Transcatheter Aortic Valve Replacement (TAVR) With Medtronic TAVR System in Patients With Severe Bicuspid Aortic Valve Stenosis and at Low Predicted Risk of Mortality With Surgical Aortic Valve Replacement (SAVR)
Phase: NA
Conditions: Bicuspid Aortic Valve
Sponsor: Medtronic Cardiovascular

Medtronic Transcatheter Aortic Valve Replacement (TAVR) Low Risk Bicuspid Study 
ClinicalTrials.gov Identifier: NCT03635424 
Clinical Investigation Plan 
Document Date: 31 Jan 2019 (Version 1E) 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
10790330DOC
Version 
1E 
Page 1 of 118 
 
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Clinical Investigation Plan 
Clinical Investigation Plan/Study Title  
Transcatheter Aortic Valve Replacement (TAVR) with 
Medtronic TAVR System in Patients with Severe Bicuspid 
Aortic Valve Stenosis and at Low Predicted Risk of Mortality 
with Surgical Aortic Valve Replacement (SAVR) 
Clinical Investigation Plan Identifier 
10790330DOC 
Sponsor/Local Sponsor 
Global Sponsor:  
Medtronic, Inc 
Coronary and Structural Heart Clinical  
8200 Coral Sea St NE, MVS 66 
Mounds View, MN  55112 
United States 
Document Version 
1E 
Document Reference Number 
10790330DOC 
Study Co-Chairs 
Jeffrey Popma, MD, Interventional Cardiologist 
Beth Israel Deaconess Medical Center, Boston MA
Michael Reardon, MD, Cardiothoracic Surgeon 
Houston Methodist Hospital, Houston TX 
Study Co-Principal Investigators 
John Forrest, MD, Interventional Cardiologist 
Yale University, New Haven CT 
Basel Ramlawi, MD, Cardiothoracic Surgeon 
Winchester Medical Center, Winchester VA 
 
Confidentiality Statement 
 
The information contained in this document is confidential and the proprietary property of Medtronic. 
Any distribution, copying, or disclosure without the prior written authorization of Medtronic is strictly 
prohibited. Persons to whom the information is disclosed must know that it is confidential and that it 
may not be further disclosed by them. 
 
 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
10790330DOC
Version 
1E 
Page 2 of 118 
 
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Table of Contents  
 
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Primary Objective ..................................................................................................................................... 16 
Primary Endpoints .................................................................................................................................... 16 
Additional Outcome Measures ................................................................................................................. 16 
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TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
10790330DOC
Version 
1E 
Page 3 of 118 
 
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8.4.1. 
Informed Consent ....................................................................................................................... 37 
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TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
10790330DOC
Version 
1E 
Page 4 of 118 
 
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10.1.1. Definitions ................................................................................................................................... 49 
 
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10.2.1. Evaluation and Documentation of Adverse Events and Device Deficiencies ............................. 50 
10.2.2. Anticipated Adverse Events ........................................................................................................ 52 
10.2.3. Adverse Event Reporting Requirements for Clinical Sites .......................................................... 52 
10.2.4. Documentation and Reporting of Device Deficiencies ............................................................... 53 
10.2.5. Emergency Contact Details for Reporting SAE, SADE, UADE, and Device Deficiencies .............. 53 
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TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
10790330DOC
Version 
1E 
Page 5 of 118 
 
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14.9.1. Early Suspension or Termination of the Study ........................................................................... 62 
14.9.2. Early Suspension or Termination of a Study Site ........................................................................ 62 
 
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14.10.1. Investigational Sites .................................................................................................................... 63 
14.10.2. Study Site Investigative Team Members .................................................................................... 63 
14.10.3. Screening Committee ................................................................................................................. 64 
14.10.4. Publication Committee ............................................................................................................... 64 
14.10.5. Clinical Investigational Agreement and Financial Disclosure ..................................................... 64 
14.10.6. Curriculum Vitae ......................................................................................................................... 65 
14.10.7. Responsibilities of the Investigator ............................................................................................ 65 
14.10.8. Responsibilities of the Sponsor ................................................................................................... 66 
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TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
10790330DOC
Version 
1E 
Page 6 of 118 
 
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3.2.2 
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List of Figures 
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Figure 4 .  Evolut R TAV .......................................................................................................................................... 24 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
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Figure 5 .  EnVeo R catheter delivery system and EnVeo R InLine sheath ................................................................. 25 
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Figure 7.  (A) and (B) Examples of measurement of pre-implant LVOT diameter. LVOT diameter is measured from the 
white-black interface of the septal endocardium to the anterior mitral leaflet, parallel to the aortic valve 
plane, approximately 0.5 cm below the level of the aortic annulus, and in mid systole (C) and (D) Post TAV 
implantation, LVOT diameter measurement is from outer edge to outer edge of the inflow aspect of the stent 
(E) and (F) post surgical valve implantation, LVOT diameter is measured from the junction of the anterior 
sewing ring and the ventricular septum to the junction of the sewing ring and the anterior mitral valve leaflet.
 ..................................................................................................................................................................... 78 
Figure 8.  (A) Sample volume placement just proximal to zone of pre-valve acceleration (illustration by Mayo Clinic, 
used with permission) (B) Optimal LVOT velocity signal showing a smooth spectral Doppler recording with a 
narrow velocity range at each time point (C) Illustration showing correct sample volume placement just 
proximal to inflow of TAV stent (D) Full-screen imaging of stent to ensure positioning of sample volume below 
the TAV stent. ............................................................................................................................................... 79 
Figure 9. (A) Aortic valve velocities interrogated from multiple transducer positions (illustration by Mayo Clinic, used 
with permission) (B) CW Doppler of severe aortic stenosis showing tracing of the velocity curve from mean 
gradient and VTI, and measurement of max velocity. ..................................................................................... 80 
Figure 10. Measurements of the left ventricle (A) and left atrium (B) using 2-D guided m-mode. ............................ 84 
Figure 11. Positioning of the sample volume for recording of mitral inflow velocities. ............................................ 85 
Figure 12. Example images in original orientation (axial, coronal, and sagittal). Red curved arrow and line indicate 
adjustment of coronal and sagittal planes to align with aortic basal annulus. ................................................. 91 
Figure 13. Example images of reformatted oblique coronal (upper left), oblique sagittal (lower left), double oblique 
axial (upper right), and 3D reconstruction (lower right). Yellow arrowheads indicate most caudal attachment of 
three leaflets of the aortic valve). .................................................................................................................. 91 
Figure 14. Example of perimeter measurement (left) and major and minor diameter measurements (right). .......... 92 
Figure 15. Example of sinus of Valsalva diameters .................................................................................................. 93 
Figure 16. Examples of sinus of Valsalva heights (A) left coronary (B) non coronary (C) right coronary .................... 94 
Figure 17. (A) Between 0 and 1/3 of the valve length outside of the capsule (B) between 1/3 and 2/3 of the valve 
length outside of the capsule (C) Point of no return: capsule marker in alignment with the spindle marker (D) 
Full recapture: entire valve resheathed into the capsule until there is no gap between capsule and the tip. . 103 
 
 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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List of terms and definitions and/or acronyms used within this document are listed below.  
Term/Acronym 
Definition 
2D 
Two dimensional 
3D 
Three dimensional 
AE 
Adverse event 
ACT 
Active clotting time 
ADE 
Adverse device effect 
AR 
Aortic regurgitation 
AS 
Aortic stenosis 
AVR  
Aortic valve replacement 
BAV 
Balloon aortic valvuloplasty 
BSA 
Body surface area 
BNP 
B-type natriuretic peptide 
CEC 
Clinical Events Committee 
CIP 
Clinical investigational plan 
CLS  
Compression loading system 
CT 
Computed tomography 
CVA 
Cerebrovascular accident 
DCS  
Delivery catheter system 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EuroSCORE 
European System for Cardiac Operative Risk Evaluation 
FDA 
U.S. Food and Drug Administration 
GCP 
Good clinical practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HIT/HITTS
Heparin-Induced Thrombocytopenia / Heparin-Induced Thrombocytopenia and 
Thrombosis 
ICF 
Informed consent form 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IFU 
Instructions for use 
ITT 
Intent-to-treat 
LBBB 
Left bundle branch block 
LVEF 
Left ventricular ejection fraction 
LVOT 
Left ventricular outflow tract 
MCS 
Medtronic CoreValve® System 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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Term/Acronym 
Definition 
MI 
Myocardial infarction 
NYHA 
New York Heart Association 
PAV 
Percutaneous aortic valve 
PCI 
Percutaneous coronary intervention 
RBBB 
Right bundle branch block 
QoL 
Quality of Life 
SAE 
Serious adverse event 
STS  
Society of Thoracic Surgeons 
TAVI 
Transcatheter aortic valve implantation 
TAVR 
Transcatheter aortic valve replacement 
TEE 
Transesophageal echocardiography 
TIA 
Transient ischemic attack 
TTE 
Transthoracic echocardiography 
UADE 
Unanticipated adverse device effect 
VKA 
Vitamin K antagonists  
 
 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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Title 
Transcatheter Aortic Valve Replacement (TAVR) with Medtronic TAVR 
System in Patients with Severe Bicuspid Aortic Valve Stenosis and at Low 
Predicted Risk of Mortality with Surgical Aortic Valve Replacement (SAVR) 
Product Name 
Medtronic TAVR System: 
x
Evolut PRO Transcatheter Aortic Valve (TAV) 23, 26, and 29 mm 
x
Evolut R 23, 26, 29, and 34 mm TAV 
x
EnVeo PRO and EnVeo R Delivery Catheter System  
x
EnVeo PRO and EnVeo R Loading System 
Sponsor  
Medtronic 
Coronary and Structural Heart Clinical
8200 Coral Sea St NE, MVS 66 
Mounds View, MN55112 
United States 
Primary Objective 
To evaluate the procedural safety and efficacy of the Medtronic TAVR system 
in patients with bicuspid aortic anatomy and severe aortic stenosis at low 
risk for SAVR  
Primary Endpoints 
Safety 
All-cause mortality or disabling stroke rate at 30 days 
 
Efficacy 
Device success rate, defined as: 
• 
Absence of procedural mortality, AND 
• 
Correct positioning of a single prosthetic heart valve into the proper 
anatomical location, AND 
• 
Absence of moderate or severe total prosthetic valve regurgitation (at 18 
hours to 7 days) 
Additional Outcome 
Measures 
1. All-cause mortality at one year, and annually through 10 years 
2. All stroke (disabling and non-disabling) at one year, and annually through 
10 years 
3. New permanent pacemaker implantation at 30 days 
4. Myocardial Infarction at 30 days 
5. Life-threatening bleeding at 30 days, one year, and annually through 10 
years 
6. Prosthetic valve endocarditis at 30 days, one year, and annually through 
10 years 
7. Prosthetic valve thrombosis at 30 days, one year, and annually through 
10 years 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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8. Valve-related dysfunction requiring repeat procedure at 30 days, one 
year, and annually through 10 years 
9. Repeat hospitalization for aortic valve disease at 30 days, one year, and 
annually through 10 years 
10.Repeat hospitalization for ascending aorta disease at 30 days, one year, 
and annually through 10 years 
11.Hemodynamic performance metrics by Doppler echocardiography 
x
Mean aortic gradient at baseline, 30 days, one year, annually 
through 5 years and at years 7 and 10 
x
Effective orifice area at baseline, 30 days, one year, annually through 
5 years and at years 7 and 10 
x
Degree of total, peri, and transvalvular prosthetic regurgitation at 
baseline, 30 days, one year, annually through 5 years and at years 7 
and 10 
12.New York Heart Association (NYHA) functional classification at baseline, 
30 days, one year and annually through 5 years and at years 7 and 10 
13.Health-related quality of life as assessed by  
x
Kansas City Cardiomyopathy (KCCQ) instrument at baseline, 30 days, 
one year, annually through 5 years 
x
EQ-5D survey at baseline, 30 days and one year 
Study Design 
Multi-center, prospective, single arm 
Investigation Sites 
Up to 40 sites in the United States 
Number of Subjects 
150 subjects with attempted implant 
Patient Population
Severe aortic stenosis subjects with bicuspid aortic anatomy and an 
indication for SAVR with a bioprosthesis whose predicted risk of mortality at 
30 days is <3% per multidisciplinary local heart team assessment  
Key Inclusion Criteria 
1. Severe aortic stenosis, defined as follows: 
For symptomatic patients: 
x
ŽƌƚŝĐǀĂůǀĞĂƌĞĂчϭ͘ϬĐŵ2 ;ŽƌĂŽƌƚŝĐǀĂůǀĞĂƌĞĂŝŶĚĞǆŽĨчϬ͘ϲ
cm2/m2), OR ŵĞĂŶŐƌĂĚŝĞŶƚшϰϬŵŵ,Ő͕OR Maximal aortic valve 
ǀĞůŽĐŝƚǇшϰ͘ϬŵͬƐĞĐďǇƚƌĂŶƐƚŚŽƌĂĐŝĐĞĐŚŽĐĂƌĚŝŽŐƌĂƉŚǇĂƚƌĞƐƚ 
For asymptomatic patients: 
x
sĞƌǇƐĞǀĞƌĞĂŽƌƚŝĐƐƚĞŶŽƐŝƐǁŝƚŚĂŶĂŽƌƚŝĐǀĂůǀĞĂƌĞĂŽĨчϭ͘ϬĐŵ2 
;ŽƌĂŽƌƚŝĐǀĂůǀĞĂƌĞĂŝŶĚĞǆŽĨчϬ͘ϲĐŵ2/m2), AND maximal aortic 
ǀĞůŽĐŝƚǇшϱ͘Ϭ ŵͬƐĞĐ͕ŽƌŵĞĂŶŐƌĂĚŝĞŶƚшϲϬŵŵ,ŐďǇ
transthoracic echocardiography at rest, OR 
x
ŽƌƚŝĐǀĂůǀĞĂƌĞĂŽĨчϭ͘ϬĐŵ2 ;ŽƌĂŽƌƚŝĐǀĂůǀĞĂƌĞĂŝŶĚĞǆŽĨчϬ͘ϲ
cm2/m2), AND ĂŵĞĂŶŐƌĂĚŝĞŶƚшϰϬŵŵ,ŐŽƌŵĂǆŝŵĂůĂŽƌƚŝĐ
ǀĂůǀĞǀĞůŽĐŝƚǇшϰ͘ϬŵͬƐĞĐďǇƚƌĂŶƐƚŚŽƌĂĐŝĐĞĐŚŽĐĂƌĚŝŽŐraphy at 
rest, AND an exercise tolerance test that demonstrates a limited 
exercise capacity, abnormal BP response, or arrhythmia OR 
x
ŽƌƚŝĐǀĂůǀĞĂƌĞĂŽĨчϭ͘ϬĐŵ2 ;ŽƌĂŽƌƚŝĐǀĂůǀĞĂƌĞĂŝŶĚĞǆŽĨчϬ͘ϲ
cm2/m2), AND ŵĞĂŶŐƌĂĚŝĞŶƚшϰϬŵŵ,Ő͕ŽƌŵĂǆŝŵĂůĂŽƌƚŝĐǀĂůǀĞ

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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ǀĞůŽĐŝƚǇшϰ͘ϬŵͬƐĞĐďǇƚƌĂŶƐƚŚŽƌĂĐŝĐĞĐŚŽĐĂƌĚŝŽŐƌĂƉŚǇĂƚƌĞƐƚ͕
AND a left ventricular ejection fraction <50%. 
2. Patient is considered low risk for SAVR, where low risk is defined as 
predicted risk of mortality for SAVR <3% at 30 days per multidisciplinary local 
heart team assessment 
3. Bicuspid aortic valve anatomy (all sub-types) confirmed by MDCT  
Key Exclusion Criteria 
1. Significant ascending aortopathy requiring surgical repair 
2. Ascending aorta diameter >4.5 cm 
3. Age <60 years 
Subject Evaluation 
 
1. Clinical assessment at pre and post-procedure, discharge, 30 days, 1 
year, and annually through 5 years and at years 7 and 10 
2. Transthoracic echo at pre and post-procedure, 30 days, 1 year, and 
annually through 5 years and at years 7 and 10 
3. Multi-Detector Computed Tomography at pre-procedure   
4. Blood samples at pre-procedure; I.N.R. for subjects on Vitamin K 
antagonists (VKA) only at discharge, 30 days and annually through 5 
years 
5. 12-lead ECG at pre-procedure, discharge, and 30 days 
Study Co-Chairs 
Jeffrey Popma, MD, Interventional Cardiologist 
Beth Israel Deaconess Medical Center, Boston MA 
Michael Reardon, MD, Cardiothoracic Surgeon 
Houston Methodist Hospital, Houston TX 
Study Co-Principal 
Investigators 
John Forrest, MD, Interventional Cardiologist 
Yale University, New Haven CT 
Basel Ramlawi, MD, Cardiothoracic Surgeon 
Winchester Medical Center, Winchester VA 
Professional Services 
x
Independent Echocardiography Core Laboratory 
x
Independent Clinical Events Committee  
x
Independent Data Safety Monitoring Committee  
x
Independent Explant Pathology Core Laboratory 
Duration 
Total study duration is estimated to be 12 years (time from first subject 
implanted to ten-year follow-up on last subject implanted) 

 


 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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Following the first implantation in 2002 [1] TAVR has evolved to become a standard procedure at 
specialized heart centers worldwide. TAVR has been established as a safe and effective treatment option 
for patients with symptomatic severe aortic stenosis who are at intermediate, high and extremely high risk 
for surgical aortic valve replacement [2-8].  
The Medtronic CoreValve TAVR system received the CE Mark in 2007, and FDA approval in 2014. To date, 
over 65,000 patients have been implanted with the Medtronic CoreValve system in over 70 countries, with 
more than 20,000 of these patients enrolled in post-approval registries or clinical studies that further 
confirm the safety and performance of the CoreValve device. There is extensive published experience 
demonstrating the CoreValve system is fulfilling its intended role with a favorable risk/benefit ratio [9-13]. 
Rigorous clinical studies have established its safety and effectiveness, with improved mortality and quality 
of life compared with medical therapy in extreme risk patients [6], superiority to SAVR among high 
operative risk patients [7] and noninferiority to surgery in patients at intermediate surgical risk [8]. 
As experience with early generation TAVR devices increased, significant improvements in TAVR outcomes 
were achieved due to better patient selection, increasing operator experience, and iterations in device 
technology, important issues remained to be addressed, including the occurrence of major procedural 
complications [14-16], stroke [17, 18], paravalvular aortic regurgitation [19, 20], vascular complications [21, 
22] and need for new permanent pacemaker implantation [23-26]. 
To this end, Medtronic developed modifications to the CoreValve frame and delivery catheter system to 
enable resheathing or full recapture of the device before release from the delivery system.  These 
modifications were incorporated in the CoreValve Evolut R system (hereafter “Evolut R system”). The ability 
to resheath or recapture the device allows the operator to reposition or remove the bioprosthesis if the 
initial implant positioning was sub-optimal (too high or too low). This feature is desirable in that it facilitates 
accurate final positioning, which has been shown to mitigate risks associated with sub-optimal positioning 
such as paravalvular leak [27, 28] acute migration [16] and AV-conduction disturbance related to implant 
depth [23]. 
A comprehensive protocol of bench and animal testing of the Evolut R system has demonstrated its 
functionality and has confirmed that changes to enable recapture have not impacted the structural 
integrity, hydrodynamic performance, or durability of the CoreValve bioprosthesis. Beginning in October 
2013, clinical studies of the Evolut 23R, 26R and 29R valve sizes involving 301 patients have been conducted 
in Australia, New Zealand, Europe, and the United States.  These clinical studies confirmed that TAVR with 
the Evolut R system can be performed with an acceptable incidence of procedural and device-related 
complications, that short term safety and clinical efficacy of the Evolut R system are similar to the predicate 
CoreValve system, and there are no new safety risks associated with the use of the resheath/recapture 
feature. Results from these studies were used to gain the CE Mark in February 2015 for the Evolut 26R and 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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29R valve sizes, and FDA approval in June of 2015 for the Evolut 23R, 26R and 29R sizes. Subsequently, the 
Evolut R 34 mm size was approved for use in the United States and Europe.  
In order to continue striving for improvement with TAVR systems, Medtronic developed additional 
modifications to the Medtronic Evolut R system. The next-generation Evolut PRO system represents an 
enhancement to the Evolut R system and the latest Medtronic TAVR technology. The Evolut PRO TAVs 
feature a porcine pericardial tissue wrap on the outside of the frame (outer wrap) that covers the first 1.5 
cells of the inflow portion of the TAV. The wrap is designed to reduce paravalvular leak (PVL). As the outer 
wrap has been added to the inflow portion of the TAV, a minor design modification has been made to the 
LS inflow cone to reduce friction during loading of the TAV. The clinical configuration of this iteration to 
Evolut R was called the Medtronic TAVR 2.0 system (TAVR 2.0).  
Medtronic completed a comprehensive protocol of bench testing that collectively demonstrated the 
functionality of TAVR 2.0, and that the changes associated with the modification to the valve did not impact 
the structural integrity, hydrodynamic performance, or durability of the TAVR 2.0 bioprosthesis. The next 
generation device was approved in US for use in clinical trials in March 2016 under the name of Medtronic 
TAVR 2.0 System and with commercial approval in March 2017 was branded as “Evolut PRO system”.  
In July 2017, the Medtronic CoreValve, Evolut R, and Evolut PRO systems were approved for use in the 
United States for subjects at intermediate risk for SAVR.  
In January 2018, FDA approved various minor modifications to the EnVeo R Delivery Catheter System (DCS) 
and EnVeo R Loading System (LS). The devices, as modified, are marketed under the trade name EnVeo PRO 
Delivery Catheter System and EnVeo PRO Loading System. With these changes, the most current generation 
of Medtronic TAVR technology became the Evolut PRO system for 23mm, 26mm and 29mm sizes used with 
the EnVeo PRO DCS and LS. Evolut R TAV 34mm is the most current generation of the 34 mm and is also 
compatible with the EnVeo PRO DCS and EnVeo PRO LS. 
Over time, regulatory approvals have been received for use of Medtronic TAVR in several additional patient 
populations (eg, transcatheter aortic valve (TAV) in failed aortic bioprosthesis, end stage renal disease, and 
patients with severe AS but presenting with low gradient and low flow) who were not included in the 
original Medtronic TAVR clinical studies. Another subset of patients excluded from the original Medtronic 
TAVR studies were patients presenting with symptomatic severe aortic stenosis and congenital bicuspid 
aortic anatomy. It is reported that over 50% of all surgical aortic valve replacements are due to bicuspid 
aortic valve disease [29], 6% of the general population over 85 years has a bicuspid valve and 2-year 
mortality for these subjects following presentation of aortic stenosis symptoms with no treatment is 50% 
[30]. In their 2014 paper, Colombo and Latib reported the prevalence of bicuspid aortic anatomy among 
patients presenting for SAVR in their 80s and 90s as 18% and 22%, respectively [31].  Current literature does 
not provide specific information regarding the prevalence of bicuspid aortic valve anatomy among patients 
considered at low risk for SAVR.  However, in their 2012 paper, Roberts et al reported a prevalence of 
bicuspid aortic valves in 51% of patients between the ages of 51 and 79 who underwent SAVR [56]. 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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Multiple publications have indicated that use of TAVR in subjects with bicuspid aortic valve anatomy is 
feasible; however, additional research is required to determine benefits of TAVR compared to SAVR [32-
35]. Wijesinghe and colleagues [32] evaluated 11 high-risk patients with a bicuspid aortic valve treated with 
a balloon-expanded TAV.  They found that 27% and 14% of subjects experienced grade 2+ paravalvular leak 
(PVL) at post-procedure and at 1 year, respectively.  Mortality was reported as 7% at 30 days and 36% at 
the 1 year.  At 1 year, all surviving subjects were either NYHA class I or II.  Similarly, Himbert and colleagues 
examined 15 bicuspid aortic valve patients deemed to be high-risk implanted with a self-expanding TAV 
[33]. They reported that 7% of subjects experienced grade 2+ PVL post-procedure.  Mortality was reported 
as 7% at 30 days and 13% at a mean follow-up time of 8 months and of the surviving patients at 8 months, 
79% were in either NYHA class I or II. Two other studies examining a total of 247 bicuspid patients who 
received a TAV reported 1-year mortality as 18% and 17% [34, 35]. These studies have reported permanent 
pacemaker implant rates from 19-40% [33-35]. The 30-day post implant rate of ш grade 2 PVL was 28.4%; 
however, it was only 17.4% in patients that had MSCT-based sizing used to determine the appropriate valve 
size. 
As an extension of the established use of the Medtronic TAVR system in extreme, high, and intermediate 
risk severe aortic stenosis patients, Medtronic initiated the TAVR in Low Risk Patients IDE in March 2016. 
The low risk IDE is ongoing and will evaluate the safety and effectiveness of the Medtronic TAVR system in 
tricuspid aortic valve patients with aortic stenosis who are at low predicted risk for mortality with SAVR. 
The current study will be conducted under the Medtronic TAVR in Low Risk Patients IDE and will evaluate 
the procedural safety and efficacy of Medtronic TAVR (Evolut PRO system and Evolut R system) in patients 
with severe bicuspid aortic valve stenosis who are at low predicted risk of mortality with SAVR.  
Data from this study will be used to support regulatory submissions related to the use of Medtronic TAVR in 
patients with severe bicuspid aortic valve stenosis who are at a low predicated risk of mortality with SAVR. 
 3XUSRVH
This study will evaluate procedural safety and efficacy of the Medtronic Transcatheter Aortic Valve 
Replacement system (Evolut PRO and Evolut R systems) in patients with severe bicuspid aortic valve 
stenosis who are at low predicted risk of mortality at 30 days with SAVR. 
 
 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
10790330DOC
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Page 16 of 118 
 
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The primary objective is to assess procedural safety and efficacy of the Medtronic TAVR system in patients 
with severe bicuspid aortic valve stenosis who are at low predicted risk of mortality at 30 days with SAVR.  
3ULPDU\(QGSRLQWV
The following endpoints will be used to evaluate the primary study objectives: 
Safety 
All-cause mortality or disabling stroke rate at 30 days 
Efficacy 
Device success rate, defined as: 
x
Absence of procedural mortality, AND 
x
Correct positioning of a single prosthetic heart valve into the proper anatomical location, AND 
x
Absence of moderate or severe total prosthetic valve regurgitation (at 18 hours to 7 days) 
$GGLWLRQDO2XWFRPH0HDVXUHV
Additional outcome measures are listed below. 
1. All-cause mortality at one year, and annually through 10 years 
2. All stroke (disabling and non-disabling) at one year, and annually through 10 years 
3. New permanent pacemaker implantation at 30 days 
4. Myocardial infarction at 30 days 
5. Life-threatening bleeding at 30 days, one year, and annually through 10 years 
6. Prosthetic valve endocarditis at 30 days, one year, and annually through 10 years 
7. Prosthetic valve thrombosis at 30 days, one year, and annually through 10 years 
8. Valve-related dysfunction requiring repeat procedure at 30 days, one year, and annually through 10 
years 
9. Repeat hospitalization for aortic valve disease at 30 days, one year, and annually through 10 years 
10.Repeat hospitalization for ascending aorta disease at 30 days, one year, and annually through 10 years 
11.Hemodynamic performance metrics by Doppler echocardiography 
x
Mean aortic gradient at baseline, 30 days, one year, annually through 5 years and at years 7 and 10 
x
Effective orifice area at baseline, 30 days, one year, annually through 5 years and at years 7 and 10 
x
Degree of total, peri, and transvalvular prosthetic regurgitation at baseline, 30 days, one year, 
annually through 5 years and at years 7 and 10 
12.New York Heart Association (NYHA) functional classification at baseline, 30 days, one year and annually 
through 5 years and at years 7 and 10 
NYHA function classification will be reported as proportions at each specified time point. 
13.Health-related quality of life as assessed by  

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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x
Kansas City Cardiomyopathy (KCCQ) instrument at baseline, 30 days, one year, annually through 5 
years 
x
EQ-5D survey at baseline, 30 days and one year 
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This is a multi-center, prospective, single-arm clinical study. The study objective will be assessed by 
evaluating procedural efficacy and safety results at 30 days. 
Study methods include the following measures to minimize potential sources of bias: 
x
An external, independent Clinical Events Committee (CEC) will review and adjudicate, at minimum, all 
deaths and endpoint-related adverse events. Safety endpoint results will be based on CEC 
adjudications. 
x
All sites will follow a standardized protocol for acquisition of echocardiographic endpoint data. 
x
An Echocardiography Core Laboratory will evaluate all echocardiograms; echocardiographic endpoint 
results will be based on Core Lab assessments. 
x
Study sites should follow their institutional procedures for maintenance of imaging and laboratory 
equipment used for assessing the study variables. 
 'XUDWLRQ
Subjects will be followed up for 10 years. The enrollment period is estimated to be between 12-24 months 
therefore the estimated total duration of the study (first subject enrolled to last subject completing his/her 
last follow-up exam) is estimated to be 12 years. 
 5DWLRQDOH
The safety and effectiveness of balloon-expandable and self-expanding TAVR systems has been established 
in patients with severe symptomatic aortic stenosis who are considered at intermediate through extreme 
risk for SAVR [2-8], and is currently being evaluated in low risk patients. However, patients with bicuspid 
aortic valve anatomy were excluded from these pivotal studies. 
Anatomical differences between bicuspid and tricuspid aortic valves include increased annular ellipticity; 
asymmetrical, bulky and heavily calcified leaflets, and commissural fusion in bicuspid patients [31]. These 
anatomical differences can present challenges for TAVR systems and can impact positioning of the 
prosthetic valve within the annulus, expansion of valve frame, and sealing of valve annulus [31]. The 
bicuspid aortic valve anatomy differences could theoretically lead to sub-optimal procedural outcomes 
resulting in higher rates of procedural mortality, stroke, paravalvular regurgitation, or implantation of 
multiple devices. Therefore, the impact of the anatomical differences between bicuspid and tricuspid aortic 
valve anatomies on the clinical performance of TAVR systems can be assessed by evaluating procedural and 
short term (30 day) clinical outcomes. 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
10790330DOC
Version 
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Page 18 of 118 
 
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Previous studies with TAVR in patients with tricuspid aortic valves have shown a consistent mortality hazard 
after the procedural period [36]. In addition, similar one and two-year mortality rates have been reported 
for patients with bicuspid and tricuspid aortic valve anatomy [37, 38]. Hence, it is reasonable to assume 
that if the procedural outcomes are similar between patients with bicuspid and tricuspid anatomies, 
outcomes beyond the procedural period will be similar.  
Therefore, the primary endpoints in this study measured at 30 days will effectively assess the clinical 
performance in patients with bicuspid aortic valve anatomy. The endpoints are clinically relevant and 
address the most important procedural safety and efficacy aspects of the Medtronic TAVR System in 
subjects with bicuspid aortic valves. In addition, the endpoints are objectively defined, measurable in the 
majority of the subjects, and consistent with current recommendations for endpoints in TAVR clinical 
studies. This observational study is not hypothesis driven; however, the results from the primary endpoints 
the Low Risk bicuspid study cohort will be compared to and analyzed in the context of the procedural safety 
and efficacy results from the TAVR arm of the Low Risk Trial randomized cohort. Therefore, the clinical 
study as described is justified. 
 
 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
10790330DOC
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The Medtronic CoreValve Evolut PRO system (hereafter “Evolut PRO system”) and CoreValve Evolut R 
system (hereafter “Evolut R system”) will be used in this study.  The systems are collectively referred to as 
“Medtronic TAVR systems”. 
The study devices include the followings and described in the following sections: 
x
Evolut PRO Transcatheter Aortic Valve (TAV) 23 mm, 26 mm, 29 mm  
x
Evolut R Transcatheter Aortic Valve (TAV) 23 mm, 26 mm, 29 mm, 34 mm 
x
EnVeo PRO and EnVeo R Delivery Catheter System (DCS)  
x
EnVeo PRO and EnVeo R Loading System (LS) 
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The Evolut PRO system has similar principles of operation and critical performance as the Evolut R system.  
The Evolut PRO system comprises the following components: 
x
Transcatheter Aortic Valve (TAV) 
x
Delivery Catheter System (DCS) 
x
Loading System (LS) 
 
A listing of the system components is provided in Table 1. 
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Component 
Model Number 
Size (mm) 
Aortic Annulus 
Diameter (mm) 
Evolut PRO TAV 
TAV-MDT2-23-C 
23 
18 – 20  
TAV-MDT2-26-C 
26 
20 – 23 
TAV-MDT2-29-C 
29 
23 – 26 
EnVeo R Catheter Delivery System with EnVeo  
InLine Sheath (20 Fr) 
EnVeoR-N-C 
DS-MDT2-C 
23, 26, and 29 
Not applicable 
EnVeo PRO Catheter Delivery System (16eFr) 
ENVPRO-16-C 
23, 26, and 29 
Not applicable 
EnVeo R Loading System (for Pro TAVs) 
LS-MDT2-23-C 
LS-MDT2-2629-C 
23, 26, and 29 
Not applicable 
EnVeo PRO Loading System (16eFr) 
 
LS-ENVPRO-
1623-C 
23 
Not applicable 
LS-ENVPRO-16-C 
26 and 29 
Not applicable 
 
 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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Version 
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Transcatheter Aortic Valve Prosthesis (TAV) 
The transcatheter aortic valve (TAV) is a single-use, implantable device. The Evolut PRO TAV is available in 
three sizes (23, 26 and 29mm), covering an aortic annulus diameter of 18 to 26 mm (Table 1). The TAV is 
comprised of three leaflets and a sealing skirt constructed from glutaraldehyde-fixated porcine 
pericardium, sewn to a compressible and self-expandable Nitinol support frame (Figure 1). The TAV is 
processed with an anti-mineralization treatment of alpha-amino oleic acid (AOA), a compound derived from 
oleic acid, a naturally occurring long-chain fatty acid. The Evolut PRO TAVs are identical to the Evolut R 
TAVs, with the exception of a minor design modification incorporated to aid in sealing of the TAV in the 
native anatomy, and a minor change in one region of suture material on the 23 mm TAV, which is also used 
on the larger Evolut R TAVs.  
 
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EnVeo PRO Delivery Catheter System with InLine Sheath 
EnVeo PRO Delivery Catheter System facilitates the placement of the TAV within the annulus of the aortic 
valve (Figure 2). The catheter assembly is flexible and compatible with a 0.035 in (0.889 mm) guidewire. The 
distal (deployment) end of the system features an atraumatic, radiopaque catheter tip and a capsule that 
covers and maintains the bioprosthesis in a crimped position. The capsule includes a distal flare to enable 
full recapture of the bioprosthesis after partial deployment. A stability layer is fixed at the handle and 
extends down the outside of the catheter shaft. It provides a barrier between the retractable catheter and 
the introducer sheath and vessel walls, thus enabling the catheter to retract freely. 
The InLine Sheath is assembled over the stability layer, which functions as a hemostatic introducer sheath 
and minimizes the access site size to the capsule diameter. The InLine Sheath is compatible with 18 Fr or 20 
Fr introducers, respectively. 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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Version 
1E 
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The delivery catheter system consists of a catheter with an integrated handle to provide the user with 
accurate and controlled deployment. The handle is on the proximal end of the catheter and is used to load, 
deploy, recapture, and reposition the bioprosthesis. The handle features a gray front grip used to stabilize 
the system. The blue actuator turns to deploy the bioprosthesis precisely. Arrows on the actuator indicate 
the direction of rotation required to deploy the bioprosthesis. If desired, the blue actuator can be turned in 
the opposite direction to recapture the bioprosthesis if the radiopaque capsule marker band has not yet 
reached the distal end of the spindle. The blue actuator also features a trigger, which can be engaged to 
make macro adjustments to the capsule position. A blue hand rest connects to the blue actuator. The end 
of the handle features a tip-retrieval mechanism, which can be used to withdraw the catheter tip to meet 
the capsule after the device has been fully deployed. 
The catheter packaging contains an integrated loading bath and a removable tray with 3 rinsing bowls for 
loading and rinsing the bioprosthesis. The integrated loading bath features a mirror, which aids in accurate 
placement of the bioprosthesis frame paddles during loading. In addition, the device packaging is swiveled 
and secured to facilitate the bioprosthesis loading procedure. 
 
 
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EnVeo PRO Loading System 
The EnVeo PRO loading system facilitates manual loading of the TAV into the deployment sheath capsule of 
the catheter delivery system by gradually reducing the diameter of the bioprosthesis radially to an optimal 
diameter (Figure 3). The manual loading is performed during the procedure prior to implantation. The 
loading procedure is performed while immersing the loading system, the TAV, and the distal end of the 
catheter delivery system in cold sterile saline. 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
10790330DOC
Version 
1E 
Page 22 of 118 
 
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The EnVeo R Catheter Delivery System and EnVeo R Loading System, also compatible with the Evolut PRO 
TAV, are described in Section 6.2. 
 
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The Evolut R System is a transcatheter aortic valve implantation system comprised of the following three 
components: 
1. Evolut R Transcatheter Aortic Valve (TAV) 
2. EnVeo R Delivery Catheter System (DCS) with EnVeo R InLine Sheath or EnVeo PRO Delivery 
Catheter System (DCS) 
3. EnVeo R Loading System (LS) or EnVeo PRO Loading System (LS) 
All of the Evolut R system components are considered investigational for the bicuspid low risk patients. 
These components are provided separately for the procedure. All components are provided sterile and are 
intended for single use only. The Evolut R TAV is loaded into the EnVeo R or EnVeo PRO delivery catheter 
system using the EnVeo R or EnVeo PRO loading system immediately prior to implantation. 
The Evolut R TAV is intended as a permanent implant throughout the patient’s life, unless there is clinical 
indication to replace it with another prosthetic valve. The delivery catheter system is in contact with the 
body only during the device introduction and deployment phase of the implant procedure, typically less 
than 90 minutes. 
The system components and associated model numbers for the clinical trial are shown in Table 2., and a 
description of the system components is provided in the following sections. 
 
 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
10790330DOC
Version 
1E 
Page 23 of 118 
 
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Component 
Model Number 
TAV Size (mm) 
Aortic Annulus 
Diameter (mm) 
Evolut R TAV 
EvolutR-23-C 
23 
18 – 20 
EvolutR-26-C 
26 
20 – 23 
EvolutR-29-C 
29 
23 – 26 
EvolutR-34-C 
34 
26 – 30 
EnVeo R Catheter Delivery 
System with EnVeo InLine Sheath 
(18 Fr) 
EnVeoR-L-C 
23, 26, and 29 
Not applicable 
EnVeo R Catheter Delivery 
System with EnVeo InLine Sheath 
(20 Fr) 
EnVeoR-N-C 
34 
Not applicable 
EnVeo PRO Catheter Delivery 
System (14eFr) 
ENVPRO-14-C 
23, 26, and 29 
Not applicable 
EnVeo PRO Catheter Delivery 
System (16eFr)  
ENVPRO-16-C 
34 
Not applicable 
EnVeo R Loading System 
LS-EnVeoR-23-C 
23 
Not applicable 
LS-EnVeoR2629-C 
26 and 29 
Not applicable 
LS-EnVeoR-34-C 
34 
Not applicable 
EnVeo PRO Loading System 
(14eFr)  
LS-ENVPRO-14-C 
23, 26, and 29 
Not applicable 
EnVeo PRO Loading System 
(16eFr)  
LS-ENVPRO-16-C 
34 
Not applicable 
 
 
 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
10790330DOC
Version 
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Page 24 of 118 
 
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Evolut R TAV  
As Evolut PRO TAV, Evolut R TAV is a single-use, implantable device. It is available in 4 sizes (23, 26, 29, 34 
mm) covering an aortic annulus diameter of 18 to 30 mm. As Evolut PRO TAV, the TAV is comprised of three 
leaflets and a sealing skirt constructed from gluteraldehyde-fixated porcine pericardium, sewn to a 
compressible and self-expandable Nitinol support frame (Figure 4). The TAV is processed with an anti-
mineralization treatment of alpha-amino oleic acid (AOA), a compound derived from oleic acid, a naturally 
occurring long-chain fatty acid.  
 
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The EnVeo R catheter delivery system facilitates the placement of the TAV within the annulus of the aortic 
valve (Figure 5). The catheter assembly is flexible and compatible with a 0.035 in (0.889 mm) guidewire. The 
distal (deployment) end of the system features an atraumatic, radiopaque catheter tip and a capsule that 
covers and maintains the bioprosthesis in a crimped position. The capsule includes a distal flare to enable 
full recapture of the bioprosthesis after partial deployment. A stability layer is fixed at the handle and 
extends down the outside of the catheter shaft. It provides a barrier between the retractable catheter and 
the introducer sheath and vessel walls, thus enabling the catheter to retract freely. 
The EnVeo R InLine Sheath is assembled over the stability layer, which functions as a hemostatic introducer 
sheath and minimizes the access site size to the capsule diameter. The EnVeo R InLine Sheath is also 
compatible with an 18 Fr introducer. 
The delivery catheter system consists of a catheter with an integrated handle to provide the user with 
accurate and controlled deployment. The handle is on the proximal end of the catheter and is used to load, 
deploy, recapture, and reposition the bioprosthesis. The handle features a gray front grip used to stabilize 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
10790330DOC
Version 
1E 
Page 25 of 118 
 
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the system. The blue actuator turns to deploy the bioprosthesis precisely. Arrows on the actuator indicate 
the direction of rotation required to deploy the bioprosthesis. If desired, the blue actuator can be turned in 
the opposite direction to recapture the bioprosthesis if the radiopaque capsule marker band has not yet 
reached the distal end of the spindle. The blue actuator also features a trigger, which can be engaged to 
make macro adjustments to the capsule position. A blue hand rest connects to the blue actuator. The end 
of the handle features a tip-retrieval mechanism, which can be used to withdraw the catheter tip to meet 
the capsule after the device has been fully deployed. 
The catheter packaging contains an integrated loading bath and a removable tray with 3 rinsing bowls for 
loading and rinsing the bioprosthesis. The integrated loading bath features a mirror, which aids in accurate 
placement of the bioprosthesis frame paddles during loading. In addition, the device packaging is swiveled 
and secured to facilitate the bioprosthesis loading procedure. 
 
)LJXUH(Q9HR5FDWKHWHUGHOLYHU\V\VWHPDQG(Q9HR5,Q/LQHVKHDWK
 


 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
10790330DOC
Version 
1E 
Page 26 of 118 
 
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The EnVeo R loading system (Figure 6) facilitates manual loading of the TAV into the deployment sheath 
capsule of the catheter delivery system by gradually reducing the diameter of the bioprosthesis radially to 
an optimal diameter. The manual loading is performed during the procedure prior to implantation. The 
loading procedure is performed while immersing the loading system, the TAV, and the distal end of the 
catheter delivery system in cold sterile saline. 
 
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The EnVeo PRO Catheter Delivery System and EnVeo PRO Loading System were described in Section 6.2. 
 
 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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1E 
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The manufacturer and design site of the Evolut PRO and Evolut R systems is as follows: 
Medtronic CoreValve LLC 
1851 E Deere Avenue 
Santa Ana, CA 92705  
USA  
/DEHOLQJ
Labeling of the Medtronic TAVR system will be provided to the clinical sites. The labeling will indicate that 
the device is for investigational use only, and only to be used by qualified investigators, and consistent with 
the regulatory requirements. 
The Instructions for Use for the Medtronic TAVR Systems used in this study will be provided as a separate 
document. If changes are made to the labeling, they will be provided under separate cover to the 
appropriate authorities per requirements. 
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Medtronic will control the supply of investigational devices and study materials (eg, Investigator Site File, 
eCRF access). Investigational devices will not be sent to the site until the site is activated. Medtronic will not 
provide any study-specific equipment to the sites. Equipment used for assessing study variables (eg, 
echocardiographic systems) should be maintained per the site’s standard procedures. 
 
 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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The Evolut PR0 and Evolut R systems used in this trial are identical to the commercial devices; however, 
they are not approved for use in low risk patients with bicuspid aortic valve anatomy; and therefore, are 
considered investigational devices. As such, they should be stored as labeled and in a secure location. The 
method of storage should prevent the use of these investigational devices for commercial applications. The 
investigator shall maintain adequate records of the receipt and disposition of all investigational devices. 
Centers are required to maintain investigational device records that contain the following information: 
x
Investigational device name 
x
TAV serial number  
x
Lot number (for delivery catheter system and loading system only) 
x
Date of receipt of device 
x
Name of person receiving the device 
x
Name of person using the device (when applicable) 
x
Date of implant or use (when applicable) 
x
ID number of subject receiving or using the device (when applicable) 
x
Disposition (implanted, disposed of, or returned to Medtronic) 
For devices that are returned to Medtronic or disposed of, centers are required to document the following 
information: 
x
TAV serial numbers  
x
Lot numbers (for delivery catheter system and loading system only) 
x
The quantity and reason for the device being returned to Medtronic or disposed of 
x
Name of the person who returned or disposed of each device 
x
Date of shipment back to Medtronic 
At the study closeout visit, the investigator must return to Medtronic any unused devices and a copy of the 
completed device inventory.  The investigator’s copy of the device reconciliation records must document 
any unused devices that have been returned to Medtronic as well as all product usage including opened but 
non-implanted devices. 
 3URGXFWDQG6WXG\7UDLQLQJ5HTXLUHPHQWV
Prior to investigational center activation or subsequent involvement in study activities, Medtronic will 
provide training to the investigative team on the study methods, procedures, and requirements. Training 
may be conducted via site initiation visits, investigator meetings, and/or other media sessions.  Medtronic 
will maintain documentation of these training sessions.  For new study team members that join the study 
after site activation, the PI may provide training on the study with permission from Medtronic.  
Additionally, Medtronic representative(s) may be present at each site’s implant procedures as part of the 
ongoing training process. 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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The method of storage shall prevent the use of investigational devices outside the applications as 
mentioned in this Clinical Investigational Plan. In addition, all information for the use, storage and handling 
of the investigational device as indicated in the Instructions for Use, must be taken into account. 
 3URGXFW5HWXUQIRU0DOIXQFWLRQRU([SODQW
In the event of a malfunction of the Medtronic TAVR system prior to implant, or in the event a product is 
explanted after implant (due to reintervention or autopsy), the affected components should be sent to 
Medtronic at the following address: 
Medtronic  
Attn: Explant Lab [PE#] 
1851 E. Deere Avenue 
Santa Ana, CA 92705-5720 
Additional details surrounding the device return process are contained within the Medtronic explant kit 
that will be provided upon notification of a device malfunction or explant. 
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The population includes males and females with severe aortic stenosis with a clinical indication for surgical 
aortic valve replacement with a bioprosthesis who are at low predicted risk of mortality at 30 days for 
surgical aortic valve replacement and have bicuspid aortic valve anatomy. 
 6XEMHFW(QUROOPHQW
The point of enrollment is when written informed consent is obtained from the subject. 
 ,QFOXVLRQ&ULWHULD
1. Prospective subjects must meet all of following inclusion criteria to be eligible for implantation:
x
Severe aortic stenosis, defined as follows: 
a) For symptomatic patients: 
Aortic valve area ч1.0 cm2 (or aortic valve area index of ч0.6 cm2/m2), OR mean gradient ш40 
mmHg, OR Maximal aortic valve velocity ш4.0 m/sec by transthoracic echocardiography at rest 
b) For asymptomatic patients: 
Very ƐĞǀĞƌĞĂŽƌƚŝĐƐƚĞŶŽƐŝƐǁŝƚŚĂŶĂŽƌƚŝĐǀĂůǀĞĂƌĞĂŽĨчϭ͘ϬĐŵ2 (or aortic valve area index of 
чϬ͘ϲĐŵ2/m2), AND ŵĂǆŝŵĂůĂŽƌƚŝĐǀĞůŽĐŝƚǇшϱ͘ϬŵͬƐĞĐ͕ŽƌŵĞĂŶŐƌĂĚŝĞŶƚш60 mmHg by 
transthoracic echocardiography at rest, OR 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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ŽƌƚŝĐǀĂůǀĞĂƌĞĂŽĨчϭ͘ϬĐŵ2 ;ŽƌĂŽƌƚŝĐǀĂůǀĞĂƌĞĂŝŶĚĞǆŽĨчϬ͘ϲĐŵ2/m2), AND a mean gradient 
шϰϬŵŵ,ŐŽƌŵĂǆŝŵĂůĂŽƌƚŝĐǀĂůǀĞǀĞůŽĐŝƚǇшϰ͘ϬŵͬƐĞĐďǇƚƌĂŶƐƚŚŽƌĂĐŝĐĞĐŚŽĐĂƌĚŝŽŐƌĂƉŚǇĂƚ
rest, AND an exercise tolerance test that demonstrates a limited exercise capacity, abnormal BP 
response, or arrhythmia OR 
ŽƌƚŝĐǀĂůǀĞĂƌĞĂŽĨчϭ͘ϬĐŵ2 ;ŽƌĂŽƌƚŝĐǀĂůǀĞĂƌĞĂŝŶĚĞǆŽĨчϬ͘ϲĐŵ2/m2), AND mean gradient 
шϰϬŵŵ,Ő͕ŽƌŵĂǆŝŵĂůĂŽƌƚŝĐǀĂůǀĞǀĞůŽĐŝƚǇшϰ͘ϬŵͬƐĞĐďǇƚƌĂŶƐƚŚŽracic echocardiography at 
rest, AND a left ventricular ejection fraction <50%. 
2. Patient is considered low risk for SAVR, where low risk is defined as predicted risk of mortality for SAVR 
<3% at 30 days per multidisciplinary local heart team assessment. 
3. Bicuspid aortic valve anatomy (all sub-types) confirmed by MDCT.  
4. The subject and the treating physician agree that the subject will return for all required post-procedure 
follow-up visits. 
([FOXVLRQ&ULWHULD
If any of the following exclusion criteria are present, the prospective subject is not eligible for implantation: 
1. Any condition considered a contraindication for placement of a bioprosthetic valve (eg, subject is 
indicated for mechanical prosthetic valve). 
2. Age less than 60 years 
3. A known hypersensitivity or contraindication to any of the following that cannot be adequately pre-
medicated: 
a.
aspirin or heparin (HIT/HITTS) and bivalirudin
b. ticlopidine and clopidogrel 
c. Nitinol (titanium or nickel) 
d. contrast media 
4. Blood dyscrasias as defined: leukopenia (WBC <1000 cells/mm3), thrombocytopenia (platelet count 
<50,000 cells/mm3), history of bleeding diathesis or coagulopathy, or hypercoagulable states. 
5. Ongoing sepsis, including active endocarditis. 
6. Any percutaneous coronary or peripheral interventional procedure with a bare metal stent or drug 
eluting stent performed within 30 days prior to screening committee approval.  
7. Multivessel coronary artery disease with a Syntax score >22 and/or unprotected left main coronary 
artery. 
8. Symptomatic carotid or vertebral artery disease or successful treatment of carotid stenosis within 10 
weeks of Heart Team assessment. 
9. Cardiogenic shock manifested by low cardiac output, vasopressor dependence, or mechanical 
hemodynamic support. 
10. Recent (within 2 months of Heart Team assessment) cerebrovascular accident (CVA) or transient 
ischemic attack (TIA). 
11. Gastrointestinal (GI) bleeding that would preclude anticoagulation. 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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12. Subject refuses a blood transfusion. 
13. Severe dementia (resulting in either inability to provide informed consent for the study/procedure, 
prevents independent lifestyle outside of a chronic care facility, or will fundamentally complicate 
rehabilitation from the procedure or compliance with follow-up visits). 
14. Estimated life expectancy of less than 24 months due to associated non-cardiac co-morbid conditions. 
15. Other medical, social, or psychological conditions that in the opinion of the investigator precludes the 
subject from appropriate consent or adherence to the protocol required follow-up exams. 
16. Currently participating in an investigational drug or another device study (excluding registries). 
17. Evidence of an ĂĐƵƚĞŵǇŽĐĂƌĚŝĂůŝŶĨĂƌĐƚŝŽŶчϯϬĚĂǇƐďĞĨŽƌĞƚŚĞstudy procedure due to unstable 
coronary artery disease (WHO criteria). 
18. Need for emergency surgery for any reason. 
19. Subject is pregnant or breast feeding. 
20. Subject is legally incompetent, or otherwise vulnerable 
Anatomical exclusion criteria: 
21. Pre-existing prosthetic heart valve in any position. 
22. Severe mitral regurgitation amenable to surgical replacement or repair. 
23. Severe tricuspid regurgitation amenable to surgical replacement or repair. 
24. Moderate or severe mitral stenosis amenable to surgical replacement or repair. 
25. Hypertrophic obstructive cardiomyopathy with left ventricular outflow gradient. 
26. Prohibitive left ventricular outflow tract calcification. 
27. Sinus of Valsalva diameter unsuitable for placement of the self-expanding bioprosthesis 
28. Aortic annulus diameter of <18 or >30 mm. 
29. Significant ascending aortopathy requiring surgical repair 
30. Ascending aorta diameter >4.5 cm 
For transfemoral or transaxillary (subclavian) access: 
31. Access vessel mean diameter <5.0 mm for Evolut 23R, 26R, or 29R mm TAV, or access vessel mean 
diameter <5.5 mm for Evolut 34R mm or Evolut PRO 23R, 26R, 29 R mm TAV. However, for transaxillary 
(subclavian) access in patients with a patent LIMA, access vessel mean diameter <5.5mm for Evolut 
23R, 26R, or 29R mm TAV, or access vessel mean diameter <6.0 mm for the Evolut 34R or Evolut PRO 
TAVi. 
                                                            
LFor subjects with a patent LIMA undergoing tranaxillary (subclavian) access, the minimal access vessel mean diameter is 5.5 mm for the Evolut 
23mm, 26mm, and 29mm TAV, and 6.0 mm for the Evolut 34mm and Evolut PRO TAV.

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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Follow-up protocol required evaluations should be performed at the study site. The protocol required 
evaluations for each study interval are listed as follows: 
Baseline/Pre-implant Required prior to Screening Committee Submission (within 12 weeks prior to 
submission to the Screening Committee; except for MDCT and coronary arteriography)ii 
x
Clinical assessment and history (eg, clinical history, STS-PROM, co-morbidities, NYHA)iii 
x
Coronary arteriography 
x
TTE 
x
Heart Team assessment 
x
MDCT (peripheral vasculature and aortic annulus) 
x
Adverse events 
Baseline/Pre-implant Required prior to Index Procedure 
x
12-lead ECG 
x
Complete blood count  
x
Modified Rankin Score 
x
Kansas City Cardiomyopathy Questionnaire (KCCQ) 
x
Euro-Qol (EQ-5D) Quality of Life survey 
x
Anti-thrombotic medications 
x
Adverse events 
Implant Procedure 
x
Post-deployment hemodynamics and aortography (final result) 
x
Adverse Events 
18 hours to 7 days Post Procedure 
x
TTE (for device success) 
x
Adverse events 
Discharge (7 days post procedure or discharge, whichever comes first) 
x
Clinical assessment (NYHA not assessed at discharge) 
x
12 lead ECG 
x
Modified Rankin Score 
LLPre-implant MDCT and Coronary arteriography should be performed within 365 days of submission to the screening committee date
iii Definitions of STS risk factors and other co-morbidities are provided in Appendix III 


 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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x
Anti-thrombotic medications
x
INR (for subjects on VKA) 
x
Adverse events 
30 days (between 30 to 45 days post implant) 
x
Clinical assessment 
x
TTE 
x
12 lead ECG 
x
Modified Rankin Score 
x
KCCQ 
x
EQ-5D 
x
Anti-thrombotic medications 
x
INR (for subjects on VKA) 
x
Adverse events 
One Year (between 365 and 395 days post implant) 
x
Clinical assessment 
x
TTE 
x
Modified Rankin Score 
x
KCCQ 
x
EQ-5D 
x
Anti-thrombotic medications 
x
INR. (for subjects on VKA) 
x
Adverse events 
Two Year (between 730 and 760 days post-implant) 
x
Clinical assessment 
x
TTE 
x
Modified Rankin Score 
x
KCCQ 
x
Anti-thrombotic medications 
x
INR. (for subjects on VKA) 
x
Adverse events 
Annually from 3 years through 5 years (between implant anniversary date and +/-60 days after) 
x
Clinical assessment 
x
TTE 
x
Modified Rankin Score 
x
KCCQ 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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x
Anti-thrombotic medications
x
INR (for subjects on VKA) 
x
Adverse events 
6 years, 8 years and 9 years (between implant anniversary date and +/-60 days after) 
x
Adverse events 
7 years and 10 years (between implant anniversary date and +/-60 days after) 
x
Clinical assessment 
x
TTE 
x
Adverse events 
Other Evaluations 
x
A Modified Rankin Score assessment should be conducted at 1 and 3 months following any suspected 
or confirmed stroke event. 
 
Visit Windows 
Baseline 
Within 12 weeks prior to submitting to the screening committee (except for MDCT and 
coronary arteriography) as noted in Section 3.3.9) 
Discharge 
Discharge from index procedure or 7 days post implant, whichever comes first 
30 Days 
Between 30 and 45 days post implant 
1 Year  
Between 365 and 395 days post implant 
2 Year  
Between 730 and 760 days post-implant 
3 – 10 Years 
Between implant anniversary date and +/-60 days after 
 
 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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Evaluation/Visit 
Baseline 
(Pre-
Implant) 
Implant 
18 Hrs to 7 
Days 
(Device 
Success) 
Discharge  
30 Days 
1 Year 
Annual 
(through 5 
Years) 
Clinical Assessment 
X 
 
 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
Coronary 
Arteriography 
X 
 
 
 
 
 
 
MDCT 
X 
 
 
 
 
 
 
TTE 
X 
 
X 
 
X 
X 
X 
12-lead ECG 
X 
 
 
X 
X 
 
 
Modified Rankin 
Score 
X 
 
 
X 
X 
X 
X 
Hemodynamics 
 
X 
 
 
 
 
 
Aortography 
 
X 
 
 
 
 
 
Complete Blood 
Count 
X 
 
 
 
 
 
 
I.N.R. 
 
 
 
X 
X 
X 
X 
Anti-thrombotic 
Medications 
X 
 
 
X 
X 
X 
X 
KCCQ
X 
 
 
 
X 
X 
X 
EQ-5D 
X 
 
 
 
X 
X 
 
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7DEOH6XPPDU\RIYLVLWVFKHGXOHDQGUHTXLUHGHYDOXDWLRQVIURPWKURXJK\HDUV
 
Years 6, 8, and 91 
Years 7 and 10 
Clinical Assessment 
X 
Adverse Events 
X 
X 
TTE 
X 
1 Follow-up visits at years 6, 8 and 9 may be conducted remotely (eg, phone call) 
 
 
 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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The process of patient screening is as follows: 
1. Patients identified by or presented to the study site with aortic stenosis will be screened by the 
investigative team for the criteria described in section 7.0 Selection of Subjects, using available medical 
records, including relevant imaging studies previously performed for diagnostic purposes. 
2. If the patient is deemed a potential candidate for the study the investigational status of the Medtronic 
TAVR System and all aspects of the study will be explained to the patient.  
3. If the patient agrees to participate, written informed consent will be obtained. This will be considered 
the point of enrollment, and the subject will be assigned a Subject ID number. 
4. The subject will undergo transthoracic echocardiography (TTE) to assess his/her degree of aortic 
stenosis. 
5. Subjects who meet the criteria for aortic stenosisi will undergo: 
a. Multi-Detector Computed Tomography (MDCT) of their peripheral vasculature and aortic 
annulus to confirm bicuspid aortic valve anatomy and assess anatomic suitability for the 
Medtronic TAVR,  
AND 
b. Local Heart Team assessment to determine his/her operative risk profile for SAVR 
6. If the local Heart Team considers the subject anatomically suitable for implantation and at low risk for 
SAVR, the subject‘s clinical information will be submitted to the Screening Committee. The Heart Team 
assessment must be documented. The following information should be submitted to the Screening 
Committee: 
x
Clinical assessments including STS-PROM, medical history and co-morbidities 
x
TTE data on degree of aortic stenosis 
x
MDCT data on anatomical suitability and bicuspid aortic valve anatomy ii 
7. The Screening Committee will review the clinical information to confirm the eligibility of the subject for 
implantation. 
8. Concomitant percutaneous coronary intervention (PCI)iii with TAVR is allowed; however, staging is left 
to the discretion of the operator. Elective intervention/repair of the mitral or tricuspid valve is not 
allowed during the TAVR procedure. 
9. Implantation should occur within 90 days of Screening Committee approval. 
 5ROHRI6SRQVRU5HSUHVHQWDWLYHV
Representatives from Medtronic will provide confirmation of anatomical criteria prior to implant of each 
subject. In addition, representatives from Medtronic may provide technical support during the implant 
                                                            
LIf a subject has balloon aortic valvuloplasty after their qualifying TTE, they must have repeat TTE to confirm he/she meets criteria for severe aortic 
stenosis as described in Section 7.3 prior to submission to the screening committee.
LLAnatomical suitability will be confirmed by Medtronic Screening Lab. Information on MDCT procedures and sizing recommendations is provided in 
Appendix II, Section 4.0.
LLLIndex PCI should be performed at the TAVR implanting center; index PCI operators will be considered investigators.

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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procedures to the implanting physicians and study site staff relative to the use of the investigational 
devices. 
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Prior to enrolling in the study, patients should be fully informed of the details of study participation as 
required by applicable regulations, the site’s IRB and by Medtronic. Informed consent must be obtained 
from each patient prior to conducting any protocol-induced activities beyond standard of care, by using the 
informed consent form (ICF) approved by that site’s IRB and by Medtronic. The ICF must be signed and 
dated by the patient and by the person obtaining the consent. Any additional persons required by the site’s 
IRB to sign the informed consent form must also comply. 
Prior to the patient signing the ICF, the investigator or authorized designee will fully explain to the patient 
the nature of the research, study procedures, anticipated benefits, and potential risks of participation in the 
study. The investigator or delegate will allow adequate time for the patient to read and review the consent 
form and to ask questions. Signing the ICF serves to document the written and verbal information that the 
investigator or authorized delegate provides to the patient, the patient’s understanding of the information, 
and his/her agreement to participate. The investigator or authorized delegate must document in the 
patient’s medical records that the patient was consented and the date on which the consent was obtained. 
The original signed consent form will be retained in the patient’s study records and a copy of the informed 
consent will be provided to the patient. 
Patients should give written consent before undergoing any protocol-required testing. However, if any of 
protocol-required baseline/screening evaluations (eg, echocardiography, MDCT, coronary arteriography, 
lab work) have been performed for clinical diagnostic purposes prior to consenting, they can be used as the 
protocol-required exams, provided they were obtained within the protocol-required time windows and 
contain the necessary information. 
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Medtronic will inform the investigators whenever information becomes available that may be relevant to 
the subject’s continued participation in the study. The revised information will be sent to the investigator 
for approval by the IRB/EC. After approval by the IRB/EC, a copy of this information must be provided to the 
participating subjects, and the informed consent process as described above needs to be repeated. The 
investigator or his/her designee should inform the subject in a timely manner. 
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Sites will maintain a log of subjects consented, date attempted and implanted, as well as the Subject ID 
numbers assigned to each patient. Subjects who are consented but are not taken to the procedure room 
for implantation will be exited from the study and will not be followed beyond the date of study exit. 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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Subjects who are taken to the procedure room for implantation but do not receive a TAV for any reason will 
be followed for safety events for 30 days post-index procedure. Subjects that have their TAV bioprosthesis 
explanted will be followed for safety events for 30 days after the explant. 
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The implantation procedure is performed according to the standard procedures of the implanting 
physicians. In countries where required, including the United States, the local heart team’s interventional 
cardiologist(s) and cardiac surgeon(s) must jointly participate in the intra-operative technical aspects of the 
TAVR procedure. Procedural aspects specific to the Medtronic TAVR system should be performed according 
to the Instructions for Use. The following variables will be collected regarding the TAVR implantation 
procedure: 
x
Name of the primary and secondary operator 
x
Anesthesia type (general or local) 
x
Delivery catheter access site and vessel diameter of access site 
x
Use of EnVeo InLine Sheath alone, OR use of separate introducer sheath size and type 
x
Pre-deployment BAV (yes/no) 
x
Use of rapid pacing during BAV and deployment (yes/no) 
x
Size of TAV implanted 
x
Post-implant dilation (yes/no) 
x
Post-implant pressures at final result (LV systolic and end-diastolic, aortic systolic and diastolic) 
x
Implantation of TAV within the desired location (yes/no) 
x
Post-implant degree of prosthetic regurgitation by angiography (Sellers criteria, 45) 
x
Post-implant degree of prosthetic paravalvular regurgitation by TEE, if performed 
x
Post-implant degree of prosthetic transvalvular regurgitation by TEE, if performed 
x
More than one TAV implanted (yes/no) 
x
Patency of coronary arteries post-implant (yes/no) 
x
Estimated contrast volume used 
x
Total procedural time(minutes): time in procedure room to exit from procedure room 
x
Information on use of resheath/recapture feature (Definitions of resheath/recapture use are provided 
in Appendix IV)  
x
Occurrence of adverse events 
x
If TAV implantation not attempted, reason why 
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The recommended post implant anti-thrombotic regimen for TAVR subjects will be 30 days or more of Dual 
Anti-Platelet Therapy (DAPT) followed by aspirin through 12 months. 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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Clinical assessment is required at the following post-implant intervals: discharge, 30 days, 1 year, 2 years, 3 
years, 4 years, 5 years, 7 years and 10 years. The following variables will be documented at each protocol-
required follow-up interval: 
x
Follow-up status 
x
NYHA functional classification (except at discharge) 
x
Modified Rankin Score (except at years 6 through 10) 
x
Prescribed antithrombotic medications (except at years 6 through 10) 
x
KCCQ (except at discharge and years 6 through 10) 
x
EQ-5D (except at discharge, and years 2 through 10) 
x
Documentation of any adverse events (adverse events will be collected via telephone at 6-year, 8-year, 
and 9-year visits) 
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Definitions, procedures of evaluation, documentation and reporting of adverse events and device 
deficiencies are presented in section 10.0 Adverse Events and Device Deficiencies. 
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Transthoracic echocardiography (TTE) is required at the following intervals: pre-implant, 18 hours to 7 days 
(for device success), 30 days, 1 year, 2 years, 3 years, 4 years, 5 years, 7 years and 10 years. Exams will be 
sent to the Echo Core Lab for central assessment. Further details of the echocardiography methods are 
provided in APPENDIX I: ECHOCARDIOGRAPHY PROCEDURES.  Sites will acquire the necessary views and 
measurements for the Echo Core Lab to assess the following variables at each protocol-required exam: 
x
Height (cm or in) and weight (kg or lb) 
x
Heart rate 
x
Left ventricular outflow tract (LVOT) diameter in mid systole 
x
Max aortic/prosthetic valve velocity (V2) by CW Doppler 
x
Aortic valve velocity time integral (VTI) by CW Doppler 
x
Mean gradient across aortic valve (MGV2) by CW Doppler 
x
LVOT VTI by PW Doppler 
x
Grade of aortic/prosthetic transvalvular regurgitation ) 
x
Grade of aortic/prosthetic paravalvular regurgitation (post-implant only) 
x
Grade of prosthetic total (transvalvular plus paravalvular) regurgitation (post-implant only) 
x
Grade of mitral regurgitation 
x
Grade of tricuspid regurgitation 
x
Max tricuspid regurgitant (TR) jet velocity (if TR is present) 
x
Left ventricular internal dimension at end diastole 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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Left ventricular internal dimension at end systole
x
Interventricular septal thickness at end diastole 
x
Left ventricular posterior wall thickness at end diastole 
x
Left atrial diameter (anterior-posterior linear dimension) at systole 
x
Left ventricular ejection fraction 
x
Grade of diastolic dysfunction (if present) 
In addition, the following variables will be derived by the central database from the appropriate 
measurements reported by the site: 
x
Body surface area (Dubois and Dubois, [39])  
x
Peak aortic pressure gradient 
x
Aortic valve area (AVA)/effective orifice area (EOA) by continuity equation 
x
Aortic valve area index (AVAI)/effective orifice area index (EOAI) 
x
Doppler Velocity Index (DVI) 
x
Estimated right ventricular systolic pressure (RVSP) 
Derived variables may be displayed on the eCRF upon entry of the appropriate raw measurements. The pre-
implant qualifying AVA or AVAI must be based on the site reported variables for LVOT diameter, LVOT VTI, 
aortic valve VTI, height, and weight. 
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Every effort should be made to ensure subjects return to the clinic for all protocol required follow-ups, with 
the exception of the 6, 8 and 9-year follow-up visits which may be conducted remotely (eg,  phone call). If 
the subject is unable to return for an in-person clinic visit, the Investigator, or designee, should document in 
the subject record the reason the subject was unable to complete the visit and, if applicable, follow the 
requirements for deviation reporting as outlined in section 8.14 Deviation Handling. 
The investigator should also make every effort to contact the subject within the visit window to collect the 
subject’s vital status as well as information related to potential adverse events, safety data, and 
hospitalizations. 
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If a subject returns to the study site or is contacted via telephone between their scheduled follow-up visits 
for an event potentially related to a study endpoint, the visit or telephone call will be treated as an 
unscheduled follow-up, and the assessments completed at this visit will be conducted at the discretion of 
the investigator. 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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Study sites will assign a unique ID number to each subject.  Records of the subject/subject ID relationship 
will be maintained by the study site. Individual subject medical information obtained as a result of this 
study will be considered confidential. 
This study will utilize an Oracle Clinical Remote Data Capture (RDC) system that is the property of 
Medtronic. Required data will be recorded on electronic case report forms (eCRFs) by authorized site 
personnel as indicated on the Delegation Task List (DTL). Study personnel delegated for eCRF completion 
and/or approval per the DTL will be trained on the use of the RDC system and thereafter provided with a 
username and password to access the system. The eCRFs must be completed and/or updated to reflect the 
latest observations on the subjects participating in the study. The investigator (or approved sub-
investigator) will approve the eCRFs by electronically signing the appropriate pages of each eCRF. 
Data from the core lab will be entered into the Oracle Clinical RDC system by core lab personnel per their 
procedures established for the study. The core lab cardiologist will approve core lab eCRFs. 
The Oracle Clinical RDC system maintains an audit trail of entries, changes, and corrections in eCRFs. If a 
person only authorized to complete eCRFs makes changes to an already signed eCRF, the investigator shall 
re-approve this eCRF. 
All study-related documents must be retained until notified by Medtronic that retention is no longer 
required. Medtronic will inform the investigator/institution when these documents are no longer required 
to be retained. 
No study document or image should be destroyed without prior written agreement between Medtronic 
and the investigator. Should the investigator wish to assign the study records to another party or move 
them to another location, advance written notice must be given to Medtronic. 
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The Device Use Notification eCRF should be completed as soon as possible after device use. Effort should 
be made for all other eCRFs to be completed and approved within 3 weeks of the applicable follow-up visit. 
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Medtronic will be responsible for the processing and quality control of the data. Data review, database 
cleaning and issuing and resolving data queries will be done according to Medtronic internal SOPs and the 
Data Management Plan for this study. The study database will be developed and validated per the Data 
Management Plan for this study, and will employ validation programs (eg, range and logic checks) on 
entered data to identify possible data entry errors and to facilitate data validation. The study database will 
maintain an audit trail of all changes made to the eCRFs. 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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Entered data must be traceable to source documents. Source documentation is defined as the first time the 
data appear and may include all clinical records, hospital records, procedural reports, autopsy reports, and 
any other material that contains original information used for study data collection or adverse event 
reporting. Identified discrepancies between source documents and the eCRFs will be resolved through the 
online query resolution process per the Data Management plan. 
The eCRFs may not serve as source documents. Source documentation for data elements not routinely 
captured in medical records (echocardiography variables, MDCT variables, catheterization, procedural data 
variables, local heart team assessment, Modified Rankin Score) may vary from center to center; therefore, 
the site may use technical worksheets if identified as source documents. 
Source documents must be retained by the investigational site and made available for monitoring or 
auditing by the sponsor’s representative or representatives of the FDA and other applicable regulatory 
agencies or IRB/EC.  
The investigator must ensure the availability of source documents from which the information on the eCRFs 
was derived. Where printouts of electronic medical records are provided as source documents, or where 
copies of source documents are retained as source documents, they should be signed and dated by a 
member of the investigation site team indicating they are a true reproduction of the original source 
document. 
Copies of source documents may be requested to support event adjudication by the Clinical Events 
Committee. In some geographies, availability of source documentation may be limited due to institutional 
policies. If a specific source document is not available, necessary information may be transcribed onto the 
relevant eCRF page. 
In addition, the medical records of study subjects should be marked or flagged in such a way to indicate 
their participation in the study. 
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All information and data sent to parties involved in study conduct concerning subjects or their participation 
in this study will be considered confidential. Study sites will assign a unique subject ID number (SID) to each 
subject. Records of the subject/SID relationship will be maintained by the study site. The SID is to be 
recorded on all study documents to link them to the subject’s medical records at the site. To maintain 
confidentiality, the subjects’ name or any other personal identifiers should not be recorded on any study 
document other than the informed consent form. In the event a subject’s name is included for any reason, 
it will be masked as applicable. In the event of inability to mask the identification (eg, digital media), it will 
be handled in a confidential manner by the authorized personnel. 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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A protocol deviation is defined as an event where the clinical investigator or site personnel did not conduct 
the study according to the protocol or the Investigator Agreement. Examples of protocol deviations include 
but are not limited to the following: 
x
Failure to obtain informed consent prior to participation 
x
Incorrect version of the informed consent form used 
x
Failure to obtain IRB approval before the start of the study 
x
Implanted subject did not meet inclusion/exclusion criteriai 
x
Required testing and/or measurements not done or incorrectly done 
x
Subject does not attend follow-up visit or follow-up visit outside window 
x
Unauthorized use of investigational devices 
x
Adverse events not reported in the required time frame as required by regulation or as specified in the 
CIP 
x
Control of study devices not maintained 
x
Source data permanently lost 
x
Enrollment of patients during lapse of IRB approval 
Investigators should obtain prior approval from Medtronic before initiating any change or deviation from 
the CIP, except where necessary to protect the life or physical well-being of a subject in an emergency 
situation. Such approval shall be documented in writing and maintained in the Investigator Site File. Prior 
approval is generally not expected in situations where unforeseen circumstances are beyond the 
investigator’s control (eg, subject did not attend scheduled follow-up visit). 
Deviations will be reported to Medtronic regardless of whether medically justifiable, pre-approved by 
Medtronic, or taken to protect the subject in an emergency. Study deviations should be reported to 
Medtronic via the Study Deviation eCRF (one eCRF for each protocol deviationii). 
Investigators should report the following deviations to Medtronic and their reviewing IRB/EC within 5 
working days of the occurrence of the deviations:  
x
Failure to obtain written informed consent 
x
Deviations to protect the life or physical well-being of a subject in an emergency 
In addition, investigators are required to adhere to local IRB/EC procedures for reporting deviations.  
Deviations are analyzed, their significance is assessed, and any corrective and/or preventative actions that 
maybe warranted are identified. Medtronic is responsible for analyzing deviations, assessing their 
                                                            
L Subjects must meet all inclusion/exclusion criteria to be eligible for implantation. However, it will not be considered a protocol deviation if study 
related testing (eg, echo, MDCT, labs, coronary arteriography, Heart Team assessment, or Screening Committee assessment) of a consented subject 
identifies implantation eligibility criteria that are not met.
LLIn the case of a missed study visit (eg, followup visit), completion of only one protocol deviation eCRF is sufficient and additional eCRFs are not 
required for each assessment missed at that visit.

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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significance, and identifying any corrective and/or preventive actions that may be warranted. Repetitive or 
serious investigator compliance issues may represent a need to initiate a corrective action plan, which may 
include suspension of enrollment or termination of the investigator’s or site’s participation in the study.
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All subjects will be encouraged to remain in the study through the last follow-up visit at 10 years. Subjects 
who discontinue participation prematurely will be included in the analysis of results (as appropriate) and 
will not be replaced in the enrollment of total study subjects. If a subject is discontinued from the study 
early, the reason for discontinuation should be documented in the subject file and a Study Exit eCRF must 
be completed. 
The study site will make every effort to have all subjects complete the follow-up visit schedule. A subject 
will not be considered lost to follow-up unless all efforts to obtain compliance are unsuccessful. At a 
minimum, the effort to obtain follow-up information must include 3 attempts to make contact via 
telephone or e-mail and if contact via these methods is not successful, a traceable letter from the 
investigator should be sent to the subject’s last known address. Should telephone, e-mail and mail efforts 
to contact the subject be unsuccessful, the subject’s primary physician should be contacted. Subjects will 
then be deemed lost to follow up. All contact efforts to obtain follow-up must be documented in the 
subject’s medical records. 
If a subject discontinues the study at any time, is withdrawn from the study early, or completes all protocol 
required follow-up they should continue to be followed by the implanting site according to their routine 
clinical practice for aortic valve patients. If, for any reason, this is not possible for a particular subject, or if 
subject needs to change their follow-up site at any time point after conclusion of the study, investigators 
should refer subjects to a local site with appropriate training and experience in managing patients with 
implanted aortic valves.  
 
 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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Description of Risk Analysis 
Risk Analysis procedures were completed in accordance with ISO 14971:2012. Medtronic has determined 
the Medtronic TAVR system to be a significant risk medical device. Therefore, Medtronic is sponsoring this 
clinical study to support approvals for the use of the Medtronic TAVR system to patients with aortic 
stenosis at low risk for 30-day mortality for SAVR and with bicuspid aortic anatomy. 
Risks 
As with any TAVR procedure, there are risks associated with participation in this study. However, the risks 
to a patient for participation in this study are not materially different than those a patient would incur if 
they underwent TAVR outside of this study. 
TAVR has been associated with serious complications, including death. In addition, complications may occur 
at varying intervals necessitating re-intervention or surgical replacement of the TAV. Known complications 
that may result from TAVR include but are not limited to the following:  
x
Death 
x
Cardiac arrest 
x
Coronary occlusion, obstruction, or vessel spasm (including acute coronary closure) 
x
Urgent surgery (eg, coronary artery bypass, heart valve replacement, valve explant) 
x
Multi-organ failure 
x
Heart failure or low cardiac output 
x
Myocardial infarction  
x
Cardiogenic stroke 
x
Respiratory insufficiency or respiratory failure 
x
Cardiovascular injury (including rupture, perforation, or dissection of vessels, ventricles, myocardium, 
or valvular structures that may require intervention) 
x
Perforation of the myocardium or a vessel 
x
Stroke or other neurological deficits 
x
Transient ischemic attack 
x
Permanent disability 
x
Urgent need for balloon valvuloplasty (note that BAV during implantation is expected) 
x
Urgent need for Percutaneous Coronary Intervention (PCI) 
x
Major or minor bleeding that may or may not require transfusion or intervention (including life-
threatening or disabling bleeding) 
x
Respiratory insufficiency or respiratory failure 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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x
Cardiac tamponade
x
Ascending aorta trauma 
x
Disturbances in the electrical system of the heart that may result in the permanent placement of a 
device (pacemaker) 
-
Atrio-ventricular node block  
-
Bundle branch block  
-
Asystole  
x
Cardiac arrhythmias  
x
Thrombosis (including valve thrombosis) 
x
Valve migration/embolization 
x
Ancillary device embolization 
x
Prosthetic valve dysfunction including but not limited to: 
-
Fracture 
-
Bending (out-of-round configuration) of the valve frame 
-
Under-expansion of the valve frame 
-
Calcification  
-
Pannus 
-
Wear, tear, prolapse or retraction in the valve leaflet 
-
Poor valve coaptation 
-
Suture breaks or disruption 
-
Leak 
-
Mal-sizing (prosthesis-patient mismatch) 
-
Malposition (either too high or too low) 
-
Valve regurgitation (paravalvular or transvalvular) 
-
Valve stenosis 
x
Mitral valve regurgitation or injury 
x
Hypotension or hypertension 
x
Renal insufficiency or renal failure (including acute kidney injury) 
x
Allergic reaction to antiplatelet agents, contrast medium, or anesthesia 
x
Infection (including septicemia or endocarditis)  
x
Vascular access site or access related complications, including but not limited to: 
 Dissection 
 Perforation 
 Pain 
 Bleeding 
 Hematoma  
 Pseudoaneurysm 
 Irreversible nerve injury 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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 Compartment syndrome 
 Arteriovenous fistula 
 Stenosis 
x
Tissue erosion 
x
Encephalopathy 
x
Pulmonary edema 
x
Pericardial effusion 
x
Pleural effusion 
x
Myocardial ischemia 
x
Peripheral ischemia 
x
Bowel ischemia 
x
Heart murmur 
x
Hemolysis 
x
Cerebral infarction-asymptomatic 
x
Non-emergent reoperation 
x
Inflammation 
x
Fever 
x
Syncope 
x
Dyspnea 
x
Anemia 
x
Angina 
x
Abnormal lab values (including electrolyte imbalance) 
x
Exposure to radiation through fluoroscopy and angiography 
x
Delivery catheter malfunction resulting in need for additional re-crossing of the aortic valve and 
prolonged procedural time 
Each of these complications has the potential to be life-threatening, and some could lead to the need for 
open heart surgery. 
Measures to Mitigate Risks to Study Subjects 
The following measures will be implemented to minimize risks to the study subjects: 
x
Implanting physicians will have considerable experience with TAVR 
x
Study sites will have significant experience with surgical SAVR and TAVR 
x
Patients will undergo thorough imaging assessment during their pre-implant workup 
x
Patients receiving study device will be followed over the course of the study 
x
An independent data safety monitoring board (DSMB) will review adverse events and interim results in 
order to advise Medtronic regarding study conduct, should safety concerns be identified 
 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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Alternatives 
Presently, therapeutic alternatives for patients participating in this clinical study include the following: 
x
Medical therapy 
x
Balloon aortic valvuloplasty 
x
Surgical aortic valve replacement 
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The primary potential benefit to subjects participating in the study is restored function of their diseased 
(stenotic) bicuspid aortic valve. TAVR with the Medtronic TAVR system has been shown to be a safe and 
effective treatment for patients with symptomatic severe aortic stenosis who are at intermediate risk 
through extreme risk for operative mortality with SAVR. 
 5LVN%HQHILW5DWLRQDOH
TAVR is now established as a safe and effective treatment option for patients with symptomatic severe 
aortic stenosis who are at intermediate, high and extremely high risk for surgical aortic valve replacement 
[2-8]. The Medtronic CoreValve system has been used widely after receiving the CE Mark in 2007, and there 
is extensive published experience demonstrating the CoreValve system is fulfilling its intended role with a 
favorable risk/benefit ratio [9-13]. Rigorous clinical studies have established its safety and effectiveness, 
with improved mortality and quality of life compared with medical therapy in extreme risk patients [6], 
superiority to SAVR among high operative risk patients [7] and noninferiority to surgery in patients at 
intermediate surgical risk [8]. 
The Evolut R and Evolut PRO systems are built upon the same fundamental design principles and mode of 
operation as the predicate Medtronic CoreValve System. The Evolut R system introduces the feature of 
recapturability, and the Evolut PRO system builds upon Evolut R and introduces a design feature for 
reduction of paravalvular regurgitation. A comprehensive protocol of bench and animal testing has 
indicated the Evolut R and PRO systems are equivalent to the CoreValve system in terms of structural 
integrity, hydrodynamic performance, and valve durability. Clinical studies of the Evolut R and PRO system 
have confirmed the safety and efficacy of the Evolut R and PRO systems to be equivalent to the CoreValve 
system, with no new clinical risks associated [40-42]. Further, no new Zone III risks were identified for 
patients with bicuspid aortic valve anatomy through Risk Analysis [43].  
The risks and benefits of the Medtronic TAVR systems in low risk patients are expected to be similar to 
those at intermediate through extreme risk for SAVR.  The Medtronic TAVR Low Risk IDE trial will evaluate 
the safety and effectiveness of the Medtronic TAVR systems in tricuspid aortic valve patients with aortic 
stenosis who are at low predicted risk for mortality with SAVR.  This study will be conducted under the 
Medtronic TAVR Low Risk IDE, and will evaluate the procedural safety and efficacy of Medtronic TAVR 
(Evolut PRO system and Evolut R system) in patients with severe bicuspid aortic valve stenosis who are at 
low predicted risk of mortality with SAVR.   

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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Although there are risks to the subjects for participation in the study, they are anticipated to be similar to 
the risks of undergoing TAVR outside of the study. The potential benefits outweigh the design and use-
related risks established through risk analysis. 
 $GYHUVH(YHQWVDQG'HYLFH'HILFLHQFLHV
Definitions for Adverse Events, Adverse Device Effects, and Device Deficiencies are provided below. 
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The definitions to be applied for the purposes of reporting adverse events are provided in Table 5. 
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Event Type 
Definition 
Adverse Event (AE)  
 
(ISO14155:2011 3.2) 
 
Any untoward medical occurrence, unintended disease or injury, or untoward clinical 
signs (including abnormal laboratory findings) in subjects, users or other parties, 
whether or not related to the investigational medical device (47)  
NOTE 1: This definition includes events related to the investigational medical device or 
the comparator. 
NOTE 2: This definition includes events related to the procedures involved. 
NOTE 3: For users or other parties, this definition is restricted to events related to 
investigational medical devices. 
Serious Adverse Event 
(SAE)  
 
(ISO14155:2011 3.37) 
 
 
Adverse event that  
a) 
led to death, 
b) 
led to a serious deterioration in the health of the subject, resulting in  
1) 
a life-threatening illness or injury, or  
2) 
a permanent impairment of a body structure or a body function, or 
3) 
in-patient or prolonged hospitalization, or  
4) 
medical or surgical intervention to prevent life-threatening illness or 
injury or permanent impairment to a body structure or a body function, 
c) 
led to fetal distress, fetal death or a congenital abnormality or birth defect (47).  
NOTE: Planned hospitalization for a pre-existing condition, or a procedure required by 
the CIP, without serious deterioration in health, is not considered a serious adverse 
event. 
Adverse Device Effect 
(ADE) 
or Device Related 
Adverse Event 
(ISO14155:2011 3.1) 
Adverse event related to the use of an investigational medical device. 
NOTE 1: This definition includes adverse events resulting from insufficient or 
inadequate instructions for use, deployment, implantation, installation, or operation, 
or any malfunction of the investigational medical device (47).  
NOTE 2: This definition includes any event resulting from an error use or from 
intentional misuse of the investigational medical device. 
Serious Adverse Device 
Effect (SADE) 
(ISO14155:2011 3.36) 
Adverse device effect that has resulted in any of the consequences characteristic of a 
Serious Adverse Event (47, 48).  
Unanticipated Adverse 
Device Effect 
Any serious adverse effect on health or safety of a patient, or any life-threatening 
problem or death caused by or associated with the device, if the effect, problem, or 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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(UADE) 
(21 CFR 812.3) 
 
death has not been previously identified in nature, severity, or degree of incidence in 
the investigational plan or application, (including a supplementary plan or application), 
or any other unanticipated serious problem associated with a device that relates to the 
rights, safety, or welfare of subjects (49).  
 
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Investigators are required to evaluate and document in the subject’s medical records all adverse events 
(AE) and device deficiencies (per the definitions in Table 5) observed in study subjects from the time they 
are enrolled until they are exited from the study. All AE should be followed through their resolution or until 
subject’s study exit. 
All AEs that occur during the study need to be reported to Medtronic via the AE eCRF. Documented pre-
existing conditions are not considered to be reportable unless there is a change in the nature or severity of 
the condition. Pre-existing events should be reported as AE in the situation where a new treatment has to 
be started or an existing treatment has to be changed to treat the adverse event and the event is 
accompanied with signs and symptoms. In addition, after the subject has completed his/her two-year 
follow-up visit, only SAEs and device-related AEs need to be reported to Medtronic. 
Unavoidable events are conditions which do not fulfill the definition of an Adverse Event, meaning those 
medical occurrences, clinical signs (including abnormal laboratory findings), diseases or injuries that are not 
untoward in nature; specifically, those resulting from the intended injury such as the index TAVR 
procedure. The events listed in Table 6 are expected for patients undergoing TAVR, and do not need to be 
reported as AE, unless they occur outside of the stated timeframe, are otherwise considered to be an AE 
according to the treating investigator, or are suspected or confirmed to be device-related. 



 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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Event 
Timeframe (hours) 
from the Index 
Procedure 
Short transient episode of arrhythmia (including ventricular fibrillation) during index 
procedure 
0 
Confusion, anxiety and/or disorientation (other than TIA/stroke) starting within 48 hours 
with or without medical intervention 
120 (5 days) 
Temporary change in mental status (other than TIA/stroke) not requiring additional 
medical interventions or new medical assessments (eg, CT) 
72 
Dizziness and/or lightheadedness with or without treatment  
24 
Headache with or without treatment 
72 
Sleep problems or insomnia with or without treatment 
120 (5 days) 
Mild dyspnea or cough with or without treatment 
72 
Oxygen supply after extubation/“forced breathing therapy” 
48 
Diarrhea with or without treatment 
48 
Obstipation/Constipation with or without treatment 
72 
Anesthesia-related nausea and/or vomiting with or without treatment  
24 
Low-grade fever (<101.3°F or <38.5°C) without confirmed infection 
48 
Low body temperature 
6 
Pain (eg, back, shoulder) related to laying on the procedure table with or without 
treatment 
72 
Incisional pain (pain at access site) with or without standard treatment and patient not 
returning to clinic to have additional treatment 
No time limit 
Pain in throat and/or trachea due to intubation 
72 
Mild to moderate bruising or ecchymosis 
168 (7 days) 
Atelectasis/Pleural Effusion not requiring punctuation 
168 (7 days) 
Edema resulting in weight increase up to 4 kg/9lbs from baseline 
168 (7 days) 
For all observed AEs, investigators should assess and document the following information on the Adverse 
Event eCRF: 
x
Date of onset or first observation 
x
Date of site’s first awareness  
x
AE code number 
x
Description of the event 
x
Seriousness of the event 
x
Causal relationship of the event to the TAV or surgical valve  
x
Causal relationship of the event to the DCS and/or LS 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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x
Causal relationship of the event to the TAVR implant procedure
x
Treatment required 
x
Outcome or status of the event 
x
Date of resolution 
x
For all deaths, investigators should assess and document the following information on the Adverse 
Event eCRF 
R Date of death 
R Primary death category 
R Causal relationship of the event to the TAV or surgical valve 
R Causal relationship of the event to the DCS and/or LS 
R Causal relationship of the event to the implant procedure 
In addition, for all endpoint-related adverse events and deaths, sites should submit relevant, de-identified 
source documents to Medtronic for the Clinical Events Committee (CEC) members to use in their 
adjudication of the event. The CEC may request source documentation on additional events at their 
discretion and according to the CEC Charter. 
Definitions of safety endpoints, the AE code list, and guidelines for accessing causal relationships are 
provided in APPENDIX V: DEFINITIONS: SAFETY ENDPOINTS AND EFFICACY EVENTS 
 $QWLFLSDWHG$GYHUVH(YHQWV
Adverse events that are anticipated for subjects participating in this study are provided in Section 9.1, Risks.  
 $GYHUVH(YHQW5HSRUWLQJ5HTXLUHPHQWVIRU&OLQLFDO6LWHV
Adverse events and device deficiencies that occur during this study are required to be reported to Medtronic 
via the AE or device deficiency eCRF, as soon as possible after the event occurs, but no later than the 
timeframes listed in Table 7 or local requirements, whichever is more stringent. 
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Event Type 
Timeframe for Reporting 
Adverse Event (AE) 
No later than 10 working days of the investigator’s/site’s first 
knowledge of the event 
Serious Adverse Event (SAE)
Immediately, but no later than 72 hours of the investigator’s/site’s 
first knowledge of the event 
Adverse Device Effect (ADE) or Device 
Related Adverse Event 
Immediately, but no later than 72 hours of the investigator’s/site’s 
first knowledge of the event 
Serious Adverse Device Effect (SADE) 
Immediately, but no later than 72 hours of the investigator’s/site’s 
first knowledge of the event 
Unanticipated Adverse Device Effect 
(UADE) 
Immediately, but no later than 72 hours of the investigator’s/site’s 
first knowledge of the event 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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Event Type 
Timeframe for Reporting 
Device Deficiency 
No later than 72 hours of the investigator’s/site’s first knowledge of 
the event 
In addition, Investigators are obligated to report adverse events in accordance with the requirements of 
their reviewing IRB/EC and local regulations. 
The Sponsor is obligated to report adverse events and device deficiencies that occur during this study to the 
Regulatory Authorities and IRB/EC as per local requirements. The applicable timeframes are described in 
the Safety Plan associated with this study.  
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Device deficiency information will be collected throughout the study and reported to Medtronic. Device 
deficiencies that led to an AE are reported on the AE eCRF. Device deficiencies that did not lead to an AE 
should be reported on a Device Deficiency eCRF (one for each device deficiency). 
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Investigators should contact their Medtronic clinical study manager or site manager if they have any 
questions regarding reportable AEs. Medtronic will provide and maintain a listing of current contact details 
for each site. 
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A Clinical Events Committee (CEC) will provide independent medical review and adjudication of adverse 
event data used in the safety assessment of the investigational device. The CEC will adjudicate, at a 
minimum, all deaths and safety endpoint-related adverse events reported by the investigators. The analysis 
of the study safety data will be based on CEC adjudicated events. Safety endpoint definitions are provided 
in APPENDIX V: DEFINITIONS: SAFETY ENDPOINTS AND EFFICACY EVENTS. 
The CEC members will be free from bias towards the study and will be independent from both the study 
and investigators and Medtronic. The committee will consist of at least 3 independent experts (non-
Medtronic employed physicians) with expertise relevant to the study. This will include experience in the 
areas of: 
• Cardiac surgery 
• Interventional cardiology 
• Neurology 
• Electrophysiology 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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A CEC charter will be established that describes the Committee roles, responsibilities, and processes. 
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A Data Safety Monitoring Board (DSMB) will assess interim study data and provide recommendations to 
Medtronic regarding study conduct, should they identify any issues that may affect the safety of the study 
subjects. DSMB members will be free from bias towards the study and will be independent from both the 
study and investigators and Medtronic.  
The DSMB will consist of a minimum of 3 members who will have experience in the areas of:  
1) a cardiologist with expertise in the management of aortic stenosis  
2) a cardiothoracic surgeon with expertise in aortic valve replacement 
3) a statistician 
A DSMB charter will be established that describes the Committee roles, responsibilities, and processes.  The 
DSMB will meet (via teleconference or in person) prior to the first subject enrollment to establish 
procedures for safety data review, chairman appointment, and guidelines for study recommendations. The 
DSMB will meet on a periodic basis to perform a comprehensive data review, including at a minimum, all 
SAEs and deaths, and will meet more frequently when needed. Safety-related endpoints may also be 
reviewed at these meetings. DSMB meetings may consist of both open and closed sessions. Medtronic 
personnel may facilitate the DSMB meeting but will not have voting privileges. 
Following each meeting, the DSMB will report to Medtronic in writing and may recommend changes in the 
conduct of the study. The DSMB recommendations may include recommendations on study status such as 
continuing the study without modifications, continuing the study with modifications, stopping or 
suspending enrollment, or recommendations regarding study conduct including recommendations around 
enrollment or protocol deviations. 
In the case of UADEs, if Medtronic and the DSMB determine that the event presents an unreasonable risk 
to the participating subjects, Medtronic must terminate the clinical study within 5 working days after 
making that determination and no later than 15 working days after Medtronic first receives notice of the 
effect. All clinical sites will be notified of this action. 
The DSMB may call additional meetings if, at any time, there is concern about any aspect of the study. All 
data presented at the meetings will be considered confidential.  
 
 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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This study will involve 150 subjects with an attempted implant with the Medtronic TAVR system.  The 
primary analysis will be performed when 150 consecutive subjects with an attempted implant have had the 
chance to complete 30-day follow-up.  Results from the primary analysis will be used for regulatory 
submissions.  Another analysis may be performed when all 150 subjects with an attempted implant have 
completed 1 year follow-up. The final analysis will be performed with all implanted subjects have 
completed 10-year follow-up. 
This is not a hypothesis-driven study, therefore the sample size of 150 for the analysis was not determined 
by statistical sample size methods. However, a sample size of 150 subjects is adequate for a descriptive 
assessment of the procedural safety and efficacy of the Medtronic TAVR system in subjects with bicuspid 
aortic valves. The results from the primary endpoints of the Low Risk bicuspid study cohort will be 
compared to the procedural safety and efficacy results from the TAVR arm of the Low Risk Trial randomized 
cohort. 
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Enrolled Subjects  
All subjects with severe aortic stenosis and bicuspid anatomy who provide an informed consent will be 
considered screened and enrolled and all available data will be entered into the Electronic Data Capture 
(EDC) system. 
Analysis Sets 
There are two different analysis sets that are defined for this study. The primary analysis will be the 
“attempted implant” analysis. Analysis sets used for each objective are defined under the corresponding 
objective section. The analysis subsets are defined as follows: 
Attempted implant set: The attempted implant set consists of all enrolled subjects with an attempted 
implant procedure, defined as when the subject is brought into the procedure room and any of the 
following have occurred: anesthesia administered, vascular line placed, TEE placed or any monitoring line 
placed. Subjects will be analyzed according to their first attempted procedure (TAVR). Day 0 is date of first 
attempted procedure. 
Implanted set: The implanted set consists of all the attempted implant subjects who are actually implanted 
with the TAV. Day 0 is date of first attempted procedure. 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
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Baseline demographic and clinical variables will be summarized for as attempted implant analysis set. All 
continuous variables will be summarized with means, medians, standard deviations, minimums, and 
maximums.  Categorical variables will be summarized with frequencies and percentages. 
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All endpoints are descriptive and no statistical hypothesis test will be performed.  
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This endpoint will be analyzed for as attempted implant set. The Kaplan-Meier rate and a 95% two-sided 
confidence interval will be calculated. 
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This endpoint will be analyzed for the implanted set. The number and percentage of subjects that meet device 
success criteria will be calculated. A 95% two-sided confidence interval for the device success rate will be 
calculated. 
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Additional Outcome Measures are listed as follows: 
1. All-cause mortality at one year, and annually through 10 years 
2. All stroke (disabling and non-disabling) at one year, and annually through 10 years 
3. New permanent pacemaker implantation at 30 days 
4. Myocardial Infarction at 30 days 
5. Life-threatening bleeding at one year, and annually through 10 years 
6. Prosthetic valve endocarditis at one year, and annually through 10 years 
7. Prosthetic valve thrombosis at one year, and annually through 10 years 
8. Valve-related dysfunction requiring repeat procedure at one year, and annually through 10 years 
9. Repeat hospitalization for ascending aorta disease at 30 days, one year, and annually through 10 years 
10.Repeat hospitalization for aortic valve disease at one year, and annually through 10 years 
11.Hemodynamic performance metrics by Doppler echocardiography 
x
Mean aortic gradient at baseline, 30 days, one year, and annually through 10 years 
x
Effective orifice area at baseline, 30 days, one year, and annually through 10 years 
x
Degree of total, peri, and transvalvular prosthetic regurgitation at baseline, 30 days, one year, and 
annually through 10 years 
12.New York Heart Association (NYHA) functional classification at baseline, 30 days, one year and annually 
through 10 years 
13.Health-related quality of life as assessed by  

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
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x
Kansas City Cardiomyopathy (KCCQ) instrument at baseline, 30 days, one year, annually through 5 
years 
x
EQ-5D survey at baseline, 30 days and one year  
 
Analyses of the additional endpoints will be descriptive. Attempted implant set will be used for safety and 
quality of life outcomes. However, the hemodynamic performance outcomes will be analyzed for the 
implanted set. Continuous variables will be summarized as the number of subjects, means, standard 
deviations, medians, minimums, maximums, and interquartile ranges. Categorical variables will be 
summarized as frequencies and percentages. A Kaplan-Meier estimate will be performed for time-to-event 
analysis. 
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Every effort will be undertaken to minimize missing data. Missing (accidentally, due to withdrawal, missing 
follow-up or loss to follow-up, etc.), unused and spurious data will remain identifiable in the database. Data 
from subjects that cannot be analyzed for a specific variable will be displayed as missing in the relevant 
summary tables. In this manner, all data for a specific variable are accounted for. 
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This study will involve up to 150 total attempted implant subjects among all active sites. No site will implant 
more than 20% of the total number of attempted subjects without prior authorization from Medtronic. 
Subjects who exit from the study after implantation will not be replaced. 
Subjects will be consented for follow-up through 10 years. The enrollment period is estimated to be 
between 12 to 24 months; therefore, the estimated total duration of the study (first subject enrolled to last 
subject completing his/her last follow-up exam) is estimated to be 12 years. The number of investigational 
TAVR systems used in the study is estimated to between 150 and 200 (based on sample size).  
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This study was designed to reflect the Good Clinical Practice (GCP) principles outlined in ISO 14155:2011. 
These include the protection of the rights, safety and well-being of human subjects, controls to ensure the 
scientific conduct and credibility of the clinical investigation and the definition of responsibilities of the 
sponsor and investigators. 
The study will be conducted according to federal, national and local laws, regulations, standards, and 
requirements of the countries/geographies where the study is being conducted. The clinical investigation 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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shall be conducted in accordance with the ethical principles that have their origin in the Declaration of 
Helsinki. The principles of the Declaration of Helsinki are implemented in this study by means of the Patient 
Informed Consent (IC) process, Institutional Review Board approval, study training, clinical study 
registration, pre-clinical testing, risk benefit assessment, and publication policy. 
The study will be conducted under an FDA Investigational Device Exemption (IDE) in compliance with 21 
CFR Parts 11, 50, 54, 56 and 812, and ISO 14155:2011.  
Regulatory authority notification/approval to conduct the study is required. Investigational sites will be not 
be activated, nor begin enrolling subjects until the required approval/favorable opinion from the regulatory 
agency has been obtained (as appropriate). Additionally, any requirements imposed by an Institutional 
Review Board shall be followed, as appropriate. 
This study will be publicly registered prior to first enrollment in accordance with the 2007 Food and Drug 
Administration Amendments Act (FDAAA) and Declaration of Helsinki on http://clinicaltrials.gov (PL 110-85, 
Section 810(a)). 
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The study will be conducted in accordance with the requirements of local IRBs. The responsible IRB at each 
investigational site must approve the study protocol and informed consent form. Study activities will not 
commence prior to receipt of documentation of IRB approval by the site and Medtronic. The Investigator 
and study staff must comply with the requirements of their IRB, including any additional requirements 
imposed by the IRB after initial approval. 
Prior to enrolling subjects, each investigation site’s IRB will be required to approve the current CIP, the 
Informed Consent form, and any other written information to be provided to the subjects. Study sites in the 
United States must also utilize IRB approved Health Insurance Portability and Accountability Act (HIPAA) 
Authorization. 
IRB approval of the clinical study must be received in the form of a letter and provided to Medtronic before 
commencement of the study at an investigation site. The approval letter must contain enough information 
to identify the version or date of the documents approved. In addition, the approval letter needs to be 
accompanied by an IRB roster or letter of compliance, to allow verification that the investigator, other 
center study staff, and/or Medtronic personnel are not members of the IRB. If they are members of the IRB, 
written documentation is required stating that he/she did not participate in the approval process. 
Investigators must inform Medtronic of any change in status of IRB approval once the investigation site has 
started enrollment. If any action is taken by an IRB with respect to the investigation, that information will 
be forwarded to Medtronic by the respective investigator.  

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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Each site must fulfill all local regulatory requirements prior to enrolling subjects. Each study site must have 
written documentation of site/investigator readiness, including but not limited to IRB approval of the 
current version of the CIP, Informed Consent form, a signed Investigator’s Agreement, current investigator 
curriculum vitae, and documentation of training. The principal investigators and their institutions shall 
agree to this CIP and any amendments and indicate their approval by signing and dating the Clinical Study 
Agreement. 
Each site is required to have documented approval from the Regulatory Authority prior to their first subject 
enrollment. Medtronic will obtain a copy of the approval letter from the Regulatory Authority. 
Other documents referred to in this CIP are listed as follows and will be made available upon request: 
x
Monitoring Plan 
x
Data Management Plan 
x
Statistical Analysis Plan 
x
Safety Plan 
x
Electronic Case Report Forms (eCRFs) 
If the regulatory authority imposes any additional requirements (eg, safety reports, progress reports), 
Medtronic will prepare the required documents and send them to the authority. 
Any revisions or amendments to the CIP or Informed Consent documents will be submitted to the 
Regulatory Authority. A final report will be submitted to the Regulatory Authority upon study closure. 
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The study will be conducted in accordance with the design and specific provisions of this protocol, in 
accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are 
consistent with Good Clinical Practice (GCP) and the applicable regulatory requirements. 
The principles of the Declaration of Helsinki have been implemented by means of the patient informed 
consent process, IRB approval, study training, clinical study registration, preclinical testing, risk benefit 
assessment, and publication policy. Pediatric, legally incompetent, or otherwise vulnerable patients are not 
eligible for the study. Further, the Medtronic TAVR system will not be used as an emergency treatment. 
 6WXG\$GPLQLVWUDWLRQ
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Investigational sites will be monitored to ensure compliance with the study protocol, adherence to 
applicable regulations, and accuracy of study data. Monitoring visits will be conducted primarily to ensure 
the safety and well-being of the subjects is preserved. Monitoring visits will also be used to verify that study 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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data submitted on case report forms are complete and accurate with respect to the subject clinical records 
and to verify device accountability. Sites should provide appropriate access to the source data. Site 
personnel will complete eCRFs following each subject visit. Study data submitted will be reviewed against 
subject charts and other sources containing original records of subject data. Source document verification 
will occur in accordance to a Monitoring Plan. 
The progress of the study will be monitored by: 
x
On-site review, as deemed appropriate by Medtronic 
x
Telephone communications between the site personnel (eg, investigator, study coordinator) and study 
monitors 
x
Review of eCRFs and the associated clinical records 
x
Review of regulatory documents 
Monitoring and monitoring oversight will be provided by Medtronic (8200 Coral Sea St NE, Mounds View, 
MN 55112). Representatives of Medtronic (ie, contractors and designees) may also act as study monitors. 
Upon completion of the study, Site Closeout Visits will be conducted, as outlined in the Monitoring Plan. 
After the study has been completed, medical care will be provided to the subjects upon the discretion of 
the treating physician. 
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Medtronic may conduct audits at participating clinical sites. The purpose of an audit is to verify the 
performance of the monitoring process and the study conduct, independent of the personnel directly 
involved in the study. Regulatory bodies, such as the Food and Drug Administration may also perform 
inspections at participating sites. The investigator and/or institution shall permit Medtronic and 
regulatory bodies direct access to source data and documents. 
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Medtronic will be responsible for the processing and quality control of the data.  Data review, database 
cleaning and issuing and resolving data queries will be done according to Medtronic internal SOPs and the 
Data Management Plan for this study. The study database will be developed and validated per the Data 
Management Plan for this study and will employ validation programs (eg range and logic checks) on 
entered data to identify possible data entry errors and to facilitate data validation. The study database will 
maintain an audit trail of all changes made to the eCRFs.   
Refer to Recording Data section for further information regarding data collection and management 
procedures.  
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All information and data sent to parties involved in study conduct concerning subjects or their participation 
in this study will be considered confidential. Study sites will assign a unique subject ID number (SID) to each 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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subject. Records of the subject/SID relationship will be maintained by the study site. The SID is to be 
recorded on all study documents to link them to the subject’s medical records at the site. To maintain 
confidentiality, the subjects’ name or any other personal identifiers should not be recorded on any study 
document other than the informed consent form. In the event a subject’s name is included for any reason, 
it will be masked as applicable. In the event of inability to mask the identification (eg, digital media), it will 
be handled in a confidential manner by the authorized personnel. 
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Medtronic, Inc. (including all wholly owned subsidiaries) maintains appropriate clinical study liability 
insurance coverage as required under applicable laws and regulations and will comply with applicable law 
and custom concerning specific insurance coverage.  If required, a Clinical Study Insurance 
statement/certificate will be provided to the IRB. 
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The investigator may propose any appropriate modification(s) of the CIP or investigational device or 
investigational device use.  Medtronic will review this proposal and decide whether the modification(s) will 
be implemented. 
Medtronic will submit any significant amendment to the CIP, including a justification for the amendment, to 
the regulatory agency and to the investigators to obtain approval from their IRB.  The investigator will only 
implement the amendment after approval of the IRB, regulatory agency, and Medtronic. Administrative 
amendments to the CIP will be submitted to the IRB for notification.  Furthermore, investigators shall sign 
any approved amendment for agreement. 
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The investigator must retain the Investigator Site File, source documents, and the records listed in 
[Responsibilities of the Investigator], until informed by Medtronic they no longer need to be retained. At a 
minimum, the investigator must retain records for at least 2 years (or for 15 years if required by local law) 
after the last approval of a marketing application and until there are no pending or contemplated 
marketing applications, or at least two years have elapsed since the formal discontinuation of clinical 
development of the investigational devices. The investigator should take measures to prevent accidental or 
early destruction of the study related materials. 
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A Publication Plan will provide detailed information about the publication committee, authorship, 
publication proposals, and requests for data. 
 Medtronic is committed to the widespread dissemination of all primary and secondary endpoint results. 
The results will be posted publicly on clinicaltrials.gov no later than 1 year after the conclusion of the 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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primary and secondary endpoints as well as no later than two years after the completion of data collection. 
A full report of the outcomes will be made public no later than three years after the completion of data 
collection as abstracts and presentations in scientific conferences publications and in peer-reviewed 
journals as described below. A Publication Plan will be implemented and followed.  
At the conclusion of the study and no later than three years after the completion of data collection, a 
multisite abstract reporting the primary results will be prepared by the Principal Investigators (in 
collaboration with others including but not limited to the echo core lab physicians, and the CEC/DSMB). A 
multisite publication will similarly be prepared for publication in a reputable scientific journal. The 
publication of the principal results from any single site experience within the study is not allowed until both 
the preparation and publication of the multisite results, and then only with written permission from 
Medtronic.  
Following analysis and presentation of the endpoint results, active participation of all participating 
investigators, CEC/DSMB committee members, and core laboratory personnel will be solicited for data 
analysis and abstract and manuscript preparation. Submission of all abstracts and publications regarding 
the primary endpoint and secondary endpoints from the study requires approval by the Principal 
Investigators after review by the Publications Committee. 
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Medtronic may decide to suspend or prematurely terminate the study (eg, if information becomes available 
that the risk to study subject is higher than initially indicated or if interim analysis indicates that the results 
significantly differ from the clinical study objectives or statistical endpoints). If the study is terminated 
prematurely or suspended, Medtronic shall promptly inform the clinical investigators and regulatory 
authorities of the termination or suspension and the reason(s) for this. The investigator shall then promptly 
inform the reviewing IRB/EC. Medtronic will, as soon as possible, provide a written statement to the 
investigators to enable prompt notification of the IRB/ECs. If study enrollment is terminated early, follow-
up visits will continue for all enrolled subjects. 
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Medtronic may decide to suspend or prematurely terminate an investigation site (eg, in case of expiring 
approval of the reviewing IRB/EC, non-compliance to the CIP, or lack of enrollment). If an investigation site 
is suspended or prematurely terminated, Medtronic shall promptly inform the investigator(s) of the 
termination or suspension and the reason(s) for this. The investigator shall then promptly inform the 
reviewing IRB/EC. 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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This study may be conducted at up to 40 sites in the United States. Investigative sites will meet the 
following criteria: 
x
The site will have extensive experience with TAVR and SAVR including the following: 
R cardiothoracic surgeon with either Ӌ100 career AVRs, or Ӌ25 AVRs in a calendar year 
R an interventional cardiologist with Ӌ20 TAVR procedures in the prior year, or Ӌ40 TAVR 
procedures in the prior two years. 
x
The site will have the presence or capacity of establishing an investigative team consisting of the 
following: 
R interventional cardiologist with expertise in transcatheter aortic valve replacement 
R cardiothoracic surgeon with expertise in aortic valve replacement 
R echocardiographer 
R study coordinator 
Information on the investigational sites (eg, name, address, PI) will be maintained in a separate document. 
6WXG\6LWH,QYHVWLJDWLYH7HDP0HPEHUV
The following is a description of the key personnel who will form the investigative team at each study site.  
 6LWH&R3ULQFLSDO,QYHVWLJDWRUV
Each site will have two Co-Principal Investigators (PI), one who is an interventional cardiologist, and one 
who is a cardiothoracic surgeon. The Co-PIs have overall responsibility for the conduct of the study at the 
site, including protecting the rights, safety, and welfare of the study subjects at their site, the integrity of 
the study data generated by their site, and for ensuring the study is conducted in compliance with the 
Clinical Investigation Plan, 21 CFR 812, and IRB/EC requirements. 
 +HDUW7HDP
Each site will utilize a local heart team to assess eligibility of the prospective subject for the study. 
At a minimum, the local Heart Team should include the following members: 
1. A cardiothoracic surgeon 
2. An interventional cardiologist 
3. An echocardiographer 
The site Co-PIs may also serve as a member of the Heart Team. 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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Each site will have a TAVR implant team with extensive experience with TAVR procedures.  Operator 1 and 
Operator 2 must meet the TAVR qualification as described in Section 14.10.1. 
 (FKRFDUGLRJUDSKHU
Each site will have a designated cardiologist whose primary responsibilities are to ensure the required 
echocardiograms are performed in accordance with the CIP, and for reviewing and approving the site 
echocardiography eCRFs, if authorized by the PI. The designated echocardiographer may also serve as a 
member of the local Heart Team. 
 6WXG\&RRUGLQDWRU
Each site will have a designated study coordinator whose responsibilities include coordination of study 
activities, follow-up evaluations, and maintaining the records defined in the CIP. 
 6FUHHQLQJ&RPPLWWHH
A Screening Committee will be used to ensure patient selection is appropriate and consistent among study 
sites. The role of the Screening Committee will include the following:  
x
Confirmation that subjects are at low predicted risk of mortality at 30 days for SAVR 
x
Confirmation that subjects are anatomically suitable for implantation for TAVR and have bicuspid aortic 
valve anatomy 
The Screening Committee will include interventional cardiologists and cardiac surgeons. The Screening 
Committee will establish a charter that describes its roles, responsibilities, and processes. 
3XEOLFDWLRQ&RPPLWWHH
A Publication Committee may provide direction and support in the development of clinical publications. 
The Publication Committee may consist of study investigators and Medtronic representatives. The 
Publication Committee may be responsible to: 
x
Define the publication plan 
x
Review, approve, and prioritize publication proposals 
x
Provide input on the scientific merit and clinical relevance of ancillary publications 
x
Identify the manuscript/abstract first author(s)/writer(s)/presenter(s) 
x
Review publications prior to submission 
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A Clinical Investigation Agreement shall be signed by the participating investigation site and/or the principal 
investigator at each investigation center per the local legal requirements, and returned to Medtronic prior 
to study center activation. The investigator is required to indicate their approval of the CIP (and any 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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subsequent amendments), by signing and dating the agreement. All investigators will be asked to complete 
financial disclosure statements provided by Medtronic prior to their participation in the study. 
&XUULFXOXP9LWDH
Signed and dated curriculum vitae shall be obtained for all investigators, including their current position at 
the investigation site in compliance with applicable local regulations.  
5HVSRQVLELOLWLHVRIWKH,QYHVWLJDWRU
The Investigator is responsible for the preparation, review, and signature (as applicable), and retention of 
the following records: 
x
All essential correspondence that pertains to the investigation 
x
Device use/disposition records 
x
Records of each subject’s case history and exposure to the device. Case histories include the eCRFs and 
supporting data (source documentation), including, for example: 
-
Signed and dated consent forms 
-
Medical records, including, for example, progress notes of the physicians, the subject’s hospital 
chart(s) and the nurses’ notes 
-
All adverse event/device deficiency information  
-
A record of the exposure of each subject to the investigational device (eg, date of implant 
procedure and follow-up assessment dates) 
x
Documentation of any deviation from the CIP, including the date and the rationale for such deviation 
x
Signed Investigator Agreement, signed and dated curriculum vitae of the PI, sub-investigator(s) and key 
members, signed Delegated Task List 
x
The approved CIP, Patient Information/Informed Consent Form, ROPI, and any amendments 
x
Insurance certificate, where applicable 
x
IRB/EC Approval documentation and voting list 
x
Regulatory authority notification and approval documentation 
x
List of sponsor contacts and monitoring contact list 
x
List of investigation sites 
x
Training records 
x
Disclosure of conflict of interest 
x
Records indicating of adequacy of echocardiography equipment 
x
Lab certificate/lab normal ranges 
x
Subject ID and enrollment log 
x
Sponsor’s statistical analyses and clinical investigation report 
The Investigator may withdraw from responsibility to maintain records by transferring custody to another 
person, who will accept responsibility for record and report maintenance. The Investigator is responsible 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
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for the preparation, review, signature, and submission of the reports listed in Table 10. These are also 
subject to inspection by government agencies and must be retained. Reports will be submitted to 
regulatory authorities per local reporting requirements/regulations. Requirements for reporting Adverse 
Events to Medtronic are described in Section 10.2 (Required timeframes for adverse event reporting to 
Medtronic). 
7DEOH,QYHVWLJDWRUUHFRUGVDQGUHSRUWLQJUHVSRQVLELOLWLHVDSSOLFDEOHWRWKH8QLWHG6WDWHV
Report 
Submit To 
Description/Constraints 
Withdrawal of IRB 
approval (either 
suspension or termination) 
Sponsor 
An investigator shall report to the sponsor, within 5 working 
days, a withdrawal of approval by the reviewing IRB of the 
investigator's part of an investigation. (21 CFR 812.150(a)(2)). 
Progress report  
Sponsor and IRB 
The investigator must submit this report to the sponsor and 
IRB at regular intervals, but in no event less than yearly. (21 
CFR 812.150 (3)).  
Study deviations  
Sponsor and IRB 
Notice of deviations from the CIP to protect the life or physical 
well-being of a subject in an emergency shall be given as soon 
as possible, but no later than 5 working days after the 
emergency occurred. (21 CFR 812.150(a)(4)) 
Failure to obtain IC prior to 
investigational device use 
Sponsor and IRBs 
If an investigator uses a device without obtaining informed 
consent, the investigator shall report such use within 5 
working days after device use. (21 CFR 812.150(a)(5)) 
Final investigator report 
Sponsor, IRB s and 
Relevant 
Authorities 
This report must be submitted within 3 months of study 
completion or termination of the investigation or the 
investigator’s part of the investigation. (21 CFR 812.150(a)(6)) 
Other 
IRB and FDA 
An investigator shall, upon request by a reviewing IRB, FDA or 
any other regulatory agency, provide accurate, complete, and 
current information about any aspect of the investigation. (21 
CFR 812.150(a)(7)) 
5HVSRQVLELOLWLHVRIWKH6SRQVRU
The Sponsor will maintain the following records, including but not limited to: 
x
All essential correspondence related to the clinical study 
x
Signed Investigator Agreement 
x
Signed and dated current curriculum vitae for each Investigator 
x
Records of device shipment and disposition (shipping receipts, material destruct records, etc.) 
x
Adverse event and device deficiency information  
x
Device complaint documentation 

 
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x
All data forms, prepared and signed by the Investigators, and received source documentation and core 
lab reports 
x
CIP, investigator brochure, and subsequent amendments 
x
Site monitoring reports 
x
Financial disclosure information 
x
Study training records for site participants and internal study staff members 
x
Contact lists of all participating investigators/investigative sites, Ethics Board information, study 
monitors and Sponsor staff members; Sponsor will maintain these lists and provide updates to the 
necessary parties.  
x
Sample of device labeling attached to investigational device 
x
Insurance certificates 
x
Ethics Board approval documentation and voting list 
x
Regulatory authority notification and approval documentation 
x
Lab certificates /Lab normal ranges 
x
Statistical analyses 
x
Clinical investigation report 
The Sponsor is responsible for the preparation of, the accuracy of the data contained in, the review of and 
the submission of the reports listed in Table 9. 
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Report 
Submit To 
Description/Constraints 
Premature 
termination or 
suspension of the 
clinical investigation 
Investigators, IRB, 
and Relevant 
authorities 
Provide prompt notification of termination or suspension and 
reason(s). (ISO 14155:2011), (MHLW Ordinance 36, Article 32)  
Unanticipated 
Adverse Device Effect 
Investigators, IRB, 
FDA, and relevant 
authorities 
Notification within ten working days after the sponsor first receives 
notice of the effect. (21 CFR 812.150(b)(1)) 
Withdrawal of IRB 
approval 
Investigators, IRB, 
FDA, and relevant 
authorities 
Notification within five working days after receipt of the 
withdrawal of approval. (21 CFR 812.150(b)(2))  
Withdrawal of FDA 
approval 
Investigators, IRB, 
and relevant 
authorities 
Notification within five working days after receipt of notice of the 
withdrawal of approval. (21 CFR 812.150(b)(3)) 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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Report 
Submit To 
Description/Constraints 
Investigator List 
FDA 
Submit at 6-month intervals, a current list of the names and 
addresses of all investigators participating in the investigation. (21 
CFR 812.150(b)(4)) 
Progress Reports 
IRB and FDA 
Progress reports will be submitted at least annually. (21 CFR 
812.150(b)(4)(5), 812.36(f)  
Recall and device 
disposition 
Investigators, IRB, 
relevant authorities, 
and FDA 
Notification within 30 working days after the request is made and 
will include the reasons for any request that an investigator return, 
repair, or otherwise dispose of any devices. (21 CFR 812.150(b)(6)) 
Failure to obtain IC  
FDA 
Investigator’s report will be submitted to FDA within five working 
days of notification. (21 CFR 812.150(b)(8)) 
Final Report 
Investigators, IRB, 
Regulatory 
authorities upon 
request, and FDA 
Medtronic will notify FDA within 30 working days of the completion 
or termination of the investigation. A final report will be submitted 
to the FDA, investigators, and IRBs within six months after 
completion or termination of this study. (21 CFR 812.150(b)(7)) 
Study deviation  
Investigators 
Ensure that all deviations from the CIP are reviewed with the 
appropriate clinical investigator(s), are reported on the case report 
forms and the final report of the clinical investigation.  
Site specific study deviations will be submitted to investigators 
quarterly. (ISO 14155:2011) 
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This study will utilize an Echo Core Lab, an Explant Pathology Core Lab, a Clinical Events Committee, and a 
Data Safety Monitoring Board. Information and contact details for each of these parties will be maintained 
in a separate document and provided to the study sites. A definitive list of all participating parties will be 
provided in clinical study reports.  
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separate document. A definitive list of all participating IRB/ECs will be maintained and provided in clinical 
reports. 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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contact details will be maintained in a separate document and provided to the study centers. 
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Report of Prior Investigations per requirements (21 CFR 812.27) for this study will be provided under a 
separate cover to the relevant sites and regulatory agencies.  
 5HIHUHQFHV
1. 
Cribier A, Eltchaninoff H, Bash A, Borenstein N, Tron C, Bauer F, et al. Percutaneous transcatheter 
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7. 
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TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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12. 
Ussia GP, Barbanti M, Petronio AS, Tarantini G, Ettori F, Colombo A, et al. Transcatheter aortic valve 
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13. 
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Eggebrecht H, Schmermund A, Voigtländer T, Kahlert P, Erbel R, Mehta RH. Risk of stroke after 
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20. 
Kodali SK, Williams MR, Smith CR, Svensson LG, Webb JG, Makkar RR, et al. Two-year outcomes 
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24. 
Fraccaro C, Buja G, Tarantini G, Gasparetto V, Leoni L, Razzolini R, et al. Incidence, predictors, and 
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TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
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25. 
Van Der Boon RM, Nuis R-J, Van Mieghem NM, Jordaens L, Rodés-Cabau J, Van Domburg RT, et al. 
New conduction abnormalities after TAVI—frequency and causes. Nature Reviews Cardiology. 
2012;9(8):454. 
26. 
Tzikas A, van Dalen BM, Van Mieghem NM, Gutierrez-Chico J-L, Nuis R-J, Kauer F, et al. Frequency of 
conduction abnormalities after transcatheter aortic valve implantation with the Medtronic-CoreValve and 
the effect on left ventricular ejection fraction. American Journal of Cardiology. 2011;107(2):285-9. 
27. 
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Journal of the American College of Cardiology. 2010;56(20):1623-9. 
28. 
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33. 
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35. 
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<ŽĐŚŵĂŶ:͕,ƵĐǌĞŬ͕_ĐŝƐųŽW͕ĂďƌŽǁƐŬŝD͕ŚŵŝĞůĂŬ͕^ǌǇŵĂŷƐŬŝW͕ĞƚĂů͘ŽŵƉĂƌŝƐŽŶŽĨŽŶĞ-and 
12-month outcomes of transcatheter aortic valve replacement in patients with severely stenotic bicuspid 
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TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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54. 
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2012;60(15):1438-54. 

 
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Stenosis and at Low Predicted Risk of Mortality with SAVR  
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55. 
Durack DT, Lukes AS, Bright DK. New criteria for diagnosis of infective endocarditis: utilization of 
specific echocardiographic findings. The American journal of medicine. 1994;96(3):200-9. 
56. 
 Roberts WC, Janning KG, Ko JM, Filardo G, Matter GJ. Frequency of congenitally bicuspid aortic 
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without aortic regurgitation) and implications for transcatheter aortic valve implantation. American Journal 
of Cardiology. 2012;109(11):1632–6 
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The list of Appendices is as follows: 
I.
Echocardiography Procedures 
II.
MDCT Acquisition Guidelines: Pre-TAVR Planning 
III.
Definitions of STS Factors and Other Co-morbidities 
IV.
Resheath and Recapture Definitions 
V.
Definitions: Safety Endpoints and Efficacy Events 
VI.
Sample Informed Consent Form 
 
 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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Transthoracic echocardiography is required at the following intervals: 
Interval 
Time Window 
Baseline (Pre-implant) 
Within 12 weeks prior to submission to Screening Committee 
Device Success 
Between 18 hours and 7 days post-procedure 
30 days 
Between 30 and 45 days post procedure 
1 year 
Between 365 and 395 days post procedure 
2 Year 
Between 730 and 760 days post procedure 
3, 4, 5, 7 and 10 years 
Between implant anniversary date and +/-60 days after 
 *HQHUDO,PDJLQJDQG5HFRUGLQJ3URFHGXUHV
x
A list of recommended images is provided in Section 2.1, List of Recommended Images. 
x
The subject’s ID number and exam interval should be annotated on the image. 
x
A simultaneous ECG with a clearly defined R-wave should be displayed on all clips. 
x
Digital cine clips should be a minimum of two cardiac cycles in length (preferably three cycles) 
x
Color Doppler images should be obtained at a minimum frame rate of 20 Hz through optimization of 
sector width and depth settings. 
x
Still frames of measured variables (eg, LVOT diameter, velocities) should be captured. In addition, still 
frames of spectral Doppler tracings without the measurements should be captured to facilitate analysis 
by the Echo Core Lab. Still frames of spectral Doppler tracings should contain a minimum of 3 cardiac 
cycles for subjects in sinus rhythm, and a minimum of 5 cardiac cycles for subjects in atrial fibrillation 
(two sequential frames per variable may be necessary). 
x
Spectral Doppler waveforms should be recorded at a minimum sweep speed of 50 mm/sec. 
x
Echocardiograms should be recorded and archived on a DICOM digital format for transmission to the 
Echo Core Lab. 
x
Exams will be transmitted to the Echo Core Lab via compact disc (CD-R) or Web-based picture archiving 
and communication system. Details of the image transmission process for each site will be established 
during site initiation process. 
x
Exams sent to the Echo Core Lab via CD-R should be DICOM files in a true or pure DICOM format. 
x
The following information should be documented on any CD-R disks sent to the Echo Core Lab: 
 Study site ID number 
 Subject ID number 
 Exam date 
 Study interval 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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Version 
1E 
Page 75 of 118 
 
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Parasternal long-axis window 
1. 2D gray scale standard view (LV in a sagittal section) 
2. 2D color Doppler for mitral regurgitation (MR) 
3. 2D color Doppler of aortic (native or prosthetic) regurgitation (AR) 
4. If AR is present, ZOOM & narrow sector with focus on vena contracta of regurgitant jet  
5. 2D gray scale ZOOM for LV outflow tract diameter (LVOT)  
6. Frozen image of measured LVOT diameter 
7. 2D gray scale; ZOOM at an intercostal space higher for aortic root/aortic prosthesis  
Parasternal short-axis window 
8. 2D grayscale LV at mitral valve level 
9. 2D grayscale LV at papillary muscle level  
10.Frozen image of measured LV dimensions (without measurements) 
11.2D grayscale LV at apical level 
12.2D grayscale aortic valve level 
13.2D color Doppler of AR: post-implant start scanning from highest position and record first visible AR jet, 
scan more downwards and look for additional jets – confirm origin of AR jets from PLAX 
Parasternal long-axis view (RV inflow) 
14.2D color Doppler of tricuspid regurgitation (TR) 
15.If TR is present, CW Doppler of TR jet (frozen image without measurements) 
16.Frozen image of TR jet velocity with measurements 
Apical 4-Chamber window 
17.2D grayscale standard view  
18.2D color Doppler of MR  
19.If MR is present, ZOOM & narrow sector 
20.If MR is present, CW Doppler of MR jet (frozen image) 
21.2D color Doppler of TR 
22.If TR is present, CW Doppler of TR jet (frozen image without measurement) 
23.Frozen image of TR jet velocity with measurements 
24.2D grayscale focussed on LV with decreased depth 
25.PW Doppler of transmitral flow at mitral valve tips (frozen image) 
26.Tissue Doppler of the septal mitral annulus (frozen image) 
27.Tissue Doppler of the lateral mitral annulus (frozen image) 
Apical long–axis view 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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Page 76 of 118 
 
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28.2D grayscale standard view 
29.2D color Doppler of AR 
30.If AR is present, ZOOM & narrow sector, shift Nyquist 35-40 for PISA measurements  
31.If AR is present, CW Doppler of AR jet (frozen image without measurement) 
32.Frozen image of CW Doppler of AR jet (with measurements) 
33.CW Doppler of aortic/prosthetic valve (frozen image without measurement) 
34.Frozen image of measured aortic/prosthetic valve velocity 
35.PW Doppler LVOT (native aortic valve): within 0.5 – 1 cm below native aortic valve (frozen image 
without measurements 
36.PW Doppler LVOT (post –implant) immediately proximal to inflow of stent or valve (frozen image 
without measurements) 
37.Frozen image: measured LVOT velocity 
Apical 2-Chamber view 
38.2D grayscale standard view 
39.2D grayscale focused on LV with decreased depth 
Sub-costal Position 
40.2D grayscale; long-axis view 
41.2D grayscale; short-axis view 
42.2D grayscale: IVC and hepatic vein 
43.If TR moderate by color Doppler, PW Doppler of hepatic vein (frozen image) 
44.IF AR mild by color Doppler, PW Doppler from descending aorta (frozen image) 
Supra-Sternal Position 
45.CW Doppler of aortic valve velocity non-imaging probe (frozen image without measurements) 
46.Frozen image: measured aortic valve velocity 
47.If AR mild by color Doppler, PW Doppler from descending aorta (frozen image) 
Right Parasternal Position 
48.CW Doppler of aortic valve velocity; non-imaging probe (frozen image without measurements) 
49.Frozen image: measured aortic valve velocity 
Results Reporting 
50.Screen prints of all results pages 
 
 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
10790330DOC
Version 
1E 
Page 77 of 118 
 
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Sites should obtain the appropriate images and Doppler recordings in order for the Echo Core Lab to assess 
and report the variables listed below. Procedures for acquiring key variables are described in Section 4, 
Acquisition of Key Variables. 
x
Height (cm) and Weight (kg) 
x
Heart rate 
x
Left ventricular outflow tract (LVOT) diameter in mid systole 
x
Max aortic/prosthetic valve velocity (V2) by CW Doppler 
x
Aortic valve velocity time integral (VTI) by CW Doppler 
x
Mean gradient across aortic valve (MGV2) by CW Doppler 
x
LVOT VTI by PW Doppler 
x
Grade of aortic/prosthetic transvalvular regurgitation (post-implant only) 
x
Grade of aortic/prosthetic paravalvular regurgitation (post-implant only) 
x
Grade of prosthetic total (transvalvular plus paravalvular) regurgitation (post-implant only) 
x
Grade of mitral regurgitation 
x
Grade of tricuspid regurgitation 
x
Max tricuspid regurgitant (TR) jet velocity (if TR is present) 
x
Left ventricular internal dimension at end diastole 
x
Left ventricular internal dimension at end systole 
x
Interventricular septal thickness at end diastole 
x
Left ventricular posterior wall thickness at end diastole 
x
Left atrial diameter (anterior-posterior linear dimension) at systole 
x
Left ventricular ejection fraction by visual estimate 
x
Grade of diastolic dysfunction (if present) 
In addition, the following variables will be derived by the central database from the appropriate 
measurements reported on the site eCRF. 
x
Body surface area (Dubois and Dubois, 46)  
x
Peak aortic pressure gradient 
x
Aortic valve area (AVA)/effective orifice area (EOA) by continuity equation 
x
Aortic valve area/effective orifice area index (EOAI) 
x
Doppler Velocity Index 
x
Estimated right ventricular systolic pressure (RVSP) 
Derived variables will be displayed on the eCRF upon entry of the appropriate raw measurements.  The pre-
implant qualifying AVA must be based on the site reported variables for LVOT diameter, LVOT VTI, aortic 
valve VTI, height, and weight. 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
10790330DOC
Version 
1E 
Page 78 of 118 
 
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Pre-implant LVOT diameter is measured from the inner edge to inner edge of the septal endocardium, and 
the anterior mitral leaflet in mid-systole (Figure 7 A and B) [44, 45].. Following implantation of the TAV, 
LVOT diameter is measured from the parasternal long-axis view, immediately proximal to the inflow aspect 
of the stent, and in mid systole (Figure 7 C and D) [44-46]. Post surgical valve implantation, LVOT diameter 
is measured from the junction of the anterior sewing ring and the ventricular septum to the junction of the 
sewing ring and the anterior mitral valve leaflet (Figure 7 E and F) [44].  
 
 
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TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
10790330DOC
Version 
1E 
Page 79 of 118 
 
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LVOT velocity is recorded with PW Doppler from the apical position, in either the apical long-axis view or in 
the anteriorly angulated four-chamber view (or “5-chamber view”). For pre-implant exams, the PW sample 
volume should be positioned just proximal to the aortic valve, with care to avoid the zone of pre-valve 
acceleration (usually 0.5 to 1.0 cm proximal to the cusps, Figure 8 A) [44].  
Post TAV implantation, the sample volume should be placed proximal to the inflow aspect of the stent [45]. 
Full-screen imaging of the TAV should be used to verify positioning of the sample volume below the stent 
before switching to spectral Doppler mode (Figure 8 C and D) [46, 47].  
The LVOT VTI is measured by tracing the modal velocity (middle of the dense signal) for use in the 
continuity equation [44].  
            
 
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TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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Version 
1E 
Page 80 of 118 
 
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Aortic valve velocity should be interrogated with CW Doppler from a minimum of 2 transducer positions 
(apical and either a parasternal or suprasternal position). The position that provides the highest velocity is 
used for measurements. A smooth velocity curve with a clear outer edge and maximal velocity should be 
recorded. The maximal velocity is measured at the outer edge of the dark signal; fine linear signals at the 
peak should not be included in measurements. The outer edge of the dark “envelope” of the velocity curve 
is traced to provide both the VTI for the continuity equation and the mean gradient (Figure 9) [44].  
 
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An integrated exam approach using color flow, pulsed-wave (PW), and continuous-wave (CW) Doppler is 
used to assess the severity of transvalvular and paravalvular aortic regurgitation (AR). Color flow Doppler 
imaging should be performed from the parasternal long and short-axis views, and the apical long-axis 
and/or 5-chamber views. In the short axis view, color imaging should be performed at multiple levels (from 
level of the leaflets to below the skirt and frame to assess paravalvular regurgitation, and at the coaptation 
point of the leaflets for transvalvular (central) regurgitation [48, 49].  
If AR is seen by color Doppler, a CW Doppler recording of the regurgitant signal should be obtained for 
measurement of pressure half-time and assessment of jet density. If the degree of AR by color Doppler 
appears more than mild by visual estimate, the velocity in the proximal descending aorta should be 
recorded with PW Doppler.  
The degree of transvalvular, paravalvular, and total (transvalvular plus paravalvular) AR will be graded as 
none, trace, mild, mild to moderate, moderate, moderate to severe, and severe based on the synthesis of 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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Version 
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the Doppler parameters shown in Table 10 [49]. The category of “trace” should be used in cases where 
regurgitation is barely detectable by color Doppler. Regurgitant signals observed to originate within the 
stent will be considered transvalvular, and regurgitant signals observed to originate outside the stent will 
be considered paravalvular.

TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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3-class Grading Scheme 
Trace 
Mild 
Mild 
Moderate 
Moderate 
Severe 
Unifying 5-Class Grading Scheme 
Trace 
Mild 
Mild-to-Moderate 
Moderate 
Moderate-to-severe 
Severe 
Doppler parameters (qualitative or 
semiquantitiative) 
 
 
 
 
 
 
 Jet Features 
 
 
 
 
 
 
   Extensive/wide jet origin 
Absent 
Absent 
Absent 
Present 
Present 
Present 
   Multiple jets 
Possible 
Possible 
Often present 
Often present 
Usually present 
Usually present 
   Jet path visible along stent 
Absent 
Absent 
Possible 
Often present 
Usually present 
Usually present 
   Proximal flow convergence visible 
Absent 
Absent 
Absent 
Possible 
Often present 
Often present 
 Vena contracta width (mm) 
<2 
<2 
2-4 
4-5 
5-6 
>6 
 Vena contracta area (mm2) 
<5 
5-10 
10-20 
20-30 
30-40 
>40 
 Jet width at origin (% LVOT diameter) 
Narrow (<5) 
Narrow (5-15) 
Intermediate (15-30) 
Intermediate (30-45) 
Large (45-60) 
Large (>60) 
 Jet density: CW Doppler 
Incomplete or faint 
Incomplete or 
faint 
Variable 
Dense 
Dense 
Dense 
 Pressure half-time (ms): CW Doppler 
Slow (>500) 
Slow (>500) 
Slow (>500) 
Variable (200-500) 
Variable (200-500) 
Steep (<200) 
 Diastolic flow reversal in descending aorta 
Absent 
Absent or brief 
early diastolic 
Intermediate 
Intermediate 
Holodiastolic (end-
diast. Vel. >20 cm/s) 
Holodiastolic 
(end-diast. Vel. 
>25 cm/s) 
 Circumferential extent of PVR (%) 
<10 
<10 
10-20 
20-30 
>30 
>30 
Doppler parameters (quantitative) 
 
 
 
 
 
 
 Regurgitant volume (ml/beat) 
<15 
<15 
15-30 
30-45 
45-60 
>60 
 Regurgitant fraction (%) 
<15 
<15 
5-10 
10-20 
20-30 
>30 
Effective regurgitant orifice area (mm2) 
<5
<5
5-10
10-20
20-30
>30

TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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Version 
1E 
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Color flow Doppler imaging of the left atrium should be performed from the parasternal long-axis view, 
and from the apical 4, 2, and long axis views. 
Mitral regurgitant (MR) jets should be recorded with CW Doppler using a velocity scale that allows 
assessment of the density, shape, duration, and peak velocity of the MR jet. If the severity appears 
moderate or greater by visual assessment, pulmonary vein velocities should be recorded with PW 
Doppler to assess for the presence of systolic flow reversal. Grading of the severity of mitral 
regurgitation should be integrative using the parameters in Table 11 [50].  
7DEOH3DUDPHWHUVIRUHYDOXDWLRQRIWKHVHYHULW\RIPLWUDOUHJXUJLWDWLRQ
Parameter 
Mild 
Moderate 
Severe 
Color flow jet area 
Small, central jet 
(usually <4 cm2 or 
<20% of LA area) 
Variable 
Large central jet 
(usually >10 cm2 or 
>40% of LA area), or variable wall-
impinging jet swirling in the LA 
Jet density (CW) 
Incomplete or faint 
Dense 
Dense 
Jet contour (CW) 
Parabolic 
Usually parabolic 
Early peaking, triangular 
Pulmonary vein flow 
Systolic dominance 
Systolic blunting 
Systolic flow reversal 
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Color flow imaging of the right atrium should be performed from the apical 4-chamber view, the 
parasternal long-axis view of the RVOT, and the parasternal short-axis view at the level of the aortic 
valve. 
Tricuspid regurgitant (TR) jets should be recorded with CW Doppler using a velocity scale that allows 
assessment of the density, shape, duration, and peak velocity of the TR jet. If the severity appears 
moderate or greater by visual assessment, hepatic vein velocities should be recorded with PW Doppler 
to assess for the presence of systolic flow reversal. Grading of the severity of tricuspid regurgitation 
should be integrative using the parameters in Table 12 [50].  
7DEOH3DUDPHWHUVIRUHYDOXDWLRQRIWKHVHYHULW\RIWULFXVSLGUHJXUJLWDWLRQ
Parameter 
Mild 
Moderate 
Severe 
Jet area (cm2)
<5
5 – 10
>10
VC width (cm) 
Not defined 
Not defined, but <0.7 
шϬ͘ϳ 
PISA Radius (cm) 
чϬ͘ϱ 
0.6 – 0.9 
>0.9 
Jet density & contour 
Soft & parabolic 
Dense, variable contour 
Dense, triangular, with early peaking 
Hepatic vein flow  
Systolic dominance 
Systolic blunting 
Systolic flow reversal 

TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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Version 
1E 
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Dimensions of the left ventricle and left atrium should be obtained by either 2-D linear measurements 
or using 2-D guided m-mode from either the parasternal long or short axis views (Figure 10). Left 
ventricular chamber dimensions, septal thickness, and posterior wall thickness are measured using the 
American Society of Echocardiography (ASE) measurement convention (blood-tissue interface, [49]). In 
addition, standard 2-D views of the left ventricle should be obtained from parasternal and apical 
transducer positions for visual estimation and quantitative assessment of left ventricular ejection 
fraction using the modified Simpson’s rule, and for assessment of regional wall motion. 
 
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A spectral Doppler recording of mitral inflow should be obtained with PW Doppler in the apical 4-
chamber view, using a 1 to 3 mm sample volume placed between the mitral leaflet tips during diastole 
(Figure 11). The spectral gain and wall filter settings should be optimized to clearly display the onset and 
cessation of left ventricular inflow. The following variables should be measured: 
x
Mitral inflow “A” velocity 
x
Mitral inflow “E” velocity 
x
Mitral inflow E-wave deceleration time 
 
A
B 

TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
10790330DOC 
Version 
1E 
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Mitral annular velocities should be obtained from the lateral and septal aspects of the mitral annulus 
using PW tissue Doppler (DTI) performed in the apical 4-chamber view. The sample volume should be 
positioned at or 1 cm within the septal and lateral insertion sites of the mitral leaflets and adjusted as 
necessary (usually 5 to 10 mm) to cover the longitudinal excursion of the mitral annulus in both systole 
and diastole. Minimal angulation (<20 degrees) should be present between the ultrasound beam and 
the plane of cardiac motion. The following variables should be measured: 
• 
Mitral annular tissue Doppler systolic velocity (septal and lateral) 
• 
Mitral annular tissue Doppler early diastolic velocity (septal and lateral) 
• 
Mitral annular tissue Doppler late diastolic velocity (septal and lateral) 
Diastolic function should be categorized as normal, mild dysfunction (impaired relaxation pattern), 
moderate dysfunction (pseudonormal filling), or severe dysfunction (restrictive filling) per the 2009 
American Society of Echocardiography recommendations [51].  
 
 

TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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Protocol-required echocardiograms will be sent to the Echo Core lab for assessment: the data generated 
by the Echo Core Lab will be the primary data used for analysis and reporting. Received 
echocardiograms will be logged in and analyzed by the Echo Core Lab according to their procedures 
determined for this study.  
The Echo Core Lab will report the following variables: 
x
Heart rate 
x
Left ventricular outflow tract (LVOT) diameter in mid systole 
x
Max aortic/prosthetic valve velocity (V2) by CW Doppler 
x
Aortic valve velocity time integral (VTI) by CW Doppler 
x
Mean gradient across aortic valve (MGV2) by CW Doppler 
x
LVOT VTI by PW Doppler 
x
Grade of aortic/prosthetic transvalvular regurgitation (post-implant only) 
x
Grade of aortic/prosthetic paravalvular regurgitation (post-implant only) 
x
Grade of prosthetic total (transvalvular plus paravalvular) regurgitation (post-implant only) 
x
Grade of mitral regurgitation 
x
Grade of tricuspid regurgitation 
x
Max tricuspid regurgitant (TR) jet velocity (if TR is present) 
x
Left ventricular internal dimension at end diastole 
x
Left ventricular internal dimension at end systole 
x
Interventricular septal thickness at end diastole 
x
Left ventricular posterior wall thickness at end diastole 
x
Left atrial diameter (anterior-posterior linear dimension) at systole 
x
Left ventricular ejection fraction by visual estimate 
x
Grade of diastolic dysfunction (if present) 
Qualitative grading of valvular regurgitation will be performed using the criteria described in Sections 
4.4 through 4.7. For reporting the degree of prosthetic regurgitation, the grading classes may be 
collapsed according to the 3-class grading scheme recommended by the American Society or 
Echocardiography (ASE)-European Association of Cardiovascular Imaging Guidelines [50, 52].  
In addition, the following variables will be derived by the central database from the appropriate 
measurements reported by the Echo Core Lab: 
x
Peak Pressure Gradient (Peak ' P) Across the Aortic Valve in mmHg 
Peak ' P = 4 x (V22) 
Where: V2 is the peak velocity across the prosthesis in m/sec 
x
Aortic Valve Area (AVA) in cm2 
AVA = LVOT diameter in cm2 x 0.785 x (VTIV1/VTIV2) 

TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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1E 
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Where: VTIV1 is the velocity time integral of the left ventricular outflow tract in cm, and VTIV2 is 
the velocity time integral of the native aortic valve in cm 
x
Aortic Valve Area Index (AVAI) in cm2/m2 
AVAI = AVA/BSA 
Where: AVA is the native aortic valve area in cm2, and BSA is the body surface area in m2i 
x
Effective Orifice Area (EOA) in cm2 
EOA = LVOT diameter2 x 0.785 x (VTIV1/VTIV2) 
Where: VTIV1 is the velocity time integral of the left ventricular outflow tract in cm, and VTIV2 is 
the velocity time integral of the aortic prosthesis in cm 
x
Effective Orifice Area Index (EOAI) in cm2/m2 
EOAI = EOA/BSA 
Where: EOA is the effective orifice area in cm2, and BSA is the body surface area in m2 
x
Doppler Velocity Index (DVI) 
DVI= VTIV1/VTIV2 
Where: VTIV1 is the velocity time integral of the left ventricular outflow tract in cm, and VTIV2 is 
the time velocity integral of the prosthetic aortic valve in cm 
x
Left Ventricular Mass (LVM) in grams
LVM = 0.83 x [(LVIDD + LVPW + IVS)3 - (LVIDD)3] +0.6 
Where: LVIDD is the left ventricular internal dimension at end diastole in cm, LVPW is the left 
ventricular posterior wall thickness at end diastole in cm, and IVS is the interventricular wall 
thickness at end diastole in cm. 
x
Left Ventricular Mass Index (LVMI) in g/m2 body surface area 
LVMI = LVM/BSA 
Where: LVM is left ventricular mass in g, and BSA is body surface area in m2 
x
Estimated Right Ventricular Systolic Pressure (RVSP) in mmHg 
RVSP = (4 x MVTR jet2) + 10 
Where: MV TR jet is the max velocity of the tricuspid regurgitant jet, and 10 = the assumed 
mean right atrial pressure in mmHg 
x
Body Surface Area (BSA) in m2 
BSA = 0.007184 x (height in cm0.725 x weight in kg0.425) 
 
L BSA derived from height and weight reported on the site eCRF 

TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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Multi-Detector Computed Tomography (MDCT) is used to evaluate aortic valve anatomy, determine 
aortic root dimensions for device sizing, and to evaluate peripheral vessel dimensions and anatomy. The 
following sections are intended as guidelines for acquiring the images for assessing anatomical 
suitability for implantation with the Medtronic TAVR systems. 
 *HQHUDO5HTXLUHPHQWV
x
Multi-detector CT scanner (64-slice minimum) with ECG-gating capability. 
x
ECG-gated contrast enhanced aortic root (slicĞƚŚŝĐŬŶĞƐƐŽĨчϭ͘Ϭŵŵ) 
x
Temporal resolution should be optimized to reduce motion artifact. 
x
Spatial resolution should be as high as possible (goal is smallest isotropic voxel size) 
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Retrospective ECG-gated scans are recommended, which allows for reconstruction in various phases of 
the cardiac cycle and optimal evaluation of anatomic dimensions and valve morphology. Recommended 
scan parameters are listed in Table 13. 
Prospective ECG-gated sequential scans (step-and-shoot) and high-pitch spiral scans with ECG-gating 
(flash spiral) are also acceptable. The following parameters are important to the optimum scan: 
x
Detector collimation 0.4-0.625 mm. 
x
Slice thickness чϭ͘Ϭŵŵ͘ 
x
The recommended coverage area is from superior to the aortic arch to inferior to the cardiac apex. 
The minimum required coverage area is from 50 mm above the aortic annulus to 10 mm below the 
aortic annulus. 
x
The recommended slice overlap is 0.4 mm (will result in isotropic voxels with a 20 cm field of view). 
 3RVWSURFHVVLQJ
x
Retrospective ECG-gated scans 
x
Verify heart rate ECG triggers are at consistent place in cardiac cycle, edit if necessary. Additional 
editing/removal of arrhythmias may be performed. 
x
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has the capability, also reconstruct a “best systolic” and “best diastolic” phase. 
x
Prospective ECG-gated scans (including flash spiral) 
x
ZĞĐŽŶƐƚƌƵĐƚǁŝƚŚŵĞĚŝƵŵƐŽĨƚŬĞƌŶĞůĂŶĚƐůŝĐĞƚŚŝĐŬŶĞƐƐчϭ͘Ϭŵŵ;ƐůŝĐĞŽǀĞƌůĂƉŽĨϬ͘ϰŵŵ
recommended) 

TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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Parameter 
Recommendation 
IV injection with iodine 
contrast 
80-100 (320mg/ml or higher), modify per patient as appropriate 
Injection rate
4-6 mL/sec 
Bolus tracking, delay 
Delay time calculated using protocol for current scanner (bolus tracking or similar) with 
peak of contrast concentration in the ascending aorta during acquisition. 
ECG-gating 
Retrospective 
Scan direction 
Cranial-caudal 
Scan coverage 
From above the aortic arch to past the cardiac apex 
Detector collimation 
0.4 – 0.625 mm 
Pitch 
0.2–0.43 adapted to the heart rate 
Dose modulation 
Modulation and full current between 30 and 80% of the cardiac cycle 
Slice thickness 
0.8 mm 
Slice overlap 
0.4 mm 
Reconstruction kernel 
Medium Smooth 
Post-processing 
Retrospective ECG gating reconstruction algorithm that minimizes motion artifact. 
Reconstruct at multiple phases (10 minimum). ZĞĐŽŶƐƚƌƵĐƚĞĚƐůŝĐĞƚŚŝĐŬŶĞƐƐчϬ͘ϴŵŵ͘ 
 5HTXLUHG$RUWLF5RRW0HDVXUHPHQWV
For the Evolut PRO TAV, the following measurements of the aortic root are obtained for assessing 
anatomical suitability: 
x
Major aortic annulus (measured at systole if retrospective gating is used) 
x
Orthogonal minor aortic annulus diameter (measured at systole if retrospective gating is used) 
x
Annulus perimeter (measured at systole if retrospective gating is used) 
x
Sinus of Valsalva diameters (measured at diastole) 
x
Sinus of Valsalva heights (measured at diastole) 
The following measurements of the aortic root are obtained for assessing anatomical suitability for the 
Evolut R TAV: 
x
Annulus perimeter (measured at systole if retrospective gating is used) 
x
Sinus of Valsalva diameters (measured at diastole) 
x
Sinus of Valsalva heights (measured at diastole) 
Dimensional sizing criteria for the Evolut PRO and Evolut R TAV are provided in Tables 16 and 17. 

TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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Reformatting of the images is as follows [53]:  
x
Site image cross-hairs on aortic root in all windows where it is visible. Lock cross-hairs so they 
remain orthogonal for all steps. 
x
In the coronal window, rotate cross-hairs (horizontal line) counter-clockwise to align with virtual 
basal plane, (Figure 12, upper left panel). 
x
In the sagittal window, the horizontal line is rotated clockwise or counter-clockwise to align with 
virtual basal plane (Figure 12, lower left panel). 
x
On the newly defined double-oblique axial image, scroll up and down through the aortic root until 
the most caudal attachment points of the three native leaflets come into view (indicated by 
arrowheads in Figure 13). If one of the leaflets comes into view at a more cranial or caudal slice, adjust 
the coronal or sagittal cross-hairs until all three leaflets come into view on the same axial slice. 
x
For confirmation of the correct aortic annulus plane, scroll through the double oblique axial images 
starting in the mid sinus and ending at the level of the aortic annulus. The sinuses should appear to 
be relatively the same size at the level of the mid-sinus and the leaflets should all disappear equally 
at the level of the annulus. 
 

TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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Sagittal 
Coronal 
Axial 
Oblique 
Coronal 
Oblique 
Sagittal 
Double-oblique axial 

TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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1E 
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x
Choose the cleanest systolic images for the aortic annulus measurements, either automatically (eg, 
best systolic) or by manually identifying. Measurement on a diastolic image is also acceptable. 
x
Aortic annulus measurements should be completed on the properly reformatted double-oblique 
axial image at aortic annulus level, as described in Section 3.2.1, Reformatting of Images. 
x
Trace the perimeter of the basal annulus (Figure 14, left). Place cross-hairs at site of basal annulus, 
create major diameter through the site, create minor diameter defined as perpendicular to major 
and through site (Figure 14, right). 
 
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Choose the best diastolic images for measurement of sinus of Valsalva diameters and heights from 
images using the same reformatting technique as described in Section 3.2.1, Reformatting of Images. 
Sinus of Valsalva Diameters 
x
Select the double oblique axial image where the widest portion of the three sinuses is visible. 
x
Measure a diameter from each commissure through the site of the root to the opposite sinus. 
Complete for all three sinuses (Figure 15).  

TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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Sinus of Valsalva Heights 
x
The sinotubular junction is typically not co-planar with the aortic annulus. Therefore, a sinus of 
Valsalva height must be measured for each of the three sinuses. This height is defined as the 
distance between the aortic annular plane and the tallest point in the sinus. 
x
Choose the double oblique axial image so that it is located at the level of the aortic annulus. The 
reformatting line representing the double oblique axial image should now be visible in the oblique 
coronal and oblique sagittal images at the level of the aortic annulus.  
x
For the left coronary and non-coronary heights, use the oblique coronal image. For the right 
coronary height, use the oblique sagittal image. 
x
To complete the measurement, scroll through the oblique coronal or sagittal image (depending on 
which sinus you are measuring) and locate the heights location of the sinotubular junction. On that 
image, measure the distance along the path of the aortic root from the aortic annular plane, marked 
by the reformatting line, to the sinotubular junction (Figure 16).

TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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1E 
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Device 
Size 
Aortic Annulus 
Sinus of Valsalva 
Perimeter 
(mm) 
Mean Diameter 
(mm) 
Mean Diameter 
(mm) 
Mean Height 
(mm) 
23 mm 
56.5 – 62.8 
18 – 20 
шϮϱ 
шϭϱ 
26 mm
62.8 – 72.3
20 – 23
шϮϳ
шϭϱ
29 mm 
72.3 – 81.6 
23 – 26 
шϮϵ 
шϭϱ 
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Device 
Size 
Aortic Annulus 
Sinus of Valsalva 
Perimeter 
(mm) 
Mean Diameter 
(mm) 
Mean Diameter 
(mm) 
Mean Height 
(mm) 
23 mm 
56.5 – 62.8 
18 – 20 
шϮϱ 
шϭϱ 
26 mm 
62.8 – 72.3 
20 – 23 
шϮϳ 
шϭϱ 
29 mm 
72.3 – 81.6 
23 – 26 
шϮϵ 
шϭϱ 
34 mm 
81.7 – 94.2 
26 – 30 
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TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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Factor 
Definition 
Heart Failure 
Physician documentation or report that the patient has been in a state of heart failure within 
the past 2 weeks. Heart failure is defined as physician documentation or report of any of the 
following clinical symptoms of heart failure described as unusual dyspnea on light exertion, 
recurrent dyspnea occurring in the supine position, fluid retention; or the description of 
rales, jugular venous 
Distension, pulmonary edema on physical exam, or pulmonary edema on chest x-ray 
presumed to be cardiac dysfunction. A low ejection fraction alone, without clinical evidence 
of heart failure does not qualify as heart failure. An elevated BNP without other supporting 
documentation should not be coded as CHF. 
Diabetes 
History of diabetes diagnosed and/or treated by a healthcare provider. The American 
Diabetes Association criteria include documentation of the following: 
1. Hemoglobin A1c ш6.5%; or 
2. Fasting plasma glucose ш126 mg/dL (7.0 mmol/L); or 
3. 2-h Plasma glucose ш200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test; or 
4. In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random 
plasma glucose ш200 mg/dL (11.1 mmol/L) 
This does not include gestational diabetes. 
Dialysis 
Subject currently (prior to surgery) undergoing dialysis 
Hypertension 
Any of the following: 
x
documented history of hypertension diagnosed and treated with medication, 
diet and/or exercise, 
x
prior documentation of blood pressure >140 mmHg systolic or 90 mmHg 
diastolic for patients without diabetes or chronic kidney disease, or prior 
documentation of blood pressure >130 mmHg systolic or 80 mmHg diastolic on 
at least 2 occasions for patients with diabetes or chronic kidney disease 
x
currently on pharmacologic therapy to control hypertension 
 

TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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1.0 STS Factors (continued) 
Factor 
Definition 
Immunocompromise 
Indicate whether immunocompromise is present due to immunosuppressive medication 
therapy within 30 days preceding the operative procedure or existing medical condition. This 
includes, but is not limited to systemic steroid therapy, anti-rejection medications and 
chemotherapy. This does not include topical steroid applications, one time systemic therapy, 
inhaled steroid therapy or preprocedure protocol. 
Arrhythmia 
History or preoperative arrhythmia (sustained ventricular tachycardia, ventricular fibrillation, 
atrial fibrillation, atrial flutter, third degree heart block, second degree heart block, sick sinus 
syndrome) that has been treated with any of the following modalities: 
x
ablation therapy 
x
AICD 
x
pacemaker 
x
pharmacologic treatment 
x
electrocardioversion, defibrillation 
Atrial 
fibrillation/atral 
flutter 
Presence of atrial fibrillation or flutter within 30 days of the procedure 
 
 
 
 
Myocardial infarction 
History of at least one documented myocardial infarction at any time prior this surgery 
Endocarditis 
Indicate whether the patient has a history of endocarditis. Endocarditis must meet at least 1 
of the following criteria: 
1. Patient has organisms cultured from valve or vegetation. 
2. Patient has 2 or more of the following signs or symptoms: fever (>38°C or >100.4°F), new 
or changing murmur*, embolic phenomena*, skin manifestations* (ie, petechiae, splinter 
hemorrhages, painful subcutaneous nodules), congestive heart failure*, or cardiac 
conduction abnormality. 
*with no other recognized cause and at least 1 of the following: 
x
organisms cultured from 2 or more blood cultures 
x
organisms seen on Gram’s stain of valve when culture is negative or not done 
x
valvular vegetation seen during an invasive procedure or autopsy 
x
positive laboratory test on blood or urine (eg, antigen tests for H mmunocom, S 
mmunocom, N mmunocompro, or Group B Streptococcus) 
x
evidence of new vegetation seen on echocardiogram and if diagnosis is made 
antemortem, physician institutes appropriate antimicrobial therapy. 
 
 

TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
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Factor 
Definition 
Chronic lung disease 
Presence of lung disease and severity level as follows: 
None 
Mild: FEV1 60% to 75% of predicted, and/or on chronic inhaled or oral bronchodilator 
therapy. 
Moderate: FEV1 50% to 59% of predicted, and/or on chronic steroid therapy aimed at 
lung disease. 
Severe: FEV1 <60 or Room Air pCO2 >50. 
CLD present, severity not documented 
Unknown 
A history of chronic inhalation reactive disease (asbestosis, mesothelioma, black lung 
disease or pneumoconiosis) may qualify as chronic lung disease. Radiation induced 
pneumonitis or radiation fibrosis also qualifies as chronic lung disease. (if above criteria 
is met) A history of atelectasis is a transient condition and does not qualify. Chronic lung 
disease can include patients with chronic obstructive pulmonary disease, chronic 
bronchitis, or emphysema. It can also include a patient who is currently being chronically 
treated with inhaled or oral pharmacological therapy (eg, beta-adrenergic agonist, anti-
inflammatory agent, leukotriene receptor antagonist, or steroid). Patients with asthma 
or seasonal allergies are not 
considered to have chronic lung disease. 
Peripheral vascular 
disease 
History of peripheral arterial disease (includes upper and lower extremity, renal, 
mesenteric, and abdominal aortic systems). This can include: 
x
claudication , either with exertion or at rest 
x
amputation for arterial vascular insufficiency 
x
vascular reconstruction, bypass surgery, or percutaneous intervention to the 
extremities (excluding dialysis fistulas and vein stripping) 
x
documented aortic aneurysm with or without repair 
x
positive noninvasive test (eg, ankle brachial index ч0.9, ultrasound, magnetic 
resonance or computed tomography imaging of >50% diameter stenosis in 
any peripheral artery, ie, renal, subclavian, femoral, iliac), or angiographic 
imaging 
*Excludes disease in the carotid cerebrovascular arteries, or thoracic aorta. PVD does not 
include deep vein thrombosis 
 

TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
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Factor 
Definition 
Cerebrovascular 
disease 
Indicate whether the patient has a current or previous history of any of the following: 
a) Stroke: Stroke is an acute episode of focal or global neurological 
dysfunction caused by brain, spinal cord, or retinal vascular injury as a 
result of hemorrhage or infarction, where the neurological dysfunction 
lasts for greater than 24 hours. 
b) TIA: is defined as a transient episode of focal neurological dysfunction 
caused by brain, spinal cord, or retinal ischemia, without acute 
infarction, where the neurological dysfunction resolves within 24 hours. 
c) Noninvasive or invasive arterial imaging test demonstratŝŶŐшϱϬй
stenosis of any of the major extracranial or intracranial vessels to the 
brain 
Previous cervical or cerebral artery revascularization surgery or percutaneous 
intervention. This does not include chronic (nonvascular) neurological diseases or other 
acute neurological insults such as metabolic and anoxic ischemic encephalopathy. 
Cardiogenic shock 
A sustained (>30 min) episode of hypoperfusion evidenced by systolic blood pressure 
<90 mm Hg and/or, if available, cardiac index <2.2 L/min per square meter determined 
to be secondary to cardiac dysfunction and/or the requirement for parenteral inotropic 
or vasopressor agents or mechanical support (eg, IABP, extracorporeal circulation, VADs) 
to maintain blood pressure and cardiac index above those specified levels. Note: 
Transient episodes of hypotension reversed with IV fluid or atropine do not constitute 
cardiogenic shock. The hemodynamic compromise (with or without extraordinary 
supportive therapy) must persist for at least 30 min. 
Resuscitation  
Patient required cardiopulmonary resuscitation before the start of the operative 
procedure which includes the institution of anesthetic management. Capture 
resuscitation timeframe: within 1 hour or 1-24 hours pre-op 
Incidence 
Indicate if this is the patient's: 
x
first surgery 
x
first re-op surgery 
x
second re-op surgery 
x
third re-op surgery 
x
fourth or more re-op surgery. 
Surgery is defined as cardiothoracic operations (heart or great vessels) surgical 
procedures performed with or without cardiopulmonary bypass (CPB). Also include lung 
procedures utilizing CPB or tracheal procedures utilizing CPB. Reoperation increases risk 
due to the presence of scar tissue and adhesions. 
 

TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
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Factor 
Definition 
Cardiac presentation 
on admission 
Indicate the patient’s cardiac symptoms at the time of this admission. 
No Symptoms: No Symptoms, no angina. 
Stable Angina: Angina without a change in frequency or pattern for the prior 6 weeks. 
Angina is controlled by rest and/or oral or transcutaneous medications. 
Unstable Angina: There are three principal presentations of unstable angina: 1. Rest 
angina (occurring at rest and prolonged, usually >20 minutes); 2. New-onset angina 
(within the past 2 months, of at least Canadian Cardiovascular Society Class III severity); 
or 3. Increasing angina (previously diagnosed angina that has become distinctly more 
frequent, longer in duration, or increased by 1 or more Canadian Cardiovascular Society 
class to at least CCS III severity). 
Non-ST Elevation MI (Non- STEMI): The patient was hospitalized for a non-ST elevation 
myocardial infarction (STEMI) as documented in the medical record. Non-STEMIs are 
characterized by the presence of both criteria: 
a. Cardiac biomarkers (creatinine kinase-myocardial band, Troponin T or I) 
exceed the upper limit of normal according to the individual hospital’s 
laboratory parameters with a clinical presentation which is consistent or 
suggestive of ischemia. ECG changes and/or ischemic symptoms may or may 
not be present. 
b. Absence of ECG changes diagnostic of a STEMI  
ST Elevation MI (STEMI): The patient ’presented with a ST elevation myocardial 
infarction (STEMI) or its equivalent as documented in the medical record. STEMIs are 
characterized by the presence of both criteria: 
ECG evidence of STEMI: New or presumed new ST segment elevation or new left bundle 
branch block not documented to be resolved within 20 minutes. ST segment elevation is 
defined by new or presumed new sustained ST-segment elevation at the J-point in two 
ĐŽŶƚŝŐƵŽƵƐĞůĞĐƚƌŽĐĂƌĚŝŽŐƌĂŵ;'ͿůĞĂĚƐǁŝƚŚƚŚĞĐƵƚŽĨĨƉŽŝŶƚƐ͗шϬ͘ϮŵsŝŶŵĞŶŽƌ
шϬ͘ϭϱŵsŝŶǁŽŵĞŶŝŶůĞĂĚƐsϮ-sϯĂŶĚͬŽƌшϬ͘ϭŵsŝŶŽƚŚĞƌůĞĂĚƐand lasting greater than 
or equal to 20 minutes. If no exact ST-elevation measurement is recorded in the medical 
chart, physician’s written documentation of ST elevation or Q waves is acceptable. If only 
one ECG is performed, then the assumption that the ST elevation persisted at least the 
required 20 minutes is acceptable. Left bundle branch block (LBBB) refers to new or 
presumed new LBBB on the initial ECG. 
Cardiac biomarkers (creatinine kinase-myocardial band, Troponin T or I) exceed the 
upper limit of normal according to the individual hospital’s laboratory parameters a 
clinical presentation which is consistent or suggestive of ischemia. 
Angina equivalent 
Other: Presentation/symptom not listed above. 

TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
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Factor 
Definition 
Status of the procedure 
Elective: The patient's cardiac function has been stable in the days or weeks prior to the 
operation. The procedure could be deferred without increased risk of compromised 
cardiac outcome.  
Urgent: Procedure required during same hospitalization in order to minimize chance of 
further clinical deterioration. Examples include but are not limited to: Worsening, 
sudden chest pain, CHF, acute myocardial infarction (AMI), anatomy, IABP, unstable 
angina (USA) with intravenous (IV) nitroglycerin (NTG) or rest angina. 
Emergent: Patients requiring emergency operations will have ongoing, refractory 
(difficult, complicated, and/or unmanageable) unrelenting cardiac compromise, with or 
without hemodynamic instability, and not responsive to any form of therapy except 
cardiac surgery. An emergency procedure is one in which there should be no delay in 
providing operative intervention. The patient’s clinical status includes any of the 
following:  
a. Ischemic dysfunction (any of the following): 
(1) Ongoing ischemia including rest angina despite maximal medical therapy (medical 
and/or IABP));  
(2) Acute Evolving Myocardial Infarction within 24 hours before surgery; or 
(3) pulmonary edema requiring intubation. 
b. Mechanical dysfunction (either of the following):  
(1) shock with circulatory support; or  
(2) shock without circulatory support. 
Emergent Salvage: The patient is undergoing CPR en route to the OR or prior to 
anesthesia induction or has ongoing ECMO to maintain life. 
 

TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
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Co-morbidity 
Definition/Criteria 
Porcelain aorta or 
severely 
atherosclerotic aorta 
Heavy circumferential calcification or severe atheromatous plaques of the entire 
ascending aorta extending to the arch such that aortic cross-clamping is not feasible. 
Frailty 
Slowness, weakness, exhaustion, wasting and malnutrition, poor endurance and 
inactivity, loss of independence 
Criteria:  
x
5-meter walking time 
x
Grip strength  
x
BMI <20 kg/m2 and/or weight loss 5 kg/yr  
x
Serum albumin <3.5 g/dL  
x
Cognitive impairment or dementia  
Sever liver 
disease/cirrhosis 
Any of the following: 
x
Child-Pugh class C  
x
D>ƐĐŽƌĞш10  
x
Portal-caval, spleno-renal, or transjugular intrahepatic portal shunt  
x
Biopsy proven cirrhosis with portal hypertension or hepatocellular 
dysfunction 
Hostile chest 
Any of the following or other reasons that make redo operation through sternotomy 
or right anterior thoracotomy prohibitively hazardous:  
x
Abnormal chest wall anatomy due to severe kyphoscoliosis or other skeletal 
abnormalities (including thoracoplasty, Potts’ disease)  
x
Complications from prior surgery  
x
Evidence of severe radiation damage (eg, skin burns, bone destruction, muscle 
loss, lung fibrosis or esophageal stricture)  
x
History of multiple recurrent pleural effusions causing internal adhesions  
IMA or other critical 
conduit(s) crossing 
midline and/or 
adherent to posterior 
table of sternum  
 
A patent IMA graft that is adherent to the sternum such that injuring it during re-
operation is likely. A patient may be considered extreme risk if any of the following 
are present:  
x
The conduit(s) are radiographically indistinguishable from the posterior table of 
the sternum.  
x
The conduit(s) are radiographically distinguishable from the posterior table of the 
sternum but lie within 2-3 mm of the posterior table. 
Severe pulmonary 
hypertension  
Severe right 
ventricular 
dysfunction  
Primary or secondary pulmonary hypertension with PA systolic pressures greater than 
2/3 of systemic pressure  
Criteria as defined by the guidelines (eg, TAPSE <15mm, RV end-systolic area >20 cm2) 
 

TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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The following definitions are applicable to the data elements on the Implant eCRF that address the use of 
the resheath and recapture feature. 
Resheath attempt 
An attempt to intentionally resheath only a portion of the TAV (including the 
frame) into the capsule of the delivery catheter (eg, with the intent to 
reposition of the valve during deployment). 
Recapture attempt 
An attempt to intentionally fully resheath the entire TAV (including the 
frame) into the capsule of the delivery catheter until there is no gap 
between capsule and the tip (eg, with the intent to enable re-crossing of the 
aortic valve or retrieval of the system, Panel D below). 
Reposition 
Repositioning of the TAV proximally or distally before final deployment 
Retrieve
Retrieval of a partially deployed TAV

TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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Definitions of adverse events to be evaluated as clinical safety endpoints, other related complications, 
and efficacy events are provided in Sections 1.0, 2.0, and 3.0, respectively [54]. The CEC and site 
investigators will code safety endpoint events according to these definitions, using the associated code 
list provided on Section 4.0, Event Code List. 
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Mortality 
Cardiovascular 
mortality
Any of the following criteria: 
1) Death due to proximate cardiac cause (eg, myocardial infarction, cardiac 
tamponade, worsening heart failure) 
2) Death caused by non-coronary vascular conditions such as neurological events, 
pulmonary embolism, ruptured aortic aneurysm, dissecting aneurysm, or other 
vascular disease 
3) All procedure-related deaths, including those related to a complication of the 
procedure or treatment for a complication of the procedure 
4) All valve-related deaths including structural or nonstructural valve dysfunction or 
other valve-related adverse events 
5) Sudden or unwitnessed death 
6) Death of unknown cause 
Non-cardiovascular 
mortality 
Any death in which the primary cause of death is clearly related to another condition 
(eg, trauma, cancer, suicide). 

TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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Stroke and TIA 
Diagnostic criteria 
1) Acute episode of a focal or global neurological deficit with at least 1 of the following:  
x change in the level of consciousness 
x hemiplegia, hemiparesis 
x numbness or sensory loss affecting 1 side of the body 
x dysphasia or aphasia 
x hemianopia 
x amaurosis fugax 
x other neurological signs or symptoms consistent with stroke 
Stroke: duration of a focal or global neurological deficit ı24 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 
2) No other readily identifiable non-stroke cause for the clinical presentation (eg, brain tumor, trauma, 
infection, hypoglycemia, peripheral lesion, pharmacological influences), to be determined by or in 
conjunction with the neurologist 
3) Confirmation of the diagnosis by at least 1 of the following: 
x Neurologist or neurosurgical specialist 
x Neuroimaging procedure (CT scan or brain MRI), but stroke may be diagnosed on clinical grounds alone 
Stroke Definitions 
Disabling stroke: an mRS score of 2 or more at 90 days and an increase in at least 1 mRS category from an 
individual’s pre-stroke baseline 
Non-disabling stroke: an mRS score of <2 at 90 days or one that does not result in an increase in at least 1 mRS 
category from an individual’s pre-stroke baseline 
Stroke Classifications 
Ischemic: an acute episode of focal cerebral, spinal, or retinal dysfunction caused by infarction of the central 
nervous system tissue 
Hemorrhagic: an acute episode of focal or global cerebral or spinal dysfunction caused by intraparenchymal, 
intraventricular, or subarachnoid hemorrhage 
Undetermined: insufficient information to allow categorization as ischemic or hemorrhagic 
 

TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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Myocardial Infarction 
Periprocedural MI 
;чϳϮŚĂĨƚĞƌƚŚĞ
index procedure) 
New ischemic symptoms (eg, chest pain or shortness of breath), or new ischemic signs 
(eg, ventricular arrhythmias, new or worsening heart failure, new ST-segment changes, 
hemodynamic instability, new pathological Q-waves in at least 2 contiguous leads, 
imaging evidence of new loss of viable myocardium or new wall motion abnormality) 
AND 
Elevated cardiac biomarkers (preferable CK-MB) within 72 h after the index procedure, 
consisting of at least 1 sample post procedure with a peak value exceeding 15x as the 
upper reference limit for troponin or 5x for CK-MB. If cardiac biomarkers are increased 
at baseline (>99th percentile), a further increase in at least 50% post procedure is 
required AND the peak value must exceed the previously stated limit. 
Spontaneous MI 
(>72 h after the 
index procedure) 
Any of the following criteria: 
1) Detection of rise and/or fall of cardiac biomarkers (preferably troponin) with at 
least 1 value above the 99th percentile URL, together with the evidence of 
myocardial ischemia with at least 1 of the following: 
x
Symptoms of ischemia 
x
ECG changes indicative of new ischemia (new ST-T changes or new left bundle 
branch block (LBBB)) 
x
New pathological Q-waves in at least 2 contiguous leads 
x
Imaging evidence of a new loss of viable myocardium or new wall motion 
abnormality 
2) 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. 
3) Pathological findings of an acute myocardial infarction  
 

TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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Bleeding Complications 
Life-threatening or 
disabling bleeding 
1) Fatal bleeding (BARC type 5) OR 
2) 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 
3) Bleeding causing hypovolemic shock or severe hypotension requiring 
vasopressors or surgery (BARC type 3b) OR 
4) Overt source of bleeding with drop in hemoglobin ı5 g/dL or whole blood or 
packed red blood cells (RBCs) transfusion ı4 units* 
(BARC type 3b) 
Major bleeding 
(BARC type 3a) 
1) 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, or causing 
hospitalization or permanent injury, or requiring surgery AND 
2) Does not meet criteria of life-threatening or disabling bleeding 
Minor bleeding 
(BARC type 2 or 3a, 
depending on the 
severity) 
Any bleeding worthy of clinical mention (eg, access site hematoma) that does not 
qualify as life-threatening, disabling, or major 
*Given one unit of packed RBC typically will raise hemoglobin concentration by 1 g/dL, an estimated decrease 
in haemoglobin will be calculated; BARC: Bleeding Academic Research Consortium29; RBC: red blood cell  
Note: With respect to blood transfusions, it is critical to acknowledge that a bleeding complication has to be the result of overt 
bleeding and cannot be adjudicated based on blood transfusions alone. 
Acute Kidney Injury (up to 7 days post procedure)
Stage 1 
1) Increase in serum creatinine to 150%-199% (1.5-1.99 x increase compared with 
ďĂƐĞůŝŶĞͿKZŝŶĐƌĞĂƐĞŽĨшϬ͘ϯŵŐͬĚ>;шϮϲ͘ϰŵŵŽůͬ>ͿKZ 
2) Urine output <0.5 mL/kg/h for >6 but <12 h 
Stage 2 
1) Increase in serum creatinine to 200%-299% (2.0-2.99 x increase compared with 
baseline) OR 
2) Urine output <0.5 mL/kg/h for >12 but <24 h 
Stage 3 
1) /ŶĐƌĞĂƐĞŝŶƐĞƌƵŵĐƌĞĂƚŝŶŝŶĞƚŽшϯϬϬй;хϯǆŝŶĐƌĞĂƐĞĐŽŵƉĂƌĞĚǁŝƚŚďĂƐĞůŝŶĞͿKZ
ƐĞƌƵŵĐƌĞĂƚŝŶŝŶĞŽĨшϰ͘ϬŵŐͬĚ>;шϯϱϰŵŵŽůͬ>ͿǁŝƚŚĂŶĂĐƵƚĞŝŶĐƌĞĂƐĞŽĨĂƚleast 
0.5 mg/dL (44 mmol/L) OR 
2) hƌŝŶĞŽƵƚƉƵƚфϬ͘ϯŵůͬŬŐͬŚĨŽƌшϮϰŚKZ 
3) ŶƵƌŝĂĨŽƌшϭϮŚ 
 

TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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Vascular Access Site and Access Related Complications
Major vascular 
complication 
1) Any aortic dissection, aortic rupture, annulus rupture, left ventricle perforation, 
or new apical aneurysm/pseudoaneurysm OR 
2) Access site or access-related vascular injury (dissection, stenosis, perforation, 
rupture, arterio-venous fistula, pseudoaneurysm, hematoma, irreversible nerve 
injury, compartment syndrome, percutaneous closure device failure) leading to 
death, life-threatening or major bleeding, visceral ischemia, or neurological 
impairment OR 
3) Distal embolization (noncerebral) from a vascular source requiring surgery or 
resulting in amputation or irreversible end-organ damage OR 
4) The use of unplanned endovascular or surgical intervention associated with 
death, major bleeding, visceral ischemia or neurological impairment OR 
5) Any new ipsilateral lower extremity ischemia documented by patient 
symptoms, physical exam, and/or decreased or absent blood flow on lower 
extremity angiogram OR 
6) Surgery for access site-related nerve injury OR 
7) Permanent access site-related nerve injury 
Minor vascular 
complication 
1) Access site or access-related vascular injury (dissection, stenosis, perforation, 
rupture, arterio-venous fistula, pseudoaneuysms, hematomas, percutaneous 
closure device failure) not leading to death, life-threatening or major bleeding*, 
visceral ischemia, or neurological impairment OR 
2) Distal embolization treated with embolectomy and/or thrombectomy and not 
resulting in amputation or irreversible end-organ damage OR 
3) Any unplanned endovascular stenting or unplanned surgical intervention not 
meeting the criteria for a major vascular complication OR 
4) Vascular repair or the need for vascular repair (via surgery, ultrasound-guided 
compression, transcatheter embolization, or stent-graft) 
Percutaneous 
closure device 
failure 
Failure of a closure device to achieve hemostasis at the arteriotomy site leading to 
alternative treatment (other than manual compression or adjunctive endovascular 
ballooning) 
*Refer to VARCII bleeding definitions [54] 
VALVE DYSFUNCTION REQUIRING REPEAT PROCEDURE
Any valve dysfunction that requires repeat procedure (eg, balloon valvuloplasty, TAVR, snare repositioning, 
placement of vascular plug paravalvular leak, or surgical AVR) 
Note: Repeat procedures are reported on the appropriate eCRF (Surgical Intervention or Catheter Reintervention) 
 

TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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Version 
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Complication 
Definition 
Conversion to open 
surgery 
Conversion to open sternotomy during the TAVR procedure secondary to any 
procedure-related complications 
Unplanned use of 
cardiopulmonary 
bypass 
Unplanned use of CPB for hemodynamic support at any time during the TAVI 
procedure 
Coronary artery 
obstruction 
Angiographic or echocardiographic evidence of a new, partial or complete, obstruction 
of a coronary ostium, either by the TAV prosthesis itself, the native leaflets, 
calcifications, or dissection, occurring during or after the TAVR procedure. 
Ventricular septal 
perforation 
Angiographic or echocardiographic evidence of a new septal perforation during or 
after the TAVR procedure 
Mitral valve 
apparatus damage or 
dysfunction 
Angiographic or echocardiographic evidence of new damage (chordae, papillary 
muscle, or leaflet) to the mitral valve apparatus or dysfunction (eg, restrictions due to 
the TAV of the mitral valve during or after the TAVR procedure 
Cardiac tamponade 
Evidence of new pericardial effusion associated with hemodynamic instability and 
clearly related to the TAVI procedure 
Prosthetic valve 
thrombosis 
Any thrombus attached to or near an implanted valve that occludes part of the blood 
flow path, interferes with valve function, or is sufficiently large to warrant treatment. 
Valve-associated thrombus identified at autopsy in a patient whose cause of death was 
not valve related should not be reported as valve thrombosis. 
Valve migration
After initial correct positioning, any observed movement (upward or downward) of the 
TAV within the aortic annulus from its initial position, with or without consequences. 
Valve embolization 
The TAV moves during or after deployment such that it loses contact within the aortic 
annulus 
Ectopic valve 
deployment 
Permanent deployment of the TAV in a location other than the aortic root 
TAV in TAV 
deployment 
Additional valve prosthesis is implanted within a previously implanted TAV because of 
sub-optimal device position and/or function, during or after the index procedure. 
Hemolysis 
Red cell destruction confirmed by lab data 
Minor hemolysis: No intervention required 
Major hemolysis: Requires intervention (eg, iron supplements, transfusion, invasive 
intervention). 
Frame fracture 
Visual evidence on radiography or at explant of loss of contact between elements 
(cells) of the stent. 
Minor frame fracture: Does not require intervention, or is not associated with 
prosthetic valve dysfunction. 
Major frame fracture: Intervention required (eg, reoperation, catheter re-
intervention) or is associated with prosthetic valve dysfunction 

TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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PROSTHETIC VALVE ENDOCARDITIS 
Any of the following: 
1) Fulfillment of the following Duke criteria for definite endocarditis [55]:  
x
Histologic and/or microbiologic evidence of infection at surgery or autopsy, or 
x
2 major criteria, or 
x
1 major criteria or 3 minor criteria, or  
x
5 minor criteria 
Major and minor criteria are as follows: 
Major Criteria: 
x
Blood cultures positive for Infective Endocarditis (IE) 
R
Typical microorganisms consistent with IE isolated from two separate blood cultures, as noted 
below 
x
Viridans streptococci, Streptococcus bovis, Staphylcoccus aureus, or HACEK group 
x
Community-acquired enterococci in the presence of a primary focus 
R
Microorganisms consistent with IE isolated from persistently positive blood cultures defined as: 
x
At least two positive cultures or blood samples obtained >12 hours apart, or 
x
All of three, or a majority of four or more separate cultures of blood, the first and last 
sample obtained > one hour apart 
R
Single blood culture positive for Coxiella burnetti or an antiphase I IG antibody titer >1:800 
x
Evidence of endocardial involvement 
R
Positive results of echocardiography for IE defined as: 
x
Oscillating intracardiac mass on a valve or supporting structures in the path of 
regurgitant jets or on implanted material in the absence of an anatomic explantation, 
or 
x
Abscess, or 
x
New partial dehiscence of a valvular prosthesis 
R
New valvular regurgitation (worsening or changing or pre-existing murmur not sufficient) 
Minor Criteria: 
 
x
Predisposition: predisposing heart condition or intravenous drug use 
x
Fever: temperature >38මC 
x
Vascular phenomena: major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, 
intracranial hemorrhage, conjunctival hemorrhages, and Janeway’s lesions 
x
Immunological phenomena: glomerulonephritis, Osler’s nodes, Roth’s spots, and rheumatoid 
factor 
x
Microbiological evidence: positive blood culture but does not meet a major criterion (as noted 
above) or serological evidence of active infection with organism consistent with infectious 
endocarditis. 
x
Echocardiographic findings: consistent with IE but do not meet a major criterion as noted above 
If only 1 major and 1-2 minor criteria are fulfilled, or if only 3-4 minor criteria are fulfilled, the event will be 
coded as “possible endocarditis” 
2) Evidence of abscess, paravalvular leak, pus, or vegetation confirmed as secondary to infection by 
histological or bacteriological studies during a re-operation 
3) Findings of abscess, pus, or vegetation involving the TAV or surgical bioprosthesis at autopsy 

TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
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PROSTHETIC VALVE DYSFUNCTION 
Stenosis: moderate/severe 
Any of the following  
1) 
Peak aortic velocity >4 m/s OR mean aortic gradient >40 
mmHg, AND EOA <0.8 cm2. 
2) 
Peak aortic velocity >4 m/s OR mean aortic gradient >40 
mmHg, AND EOA ш0.8 cm2, and DVI <0.25, 
3) 
Peak aortic velocity ч4 m/s and mean aortic gradient ч 40 
mmHg, AND EOA <0.8 cm2, and DVI <0.25 
Paravalvular regurgitation: moderate 
Moderate paravalvular regurgitation (per echo criteria in Table 10, 3 
grade scheme) 
Paravalvular regurgitation: severe 
Severe paravalvular regurgitation (per echo criteria in Table 10, 3 
grade scheme) per echo criteria in CIP) 
Transvalvular regurgitation: 
moderate 
Moderate paravalvular regurgitation (per echo criteria in Table 10, 3 
grade scheme)  
Transvalvular regurgitation: severe 
Severe transvalvular regurgitation (per echo criteria in Table 10, 3 
grade scheme) 
Total regurgitation: moderate 
Moderate total regurgitation (per echo criteria in Table 10, 3 grade 
scheme) 
Total regurgitation: severe 
Severe total regurgitation (per echo criteria in Table 10, 3 grade 
scheme) 
Notes: 
 
1. 
DVI = Doppler Velocity Index (LVOT VTI/valve VTI) 
2. 
For subjects with BSA <1.6 m2, the EOA criteria for significant (moderate or severe) stenosis is <0.6 cm2 
3. 
For subjects with LVOT diameter >2.5 cm, the DVI criteria for significant (moderate or severe) stenosis is <0.2 cm2 
4. 
Reporting of prosthetic valve dysfunction will be based on core lab results. 
5. 
Prosthetic valve dysfunction events are not reported as adverse events, unless the dysfunction is accompanied with clinical 
sequelae at the time of event detection, and the clinical sequelae are chronologically and physiologically associated with 
the dysfunction. However, prosthetic dysfunctions that are associated with adverse events, and that meet the definition of 
a serious adverse event, should be reported as such. 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
10790330DOC
Version 
1E 
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Myocardial Infarction 
100
Peri-procedural myocardial infarction 
101
Spontaneous myocardial infarction 
 
Stroke and TIA 
102
Disabling stroke: ischemic 
103
Disabling stroke: hemorrhagic 
104
Disabling stroke: undetermined origin 
105
Non-disabling stroke: ischemic 
106
Non-disabling stroke: hemorrhagic 
107
Non-disabling stroke: undetermined origin 
108
Transient ischemic attack 
 
Bleeding Complications 
110 
Life threatening or disabling bleed event 
111 
Major bleeding event  
112 
Minor bleeding event 
 
Acute Kidney Injury 
113 
Acute kidney injury: stage 1 
114 
Acute kidney injury: stage 2 
115 
Acute kidney injury: stage 3 
 
Vascular Access and Access Site Complications 
Major 
120 
Major vascular complication: aortic dissection, aortic 
rupture, LV perforation, or new apical 
aneurysm/pseudoaneurysm 
121 
Major vascular complication: access site or access site-
related vascular injury (dissection, stenosis, 
perforation, etc) 
122 
Major vascular complication: distal embolization from 
vascular source 
123 
Unplanned endovascular or surgical intervention 
124 
New ipsilateral lower extremity ischemia 
125 
Surgery for access site-related nerve injury 
126 
Permanent access site-related nerve injury 
127 
Other major vascular complication 
Minor 
130 
Minor vascular complication: access site or access site-
related vascular injury 
131 
Minor vascular complication: distal embolization from 
vascular source 
132 
Unplanned endovascular stenting or unplanned 
surgical intervention not meeting criteria for major 
complication 
133 
Vascular repair or need for vascular repair 
134 
Other minor vascular access site complication 
140 
Failure of closure device leading to alternative 
treatment 
 
 
Other TAVR-Related Complications 
150 
Conversion to open surgery 
151 
Unplanned used of CPB 
152 
Coronary artery obstruction 
153 
Ventricular septal perforation 
154 
Mitral valve apparatus damage 
155 
Cardiac tamponade 
156 
Prosthetic valve thrombosis 
157 
Valve migration 
158 
Valve embolization 
159 
Ectopic valve deployment 
160 
TAV in TAV deployment 
161 
Major hemolysis 
162 
Minor hemolysis 
163 
Prosthetic valve endocarditis: definite 
164 
Prosthetic valve endocarditis: possible 
165 
Major frame fracture 
166 
Minor frame fracture 
167 
Other TAVR-related complication 
Conduction Disturbances and Arrhythmias 
170 
Atrio-ventricular block, 1q 
171 
Atrio-ventricular block, 2q 
172 
Atria-ventricular block, 3q 
173 
LBBB 
174 
RBBB 
175 
Left anterior fascicular block 
176 
Left posterior fascicular block 
180 
Atrial fibrillation 
181 
Atrial flutter 
182 
Junctional rhythm (<100 bpm) 
183 
Junctional rhythm (t100 bpm) 
184 
Sinus bradycardia (<50 bpm) 
185 
Supraventricular tachycardia 
186 
Ventricular fibrillation 
187 
Ventricular premature beats 
188 
Ventricular tachycardia 
189 
Other arrhythmia 
 
 
Prosthetic Valve Dysfunction 
191 
Moderate/severe stenosis 
192 
Moderate paravalvular regurgitation 
193 
Severe paravalvular regurgitation 
194 
Moderate transvalvular regurgitation 
195 
Severe transvalvular regurgitation 
196 
Moderate total regurgitation 
197 
Severe total regurgitation 
 
 
 

 
TAVR with Medtronic TAVR System in Patients with Severe Bicuspid Aortic Valve 
Stenosis and at Low Predicted Risk of Mortality with SAVR  
Clinical Investigation Plan 
 
10790330DOC
Version 
1E 
Page 113 of 118 
 
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Other Implantation/Catheterization Procedure-Related 
Adverse Events 
200 
Brachial plexus injury 
201 
Hypovolemia 
202 
Hypotension requiring intervention 
203 
Air embolism 
204 
Venous thrombosis, definite 
205 
Venous thrombosis, suspected 
206 
Metabolic acidosis 
207 
Catheter induced arrhythmia 
208 
Hemothorax 
209 
Radiation-induced erythema 
210 
Other implantation/catheterization 
 
 
Other Cardiac Adverse Events 
300 
Cardiac arrest 
301 
Congestive heart failure 
302 
Cardiogenic shock 
303 
Valvular regurgitation, mitral 
304 
Valvular regurgitation, tricuspid 
307 
Syncope 
308 
Palpitations 
309 
Cyanosis 
310 
Chest pain 
311 
Pericardial effusion, hemorrhagic 
312 
Pericardial effusion, non-hemorrhagic 
313 
Intracardiac mass 
399 
Other cardiac event 
 
 
Respiratory/Pulmonary Adverse Events 
400 
Respiratory arrest 
401 
Pneumothorax 
402 
Chronic pulmonary disease 
403 
Bronchospasm/asthma 
404 
Pleural effusion 
405 
Hemoptysis 
406 
Respiratory failure 
407 
Atelectasis 
408 
Hemothorax 
409 
Respiratory insufficiency 
410 
Apnea/hypoventilation 
499 
Other respiratory/pulmonary 
 
 
Other Neurologic Adverse Events 
500 
Seizure(s) 
502 
Meningitis, infectious 
504 
Headaches 
505 
Dizziness 
599 
Other central nervous system 
 
 
Gastrointestinal Adverse Events 
600 
Vomiting 
601 
Diarrhea 
602 
Protein losing enteropathy 
603 
Liver disease 
604 
Liver failure 
699 
Other gastrointestinal 
 
 
Hematologic/Oncologic Adverse Events 
700 
Cancer/malignancy 
701 
Coagulopathy 
702 
Anemia (Hgb <10g or Hct <30%) 
703 
Thrombocytopenia 
704 
Transfusion reaction 
799 
Other hematologic/oncologic 
 
 
Infection Adverse Events 
801 
Fever 
802 
Sepsis, confirmed (positive blood culture) 
803 
Sepsis, suspected (by clinical findings) 
804 
Endocarditis, other than the TAV or surgical valve 
805 
Urinary tract infection 
806 
Pneumonia 
807 
Gastroenteritis 
808 
Hepatitis 
809 
Upper respiratory tract infection 
899 
Other infection 
 
 
Other Renal Adverse Events (Exclusive of AKI) 
900 
Renal insufficiency 
902 
Chronic renal failure 
903 
Proteinuria 
904 
Urinary retention 
999 
Other renal 
 
 
Allergic Reactions 
1000 Anaphylaxis 
1001 Pruritus 
1002 Rash 
1003 Contrast reaction/allergy 
1004 Medication reaction/allergy 
1099 Other allergic reaction 
 
 
Other 
1200 Multi organ failure 
1299 Other 

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The following definitions are intended as guidelines for classifying causal relationships between the 
event and the TAV, the catheter delivery system, and the TAVR implant procedure. Timeframe for 
assessing implant procedure relationships begin when subject is being prepared for the TAVR implant 
(or re-implant) procedure. 
&DXVDOUHODWLRQVKLSVEHWZHHQHYHQWDQGWKH7$9
Not related to the TAV 
The relationship to TAV can be excluded when: 
x
the event is not a known side effect of the TAV product category the device 
belongs to or of similar devices; 
x
The event has no temporal relationship with the TAV  
x
The event does not follow a known response pattern to the TAV is biologically 
implausible;  
x
The event involves a body-site or an organ not expected 
In order to establish non-relatedness, not all the criteria listed above might be met at 
the same time. 
Unlikely to be related to 
the TAV 
The relationship with the TAV seems not relevant and/or the event can be reasonably 
explained by another cause, but additional information may be obtained. 
Possibly related to the 
TAV 
The relationship with the TAV is weak but cannot be ruled out completely. Alternative 
causes are also possible (eg, an underlying or concurrent illness/ clinical condition 
or/and an effect of another device, drug or treatment). Cases were relatedness cannot 
be assessed or no information has been obtained should also be classified as possible. 
Probably related to the 
TAV 
The relationship with TAV seems relevant and/or the event cannot reasonably 
explained by another cause, but additional information may be obtained. 
Causal relationship 
“Related” to the TAV 
The event is associated with the TAV beyond reasonable doubt when:  
x
the event is a known side effect of the TAV product category the device 
belongs to or of similar devices; 
x
the event has a temporal relationship with investigational device 
use/application or procedures; 
x
the event involves a body-site or organ that  
x
the TAV or surgical valve is applied to;  
x
the TAV of surgical valve has an effect on; 
x
the event follows a known response pattern to the TAV; 
x
other possible causes (eg, an underlying or concurrent illness/clinical 
condition or an effect of another device, drug, or treatment) have been 
adequately ruled out 
x
harm to the subject is due to error in use 
In order to establish relatedness, not all the criteria listed above might be met at the 
same time. 

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Not related to the TAVR 
delivery system 
The relationship with the TAVR delivery system can be excluded when:  
x
the event is not a known side effect of the TAVR delivery system product category 
the device belongs to or of similar devices; 
x
The event has no temporal relationship with the use of the TAVR delivery system 
x
The event does not follow a known response pattern to the TAVR delivery system 
and is biologically implausible;  
x
The event involves a body-site or an organ not expected 
In order to establish non-relatedness, not all the criteria listed above might be met at 
the same time 
Unlikely to be related to 
the TAVR delivery 
system 
The relationship with the TAVR delivery system seems not relevant and/or the event 
can be reasonably explained by another cause, but additional information may be 
obtained. 
Possibly related to the 
TAVR delivery system 
The relationship with the TAVR delivery system is weak but cannot be ruled out 
completely. Alternative causes are also possible (eg, an underlying or concurrent 
illness/ clinical condition or/and an effect of another device, drug or treatment). Cases 
were relatedness cannot be assessed or no information has been obtained should also 
be classified as possible. 
Probably related to the 
TAVR delivery system 
The relationship with the TAVR delivery system seems relevant and/or the event 
cannot reasonably explained by another cause, but additional information may be 
obtained. 
Causal relationship 
“Related” to the TAVR 
delivery system 
The event is associated with the TAVR delivery system reasonable beyond doubt 
when: 
x
the event is a known side effect of the product category the device 
belongs to or of similar devices; 
x
the event has a temporal relationship with the TAVR delivery system 
use/application; 
x
the event involves a body-site or organ that  
x
the TAVR delivery system is applied to;  
x
the TAVR delivery system has an effect on; 
x
the event follows a known response pattern to the TAVR delivery system; 
x
other possible causes (eg, an underlying or concurrent illness/clinical 
condition or an effect of another device, drug, or treatment) have been 
adequately ruled out 
x
harm to the subject is due to error in use 
In order to establish relatedness, not all the criteria listed above might be met at the 
same time. 
 

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Not related to the TAVR 
implant procedure 
The relationship with the TAVR implant procedure can be excluded when:  
x
the event is not a known side effect of the TAVR implant procedure; 
x
The event has no temporal relationship with the TAVR implant relationship 
x
The event does not follow a known response pattern to the TAVR implant 
procedure and is biologically implausible;  
x
The event involves a body-site or an organ not expected 
In order to establish non-relatedness, not all the criteria listed above might be met at 
the same time. 
Unlikely to be related to 
the TAVR implant 
procedure 
The relationship with the TAVR implant procedure seems not relevant and/or the 
event can be reasonably explained by another cause, but additional information may 
be obtained. 
Possibly related to the 
TAVR implant procedure 
The relationship with the TAVR implant procedure is weak but cannot be ruled out 
completely. Alternative causes are also possible (eg, an underlying or concurrent 
illness/ clinical condition or/and an effect of another device, drug or treatment). Cases 
were relatedness cannot be assessed or no information has been obtained should also 
be classified as possible. 
Probably related to the 
TAVR implant procedure 
The relationship with TAVR implant procedure seems relevant and/or the event 
cannot reasonably explained by another cause, but additional information may be 
obtained. 
Causal relationship 
“Related” to the TAVR 
delivery system 
The event is associated with the TAVR implant procedure beyond reasonable doubt 
when:  
x
the event is a known side effect of the TAVR implant procedure; 
x
the event has a temporal relationship with the TAVR implant procedure; 
x
the event involves a body-site or organ that  
x
the TAVR is applied to;  
x
the TAVR implant procedure has an effect on; 
x
the event follows a known response pattern to the TAVR implant 
procedure; 
x
other possible causes (eg, an underlying or concurrent illness/clinical 
condition or an effect of another device, drug, or treatment) have been 
adequately ruled out 
x
harm to the subject is due to error in use 
In order to establish relatedness, not all the criteria listed above might be met at the 
same time. 
Note: Procedure related events refer to the procedure related to the initial application of the investigational medical device only and therefore 
not to any other procedures or treatments applied later throughout the clinical investigation, for instance to treat (serious) adverse events. 
 
 

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Document # 10790330DOC 
Version 1E 
Page 117 of 118 
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An informed consent form template will be provided under separate cover. 
 

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Document # 10790330DOC 
Version 1E 
Page 118 of 118 
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Version 
Summary of Changes 
Author(s)/Title 
1A 
Not Applicable, New Document 
Hatice Bilgic Lim, PhD, Principal 
Clinical Research Specialist 
1B 
Revised sample size to 150 subjects with 
attempted implant 
Documented that the primary endpoint results 
from the TAVR Bicuspid Low Risk cohort will be 
compared to the results from the from TAVR 
arm of randomized Low Risk cohort 
Documented that Enveo R and Enveo PRO 
delivery catheter systems could be used in the 
study. 
Charles Boldt, MA, Sr Clinical 
Program Manager 
1C 
Added “Myocardial infarction at 30 days” as an 
additional outcome measure 
 
Clarified the required follow-up evaluations for 
the KCCQ and EQ-5D to provide consistency 
throughout the protocol that KCCQ instrument 
will be performed at baseline, 30 days, one 
year, annually through 5 years; and EQ-5D 
survey will be performed at baseline, 30 days 
and 1 year  
 
Added information regarding the prevalence 
of bicuspid valve anatomy at specific risk 
populations and ages into Background section 
 
Clarified timeline of when the endpoint results 
will be publicly posted for the trial 
Hatice Bilgic Lim, PhD, Principal 
Clinical Research Specialist 
1D 
Removed Exclusion Criteria: Age >65  
 
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Hatice Bilgic Lim, PhD, Principal 
Clinical Research Specialist 
1E 
Added Exclusion Criteria: Age <60 years 
Hatice Bilgic Lim, PhD, Principal 
Clinical Research Specialist