, incomplete right bundle branch block, right bundle branch 
block, intraventricular conduction delay, left bundle branch block, 
left anterior fascicular block, or left posterior fascicular block, 
including AV block requiring a permanent pacemaker implant 
• 
Persistent or transient high-degree AV block. High-grade AV block is 
persistent if present every time the underlying rhythm is checked 
• 
New permanent pacemaker implantation, with precise 
documentation of the clinical indication and the number of days from 
the index procedure to the pacemaker implant 
• 
New-onset atrial fibrillation (or flutter) 
• 
Any new arrhythmia resulting in hemodynamic instability or 
requiring therapy 
Other TAVI-
related 
complications 
Conversion to open surgery 
      Conversion to open sternotomy during the TAVI procedure  
      secondary to any procedure-related complications 
Unplanned use of cardiopulmonary bypass (CPB) 
      Unplanned use of CPB for hemodynamic support at any time 
      during the TAVI procedure 
Coronary obstruction      
     Angiographic or echocardiographic evidence of a new, partial  
       or complete, obstruction of a coronary ostium, either by the  
       valve prosthesis itself, the native leaflets, calcifications or  
       dissection, occurring during or after the TAVI procedure 
Ventricular septal perforation 
       Angiographic or echocardiographic evidence of a new septal  
        perforation during or after the TAVI procedure 
Mitral valve apparatus damage or dysfunction          
        Angiographic or echocardiographic evidence of new damage  
        (chordae papillary muscle, or to the leaflet) to the mitral  
        valve apparatus or dysfunction (e.g. restrictions due to the  
        THV) of the mitral valve during or after the TAVI procedure 
Cardiac tamponade 
         Evidence of a new pericardial effusion associated with  
         hemodynamic instability and clearly related to the TAVI 
         procedure 
Endocarditis 
Any one of the following: 
• 
Fulfilment of the Duke endocarditis criteria 
• 
Evidence of abscess, paravalvular leak, pus, or vegetation   
confirmed as secondary to infection by histological or  
bacteriological studies during a re-operation 
• 
Findings of abscess, pus, or vegetation involving a repaired  
          or replaced valve during an autopsy 
Valve thrombosis 

 
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Term 
Definition 
          Any thrombus attached to or near an implanted valve that  
          occludes part of the blood flow path, interferes with valve  
          function or is sufficiently large to warrant treatment. Note  
          that valve-associated thrombus identified at autopsy in a  
          patient whose cause of death was not valve-related should  
          not be reported as valve thrombosis 
Valve malpositioning 
          After initial correct positioning, the valve prosthesis moves  
          upwards or downwards, within the aortic annulus from its  
          initial position, with or without consequences 
Valve embolization 
           The valve prosthesis moves during or after deployment such  
           that it loses contact with the aortic annulus 
Ectopic valve deployment 
          Permanent deployment of the valve prosthesis in a location  
          other than the aortic root 
TAV-in-TAV deployment 
          An additional valve prosthesis is implanted within a  
          previously implanted prosthesis because of suboptimal  
          device position and/or function, during or after the index  
          procedure 

 
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REFERENCES 
 
[1]  Iung B, Baron G, Butchart E, Delahaye F, Gohlke C-Barwolf C, Levang O, Tornos P, Jet al. A 
prospective survey of patients with valvular heart disease in Europe: The Euro Heart 
Survey on Valvular Heart Disease. Eur Heart J.2003;24:1231-43.  
[2]  Lindroos M, Kupari M, Heikkila J and Tilvis R, Prevalence of aortic valve abnormalities in 
the elderly: an echocardiographic study of a random population sample. J Am Coll Cardiol. 
1993;21:1220-25.  
[3]  Vahanian A, Baumgartner H, Bax J, Butchart E, Dion R, Filippatos G, Flachskampf F, R, 
Guidelines on the management of valvular heart disease: The Task Force on the 
Management of Valvular Heart Disease of the European Society of Cardiology. Eur Heart J. 
2002;28:230-68.  
[4]  Frank S, Johnson A and  Ross J. Natural history of valvular aortic stenosis. Br Heart J. 1973; 
35:41-46.  
[5]  Schwarz F, Baumann P, Manthey J, Hoffmann M, Schuler G, Mehmel H, Schmitz W and 
Kubler W. The effect of aortic valve replacement on survival. Circulation 1982;66:1105-10.  
[6]  Bernard Y, Etievent J, Mourand J, Anguenot T, Schiele F, Guseibat M and Bassand J. Long-
term results of percutaneous aortic valvuloplasty compared with aortic valve replacement 
in patients more than 75 years old. J Am Coll Cardiol.1992;20:796-801.  
[7]  Roques F, Nashef S, Michel P, Gauducheau, de Vincentiis C, Baudet E, Cortina J, et al. Risk 
factors and outcome in European cardiac surgery: analysis of the EuroSCORE multinational 
database of 19.030 patients. Eur J Cardiothorac Surg.199; 15:816-22.  
[8]  Vaquette B, Corbineau, Laurent, Lelong B, Langanay T, de Place C, Froger-Bompas C, et al. 
Valve replacement in patients with critical aortic stenosis and depressed left ventricular 
function: predictors of operative risk, left ventricular function recovery, and long term 
outcome. Heart.2005; 91:1324-9.  
[9]  Piazza N, Grube E, Gerckens U, den Heijer P, Linke A, Luha O, Ramondo A, et al. Procedural 
and 30-day outcomes following transcatheter aortic valve implantation using the third 
generation (18 F) CoreValve Revalving System: results from the multicentre, expanded 
evaluation registry 1-year following CE mark approval. EuroInterv. 2008; 4:242-9.  
[10] Bauernschmitt R, Bleiziffer S, Ruge H, Mazzitelli D, Schreiber C, Tassani-Prell P, Hutter A, et 
al.Kathetergestützter Aortenklappenersatz: Alternative zur offenen Chirurgie bei 
Hochrisikopatienten. Z Herz- Thorax- Gefäßchir.2009; 23:2-8.  
[11] Smith CR, Leon MB, Mack MJ, Miller DC, Moses JW, Svensson LG, Tuzcu EM, Jet al. 
Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med. 
2011;364(23): 2187-98.  
[12] Leon MB, Smith CR, Mack MJ, Miller DC, Moses JW, Svensson LG, Tuzcu EM, et al. 
Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo 
surgery. N Engl J Med. 2010;363(17):1597-607.  
[13] Holmes DR, Mack MJ, Kaul S, Agnihotri A, Alexander KP, Bailey SR, et al. 2012 
ACCF/AATS/SCAI/STS expert consensus document on transcatheter aortic valve 
replacement: developed in collabration with the AHA, ASE, EACTS, HFSA, MH, SCA, SCCT, 
SCMR. J Thorac Cardiovasc Surg. 2012; 144(3):e29-84.  

 
Page 50 of 50 
Rev. J [Jul 2019] 
Confidential 
[14] Di Mario C, Eltchaninoff H, Moat N, Goicolea J, et al. The 2011-12 pilot European Sentinel 
Registry of Transcatheter Aortic Valve Implantation: in-hospital results in 4,571 patients. 
EuroIntervention, 2013; 22:1362-71.  
[15] Treede H, Mohr FW, Baldus S, et al.  Transapical transcatheter aortic valve implantation 
using the JenaValve™ system: acute and 30-day results of the multicentre CE-mark study.  
Eur J Cardiothorac Surg. 41 (2012) e131–e138.  
[16] Seiffert M, Bader R, Kappert U, et al.  Initial German experience with transapical 
implantation of a second-generation transcatheter heart valve for the treatment of aortic 
regurgitation.   J Am Coll Cardiol Cardiovasc Interv. 2014;7:1168-74.  
[17] Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC Guideline for the Management 
of Patients With Valvular Heart Disease: A Report of the American College of 
Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 
2014;129:e521–e643.  
[18] Osnabrugge RL, Mylotte D, Head SJ, et al. Aortic stenosis in the elderly: disease prevalence 
and number of candidates for transcatheter aortic valve replacement: a meta-analysis and 
modeling study. J Am Coll Cardiol. 2013;62(11):1002-1012. 
[19] Jacobsen LA, Kent M, Lee M, and Mather M. America's Aging Population. Population 
Bulletin 2011. Available at: www.prb.org. 
[20] Kappetein AP, Head SJ, Genereaux P, et al. Updated standardized endpoint definitions for 
transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 
consensus document. Eur Heart J. 2012;33:2403-18. 
[21] Miriam Silaschi, Hendrik Treede, et al. The JUPITER Registry: 1-year results of tansapcial 
aortic valve implantation using a second-generation transcatheter heart valve in patients 
with aortic stenosis. Eur J Cardiothorac Surg. 50 (2016) 874-881.