Cerebral Protection in Transcatheter Aortic Valve Replacement - The PROTEMBO C Trial
Phase: NA
Conditions: Valvular Heart Disease
Sponsor: Protembis GmbH

CLINICAL INVESTIGATION PROTOCOL 
Cerebral Protection in Transcatheter Aortic Valve 
Replacement 
The PROTEMBO C Trial
Protocol Number: CIP_00105, Revision 01, Version 03, Date: 9 October 2020 
NCT Number: NCT04618718
Product Name: 
ProtEmbo® Cerebral Protection System 
Sponsor: 
Protembis GmbH 
Pauwelsstraße 17 
D-52074 Aachen
Telephone: +49 241 99033622 
Fax: +49 241 99033623 
Email: info@protembis.com 
This document contains confidential and proprietary information and may not be copied or reproduced in 
whole or in part without the express written permission of Protembis GmbH, Aachen, Germany. 

 
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Table of Contents 
1. 
PROTOCOL SYNOPSIS .................................................................................. 7 
2. 
INTRODUCTION AND BACKGROUND ........................................................ 13 
2.1. 
Rationale behind Proposed Research .................................................................14 
2.2. 
Study Objective ...................................................................................................15 
2.3. 
Background .........................................................................................................15 
2.3.1. 
Previous Clinical Experience .......................................................................15 
2.3.1.1. Previous Clinical Experience with the ProtEmbo Device ............................17 
2.3.2. 
Summary: Previous Experience with Embolic Protection Devices in TAVR..18 
2.3.3. 
Preclinical Experience with the ProtEmbo Device ........................................18 
3. 
TEST SYSTEM (INVESTIGATIONAL DEVICE) ............................................. 19 
3.1. 
Name of Investigational Device ...........................................................................19 
3.1.1. 
Model and version .......................................................................................19 
3.2. 
Intended Use .......................................................................................................19 
3.3. 
Classification .......................................................................................................19 
3.4. 
System Components ...........................................................................................19 
3.5. 
Device Accountability ..........................................................................................22 
3.6. 
Return of Devices ...............................................................................................22 
4. 
STUDY OVERVIEW ....................................................................................... 22 
4.1. 
Study Design .......................................................................................................23 
4.2. 
Primary Study Endpoints .....................................................................................23 
4.2.1. 
Safety ..........................................................................................................23 
4.2.2. 
Performance ................................................................................................23 
4.3. 
Secondary Study Endpoints ................................................................................24 
4.3.1. 
Efficacy: .......................................................................................................24 
4.4. 
Number of Subjects and Sites .............................................................................24 
4.5. 
Study Population .................................................................................................24 
4.6. 
Enrollment Criteria ..............................................................................................24 
4.6.1. 
Inclusion Criteria ..........................................................................................24 
4.6.2. 
Exclusion Criteria .........................................................................................25 
4.6.2.1. General Exclusion Criteria .........................................................................25 
4.6.2.2. Neurological Exclusion Criteria ..................................................................26 
4.6.2.3. Angiographic Exclusion Criteria .................................................................26 
4.6.2.4. Magnetic Resonance Imaging Exclusion Criteria .......................................26 
4.7. 
Written Informed Consent ...................................................................................27 
4.8. 
Unique Study Identification Code ........................................................................28 
4.9. 
Subject Recruitment ............................................................................................28 
4.10. 
Subject Reimbursement ......................................................................................28 
4.11. 
Enrollment ...........................................................................................................28 
4.12. 
Duration of Subject Participation .........................................................................29 
4.13. 
Study Duration ....................................................................................................29 
4.14. 
Withdrawal of Subjects ........................................................................................29 
4.15. 
Loss to Follow-up Considerations .......................................................................29 
4.16. 
Subject Confidentiality .........................................................................................29 
4.17. 
Study Procedures ...............................................................................................30 

 
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4.17.1. Screening and Enrollment ..........................................................................30 
4.17.2. Consent Phase ...........................................................................................31 
4.17.3. Screening Phase ........................................................................................31 
4.17.4. Eligibility Assessments ...............................................................................31 
4.17.5. CT/ Angiographic Eligibility .........................................................................31 
4.17.6. Sheath Access Eligibility .............................................................................31 
4.18. 
Procedural Treatment and Timing .......................................................................32 
4.18.1. Medication Regimen ...................................................................................32 
4.18.2. MRI Timing .................................................................................................32 
4.19. 
TAVR and ProtEmbo Procedure .........................................................................32 
4.19.1. Schedule of Events .....................................................................................33 
4.19.2. Study Exit or Premature Withdrawal ...........................................................33 
5. 
RISK BENEFIT ASSESSMENT ..................................................................... 34 
5.1. 
Potential Adverse Events ....................................................................................34 
5.2. 
Potential Risks to Subject Confidentiality and Privacy .........................................37 
5.3. 
Minimization of Anticipated Risks ........................................................................37 
5.4. 
Potential Benefits ................................................................................................38 
6. 
STATISTICAL ANALYSIS PLAN ................................................................... 38 
6.1. 
Overview .............................................................................................................38 
6.2. 
Primary Safety Endpoint......................................................................................38 
6.3. 
Primary Performance Endpoint ...........................................................................39 
6.4. 
Secondary Efficacy Endpoint ..............................................................................40 
6.5. 
Demographic, Safety, Feasibility and Efficacy Data ............................................41 
6.6. 
Imputation of Missing Data ..................................................................................42 
7. 
ADVERSE EVENT AND INCIDENT REPORTING ......................................... 42 
7.1. 
Adverse Event (AE) .............................................................................................42 
7.2. 
Serious Adverse Events (SAE)............................................................................42 
7.3. 
Serious Adverse Device Effect (SADE) ...............................................................43 
7.4. 
Unanticipated Serious Adverse Device Effect (USADE) ......................................43 
7.5. 
Anticipated Serious Adverse Device Effect (ASADE) ..........................................43 
7.6. 
Unanticipated Adverse Device Effect (UADE) .....................................................43 
7.7. 
Anticipated Adverse Device Effect (AADE) .........................................................43 
7.8. 
Reporting of Adverse Events (AEs) and Serious Adverse Events (SAEs) ...........43 
7.9. 
Reporting of Device Failures and Malfunctions ...................................................44 
7.10. 
Documentation, Evaluation and Notification of Serious Adverse Events ..............44 
8. 
MONITORING................................................................................................. 45 
9. 
STUDY MANAGEMENT ................................................................................. 46 
9.1. 
Key Contributors .................................................................................................46 
9.1.1. 
Study Sponsor .............................................................................................46 
9.1.2. 
Authorized CRO / Representative ................................................................46 
9.1.3. 
Clinical Sites ................................................................................................46 
9.1.4. 
MRI Core Laboratory ...................................................................................46 
9.1.5. 
Histopathology Core Laboratory ..................................................................46 
9.1.6. 
CT Core Laboratory .....................................................................................47 
9.2. 
Ethical Considerations ........................................................................................47 

 
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9.3. 
Insurance ............................................................................................................47 
9.4. 
Study Conduct ....................................................................................................47 
9.5. 
Audits and Inspections ........................................................................................47 
9.6. 
Sponsor Responsibilities .....................................................................................48 
9.7. 
Monitor Responsibilities ......................................................................................48 
9.8. 
Investigator Responsibilities ................................................................................49 
9.9. 
Study Funding .....................................................................................................51 
9.10. 
Investigator Training ............................................................................................51 
9.11. 
Medical Monitor ...................................................................................................51 
9.12. 
Data Management...............................................................................................51 
9.13. 
Study Suspension or Early Termination ..............................................................52 
9.14. 
Criteria for Suspending / Terminating a Study Center .........................................52 
9.15. 
Final Report ........................................................................................................52 
9.16. 
Protocol Deviations .............................................................................................53 
10. 
REGULATORY CONSIDERATIONS ............................................................. 53 
10.1. 
Maintaining Records ...........................................................................................53 
10.2. 
Site Record Retention Policy ...............................................................................53 
10.3. 
Ethics Committee (EC) and Competent Authority (CA) Approval .........................54 
11. 
PUBLICATIONS ............................................................................................. 54 
12. 
DEFINITIONS ................................................................................................. 55 
13. 
ACRONYMS ................................................................................................... 60 
14. 
BIBLIOGRAPHY ............................................................................................ 63 
 
 
 

 
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Appendices 
 
Appendix A 
List of Clinical Sites and Investigators 
Appendix B 
Financial Disclosure Forms (FDF) 
Appendix C 
Clinical Investigation Protocol (CIP) Signature Pages 
 
 
 
 

 
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Table of Tables 
 
Table 1: ProtEmbo System components and materials in contact with the patient’s blood or 
tissues. .................................................................................................................................22 
Table 2: Schedule of Events. ................................................................................................33 
 
 
 

 
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Table of Figures 
 
Figure 1. ProtEmbo Cerebral Protection System position in the aortic arch (illustration). ......20 
Figure 2. ProtEmbo Cerebral Protection System functional parts (illustration). .....................20 
Figure 3. ProtEmbo Cerebral Protection System Handle (illustration). ..................................21 
Figure 4: Screening and Enrollment Scheme. ......................................................................30 
 
 

 
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1. Protocol Synopsis 
 
Title:  
Cerebral 
Protection 
in 
Transcatheter 
Aortic 
Valve 
Replacement: The PROTEMBO C Trial 
Investigational Device: ProtEmbo Cerebral Protection System (also called ‘ProtEmbo 
System’) 
Intended Use: 
The ProtEmbo System is intended for use as a temporary filter 
device to deflect embolic material in the aortic arch. 
Objective: 
The primary objective of this study is to assess the safety and 
performance of the ProtEmbo Cerebral Protection System used for 
embolic protection during Transcatheter Aortic Valve Replacement 
(TAVR) compared to TAVR standard of care (without embolic 
protection). 
The Secondary objective is to assess the efficacy of the ProtEmbo 
system by comparing the median new lesion volume in the brain and 
the rate of death or all strokes compared to historical data. 
Design: 
Exploratory, international, multi-center, single-arm study of the 
safety and performance of using the ProtEmbo System in subjects 
with severe symptomatic native aortic valve stenosis indicated for 
TAVR. 
Study Treatments: 
Subjects included in the study will be undergoing TAVR following 
placement of the ProtEmbo System for cerebral embolic protection 
during TAVR. 
Number of Patients: 
Up to 60 patients who complete the TAVR procedure using the 
ProtEmbo System. 
Duration: 
12 months 
Primary Endpoints: 
Safety: 
Major Adverse Cardiac and Cerebrovascular Events (MACCE) at 30 
days defined by VARC-2 including all-cause mortality, all stroke, life-
threatening or disabling bleeding, vascular injury and acute kidney 
injury (stage 2 or 3).  
Stroke severity will be quantified according to the National Institutes 
of Health Stroke Scale (NIHSS) score and the occurrence of other 
Serious Adverse Events up to 30 days. 
Performance: 
Technical success, defined as ability to safely deliver, deploy, and 
remove the device, ability to secure positioning and stability of the 
position throughout the procedure and ability to deflect embolic 
material, as assessed by adequate coverage, while not impeding 
blood flow. 

 
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Secondary Endpoints: Efficacy: 
MR Imaging: 
Comparison between the median new lesion volume in the brain 
assessed by diffusion weighted magnetic resonance images (DW-
MRI) at 2 to 7 days and historical data; the total new lesion volume 
is defined as the sum of all diffusion-positive new cerebral lesions in 
post-procedural DW-MRI relative to the pre-TAVR DW-MRI. 
Death or All Stroke: 
Death or all stroke according to VARC-2 criteria (to define 
occurrence and type stroke) within 3 days (72 hours) of the TAVR 
procedure compared to historical data; Stroke severity will be 
quantified according to the National Institutes of Health Stroke Scale 
(NIHSS) score. 
 
Enrollment Criteria: 
Inclusion Criteria: 
1. The heart team recommends transcatheter valve aortic valve 
replace consistent with the 2017 ESC/EACTS Guidelines for the 
management of valvular heart disease. 
2. Compatible left subclavian artery (≥ 4 mm diameter) without 
significant stenosis (> 70%) and distance between the origin of 
left subclavian artery and valve plain of ≥ 90mm as determined 
by Multi-Slice Computed Tomography (MSCT) scan or 
equivalent imaging modality. 
3. The subject and the treating physician agree that the subject will 
undergo the scheduled pre-procedural testing and return for all 
required post-procedure follow-up visits. 
4. The subject is able to provide informed consent, has been 
informed of the nature of the trial, agrees to its provisions and 
has provided written informed consent as approved by the 
relevant regulatory authority of the respective clinical site. 
5. Subject is a minimum of 18 years of age. 
 
Exclusion Criteria: 
General: 
1. Left upper limb vasculature in the left extremity precluding 6Fr 
sheath radial / brachial / subclavian access. 
2. Inadequate circulation to the left extremity as evidenced by signs 
of artery occlusion (modified Allen’s test) or absence of radial/ 
brachial pulse. 

 
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3. Hemodialysis shunt, graft, or arterio-venous fistula involving the 
upper extremity vasculature. 
4. TAVR 
conducted 
via 
other 
than 
transfemoral 
access 
(subclavian, 
axillar, 
transapical, 
transaortic, 
carotid 
or 
transcaval). 
5. Evidence of an acute myocardial infarction ≤ 1 month before the 
intended treatment. 
6. Aortic valve is a congenital unicuspid or bicuspid valve. 
7. Mixed aortic valve disease (aortic stenosis and aortic 
regurgitation with predominant aortic regurgitation >3+). 
8. Any therapeutic invasive cardiac procedure resulting in a 
permanent implant that is performed within 30 days of the index 
procedure (unless part of planned strategy for treatment of 
concomitant coronary artery disease). 
9. Blood dyscrasias as defined: Leukopenia, acute anemia, 
thrombocytopenia, history of bleeding diathesis or coagulopathy. 
10. Hemodynamic 
instability 
requiring 
inotropic 
support 
or 
mechanical heart assistance. 
11. Need for emergency surgery for any reason. 
12. Severe hypertrophic cardiomyopathy with or without obstruction. 
13. Severe ventricular dysfunction with LVEF ≤30%. 
14. Echocardiographic evidence of intracardiac or aortic mass, 
thrombus, or vegetation. 
15. Symptomatic or asymptomatic severe (≥ 70%) occlusive carotid 
disease requiring concomitant CEA / stenting. 
16. Subject 
has 
undergone 
carotid 
stenting 
or 
carotid 
endarterectomy within the previous 6 weeks. 
17. Active peptic ulcer or upper GI bleeding within the prior 6 
months. 
18. A known hypersensitivity or contraindication to aspirin, heparin, 
ticlopidine, or clopidogrel, device component material, or 
sensitivity to contrast media, which cannot be adequately pre-
medicated. 
19. Recent (within 6 months) CVA or a TIA. 
20. Renal insufficiency (creatinine > 3.0 mg / dL or GFR < 30) and / 
or renal replacement therapy at the time of screening. 
21. Life expectancy < 12 months due to non-cardiac co-morbid 
conditions. 
22. Subjects in whom anti-platelet and / or anticoagulant therapy is 
contraindicated, or who will refuse transfusion. 
23. Subjects who have active bacterial endocarditis or other active 
infections. 
24. Currently participating in an investigational drug or another 
device study. 

 
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25. Subjects who have a planned treatment with any other 
investigational device or procedure during the study follow-up 
period (30 days). 
26. Subjects with planned concomitant surgical or transcatheter 
ablation for Atrial Fibrillation during the study follow-up period 
(30 days). 
27. Any subject with a balloon valvuloplasty (BAV) within 30 days of 
the procedure. 
28. Subject is a woman of child-bearing potential. 
29. Patient with Heparin-Induced Thrombocytopenia Syndrome. 
30. Inner diameter of aortic arch is less than 25mm. 
31. Brachiocephalic trunk originating from the aortic arch that splits 
into the bilateral subclavian arteries and a bicarotid trunk (Origin 
D). 
32. Hepatic failure (defined as liver enzyme elevations two times the 
upper limit of normal) or active infectious hepatitis 
33. Cardiogenic shock or severe hypotension (systolic blood 
pressure < 90 mm Hg) at the time of the index procedure 
34. Subjects who have a planned concomitant cardiac surgical or 
interventional procedure (e.g., coronary revascularization) 
during the TAVI procedure 
35. Subjects who have a pre-existing prosthetic heart valve in any 
position 
Neurological: 
1. Subject had active major psychiatric disease. 
2. Subject has severe visual, auditory, or learning impairment and 
is unable to comprehend English or local language and therefore 
unable to be consented for the study. 
3. Subjects 
with 
neurodegenerative 
or 
other 
progressive 
neurological disease or history of significant head trauma 
followed by persistent neurologic defaults or known structural 
brain abnormalities. 
Angiographic: 
1. Excessive tortuosity or severe peripheral arterial disease in the 
left radial / brachial / subclavian artery preventing ProtEmbo 
System access and insertion. 
2. Subject whose left radial / brachial / subclavian artery reveals 
significant stenosis, calcification, ectasia, dissection, occlusion 
or aneurysm, in particular at or within 3 cm of the aortic ostium. 
3. Subject with significant stenosis, ectasia, dissection, or 
aneurysm in the ascending aorta or in the aortic arch, or with 
abnormal aortic arch angulation or abnormal anatomical 
conditions of the aorta. 

 
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Magnetic Resonance Imaging: 
1. Subject Body Mass Index (BMI) precluding imaging in scanner. 
2. Contraindications to MRI (subjects with any implantable 
temporary or permanent pacemaker or defibrillator, metal 
implants in field of view, metallic fragments, clips, or devices in 
the brain or eye before TAVR procedure). 
3. Subjects who have a high risk of complete AV block after TAVR, 
with the need of permanent pacemaker (e.g. subjects with pre-
existing bifascicular block or complete right bundle branch block 
plus any degree of AV block). 
4. Planned implantation of a pacemaker or defibrillator implantation 
within the first 4 days after TAVR. 
5. Claustrophobia precluding MRI scanning. 
6. No scanner hardware, software, coil or protocol changes during 
the course of the study. 
Medication 
Administration of anticoagulant medicines and monitoring of 
activated clotting time (ACT) per institution guidelines shall be 
performed throughout the TAVR procedures. A target ACT of at 
least 250 seconds should be maintained for the duration of the 
procedure. For those patients not receiving chronic oral 
anticoagulation prior TAVR, a dual antiplatelet therapy before and 
after the procedure is recommended.  
For those patients with chronic dual antiplatelet therapy (DAPT) use, 
it is recommended to continue with acetylsalicylic acid and 
clopidogrel therapy for at least 1 month after TAVR, as per the 
standard practice of the institution. 
For those patients without chronic DAPT use, it is recommended to 
administer 300 mg of each acetylsalicylic acid and clopidogrel within 
24 hours (and at least 2 hours) before the procedure or the 
equivalent as per the standard of care at the institution. 
No modification of the patient’s ongoing medical treatment is 
required as a result of participation in the PROTEMBO C Trial. 
 
 
Sponsor: 
Protembis GmbH, Pauwelsstr. 17, 52074 Aachen, Germany 
 
CRO: 
MAXIS Medical GmbH, Stichlingstrasse 1 , 60327 Frankfurt am 
Main, Germany 
 
Principal Investigators:  See list of investigators in Appendix A. 
 
 
 
Core Laboratories: 
MR Imaging: 

 
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Robert Zivadinov, M.D. 
Buffalo Neuroimaging Analysis Center 
University at Buffalo 
State University of New York 
100 High Street 
Buffalo, NY 14203 
Office Phone: +1-716-859-3579 
 
Histopathology: 
 
Renu Virmani, M.D. 
CVPath Institute, Inc. 
19 Firstfield Road 
Gaithersburg, MD 20878 
Office Phone: +1-301-208-3570 
 
Computed Tomography: 
 
AngioConsult GmbH 
Heydenreichstr. 5 
67346 Speyer 
Germany 
Office Phone: +49-6232-6042890 
 
 
Medical Monitor: 
James C. Leiter, M.D. 
Geisel School of Medicine at Dartmouth 
Lebanon, NH 03756 
Office Phone: +1-603-650-8533 
 
Statistical  
Assumptions: 
 
 
Safety  
Endpoint 
Performance 
Endpoint 
Comparator 
Rate 
15% 
90% 
Delta 
10% 
15% 
Performance 
goal (PG) 
25% 
75% 
Power 
85% 
85% 
Estimated 
ProtEmbo rate 
10.4% 
89% 
Sample Size 
60 
42 
 

 
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2. Introduction and Background 
According to the Centers for Disease Control, an estimated 795,000 strokes occur each year 
in the United States. According to Bergman et al. lifetime direct costs of stroke per patient 
amount to circa € 33,000 for females and circa € 29,000 for males (Bergman et al., 1995). 
Approximately 3% of a country’s total health expenditure is attributable to all-cause stroke 
treatment, a figure that typically represents 0.2–0.3% of gross domestic product (Evers et al., 
2004). The cost of cerebrovascular diseases to healthcare systems was € 21 billion in 2003 in 
the 25 EU member states. Eighty-two percent of this figure was due to inpatient care, which 
represented 2.4% of total healthcare costs (Leal et al., 2006). In 2010, strokes cost in the 
United States was estimate at $ 53.9 billion dollars (Bendszus & Stoll, 2006). Thus, mitigation 
of stroke risk has the potential to improve the lives of patients and reduce health care costs 
significantly. 
Stroke can occur in subjects undergoing interventional cardiovascular procedures such as 
vascular stenting, catheter ablation for atrial fibrillation, endovascular stent grafting, balloon 
aortic valvuloplasty, and transcatheter aortic valve replacement (TAVR). Procedure-
associated cerebrovascular events are usually embolic and embolic protection devices (EPD) 
are intended to reduce the risk of cerebral embolization. Major adverse events (mortality, 
stroke, and myocardial infarction) have been reduced during carotid and saphenous vein graft 
stenting when embolic protection devices were used (Baim et al., 2002; Stone et al., 2003; 
Gurm et al., 2008). 
The advent of transcatheter treatments for valvular heart disease has been a minor revolution 
in the care of patients, especially for patients with disabilities or intercurrent illnesses that 
precluded undergoing open cardiac surgical procedures. TAVR was initially introduced to treat 
patients with severe aortic stenosis who were not candidates for surgical replacement of the 
aortic valve because of the high risk of morbidity and mortality associated with open heart 
surgery and cardiopulmonary bypass (Holmes et al., 2012). As TAVR devices have improved 
and the procedure to place the valves has improved, especially sizing the replacement valve 
properly, the indications for TAVR have been expanding, and patients with lower preoperative 
risks, who might actually tolerate an open heart surgery, are nonetheless selecting the TAVR 
procedure because it offers an acceptable, functional aortic valve replacement, and it is less 
invasive and causes less morbidity (Eggebrecht & Mehta, 2016; Leon et al., 2016). 
Despite the improvements in TAVR procedures and outcomes, the occurrence of stroke 
represents a significant morbidity of the TAVR procedure. The incidence of stroke or transient 
ischemic attack (TIA) was 3.3% in a large meta-analysis (Bendszus & Stoll, 2006; Eggebrecht 
et al., 2012), but may be as high as 10% in some series (Tamburino et al., 2011; Leon et al., 
2016), and when stroke occurs, the 30-day mortality following TAVR is increased 3.5 fold 
(Eggebrecht et al., 2012; Sabate et al., 2013). In a meta-analysis of randomized controlled 
trials in which embolic protection was used (Giustino et al., 2017), embolic protection was 
associated with significantly lower risk of death or stroke, and the estimated number needed 
to treat with embolic protection was 22 patients to prevent 1 death or stroke. Stroke associated 
with the TAVR procedure may occur when vascular material or debris is dislodged during 
TAVR so the cerebrovascular events are usually embolic, and the emboli consist of cholesterol 
particles, air, atherosclerotic plaque material, thrombus and/or calcified valve material (Clark 
et al., 1995; Barbut et al., 1997; Leon et al., 2010; Eltchaninoff et al., 2011; Nuis et al., 2012; 
Van Mieghem et al., 2013). Clinically detectable strokes represent only a small fraction of the 

 
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embolic events that occur during TAVR – many of the emboli occlude cerebral vessels in ‘silent’ 
areas of the brain that, nonetheless, have adverse long-term effects on cognitive and motor 
function (Gass et al., 2004; Ghanem et al., 2010; Kahlert et al., 2010; Fairbairn et al., 2012). 
Investigators have turned to diffusion weighted magnetic resonance imaging (DW-MRI) to 
count the number and assess the volume of new brain lesions following TAVR. DW-MRI is 
more sensitive to the occurrence of cerebrovascular events than the clinical exam and reflects 
more accurately the risk of subsequent cognitive decline (Kahlert et al., 2012; Abdul-Jawad 
Altisent et al., 2016) and was the recommended imaging modality for embolic protection 
devices in a recent consensus statement (Lansky et al., 2017). DW-MRI obtained in the 
immediate post-TAVR period (generally within a week of the index procedure) have revealed 
the extent of embolic events during and following TAVR; new ischemic infarcts, often small, 
can be identified in almost every patient undergoing TAVR even though the incidence of 
clinically detectable stroke is 10% or less (Ghanem et al., 2010; Kahlert et al., 2012; Abdul-
Jawad Altisent et al., 2016). After 30 days, many of the embolic infarcts have resolved and are 
no longer detectable by DW-MRI (Lansberg et al., 2001; Gass et al., 2004; Kahlert et al., 2012; 
Rodes-Cabau et al., 2014), and other MRI imaging sequences (FLAIR MRI) may be preferred 
(Lansky et al., 2017). Despite the sensitivity of DW-MRI, the current AHA guidelines do not 
recommend routine acquisition of the DW-MRIs or routine assessment of cognitive function 
and suggest that clinicians rely on a careful neurological assessment (Sacco et al., 2013). 
In summary, there is abundant evidence that TAVR is associated with embolic events in 
patients. New ischemic lesions can be detected in DW-MRIs in most patients, but the incidence 
of clinically detectable neurological events is lower (probably between 4 to 7%). Embolic 
protection devices seem to reduce the number and/or volume of new ischemic events detected 
by DW-MRI, but the clinical significance of this reduction cannot be assessed because there 
are too few patients to date treated with embolic protection during TAVR, and the duration of 
follow-up of patients treated with embolic protection devices during TAVR is too short. 
Nevertheless, the high frequency of embolic events and the emerging evidence of a consistent 
reduction in volume of ischemic brain tissue following TAVR when embolic protection devices 
were used indicate that further work is merited, especially for devices that protect all three of 
the great vessels, which originate in the arch of the aorta and supply the cerebral circulation. 
Devices that protect all three vessels provide greater protection of all regions of the cerebral 
circulation. 
2.1. Rationale behind Proposed Research 
The ProtEmbo is an adjunctive device used during the TAVR procedure and removed following 
completion of valve replacement. Based on the Edwards Lifesciences SAPIEN PARTNER A 
trial, 50% of strokes occurred in the first 24 hours, 96% in the first 9 days, 100% in the first 28 
days (Miller et al., 2012). Embolic filters have an established basis of clinical safety and efficacy 
in carotid filtration. Therefore, carotid filtration during TAVR should also provide benefits. 
In addition, new cerebral lesions detected with MRI are reported in 48% of patients after valve 
surgery and in up to 70 – 80% after TAVR (Ghanem et al., 2010; Kahlert et al., 2012). Most of 
these lesions have no immediate clinical consequences, but the potential for neurocognitive 
decline in the long-term remains to be investigated. Several studies have linked (initially 
subclinical) micro-emboli after heart surgery to neurocognitive outcomes (Clark et al., 1995; 
Barbut et al., 1997). Vascular cognitive impairment (VCI) could also result from multiple, initially 

 
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subclinical, cerebral emboli. Liberation of debris to the cerebrovascular or peripheral vascular 
systems clearly provides no benefit to the patient and can only cause potential harm. 
The ProtEmbo System was developed in an effort to deflect embolic debris during TAVR. 
Given low peri-procedural complication rates and the lack of reported procedural strokes when 
using comparable embolic protection devices, an embolic protection device could be highly 
beneficial for patients undergoing endovascular procedures such as TAVR (Van Mieghem et 
al., 2013). 
2.2. Study Objective 
The primary objective of this exploratory study is to assess the safety and performance of the 
ProtEmbo Cerebral Protection System used for embolic protection during Transcatheter Aortic 
Valve Replacement (TAVR) compared to TAVR standard of care (without embolic protection). 
The secondary objective of this study is to assess the efficacy of the ProtEmbo system by 
comparing the median new lesion volume in the brain and the rate of death or all strokes 
compared to historical data. 
2.3. Background 
2.3.1. Previous Clinical Experience 
Many devices have been developed to reduce the occurrence of stroke by catching the emboli 
during endovascular or cardiac valvular procedures or by deflecting the emboli produced 
during these procedures toward less vulnerable circulations. All embolic protection devices 
developed to date use a mesh filter of some sort to capture emboli or to cover the orifices of 
the great vessels supplying the brain. Embolic protection devices have some risks of their own. 
In the presence of diffuse atherosclerosis in the aorta and great vessels supplying the brain, 
placement of the embolic protection device may dislodge emboli independent of any 
embolization associated with TAVR (Steinvil et al., 2016). Investigators in the field are 
generally skeptical about the benefits of embolic protection devices since existing devices have 
not shown benefit in cardiac surgery (Banbury et al., 2003) or in carotid artery stenting (Stabile 
et al., 2014). On the other hand, the sheer number and volume of emboli collected during 
TAVR has led a variety of companies to develop and test embolic protection devices to be 
used during TAVR. Using such devices during TAVR has reduced the number and /or volume 
of infarcts seen in DW-MRIs, but whether the reduction in the number or volume of acute 
infarcts detected by DW-MRI will translate into a clinically meaningful preservation of cognitive 
or motor function has not yet been determined. A recent study-level meta-analysis of all 
randomized control trials for cerebral embolic protection to date found that, as a class, embolic 
protection devices used during TAVR decreased the risk of stroke and mortality compared to 
unprotected TAVR, which corresponded to an approximately 4.0 % reduction in absolute risk 
(Giustino et al., 2017). When patients from the Sentinel US IDE, Clean-TAVI, and Sentinel-
Ulm studies were combined, a propensity-matched cohort of patients revealed significant 
reductions in all-stroke risk and in combined all-cause mortality and all-stroke risk in patients 
who received treatment with an embolic filter protection device during TAVR compared to those 
who did not. The relative risk reduction for all-stroke risk was 65% in patients with treated with 
embolic protection compared to the risk of all-stroke in those without embolic protection during 

 
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TAVR and a similar relative risk reduction of 66% in all-cause mortality and all-stroke (Seeger 
et al., 2019). 
The Embrella device (Edwards Life Sciences) is a deflection device that is placed over the 
orifices of the brachiocephalic trunk and the left common carotid artery. The device is deployed 
through the right radial or brachial artery using a 6 Fr. delivery sheath. Two ‘petals’ are opened 
to cover the orifices of the great vessels once the device is in the aorta. Two published reports 
using the Embrella are available (Rodes-Cabau et al., 2014; Samim et al., 2016). In the 
ProTAVI-C study, the Embrella device was implanted in 41 patients and 11 other patients 
constituted a control group. Samin et al. reported results from a single center in 15 patients 
treated with the Embrella device and compared results to 37 patients who had previously had 
TAVR without embolic protection, but in whom DW-MRIs had been obtained after the TAVR 
(Samim et al., 2015). The Embrella device was feasible to use; it was deployed successfully, 
and no new problems were introduced in patients undergoing TAVR in whom the Embrella 
device was also deployed. However, the number of strokes was not reduced. In the ProTAVR-
C study, the number of high intensity transient signals detected by transcranial Doppler (an 
indication of cerebral ischemia) was actually increased in the Embrella treatment group – 
consistent with the idea that deployment of embolic protection devices may initiate some 
embolization all by itself. Even though the number of infarcts identified by DW-MRI when the 
Embrella device was deployed was not different, the volume of ischemic tissue was 
significantly reduced in the Embrella treated groups. 
The TriGuard device (Keystone Heart, now Venus Medtech) is also a deflection device placed 
across the orifices of the great vessels. The TriGuard device is mechanically more complex, 
but it covers the brachiocephalic, the left common carotid and the left subclavian artery orifices 
consistently (the Embrella device does not consistently cover the opening of the left subclavian 
artery). The TriGuard device is introduced through the femoral artery and requires a 9 Fr. 
delivery sheath. The TriGuard device was studied in the DEFLECT I trial, a single arm, 
multicenter observational trial (Baumbach et al., 2015), and a CE mark was obtained based 
on results from the first 20 patients. In a subsequent, randomized, controlled trial, the 
DEFLECT III Trial, there were 39 patients in the control group (TAVR without embolic 
protection) and 26 patients in the TriGuard plus TAVR treatment group (Lansky et al., 2015). 
The TriGuard was deployed successfully to cover all three orifices of the great vessels in ~90% 
of the patients. The number of strokes and the clinically detected neurological impairment did 
not differ between groups. The volume of new lesions detected by DW-MRI was significantly 
less in the TriGuard treatment group (although the number of large ischemic lesions was not 
different between groups). Many subjects were lost to follow-up in one endpoint or another, 
and so the assessment of neurological outcomes was incomplete. 
The Sentinel device (Claret Medical, now Boston Scientific) is an embolic capture device that 
protects the brachiocephalic and left common carotid arteries (there is no filter or embolic 
collection placed within or across the opening of the left subclavian artery). The Sentinel device 
is placed through the right radial brachial artery through a 6 Fr. sheath. The Sentinel device 
has been studied more extensively than the other devices using a variety of TAVR devices in 
3 randomized controlled trials (CLEAN-TAVI, MISTRAL-C, SENTINEL). The CLEAN-TAVI 
Trial was completed on an earlier generation of the device (Montage device), there were 50 
patients in the device plus TAVR group and 50 patients in the TAVR alone, control group) 
(Haussig et al., 2016). The device was deployed successfully ~90% of the time. The contents 
of the filter / capture device confirmed the ubiquity of emboli associated with TAVR. There were 

 
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no significant differences in neurological symptoms between the TAVR alone and TAVR plus 
Sentinel device, and no reduction in the incidence of new lesions detected by DW-MRI. 
However, the number of new lesions in each patient was reduced in the Sentinel device group 
compared to the TAVR alone group. The MISTRAL-C Trial also reported both a reduction in 
the number and volume of new brain lesions on DW-MRI 5 days post-procedure, and a smaller 
decline in cognitive function measured at 3 months post-procedure in Sentinel device 
treatment group. The SENTINEL Trial was a large multicenter randomized control trial, and in 
this trial as well, debris was captured in the devices in 99% of the cases, and patients treated 
with the Sentinel device had a lower volume of new cerebral lesions. Moreover, the MACCE 
rate was slightly lower in the Sentinel treatment group, and the incidence of strokes was 
reduced compared to unprotected TAVR procedures. It was demonstrated for the first time, 
that there is a correlation between new lesion volume and neurocognitive decline (Demir et al., 
2018), and on the individual device level, the Sentinel demonstrated a significantly higher rate 
of stroke-free survival when the Sentinel device was used during TAVR compared to 
unprotected TAVR (Seeger et al., 2019). 
2.3.1.1. 
Previous Clinical Experience with the ProtEmbo Device 
The Sponsor completed a First in Human study, ‘Cerebral Protection in Transcatheter Aortic 
Valve Replacement – The PROTEMBO SF Trial,’ in October 2018. The primary objective of 
The PROTEMBO SF Trial was to evaluate the safety and feasibility of the ProtEmbo Cerebral 
Protection System used for embolic protection during TAVR. The indication for use of the 
ProtEmbo device was identical to the current study – the ProtEmbo device is indicated as a 
temporary intra-aortic filter placed within the arch of the aorta to deflect embolic material in 
patients undergoing cardiovascular procedures. Five (5) subjects with severe symptomatic 
native aortic valve stenosis, selected by the Heart Team at each study center, who met the 
approved indications for TAVR and complied with the inclusion/ exclusion criteria, were 
enrolled in the trial. The trial was a prospective, observational, multi-center, intention-to-treat 
clinical investigation of the safety and feasibility of the ProtEmbo used in subjects with severe 
symptomatic native aortic valve stenosis indicated for TAVR. The inclusion and exclusion 
criteria were identical (the wording of the inclusion and exclusion criteria were changed for the 
PROTEMBO C Trial, but the patients included and excluded were not altered by these editorial 
changes). 
This First in Human trial demonstrated that the ProtEmbo System and, specifically, the 
ProtEmbo device were safe for use in humans. There were no Serious Adverse Events 
attributable to the ProtEmbo device. There were no MACCE and no new strokes and no 
cognitive decline among the patients in the trial. TAVR was successfully performed in all 
patients. The ProtEmbo did not limit or interfere with the capacity to perform TAVR 
successfully. A ProtEmbo was successfully implanted and deployed in four of five subjects in 
the study. One patient was unable to receive the ProtEmbo as excessive calcification of the 
left radial artery precluded insertion of a commercially available guiding sheath through which 
the ProtEmbo device must be delivered. The PROTEMBO SF Trial was not designed to 
evaluate the effectiveness of embolic protection, but the study design did successfully model 
the neurological evaluations and MR images that will be required for a formal evaluation of the 
ProtEmbo when used during TAVR procedures. The number of pre-existing lesions was 
relatively large in this particular group of patients compared to the studies summarized above, 
and the MR images indicated that new cerebral lesions followed each TAVR (as other studies 
have also demonstrated). Although new lesions were apparent in MR images following each 

 
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TAVR, there were no new strokes and no changes in cognitive function in any of the subjects 
following TAVR performed using the ProtEmbo. Thus, the safety and feasibility of the 
ProtEmbo was demonstrated in four subjects enrolled in the PROTEMBO SF Trial. Moreover, 
the responses of the four patients treated within the PROTEMBO SF Trial did not lead to 
identification of any new or unanticipated risks. 
2.3.2. Summary: Previous Experience with Embolic Protection Devices in 
TAVR 
In summary, embolic protection devices consistently reduce the volume or number of new 
emboli ischemic lesions on DW-MRI images of the brain and appear to reduce the incidence 
of stroke and MACCE events following TAVR. The clinical findings are only trends thus far (the 
studies were not powered for some of these endpoints). Nevertheless, embolic protection 
devices used during the TAVR procedure appear to be safe and feasible, and the early 
surrogate and clinical efficacy measures suggest that there will be clinical benefit when 
sufficiently large numbers of subjects are studied. The benefits of embolic protection appear 
to outweigh the risks of using these devices based on the data available at this time. Thus, 
there is good justification for the Sponsor to move forward with the PROTEMBO C Trial. 
2.3.3. Preclinical Experience with the ProtEmbo Device 
The ProtEmbo Cerebral Protection System has been subjected to a comprehensive pre-clinical 
testing program to verify design, safety, and performance against pre-specified engineering, 
mechanical and system requirements. Pre-clinical testing included bench, biocompatibility, 
animal, and sterilization testing. In addition to evaluation against internal specifications and 
international standards, the ProtEmbo System was also tested in accordance with the US Food 
and Drug Administration Center For Devices and Radiological Health’s Embolic Protection 
Device (EPD) guidance document - Guidance for Industry and Staff – Coronary and Carotid 
Embolic Protection Devices – Premarket Notification [510(k)] Submissions (February 15, 2008) 
where applicable. 
Bench testing included embolic filter performance (deflection efficiency, flow characteristics, 
resistance to rupture), simulated use (deployment and retrieval forces, TAVR system and 
accessory device compatibility, kink resistance, tensile strength). All required bench testing 
was successfully completed and demonstrated compliance with the predetermined 
performance specifications. 
Acute animal studies have been performed to further support the safety and performance of 
the ProtEmbo System. Multiple developmental studies and a verification study were performed 
to verify the safety and feasibility of deployment and retrieval of the device and 
histopathological responses of the device. The device elicited no adverse blood or tissue 
response, and no gross vascular injuries were associated with the placement or removal of the 
device, thereby demonstrating the safety and feasibility of the device in an animal model. In 
summary, pre‐clinical animal studies have been conducted and support the safety and 
performance of the ProtEmbo System through simulated use under in‐vivo conditions in a 
porcine model. 

 
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Complete biocompatibility testing was performed for the ProtEmbo System according to ISO‐
10993, Biological Evaluation of Medical Devices Part 1: Evaluation and Testing requirements 
for externally communicating devices in limited contact with circulating blood, and Good 
Laboratory Practices. These tests include cytotoxicity, sensitization, irritation, acute system 
toxicity, hemocompatibility (hemolysis, complement activation, in-vivo thromboresistance), and 
pyrogenicity. All required biocompatibility tests for the ProtEmbo System were performed and 
the results met the testing requirements; therefore, the ProtEmbo System can be considered 
biocompatible for its intended use. 
In conclusion, the ProtEmbo System has been fully evaluated through pre-clinical testing per 
the identified risks and demonstrates compliance with its predetermined performance 
specifications. 
3. Test System (Investigational Device) 
3.1. Name of Investigational Device 
ProtEmbo Cerebral Protection System (also called ‘ProtEmbo System’ or ‘ProtEmbo Device’ 
or ‘System’ or ‘Device’). 
3.1.1. Model and version 
Product Name: ProtEmbo® Cerebral Protection System  
Product Reference (REF): 10100 
Product Model Number: PRS_10100_ProtEmbo_System, Final Packaging 
3.2. Intended Use 
The ProtEmbo System is indicated for use as a temporary intra-aortic filter device to deflect 
embolic material in patients undergoing cardiovascular procedures. 
3.3. Classification 
The ProtEmbo System is classified in class III in accordance with Rule 7 of MEDDEV 2. 4/1 
Rev. 9 and Rule 6 of Regulation (EU) 2017/745, Annex VIII, Chapter III. 
3.4. System Components 
The ProtEmbo System is a temporary use, non-active, intra-aortic embolic protection deflection 
filter device that is positioned across the orifices of the major vessels exiting the aortic arch 
(Truncus Brachiocephalicus, Left Common Carotid Artery and Left Subclavian Artery), refer to 
Figure 1. The device is placed in the central arterial system as an adjunctive device at the 
beginning of an index procedure to deflect embolic particles during the procedure and removed 
following the completion of the procedure. 
 

 
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Figure 1. ProtEmbo Cerebral Protection System position in the aortic arch (illustration). 
The ProtEmbo System comprises three main components (Device, Shaper and Handle), refer 
to Figure 2 and Figure 3. 
The ProtEmbo Device comprises a Filter (1), a Frame (2) with Radiopaque Marks (3 a-e) 
and a Shaft (4). The filter consists of a porous material that allows free passage of the blood 
cells through it, but blocks embolic particles. The Shaft is connected to the Frame and enables 
delivery of the unexpanded Device via a Delivery Catheter and placement (expansion) of the 
Device in the aortic arch of a patient. In its expanded state the Frame spans the Filter to cover 
all 3 side branch vessels of the aortic arch (Truncus Brachiocephalicus, Left Common Carotid 
Artery and Left Subclavian Artery). Radiopaque Markers on the Frame enable fluoroscopic 
visualization to allow for correct placement and positioning of the Device.  
The ProtEmbo Shaper (5) is used to prepare the Device for placement into the inner lumen 
of the distal end of a delivery catheter. The Shaper is a sterile placement tool with a dedicated 
folding mechanism; produced and provided by Protembis GmbH. Markers at the distal end of 
the Shaper indicate the first point of contact with the proximal end of the device Shaft. 
 
Figure 2. ProtEmbo Cerebral Protection System functional parts (illustration). 
1 
2 
3c 
3e
3d
3a,b 
4 
5 

 
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The ProtEmbo Handle (“Handle”) (6) is used to guide the ProtEmbo Device into the inner 
lumen of the distal end of a delivery catheter, position the Device tip during deployment and 
enhance the positioning of the device within the aortic arch. The Handle is connected to the 
delivery catheter and provides the user interface with a dedicated push, pull and torque 
functionality as well as flushing and de-aering the system; produced and provided by Protembis 
GmbH. 
 
 
Figure 3. ProtEmbo Cerebral Protection System Handle (illustration). 
The ProtEmbo System Components are single-use and sterilized by ethylene oxide 
sterilization. The materials that have contact with the patient’s blood or tissues are shown 
below: 
Device Component 
Material 
Shaft 
Stainless Steel 
Shaft Coating 
Polyether block amide (PEBA) 
Frame 
Nitinol 
Filter 
Polyamide 
Filter Coating 
Heparin (porcine source) 
Radiopaque Marker 
90% platinum/ 10% iridium 
Distal Frame Fixation Yarn 
Polyethylene Terephthalate (PET) / D&C Green No. 6 
Frame/Filter Glue 
Polyurethane 
Filter Glue 
Polyurethane 
Filter/Shaft Glue 
Polyurethane 
Catheter Lock 
Slider Lock 
Device 
Lock 
Flush Port 
Handle Body 
Handle Slider 
6 

 
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Device Component 
Material 
Frame/Shaft Glue 
Polyurethane 
Filter/Shaft Fixation Wire 
Stainless Steel 
Table 1: ProtEmbo System components and materials in contact with the patient’s blood or tissues. 
3.5. Device Accountability 
Access to ProtEmbo System inventory will be controlled and will be housed in a secure 
location. Records will be maintained to document the physical location of inventory from 
shipment / removal from Sponsor facility through use and / or return or disposal. 
The site will be responsible for keeping a Device Accountability Log provided by the Sponsor 
or its designated representative in which will be recorded, at a minimum, date of receipt, 
ProtEmbo System identification number, expiration date, date of use, subject unique identity 
code and date of disposal of the device. 
If there is a product malfunction or other need to return the system or system components to 
the Sponsor, the Sponsor should be contacted for safe product disposal and / or return details. 
Such disposal does not include the used ProtEmbo Devices which are to be fixed and 
submitted to the histopathology lab for analysis. 
NOTE: Please contact Sponsor at +49 241 99033622 or CRO at +49 69 2400 3626 
immediately for instructions if a device malfunction / failure has occurred. 
The Investigator is responsible for ensuring that the investigational devices are used only under 
the Investigator’s supervision and are only used according to this protocol and any approved 
amendments. The Investigator will not supply an investigational device to any person not 
authorized to participate in the study. The Investigator shall document in the electronic Case 
Report Forms (eCRFs) the lot numbers of the devices used during each case. 
3.6. Return of Devices 
All unused investigational devices will be returned to the study Sponsor upon completion of 
the clinical study. All used investigational devices will be returned to the study Sponsor for 
analysis. Any investigational device that fails to perform correctly will be equally returned to 
the study Sponsor for analysis. The Investigator or his / her designated representative is 
responsible for device accountability and disposition of all used and unused devices. The study 
Sponsor or its designated representative will conduct device reconciliation at the completion 
of subject enrollment or at the conclusion of the study. 
4. Study Overview 
Sponsor plans to conduct a clinical trial of the ProtEmbo Cerebral Protection System used as 
an adjunctive device for embolic protection during Transcatheter Aortic Valve Replacement 
(TAVR). The study plan was developed according to the guidance given by Medical Device 
Regulation (EU) 2017/745, Annex XV. The rationale for the trial design, endpoints and 

 
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variables selected for study are described below. The justification for the study design and the 
content of the study were fully described in the Protembis Clinical Evaluation Plan. 
4.1. Study Design 
The PROTEMBO C Trial is an exploratory, international, multi-center, single-arm study of the 
safety and performance of using the ProtEmbo System in subjects with severe symptomatic 
native aortic valve stenosis indicated for TAVR. As described in the Protembis Clinical 
Evaluation Plan, an adequate body of historical data pertaining to embolic protection devices 
exists against which Protembis can test the safety and performance of the ProtEmbo System 
in a single-arm trial. 
As described in the Clinical Evaluation Plan and the Background for the current study, the 
appropriate safety endpoint for embolic protection devices used during TAVR is defined as 
Major Adverse Cardiac and Cerebrovascular Events (MACCE) at 30 days defined by VARC-2 
including all-cause mortality, all stroke, life-threatening or disabling bleeding, vascular injury 
and acute kidney injury (stage 2 or 3). Previous studies have used a similar definition of safety 
and, therefore, results of these previous studies provide useful historical comparison data to 
evaluate the safety of the ProtEmbo System. Similarly, performance is defined as the ability to 
deliver, deploy, and remove the device successfully, the ability to secure positioning and 
stability of the position throughout the procedure, and the ability to deflect embolic material, as 
assessed by adequate coverage, while not impeding blood flow. Results from previous studies 
of embolic protection devices used during TAVR provide useful historical comparison data 
against which the performance of the ProtEmbo System can be compared.  
4.2. Primary Study Endpoints 
4.2.1. Safety 
Major Adverse Cardiac and Cerebrovascular Events (MACCE) at 30 days defined by VARC-2 
including all-cause mortality, all stroke, life-threatening or disabling bleeding, vascular injury 
and acute kidney injury (stage 2 or 3).  
Stroke severity will be quantified according to the National Institutes of Health Stroke Scale 
(NIHSS) score and the occurrence of other Serious Adverse Events up to 30 days. 
4.2.2. Performance 
Technical success, defined as ability to safely deliver, deploy, and remove the device, ability 
to secure positioning and stability of the position throughout the procedure and ability to deflect 
embolic material, as assessed by adequate coverage, while not impeding blood flow. 

 
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4.3. Secondary Study Endpoints 
4.3.1. Efficacy: 
The secondary efficacy endpoints for this clinical investigation will be based on magnetic 
resonance (MR) imaging and a composite of death or strokes, each compared to historical 
data: 
For the MR imaging endpoint, the median new lesion volume in the brain assessed by diffusion 
weighted magnetic resonance images (DW-MRI) at 2 to 7 days will be compared historical 
data; The total new lesion volume is defined as the sum of all diffusion-positive new cerebral 
lesions in post-procedural DW-MRI relative to the pre-TAVR DW-MRI. 
For the composite death or stroke endpoint, the rate of death or all strokes according to VARC-
2 criteria (to define occurrence and type stroke) within 3 days (72 hours) of the TAVR 
procedure will be compared to historical data; Stroke severity will be quantified according to 
the National Institutes of Health Stroke Scale (NIHSS) score. 
4.4. Number of Subjects and Sites 
Up to 60 treated patients in whom the ProtEmbo device is used during a TAVR procedure may 
be enrolled at up to 10 clinical study centers. 
4.5. Study Population 
The study population comprises of subjects with severe symptomatic calcified native aortic 
valve stenosis who meet the approved indications for TAVR with commercially available 
transcatheter aortic valves by transfemoral route. 
4.6. Enrollment Criteria 
A potential subject must meet all of the inclusion criteria and none of the exclusion criteria as 
outlined below in order to be considered eligible to participate in this study. 
4.6.1. Inclusion Criteria 
Subjects eligible to participate must meet all of the following at screening and / or baseline 
visits: 
1. The heart team recommends transcatheter valve aortic valve replace consistent with 
the 2017 ESC/EACTS Guidelines for the management of valvular heart. 
2. Compatible left subclavian artery (≥ 4 mm diameter) without significant stenosis (> 
70%) and distance between the origin of left subclavian artery and valve plain of ≥ 
90mm as determined by Multi-Slice Computed Tomography (MSCT) scan or equivalent 
imaging modality. 
3. The subject and the treating physician agree that the subject will undergo the scheduled 
pre-procedural testing and return for all required post-procedure follow-up visits. 

 
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4. The subject is able to provide informed consent, has been informed of the nature of the 
trial, agrees to its provisions and has provided written informed consent as approved 
by the relevant regulatory authority of the respective clinical site. 
5. Subject is a minimum of 18 years of age. 
4.6.2. Exclusion Criteria 
Potential subjects with one or more of the following shall be excluded from the study even if 
they meet the inclusion criteria: 
4.6.2.1. 
General Exclusion Criteria 
1. Left upper limb vasculature in the left extremity precluding 6Fr sheath radial / brachial 
/ subclavian access. 
2. Inadequate circulation to the left extremity as evidenced by signs of artery occlusion 
(modified Allen’s test) or absence of radial / brachial pulse. 
3. Hemodialysis shunt, graft, or arterio-venous fistula involving the upper extremity 
vasculature. 
4. TAVR conducted via other than transfemoral access (subclavian, axillar, transapical, 
transaortic, carotid or transcaval). 
5. Evidence of an acute myocardial infarction ≤ 1 month before the intended treatment. 
6. Aortic valve is a congenital unicuspid or bicuspid valve. 
7. Mixed aortic valve disease (aortic stenosis and aortic regurgitation with predominant 
aortic regurgitation >3+). 
8. Any therapeutic invasive cardiac procedure resulting in a permanent implant that is 
performed within 30 days of the index procedure (unless part of planned strategy for 
treatment of concomitant coronary artery disease). 
9. Blood dyscrasias as defined: Leukopenia, acute anemia, thrombocytopenia, history of 
bleeding diathesis or coagulopathy. 
10. Hemodynamic instability requiring inotropic support or mechanical heart assistance. 
11. Need for emergency surgery for any reason. 
12. Severe hypertrophic cardiomyopathy with or without obstruction. 
13. Severe ventricular dysfunction with LVEF ≤30%. 
14. Echocardiographic evidence of intracardiac or aortic mass, thrombus, or vegetation. 
15. Symptomatic or asymptomatic severe (≥ 70%) occlusive carotid disease requiring 
concomitant CEA / stenting. 
16. Subject has undergone carotid stenting or carotid endarterectomy within the previous 
6 weeks. 
17. Active peptic ulcer or upper GI bleeding within the prior 6 months. 
18. A known hypersensitivity or contraindication to aspirin, heparin, ticlopidine, or 
clopidogrel, device component material, or sensitivity to contrast media, which cannot 
be adequately pre-medicated. 
19. Recent (within 6 months) CVA or a TIA. 
20. Renal insufficiency (creatinine > 3.0 mg / dL or GFR < 30) and / or renal replacement 
therapy at the time of screening. 
21. Life expectancy < 12 months due to non-cardiac co-morbid conditions. 

 
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22. Subjects in whom anti-platelet and / or anticoagulant therapy is contraindicated, or who 
will refuse transfusion. 
23. Subjects who have active bacterial endocarditis or other active infections. 
24. Currently participating in an investigational drug or another device study. 
25. Subjects who have a planned treatment with any other investigational device or 
procedure during the study follow-up period (30 days). 
26. Subjects with planned concomitant surgical or transcatheter ablation for Atrial 
Fibrillation during the study follow-up period (30 days). 
27. Any subject with a balloon valvuloplasty (BAV) within 30 days of the procedure. 
28. Subject is a woman of child-bearing potential. 
29. Patient with Heparin-Induced Thrombocytopenia Syndrome. 
30. Inner diameter of aortic arch is less than 25mm. 
31. Brachiocephalic trunk originating from the aortic arch that splits into the bilateral 
subclavian arteries and a bicarotid trunk (Origin D).  
32. Hepatic failure (defined as liver enzyme elevations two times the upper limit of normal) 
or active infectious hepatitis 
33. Cardiogenic shock or severe hypotension (systolic blood pressure < 90 mm Hg) at the 
time of the index procedure 
34. Subjects who have a planned concomitant cardiac surgical or interventional procedure 
(e.g., coronary revascularization) during the TAVI procedure 
35. Subjects who have a pre-existing prosthetic heart valve in any position 
4.6.2.2. 
Neurological Exclusion Criteria 
1. Subject had active major psychiatric disease. 
2. Subject has severe visual, auditory, or learning impairment and is unable to 
comprehend English or local language and therefore unable to be consented for the 
study. 
3. Subjects with neurodegenerative or other progressive neurological disease or history 
of significant head trauma followed by persistent neurologic defaults or known 
structural brain abnormalities. 
4.6.2.3. 
Angiographic Exclusion Criteria 
1. Excessive tortuosity or severe peripheral arterial disease in the left radial / brachial / 
subclavian artery preventing ProtEmbo System access and insertion. 
2. Subject whose left radial / brachial / subclavian artery reveals significant stenosis, 
calcification, ectasia, dissection, occlusion or aneurysm, in particular at or within 3 cm 
of the aortic ostium.  
3. Subject with significant stenosis, ectasia, dissection, or aneurysm in the ascending 
aorta or in the aortic arch, or with abnormal aortic arch angulation or abnormal 
anatomical conditions of the aorta. 
4.6.2.4. 
Magnetic Resonance Imaging Exclusion Criteria 
1. Subject Body Mass Index (BMI) precluding imaging in scanner. 

 
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2. Contraindications to MRI (subjects with any implantable temporary or permanent 
pacemaker or defibrillator, metal implants in field of view, metallic fragments, clips, or 
devices in the brain or eye before TAVR procedure). 
3. Subjects who have a high risk of complete AV block after TAVR, with the need of 
permanent pacemaker (e.g. subjects with pre-existing bifascicular block or complete 
right bundle branch block plus any degree of AV block). 
4. Planned implantation of a pacemaker or defibrillator implantation within the first 4 days 
after TAVR. 
5. Claustrophobia precluding MRI scanning. 
6. No scanner hardware, software, coil or protocol changes should occur during the 
course of the study. 
4.7. Written Informed Consent 
Subjects cannot be asked to sign the Informed Consent document until the trial has been fully 
approved by the respective institution’s EC. Subjects who meet all of the inclusion criteria and 
none of the exclusion criteria will be asked to sign a Patient Informed Consent form as 
approved by the relevant regulatory authorities before any study-specific tests or procedures 
are performed. The Investigator or a designated member of his / her staff should approach the 
subject to obtain written informed consent. As far as possible, non-technical language shall be 
used that is understandable to the subject. The background of the proposed study and the 
benefits and risks of the procedures and study should be explained. The subject should be 
provided with ample time to read the consent form and discuss it with their family and 
physician. The subject shall be informed that his / her participation in the clinical investigation 
is confidential. The Informed Consent Form must be read and understood by the subject and 
the subject’s questions answered and must include information and a separate explicit consent 
regarding the patient’s rights under the GDPR and/or national data protection laws or 
regulations. The form must be signed and dated by both the subject and investigator 
conducting informed consent before the subject undergoes any study related procedures. All 
subjects are to receive copies of their signed and dated Informed Consent Form. A copy of the 
approved informed consent form along with a copy of each patient’s signed consent form will 
be maintained by each Investigator in a designated clinical study administrative file. The 
subject and the investigator must sign the consent form prior to enrollment. Subjects may not 
be consented after receiving any medication that might alter their ability to comprehend the 
consent form (e.g. sedatives, narcotics, etc.). Study personnel should explain that even if a 
subject agrees to participate in the study and signs the Patient Informed Consent form, the 
subject may not be eligible to participate if he / she fails to meet the screening criteria. 
Written informed consent must be obtained prior to performing any protocol driven tests or any 
procedures that are not standard of care for a TAVR procedure. 
Once written consent has been obtained, the subject will be entered on a Screening Log, which 
will be maintained at each site. All subjects who provide written informed consent will be 
entered on the screening log regardless of whether or not they are enrolled in the study. 
As appropriate, important and new information will be provided to new and existing subjects 
throughout the duration of the study. 

 
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4.8. Unique Study Identification Code 
Each subject will be assigned a unique study identification code in an effort to protect subject 
confidential information. The unique study identity code will be pseudonymized and will not 
include date of birth or subject’s first and last initials and will be used to link study data and 
other study information to the subject in lieu of the subject name. The Subject Name Log will 
be used to link the unique study identity code to the subject and will be maintained at each 
site. This log will remain confidential and will not be provided to the Sponsor, but only used for 
reference when monitoring at the study site. 
4.9. Subject Recruitment 
Subjects who present with severe symptomatic calcified native aortic valve stenosis who the 
heart team recommends transcatheter valve aortic valve replace (TAVR) consistent with the 
2017 ESC/EACTS Guidelines for the management of valvular heart disease and who have no 
concomitant cardiac valvular intervention or pre-existing prosthetic heart valve in any position 
will be considered potential study candidates. Due to the nature of this procedure, the Sponsor 
does not intend to advertise or otherwise actively recruit subjects. 
4.10. 
Subject Reimbursement 
Subjects will not be reimbursed or compensated for participating in the trial. Reasonable travel 
costs associated with follow-up visits will be reimbursed upon request. 
4.11. 
Enrollment 
Initial screening at each site will determine whether a patient is suitable for inclusion in the 
PROTEMBO C Trial. No PROTEMBO C Trial required assessments (baseline DW-MRI) will 
be performed until the patient has signed an informed consent form. After the patient has 
signed the informed consent, the patients will be considered enrolled in the study at the time 
just preceding the baseline DW-MRI assessment. 
Subjects who sign consent but are excluded before enrollment will not be included in the 
primary analysis of the study endpoints. The reason for exclusion will be documented in the 
Screening Log and the consent document maintained in the site’s study records. 
Subjects who sign a consent form and are enrolled in the study will be considered part of the 
safety cohort of the study. Patients who withdraw or are lost from the study for any reason 
before use of the ProtEmbo device during the TAVR procedure will be replaced so that the 
target enrollment of 60 treated patients in whom the ProtEmbo device is used during the TAVR 
procedure may be achieved. Patients who are enrolled and in whom the skin is broken to insert 
the ProtEmbo Device, i.e. as soon as the device is inserted in the preplaced 6 Fr. equivalent 
guiding sheath of the radial / brachial / subclavian artery access, will form the intention to treat 
cohort, and patients who complete both the baseline and follow-up DW-MRI after completion 
of the TAVR procedure will constitute a per protocol cohort. 

 
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4.12. 
Duration of Subject Participation 
Subjects enrolled in the trial will participate for approximately 30 days. 
4.13. 
Study Duration 
This study is expected to enroll up to 60 subjects in the intention to treat cohort within approx. 
12 months. The closeout phase of the study is expected to be completed within 2 months 
following the last subject follow-up visit. The total duration of the study is estimated to be 14 
months. 
4.14. 
Withdrawal of Subjects 
Each subject may voluntarily withdraw his / her participation from the study at any time. 
Investigators may discontinue a subject’s participation in the study as deemed appropriate for 
safety considerations and / or if the subject’s medical condition contraindicates further study 
participation. All enrolled subjects will undergo the complete study follow-up for safety 
evaluation. 
4.15. 
Loss to Follow-up Considerations 
A subject will be considered lost to follow-up and terminated from the study when all of the 
following criteria have been met: 
• 
Documentation of three unsuccessful attempts on three different days over a period 
of three (3) months by the Investigator or his / her designee to contact the subject 
or next of kin, one of which should be by certified mail with signature confirmation. 
• 
Prior agreement of the Sponsor to remove the subject from the clinical investigation. 
If permitted by the subject in the informed consent, contact with the family doctor may be made 
only after three unsuccessful attempts have been made to contact the study subject.  
4.16. 
Subject Confidentiality 
All information concerning subjects or their participation in this trial will be considered 
confidential. Only authorized representatives, designated personnel of CRO, designated 
consultants, or regulatory agencies will have access to these confidential files. Subject names 
or other non-pseudonymous data that could directly identify a patient will not be captured on 
the case report forms. In addition, all patient identifiers except the unique study identification 
code will be redacted from any x-ray, CT and MRI images submitted from the participating site 
to the Sponsor or the Sponsor’s designated reviewers for analysis. 
 

 
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4.17. 
Study Procedures 
4.17.1. Screening and Enrollment 
The overall screening and enrollment scheme for the study is shown in schematic form in 
Figure 4 and identifies the various phases for screening, consenting, continued eligibility 
assessment and assignment into the subject cohorts for the study. 
 
Figure 4: Screening and Enrollment Scheme. 
CT/ Angiographic Eligibility 
during TAVR 
Not eligible 
Baseline Assessments 
Sheath Access 
Eligibility 
Assessments 
CT/ 
Angiographic 
Eligibility 
Sheath Access 
Eligibility 
Sheath access not 
possible 
Subject inclusion 
Intention-to-
treat 
Medical records and MRI 
eligibility 
Exclusion criteria in clinical 
data or MRI ineligible, 
screen failure 
Screening 
Phase 
Patient fulfills 2017 ESC/EACTS criteria for TAVR: 
Patient Informed Consent 
Consent 
Phase 

 
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4.17.2. Consent Phase 
Prior to obtaining written informed consent, the subject’s existing medical records may be 
reviewed by the site to determine whether or not the subject might be an acceptable candidate 
for this study. 
If initial review of the medical records indicate that the subject may be eligible (i.e., the heart 
team recommends transcatheter valve aortic valve replace consistent with the 2017 
ESC/EACTS Guidelines for the management of valvular heart disease and no concomitant 
cardiac valvular intervention or pre-existing prosthetic heart valve in any position), the informed 
consent process may commence. 
4.17.3. Screening Phase 
Each patient’s medical records will be reviewed to assess compliance with the eligibility of the 
PROTEMBO C Trial, and the patient’s ability to undergo MRI will be assessed. Patients who 
are eligible based on the study enrollment criteria and are capable of undergoing MRI will 
proceed to the next phase of the study. 
4.17.4. Eligibility Assessments 
Baseline evaluation will be performed after the subject has provided written informed consent 
in order to ensure that the subject is an appropriate candidate for this study and to obtain 
baseline values for study endpoint evaluation. 
If the subject continues to meet the study’s enrollment criteria and continues to be willing and 
able to participate in the study protocol, the subject will be enrolled. 
All subjects will undergo a series of baseline evaluations (if not already available as part of the 
existing medical records). Baseline visit and data collection can occur anytime within 14 days 
before the TAVR procedure (unless otherwise indicated). 
4.17.5. CT/ Angiographic Eligibility 
Computed tomographic images of the aorta will be reviewed by the angiographic core lab and 
the aortic angiogram will be reviewed to confirm that the subject is eligible for participation in 
the PROTEMBO C Trial. 
4.17.6. Sheath Access Eligibility 
Computed tomographic images of the aorta will be reviewed by the angiographic core lab and 
an angiogram of the left radial artery will be reviewed to confirm that the subject can have a 
commercially available vascular sheath inserted into the left radial, brachial or subclavian 
artery and is, therefore, eligible for participation in the PROTEMBO C Trial. 

 
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4.18. 
Procedural Treatment and Timing 
4.18.1. Medication Regimen 
Administration of anticoagulation medication and monitoring of activated clotting time (ACT) 
per institution guidelines is to be performed throughout the procedure. Anticoagulant therapy 
should be administered pre-, peri- and post-procedure to maintain an Activated Clotting Time 
of at least 250 seconds for the duration of the procedure. Refer to the Instructions for Use for 
additional procedure specific information. 
For those patients who are not under chronic oral anticoagulation prior TAVR, the use of dual 
antiplatelet therapy (DAPT) before and after the procedure is recommended. Those patients 
with chronic DAPT should continue with acetylsalicylic acid and clopidogrel therapy for at least 
1 month after TAVR, as per the standard practice of the institution. 
For those patients who are not taking chronic DAPT, it is recommended to administer 300 mg 
of each acetylsalicylic acid and clopidogrel within 24 hours (and at least 2 hours) before the 
procedure or the equivalent as per the standard of care at the institution. 
Refer to hospital protocol for dual antiplatelet therapy. 
4.18.2. MRI Timing 
Standardization of the timing of scans across study sites is required to maintain integrity of the 
MRI analysis. The primary evaluation of the MRI scan will be performed by the MRI core lab 
(independent expert). 
MRI will be performed at baseline and at 2-7 days following TAVR procedure. To avoid imaging 
any new lesions on the baseline MRI caused by the diagnostic catheterization, the baseline 
MRI exam should take place within two weeks before the TAVR procedure and no sooner than 
5 days after any diagnostic catheterization, and there should be no diagnostic catheterization 
in between baseline MRI and TAVR procedure. 
4.19. 
TAVR and ProtEmbo Procedure 
Study subjects will be asked to undergo evaluation prior to and during the course of the clinical 
study. Such tests and procedures are outlined in the Schedule of Events and are consistent 
with standard of care for TAVR subjects. 
The ProtEmbo device should be used strictly as described in the Instructions for Use (IFU), 
including the preparation, insertion, dwell time and removal of the device, specifically as 
detailed on pages 10-17 of the IFU. The ProtEmbo device should be inserted prior to the 
insertion of the TAVR device and left in place until after the deployment and removal if the 
TAVR device. 

 
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4.19.1. Schedule of Events 
 
Screening Period 
Treatment 
Period 
Post-procedure Period 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
Study Procedure 
Baseline 
Baseline 
MRI 
TAVR 
Procedure 
< 24 Hour 
Follow- up 
2-7 Days 
Discharge 
30 Day  
(± 7 Days) 
Informed consent 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
 
 
 
 
 
 
 
Medical history/ baseline characteristics 
 
 
 
 
 
 
 
Medication profile 
 
 
 
 
 
 
 
Physical exam 
 
 
 
 
 
 
 
STS score 
 
 
 
 
 
 
 
Blood work (Chemistry Panel) 
 
 
 
 
 
 
 
ECG  
 
 
 
 
 
 
 
Diagnostic Transthoracic Echocardiogram 
within 3 months of TAVR1 
 
 
 
 
 
 
 
Modified Allen’s Test 
 
 
 
 
 
 
 
NIHSS2 
 
 
 
 
 
 
 
Adverse Event (AE) review 
 
 
 
 
 
 
 
Angiogram 
 
 
 
 
 
 
 
Multi-Slice or Multi Detector CT3 
 
 
 
 
 
 
 
MRI4 
 
 
 
 
 
 
 
ProtEmbo insertion, dwell and removal 
times 
 
 
 
 
 
 
 
ProtEmbo contrast use 
 
 
 
 
 
 
 
Filter specimen preparation & shipping for 
histopathology 
 
 
 
 
 
 
 
Study Exit 
 
 
 
 
 
 
 
Table 2: Schedule of Events. 
4.19.2. Study Exit or Premature Withdrawal 
Subjects will be exited from the study by completion of a Study Exit eCRF at the time of study 
completion provided the subject has not experienced an adverse event that is ongoing and 
unexplained. 
Subjects may be prematurely terminated or withdrawn from the study for, including but not 
limited to, the following reasons: 
• 
Subject death. 
• 
Voluntary withdrawal – meaning that the subject voluntarily chooses not to further 
participate in the study. 
• 
Preplacement of a 6 Fr. equivalent guiding sheath for radial / brachial / subclavian 
artery access is attempted but is not possible to complete. 
 
1 Conducted as part of the TAVR work up as per institution standard of care and not a dedicated study procedure. 
2 NHISS must be conducted by a neurologist. For the secondary efficacy endpoint NHISS score must be taken both on day 3 after TAVR and 
on the same day as the follow up MRI assessment, i.e. at 2-7 days. If MRI happens on day 3 post TAVR one singe NHISS score will suffice.   
3 Conducted as part of the TAVR work up and not a dedicated study procedure. CT should include imaging from chin to diaphragm and be 
done prior as per institutional standard of care ≤ 1 year of the procedure. 
4 Must be conducted on a MRI core laboratory certified scanner. 

 
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• 
Lost to follow-up – meaning that the subject is more than 14 days late to a study 
visit and 3 documented attempts to contact the subject are unsuccessful. A subject 
who misses a study visit but attends a subsequent visit will no longer be considered 
lost to follow-up. A missed visit will be considered a protocol deviation and the 
deviation will be documented and reported. 
• 
In the physician’s opinion, it is not in the best interest of the subject to continue 
study participation. 
All subjects enrolled (including those withdrawn or lost to follow-up) shall be accounted for and 
documented. 
5. Risk Benefit Assessment 
Sponsor has conducted an analysis of the benefits and risks of the ProtEmbo Cerebral 
Protection System and procedure. A detailed Risk Assessment has been completed and 
reviewed with physicians and interventional cardiologists with significant TAVR experience, 
and potential study investigators. The conclusion of this review is that this research study is 
justified because the overall potential benefit to the population outweighs its attendant risks. 
5.1. Potential Adverse Events 
The ProtEmbo System is introduced to the vascular system via radial / brachial / subclavian 
vascular access which is standard medical practice for contemporary coronary-related 
interventions (e.g. PCI). The risks of this access route are well known and tolerated (Bavishi 
et al., 2016). In addition, the ProtEmbo System does not have any associated unique clinical 
risks associated with this access route. Procedural risks are reduced by non-femoral access, 
the main thoroughfare during TAVR procedures where valve delivery systems and catheter-
based accessory devices have the potential for interaction and entanglement. Additionally, the 
closure of a 6 French radial / brachial access is generally accepted as lower risk than closure 
of a femoral access. 
There are Adverse Events associated with any endovascular / cardiovascular intervention and 
complications may develop. The following anticipated events have been identified as possible 
complications of transcatheter procedures in general and these and others may be associated 
with the ProtEmbo System: 
• 
Acute cardiovascular surgery (need for) 
• 
Acute neurological events such as: Stroke or transient ischemic attack (TIA) 
• 
Allergic reactions to contrast, antiplatelet therapy or device component materials 
• 
Aneurysm or pseudo-aneurysm 
• 
Aortic dissection 
• 
Arteriovenous fistula 
• 
Ascending or descending aorta trauma 
• 
Atrial or ventricular arrhythmias or fibrillation, hearth palpitations (sustained requiring 
therapy) 
• 
Bleeding complications such as hematoma and hemorrhage 

 
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• 
Blood loss requiring transfusion 
• 
Blue toe syndrome or blue discoloration of a toe 
• 
Bowel ischemia 
• 
Death 
• 
Device failure and subsequent need to use a snare or other medical interventional 
techniques to retrieve the pieces 
• 
Dissection of the left radial, left brachial, or left subclavian artery  
• 
Embolism (air, tissue, device, or thrombus) 
• 
Hemodynamic changes 
• 
Infection, including endocarditis and septicemia 
• 
Local trauma to the aortic wall due to device migration 
• 
Peripheral ischemia, peripheral nerve damage 
• 
Pyrogenic reactions, fever 
• 
Renal complications, injury, or failure 
• 
Systemic embolization 
• 
Vascular complications which may require vessel repair 
• 
Vessel spasm (sustained, not responding to therapy) 
 
The following anticipated events have been identified as possible complications of 
transcatheter procedures in general and these and others may be associated with the TAVR 
procedure: 
• 
Access site complication or injury including infection or thrombus 
• 
Acute cardiovascular surgery (need for) 
• 
Acute coronary or other artery occlusion 
• 
Acute myocardial infarction 
• 
Acute neurological events such as: Stroke, transient ischemic attack (TIA), 
encephalopathy 
• 
Allergic reactions to contrast, antiplatelet therapy or device component materials 
• 
Anesthesia reactions 
• 
Aneurysm or pseudo-aneurysm 
• 
Angina pectoris 
• 
Aortic dissection 
• 
Arteriovenous fistula 
• 
Ascending or descending aorta trauma 
• 
Atrial or ventricular arrhythmias or fibrillation, hearth palpitations (sustained requiring 
therapy) 
• 
Bleeding complications such as hematoma and hemorrhage 
• 
Blood loss requiring transfusion 
• 
Blue toe syndrome or blue discoloration of a toe 
• 
Bowel ischemia 
• 
Cardiac tamponade 
• 
Cardiac conduction abnormalities requiring temporary or permanent pacemaker 

 
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• 
Cardiogenic Shock 
• 
Conduction system injury 
• 
Congestive Heart Failure 
• 
Coronary artery or other vascular injury, dissection, or perforation which may need 
repair 
• 
Death 
• 
Device failure and subsequent need to use a snare or other medical interventional 
techniques to retrieve the pieces 
• 
Embolism (air, tissue, device, or thrombus) 
• 
Encephalopathy 
• 
Femoral nerve damage 
• 
Hemodynamic changes 
• 
Hypertension or hypotension (sustained requiring therapy) 
• 
Infection, including endocarditis and septicemia 
• 
Pain (at puncture site, adnominal, back or other) 
• 
Percutaneous coronary intervention (need for) 
• 
Pericardial effusion 
• 
Peripheral ischemia, peripheral nerve damage 
• 
Pneumonia 
• 
Pulmonary edema or embolism 
• 
Pyrogenic reactions, fever 
• 
Radiation injury 
• 
Renal complications, injury, or failure 
• 
Renal insufficiency / failure due to excessive contrast load 
• 
Respiratory insufficiency or failure 
• 
Systemic embolization 
• 
Unstable angina 
• 
Vascular complications which may require vessel repair 
• 
Vessel spasm (sustained, not responding to therapy) 
There are standard risks associated with any interventional procedures and TAVR as well as 
risks specific to the ProtEmbo System and procedure. Risks associated with any interventional 
procedure include access site hemorrhage or hematoma, access site pain, acute vessel 
closure, infection, renal insufficiency / failure due to excessive contrast load, and death. The 
risks stated below concern each system manufactured by Sponsor and their use in the 
ProtEmbo procedure. 
Possible risks related to the delivery system used to deliver the ProtEmbo Device include, but 
are not limited to, the following: Vessel dissection, perforation or wall trauma, embolism, 
infection, bruising or hemorrhage at the procedural access site, vessel thrombosis, bleeding 
or infection. 
Possible risks related to the ProtEmbo Device include, but are not limited to, the following: 
Vessel thrombosis, stenosis or occlusion, vessel dissection, perforation or wall trauma, 
embolism, bleeding infection or arterial side branch occlusion. 

 
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Additionally, subjects will be exposed to risks associated with conscious sedation, use of 
radiographic contrast and procedural medications. An Investigator will discuss with each 
subject the standard risks associated with these procedures and medications. 
Non-contrast MRI may cause feelings of anxiety or claustrophobia during the MRI. 
5.2. Potential Risks to Subject Confidentiality and Privacy 
In all clinical studies, confidentiality of protected health information may be breached due to 
study-related activities beyond those of routine clinical care. This also includes risks of privacy 
and release of protected health information (PHI). This risk will be minimized through the use 
of a unique and anonymous study identification code. No identifying information will be 
reported on electronic Case Report Forms (eCRFs) or other study related documentation that 
is provided to the Sponsor. 
5.3. Minimization of Anticipated Risks 
Efforts to minimize risk include the following: 
• 
Clearly defining the subject inclusion / exclusion criteria. 
• 
Selecting a sufficient number of at least 3 intended users and only qualified, 
experienced Investigators who have participated in an extensive training program to 
assure thorough knowledge of the Investigational Plan and proper technique for 
implantation of the ProtEmbo System. 
• 
Monitoring angiographic, electrocardiographic and hemodynamic parameters during 
placement of the device to evaluate for any compromise of the subject’s condition. 
• 
Attending to arterial access techniques to minimize the trauma to vascular structures. 
• 
Ensuring that treatment and follow-up of subjects is consistent with standard and 
current medical practice. 
• 
Providing clinical support for device related guidance during the implant procedure. 
• 
Safety oversight by Medical Monitor, for individual subjects as well as across the entire 
study population. 
• 
If the Investigator and / or the Medical Monitor determine that an AE is sufficiently 
severe to remove the subject from the study, a termination assessment will be 
performed. The subject will then be given appropriate treatment under medical 
supervision. 
• 
If the Medical Monitor determines a negatively high rate for a particular safety issue 
across the subject population, a termination assessment will be performed, and the 
Medical Monitor may recommend enrollment in the study to be stopped. PHI protection 
measures such as use of a unique study identification code and a commitment from all 
participants to protect subject confidentiality at every step during the investigation. 
• 
PHI protection measures such as use of a unique study identification code and a 
commitment from all participants to protect subject confidentiality at every step during 
the investigation. 
 

 
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5.4. Potential Benefits 
Based upon literature review and pre-clinical evaluations performed to date, it is expected that 
the ProtEmbo System may provide benefit to the subject by deflecting potentially harmful 
embolic debris liberated during the TAVR procedure. Without the ProtEmbo System, embolic 
debris would otherwise travel unimpeded via the cerebral circulation to the brain and could 
lead to cerebral vascular events such as stroke and / or TIA. There is currently no FDA cleared 
treatment option for embolic protection during TAVR. The potential benefits include a reduction 
in median total new cerebral lesion volume as assessed by DW-MRI, which may lead to a 
decrease in cerebral vascular events, such as stroke or TIA and neurocognitive deficits after 
the TAVR procedure. 
However, the actual benefits are not known and are the subject of this investigational study. 
There may be no direct benefits of study participation. However, subject participants will 
undergo an enhanced level of clinical scrutiny of health compared to routine clinical care, which 
may provide some indirect health benefits. 
6. Statistical Analysis Plan 
6.1. Overview 
The primary objective of this study is to assess the safety and performance of the ProtEmbo 
Cerebral Protection System used for embolic protection during Transcatheter Aortic Valve 
Replacement (TAVR) compared to TAVR standard of care (without embolic protection). The 
secondary objective of the study is to assess the efficacy of the ProtEmbo system by 
comparing the median new lesion volume in the brain and the rate of death or all strokes 
compared to historical data. 
All enrolled subjects will form the safety cohort. All subjects in whom the skin is broken to insert 
the ProtEmbo Device, i.e. as soon as the device is inserted in the preplaced 6 Fr. equivalent 
guiding sheath of the radial / brachial / subclavian artery access will be followed on an intent-
to-treat basis. Those subjects who complete the baseline and follow-up DW-MRI studies after 
completion of the TAVR procedure constitute the per protocol cohort. The device safety will be 
assessed based on an analysis of the primary safety endpoint within the safety cohort. The 
primary performance endpoint will be assessed in the intention to treat cohort, and secondary 
efficacy endpoints will be assessed based on a per protocol analysis. 
Standard summary statistics will be calculated for all study variables. For continuous variables, 
statistics will include means, standard deviations, medians and ranges. Categorical variables 
will be summarized using frequency distributions. 
6.2. Primary Safety Endpoint 
The primary safety endpoint is Major Adverse Cardiac and Cerebrovascular Events (MACCEs) 
at 30 days as defined by VARC-2, including all-cause mortality, all stroke and acute kidney 
injury (stage 3). The objective is to assess whether MACCE rate at 30 days for the ProtEmbo 
System meets the Performance Goal (PG). The null and alternative hypotheses are given by:  
 
H0: π ≥ PG 

 
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HA: π < PG, 
 
Where π is the ProtEmbo System MACCE rate at 30 days and the performance goal (PG) is 
25%. 
 
The safety hypothesis will be tested in the safety cohort (all enrolled subjects) by calculating 
the one-sided upper 95% confidence limit using the Wilson Method. The null hypothesis will 
be rejected if the upper limit of the 95% confidence interval is less than the PG. 
 
Derivation of the Performance Goal (PG): 
The PG for the primary endpoint was established based upon data available in the literature 
for patients undergoing embolic protection for TAVR using the Sentinel and the TriGuard 
embolic protection devices.  
In the randomized controlled SENTINEL trial (Sentinel device) of 363 patients, the rate of 
MACCE (defined as death from any cause, any type of stroke, or stage-3 acute kidney injury 
[AKI]) in the cerebral protection group (7% [17/234]) was not statistically significantly different 
from that of the control group (10% [11/111]) at 30 days (p=0.40). 
In the randomized controlled DEFLECT III trial (TriGuard device) of 85 patients, the rate of in-
hospital MACCE (defined as all-cause mortality, all stroke, life-threatening or disabling 
bleeding, stage-2 or stage-3 AKI, or major vascular complications) was similar in both groups 
(control TAVR group without TriGuard device versus TAVR plus TriGuard device): 22% 
compared with 31% (RR 0.71, 95% CI 0.34 to 1.46; p=0.34). The rates of 30-day MACCE were 
also similar: 26% compared with 31% (RR 0.83, 95% CI 0.37 to 1.84; p=0.62). 
The MACCE rate of individuals undergoing TAVR without embolic protection is the appropriate 
MACCE rate to set the PG for the ProtEmbo System. Based on the number of subjects treated 
in the control groups of both trials, we estimate a weighted MACCE rate of 15% (23/150), 95% 
CI: 10%, 22%. 
To establish the PG for ProtEmbo System, a statistical margin of 10% is added to 15% to 
obtain a PG of 25% for the primary safety endpoint. 
Sample Size: 
Under a desired power of 85% and a one-sided test of the hypothesized MACCE rate for the 
ProtEmbo System of 10% at alpha = 0.025, a sample size of 60 treated patients is required 
(Chow et al., 2008).  
6.3. Primary Performance Endpoint 
The primary performance endpoint is technical success, defined as ability to safely deliver, 
deploy, and remove the device, ability to secure positioning and stability of the position 
throughout the transcatheter intracardiac procedure and ability to deflect embolic material as 
assessed by adequate coverage while not impeding blood flow. The objective is to assess 
whether rate of technical success for the ProtEmbo System meets the Performance Goal (PG). 
The null and alternative hypotheses are given by:  
H0: π ≤ PG 

 
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HA: π > PG, 
where π is the ProtEmbo System success rate and the performance goal (PG) is 75%. 
The performance hypothesis will be tested in the intention to treat cohort by calculating the 
one-sided lower 95% confidence limit using the Wilson Method. The null hypothesis will be 
rejected if the lower limit of the 95% confidence interval is greater than the PG. 
Derivation of the Performance Goal (PG): 
The PG for the primary performance endpoint was established based upon data available in 
the literature for patients undergoing embolic protection for TAVR using the TriGuard embolic 
protection device.  
In the randomized controlled DEFLECT III trial of 85 patients, 45 TriGuard devices were used 
in 44 patients; 2 randomized patients withdrew consent before device introduction, and 1 
patient received 2 TriGuard devices over the course of a valve-in-valve procedure. The device 
was successfully positioned and maintained in position throughout prosthetic-valve 
deployment, implantation, and retrieval in 89% (40/45, 95% CI [75% to 96%]) of patients. There 
were no device failures. 
The performance success rate of the test arm is the appropriate rate to set the PG for the 
ProtEmbo System. The comparator rate is therefore set at 90%. 
To establish the PG for the ProtEmbo System, a statistical margin of 15% is subtracted from 
90% to obtain a PG of 75% for the primary performance endpoint, which is the lower limit of 
the 95% confidence interval for the DEFLECT III trial. 
Under a desired power of 85% and a one-sided test of the hypothesized success rate for the 
ProtEmbo System of 89% at alpha = 0.025, the required sample size is 42 (Chow et al., 2008). 
The sample size necessary to test the Primary Safety Endpoint requires a larger number of 
subjects, and the PROTEMBO C Trial will, therefore, be adequately powered to test the null 
and alternate hypotheses for the Primary Performance Endpoint. 
6.4. Secondary Efficacy Endpoint 
The use of magnetic resonance imaging (MRI) is a well‐established tool for quantifying 
ischemic lesions in the brain. Diffusion weighted MRI (DW‐MRI) is used to characterize 
ischemic lesions that have occurred within the first several days of an embolic event (Lansky 
et al., 2017). Total lesion volume and likelihood of neurological deficit are strongly associated. 
The occurrence of a single or few small lesions may result in large total lesion volumes. 
Therefore, the number of lesions may not correlate well to the total volume or clinical outcome 
and will not be of primary interest. The use of DW‐MRI as a surrogate endpoint for risk of sub‐
clinical stroke has been proposed (Lansky, 2017), and the DW-MRI analysis of new lesion 
volume will use the standard assessments as outlined by Lansky et al. Therefore, a secondary 
efficacy endpoint for this clinical investigation will be based on magnetic resonance (MR) 
imaging comparing the median new lesion volume in the brain assessed by diffusion weighted 
magnetic resonance images (DW-MRI) at 2 to 7 days with historical data. The total new lesion 
volume will be defined as the sum of all diffusion-positive new cerebral lesions in post-
procedural DW-MRI relative to the pre-TAVR DW-MRI. The analyses of secondary endpoints 
will be conducted in the per protocol cohort. 

 
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The median value of lesions among patients has been selected because the distribution of 
new lesions is not normally distributed and the median value appears to represent the 
distribution of lesion volumes among patients (Kapadia et al., 2017). Nevertheless, the number 
of new lesions, the mean of new lesion volumes, and the variances of these measures will also 
be analyzed. 
The severity of pre-existing central nervous system lesions on baseline T2-weighted MRI 
(FLAIR) is an independent predictor of the number of lesions on DW-MRI obtained 3 days after 
TAVR (Dwyer et al., 2017); patients with a large number of vascular / embolic lesions at 
baseline tend to have a large number of new lesions after TAVR. FLAIR-MRI can be used to 
account for baseline lesions and has been proposed as a mechanism of differentiating silent 
cerebral events (regions of increased intensity on the DW-MRI) from silent cerebral lesions 
(more permanent white matter changes identifiable on FLAIR-MRI) (Deneke et al., 2015). To 
account for the presence and predictive power of pre-TAVR lesions, multilevel mixed effects 
models in which time will be a repeated within subject factor and subject will be treated as a 
random effect (a random intercept model) will be used to evaluate median, and mean lesion 
volumes and number of new lesions. Separate analyses will be performed for the main 
secondary MRI endpoint (median new lesion volume) and subsidiary analyses (mean new 
lesion volume, number of new lesions and variances of these measures). We will make no 
assumption about the structure of the covariance matrix. This regression model permits us to 
determine the rate of new lesion occurrence after TAVR (the slope of the regression) and the 
effect of baseline lesion values on the number of lesions after TAVR (the random subject effect 
/ random intercept). We will include demographic data (e.g. age and pre-existing cerebral 
lesions determined from the FLAIR-MRI) and other relevant variables as covariates in these 
models, and we will stratify outcomes a priori based on the type of valve used during the TAVR. 
An additional secondary efficacy endpoint for this clinical investigation is defined as the 
composite rate of death or all strokes according to VARC-2 criteria, to define occurrence and 
type stroke, within 3 days (72 hours) of the TAVR procedure compared to historical data. 
Stroke severity will be quantified according to the National Institutes of Health Stroke Scale 
(NIHSS) score. 
In previous studies, such as the SENTINEL US IDE trial, stroke rates of 9.1% have been 
reported for patients receiving no embolic protection at 30 days (111 patients in control arm 
and 234 in device arm). All assessments were assessed by neurologists. A patient-level pooled 
analysis for the SENTINEL US IDE, the CLEAN-TAVI and the SENTINEL-Ulm studies was 
also conducted (Seeger et al.). A total of 1,066 patients were analyzed in this study (533 with 
Sentinel versus 533 control). The rate for all-strokes for patients without embolic protection 
within 3 days was 5.44% (29/533). The rate of all-cause mortality or stroke within 3 days was 
6.0% for patients with no embolic protection (32/533). 
6.5. Demographic, Safety, Feasibility and Efficacy Data 
Demographic and baseline clinical and disease characteristics will be summarized in tables. 
For continuous variables, the summary will include number, mean, and standard deviation and 
95% confidence intervals. Summaries for categorical variables will include the number and 
percent of subjects in each category. 

 
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6.6. Imputation of Missing Data 
Missing data will be replaced using the “worst” value in each subject. 
7. Adverse Event and Incident Reporting 
The occurrence of Adverse Events will be monitored during this study. All Adverse Events will 
be recorded on the Complication / Adverse Event Form at onset and at each follow-up visit 
until resolved. To meet the objectives of this study, the following definitions will apply (DIN EN 
ISO 14155:2012-01 Clinical investigation of medical devices for human subjects - Good 
Clinical Practice, including DIN EN ISO 14155:2018-08 – draft 18-06-29). 
7.1. Adverse Event (AE) 
An Adverse Event (AE) is any untoward medical occurrence, unintended disease or injury or 
any untoward clinical signs (including an abnormal laboratory finding) in subjects, users or 
other persons whether or not related to the medical device. This includes events related to the 
device or events related to the procedures involved. 
An Adverse Device Effect is an adverse event related to the use of a medical device, including 
adverse events resulting from insufficient or inadequate Instructions for Use, deployment, 
implantation, installation or operation, or any malfunction of the medical device or any event 
resulting from user error or intentional misuse of the medical device. 
The Investigator is responsible for assessing the severity of the AE, the causal relationship 
between any events and the clinical study procedure, activities or device. Additionally, the 
Investigator is responsible for providing appropriate treatment for the event and for adequately 
following the event until resolution. The following categories of adverse event severity are to 
be used: 
1. Mild: Awareness of a sign or symptom that does not interfere with the subject’s usual 
activity or is transient, resolved without treatment and with no clinical sequelae. 
2. Moderate: Interferes with the subject’s usual activity. 
3. Serious: Any fatal or immediately life-threatening clinical experience that requires a 
subject to be hospitalized, or hospitalization is unduly prolonged because of potential 
disability or danger to life or because an intervention has been necessitated. This 
includes any permanently disabling event. 
7.2. Serious Adverse Events (SAE) 
A Serious Adverse Event (SAE) is any problem or unwanted event encountered in a clinical 
trial or a performance evaluation that has led, or could have led, directly or indirectly to death 
or to a serious deterioration in the health of a subject or user or any other person, without 
regard to whether the event was caused by a medical product. The following events (including 
laboratory results and outcome events) will be considered to be SAEs and must immediately 
(within 24 hours) be reported to the study Sponsor and / or designated representative by 
telephone, fax and / or email. These events must be reported whether or not the Investigator 
believes they are related to study procedures, activities or device: 

 
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• 
Death 
• 
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. 
7.3. Serious Adverse Device Effect (SADE) 
A Serious Adverse Device Effect is an adverse device effect that has resulted in any of the 
consequences of a Serious Adverse Event. 
NOTE: Planned hospitalization for a pre-existing condition, a condition unrelated to the 
treatment or a procedure required by this study, that is without serious deterioration in health, 
is not considered a serious adverse event. 
7.4. Unanticipated Serious Adverse Device Effect (USADE) 
Unanticipated Serious Adverse Device Effect (USADE): Serious adverse device effect 
which, by its nature, incidence, severity or outcome has not been identified in the risk analysis. 
7.5. Anticipated Serious Adverse Device Effect (ASADE) 
Anticipated Serious Adverse Device Effect (ASADE): An effect, which by its nature, 
incidence, severity or outcome has been identified in the risk analysis report. 
7.6. Unanticipated Adverse Device Effect (UADE) 
Unanticipated Adverse Device Effect (UADE): An adverse device effect which by its nature, 
incidence, severity or outcome has not been identified in the risk analysis report. 
7.7. Anticipated Adverse Device Effect (AADE) 
Anticipated Adverse Device Effect (AADE): An effect, which by its nature, incidence, 
severity or outcome has been identified in the risk analysis report. 
7.8. Reporting of Adverse Events (AEs) and Serious Adverse Events (SAEs) 
Documentation of all AEs / SAEs: All incidents will be captured as a part of this clinical study. 
At each contact with the subject, the Investigator will seek information on adverse device 
effects by specific questioning and, as appropriate, by examination. Information on all adverse 
device effects will be recorded immediately in the source document, and also in the appropriate 
adverse effect electronic Case Report Form (eCRF). All clearly related signs, symptoms, and 
abnormal diagnostic procedures results should be recorded in the source document. 
Reporting of SAEs: All SAEs, UADEs and possible device and / or procedure- related adverse 
events must be recorded on the Adverse Event eCRF by the Investigator (or his / her designee) 
and reported to the Sponsor and its designated representative (MAXIS Medical GmbH) within 

 
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24 hours via fax or email. The report should include: Description of incident, severity, duration, 
action taken, treatment outcome and relationship of the adverse event to the study device, 
procedure, concomitant medications, pre-existing condition, etc. (i.e., unrelated, relation or 
relationship unknown). 
In the case of serious adverse events (SAE), procedure and / or device failures and 
malfunctions, medical record documentation (e.g., procedure notes, operative notes, 
discharge summary, relevant progress notes, imaging or lab studies) must be provided to the 
Sponsor and its designated representative, if requested .This information shall be faxed or 
send by email as requested as soon as possible but latest within 24 hours to the Study Monitor 
/ Sponsor. If appropriate, Sponsor shall inform the Competent Authority and the relevant Ethics 
Committee about the event within the appropriate timelines. In accordance with MEDDEV 2.7/3 
rev.3 (May 2015), the Sponsor must report: 
• 
all reportable events as described in section 5.1 which indicate an imminent risk of 
death, serious injury, or serious illness and that requires prompt remedial action for 
other patients / subjects, users or other persons or a new finding to it, 
• 
to the National Competent Authorities where the clinical investigation has commenced, 
• 
Immediately, but not later than 2 calendar days after awareness by Sponsor of a new 
reportable event or of new information in relation with an already reported event. 
7.9. Reporting of Device Failures and Malfunctions  
All reported device malfunctions or failures of the ProtEmbo System are required to be 
documented in the eCRF and must be immediately reported to the study sponsor and its 
designated representative (MAXIS Medical GmbH) by telephone, fax and / or email within 24 
hours. Device failures and malfunctions should also be documented in the subject’s medical 
record. Instructions for returning the investigational device will be provided. 
NOTE: Device failures or malfunctions are NOT to be reported as adverse events. However, 
if there is an adverse event that results from a device failure or malfunction, that specific event 
would be recorded in the usual way as per the previous chapter. 
7.10. 
Documentation, Evaluation and Notification of Serious Adverse 
Events 
The Investigator shall report all serious adverse events (anticipated or unanticipated) to 
Sponsor and Sponsor’s designated representative within 24 hours upon becoming aware of 
events. 
Authorized Representative / CRO Contact Information: 
MAXIS Medical GmbH 
Stichlingstrasse 1 
60327 Frankfurt am Main 
Germany 
Tel: +49 69 2400 3626 
Fax: +49 69 2400 3627 
Email: maxisoperations@maxismedical.com 

 
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Sponsor: 
Protembis GmbH 
Pauwelsstraße 17 
D-52074 Aachen 
Germany 
Tel: +49 241 99033622 
Fax: +49 241 99033623 
Email: info@protembis.com 
 
The Sponsor and / or its designated representative will ensure compliance with all country-
specific reporting requirements to the appropriate Ethical Committees and Competent 
Authorities. 
8. Monitoring 
The Sponsor or its designated representative, qualified by training and experience, will be 
responsible for monitoring and overseeing the conduct of the trial. The accuracy of all collected 
data will be verified for: 
• 
Eligibility criteria 
• 
Baseline characteristics 
• 
Primary safety and feasibility endpoints 
• 
Adverse events 
• 
Secondary endpoints 
with source documents including, but not limited to, medical records, office / clinic notes, 
procedure reports, laboratory results, physician and nursing progress notes. Verification and 
quality of data, monitoring of clinical study progress and Investigator compliance with the 
approved protocol will be conducted by the Sponsor or its designated representative. 
The Sponsor or its designated representative must be allowed to visit the clinical site and have 
direct access to all study records throughout the duration of the study. The monitor will review 
all source data and compare them to the data documented in the case report forms, in addition 
to performing a review of the Regulatory Binder and conducting device accountability. The 
Investigator and / or institution will provide direct access to source data / documents for trial-
related monitoring, audits, and regulatory review and inspection. 
It is important that the Investigator and relevant study personnel are available during the 
monitoring visits and that sufficient time is devoted to the process. 
Additionally, telephone, email contact, and onsite visits will be conducted on a regular basis 
with the Investigator and the site staff to ensure that the protocol is being followed and to 
address any issues that may occur during the trial. 
If a deficiency is noted during the course of the trial the clinical monitor is required to discuss 
the situation with the site and the Sponsor (if required) to secure compliance. 

 
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9. Study Management 
The Sponsor has overall responsibility for the conduct of the study according to Good Clinical 
Practice Guidelines (ICH E6 Consolidated Guidance to Good Clinical Practice) as well as any 
conditions imposed by local and national regulatory authorities. 
For this study, Sponsor will have direct responsibilities and will delegate other responsibilities 
to appropriate and qualified consultants, contractors and / or Contract Research Organizations 
(CROs). Together, the Sponsor, consultants and CROs will ensure that the study is conducted 
according to the Clinical Investigational Plan and all applicable and governing regulations. All 
personnel to participate in the conduct of this clinical trial will be qualified by education and / 
or experience to perform their tasks. 
9.1. Key Contributors 
9.1.1. Study Sponsor 
Protembis GmbH, Pauwelsstraße 17, 52074 Aachen 
Phone: +49 241 99033622; Email: info@protembis.com 
9.1.2. Authorized CRO / Representative 
MAXIS Medical GmbH, Karpfenweg 12, D-60327 Frankfurt am Main 
Office Phone: +49 69 2400 3626; Fax: +49 69 2400 3627 
Email: MaxisOperations@maxismedical.com 
9.1.3. Clinical Sites 
A complete listing of all clinical sites will be maintained by the Sponsor and will be available 
upon request. 
9.1.4. MRI Core Laboratory 
Robert Zivadinov, M.D., Buffalo Neuroimaging Analysis Center, University at Buffalo, State 
University of New York, 100 High Street, Buffalo, NY 14203; Office Phone: +1-716-859-3579 
An MRI Core Laboratory will be utilized in this clinical study for the independent confirmation 
of MRI findings at the site level. The independently confirmed findings will be utilized in the 
reporting of the clinical data. A standard measurement process will be designed by the 
independent reviewer and each investigative site will receive training on the acquisition and 
transmission of images. 
9.1.5. Histopathology Core Laboratory 
Renu Virmani, M.D., CVPath Institute, Inc., 19 Firstfield Road, Gaithersburg, MD 20878; Office 
Phone: +1-301-208-3570 
A Histopathology Core Laboratory will be used in this clinical study for the independent review 
of the ProtEmbo System. The independently confirmed findings will be utilized in the reporting 
of the clinical data. 

 
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9.1.6. CT Core Laboratory 
AngioConsult GmbH, Heydenreichstr. 5, 67346 Speyer, Germany; Office Phone: +49-6232-
6042890 
A CT Core Laboratory will be used in this clinical study to assess the including and exclusion 
criteria based on CT data. The independently confirmed assessment will be utilized in the 
enrollment process. 
9.2. Ethical Considerations 
The rights, safety and well-being of clinical investigation subjects shall be protected consistent 
with the ethical principles as defined in the Declaration of Helsinki 2013. These principles shall 
prevail over interests of science and society and shall be understood, observed and applied at 
every step in this clinical investigation. 
It is expected that all parties will share in the responsibility for ethical conduct in accordance 
with their respective roles in the investigation. The Sponsor and the Investigator(s) shall avoid 
improper influence or inducement of the subject, monitor, the clinical investigator(s) or other 
parties participating in or contributing to the clinical investigation. 
9.3. Insurance 
The Sponsor will maintain the appropriate and necessary insurance coverage for the duration 
of the study. 
9.4. Study Conduct 
This study will be performed in accordance with the relevant parts of the ICH E6 Guidelines 
for Good Clinical Practices (GCP), DIN EN ISO 14155:2012-01 Clinical investigation of medical 
devices for human subjects - Good Clinical Practice (including DIN EN ISO 14155:2018-08 – 
draft 18-06-29), the Declaration of Helsinki 2013, and any regional and / or national regulations. 
The clinical investigation shall not begin until the required approval has been obtained from 
the relevant national regulatory authority and the local Ethical Committee. Any additional 
requirements imposed by the regulatory authority or EC shall be followed. 
9.5. Audits and Inspections 
The principal Investigator will also allow and support representatives of the governing EC, the 
Competent Authority, and other applicable regulatory agencies to inspect all study records, 
eCRFs, and corresponding portions of the subject’s office and / or hospital medical records at 
regular intervals throughout the trial. The principal investigator will provide direct access to 
source data / documents. These inspections are for the purpose of verifying adherence to the 
protocol, completeness and exactness of the data being entered onto the eCRFs and 
compliance with European Union or other regulatory agency regulations. 
The principal investigator will inform the Sponsor or the Sponsor’s designee should they be 
inspected by any regulatory agencies. The Sponsor or the Sponsor’s designee will also inform 
the site if they are made aware of a pending inspection by a regulatory agency. 

 
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Audits may also be conducted by the Sponsor or the Sponsor’s designee to evaluate 
compliance with the protocol, written procedures, ICH Guidelines for Good Clinical Practices, 
the European Standard ISO 14155:2012, and other applicable regulatory requirements. These 
audits are independent of and separate from routine monitoring visits. The audit results will be 
documented and communicated to relevant parties, if applicable. 
9.6. Sponsor Responsibilities 
Sponsor has the overall responsibility of the study and will: 
• 
Select qualified Principal Investigators, clinical investigators and study sites 
• 
Select qualified monitors 
• 
Provide the Investigational Plan and any subsequent amendments 
• 
Provide appropriate information and System training to Investigators and study site 
staff, including on-site clinical/technical support by qualified staff of Sponsor or 
Sponsor’s representative for each clinical case in the study 
• 
Ensure that all deviations from the Investigational Plan are reviewed with the 
appropriate Investigator(s) and reported in the eCRF and the final report and that any 
necessary preventative or corrective action is taken 
• 
Ensure that all adverse events and all adverse device effects (ADEs) are reported and 
reviewed with the Investigator(s), and where appropriate, that all serious adverse 
events (SAEs) and all serious adverse device effects (SADEs) are appropriately 
reported 
• 
During the course of the investigation, inform in writing all Investigators about adverse 
events and adverse device effects that have been reported to Sponsor (this information 
shall be sent to each Investigator based on perceived risk) 
• 
Promptly inform the Investigators and where applicable, any regulatory authorities, if 
the study is prematurely terminated or suspended and the reason for the termination 
or suspension 
• 
Ensure proper device usage, uniform data collection and protocol compliance 
• 
Provide protocol initiation training to include review of the ProtEmbo System 
instructions for use, the Investigational Plan, eCRF completion guidelines, and 
guidelines for obtaining informed consent 
• 
Provide the ProtEmbo System to participating study sites, in quantities to support study 
activities 
• 
Coordinate ongoing communication with CRO(s), consultants and study sites to resolve 
any problems concerning the protocol or data collection 
• 
Every effort will be made to ensure compliance with the protocol 
• 
Retain ownership of all clinical data generated in this study, and control the use of the 
data for purposes of regulatory submissions to CAs 
• 
Protect subject confidentiality 
9.7. Monitor Responsibilities 
The Sponsor has contracted MAXIS Medical as the Clinical Monitor to support the Sponsor in 
implementing and monitoring the clinical investigation until its termination. Clinical monitors, 

 
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qualified by training and experience, will be responsible for monitoring and overseeing the 
conduct of the trial. 
Clinical monitors will conduct site initiation visits at each investigational site to ensure that the 
principal investigator and other investigational site personnel involved in the conduct of this 
investigation have received and understood the requirements and contents of this clinical 
investigational protocol, the Investigator’s Brochure, the patient informed consent form, the 
eCRFs, the Instructions for Use and the institution and / or investigator agreement. 
Clinical monitors will ensure that the site facilities are adequate for the conduct of this 
investigation and that resources, laboratories, equipment and personnel remain adequate 
throughout the investigation. 
The clinical monitors will conduct routine on-site monitoring visits and phone calls to evaluate 
compliance with the protocol, any specific recommendations made by the site’s Ethics 
Committee (EC) and the signed Institution and/or Investigator Agreement and to ensure that 
the protocol is being followed and that any protocol deviations are properly documented on 
respective form. Clinical monitoring will include a verification that Informed Consent Form was 
properly obtained for all enrolled trial participants, a review of clinical records for accuracy and 
completeness, resolution of missing or inconsistent results and a review of source documents. 
Clinical monitoring will include a review of all adverse events and device malfunctions to ensure 
that all information has been reported to the sponsor, EC and regulatory authorities as required 
by this investigational plan and applicable standards and laws. 
The clinical monitor will verify that the electronic Case Report Forms (eCRFs) are complete 
and in agreement with the source documentation and other records. The clinical monitor will 
ensure that all eCRFs have been electronically signed and dated by the investigator. 
The investigator will make available to the clinical monitor for review all Informed Consent 
documents, all completed eCRFs, source documentation and other relevant records for all 
enrolled subjects at the site. It is important that the investigator and other relevant site 
personnel are available for consultation with the clinical monitors during the monitoring visits 
and that sufficient time is devoted at the site for the monitoring process. 
If a deficiency is noted during an on-site visit or at any other time during the course of the trial, 
the clinical monitor is required to discuss the situation with the investigator and the Sponsor, 
and to subsequently monitor the implementation of corrective actions that are required to 
address the situation. 
All monitoring activities will be documented by the clinical monitor and will include, at a 
minimum, the date, investigational site visited, names of all personnel involved in the visit, a 
listing of all documents reviewed and a summary of all findings, facts, deviations conclusions 
and recommended actions to be taken. Key findings will be reviewed with the clinical 
investigator. 
Upon completion of the study, a study close out visit will be conducted to ensure that all data 
collection and study requirements are complete. 
9.8. Investigator Responsibilities 
At a minimum, the following documents will be provided by the investigational site to the 
Sponsor prior to study start (consent of the first subject): 

 
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• 
Signed Clinical Trial Agreements 
• 
Signed Financial Disclosure Form 
• 
Signed Clinical Investigational Plan Signature Page 
• 
Relevant regulatory approvals 
• 
Investigator and Co-Investigator’s current Curriculum Vitae 
• 
Any other additional documents as required by the Sponsor 
The Investigator is responsible for ensuring that the investigation is conducted according to all 
signed agreements, the study protocol, governing regulations, data protection regulations, the 
medical device laws, the Declaration of Helsinki and any other conditions imposed by the 
relevant regulatory authorities. The Investigator is responsible for maintaining medical and 
study records for every subject participating in the clinical study (including information 
maintained electronically such as digital imaging). The Investigator will also maintain original 
source documents from which study-related data are derived. 
The Investigator(s) shall be responsible for the day to day conduct of the investigation as well 
as for the safety and well-being of the human subjects involved in the clinical investigation. 
The Investigator(s) shall: 
• 
Have the resources to conduct the investigation properly 
• 
Ensure that conducting the investigation will not give rise to a conflict of interest 
• 
Obtain from the Sponsor the information which the Investigator(s) judges essential 
about the device and be familiar with this information 
• 
Be well acquainted with the Clinical Investigation Protocol (CIP) before signing the 
signature page 
• 
Support the monitor, auditor, if applicable, in their activities to verify compliance with 
the CIP, to perform source data verification and to correct the eCRF where 
inconsistencies or missing values are identified 
• 
Discuss with the Sponsor management any question of modification of the CIP 
• 
Make sure that the CIP is followed by all responsible for the conduct of the study at his 
/ her institution. Any deviation shall be documented and reported to the study Sponsor 
• 
Make the necessary arrangements to ensure the proper conduct and completion of the 
investigation 
• 
Make the necessary arrangements for emergency treatment, as needed, to protect the 
health and welfare of the subject 
• 
Ensure that appropriate regulatory approval is obtained prior to the start of the 
investigation 
• 
Provide regulatory approvals to the Sponsor 
• 
Inform Sponsor about adverse events in a timely manner 
• 
Endeavor to ensure an adequate recruitment of subjects 
• 
Ensure that the subject has adequate information to give informed consent 
• 
Ensure that informed consent is obtained and documented 
• 
Ensure that clinical records are clearly marked to indicate that the subject is enrolled in 
this study 
• 
Provide subjects with well-defined procedures for any emergency situation and 
safeguard the subject’s interest. Under these circumstances, deviations from the CIP 

 
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shall not require the prior approval of the Sponsor or the national and local regulatory 
authorities. Such deviations shall not be considered as a breach of agreement but shall 
be documented and reported to Sponsor 
• 
Ensure that information which becomes available as a result of the clinical investigation 
which may be of importance to the health of a subject and the continuation of the 
investigation shall be made known to the Sponsor and, if pertinent to the safety or well-
being of the subject, and the private clinician 
• 
Inform the subject and / or the subject’s physician about any premature termination or 
suspension of the investigation with a rationale for study termination 
• 
Have primary responsibility for the accuracy, legibility and security of all investigation 
data, documents and subject records both during and after the investigation 
• 
Sign each subject’s eCRF, as applicable 
• 
Be responsible for the supervision and assignment of duties at his / her clinical center 
• 
Ensure that all investigational devices are kept in a secure location and that all Systems 
are accounted for (number of devices used, discarded and returned to Sponsor) 
9.9. Study Funding 
This clinical investigation is fully funded by the Sponsor. The Sponsor or its designated 
representative will enter into clinical research / clinical trial agreements with all clinical sites 
participating in the study. Comparable research agreements will be executed with core 
laboratories or other contributors in this clinical investigation. 
9.10. 
Investigator Training 
The ProtEmbo System is intended for use by experienced physicians. A limited number of 
Investigators at each site will be authorized to use the study device. These investigators will 
be provided with comprehensive training by Sponsor personnel (or designated representative) 
in the use of the device with a bench top model or equivalent prior to their participation in the 
clinical study. 
9.11. 
Medical Monitor 
A Medical Monitor will be responsible for overseeing the overall progress of the protocol. The 
Medical monitor will review patient recruitment, any Serious Adverse Events, any 
Unanticipated Adverse Events, and non-compliance with the protocol at individual centers. All 
Serious Adverse Events will be reviewed and adjudicated by the Medical Monitor. 
9.12. 
Data Management 
Electronic Data Capture (EDC) will be used for collection of primary data at all participating 
sites. Data Management procedures for computerized system are in compliance according to 
DIN EN ISO 14155:2012-01, including DIN EN ISO 14155:2018-08 – draft 18-06-29, GDPR 
(EU) 2016/679 and MDR (EU) 2017/745 (CRO Maxis Medical).  
Investigators are responsible for the accurate completion and timely submission of the data 
collected during the trial. All data from the trial will be entered via electronic CRFs (eCRFs) 
into a central database. Incoming data will be frequently reviewed to identify inconsistent or 

 
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missing data and any adverse events. Any data issues are to be promptly addressed with the 
investigator by the CRO (MAXIS Medical). By Quality assurance procedures it is ensured that 
complete, accurate and timely data are submitted; that protocol requirements are followed; and 
that complications, adverse events and adverse device effects are correctly reported and 
investigated, as appropriate.  
9.13. 
Study Suspension or Early Termination 
The study can be discontinued at the discretion of the Investigator or study Sponsor for reasons 
including, but not limited to, the following: 
• 
Occurrence of adverse events unknown to date in respect to their nature, severity, or 
duration, or the unexpected incidence of known adverse events 
• 
Obtaining new scientific knowledge that shows that the study is no longer valid or 
necessary 
• 
Data demonstrates a benefit to subjects who undergo TAVR with the ProtEmbo System 
making treatment without the ProtEmbo unethical 
• 
Insufficient recruitment of subjects 
• 
Unanticipated adverse device effect (UADE) presenting an unreasonable risk to 
subjects (Sponsor may terminate the study immediately) 
• 
Persistent non-compliance with the protocol 
• 
Persistent non-compliance with regulatory requirements 
If the study is discontinued or suspended prematurely, the Sponsor shall promptly inform all 
clinical investigator(s) / investigational center(s) of the termination or suspension and the 
reason(s) for this. The national and local regulatory authorities shall also be informed promptly 
and provided with the reason(s) for the termination or suspension by the Sponsor or by the 
clinical investigator / investigation center(s). 
9.14. 
Criteria for Suspending / Terminating a Study Center 
Sponsor reserves the right to stop the screening of subjects at a study center at any time after 
the study initiation visit if no subjects have been enrolled or if the center has multiple or severe 
protocol violations without justification or fails to follow remedial actions. 
Possible reasons for suspending / terminating a study center include, but are not limited to: 
• 
Repeated failure to complete case report forms prior to scheduled monitoring visits; 
• 
Failure to obtain written Informed Consent; 
• 
Failure to report SAEs / UADEs to Sponsor within 24 hours of knowledge; 
• 
Loss of (or unaccounted for) investigational product inventory. 
9.15. 
Final Report 
A Final Report will be prepared even if the study is prematurely terminated. The Final Report 
will be submitted to each participating Investigator, and regulatory agencies, as required. 

 
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9.16. 
Protocol Deviations 
A protocol deviation is defined as an event where the Investigator or site personnel did not 
conduct the study according to the protocol. 
Investigators shall be required to obtain prior approval from Sponsor or its designated 
representative before knowingly deviating from the protocol, except where necessary to protect 
the life or physical well-being of a subject in an emergency. Such approval shall be 
documented in writing and maintained in clinical study management and Investigator files. 
Prior approval is generally not expected in situations where unforeseen circumstances are 
beyond the Investigator’s control, (e.g., subject was not available for scheduled follow-up office 
visit, blood sample lost by laboratory, etc.); however, the event is still considered a deviation 
and will be reported via the appropriate eCRF. 
Deviations must be reported to Sponsor or designated representative regardless of whether 
medically justifiable, pre- approved by Sponsor or designated representative, or taken to 
protect the subject in an emergency. Subject specific deviations will be reported on the Protocol 
Deviation case report form. Non-subject specific deviations, (e.g., unauthorized use of an 
investigational device outside the study, unauthorized use of an investigational device by a 
physician who has not signed an Investigator agreement or not been trained in the use of the 
device, etc.), will be reported to Sponsor or designated representative. Investigators will also 
adhere to procedures for reporting study deviations to their Ethics Committee or Competent 
Authority, where required, in accordance with their specific reporting policies and procedures. 
Regulations require that Investigators maintain accurate, complete and current records, 
including documents showing the dates of and reasons for each deviation from the protocol. 
10. 
Regulatory Considerations 
10.1. 
Maintaining Records 
The Sponsor will maintain copies of critical correspondence, clinical data, shipment of devices, 
serious adverse device effects and other records related to the clinical trial. 
10.2. 
Site Record Retention Policy 
The Sponsor and clinical sites will maintain all records pertaining to this study in accordance 
with local and national regulations. The Sponsor will ensure that the CRFs will be kept available 
for review by the authorities for 10 years after completion or early termination of the study, in 
accordance with §10(7) MPKPV, and that the information regarding the investigational devices 
listed in Section 3.2 of Appendix VIII of Directive 93/42/EEC will be kept available for a 
minimum of 5 years in accordance with Section 4 of Appendix VIII and with §12(2) MPG. Prior 
to the destruction of study records the investigator or his representative should contact the 
Sponsor to ensure that they no longer need to be retained. In addition, Sponsor should be 
contacted if the Investigator plans to leave the investigational site so that arrangements can 
be made for the handling or transfer of study records. 

 
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10.3. 
Ethics Committee (EC) and Competent Authority (CA) Approval 
Regulatory approvals must be obtained prior to enrolment of the first patient. The Sponsor is 
responsible for obtaining regulatory and local approvals for the study. The Sponsor or its 
designated representative will require a copy of any Ethics Committee and Competent 
Authority correspondence, as well as the final approval letter from the Ethics Committee and 
Competent Authority, where applicable. The Sponsor confirms and is aware that the 
Competent Authority may contact the Ethics Committee that is assessing or has assessed the 
application. 
An Investigator may not make protocol changes without prior approval by Sponsor. All 
significant protocol changes that may affect the following must be submitted and approved by 
the Ethics Committee and Competent Authority before initiating the change: 
• 
Validity of the data or information resulting from the completion of the approved 
protocol; 
• 
Relationship of the likely subject risk to benefit relied upon to approve the protocol; 
• 
Scientific soundness of the investigational plan; 
• 
Rights, safety, or welfare of the human subjects involved in the investigation. 
The Sponsor may make certain administrative changes to the protocol without prior approval 
of the relevant Ethics Committee and Competent Authority. The Sponsor will notify all 
investigative sites of such changes to ensure the study continues to be conducted consistently 
across all sites. 
11. 
Publications 
The Sponsor’s publications policy for this study is as follows: Following the earliest of a) receipt 
of a notice from Sponsor stating that the study has been terminated or, b) twenty-four (24) 
months after completion or termination of the study at all Investigative sites, Investigators shall 
have the right to publish, in appropriate scientific journals or other professional publications, 
information and data collected or produced at their site as a result of their participation in the 
study, provided that drafts of the publications have been delivered to Sponsor for purposes of 
review and comment at least sixty (60) days prior to the first submission for publication or public 
release, to which investigating parties shall give due consideration. Sponsor shall return 
comments to the Investigator within forty-five (45) days upon receipt of the draft. In addition, 
the Investigator shall delay any proposed publication / presentation in the event Sponsor so 
requests to enable Sponsor to secure patent or other proprietary protection. In all such 
publications, credit shall be given to Sponsor for its sponsorship of the study. Similarly, in 
publications by Sponsor regarding the study, appropriate recognition will be given of the 
contribution made by the institutions and principal Investigators, as applicable. Sponsor may 
use, refer to, and disseminate reprints of scientific, medical, and other published articles 
relating to the study, including such reprints that disclose the name of Investigators and / or 
the relevant institution. 
A description of this clinical study is available on http://clinicaltrials.gov. 
 
 

 
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12. 
Definitions 
Acute Cardiovascular Surgery 
An immediate transfer from the catheterization lab to the operative room during the initial 
treatment phase due to the need for emergency coronary artery bypass graft surgery, cardiac 
valve surgery, or other vascular surgical intervention. 
Access Related 
Any adverse clinical consequence possibly associated with any of the access sites used during 
the procedure. 
Access Site 
Any location (arterial or venous) traversed by a guide wire, a catheter or a sheath, including 
the left ventricular (LV) apex and the aorta. 
Allergic Reaction 
An overreaction of the body’s immune system to a component of an investigational device 
(e.g., nitinol metal, polyester, plastics), contrast agents and / or anesthesia medication given 
to the subject for completion of a study related procedure (e.g., MSCT, angiogram, 
investigational device), which requires medical intervention to treat the allergic reaction. 
Acute Kidney Injury (AKI) 
• 
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 µmol / L) OR Urine output <0.5 ml / 
kg per hour for >6 but <12 hours 
• 
Stage 2: Increase in serum creatinine to 200–299% (2.0– 2.99 × increase compared 
with baseline) OR Urine output <0.5 ml / kg per hour for >12 but <24 hours 
• 
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 per hour for ≥24 hours OR 
Anuria for ≥12 hours [Subjects receiving renal replacement therapy are considered to 
meet Stage 3 criteria irrespective of other criteria] 
AV Block 
Atrioventricular block is a type of heart block in which the conduction between the atria and 
ventricles of the heart is impaired. 
Blood Loss 
• 
Major Blood Loss – Defined as transfusion of >2 units packed red blood cells (PRBC)). 
• 
Estimated Procedural Blood Loss – Defined as the total estimated blood loss (mL) 
during the index procedure. Includes blood loss resulting from adjunctive procedures 
performed during the index-procedure. 
Bleeding 
• 
Life-threatening or disabling bleeding: 
o Fatal bleeding (BARC type 5) OR 

 
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o Bleeding in a critical organ, such as intracranial, intraspinal, intraocular, or 
pericardial 
necessitating 
pericardiocentesis, 
or 
intramuscular 
with 
compartment syndrome (BARC type 3b and 3c) OR 
o Bleeding causing hypovolemic shock or severe hypotension requiring 
vasopressors or surgery (BARC type 3b) OR 
o Overt source of bleeding with drop in haemoglobin of ≥5 g / dL or whole 
blood or packed red blood cells (RBCs) transfusion ≥4 units* (BARC type 
3b) 
o Given one unit of packed RBC typically will raise blood hemoglobin 
concentration by 1 g / dL, an estimated decrease in hemoglobin will be 
calculated; BARC: Bleeding Academic Research Consortium. 
• 
Major bleeding: 
o Overt bleeding either associated with a drop in the hemoglobin level of at 
least 3.0 g / dL or requiring transfusion of 2 or 3 units of whole blood / RBC, 
of causing hospitalization or permanent injury, or requiring surgery AND 
o Does not meet criteria of life-threatening or disabling bleeding. 
• 
Minor bleeding: 
o Any bleeding worthy of clinical mention (e.g. access site hematoma) that 
does not qualify as life-threatening, disabling or major. 
Cerebral Infarction 
Evidence of brain cell death from imaging studies or pathological examination. If there are 
clinical symptoms, then it is a stroke; otherwise, it is an asymptomatic cerebral infarction. 
Contrast Volume 
Total volume of contrast (mL) administered during the index procedure. Includes contrast 
administered for adjunctive procedures performed during the index procedure. 
Death 
Death is divided into two categories and will be reported anytime in a subject’s study 
participation: 
• 
Device or procedure related death - Death related to the Study Device or to any 
procedure (index or subsequent) intended to treat the target vessel. 
• 
Non-device or procedure related death – Death NOT related to any procedure (index 
or subsequent) intended to treat the target vessel or death not related to the Study 
Device. 
Device Deficiency 
Inadequacy of the Study Device with respect to its identity, quality, durability, reliability, safety 
or performance. Device deficiencies include malfunctions, use errors, and inadequate labeling. 
Device Time 
Number of minutes from initial study device insertion to final study device removal. It does not 
include time needed to perform adjunctive procedures. 
Explant 

 
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Removal of the study device implant for any reason. 
Fluoroscopy Time 
Total fluoroscopy time (minutes) used during the index procedure and includes time utilized for 
adjunctive procedures performed during the index procedure. 
Major Adverse Cardiovascular and Cerebrovascular Event (MACCE) 
MACCE is defined as: 
• 
All-cause mortality 
• 
All strokes (major, minor and TIA) 
• 
Acute kidney injury – Stage 3 (including renal replacement therapy) 
Myocardial Infarction (MI) 
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), 
• 
Elevated cardiac biomarkers (preferably CK-MB) within 72 h after the index procedure, 
consisting of at least one sample post-procedure with a peak value exceeding 15x 
upper reference limit (troponin) or 5x for CK-MB. If cardiac biomarkers are increased 
at baseline (> 99th percentile), a further increase of 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 evidence of myocardial 
ischemia with at least one of the following: 
o Symptoms of ischemia 
o ECG changes indicative of new ischemia [new ST-T changes or new left 
bundle branch block [LBBB] 
o New pathological Q waves in at least two contiguous leads 
o Imaging evidence of 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 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. 
Post-Procedure Intensive Care Unit Time 

 
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Number of hours a patient is in an intensive care unit prior to discharge or moving to a step 
down or standard care unit. 
Post-Procedure Length of Hospital Stay 
Number of days from the end of the procedure until the patient is discharged from the hospital. 
This does not include time spent in a skilled care facility. 
Procedural Success 
Successful delivery of the investigational devices to the identified area and removal of delivery 
system in the absence of in-hospital SAEs. 
Procedure Time 
Number of minutes needed to perform the index procedure from time of initial vessel cut down 
time to time of final guidewire removal. Also referred to as skin-to-skin time. 
Renal Failure 
Need for dialysis or a laboratory finding of serum creatinine > 3.5 mg / dL. 
Respiratory Failure 
The need for mechanical ventilation beyond the first 24 hours post-index procedure (and / or 
reintervention) or the need for re-intubation or ventilator support after the first 24 hours (unless 
the subject was ventilator dependent pre-procedure). 
Stroke Diagnostic Criteria: 
• 
Acute episode of a focal or global neurological deficit with at least one of the following: 
Change in 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 designated neurologist 
• 
Confirmation of the diagnosis by at least one of the following: 
o Neurologist or neurosurgical specialist 
o Neuroimaging procedure (CT scan or brain MRI), but stroke may be diagnosed 
on clinical grounds alone 
 
• 
Ischemic Stroke: 
o An acute symptomatic episode of focal cerebral, spinal, or retinal dysfunction 
caused by an infarction of central nervous system tissue. 
• 
Hemorrhagic Stroke: 
o An acute symptomatic episode of focal or global cerebral or spinal dysfunction 
caused by an intraparenchymal, intraventricular, or subarachnoid hemorrhage. 

 
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(A stroke may be classified as undetermined if there is insufficient information to allow 
categorization as ischemic or hemorrhagic) 
Transient Ischemic Attack (TIA) 
A transient (<24 hours) episode of neurological dysfunction caused by focal brain, spinal cord, 
or retinal ischemia, without acute infarction. No evidence of infarction if imaging performed. 
Vascular Access Site and Access-related Complications 
• 
Major Vascular Complications: 
o Any thoracic aortic dissection 
o Access site or access-related vascular injury (dissection, stenosis, 
perforation, rupture, arteriovenous fistula, pseudoaneurysm, hematoma, 
irreversible nerve injury, or compartment syndrome) leading to either death, 
need for significant blood transfusions (≥4 U), unplanned percutaneous or 
surgical intervention, or irreversible end-organ damage (e.g., hypogastric 
artery occlusion causing visceral ischemia or spinal artery injury causing 
neurological impairment) 
o Distal embolization (noncerebral) from a vascular source requiring surgery 
or resulting in amputation or irreversible end-organ damage 
• 
Minor Vascular Complications: 
o Access site or access-related vascular injury (dissection, stenosis, 
perforation, rupture, arteriovenous fistula or pseudoaneurysms requiring 
compression or thrombin injection therapy, or hematomas requiring 
transfusion of ≥2 but not 4 U) not requiring unplanned percutaneous or 
surgical intervention and not resulting in irreversible end-organ damage 
o Distal embolization treated with embolectomy and / or thrombectomy and 
not resulting in amputation or irreversible end-organ damage 
o Failure of percutaneous access site closure resulting in interventional (e.g., 
stent-graft) or surgical correction and not associated with death, need for 
significant blood transfusions (≥4 U), or irreversible end-organ damage 
 
 

 
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13. 
Acronyms 
ACT 
 Activated clotting time 
AE 
 Adverse Event 
AKI 
 Acute kidney injury 
AMI 
 Acute myocardial infarction 
ASA 
 Acetylsalicylic acid 
AV 
 Atrioventricular 
BAV 
 Balloon aortic valvuloplasty 
BMI 
 Body mass index 
CA 
 Competent Authority 
CEA 
 Carotid endarterectomy 
CIP 
 Clinical Investigation Protocol 
CK 
 Creatine kinase 
CK-MB 
 Creatine kinase-MB fraction 
CRF 
 Case Report Form 
CRO 
 Contract Research Organization 
CT 
 Computed tomography 
CVA 
 Cerebrovascular accident 
DAPT 
 Dual antiplatelet therapy 
DW-MRI 
 Diffusion-weighted magnetic resonance imaging 
EC 
 Ethics Committee 
ECG 
 Electrocardiogram 
eCRF 
 electronic Clinical Report Form 
EDC 
 Electronic Data Capture 
EPD 
 Embolic protection device 

 
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GFR 
 Glomerular Filtration Rate 
EU 
 European Union 
FLAIR-MRI 
 Fluid attenuated inversion recovery magnetic resonance imaging 
Fr 
 French 
GI 
 Gastro-intestinal 
IFU 
 Instructions for Use 
IV 
 Intravenous 
LBBB 
 Left bundle branch block 
LVEF 
 Left ventricular ejection fraction 
MACCE 
 Major Adverse Cardiac and Cerebrovascular Events 
MI 
 Myocardial Infarction 
MoCA 
 Montreal Cognitive Assessment 
MSCT 
 Multi-Slice Computed Tomography 
MRI 
 Magnetic Resonance Imaging 
NIHSS 
 National Institutes of Health Stroke Scale 
PCI 
 Percutaneous coronary intervention 
PHI 
 Protected health information 
PRBC 
 Packed red blood cells 
RBBB 
 Right bundle branch block 
RBC 
 Red blood cells 
SAE 
 Serious Adverse Event 
TAVR / TAVI 
 Transcatheter aortic valve replacement (TAVR) or transcatheter
aortic valve implantation (TAVI) 
TIA 
 Transient ischemic attack 
VARC 
 Valve Academic Research Consortium 
VCI 
 Vascular cognitive impairment 

 
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