PROTECTED TAVR: Stroke PROTECTion With SEntinel During Transcatheter
Phase: NA
Conditions: Stroke
Sponsor: Boston Scientific Corporation

Confidential 
Form/Template 92120219_Rev/Ver C 
PROTECTED TAVR Study-Specific Protocol 
92365019 Rev/Ver B 
Page 1 of 76 
PROTECTED TAVR: Stroke PROTECTion with SEntinel During 
Transcatheter Aortic Valve Replacement 
PROTECTED TAVR 
S2453 
CLINICAL INVESTIGATION PLAN 
NCT04149535
Sponsor: 
Boston Scientific Corporation  
300 Boston Scientific Way 
Marlborough, MA 01752 USA 
Boston Scientific International SAS 
2 Rue René Caudron, Bâtiment H 
78960 Voisins-le-Bretonneux, France 
Australian Representative 
Boston Scientific Pty. Ltd. 
Building 1, Level 6 
191 O’Riordan Street 
Mascot, NSW 2020, Australia 
This protocol contains confidential information for use by the Investigators and their 
designated representatives participating in this clinical investigation. The protocol should 
be held confidential and maintained in a secure location. 
Do not copy or distribute without written permission from Boston Scientific Corporation. 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 1 of 76

Confidential  
Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
  
Page 2 of 76 
  
 
Contact Information 
 
Role 
Contact  
Clinical 
Contacts 
Peyton Willert 
Senior Clinical Trial Manager, Interventional Cardiology 
Boston Scientific Corporation 
1745 Copperhill Pkwy, Suite 1 
Santa Rosa, CA 95403 USA 
Beth Lawson 
Clinical Trial Manager, Interventional Cardiology 
Boston Scientific Corporation 
100 Boston Scientific Way 
Marlborough, MA 01752-1234 USA 
Blessie Concepcion 
Director, Clinical Trials, Structural Heart – Interventional Cardiology 
Boston Scientific Corporation 
160 Knowles Drive 
Los Gatos, CA 95032 USA 
Study 
Coordinating 
Principal 
Investigators 
Study Principal Investigator 
Samir Kapadia, MD 
Cleveland Clinic Foundation 
9500 Euclid Ave 
Cleveland, OH 44195 
Study Co-Principal Investigator 
Axel Linke, MD 
Herzzentrum Dresden Universitätsklinik 
Fetscherstraße 76 
01307 Dresden, Germany 
 
Original Release: 18-Oct-2019 
Current Version: 06-Nov-2019 
 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 2 of 76

Confidential 
Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 3 of 76 
 
 
Revision History 
Revision 
Version 
Protocol 
Date 
Template 
Number and 
Version 
Protocol Sections 
Modified 
Summary of Changes 
Justification for 
Changes 
A 
18-Oct-2019 
92120219 
Rev/Ver C 
– 
Not applicable. 
– 
B 
06-Nov-2019 
92120219 
Rev/Ver C 
Section 2, Synopsis, 
Planned Number of 
Centers 
Up to 100 study centers in North America, Western Europe, 
and… 
Allow for additional 
centers. 
Section 2, Synopsis, 
Additional 
Measurements 
This section describes additional measurements to be 
performed… 
• Health status as evaluated by EQ-5D Quality of Life 
questionnaire at baseline 
Health economics 
analysis 
Section 6.2.2 
Additional 
Measurements 
The additional measurements shown below… 
• Health status as evaluated by EQ-5D Quality of Life 
questionnaire at baseline 
Section 7.3, 
Justification for the 
Study Design 
In order to support the stated objectives… at up to 100 centers 
in North America, Western Europe, and… 
Allow for additional 
centers. 
Section 10.1, Data 
Collection 
Figure 10.1-1: Updated figure to include EQ-5D at baseline 
Table 10.1-1: Added table row to collect the EQ-5D Quality of 
Life questionnaire at baseline 
Added footnote j: EQ-5D Quality of Life questionnaire at 
baseline 
Health economics 
analysis 
Section 10.4, 
Baseline 
Assessments 
The following assessments… 
• Quality of Life Survey (EQ-5D27, 28) should be administered 
within 30 days prior to the procedure 
Section 11.3.2 
Interim Analyses 
One formal interim analysis is planned… Additional analyses 
not defined in the protocol may also be conducted for 
regulatory agency review. 
Allow for additional 
regulatory agency 
analyses. 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 3 of 76

Confidential  
Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
  
Page 4 of 76 
  
Revision History 
Revision 
Version 
Protocol 
Date 
Template 
Number and 
Version 
Protocol Sections 
Modified 
Summary of Changes 
Justification for 
Changes 
Section 12. Health 
Economics 
Outcomes 
A formal health economics… healthcare resource utilization 
associated with periprocedural stroke subjects with  
through discharge (with a maximum of up to 30 days if the 
subject is hospitalized longer than 30 days) of follow up for 
both the Test and Control groups. Medical billing information 
(e.g., UB-04 billing claim form) through the TAVR index 
hospitalization may be collected at centers in the United States 
for health economics analyses. 
Health economics 
analysis 
Section 24, 
Bibliography 
Add 2 new references for EQ-5D (27 and 28) 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 4 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 5 of 76 
  
2. Protocol Synopsis 
PROTECTED TAVR: Stroke PROTECTion with SEntinel During Transcatheter 
Aortic Valve Replacement 
Study 
Objective 
The objective of this study is to demonstrate that use of the Sentinel® 
Cerebral Protection System significantly reduces the risk of peri-
procedural stroke (≤72 hours) after transcatheter aortic valve 
replacement (TAVR). 
Indications 
for Use 
The Sentinel® Cerebral Protection System is indicated for use as a 
cerebral protection device to capture and remove embolic material 
while performing transcatheter aortic valve procedures in order to 
reduce ischemic injury to the brain peri-procedurally.  
Commercial 
Device Applied 
as Standard of 
Care (Test 
Cohort) 
Commercially available Sentinel® Cerebral Protection System 
(Sentinel; Boston Scientific Corporation, Marlborough, MA, USA) 
Note 1: In the Test cohort, subjects will undergo TAVR with 
Sentinel. The participating investigator must be a trained, 
experienced Sentinel user. 
Control 
Applied as 
Standard of 
Care (Control 
Cohort) 
Subjects in the Control cohort will undergo TAVR with no cerebral 
protection device. 
Study Design 
PROTECTED TAVR is a prospective, post-market, multicenter 
randomized controlled trial (RCT) evaluating use of the Sentinel 
Cerebral Protection System in subjects with aortic valve stenosis 
who are treated with a commercially available TAVR device. 
Subjects to be treated via a transfemoral approach will be 
randomized 1:1 into a Test cohort using the commercially available 
Sentinel or a Control cohort with no cerebral protection system. A 
subject who provides an Informed Consent Form (ICF) signed by the 
subject or the subject’s legally authorized representative is 
considered enrolled in the study upon randomization, which will 
occur at the index procedure prior to procedural puncture/incision. 
enrolled subjects will be followed through 72 hours or hospital 
discharge, whichever comes first (see Additional Measurements 
below for information regarding subjects with suspected stroke).  
An overview of the study design is shown below. Every subject must 
be deemed treatable with the Sentinel device (have suitable anatomy 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 5 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 6 of 76 
  
PROTECTED TAVR: Stroke PROTECTion with SEntinel During Transcatheter 
Aortic Valve Replacement 
per the Sentinel Instructions For Use [IFU]). All eligible subjects 
(see below) should be approached for participation in the trial. 
 
PROTECTED TAVR Study Design Overview 
An initial enrollment of up to 3000 randomized subjects is planned. 
There will be 1 planned formal interim analysis performed on the 
first 70% of enrolled subjects by the Independent Safety and 
Statistical Monitor. The study will be stopped if a significant 
difference in favor of the test arm is observed. If the study cannot be 
stopped after the interim analysis, sample size re-estimation may be 
performed as discussed below (see Statistical Methods). A final 
analysis will be performed on all enrolled subjects if the trial is not 
stopped after the interim analysis. 
The PROTECTED TAVR study will be conducted in accordance 
with 21 CFR Parts 11, 50, and 54; the relevant parts of the 
International Conference on Harmonisation (ICH) Guidelines for 
Good Clinical Practices (GCP); the International Standard ISO 
14155 Clinical Investigation of Medical Devices for Human 
Subjects – Good Clinical Practice; ethical principles that have their 
origins in the Declaration of Helsinki; and pertinent individual 
country/state/local laws and regulations. The study shall not begin 
until the required approval/favorable opinion from the Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC)/Human 
Research Ethics Committee (HREC) and/or regulatory authority has 
been obtained, if appropriate. 
Planned 
Number of 
Subjects 
An initial enrollment of up to 3000 randomized subjects is planned. 
If sample size re-estimation is needed (see Statistical Methods 
below), the planned maximum enrollment will be up to 6000 
randomized subjects. 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 6 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 7 of 76 
  
PROTECTED TAVR: Stroke PROTECTion with SEntinel During Transcatheter 
Aortic Valve Replacement 
Planned 
Number of 
Centers  
Up to 100 study centers in North America, Europe, and Australia 
will participate in PROTECTED TAVR. 
Primary 
Endpoint 
The primary endpoint is all stroke (hemorrhagic, ischemic, or 
undetermined status; disabling or nondisabling) through 72 hours 
post TAVR procedure or discharge (whichever comes first), as 
adjudicated by an independent Clinical Events Committee (CEC) 
and using Neurologic Academic Research Consortium (NeuroARCa) 
definitions. 
a: Lansky AJ, et al. J Am Coll Cardiol. 2017;69:679–691 
Additional 
Measurements 
This section describes additional measurementsa,b to be performed in 
the PROTECTED TAVR study. Measurements will be assessed 
through 72 hours post TAVR procedure or hospital discharge 
(whichever comes first). Mortality (cardiovascular and non-
cardiovascular), neurological endpoints (stroke, transient ischemic 
attack, and delirium), acute kidney injury, and Sentinel access site 
major vascular complications will be adjudicated by an independent 
CEC.  
• All-cause mortality (cardiovascular and non-cardiovascularb) 
• Neurological endpointsa (see Note 2 below) 
o Stroke (disabling and non-disabling) 
o Transient ischemic attack (TIA) 
o Delirium 
• Safety composite of all-cause mortality and all stroke  
• Neurological and neurocognitive status as determined by the 
following assessmentsa (see Note 2 below):  
o Neurological physical examination  
o Modified Rankin Scale (mRS) score  
o National Institutes of Health Stroke Scale (NIHSS)  
o Confusion Assessment Method for Intensive Care Unit Patients 
(CAM-ICU) 
o Montreal Cognitive Assessment (MoCA) 
• Neurological complications composite of all stroke, TIA, and 
delirium  
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 7 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 8 of 76 
  
PROTECTED TAVR: Stroke PROTECTion with SEntinel During Transcatheter 
Aortic Valve Replacement 
• Acute kidney injury based on the AKIN System Stage 3 
(including renal replacement therapy) and Stage 2b 
• Sentinel access site vascular complications related to the 
procedure (major and minor)c  
• Sentinel system acute delivery and retrieval (categorized as 
successful deployment of both filters, 1 filter, or no filter and 
retrieval of the system)  
• Health status as evaluated by EQ-5D Quality of Life questionnaire 
at baseline 
Note 2: The neurological physical examination must be carried out by 
a neurology professional (board certified/board eligible neurologist, 
neurology fellow, neurology physician assistant, or neurology nurse 
practitioner). The NIHSS, mRS, and MoCA must be performed by 
certified personnel. The CAM-ICU must be performed by personnel 
with appropriate training. In all subjects where stroke is suspected, a 
formal neurology/stroke consult should be obtained, and the subject 
should be further assessed and treated per standard of care. In subjects 
diagnosed with post-procedural stroke, mRS must also be administered 
30±7 days following the stroke; the simplified mRS questionnaired 
may be used for this follow-up assessment.   
a: Lansky AJ, et al. J Am Coll Cardiol. 2017;69:679–691 
b: Mehta RL, et al. Crit Care. 2007;11:R31 
c: Kappetein AP, et al. J Am Coll Cardiol. 2012;60:1438–1454 
 
Leon M, et al. J Am Coll Cardiol. 2011;57:253–269 
d: Bruno A, et al. Stroke 2011;42:2276–2279 
Method of 
Assigning 
Subjects to 
Treatment 
Subjects to be treated with a commercially available TAVR device 
will be randomized 1:1 at the index procedure prior to procedural 
puncture/incision into a Test cohort using the commercially 
available Sentinel or a Control cohort with no cerebral protection 
system. Randomization will be stratified by center, by operative risk 
and by intended TAVR valve type. 
Follow-up 
Schedule 
All subjects will be assessed at baseline, peri- and post-procedure, 
and through 72 hours or discharge (whichever comes first). 
Study 
Duration 
Subjects will be followed through 72 hours or hospital discharge 
post TAVR procedure (whichever comes first). 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 8 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 9 of 76 
  
PROTECTED TAVR: Stroke PROTECTion with SEntinel During Transcatheter 
Aortic Valve Replacement 
The planned initial enrollment of 3000 subjects is expected to be 
completed in approximately 30 months; therefore, the study duration 
is estimated to be less than 32 months (see Note 3 below). 
Note that enrollment may be extended based on the planned interim 
analysis (see Statistical Methods below). 
Participant 
Duration 
The study duration for each subject is expected to be through 
72 hours or hospital discharge post TAVR procedure (whichever 
comes first). 
Note 3: In subjects diagnosed with a stroke, mRS must be 
administered at 30±7 days after the stroke. For these subjects, study 
duration will be through 30±7 days post stroke. 
Subject 
Inclusion 
Criteria 
All eligible subjects should be approached for participation in the 
trial. Subjects who meet all of the following criteria will be 
evaluated for enrollment in this trial, provided no exclusion criterion 
(below) is met. 
IC1.  Subject has documented aortic valve stenosis and is treated with 
an approved TAVR device via transfemoral access. 
IC2.  Subject has the recommended artery diameter at the site of filter 
placement per the Sentinel® Cerebral Protection System 
Instructions For Use: 9–15 mm for the brachiocephalic artery and 
6.5–10 mm in the left common carotid artery. 
IC3. Subject (or legal representative) provides written informed 
consent. 
Subject 
Exclusion 
Criteria 
Subjects who meet any one of the following criteria (listed as 
contraindications in the Sentinel® Cerebral Protection System IFU) 
will be excluded from this clinical trial. 
EC1.  Subject has arterial stenosis >70% in either the left common 
carotid artery or the brachiocephalic artery. 
EC2.  Subject’s brachiocephalic or left carotid artery reveals 
significant stenosis, ectasia, dissection, or aneurysm at the aortic 
ostium or within 3 cm of the aortic ostium. 
EC3. Subject has compromised blood flow to the right upper 
extremity. 
EC4. Subject has access vessels with excessive tortuosity. 
EC5.  Subject has uncorrected bleeding disorders. 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 9 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 10 of 76 
  
PROTECTED TAVR: Stroke PROTECTion with SEntinel During Transcatheter 
Aortic Valve Replacement 
EC6. Subject is contraindicated for anticoagulant and antiplatelet 
therapy. 
Note 4: Use of general anesthesia during TAVR may affect 
neurocognitive function shortly after the procedure. While not an 
exclusion criterion, it is recommended that general anesthesia not be 
used if possible.  
Adjunctive 
Pharmacologic 
Therapy 
Management of subjects in both groups, including antiplatelet and 
anticoagulant medications, is left to the discretion of the treating 
physician. 
Statistical Methods 
Analysis Sets 
Analysis sets are listed below. 
Intention-To-Treat (ITT): This population includes all subjects who 
sign an ICF and are enrolled in the trial (randomized), whether or not 
the assigned treatment is received. 
Per-Protocol: This population includes all ITT subjects who undergo 
TAVR and who are treated as assigned in the randomization process 
(excludes crossovers). 
Statistical 
Hypothesis for 
the Primary 
Endpoint  
The rate of the primary endpoint (all stroke through 72 hours post 
TAVR procedure or hospital discharge [whichever comes first] as 
adjudicated by an independent CEC) in the Sentinel (Test) cohort is 
superior to that in the Control cohort. 
Statistical Test 
Method for the 
Primary 
Endpoint 
A chi-square test will be used to test the two-sided hypothesis of 
superiority of Sentinel versus the Control: 
 
H0: PSentinel = PControl 
 
H1: PSentinel ≠ PControl  
where PSentinel and PControl correspond to the rates of the primary 
endpoint for the Sentinel group (test) and the Control group (no 
cerebral protection), respectively. 
The primary analysis set is the ITT analysis set; this endpoint will 
also be analyzed for the Per-Protocol analysis set. 
Sample Size 
Parameters for 
the Primary 
Endpoint 
Sample size parameters are listed below. 
• Expected Control rate PControl: 4% 
• Expected Sentinel (test) rate PSentinel: 2% (50% relative reduction) 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 10 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 11 of 76 
  
PROTECTED TAVR: Stroke PROTECTion with SEntinel During Transcatheter 
Aortic Valve Replacement 
• Test significance level (α): 0.05 (2-sided) 
• Power (1−β): > 0.90 (see Note 5 below) 
• Test to Control ratio: 1:1 (see Note 6 below) 
• Number of evaluable subjects: Maximum enrollment of up to 
6000 with sample size re-estimationd 
• Planned enrollment: 3000 (N=1500 per cohort) 
The statistical approach uses an adaptive group sequential design. 
There will be 1 planned formal interim analysis performed on the first 
70% of enrolled subjects (N=2100) by the Independent Safety and 
Statistical Monitor. The study will be stopped if a significant 
difference in favor of the test arm is observed after this interim 
analysis. Based on the results of the interim analysis, sample size re-
estimationd may be performed and the sample size may be increased 
up to a maximum of 6000 subjects. Details of this adaptive approach 
are pre-specified in the Independent Safety and Statistical Monitor 
charter. A final analysis will be performed on all enrolled subjects if 
the study is not stopped after the interim analysis. 
Note 5: Power calculation includes sample size re-estimationd 
Note 6: To avoid selection/treatment bias, randomization will occur 
at the index procedure (prior to procedural puncture/incision). 
d: Mehta CR and Pocock SJ. Statist Med 2011;30:3267–3284 
 
Mehta CR, et al. Circulation 2009;119:597–605 
Success 
Criteria for 
the Primary 
Endpoint 
One planned formal interim analysis for the primary endpoint will be 
conducted on the first 70% of enrolled subjects (N=2100). A final 
analysis will be conducted on all enrolled subjects if the study is not 
stopped after the interim analysis. The Lan-Demets spending 
functione with O’Brien-Fleming boundaries is used to adjust the 
alpha-level for the interim analysis and the final analysis: 0.0148 and 
0.0455, respectively. If the P value from the chi square test is less 
than alpha and the rate in the Sentinel group is less than the rate in 
the Control group, the Sentinel group will be concluded to have a 
lower rate of all stroke through 72 hours or discharge (whichever 
comes first) versus the Control group. 
e: Kim K and DeMets DL. Biometrika 1987;74:149–154 
EAST® 6.5 Software, Cytel, Inc. 2018 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 11 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 12 of 76 
  
3. Table of Contents 
1. 
TITLE PAGE  .......................................................................................................................1 
2. 
PROTOCOL SYNOPSIS .........................................................................................................5 
3. 
TABLE OF CONTENTS .......................................................................................................12 
3.1. Table of Figures .....................................................................................................15 
3.2. Table of Tables ......................................................................................................15 
4. 
INTRODUCTION ................................................................................................................16 
4.1. Background ............................................................................................................16 
4.2. Study Rationale .....................................................................................................18 
5. 
COMMERCIAL DEVICE DESCRIPTION (PART OF STANDARD OF CARE) ..........................19 
5.1. Overview of the Sentinel® Cerebral Protection System.....................................19 
5.2. Device Labeling .....................................................................................................20 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................................20 
6.1. Study Objectives ....................................................................................................20 
6.2. Study Endpoints ....................................................................................................20 
6.2.1. 
Primary Endpoint ......................................................................................20 
6.2.2. 
Additional Measurements .........................................................................20 
6.3. Overview of Objectives and Endpoints ...............................................................21 
7. 
STUDY DESIGN .................................................................................................................22 
7.1. Scale and Duration ................................................................................................22 
7.2. Treatment Assignment .........................................................................................23 
7.3. Justification for the Study Design ........................................................................23 
8. 
SUBJECT SELECTION ........................................................................................................24 
8.1. Inclusion Criteria ..................................................................................................24 
8.2. Exclusion Criteria .................................................................................................24 
9. 
SUBJECT ACCOUNTABILITY .............................................................................................25 
9.1. Point of Enrollment ...............................................................................................25 
9.2. Withdrawal ............................................................................................................25 
9.3. End-of-Study Definition .......................................................................................25 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 12 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 13 of 76 
  
10. STUDY METHODS .............................................................................................................26 
10.1. Data Collection ......................................................................................................26 
10.2. Study Subject Screening .......................................................................................29 
10.3. Subject Informed Consent ....................................................................................29 
10.4. Baseline Assessments ............................................................................................30 
10.5. Index Procedure ....................................................................................................31 
10.6. Post-Procedure (≤ 72 Hours)/Prior to Hospital Discharge ................................31 
10.7. Post-Stroke (30±7 Days) .......................................................................................32 
10.8. Study Completion ..................................................................................................32 
10.9. Source Documents .................................................................................................32 
11. STATISTICAL CONSIDERATIONS ......................................................................................33 
11.1. Endpoints ...............................................................................................................33 
11.1.1. Primary Endpoint ......................................................................................33 
11.1.1.1. Statistical Hypothesis for the Primary Endpoint ......................33 
11.1.1.2. Sample Size Parameters for the Primary Endpoint ..................33 
11.1.1.3. Success Criteria for the Primary Endpoint ...............................34 
11.1.1.4. Statistical Methods – Primary Endpoint ..................................34 
11.1.2. Post-procedure Measurements ..................................................................34 
11.2. General Statistical Methods .................................................................................34 
11.2.1. Analysis Sets .............................................................................................35 
11.2.2. Control of Systematic Error/Bias ..............................................................35 
11.2.3. Number of Subjects per Investigative Center ...........................................35 
11.2.4. Randomization Scheme ............................................................................35 
11.3. Data Analyses ........................................................................................................35 
11.3.1. Other Endpoints/Measurements ................................................................35 
11.3.2. Interim Analyses .......................................................................................36 
11.3.3. Subgroup Analyses ...................................................................................36 
11.3.4. Justification of Pooling .............................................................................36 
11.3.5. Changes to Planned Analyses ...................................................................37 
12. HEALTH ECONOMICS OUTCOMES ...................................................................................37 
13. DATA MANAGEMENT .......................................................................................................37 
13.1. Data Collection, Processing, and Review ............................................................37 
13.2. Data Retention .......................................................................................................38 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 13 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 14 of 76 
  
14. DEVIATIONS .....................................................................................................................38 
15. DEVICE ACCOUNTABILITY ..............................................................................................38 
16. COMPLIANCE ....................................................................................................................38 
16.1. Statement of Compliance ......................................................................................38 
16.2. Investigator Responsibilities ................................................................................39 
16.2.1. Delegation of Responsibility ....................................................................40 
16.3. Institutional Review Board/Independent Ethics Committee ............................41 
16.4. Sponsor Responsibilities .......................................................................................41 
16.4.1. Role of Boston Scientific Corporation Representatives ...........................41 
16.4.2. Training .....................................................................................................42 
16.5. Insurance ................................................................................................................42 
17. MONITORING ....................................................................................................................42 
18. POTENTIAL RISKS AND BENEFITS ...................................................................................43 
18.1. Instructions for Use ...............................................................................................43 
18.2. Risks Associated with Participation in the Clinical Study ................................43 
18.3. Possible Interactions with Concomitant Medical Treatments ..........................43 
18.4. Risk Minimization Actions ...................................................................................43 
18.5. Anticipated Benefits ..............................................................................................43 
19. SAFETY REPORTING .........................................................................................................44 
19.1. Reportable Events by Investigational Center to Boston Scientific ...................44 
19.2. Definitions and Classification ..............................................................................45 
19.3. Relationship to Device(s) ......................................................................................46 
19.4. Investigator Reporting Requirements .................................................................47 
19.5. Boston Scientific Device Deficiencies ...................................................................49 
19.6. Reporting to Regulatory Authorities / IRBs and IECs / Investigators ............49 
20. INFORMED CONSENT ........................................................................................................49 
21. COMMITTEES ...................................................................................................................51 
21.1. Safety Monitoring Process ....................................................................................51 
21.1.1. Clinical Events Committee .......................................................................51 
21.2. Steering Committee ...............................................................................................51 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 14 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 15 of 76 
  
21.3. Independent Safety and Statistical Monitor .......................................................52 
22. SUSPENSION OR TERMINATION ........................................................................................52 
22.1. Premature Termination of the Study ..................................................................52 
22.1.1. Criteria for Premature Termination of the Study ......................................52 
22.2. Termination of Study Participation by the Investigator or Withdrawal of 
IRB/IEC/HREC Approval ...................................................................................52 
22.3. Requirements for Documentation and Subject Follow-up ................................53 
22.4. Criteria for Suspending/Terminating a Study Center .......................................53 
23. PUBLICATION POLICY ......................................................................................................53 
24. BIBLIOGRAPHY .................................................................................................................54 
25. ABBREVIATIONS AND DEFINITIONS .................................................................................58 
25.1. Abbreviations and Acronyms ..............................................................................58 
25.2. Definitions ..............................................................................................................59 
3.1. 
Table of Figures 
Figure 5.1-1: Diagram of the Sentinel System........................................................................ 19 
Figure 5.1-2: Positioning of the Sentinel Device .................................................................... 19 
Figure 7.1-1: PROTECTED TAVR Study Design Summary ................................................ 23 
Figure 10.1-1: PROTECTED TAVR Study Event Schedule ................................................. 27 
3.2. 
Table of Tables 
Table 6.3-1: Overview of Objectives and Endpoints .............................................................. 21 
Table 8.1-1: PROTECTED TAVR Inclusion Criteria ............................................................ 24 
Table 8.2-1: PROTECTED TAVR Exclusion Criteria ........................................................... 24 
Table 10.1-1: PROTECTED TAVR Study Event Schedule ................................................... 28 
Table 10.9-1: Source Documentation Requirements .............................................................. 32 
Table 19.2-1: Safety Definitions ............................................................................................. 45 
Table 19.3-1: Criteria for Assessing Relationship of Study Device or Procedure to Adverse 
Event ............................................................................................................... 46 
Table 19.4-1: Investigator Reporting Requirements ............................................................... 48 
Table 25.1-1: Abbreviations and Acronyms ........................................................................... 58 
Table 25.2-1: Definitions ........................................................................................................ 59 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 15 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 16 of 76 
  
4. Introduction 
This protocol specifies procedures and contains information relevant to the postmarket 
multicenter PROTECTED TAVR randomized controlled trial (PROTECTED TAVR: Stroke 
PROTECTion with SEntinel During Transcatheter Aortic Valve Replacement). The study 
device is the Sentinel® Cerebral Protection System (Sentinel) designed and manufactured by 
Boston Scientific Corporation, Marlborough, MA, USA (BSC). It is a percutaneously 
delivered filter device designed to capture any debris or thrombus that may embolize to the 
innominate and left common carotid arteries during a transcatheter aortic valve replacement 
(TAVR) procedure. The objective of the study is to demonstrate that use of Sentinel 
significantly reduces the risk of post-TAVR peri-procedural (≤72 hours) stroke. 
4.1. 
Background 
Stroke is a feared occurrence that can complicate both surgical and catheter-based therapies 
for aortic stenosis1,2. With first generation TAVR devices, the reported incidence of major 
stroke within 30 days ranged from 3% to 7%3. Increased short-term and long-term mortality 
have been associated with post-TAVR stroke4,5. Growing operator experience and improved 
device designs have lowered but not eliminated the TAVR stroke risk6. 
Cerebral embolic protection devices (CEPD) are intended to prevent cerebral embolization 
and have demonstrated efficacy in carotid and saphenous vein graft stenting with clinically 
significant reductions in mortality, stroke, and myocardial infarction7-9. Use of CEPD is an 
emerging strategy to mitigate post-TAVR neurologic risk10 and 5 randomized controlled 
trials (RCT) have directly investigated the safety and efficacy of CEPD in TAVR (protection 
devices include the Sentinel® Cerebral Protection System [Sentinel], Claret Montage™ Dual 
Filter System [an earlier iteration of Sentinel], TriGuard™ HDH Embolic Deflection Device, 
and EMBOL-X™ Intra-aortic Filter)11-15. Four of these RCTs assessed 100 or fewer subjects. 
In the multicenter DEFLECT III RCT (TriGuard; N=85), the primary safety endpoint (death, 
stroke, life-threatening or disabling bleeding, stage 2 or 3 acute kidney injury, or major 
vascular complications) was numerically lower in the protected cohort (21.7% versus 30.8%, 
P=0.34)14. Subjects with complete three-vessel cerebral coverage had fewer new neurologic 
deficits detected by the National Institutes of Health Stroke Scale (NIHSS; 3.1% vs. 15.4%) 
and a >2-fold increase in recovery of normal cognitive function (Montreal Cognitive 
Assessment [MoCA] score >26) at 30 days. In a single-center RCT (N=30), use of EMBOL-
X appeared to reduce both the incidence and volume of new cerebral lesions15. In another 
single-center RCT (CLEAN-TAVI; N=100), use of Claret Montage was associated with a 
significant reduction (P < 0.001) in the number of new lesions13. In the multicenter 
MISTRAL-C RCT (N=65), use of Sentinel resulted in fewer new lesions and a smaller total 
lesion volume as well as less neurocognitive deterioration (4% vs. 27%, P=0.017)12.  
The pivotal multicenter SENTINEL RCT was larger (N=363) than the aforementioned RCTs 
and showed that Sentinel use during TAVR was safe with no increased procedural 
complications11. Subjects were prospectively randomized 1:1:1 into a safety arm (N=123, 
Sentinel only) and 2 imaging cohorts (device arm [N=121] and control arm without Sentinel 
[N=119]). The primary safety endpoint was 30-day major adverse cardiac and 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 16 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 17 of 76 
  
cerebrovascular events (MACCE; defined as all death, all stroke, and stage 3 acute kidney 
injury [AKI] per Valve Academic Research Consortium [VARC-2] definitions16). Stroke 
occurrence was assessed by NIHSS and modified Rankin scale (mRS) score as administered 
by a neurologist. In the combined safety and device arms, the MACCE rate of 7.3% was non-
inferior (P < 0.001) to the prespecified performance goal of 18.3% and similar to the control 
rate (9.9%; P=0.41). As Sentinel is a temporary accessory device, a post hoc analysis was 
performed to assess stroke at the time most applicable to device usage. The stroke rate at 
≤72 hours was 3.0% in the combined safety and device arms compared to 8.2% in the control 
arm, demonstrating a relative reduction of 63% in stroke rates in favor of Sentinel. At 
30 days, event rates for subjects with Sentinel were similar to rates in the control arm for 
mortality (1.3% vs. 1.8%, respectively, P=0.25), stroke (5.6% vs. 9.1%, P=0.25), stage 3 
AKI (0.4% vs. 0.0%, P=1.00), and major vascular complications (8.6% vs. 5.9%, P=0.53).  
The primary efficacy endpoint in the SENTINEL RCT was reduction in median total new 
lesion volume in protected territories in the device versus the control arm. This was assessed 
by diffusion-weighted magnetic resonance imaging (MRI) at 2 to 7 days after TAVR. This 
quantitative MRI analysis was intended to serve as a surrogate endpoint for the clinically 
meaningful endpoint of stroke. While the median total new lesion volume in protected 
territories was 42% lower in subjects with Sentinel, the new MRI lesion volume (102.8 mm3) 
was not significantly different from that of the control group (178.0 mm3, P=0.33). Notably, 
randomization was not stratified by valve category and MRI results in the control arm as well 
as the response to embolic protection appeared to differ with varying TAVR systems. Post-
hoc multivariable analyses of MRI data also indicated that the T2/fluid-attenuated inversion 
recovery (FLAIR) lesion volume at baseline, a marker of previous injury and gliosis, was the 
strongest predictor of new lesion volume after TAVR. After adjusting for valve type, 
baseline T2/FLAIR lesion volume, and an interaction between valve type and treatment arm, 
there were significant reductions in new lesion volume in the device versus control arms 
(protected territories: P=0.025, all territories: P=0.050)11. Debris was found within the study 
device filters in 99% of subjects in the SENTINEL RCT. The debris components included 
acute thrombus with tissue elements, artery wall, valve tissue, calcification, and foreign 
materials.  
Published reports have also described use of CEPD with TAVR in real-world experiences. In 
the single-center SENTINEL-Ulm registry, the Sentinel device was used in 280 of 802 
(34.9%) consecutive patients. In a propensity-matched population (N=280 with Sentinel, 
N=280 unprotected), use of Sentinel was associated with a 70% reduction in the odds of 
death or stroke within 7 days of TAVR (odds ratio [OR] 0.30, 95% confidence interval [CI] 
0.12–0.77; 2.1% vs. 6.8%, P=0.01)17. The overall stroke rate was reduced from 4.6% to 1.4% 
with Sentinel (P=0.03, OR 0.29, 95% CI 0.10–0.93) and there was a significant reduction in 
disabling stroke (3.2% vs. 0.4%, P=0.01). Stroke within 48 hours of TAVR was also 
significantly lower with Sentinel (1.1%) compared with unprotected procedures (3.6%, 
P=0.03). By multivariate analysis, TAVR without protection was an independent risk factor 
for stroke within 7 days (P=0.04)17. In a 2-center registry in the Netherlands (333 propensity-
matched pairs), patients with Sentinel experienced fewer neurological events (stroke and 
transient ischemia attack [TIA]) compared to those without protection at 24 hours post 
TAVR (0.9% vs. 3.6%; P=0.035) and at 30 days (2.7% vs. 6.6%; P=0.029)18. There were 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 17 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 18 of 76 
  
significantly fewer disabling strokes in protected patients at 30 days (0.9% vs. 4.2%; 
P=0.039). By multiple regression analysis, use of Sentinel was associated with fewer 
neurological events at 24 hours after TAVR (P=0.015, OR 0.20, 95% CI 0.06–0.73). Patients 
who experienced a clinically significant neurological event underwent computed 
tomographic (CT) analysis of the brain. At 24 hours post TAVR, patients in the Sentinel 
cohort had fewer neurological events (2 of 3 [67%]) in the protected areas of the brain (those 
not dependent on the left vertebral artery) compared to patients without Sentinel (10 of 12 
[83%]). After 24 hours the localization of new neurological events was similar between the 2 
cohorts18.  
The randomized trials mentioned above were not powered to demonstrate a reduction in 
stroke rates. A recent study-level meta-analysis with these RCTs found that use of CEPD was 
associated with a nonsignificant trend towards lower risk for death or stroke on both relative 
(6.1% vs. 9.6%; relative risk: 0.61; 95% confidence interval [CI]: 0.35 to 1.07; P=0.08; 
I2=0%) and absolute (absolute risk difference: –3.5%; 95% CI: –7.9% to 0.9%; number 
needed to treat: 28) terms19. Outcomes were recently reported from a patient level pooled 
analysis of subjects from the SENTINEL and CLEAN-TAVI RCTs, and the SENTINEL-
Ulm registry20. Propensity score matching was performed to adjust for possible confounders 
(N=553 per cohort). In patients undergoing TAVR with Sentinel, the stroke rate within 72 
hours was significantly reduced compared with unprotected procedures (1.88% vs. 5.44%, 
OR 0.35, 95% CI 0.17–0.72, relative risk reduction 65%, absolute risk reduction 3.54%; 
P=0.0028). The authors noted that their findings suggest that TAVR with Sentinel is 
associated with a significantly lower rate of periprocedural stroke compared to unprotected 
TAVR. They remarked, however, that due to differences in methodology between the 
studies, results should be considered hypothesis generating and to prove the hypothesis, a 
large RCT on use of CEPD in TAVR is required. 
Based on observations in the SENTINEL trial, the United States Food and Drug 
Administration (FDA) in June 2017 approved the Sentinel® Cerebral Protection System for 
use in TAVR as a cerebral protection device to capture and remove embolic material while 
performing transcatheter aortic valve procedures in order to reduce ischemic injury to the 
brain peri-procedurally. However, while results from the SENTINEL trial provided 
reassuring evidence of the safety of dual-filter neuroprotection therapy and confirmed the 
high frequency of embolic debris capture, the effectiveness of the Sentinel CEPD at reducing 
stroke risk after TAVR remains uncertain. 
4.2. 
Study Rationale 
As noted above, although Sentinel was approved by FDA for capturing debris during TAVR, 
the pivotal RCT missed its primary endpoint. In the same trial, post hoc analysis showed 
clinical benefit with reduction in procedural stroke. However, prospective data to prove 
clinical benefit are lacking. The objective of the PROTECTED TAVR study is to 
demonstrate that use of Sentinel significantly reduces the risk of peri-procedural stroke 
(≤72 hours) after TAVR. 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 18 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 19 of 76 
  
5. Commercial Device Description (part of Standard of Care) 
The Sentinel® Cerebral Protection System is indicated for use as a cerebral protection device 
to capture and remove embolic material while performing transcatheter aortic valve 
procedures in order to reduce ischemic injury to the brain peri-procedurally. 
5.1. 
Overview of the Sentinel® Cerebral Protection System 
The commercially available Sentinel Cerebral Protection System (Sentinel; Boston Scientific 
Corporation, Marlborough, MA, USA) is designed to capture and remove debris dislodged 
during endovascular procedures. It consists of 2 filters within a single 6-F delivery catheter 
percutaneously placed from the right radial or brachial artery over a 0.014-inch guidewire.  
The major features of the system are shown in Figure 5.1-1. The articulating sheath tip, 
proximal sheath tip, proximal filter hoop, proximal articulating sheath marker, distal filter 
hoop and distal filter tip are radiopaque to enable visualization during use. The filters are 
positioned in the brachiocephalic artery (proximal filter) and the left common carotid artery 
(distal filter) before the TAVR procedure (Figure 5.1-2) and are withdrawn into the catheter 
and removed after TAVR. Additional product information can be found in the commercial 
Instructions For Use (IFU). 
 
Figure 5.1-1: Diagram of the Sentinel System 
The pore size of the filters is 140 µm. 
 
Figure 5.1-2: Positioning of the Sentinel Device 
The proximal filter is placed in the brachiocephalic artery and the distal filter is placed in the left carotid artery. 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 19 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 20 of 76 
  
5.2. 
Device Labeling 
A basic description of the device and a comprehensive set of instructions (IFU) are contained 
in each product package. 
6. Study Objectives and Endpoints 
6.1. 
Study Objectives 
The objective of the PROTECTED TAVR study is to demonstrate that use of the Sentinel® 
Cerebral Protection System significantly reduces the risk of peri-procedural stroke 
(≤72 hours) after transcatheter aortic valve replacement (TAVR). 
6.2. 
Study Endpoints 
Outcomes will be assessed on an intention-to-treat (ITT) basis and on a per-protocol basis. 
The ITT analysis set includes all subjects who sign an Informed Consent Form (ICF; see 
Section 20) approved by the Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC)/Human Research Ethics Committee (HREC) and are enrolled upon 
randomization (see Section 9.1 for point of enrollment), whether or not the assigned 
treatment is received. The Per-Protocol analysis set includes all ITT subjects who receive the 
assigned treatment (excludes crossovers). 
6.2.1. 
Primary Endpoint 
The primary endpoint is all stroke (hemorrhagic, ischemic, or undetermined status) through 
72 hours post TAVR procedure or discharge (whichever comes first) as adjudicated by an 
independent Clinical Events Committee (CEC) and using Neurologic Academic Research 
Consortium (NeuroARC)21 definitions. 
The primary analysis set for the primary endpoint is the ITT analysis set.  
6.2.2. 
Additional Measurements 
The additional measurements shown below are based on NeuroARC21 and Valve 
Academic Research Consortium (VARC)16,22 endpoints and definitions and will be 
assessed through 72 hours post TAVR procedure or discharge (whichever comes first). 
Mortality (cardiovascular and non-cardiovascular), neurological endpoints (stroke, 
transient ischemic attack [TIA], and delirium), acute kidney injury, and Sentinel access site 
major vascular complications will be adjudicated by an independent CEC. 
• All-cause death (cardiovascular and non-cardiovascular) 
• Neurological endpoints (see Note 1 below) 
o Stroke (disabling and non-disabling) 
o Transient ischemic attack 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 20 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 21 of 76 
  
o Delirium 
• Safety composite of all-cause mortality and all stroke  
• Neurological status as determined by the following (see Note 1 below): 
o Neurological physical examination 
o Modified Rankin Scale (mRS) score  
o National Institutes of Health Stroke Scale (NIHSS)  
o Confusion Assessment Method for Intensive Care Unit Patients (CAM-ICU)23,24 
o Montreal Cognitive Assessment (MoCA)25 
• Acute kidney injury based on the AKIN System26 Stage 3 (including renal replacement 
therapy) and Stage 2 
• Sentinel access site vascular complications related to the procedure (major and minor)  
• Sentinel system acute delivery and retrieval (categorized as successful deployment of 
both filters, 1 filter, or no filter and retrieval of the system)  
• Health status as evaluated by EQ-5D27,28 Quality of Life questionnaire at baseline 
Note 1: The neurological physical examination must be carried out by a neurology 
professional (board certified/board eligible neurologist, neurology fellow, neurology 
physician assistant, or neurology nurse practitioner). The NIHSS, mRS, and MoCA must 
be performed by certified personnel. The CAM-ICU must be done by personnel with 
appropriate training as documented by the sponsor. In all subjects where stroke is 
suspected, a formal neurology/stroke consult should be obtained, and the subject should 
be further assessed and treated per standard of care. In subjects diagnosed with post-
procedural stroke, mRS must also be administered 30±7 days following the stroke; the 
simplified mRS questionnaire29 may be used for this follow-up assessment. 
6.3. 
Overview of Objectives and Endpoints 
Table 6.3-1 provides an overview of the aforementioned study objectives and endpoints and 
a rationale for the specific endpoints. 
Table 6.3-1: Overview of Objectives and Endpoints 
Objective 
Endpoint 
Rationale for Endpoint 
Primary Endpoint  
Evaluate effectiveness of the 
cerebral protection device during 
TAVR procedures 
All stroke to 72 hours post-
TAVR procedure 
Demonstrate significant reduction of 
peri-procedural stroke (≤72 hours) 
after TAVR, which is a critical acute 
safety event observed in the 
population undergoing TAVR. 
Additional Measurements of Safety and Effectiveness 
Evaluate safety of the cerebral 
protection device 
Safety measures peri- and 
post- TAVR procedure and at 
discharge 
Confirm safety based on assessments 
recommended by VARC16,22 and 
NeuroARC21 for this elderly 
population.  
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 21 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 22 of 76 
  
Table 6.3-1: Overview of Objectives and Endpoints 
Objective 
Endpoint 
Rationale for Endpoint 
Evaluate effectiveness of the 
cerebral protection device  
Device performance and other 
effectiveness measures peri- 
and post TAVR procedure and 
at discharge 
Effectiveness assessments 
recommended by VARC16,22 and 
NeuroARC21 for this elderly 
population.  
Abbreviation: NeuroARC=Neurologic Academic Research Consortium; TAVR=transcatheter aortic valve 
replacement; VARC=Valve Academic Research Consortium 
 
7. Study Design 
PROTECTED TAVR is a prospective, post-market, multicenter randomized controlled trial 
(RCT) evaluating use of the Sentinel® Cerebral Protection System in subjects with aortic 
valve stenosis who are treated with an approved TAVR device.  
7.1. 
Scale and Duration 
An initial enrollment of up to 3000 randomized subjects in up to 100 study centers is 
planned (see Note 1 below). A single center may enroll up to 15% of the total enrollment; 
approval from the Sponsor is required for additional enrollment. Subjects to be treated via 
a transfemoral approach with a commercially available TAVR device will be randomized 
1:1 into a Test cohort using the commercially available Sentinel or a Control cohort with 
no cerebral protection system. A subject who provides an ICF signed by the subject or the 
subject’s legally authorized representative is considered enrolled in the study upon 
randomization, which will occur at the index procedure prior to procedural 
puncture/incision. The study duration for each subject is expected to be through 72 hours 
or hospital discharge, whichever comes first. In subjects diagnosed with a stroke, mRS 
must be administered at 30±7 days after the stroke. For these subjects, study duration will 
be through 30±7 days post stroke. 
Note 1: If sample size re-estimation is needed (see Section 11.1.1.2), the planned 
maximum enrollment will be up to 6000 randomized subjects. 
Figure 7.1-1 summarizes the study design. The treating physician must be a trained, 
experienced Sentinel user. Every subject must be deemed treatable with the Sentinel device 
(have suitable anatomy per the Sentinel Instructions For Use [IFU]). All eligible subjects (see 
Section 8) should be approached for participation in the trial. 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 22 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 23 of 76 
  
 
Figure 7.1-1: PROTECTED TAVR Study Design Summary 
 
The planned initial enrollment of 3000 subjects is expected to be completed in approximately 
30 months; therefore, the study duration is estimated to be less than 32 months (see Note 1 in 
Section 6.2.2 regarding subjects diagnosed with a stroke). Enrollment may be extended based 
on the planned interim analysis (see Section 11.1.1.2).  
The PROTECTED TAVR study will be registered at ClinicalTrials.gov prior to enrollment 
of the first subject. 
7.2. 
Treatment Assignment 
Subjects who are to be treated with a commercially available TAVR device and who have 
suitable anatomy for the Sentinel device will be randomized 1:1 into a Test cohort using the 
commercially available Sentinel or a Control cohort with no cerebral protection system. 
Randomization will occur at the index procedure (prior to procedural puncture/incision) to 
avoid selection/treatment bias. The randomization schedules will be computer-generated, 
using a pseudo-random number generator. Randomization will be stratified by center, by 
operative risk, and by intended TAVR valve type (Section 11.2.4). All randomized subjects 
will have unique identification numbers. Random permuted blocks will be employed to 
ensure approximate balance of treatment allocation within each stratum. Instructions on 
randomization are provided in the Manual of Operations. See Section 5 for a detailed 
description of the Sentinel device. 
7.3. 
Justification for the Study Design 
In order to support the stated objectives of this study (see Section 6.1) while also limiting the 
potential exposure of study subjects to risk, an initial enrollment of up to 3000 randomized 
subjects at up to 100 centers in North America, Europe, and Australia is planned. Treating 
physicians will be appropriately trained and have relevant clinical experience with the 
Sentinel device before enrolling trial subjects. Safety and effectiveness results will be 
reported on all enrolled subjects (see Section 19 for information on safety reporting). One 
planned formal interim analysis for the primary endpoint will be conducted on the first 70% 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 23 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 24 of 76 
  
of enrolled subjects (N=2100). The study will be stopped early if a significant difference in 
favor of the test arm is observed after this interim analysis. 
Management of subjects in both groups, including antiplatelet and anticoagulant medications, 
will be left to the discretion of the treating physician in this post-market study. 
8. Subject Selection  
Subjects will be evaluated for eligibility for commercial TAVR by the center heart team per 
the local standard of practice. All eligible subjects should be approached for participation in 
PROTECTED TAVR. Subjects who meet all of the inclusion criteria (see Section 8.1) will 
be evaluated for enrollment in this trial, provided no exclusion criterion (see Section 8.2) is 
met. All subjects will have unique identification numbers. 
8.1. Inclusion Criteria 
Subjects who meet all of the following criteria (Table 8.1-1) may be given consideration for 
inclusion in this clinical investigation, provided no exclusion criterion (see Table 8.2-1) is 
met. 
Table 8.1-1: PROTECTED TAVR Inclusion Criteria 
IC1.  Subject has documented aortic valve stenosis and is treated with an approved transcatheter aortic valve 
replacement device via transfemoral access. 
IC2.  Subject has the recommended artery diameter at the site of filter placement per the Sentinel® Cerebral 
Protection System Instructions For Use: 9–15 mm for the brachiocephalic artery and 6.5–10 mm in the 
left common carotid artery as determined by computed tomography or per local standard of care. 
IC3.  Subject (or legal representative) provides written informed consent. 
 
8.2. Exclusion Criteria 
Subjects who meet any one of the criteria in Table 8.2-1 (listed as contraindications in the 
Sentinel® Cerebral Protection System IFU) will be excluded from this clinical study. 
Table 8.2-1: PROTECTED TAVR Exclusion Criteria 
EC1.  Subject has arterial stenosis >70% in either the left common carotid artery or the brachiocephalic 
artery. 
EC2.  Subject’s brachiocephalic or left carotid artery reveals significant stenosis, ectasia, dissection, or 
aneurysm at the aortic ostium or within 3 cm of the aortic ostium. 
EC3. Subject has compromised blood flow to the right upper extremity. 
EC4. Subject has access vessels with excessive tortuosity. 
EC5.  Subject has uncorrected bleeding disorders. 
EC6. Subject is contraindicated for anticoagulant and antiplatelet therapy. 
Note:  Use of general anesthesia during TAVR may affect neurocognitive function shortly after the 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 24 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 25 of 76 
  
Table 8.2-1: PROTECTED TAVR Exclusion Criteria 
procedure. While not an exclusion criterion, it is recommended that general anesthesia not be used if 
possible. 
9. Subject Accountability 
9.1. 
Point of Enrollment 
A subject who provides an ICF signed by the subject or the subject’s legally authorized 
representative is considered enrolled in the study upon randomization, which will occur at the 
index procedure prior to procedural puncture/incision.  
9.2. 
Withdrawal 
All subjects enrolled in the clinical study (including those withdrawn from the clinical study) 
shall be accounted for and documented. If a subject withdraws from the clinical investigation 
the reason(s) shall be reported. Reasons for withdrawal include but are not limited to 
physician discretion, subject choice to withdraw consent, or death. If such withdrawal is due 
to problems related to device safety or performance, the investigator shall ask for the 
subject’s permission to follow his/her status/condition outside of the clinical study.   
While all efforts will be made to minimize attrition, subjects may withdraw from the study at 
any time, with or without reason, and without prejudice to further treatment. Withdrawn 
subjects will not undergo any additional study follow-up, nor will they be replaced. The 
investigator may discontinue a subject from participation in the study if the investigator feels 
that the subject can no longer fully comply with the requirements of the study or if any of the 
study procedures are deemed potentially harmful to the subject. Data that have already been 
collected on withdrawn subjects will be retained and may be used for analysis, unless local 
regulations apply. No new data will be collected after subject withdrawal.   
All applicable case report forms up to the point of subject withdrawal and an “End of Study” 
form for the subject must be completed. If the withdrawal is due to investigator discretion, 
the investigator should follow-up with the subject per standard of care.  
9.3. 
End-of-Study Definition  
This clinical study will be considered completed when the last subject has concluded 
assessments as outlined in the data collection schedule in Table 10.1-1 (see Note 1 below). 
Note 1: In subjects diagnosed with a stroke, mRS must be administered at 30±7 days after 
the stroke; mortality plus device related adverse events (including adverse device effects 
[ADE], serious adverse device effects [SADE], unanticipated adverse device effects 
[UADE], and unanticipated serious adverse device effects [USADE]; see Section 19) through 
30±7 days post stroke must be reported to BSC. For these subjects, study duration will be 
through 30±7 days post stroke. 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 25 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 26 of 76 
  
10. Study Methods 
10.1. Data Collection 
This section indicates the data needed to fulfill the objectives of this clinical study. Boston 
Scientific Corporation considers data collected from clinical trial subjects to be personal data 
(see definitions of different data categories in Table 25.2-1) and compliance with privacy 
and data protection laws and regulations (for example, the General Data Protection 
Regulation [GDPR], see Table 25.2-1) to be critically important. Data collection for this 
clinical study has been carefully considered to comply with data privacy laws. 
The data collection schedule is shown in Figure 10.1-1 and in Table 10.1-1. Additional 
information is provided in Section 10.2 through Section 10.9. The methods are based on 
NeuroARC metrics21, VARC metrics16,22, and/or guideline recommendations30-32. 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 26 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 27 of 76 
  
 
Figure 10.1-1: PROTECTED TAVR Study Event Schedule 
See Table 10.1-1 for additional information. 
Abbreviations: ADE=adverse device effect; CAM-ICU=Confusion Assessment Method for Intensive Care Unit 
Patients; CEC=Clinical Events Committee; CPS=cerebral protection system; CT=computed tomography; 
MoCA=Montreal Cognitive Assessment; NIHSS=National Institutes of Health Stroke Scale; SADE=serious 
adverse device effect; SAE=serious adverse event; UADE=unanticipated adverse device effect; 
USADE=unanticipated serious adverse device effect; TAVR=transcatheter aortic valve replacement 
 
 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 27 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 28 of 76 
  
Table 10.1-1: PROTECTED TAVR Study Event Schedule 
Assessment 
Baselinea 
Index 
Procedure 
≤72 Hours / 
Discharge 
30±7 Days 
Post Strokeb 
Signed Informed Consent Form 
X 
− 
− 
− 
Clinical Assessments 
 Demographics and medical history 
X 
− 
− 
− 
 Physical assessment 
X 
− 
− 
− 
 Risk assessmentc 
X 
− 
− 
− 
Imaging Assessments 
 Anatomic suitability for the Sentinel deviced 
X 
− 
− 
− 
Neurological Assessmentse 
 Neurological physical examinationf 
X 
− 
X 
− 
 Modified Rankin Scale scoreg 
X 
− 
X 
Xb 
 NIHSSg 
X 
− 
X 
− 
 CAM-ICUh  
X 
− 
X 
− 
 MoCAi 
X 
− 
X 
− 
Quality of Life Surveyj 
X 
 
 
 
Adverse event assessment 
– 
Xk 
Xk 
Xb 
Note 1: X = should be performed, – = not required.  
a: Within 30 days prior to index procedure (unless otherwise specified). 
b: In all subjects where stroke is suspected, a formal neurology/stroke consult should be obtained, and the 
subject should be further assessed and treated per standard of care. In subjects diagnosed with post-
procedural stroke, mRS must also be administered at 30±7 days after the stroke; the simplified mRS 
questionnaire29 may be used for this follow-up evaluation. In these subjects, mortality and an assessment 
of device related adverse events (ADE, SADE, UADE, and USADE; see Table 25.2-1 for definitions) 
must be reported to BSC from the time of enrollment through 30±7 days post stroke. 
c: Data from the STS33 risk score assessment must be collected (see definition of surgical risk in Table 
25.2-1); euroSCORE II34 risk score data may be collected if performed per local standard of care; height 
and weight must be collected (to determine body mass index). 
d: Anatomic assessment must be carried out using CT or per local standard of care to determine if subject 
has the recommended artery diameter at the site of filter placement per the study Inclusion Criteria (Table 
8.1-1). 
e: Follow-up neurological assessments must be performed within 72 hours post index procedure but may be 
performed earlier if deemed necessary. These post-procedure assessments should be performed only when 
the subject is no longer drowsy from procedural medication. 
f: Assessment must be carried out by a neurology professional (board certified/board eligible neurologist, 
neurology fellow, neurology physician assistant, or neurology nurse practitioner). 
g:  Assessment must be carried out by certified personnel.  
h: The Confusion Assessment Method for ICU Patients (CAM-ICU)23,24 should be done at baseline and on 
day 1 post procedure; it must be performed by personnel with appropriate training as documented by the 
sponsor. 
i: The Montreal Cognitive Assessment25 (MoCA) must be carried out by certified personnel. 
j: EQ-5D questionnaire is conducted at baseline27,28 
k: The adverse event assessment includes SAE, ADE, SADE, UADE, USADE, device deficiencies, and 
CEC events; safety events will be monitored and reported to BSC from the time of enrollment through 
72 hours or subject discharge (whichever comes first). Please refer to Section 19.1 for reportable events, 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 28 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 29 of 76 
  
Table 10.1-1: PROTECTED TAVR Study Event Schedule 
Assessment 
Baselinea 
Index 
Procedure 
≤72 Hours / 
Discharge 
30±7 Days 
Post Strokeb 
including a list of CEC events, and to Table 25.2-1 for definitions of these events, which specify data 
required for CEC adjudication. 
Abbreviations: ADE=adverse device effect; BSC=Boston Scientific Corporation; CAM-ICU=Confusion 
Assessment Method for Intensive Care Unit Patients; CEC=Clinical Events Committee; CT=computed 
tomography; MoCA=Montreal Cognitive Assessment; mRS=modified Rankin Scale; NIHSS=National 
Institutes of Health Stroke Scale; SADE=serious adverse device effect; SAE=serious adverse event; 
STS=Society of Thoracic Surgeons; UADE=unanticipated adverse device effect; USADE=unanticipated 
serious adverse device effect 
 
10.2. Study Subject Screening 
Subjects will be evaluated for eligibility for commercial TAVR by the center heart team per 
the local standard of practice. Subjects with documented aortic valve stenosis who are to be 
treated with a commercially available TAVR device and who sign the IRB/IEC/HREC-
approved ICF will be assessed for enrollment in the clinical study. Inclusion and exclusion 
criteria are provided in Section 8. Every subject must be deemed treatable with the Sentinel 
study device. 
Once written informed consent has been obtained, a subject will be entered into a screening 
log, which will be maintained at the center. A subject who provides written informed consent 
will be entered into the screening log whether or not the subject is randomized into the study. 
For consented subjects not enrolled in the trial, the reason for screen failure will be 
documented in the screening log.  
It is estimated that nearly 5% of elderly ≥75 years of age have aortic stenosis and its 
prevalence is expected to increase due to an aging population35,36. Because aortic stenosis 
most commonly occurs in the very elderly, women are well represented in TAVR studies. As 
the very elderly will represent the majority of enrolled subjects, traditionally 
underrepresented populations are expected to be included in the subject population as 
allowed by governing law/national regulation. 
10.3. Subject Informed Consent 
Written informed consent (see Section 20) must be obtained for all qualified subjects who are 
potential study candidates prior to the subject’s index procedure.  
The Investigator/designee who has been trained on the protocol will explain the nature and 
scope of the study, potential risks and benefits of participation, and answer questions for the 
subject. If the subject agrees to participate, the IRB/IEC/HREC-approved ICF must be signed 
and personally dated by the subject or his/her legally authorized representative. The 
Investigator/designee must also sign the ICF prior to subject enrollment. Any additional 
persons required by the center’s IRB/IEC/HREC to sign the ICF must also comply. 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 29 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 30 of 76 
  
10.4. Baseline Assessments 
The following assessments must be completed within 30 days prior to the index procedure 
per local standard of care for TAVR unless otherwise indicated. The study electronic case 
report forms (eCRFs) identify the specific data points to be collected. 
• Confirmation of eligibility and contraindications per the Sentinel® Cerebral Protection 
System IFU (see Note 1 below) 
• Clinical assessments  
o Demographics including age and gender 
o Medical history   
o Physical assessment 
o Risk assessments  
 Society of Thoracic Surgeons (STS) risk score33 
 EuroSCORE II34 (if performed per local standard of care) 
 Nutritional assessment (height and weight) 
• Imaging assessments 
o Anatomic suitability for the Sentinel device (computed tomography [CT] assessment 
as performed per local standard of care) 
• Neurological assessments  
o Neurological physical exam (see Note 2 below) 
o mRS score (see Note 2 below) 
o NIHSS score (see Note 2 below) 
o CAM-ICU (see Note 3 below) 
o MoCA (see Note 4 below) 
• Quality of Life Survey (EQ-5D27,28) should be administered within 30 days prior to the 
procedure 
Note 1: Every subject must be deemed treatable with the Sentinel device (have suitable 
anatomy per the IFU). 
Note 2: The neurological physical exam must be performed by a neurology professional 
(board certified/board eligible neurologist, neurology physician assistant, or neurology 
nurse practitioner). The NIHSS and mRS must be performed by certified personnel 
(external certification for NIHSS; internal or external certification for mRS).  
Note 3: The delirium assessment consists of the Confusion Assessment Method for ICU 
Patients (CAM-ICU)23,24 and must be performed by personnel with appropriate training as 
documented by the sponsor. 
Note 4: The cognitive assessment consists of the Montreal Cognitive Assessment25(MoCA) 
and must be carried out by certified personnel (external certification). 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 30 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 31 of 76 
  
10.5. Index Procedure 
The preparation of the subject for the percutaneous procedure will be performed following 
standard techniques. Refer to the Sentinel IFU for instructions on preparation and use of the 
cerebral protection system test device. Refer to the specific valve Directions/Instructions For 
Use for instructions on preparation and placement of the commercial TAVR valve. Subject 
randomization will occur prior to procedural puncture/incision; see Section 11.2.4 for 
information on stratification. Study device deficiencies and safety events during the 
procedure (includes SAE, SADE, UADE, USADE, ADE, and CEC events; see Section 19) 
along with the associated treatment must be reported to BSC. The end of the index procedure 
is defined as vessel closure and hemostatic control. 
Note 1: Use of general anesthesia during TAVR may affect neurocognitive function shortly 
after the procedure. While not an exclusion criterion, it is recommended that general 
anesthesia not be used if possible. 
10.6. Post-Procedure (≤ 72 Hours)/Prior to Hospital Discharge 
Within 72 hours post TAVR procedure or before discharge (whichever comes first), the 
following neurological assessments must be performed (see Note 1 below).  
• Neurological physical exam (see Note 2 in Section 10.4 and Note 2 below) 
• mRS score (see Note 2 in Section 10.4 and Note 2 below) 
• NIHSS score (see Note 2 in Section 10.4 and Note 2 below) 
• CAM-ICU (see Note 3 in Section 10.4 and Note 3 below) 
• MoCA (see Note 4 in Section 10.4) 
Note 1: Follow-up neurological assessments must be performed within 72 hours post 
TAVR procedure but may be performed earlier if deemed necessary. These post-procedure 
assessments should be performed only when the subject is no longer drowsy from 
procedural medication. The neurological assessor should be blinded to the subject’s 
cerebral protection device treatment group. 
Note 2: In all subjects where stroke is suspected, a formal neurology/stroke consult should 
be obtained, and the subject should be further assessed and treated per standard of care. In 
subjects diagnosed with post-procedural stroke, mRS must also be administered at 30±7 
days following the stroke (see Section 10.7 below). The simplified mRS questionnaire29 
may be used for this follow-up assessment. 
Note 3: This delirium assessment should be done on day 1 post TAVR procedure. 
A complete safety event assessment, including any SAE, ADE, SADE, UADE, USADE, 
device deficiency with associated treatment, and any CEC event regardless of seriousness 
and device relationship (see Section 19) must be carried out and reported to BSC from the 
time of enrollment through 72 hours post TAVR procedure or subject discharge (whichever 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 31 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 32 of 76 
  
comes first). Please see Section 10.7 below for additional information regarding subjects with 
stroke. 
The subject may be discharged from the hospital when clinically stable, at the Investigator’s 
discretion per local standard of care. Pharmacologic management of subjects in both 
treatment groups, including antiplatelet and anticoagulant medications, is left to the 
discretion of the treating physician.  
10.7. Post-Stroke (30±7 Days) 
In all subjects where stroke is suspected (≤72 hours post TAVR procedure or through 
discharge, whichever comes first), a formal neurology/stroke consult should be obtained, and 
the subject should be further assessed and treated per standard of care. In subjects diagnosed 
with post-procedural stroke, mRS must also be administered at 30±7 days after the stroke. 
The simplified mRS questionnaire29 may be used for this follow-up assessment. For subjects 
with stroke, mortality plus device related adverse events (ADE, SADE, UADE, and USADE; 
see Table 25.2-1 for definitions) through 30±7 days post stroke must be reported to BSC. 
10.8. Study Completion 
All subjects will be followed through 72 hours post TAVR procedure or hospital discharge 
(whichever comes first). A subject’s participation in the study will be considered complete 
after 72 hours or hospital discharge (whichever comes first). See Section 10.7 regarding 
additional follow-up for subjects who experience a stroke. For those subjects, study 
duration will be through 30±7 days after the stroke. 
10.9. Source Documents 
It is preferable that original source documents, when available, are maintained at the 
investigative center. In lieu of original source documents, certified copies are required to be 
maintained. A certified copy is a copy (irrespective of the type of media used) of the original 
record that has been verified (i.e., by a dated signature or by generation through a validated 
process) to have the same information, including data that describe the context, content, and 
structure, as the original. Source documentation includes but is not limited to those items 
noted in Table 10.9-1. Source documentation provided to the Sponsor for 
assessment/adjudication will be deidentified per local law and regulations. 
Table 10.9-1: Source Documentation Requirements 
Requirement 
Disposition 
Printed, optical, or electronic document containing source data. Examples may include but 
are not limited to: hospital records, laboratory notes, device accountability records, 
photographic negatives, radiographs, records kept at the investigation center, at the 
laboratories and at the medico-technical departments involved in the clinical investigation. 
Retain at center. 
Note: Please see Table 25.2-1 for definitions of “source data” and “source document.” 
 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 32 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 33 of 76 
  
11. Statistical Considerations 
11.1. Endpoints 
11.1.1. Primary Endpoint 
The study is powered to assess the primary endpoint, which is all stroke (hemorrhagic, 
ischemic, or undetermined status; disabling or nondisabling) through 72 hours post TAVR 
procedure or hospital discharge (whichever comes first) as adjudicated by an independent 
CEC using NeuroARC definitions. 
11.1.1.1. Statistical Hypothesis for the Primary Endpoint 
The primary statistical hypothesis is that the rate of the primary endpoint (all stroke through 
72 hours post TAVR procedure or discharge [whichever comes first]) in the Sentinel (Test) 
cohort is superior to that in the Control cohort. The null and alternative hypotheses for the 
primary endpoint are as follows: 
 
H0: PSentinel = PControl 
 
H1: PSentinel ≠ PControl 
where PSentinel and PControl correspond to the rates of the primary endpoint for the Sentinel 
cohort (test) and the Control cohort (no cerebral protection), respectively.   
Testing will be done for the primary endpoint as described in the statistical analysis plan. A 
chi-square test will be used. The primary analysis population for the primary endpoint is the 
ITT analysis set; this endpoint will also be analyzed for the Per-Protocol analysis set (see 
Section 11.2.1 for description of analysis sets).    
11.1.1.2. Sample Size Parameters for the Primary Endpoint 
The sample size parameters for the primary endpoint are shown below. 
• Expected Control rate PControl: 4% 
• Expected Sentinel (test) rate PSentinel: 2% (50% relative reduction)  
• Test significance level (α): 0.05 (2-sided) 
• Power (1 – β): > 0.90 (see Note 1 below) 
• Test to Control ratio: 1:1 (see Note 2 below) 
• Number of evaluable subjects: up to 6000 maximum enrollment with sample size re-
estimation37,38 
• Planned enrollment: = 3000 subjects (N=1500 per cohort) 
The statistical approach uses an adaptive group sequential design37,38. There will be 1 
planned formal interim analysis performed on the first 70% of enrolled subjects (N=2100) by 
the Independent Safety and Statistical Monitor (see Section 21.3). The study will be stopped 
if a significant difference in favor of the test arm is observed after this interim analysis. 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 33 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 34 of 76 
  
Based on the results of the interim analysis, sample size re-estimation37,38 may be performed 
and the sample size may be increased up to a maximum of 6000 subjects. Details of this 
adaptive approach are pre-specified in the Independent Safety and Statistical Monitor charter. 
A final analysis will be performed on all enrolled subjects if the study is not stopped after the 
interim analysis (see Section 11.1.1.3 and Section 11.3.2 below). 
Note 1: This power calculation includes sample size re-estimation37,38.  
Note 2: Randomization will occur at the index procedure (prior to procedural 
puncture/incision) to avoid selection/treatment bias. 
11.1.1.3. Success Criteria for the Primary Endpoint 
As noted above, 1 planned formal interim analysis for the primary endpoint will be 
conducted on the first 70% of enrolled subjects and a final analysis will be conducted on all 
enrolled subjects if the study is not stopped after the interim analysis. The alpha-level for the  
interim analysis and the final analysis is adjusted using the Lan-Demets spending function 
with O’Brien-Fleming boundaries39,40 as detailed below in Section 11.3.2. If the P value from 
the chi square test is less than alpha and the rate in the Sentinel group is less than the rate in 
the Control group, the group with Sentinel will be concluded to have a lower rate of all stroke 
through 72 hours post TAVR procedure or hospital discharge (whichever comes first) 
compared to the Control group. 
11.1.1.4. Statistical Methods – Primary Endpoint 
All subjects who are enrolled will be eligible for evaluation. Handling of dropouts and 
missing data will depend on their frequency and the nature of the outcome measure. Methods 
to eliminate or minimize bias will be implemented and described completely, if applicable.  
Outlier values will be evaluated for their validity. Suspected invalid data will be queried and 
corrected in the database prior to statistical analysis. 
11.1.2. Post-procedure Measurements 
Post-procedure data will be collected as detailed in the clinical study schedule (Table 10.1-1) 
and will be summarized using descriptive statistics for continuous variables (e.g., mean, 
standard deviation, n, minimum, maximum) and frequency tables or proportions for discrete 
variables. Adverse event and SAE rates will be reported. 
11.2. General Statistical Methods 
All statistical analyses will be performed using the SAS System software, version 9.2 or later 
(Copyright© 2000 SAS Institute Inc., SAS Campus Drive, Cary, North Carolina 27513, USA. 
All rights reserved).  
All statistical analyses will be conducted according to applicable Standard Operating 
Procedures, Work Instructions, and the study-specific statistical analysis plan. 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 34 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 35 of 76 
  
11.2.1. Analysis Sets 
The primary endpoint and the additional measurements will be analyzed on an ITT basis and 
a Per-Protocol basis. For ITT analyses, all subjects who sign the IRB/IEC/HREC-approved 
study ICF (see Section 10.3) and are enrolled in the trial (see Section 9.1) will be included in 
the analysis, whether or not the assigned treatment is received. For Per-Protocol analyses, 
ITT subjects who undergo TAVR and who are treated as assigned in the randomization 
process (excludes crossovers) will be included in the analysis. 
11.2.2. Control of Systematic Error/Bias 
The selection of subjects will be made from the Investigator’s usual case load. All subjects 
who have signed the ICF, are deemed treatable with the Sentinel device (have suitable 
anatomy per the IFU) and are selected to undergo TAVR with a commercial TAVR device 
will be eligible for enrollment in the study. The study center’s heart team assessments and 
imaging measurements before device placement will contribute to the determination of 
subject eligibility for the study.  
To control for inter-observer variability, an independent CEC (see Section 21.1) will 
adjudicate pre-determined endpoints. 
11.2.3. Number of Subjects per Investigative Center 
A single center may enroll up to 15% of the total enrollment; approval from the Sponsor is 
required for additional enrollment. 
11.2.4. Randomization Scheme 
Using a computer-generated list of random treatment allocations (i.e., a randomization 
schedule) subjects to be treated with a commercially available TAVR device will be 
randomized 1:1 into a Test cohort using the commercially available Sentinel device or a 
Control cohort with no cerebral protection system. Randomization will be stratified by 
center, by operative risk (low risk and intermediate or higher risk; see surgical risk 
definitions in Table 25.2-1), and by intended TAVR valve type (balloon-expandable device 
and non-balloon expandable device). Additional information is provided in the study Manual 
of Operations.  
11.3. Data Analyses 
Baseline and outcome variables will be summarized using descriptive statistics for 
continuous variables (mean, standard deviation, number of observations, minimum and 
maximum) and discrete variables (percentage and count/sample). See Section 11.1.1 for a 
discussion on analysis of the primary endpoint. 
11.3.1. Other Endpoints/Measurements  
Other measurements not driven by statistical hypotheses are listed in Section 6.2.2. 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 35 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 36 of 76 
  
11.3.2. Interim Analyses  
One formal interim analysis is planned for the purpose of stopping this trial early for 
effectiveness. This analysis will be performed by the Independent Safety and Statistical 
Monitor (see Section 21.3). The interim analysis for the primary endpoint will be conducted 
on the first 70% of enrolled subjects; a final analysis will be conducted on all enrolled 
subjects if the study is not stopped after the interim analysis.  
The Lan-Demets spending function with O’Brien-Fleming boundaries39 is used to adjust the 
alpha-level for the interim analysis and the final analysis (if needed): 0.0148 and 0.0455, 
respectively. If the P value from the chi-square test is less than alpha, and the rate in the 
Sentinel group is less than the rate in the Control group, the group with Sentinel will be 
concluded to have a lower rate of all stroke through 72 hours post TAVR procedure or 
discharge (whichever comes first) versus the Control group and the study will be stopped. If 
the study is not stopped after the interim analysis, sample size re-estimation may be 
performed contingent on the results of the interim analysis (see Section 11.1.1.2). 
The planned interim analysis is pre-specified to provide a formal hypothesis testing approach 
to examine the primary endpoint with the adjusted significance level and stop the trial early 
for effectiveness if appropriate. This pre-specified interim analysis allows for sample size re-
estimation per the study’s adaptive group sequential design37,38. 
Additional analyses not defined in the protocol may also be conducted for regulatory agency 
review. 
11.3.3. Subgroup Analyses 
The primary endpoint and pre-specified additional measurements (see Section 6.2) will be 
summarized for the following subgroups.  
• Operative risk (low, intermediate, high/extreme; treatment by subgroup interaction 
analysis)  
• Gender 
No adjustments for multiple comparisons will be made. Additional subgroup analyses may 
be performed as appropriate. 
11.3.4. Justification of Pooling 
Analyses for the primary endpoint will be presented using data pooled across centers and 
intended TAVR valve types. An assessment of the poolability of subjects across centers and 
intended TAVR valve types will be made using logistic regression. Main effects for the 
center (intended TAVR valve type) and treatment and the interaction of the center (intended 
TAVR valve type) by treatment will be included in separate logistic regression models with 
the primary endpoint as the outcome. If the P value for center (intended TAVR valve type) 
by treatment interaction is ≥0.1, it can be concluded that the treatment effect is not different 
across the centers (intended TAVR valve types) and the data can be pooled. In the analysis to 
justify pooling across centers, the centers with fewer than 10 subjects enrolled in the study 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 36 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 37 of 76 
  
will be combined into “virtual centers” based on geographic region so that “virtual centers” 
have ≥10 subjects but no more than the largest enrolling center. 
11.3.5. Changes to Planned Analyses 
Any changes to the planned statistical analyses made prior to performing the analyses will be 
documented in an amended statistical analysis plan approved before performing the analyses. 
Changes from the planned statistical methods after performing the analyses will be 
documented in the clinical study report along with a reason for the change. 
12. Health Economics Outcomes 
A formal health economics analysis may be completed as part of this study, provided 
meaningful healthcare resource utilization data are obtained. This will take into consideration 
healthcare resource utilization through discharge (with a maximum of 30 days if the subject 
is hospitalized for longer than 30 days) for both the Test and Control groups. Medical billing 
information (e.g., UB-04 billing claim form) through the TAVR index hospitalization may be 
collected at centers in the United States for health economics analyses. 
13. Data Management 
13.1. Data Collection, Processing, and Review 
Subject data will be recorded in a limited access secure electronic data capture (EDC) 
system. Only personnel trained and authorized will have access to the system. 
The clinical database will reside on a production server hosted by Medidata EDC System 
(New York, NY, USA). All changes made to the clinical data will be captured in an 
electronic audit trail and available for review by BSC or its representative. The associated 
RAVE software and database have been designed to meet regulatory compliance for 
deployment as part of a validated system compliant with laws and regulations applicable to 
the conduct of clinical studies pertaining to the use of electronic records and signatures. 
Database backups are performed regularly. 
The Investigator provides his/her electronic signature on the appropriate eCRFs in 
compliance with local regulations. A written signature on printouts of the eCRFs must also 
be provided if required by local regulation. Changes to data previously submitted to BSC 
require a new electronic signature by the Investigator acknowledging and approving the 
changes. 
Visual and/or electronic data review will be performed to identify possible data 
discrepancies. Manual and/or automatic queries will be created in the Medidata EDC system 
and will be issued to the center for appropriate response. Center staff will be responsible for 
resolving all queries in the database. 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 37 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 38 of 76 
  
13.2. Data Retention 
The Principal Investigator or his/her designee or investigational center will maintain all 
essential study documents and source documentation that support the data collected on the 
study subjects in compliance with applicable regulatory requirements. 
The Principal Investigator or his/her designee will take measures to prevent accidental or 
premature destruction of these documents. If for any reason the Principal Investigator or 
his/her designee withdraws responsibility for maintaining these essential documents, custody 
must be transferred to an individual who will assume responsibility and BSC must receive 
written notification of this custodial change. Centers are required to inform BSC in writing 
where paper or electronic files are maintained in case files are stored off site and are not 
readily available. 
14. Deviations 
An Investigator must not make any changes or deviate from this protocol, except to protect 
the life and physical well-being of a subject in an emergency. An investigator shall notify 
BSC and the reviewing IRB/IEC/HREC of any deviation from the investigational plan to 
protect the life or physical well-being of a subject in an emergency, and those deviations 
which affect the scientific integrity of the clinical investigation. Such notice shall be given as 
soon as possible, but no later than 5 working days after the emergency occurred, or per 
prevailing local requirements, if sooner than 5 working days. 
All deviations from the investigational plan, with the reason for the deviation and the date of 
occurrence, must be documented and reported to BSC using the EDC eCRF. Centers may 
also be required to report deviations to the IRB/IEC/HREC, per local guidelines and 
government regulations. 
Deviations will be reviewed and evaluated on an ongoing basis and, as necessary, appropriate 
corrective and preventive actions (including IRB/IEC/HREC notification, center re-training, 
or center discontinuation/termination) will be put into place by BSC. 
15. Device Accountability 
The Sentinel® Cerebral Protection System is a commercially available product. The study 
eCRF identifies the required device information. 
16. Compliance 
16.1. Statement of Compliance 
The PROTECTED TAVR study will be conducted in accordance with 21 CFR Parts 11, 50, 
and 54; the relevant parts of the International Conference on Harmonisation (ICH) 
Guidelines for Good Clinical Practices (GCP); the International Standard ISO 14155 Clinical 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 38 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 39 of 76 
  
Investigation of Medical Devices for Human Subjects – Good Clinical Practice; ethical 
principles that have their origins in the Declaration of Helsinki; and pertinent individual 
country/state/local laws and regulations. The study shall not begin until the required 
approval/favorable opinion from the IRB/IEC/HREC and/or regulatory authority has been 
obtained, if appropriate. Investigator responsibilities are detailed in Section 16.2. 
16.2. Investigator Responsibilities 
The Principal Investigator of an investigational center is responsible for ensuring that the 
study is conducted in accordance with the Clinical Study Agreement, the clinical 
investigation plan/protocol, ISO 14155 or ICH/GCP, ethical principles that have their origins 
in the Declaration of Helsinki, any conditions of approval imposed by the reviewing 
IRB/IEC/HREC, and prevailing local and/or country laws and/or regulations, whichever 
affords the greater protection to the subject. 
The Principal Investigator’s responsibilities include, but are not limited to, the following. 
• Prior to beginning the study, sign the Clinical Study Agreement and comply with the 
Investigator responsibilities as described in such Agreement.   
• Provide his/her qualifications and experience to assume responsibility for the proper 
conduct of the study and that of key members of the site team through up-to-date 
curriculum vitae or other relevant documentation and disclose potential conflicts of 
interest, including financial, that may interfere with the conduct of the clinical study or 
interpretation of results. 
• Complete commercial training requirements associated with the Sentinel® Cerebral 
Protection System. 
• Make no changes in or deviate from this protocol, except to protect the life and physical 
well-being of a subject in an emergency; document and explain any deviation from the 
approved protocol that occurred during the course of the clinical investigation. 
• Create and maintain source documents throughout the clinical study and ensure their 
availability with direct access during monitoring visits or audits; ensure that all clinical-
investigation-related records are retained per requirements. 
• Ensure the accuracy, completeness, legibility, and timeliness of the data reported to 
BSC in the CRFs and in all required reports. 
• Record, report, and assess (seriousness and relationship to the device/procedure) every 
adverse event as applicable per the protocol and observed device deficiency. 
• Report to BSC, per the protocol requirements, all ADEs, SAEs, SADEs, USADEs, 
CEC events, and device deficiencies. 
• Report to the IRB/IEC/HREC and regulatory authorities any SAEs and device 
deficiencies that could have led to a SADE and potential USADE, if required by 
applicable laws or regulations or this protocol or by the IRB/IEC/HREC, and supply 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 39 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 40 of 76 
  
BSC with any additional requested information related to the safety reporting of a 
particular event. 
• Allow BSC and its representatives to perform monitoring and auditing activities and be 
accessible to the clinical research monitor or auditor and respond to questions during 
monitoring visits or audit(s). 
• Allow and support regulatory authorities and the IRB/IEC/HREC when performing 
auditing activities. 
• Ensure that informed consent is obtained in accordance with applicable laws, this 
protocol, and local IRB/IEC/HREC requirements. 
• Provide adequate medical care to a subject during and after a subject’s participation in a 
clinical study in the case of adverse events, as described in the ICF. 
• Inform the subject of the nature and possible cause of any adverse events experienced. 
• Inform the subject of any new significant findings occurring during the clinical 
investigation, including the need for additional medical care that may be required. 
• Provide the subject with well-defined procedures for possible emergency situations 
related to the clinical study, and make the necessary arrangements for emergency 
treatment, including decoding procedures for blinded/masked clinical investigations, as 
needed. 
• Ensure that clinical medical records are clearly marked to indicate that the subject is 
enrolled in this clinical study. 
• Ensure that, if appropriate, subjects enrolled in the clinical investigation are provided 
with some means of showing their participation in the clinical investigation, together 
with identification and compliance information for concomitant treatment measures 
(contact address and telephone numbers shall be provided). 
• Inform, with the subject’s approval or when required by national regulations, the 
subject’s personal physician about the subject’s participation in the clinical 
investigation. 
• Make all reasonable efforts to ascertain the reason(s) for a subject’s premature 
withdrawal from clinical investigation while fully respecting the subject’s rights. 
• Ensure that an adequate investigation site team and facilities exist and are maintained 
and documented during the clinical investigation. 
16.2.1. Delegation of Responsibility 
When specific tasks are delegated by an investigator, including but not limited to conducting 
the informed consent process, the Principal Investigator is responsible for providing 
appropriate training, so the delegate is competent to perform the tasks they have been 
delegated and adequate supervision of those to whom tasks are delegated. Where there is a 
sub-investigator at a center, the sub-investigator should not be delegated the primary 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 40 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 41 of 76 
  
supervisory responsibility for the center. The investigator is accountable for regulatory 
violations resulting from failure to adequately supervise the conduct of the clinical study.  
16.3. Institutional Review Board/Independent Ethics Committee 
The investigational center will obtain the written and dated approval/favorable opinion of the 
IRB/IEC/HREC for the clinical investigation before recruiting subjects and implementing all 
subsequent amendments, if required. 
A copy of the written IRB/IEC/HREC and/or competent authority approval of the protocol 
(or permission to conduct the study) and ICF must be received by BSC before recruitment of 
subjects into the study. Prior approval must also be obtained for other materials related to 
subject recruitment or which will be provided to the subject. 
Any amendment to the protocol will require review and approval by the IRB/IEC/HREC 
before the changes are implemented in the study. All changes to the ICF will be 
IRB/IEC/HREC approved; a determination will be made regarding whether a new ICF needs 
to be obtained from subjects who provided consent using a previously approved ICF.  
Annual IRB/IEC/HREC approval and renewals will be obtained throughout the duration of 
the study as required by applicable local/country laws or regulations or IRB/IEC/HREC 
requirements. Copies of the study reports and the IRB/IEC/HREC continuance of approval 
must be provided to BSC.  
16.4. Sponsor Responsibilities 
All information and data sent to BSC concerning subjects or their participation in this study 
will be considered confidential by BSC and will be kept confidential in accordance with all 
applicable laws and regulations. Only authorized BSC personnel and/or a BSC representative 
including, but not limited to, a contract research organization [CRO]) will have access to this 
information. Authorized regulatory personnel have the right to inspect and copy all records 
pertinent to this study. Study data collected during this study may be used by BSC for the 
purposes of this study, publication, and to support future research and/or other business 
purposes, such as overseeing and improving the performance of its device, new medical 
research, and proposals for developing new medical products and procedures. All data used 
in the analysis and reporting of this study or shared with a third-party researcher will be 
without identifiable reference to specific subjects. 
Information received during the study will not be used to market to subjects; subject names 
will not be placed on any mailing lists or sold to anyone for marketing purposes.  
16.4.1. Role of Boston Scientific Corporation Representatives 
Boston Scientific Corporation personnel (including field clinical engineers) who are trained 
in the use of the Sentinel Cerebral Protection System will provide training and technical 
support to the investigator and other healthcare professionals (collectively HCP) as needed 
(see Section 16.4.2), addressing HCP questions, or providing clarifications to HCPs 
concerning the operation of BSC equipment/devices.  
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 41 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 42 of 76 
  
In addition, BSC personnel may perform certain activities to ensure study quality. These 
activities may include observing testing or medical procedures to provide information 
relevant to the IFU. 
Boston Scientific personnel will not do the following.  
• Practice medicine 
• Provide medical diagnosis or treatment to subjects 
• Discuss a subject’s condition or treatment with a subject without the approval and 
presence of the investigator.  
• Independently collect critical study data (defined as primary or secondary endpoint 
data) 
• Enter data in electronic data capture systems or on paper case report forms 
16.4.2. Training 
Boston Scientific has established a commercial training program to provide the physicians 
and staff with the information and experience necessary to control user-associated risks when 
the Sentinel Cerebral Protection System is used in accordance with the commercial IFU. In 
the current study, treating physicians will have already received the required training and 
have relevant clinical experience with the Sentinel device before enrolling trial subjects. 
Personnel involved in the administration of the neurocognitive examinations (MoCA), the 
delirium assessments (CAM-ICU), and the NIHSS and mRS stroke assessments will undergo 
the necessary study training and, where applicable, confirmation will be provided to show 
that the personnel are appropriately certified to administer such exams. 
16.5. Insurance  
Where required by local/country regulation, proof and type of insurance coverage by BSC for 
subjects in the study will be obtained. 
17. Monitoring 
Monitoring will be performed during the study to assess continued compliance with the 
protocol and applicable regulations. In addition, the clinical research monitor verifies that 
study records are adequately maintained, that data are reported in a satisfactory manner with 
respect to timeliness, adequacy, and accuracy, and that the Principal Investigator continues to 
have sufficient staff and facilities to conduct the study safely and effectively. The Principal 
Investigator/institution guarantees direct access to original source documents by BSC 
personnel, their designees, and appropriate regulatory authorities. 
The study may also be subject to a quality assurance audit by BSC or its designees, as well as 
inspection by appropriate regulatory authorities. It is important that the Principal Investigator 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 42 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 43 of 76 
  
and relevant study personnel are available during on-site monitoring visits or audits and that 
sufficient time is devoted to the process. 
18. Potential Risks and Benefits 
18.1. Instructions for Use 
Please refer to the Sentinel Cerebral Protection System IFU for an overview of anticipated 
adverse (device) effects, and risks associated with the commercial device. 
18.2. Risks Associated with Participation in the Clinical Study 
Risks associated with TAVR and use of the commercial Sentinel Cerebral Protection System 
are listed in the IFU and in the ICF. There are no incremental risks associated with 
participation in this clinical study. 
18.3. Possible Interactions with Concomitant Medical Treatments 
Medications to be used in PROTECTED TAVR constitute standard of care for TAVR as 
described in society guidelines30,31. 
18.4. Risk Minimization Actions 
Additional risks may exist. Risks can be minimized through compliance with this protocol, 
performing procedures in the appropriate hospital environment, adherence to subject 
selection criteria, close monitoring of the subject's physiologic status during research 
procedures and/or follow-ups and by promptly supplying BSC with all pertinent information 
required by this protocol. 
Data will be monitored as they are submitted to BSC. Qualified employees of BSC, or a 
designee under contract, will conduct monitoring visits at the initiation of the study and at 
interim intervals described in the monitoring plan throughout the course of the study to 
evaluate protocol compliance and determine if there are any issues that could affect the safety 
or welfare of any subject in the study. A dynamic safety review process including CEC 
(Section 21.1) adjudication of specified events as recommended by VARC16,22 and/or 
NeuroARC21 will support risk mitigation. 
18.5. Anticipated Benefits 
It is expected that the commercially available Sentinel Cerebral Protection System may 
provide benefit to the subject by capturing potentially harmful embolic debris liberated 
during the TAVR procedure. Without such protection, embolic debris could travel 
unimpeded via the cerebral circulation to the brain; this could lead to cerebral vascular events 
such as stroke and/or TIA.  
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 43 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 44 of 76 
  
19. Safety Reporting 
19.1. Reportable Events by Investigational Center to Boston Scientific 
It is the responsibility of the investigator to assess and report to BSC any event that occurs in 
any of following categories: 
• All serious adverse events (SAE) 
• All device-related adverse events  
• All device deficiencies  
• Unanticipated adverse device effects (UADE)/unanticipated serious adverse device 
effects (USADE) 
• All CEC events (see below) 
• New findings/updates in relation to already reported events 
When possible, the medical diagnosis should be reported as the Event Term instead of 
individual symptoms. 
If it is unclear whether or not an event fits one of the above categories, or if the event cannot 
be isolated from the device or procedure, it should be submitted as an adverse event (AE) 
and/or device deficiency. 
Any AE required by the protocol, experienced by the study subject after informed consent 
and once considered enrolled in the study, whether during or subsequent to the procedure, 
must be recorded in the eCRF. Collection of safety events includes all CEC events (see 
below), regardless of seriousness and device relationship. 
Underlying diseases are not reported as AEs unless there is an increase in severity or 
frequency during the course of the investigation. Death should not be recorded as an AE but 
should only be reflected as an outcome of one (1) specific SAE (see Table 19.2-1 for AE 
definitions).  
Refer to the Instructions For Use for the known risks associated with the commercial device. 
The endpoints (see endpoint definitions in Table 25.2-1) requiring adjudication by the CEC 
include the following. 
• Death: cardiovascular and non-cardiovascular 
• Stroke: disabling and non-disabling  
• Transient ischemic attack 
• Delirium 
• Acute kidney injury (Stage 2 and Stage 3) 
• Sentinel access site major vascular complications related to the procedure  
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 44 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 45 of 76 
  
Details on the CEC events and procedures are outlined in the CEC charter. Tests and images 
required to adjudicate these events are specified in the event definitions (see Table 25.2-1). 
19.2. Definitions and Classification 
Adverse event definitions are provided in Table 19.2-1. Administrative edits were made to 
the safety definitions from ISO 14155 and MEDDEV 2.7/3 for clarification purposes. 
Table 19.2-1: Safety Definitions 
Term 
Definition 
Adverse Event (AE) 
Ref: ISO 14155 
Ref: MEDDEV 2.7/3  
 
 
Any untoward medical occurrence, unintended disease or injury, or any untoward 
clinical signs (including an abnormal laboratory finding) in subjects, users or 
other persons, whether or not related to the study medical device.  
Note 1: This includes events related to the study medical device or comparator. 
Note 2: This definition includes events related to the procedures involved. 
Note 3: For users or other persons, this definition is restricted to events related to 
the study medical device.  
Adverse Device Effect 
(ADE) 
Ref: ISO 14155 
Ref: MEDDEV 2.7/3  
Adverse event related to the use of the study medical device 
Note 1: This includes any adverse event resulting from insufficiencies or 
inadequacies in the instructions for use, the deployment, the implantation, the 
installation, the operation, or any malfunction of the study medical device. 
Note 2: This definition includes any event resulting from use error or intentional 
abnormal use of the study medical device. 
Serious Adverse Event 
(SAE) 
Ref: ISO 14155 
Ref: MEDDEV 2.7/3  
Note 1: This definition meets the reporting objectives and requirements of ISO 
14155 and MEDDEV 2.7/3. 
Adverse event that: 
a) Led to death, 
b) Led to serious deterioration in the health of the subject as defined by either: 
1) a life-threatening illness or injury, or 
2) a permanent impairment of a body structure or a body function, or 
3) in-patient hospitalization or prolongation of existing 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. 
Note 2: Planned hospitalization for a pre-existing condition, or a procedure 
required by the clinical investigational plan, without a serious deterioration in 
health, is not considered a serious adverse event.  
Serious Adverse 
Device Effect (SADE) 
Ref: ISO 14155 
Ref: MEDDEV 2.7/3  
Adverse device effect that has resulted in any of the consequences characteristic 
of a serious adverse event. 
 
Unanticipated Adverse 
Device Effect (UADE) 
Ref: 21 CFR Part 812 
Any serious adverse effect on health or safety or any life-threatening problem or 
death caused by, or associated with, a device, if that effect, problem, or death was 
not previously identified in nature, severity, or degree of incidence in the 
investigational plan or application (including a supplementary plan or 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 45 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 46 of 76 
  
Table 19.2-1: Safety Definitions 
Term 
Definition 
application), or any other unanticipated serious problem associated with a device 
that relates to the rights, safety, or welfare of subjects.   
Unanticipated Serious 
Adverse Device Effect 
(USADE) 
Ref: ISO 14155 
Ref: MEDDEV 2.7/3  
Serious adverse device effect which by its nature, incidence, severity, or outcome 
has not been identified in the current version of the risk analysis report. 
Note: Anticipated serious adverse device effect (ASADE) is an effect which by its 
nature, incidence, severity or outcome has been identified in the risk analysis 
report. 
Device Deficiency 
Ref: ISO 14155 
Ref: MEDDEV 2.7/3  
An inadequacy of the study medical device related to its identity, quality, 
durability, reliability, safety or performance. This may include malfunctions, use 
error, or inadequacy in the information supplied by the manufacturer. 
 
19.3. Relationship to Device(s) 
The Investigator must assess the relationship of the reportable AE to the Sentinel System or 
procedure. See criteria in Table 19.3-1. 
Table 19.3-1: Criteria for Assessing Relationship of Study Device or Procedure to 
Adverse Event 
Classification 
Description 
Not Related 
Ref: MEDDEV 2.7/3 
Relationship to the device or procedures can be excluded when: 
• the event is not a known side effect of the product category the device belongs 
to or of similar devices and procedures; 
• the event has no temporal relationship with the use of the study device or the 
procedures; 
• the serious event does not follow a known response pattern to the medical 
device (if the response pattern is previously known) and is biologically 
implausible; 
• the discontinuation of medical device application or the reduction of the level 
of activation/exposure – when clinically feasible – and reintroduction of its use 
(or increase of the level of activation/exposure), do not impact on the serious 
event; 
• the event involves a body-site or an organ not expected to be affected by the 
device or procedure;  
• the serious event can be attributed to another cause (e.g. an underlying or 
concurrent illness/clinical condition, an effect of another device, drug, 
treatment or other risk factors); 
• the event does not depend on a false result given by the study device used for 
diagnosis, when applicable; harms to the subject are not clearly due to use 
error; 
• In order to establish the non-relatedness, not all the criteria listed above might 
be met at the same time, depending on the type of device/procedures and the 
serious event. 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 46 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 47 of 76 
  
Table 19.3-1: Criteria for Assessing Relationship of Study Device or Procedure to 
Adverse Event 
Classification 
Description 
Unlikely Related 
Ref: MEDDEV 2.7/3 
The relationship with the use of the device seems not relevant and/or the event can 
be reasonably explained by another cause, but additional information may be 
obtained. 
Possibly Related 
Ref: MEDDEV 2.7/3 
The relationship with the use of the study device is weak but cannot be ruled out 
completely. Alternative causes are also possible (e.g. 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 
Ref: MEDDEV 2.7/3 
The relationship with the use of the study device seems relevant and/or the event 
cannot be reasonably explained by another cause, but additional information may 
be obtained. 
Causal Relationship 
Ref: MEDDEV 2.7/3 
The serious event is associated with the study device or with procedures beyond 
reasonable doubt when: 
• the event is a known side effect of the product category the device belongs to 
or of similar devices and procedures; 
• the event has a temporal relationship with the study device use/application or 
procedures; 
• the event involves a body-site or organ that 
- the study device or procedures are applied to; 
- the study device or procedures have an effect on; 
• the serious event follows a known response pattern to the medical device (if 
the response pattern is previously known); 
• the discontinuation of medical device application (or reduction of the level of 
activation/exposure) and reintroduction of its use (or increase of the level of 
activation/exposure), impact on the serious event (when clinically feasible); 
• other possible causes (e.g. an underlying or concurrent illness/ clinical 
condition or/and an effect of another device, drug or treatment) have been 
adequately ruled out; 
• harm to the subject is due to error in use; 
• the event depends on a false result given by the study device used for 
diagnosis, when applicable; 
• In order to establish the relatedness, not all the criteria listed above might be 
met at the same time, depending on the type of device/procedures and the 
serious event. 
 
19.4. Investigator Reporting Requirements 
The communication requirements for reporting to BSC are as shown in Table 19.4-1. 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 47 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 48 of 76 
  
Table 19.4-1: Investigator Reporting Requirements 
Event Classification 
Communication Method 
Communication Timeline (post-market 
studies) 
(MEDDEV 2.12/2: GUIDELINES ON A 
MEDICAL DEVICE VIGILANCE SYSTEM) 
Unanticipated Adverse 
Device Effect (UADE) 
Unanticipated Serious 
Adverse Device Effect 
(USADE) 
Complete AE eCRF page 
with all available new and 
updated information.  
• Within 1 business day of first becoming 
aware of the event. 
• Terminating at the end of the study 
Provide all relevant source 
documentation (de-
identified/ 
pseudonymized) for 
reported event.  
• At request of Sponsor.  
Serious Adverse Event  
(SAE) 
Clinical Events Committee 
Event (see Section 19.1) 
(CEC event) 
Complete AE eCRF page 
with all available new and 
updated information.  
• Within 10 business days after becoming 
aware of the event or as per local/regional 
regulations.  
• Reporting required through the end of the 
study 
Provide all relevant source 
documentation (de-
identified/ 
pseudonymized) for 
reported event. 
• When documentation is available 
Serious Adverse Device 
Effect (SADE) and serious 
VARC event 
 
Complete AE eCRF page 
with all available new and 
updated information. 
• Within 2 business days of first becoming 
aware of the event or as per local/regional 
regulations.  
• Reporting required through the end of the 
study 
Provide all relevant source 
documentation (de-
identified/ 
pseudonymized) for 
reported event.  
• When documentation is available 
Device Deficiencies 
(including but not limited to 
failures, malfunctions, and 
product nonconformities) 
Note: Any device deficiency 
that might have led to a 
serious adverse event if a) 
suitable action had not been 
taken or b) intervention had 
not been made or c) if 
circumstances had been less 
fortunate is considered a 
reportable event. 
Complete applicable CRF 
fields/forms with all 
available new and updated 
information.  
• Within 1 business day of first becoming 
aware of the event. 
• Reporting required through the end of the 
study 
Provide all relevant source 
documentation (de-
identified/ 
pseudonymized) for 
reported event. 
• At request of Sponsor  
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 48 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 49 of 76 
  
Table 19.4-1: Investigator Reporting Requirements 
Event Classification 
Communication Method 
Communication Timeline (post-market 
studies) 
(MEDDEV 2.12/2: GUIDELINES ON A 
MEDICAL DEVICE VIGILANCE SYSTEM) 
Adverse Event (AE) including 
Adverse Device Effect (ADE) 
and non-serious VARC event  
Complete AE eCRF page, 
which contains such 
information as date of AE, 
treatment of AE,  
resolution, assessment of 
seriousness and 
relationship to the device.  
• In a timely manner (e.g., recommend 
within 10 business days) after becoming 
aware of the information 
• Reporting required through the end of the 
study 
Provide all relevant source 
documentation (de-
identified/pseudonymized) 
for reported event.  
• At request of Sponsor 
Abbreviations: AE=adverse event; eCRF=electronic case report form; VARC=Valve Academic Research 
Consortium 
 
19.5. Boston Scientific Device Deficiencies 
Device deficiencies (Sentinel) will be documented and reported to BSC. If possible, the 
device(s) should be returned to BSC for analysis. Instructions for returning the device(s) will 
be provided in the investigative site files. Device deficiencies should also be documented in 
the subject’s source records. 
Device deficiencies are not adverse events. However, an AE that results from a device 
deficiency would be recorded as an AE on the appropriate eCRF. 
19.6. Reporting to Regulatory Authorities / IRBs and IECs / Investigators 
Boston Scientific Corporation is responsible for reporting adverse event information to all 
participating Principal Investigators, IRBs/IECs, and regulatory authorities, as applicable 
according to local reporting requirements.  
The Principal Investigator is responsible for informing the IRB/IEC/HREC and regulatory 
authorities of UADEs/USADEs and SAEs as required by local/regional regulations. 
20. Informed Consent 
Subject participation in this clinical study is voluntary. Informed Consent is required from 
each subject or his/her legally authorized representative. The Investigator is responsible for 
ensuring that Informed Consent is obtained prior to the use of any study devices, study-
required procedures and/or testing, or data collection.  
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 49 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 50 of 76 
  
The obtaining and documentation of Informed Consent must be in accordance with the 
principles of the Declaration of Helsinki, ISO 14155, any applicable national regulations, and 
local IRB/IEC/HREC and/or Regulatory authority, as applicable. The ICF must be accepted 
by BSC or its delegate (e.g., CRO), and approved by the center’s IRB/IEC/HREC or central 
IRB/IEC/HREC, if applicable. 
Boston Scientific Corporation will provide a study-specific template of the ICF to 
investigators participating in this study. The ICF template may be modified to meet the 
requirements of the investigative center’s IRB/IEC/HREC. Any modification requires 
acceptance from BSC prior to use of the form. The ICF must be in a language understandable 
to the subject and if needed, BSC will assist the center in obtaining a written consent 
translation. Translated consent forms must also have IRB/IEC/HREC approval prior to their 
use.  Privacy language shall be included in the body of the form or as a separate form as 
applicable.   
The process of obtaining Informed Consent shall at a minimum include the following steps, 
as well as any other steps required by applicable laws, rules, regulations and guidelines: 
• be conducted by the Principal Investigator or designee authorized to conduct the 
process,  
• include a description of all aspects of the clinical study that are relevant to the subject’s 
decision to participate throughout the clinical study, 
• avoid any coercion of or undue influence of subjects to participate, 
• not waive or appear to waive subject’s legal rights, 
• use native language that is non-technical and understandable to the subject or his/her 
legal representative, 
• provide ample time for the subject to consider participation and ask questions if 
necessary, 
• ensure important new information is provided to new and existing subjects throughout 
the clinical study.  
The ICF shall always be signed and personally dated by the subject or legal representative 
competent to sign the ICF under the applicable laws, rules, regulations and guidelines and by 
the investigator and/or an authorized designee responsible for conducting the informed 
consent process. If a legal representative signs the ICF, the subject shall be asked to provide 
informed consent for continued participation as soon as his/her medical condition allows. 
The original signed ICF will be retained by the center and a copy of the signed and dated 
document and any other written information must be given to the person signing the form.  
Failure to obtain subject consent will be reported by BSC to the applicable regulatory 
authority according to their requirements. Any violations of the informed consent process 
must be reported as deviations to the sponsor and local regulatory authorities (e.g., 
IRB/IEC/HREC), as appropriate. 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 50 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 51 of 76 
  
If new information becomes available that can significantly affect a subject's future health 
and medical care, that information shall be provided to the affected subject(s) in written form 
via a revised ICF or, in some situations, enrolled subjects may be requested to sign and date 
an addendum to the ICF. In addition to new significant information during the course of a 
study, other situations may necessitate revision of the ICF, such as if there are amendments 
to the applicable laws, protocol, a change in Principal Investigator, administrative changes, or 
following annual review by the IRB/IEC/HREC. The new version of the ICF must be 
approved by the IRB/IEC/HREC. Acceptance by Boston Scientific is required if changes to 
the revised ICF are requested by the center’s IRB/IEC/HREC. The IRB/IEC/HREC will 
determine the subject population to be re-consented. 
21. Committees 
21.1. Safety Monitoring Process 
To promote early detection of safety issues, the Clinical Events Committee (CEC; see below) 
will provide evaluations of safety events. Success of this program requires dynamic 
collection of unmonitored data as soon as the event is reported. This is expedited through 
BSC or its designee, which is responsible for coordinating the collection of information for 
the subject dossier from the centers and core laboratory. During regularly scheduled 
monitoring visits clinical research monitors will support the dynamic reporting process 
through their review of source documents and other data information. The BSC Medical 
Safety group includes physicians with expertise in cardiology and with the necessary 
therapeutic and subject matter expertise to evaluate and classify the events into the categories 
outlined above (Section 19).  
21.1.1. Clinical Events Committee 
A CEC will be used in this study. The CEC is an independent group of individuals with 
pertinent expertise, including cardiovascular interventional therapy, cardiovascular surgery, 
and neurology, which reviews and adjudicates important endpoints and relevant adverse 
events reported by study investigators. The CEC will review a safety event dossier, which 
may include copies of subject source documents provided by study centers and adjudicate 
study endpoint related clinical events. The responsibilities, qualifications, membership, and 
committee procedures of the CEC are outlined in the CEC Charter. 
21.2. Steering Committee 
A Steering Committee consisting of Sponsor Clinical Management, the Study Coordinating 
PIs, a neurologist, cardiac surgeons, and other investigators experienced in TAVR will be 
convened. Responsibilities may include oversight of the overall conduct of the study with 
regard to protocol development, study progress, subject safety, overall data quality and 
integrity, as well as disseminating any study results through appropriate scientific sessions 
and publications. Steering Committee members may participate in the review and approval of 
all requests for data analysis, abstract and manuscript preparation and submission. 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 51 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 52 of 76 
  
21.3. Independent Safety and Statistical Monitor  
The unblinded data from the first 70% of enrolled subjects will be reviewed by the 
Independent Safety and Statistical Monitor (independent of the project team). The study will 
be stopped if a significant difference in favor of the test arm is observed after this interim 
analysis (see Section 11.3.2). Based on the results of the interim analysis, sample size re-
estimation37,38 may be performed and the sample size may be increased up to a maximum of 
6000 subjects. Details of this adaptive approach are pre-specified in the Independent Safety 
and Statistical Monitor charter. 
22. Suspension or Termination 
22.1. Premature Termination of the Study 
Boston Scientific Corporation reserves the right to terminate the study at any stage but 
intends to exercise this right only for valid scientific or business reasons and reasons related 
to protection of subjects. Investigators, associated IRBs/IECs/HRECs, and regulatory 
authorities, as applicable, will be notified in writing in the event of study termination. 
22.1.1. Criteria for Premature Termination of the Study 
Possible reasons for premature study termination include, but are not limited to, the 
following: 
• The occurrence of unanticipated adverse device effects that present a significant or 
unreasonable risk to subjects enrolled in the study. 
• An enrollment rate far below expectation that prejudices the conclusion of the study.  
• A decision on the part of BSC to suspend or discontinue development/marketing of the 
device. 
This trial may also be stopped early for effectiveness if upon interim analysis a significant 
difference in favor of the test arm is observed after enrollment of the first 70% of subjects. 
Please see Section 11.3.2 for additional information.  
22.2. Termination of Study Participation by the Investigator or Withdrawal of 
IRB/IEC/HREC Approval 
Any investigator, or associated IRB/IEC/HREC or regulatory authority may discontinue 
participation in the study or withdraw approval of the study, respectively, with suitable 
written notice to BSC. Investigators, associated IRBs/IECs/HRECs, and regulatory 
authorities, as applicable, will be notified in writing in the event of these occurrences. 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 52 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 53 of 76 
  
22.3. Requirements for Documentation and Subject Follow-up 
In the event of premature study termination, a written statement as to why the premature 
termination has occurred will be provided to all participating sites by BSC. The 
IRB/IEC/HREC and regulatory authorities, as applicable, will be notified. Detailed 
information on how enrolled subjects will be managed thereafter will be provided.  
In the event an IRB/IEC/HREC terminates participation in the study, participating 
investigators, associated IRBs/IECs/HRECs, and regulatory authorities, as applicable, will be 
notified in writing. Detailed information on how enrolled subjects will be managed thereafter 
will be provided by BSC. 
In the event a Principal Investigator terminates participation in the study, study responsibility 
will be transferred to another investigator, if possible. In the event there are no opportunities 
to transfer Principal Investigator responsibility, detailed information on how enrolled 
subjects will be managed thereafter will be provided by BSC. 
The Principal Investigator or his/her designee must return all study-related documents and 
devices, if supplied by BSC, unless this action would jeopardize the rights, safety, or welfare 
of the subjects. 
22.4. Criteria for Suspending/Terminating a Study Center 
Boston Scientific Corporation reserves the right to stop the inclusion of subjects at a study 
center at any time after the study initiation visit if no subjects have been enrolled for a period 
beyond 3 months after center initiation, or if the center has multiple or severe protocol 
violations/noncompliance without justification and/or fails to follow remedial actions. 
In the event of termination of center participation, all devices and testing equipment, as 
applicable, will be returned to BSC unless this action would jeopardize the rights, safety or 
well-being of the subjects. The IRB/IEC/HREC and regulatory authorities, as applicable, will 
be notified. Study participants will be contacted, as applicable, and be informed of changes to 
study visit schedule. 
23. Publication Policy 
Boston Scientific Corporation requires disclosure of its involvement as a sponsor or financial 
supporter in any publication or presentation relating to a BSC study or its results. Boston 
Scientific Corporation will submit study results for publication (regardless of study outcome) 
following the conclusion or termination of the study. Boston Scientific Corporation adheres 
to the Contributorship Criteria set forth in the Uniform Requirements of the International 
Committee of Medical Journal Editors (ICMJE; http://www.icmje.org). In order to ensure the 
public disclosure of study results in a timely manner, while maintaining an unbiased 
presentation of study outcomes, BSC personnel may assist authors and investigators in 
publication preparation provided the following guidelines are followed.  
• All authorship and contributorship requirements as described above must be followed. 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 53 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 54 of 76 
  
• BSC involvement in the publication preparation and the BSC Publication Policy should 
be discussed with the Coordinating Principal Investigator(s) and/or Executive/Steering 
Committee at the onset of the project. 
• The First and Senior authors are the primary drivers of decisions regarding publication 
content, review, approval, and submission.  
The data, analytic methods, and study materials for this clinical trial may be made available 
to other researchers in accordance with the Boston Scientific Data Sharing Policy 
(http://www.bostonscientific.com/). 
24. Bibliography 
1. 
Bendszus M, Stoll G. Silent cerebral ischaemia: hidden fingerprints of invasive medical 
procedures. Lancet Neurol 2006;5:364-72. 
2. 
Mastoris I, Schoos MM, Dangas GD, Mehran R. Stroke after transcatheter aortic valve 
replacement: Incidence, risk factors, prognosis, and preventive strategies. Clin Cardiol 
2014;37:756-64. 
3. 
Lansky AJ, Ghare MI, Pietras C. Carotid disease and stroke after transcatheter aortic 
valve replacement. Circ Cardiovasc Interv 2018;11:e006826. 
4. 
Kapadia S, Agarwal S, Miller DC, et al. Insights into timing, risk factors, and outcomes 
of stroke and transient ischemic attack after transcatheter aortic valve replacement in 
the PARTNER Trial (Placement of Aortic Transcatheter Valves). Circ Cardiovasc 
Interv 2016;9:e002981. 
5. 
Kleiman NS, Maini BJ, Reardon MJ, et al. Neurological events following transcatheter 
aortic valve replacement and their predictors: a report from the CoreValve trials. Circ 
Cardiovasc Interv 2016;9:e003551. 
6. 
Carroll JD, Vemulapalli S, Dai D, et al. Procedural experience for transcatheter aortic 
valve replacement and relation to outcomes: The STS/ACC TVT Registry. J Am Coll 
Cardiol 2017;70:29-41. 
7. 
Baim DS, Wahr D, George B, et al. Randomized trial of a distal embolic protection 
device during percutaneous intervention of saphenous vein aorto-coronary bypass 
grafts. Circulation 2002;105:1285-90. 
8. 
Stone GW, Rogers C, Hermiller J, et al. Randomized comparison of distal protection 
with a filter-based catheter and a balloon occlusion and aspiration system during 
percutaneous intervention of diseased saphenous vein aorto-coronary bypass grafts. 
Circulation 2003;108:548-53. . 
9. 
Gurm HS, Yadav JS, Fayad P, et al. Long-term results of carotid stenting versus 
endarterectomy in high-risk patients. N Engl J Med 2008;358:1572-9. 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 54 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 55 of 76 
  
10. Demir OM, Iannopollo G, Mangieri A, et al. The role of cerebral embolic protection 
devices during transcatheter aortic valve replacement. Front Cardiovasc Med 
2018;5:150:doi: 10.3389/fcvm.2018.00150. 
11. Kapadia SR, Kodali S, Makkar R, et al. Protection against cerebral embolism during 
transcatheter aortic valve replacement. J Am Coll Cardiol 2017;69:367-77. 
12. Van Mieghem NM, van Gils L, Ahmad H, et al. Filter-based cerebral embolic 
protection with transcatheter aortic valve implantation: the randomised MISTRAL-C 
trial. EuroIntervention 2016;12:499-507. 
13. Haussig S, Mangner N, Dwyer MG, et al. Effect of a cerebral protection device on 
brain lesions following transcatheter aortic valve implantation in patients with severe 
aortic stenosis: the CLEAN-TAVI randomized clinical trial. JAMA 2016;316:592-601. 
14. Lansky AJ, Schofer J, Tchétché D, et al. A prospective randomized evaluation of the 
TriGuard HDH embolic DEFLECTion device during transcatheter aortic valve 
implantation: results from the DEFLECT III trial. Eur Heart J 2015;36:2070-8. 
15. Wendt D, Kleinbongard P, Knipp S, et al. Intraaortic protection from embolization in 
patients undergoing transaortic transcatheter aortic valve implantation. Ann Thorac 
Surg 2015;100:686-91. 
16. Kappetein AP, Head SJ, Genereux P, et al. Updated standardized endpoint definitions 
for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 
consensus document. J Am Coll Cardiol 2012;60:1438-54. 
17. Seeger J, Gonska B, Otto M, Rottbauer W, Wöhrle J. Cerebral embolic protection 
during transcatheter aortic valve replacement significantly reduces death and stroke 
compared with unprotected procedures. J Am Coll Cardiol Intv 2017;10:2297-303. 
18. Kroon HG, van der Werf HW, Hoeks SE, et al. Early clinical impact of cerebral 
embolic protection in patients undergoing transcatheter aortic valve replacement. Circ 
Cardiovasc Interv 2019;12:e007605. 
19. Giustino G, Sorrentino S, Mehran R, Faggioni M, Dangas G. Cerebral embolic 
protection during TAVR: a clinical event meta-analysis. J Am Coll Cardiol 
2017;69:465-6. 
20. Seeger J, Kapadia SR, Kodali S, et al. Rate of peri-procedural stroke observed with 
cerebral embolic protection during transcatheter aortic valve replacement: a patient-
level propensity-matched analysis. Eur Heart J 2019;40:1334-40. 
21. Lansky AJ, Messé SR, Brickman AM, et al. Proposed standardized neurological 
endpoints for cardiovascular clinical trials: an Academic Research Consortium 
initiative. J Am Coll Cardiol 2017;69:679-91. 
22. Leon MB, Piazza N, Nikolsky E, et al. Standardized endpoint definitions for 
transcatheter aortic valve implantation clinical trials: a consensus report from the Valve 
Academic Research Consortium. J Am Coll Cardiol 2011;57:253-69. 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 55 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 56 of 76 
  
23. Inouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP, Horwitz RI. Clarifying 
confusion: the confusion assessment method. A new method for detection of delirium. 
Ann Intern Med 1990;113:941-8. 
24. Ely EW, Inouye SK, Bernard GR, et al. Delirium in mechanically ventilated patients: 
validity and reliability of the confusion assessment method for the intensive care unit 
(CAM-ICU). JAMA 2001;286:2703-10. 
25. Nasreddine ZS, Phillips NA, Bedirian V, et al. The Montreal Cognitive Assessment, 
MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 
2005;53:695-9. 
26. Mehta RL, Kellum JA, Shah SV, et al. Acute Kidney Injury Network: report of an 
initiative to improve outcomes in acute kidney injury. Crit Care 2007;11:R31. 
27. EuroQol Group. EuroQol-a new facility for the measurement of health-related quality 
of life. Health Policy 1990;16:199-208. 
28. Devlin NJ, Brooks R. EQ-5D and the EuroQol group: past, present and future. Appl 
Health Econ Health Policy 2017;15:127-37. 
29. Bruno A, Akinwuntan AE, Lin C, et al. Simplified modified Rankin scale 
questionnaire. Reproducibility over the telephone and validation with Quality of Life. 
Stroke 2011;42:2276-9. 
30. Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC Guideline for the 
management of patients with valvular heart disease: a report of the American College 
of Cardiology/American Heart Association task force on practice guidelines. J Am Coll 
Cardiol 2014;63:e57-185. 
31. Baumgartner H, Falk V, Bax JJ, et al. 2017 ESC/EACTS Guidelines for the 
management of valvular heart disease. Eur Heart J 2017;38:2739-91. 
32. Hicks KA, Mahaffey KW, Mehran R, et al. 2017 Cardiovascular and stroke endpoint 
definitions for clinical trials. J Am Coll Cardiol 2018;71:1021-34. 
33. O'Brien SM, Shahian DM, Filardo G, et al. The Society of Thoracic Surgeons 2008 
cardiac surgery risk models: Part 2-isolated valve surgery. Ann Thorac Surg 
2009;88:S23-42. 
34. Nashef SA, Roques F, Sharples LD, et al. EuroSCORE II. Eur J Cardiothorac Surg 
2012;41:734-44. 
35. Joseph J, Naqvi SY, Giri J, Goldberg S. Aortic stenosis: pathophysiology, diagnosis, 
and therapy. Am J Med 2017;130:253-63. 
36. Kanwar A, Thaden JJ, Nkomo VT. Management of patients with aortic valve stenosis. 
Mayo Clin Proc 2018;93:488-508. 
37. Mehta CR, Pocock SJ. Adaptive increase in sample size when interim results are 
promising: A practical guide with examples. Statist Med 2011;30:3267-84. 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 56 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 57 of 76 
  
38. Mehta CR, Gao P, Bhatt DL, Harrington RA, Skerjanec S, Ware JH. Optimizing trial 
design. Sequential, adaptive, and enrichment strategies. Circulation 2009;119:597-605. 
39. Kim K, DeMets DL. Design and analysis of group sequential tests based on the type I 
error spending rate function. Biometrika 1987;74:149-54. 
40. EAST® 6.5 Software, Cytel, Inc. 2018. 
41. Mehran R, Rao SV, Bhatt DL, et al. Standardized bleeding definitions for 
cardiovascular clinical trials: a consensus report from the Bleeding Academic Research 
Consortium. Circulation 2011;123:2736-47. 
42. Ndrepepa G, Schuster T, Hadamitzky M, et al. Validation of the Bleeding Academic 
Research Consortium definition of bleeding in patients with coronary artery disease 
undergoing percutaneous coronary intervention. Circulation 2012;125:1424-31. 
43. Witlox J, Eurelings LS, de Jonghe JF, Kalisvaart KJ, Eikelenboom P, van Gool WA. 
Delirium in elderly patients and the risk of postdischarge mortality, institutionalization, 
and dementia: a meta-analysis. JAMA 2010;304:443-51. 
44. Saczynski JS, Marcantonio ER, Quach L, et al. Cognitive trajectories after 
postoperative delirium. N Engl J Med 2012;367:30-9. 
45. Durack DT, Lukes AS, Bright DK. New criteria for diagnosis of infective endocarditis: 
utilization of specific echocardiographic findings. Duke Endocarditis Service. Am J 
Med 1994;96:200-9. 
46. Thygesen K, Alpert JS, White HD. Universal definition of myocardial infarction. Eur 
Heart J 2007;28:2525-38. 
47. Bonow RO, Brown AS, Gillam LD, et al. ACC/AATS/AHA/ASE/EACTS/HVS/SCA/ 
SCAI/SCCT/SCMR/STS 2017 Appropriate use criteria for the treatment of patients 
with severe aortic stenosis: a report of the American College of Cardiology Appropriate 
Use Criteria Task Force, American Association for Thoracic Surgery, American Heart 
Association, American Society of Echocardiography, European Association for Cardio-
Thoracic Surgery, Heart Valve Society, Society of Cardiovascular Anesthesiologists, 
Society fior Cardiovascular Angiography and Interventions, Society of Cardiovascular 
Computed Tomography, Society for Cardiovascular Magnetic Resonance, and Society 
of Thoracic Surgeons. J Am Coll Cardiol 2017;70:2566-98. 
48. Sharp AS, Michev I, Maisano F, et al. A new technique for vascular access 
management in transcatheter aortic valve implantation. Catheter Cardiovasc Interv 
2010;75:784-93. 
49. Généreux P, Kodali S, Leon MB, et al. Clinical outcomes using a new crossover 
balloon occlusion technique for percutaneous closure after transfemoral aortic valve 
implantation. J Am Coll Cardiol Intv 2011;4:861-7. 
 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 57 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 58 of 76 
  
25. Abbreviations and Definitions  
25.1. Abbreviations and Acronyms 
Abbreviations and acronyms are shown in Table 25.1-1.  
 
 
Table 25.1-1: Abbreviations and Acronyms 
Abbreviation/Acronym 
Definition 
ADE 
adverse device effect 
AE 
adverse event 
AKI 
acute kidney injury 
BSC 
Boston Scientific Corporation 
CAM-ICU 
Confusion Assessment Method for Intensive Care Unit Patients 
CEC 
Clinical Events Committee 
CEPD 
cerebral embolic protection device 
eCRF 
electronic case report form 
EDC 
electronic data capture 
FLAIR 
fluid-attenuated inversion recovery 
GCP 
Good Clinical Practices 
GDPR 
General Data Protection Regulation 
HREC 
Human Research Ethics Committee 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IFU 
Instructions for Use 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization 
ITT 
intention to treat 
MACCE 
major adverse cardiac and cerebrovascular events 
MoCA 
Montreal Cognitive Assessment 
mRS 
Modified Rankin Scale  
NeuroARC 
Neurologic Academic Research Consortium 
NIHSS 
National Institutes of Health Stroke Scale 
SADE 
serious adverse device effect 
SAE 
serious adverse event 
SOP 
standard operating procedure 
TAVR 
transcatheter aortic valve replacement 
TIA 
transient ischemic attack 
UADE 
unanticipated adverse device effect 
USADE 
unanticipated serious adverse device effect 
VARC 
Valve Academic Research Consortium 
 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 58 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 59 of 76 
  
25.2. Definitions 
Terms are defined in Table 25.2-1. See Table 25.1-1 for a list of abbreviations.  
Table 25.2-1: Definitions 
Term 
Definition 
ACUTE KIDNEY 
INJURY (AKI) 
(AKIN System26) 
Change in serum creatinine (up to 7 days) compared to baseline: 
• Stage 1: Increase in serum creatinine to 150–199% (1.5–1.99 × increase 
compared with baseline) OR increase of ≥0.3 mg/dl (≥26.4 mmol/L)  
• Stage 2: Increase in serum creatinine to 200–299% (2.0–2.99 × increase 
compared with baseline) 
• Stage 3: Increase in serum creatinine to ≥300% (>3 × increase compared with 
baseline) OR serum creatinine of ≥4.0 mg/dL (≥354 mmol/L) with an acute 
increase of at least 0.5 mg/dL (44 mmol/L) 
-OR-  
Based on urine output (up to 7 days): 
• Stage 1: <0.5 ml/kg per hour for >6 but <12 hours 
• Stage 2: <0.5 ml/kg per hour for >12 but <24 hours 
• Stage 3: <0.3 ml/kg per hour for ≥24 hours or anuria for ≥12 hours 
Note 1: Subjects receiving renal replacement therapy are considered to meet Stage 
3 criteria irrespective of other criteria. 
ACUTE VESSEL 
OCCLUSION 
The state of complete luminal obstruction with no antegrade blood flow 
ADVERSE EVENT 
(AE) 
Ref: ISO 14155 
Ref: MEDDEV 2.7/3 
Any untoward medical occurrence, unintended disease or injury, or any untoward 
clinical signs (including an abnormal laboratory finding) in subjects, users or other 
persons, whether or not related to the study medical device.  
Note 1: This includes events related to the study medical device or comparator. 
Note 2: This definition includes events related to the procedures involved. 
Note 3: For users or other persons, this definition is restricted to events related to 
the study medical device. 
ADVERSE DEVICE 
EFFECT (ADE) 
Ref: ISO 14155 
Ref: MEDDEV 2.7/3 
Adverse event related to the use of the study medical device 
Note 1: This includes any adverse event resulting from insufficiencies or 
inadequacies in the instructions for use, the deployment, the implantation, the 
installation, the operation, or any malfunction of the study medical device. 
Note 2: This definition includes any event resulting from use error or intentional 
abnormal use of the study medical device. 
AORTIC 
DISSECTION 
Intimal tear resulting in blood splitting the aortic media and producing a false 
lumen that can progress in an antegrade or retrograde direction Aortic dissection is 
further classified using Stanford classification (Types A and B depending on 
whether ascending or descending aorta involved) or DeBakey classification 
(Types I, II and III) [see Figure below]. 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 59 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 60 of 76 
  
Table 25.2-1: Definitions 
Term 
Definition 
 
AORTIC 
REGURGITATION 
(AR) 
The leaking of the aortic valve that causes blood to flow in the reverse direction 
during ventricular diastole, from the aorta into the left ventricle. The 
echocardiographic findings in severe aortic regurgitation include the following. 
• An AR color jet dimension >60% of the left ventricular outflow tract diameter 
(may not be true if the jet is eccentric)  
• The pressure half-time of the regurgitant jet is <250 msec  
• Early termination of the mitral inflow (due to increase in LV pressure due to 
the AR)  
• Early diastolic flow reversal in the descending aorta.  
 
• Regurgitant volume >60 mL 
• Regurgitant fraction >55% 
ARRHYTHMIA 
Any variation from the normal rhythm of the heartbeat, including sinus 
arrhythmia, premature beat, heart block, atrial fibrillation, atrial flutter and 
tachycardia. Complete heart block, ventricular tachycardia and ventricular 
fibrillation are considered major arrhythmias. Data should be collected on any 
new arrhythmia resulting in hemodynamic instability or requiring therapy (therapy 
includes electrical/medical cardioversion or initiation of a new medication [oral 
anticoagulation, rhythm or rate controlling therapy]).  
New onset atrial fibrillation or atrial flutter (AF) is diagnosed as any arrhythmia 
within hospitalization that has the ECG characteristics of AF and lasts sufficiently 
long to be recorded on a 12-lead ECG, or at least 30 seconds on a rhythm strip.  
The therapeutic approach to new-onset AF (spontaneous conversion, electrical or 
medical cardioversion, initiation of oral anticoagulation, and rate or rhythm 
control medications) and any clinical consequences should be documented.   
Note 1: See also definitions for conductance disturbance and permanent 
pacemaker. 
BLEEDING   
Life-threatening or Disabling Bleeding 
• Fatal bleeding (Bleeding Academic Research Consortium [BARC] type 541,42) 
• Bleeding in a critical organ, such as intracranial, intraspinal, intraocular, or 
pericardial necessitating pericardiocentesis, or intramuscular with compartment 
syndrome (BARC type 3b and 3c)  
• Bleeding causing hypovolemic shock or severe hypotension requiring 
vasopressors or surgery (BARC type 3b)  
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 60 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 61 of 76 
  
Table 25.2-1: Definitions 
Term 
Definition 
• Overt source of bleeding with drop in hemoglobin of ≥5 g/dL or whole blood or 
packed red blood cells (RBC) transfusion ≥4 units (BARC type 3b)* 
Major Bleeding (BARC type 3a) 
• Overt bleeding either associated with a drop in the hemoglobin level of at least 
3.0g/dL or requiring transfusion of 2 or 3 units of whole blood/RBC, or causing 
hospitalization or permanent injury, or requiring surgery AND does not meet 
criteria of life-threatening or disabling bleeding  
Minor Bleeding (BARC type 2 or 3a, depending on the severity) 
• Any bleeding worthy of clinical mention (e.g., access site hematoma) that does 
not qualify as life-threatening, disabling, or major 
* Given one unit of packed RBC typically will raise blood hemoglobin 
concentration by 1 g/dL, an estimated decrease in hemoglobin will be calculated. 
CARDIAC 
DECOMPENSATION 
Inability of the heart to maintain adequate circulation 
CARDIAC 
TAMPONADE 
Evidence of a new pericardial effusion associated with hemodynamic instability 
and clearly related to the TAVR procedure. Clinical syndrome caused by the 
accumulation of fluid in the pericardial space, resulting in reduced ventricular 
filling and subsequent hemodynamic compromise. 
CARDIOGENIC 
SHOCK 
An insufficient forward cardiac output to maintain adequate perfusion of vital 
organs to meet ongoing demands for oxygenation and metabolism. Cardiogenic 
shock is due to either inadequate left ventricular pump function (such as in 
congestive heart failure) or inadequate left ventricular filling (such as in cardiac 
tamponade). Cardiogenic shock is defined as sustained hypotension (>30 minutes) 
with evidence of tissue hypoperfusion including oliguria (<30 mL/h), cool 
extremities, cyanosis, and altered mental status. 
CEREBRAL 
INFARCTION 
Evidence of brain cell death from imaging studies or pathological examination. If 
there are clinical symptoms, then it is a stroke; otherwise, it is an asymptomatic 
cerebral infarction.  
CHRONIC RENAL 
INSUFFICIENCY 
Subject has chronic impairment of kidney function. 
CLINICAL EVENTS 
COMMITTEE (CEC) 
EVENT 
Includes the following: mortality, stroke/transient ischemic attack, delirium 
CONDUCTION 
DISTURBANCES  
Implant-related new or worsened cardiac conduction disturbances include new or 
worsened first degree atrioventricular (AV) block, second degree AV block 
(Mobitz I or Mobitz II), third degree AV block, incomplete right bundle branch 
block (RBBB), RBBB, intraventricular conduction delay, left bundle branch block 
(LBBB), left anterior fascicular block, or left posterior fascicular block, including 
block requiring permanent pacemaker implant 
Note 1: High grade AV block is considered persistent if it is present every time 
the underlying rhythm is checked. 
Note 2: See also definitions for arrhythmia and permanent pacemaker. 
CONVERSION TO 
OPEN SURGERY 
Conversion to open sternotomy during the TAVR procedure secondary to any 
procedure-related complications 
CORONARY 
OBSTRUCTION 
Angiographic or echocardiographic evidence of a new, partial or complete, 
obstruction of a coronary ostium, either by the valve prosthesis itself, the native 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 61 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 62 of 76 
  
Table 25.2-1: Definitions 
Term 
Definition 
leaflets, calcifications, or dissection, occurring during or after the TAVR 
procedure. 
Mechanical coronary artery obstruction following TAVR or surgical AVR that 
typically occurs during the index procedure. Possible mechanisms for mechanical 
coronary obstruction include the following.  
• Impingement of the coronary ostia by the valve support structure in the setting 
of suboptimal valve positioning and/or ‘small aortic root’ anatomy  
• Embolization from calcium, thrombus, air, or endocarditis displacement of 
native aortic valve leaflets towards the coronary ostia during TAVR  
• Suture-related kinking or obstruction or cannulation related obstruction of the 
coronary ostia associated with surgical AVR 
The diagnosis of TAVR-associated coronary obstruction can be determined by 
imaging studies (coronary angiography, intravascular ultrasound, multi-slice CT 
angiography, or echocardiography), surgical exploration, or autopsy findings. 
Cardiac biomarker elevations and ECG changes indicating new ischemia provide 
corroborative evidence. 
DATA CATEGORIES 
Data categories as defined by GDPR are listed below. 
Personal Data: 
GDPR defines “Personal Data” to be any information relating to an identified or 
identifiable natural person (‘data subject’); an identifiable natural person is one 
who can be identified, directly or indirectly, in particular by reference to an 
identifier such as a name, an identification number, location data, an online 
identifier or to one or more factors specific to the physical, physiological, genetic, 
mental, economic, cultural or social identity of that natural person. 
Sensitive Personal Data: 
GDPR defines “Sensitive Personal Data” as a subset of Personal Data, which, due 
to their nature have been classified as deserving additional privacy and security 
protections because their processing may create a risk for an individual’s 
fundamental right and freedom. This subset includes but is not limited to the 
following: racial, ethnic origin or ethnicity; political opinions; religious or 
philosophical beliefs; trade union membership; genetic data; biometric data for the 
purpose of uniquely identifying a natural person; health data (including gender, 
family medical history, etc.); sex life or sexual orientation; criminal records or 
allegations of crimes (requires an even higher standard of protection). 
Identifiers: 
“Identifiers” are Personal Data that can be used alone or in combination with other 
identifiers to identify an individual. Identifiers include but are not limited to the 
following:  
• All government-issued identification numbers (including but not limited to 
names, social security number, certificate/license numbers, passport, national 
ID) 
• All financial account numbers (including but not limited to bank account 
numbers, payment numbers, bank or credit card numbers)  
• All geographic subdivisions smaller than a state, including street address, 
city, county, precinct, ZIP code, and their equivalent geocodes, except for the 
initial three digits of the ZIP code if, according to the current publicly 
available data from the Bureau of the Census, the geographic unit formed by 
combining all ZIP codes with the same three initial digits contains more than 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 62 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 63 of 76 
  
Table 25.2-1: Definitions 
Term 
Definition 
20,000 people and/or the initial three digits of a ZIP code for all such 
geographic units containing 20,000 or fewer people is changed to 000 
• All elements of dates (except year) for dates that are directly related to an 
individual, including birth date, admission date, discharge date, death date, 
and all ages over 89 and all elements of dates (including year) indicative of 
such age, except that such ages and elements may be aggregated into a single 
category of age 90 or older 
• Telephone numbers 
• Fax numbers 
• Device identifiers and serial numbers 
• E-mail addresses 
• Web Universal Resource Locators (URLs) 
• Internet Protocol (IP) addresses 
• Medical record numbers 
• Biometric identifiers, including finger and voice prints 
• Health plan beneficiary numbers 
• Full-face photographs and any comparable images 
• Any other unique identifying number, characteristic, or code (including 
subject ID number) 
DEATH  
All-cause Death 
Death from any cause after a valve intervention. 
Cardiovascular Death 
Any one of the following criteria is met. 
• Any death due to proximate cardiac cause (e.g., myocardial infarction, cardiac 
tamponade, worsening heart failure) 
• Sudden or unwitnessed death  
• Death of unknown cause 
• Death caused by noncoronary vascular conditions such as neurological events, 
pulmonary embolism, ruptured aortic aneurysm, dissecting aneurysm, or other 
vascular disease  
• All procedure-related deaths, including those related to a complication of the 
procedure or treatment for a complication of the procedure  
• All valve-related deaths including structural or nonstructural valve dysfunction 
or other valve-related adverse events  
Non-cardiovascular Death 
• Any death in which the primary cause of death is clearly related to another 
condition (e.g. trauma, cancer, suicide) 
DELIRIUM 
Per NeuroARC21, while multifactorial, delirium (global neurological dysfunction) 
without central nervous system injury should be adjudicated and reported due to 
its prognostic implications43,44. Assessment tools include the Confusion 
Assessment Method for ICU Patients (CAM-ICU)23,24. 
DEVICE 
DEFICIENCY 
Inadequacy of a medical device with respect to its identity, quality, durability, 
reliability, safety or performance.  
Note 1: Device deficiencies include malfunctions, use errors, and inadequate 
labeling. 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 63 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 64 of 76 
  
Table 25.2-1: Definitions 
Term 
Definition 
DEVICE FAILURE 
A device failure is identified whenever the criteria for device success are not met.  
DEVICE MIGRATION 
Device migration is defined as an upward or downward displacement of the 
implanted valve from its original implant location, after initial correct positioning 
within the aortic annulus from its initial position, with or without consequences. 
This can be confirmed by X-ray, echocardiography, CT scan or MRI or valve 
migration demonstrated by direct assessment during open heart surgery or at 
autopsy. 
DEVICE RELATED 
COMPLICATIONS 
Complications associated with the device as it relates to delivery, placement, 
efficacy or durability; these may involve the implanted device or the delivery 
system.   
DEVICE SUCCESS 
Device Success for TAVR as defined by VARC post-implant procedure. 
VARC 122 
• Successful vascular access, delivery and deployment of the device and 
successful retrieval of the delivery system 
• Correct position of the device in the proper anatomical location 
• Intended performance of the prosthetic heart valve (aortic valve area >1.2 cm2 
and mean aortic valve gradient <20 mmHg or peak velocity <3 m/s, without 
moderate or severe prosthetic valve aortic regurgitation) 
• Only one valve implanted in the proper anatomical location 
VARC 216 
• Absence of procedural mortality 
• Correct positioning of a single transcatheter valve into the proper anatomical 
location 
• Intended performance of the Lotus Valve (indexed effective orifice area >0.85 
cm2/m2 [>0.7 cm2/m2 for BMI ≥30 kg/ m2] plus either a mean aortic valve 
gradient <20 mm Hg or a peak velocity <3m/sec, without moderate or severe 
prosthetic valve aortic regurgitation) 
ECTOPIC VALVE 
DEPLOYMENT 
Permanent deployment of the valve prosthesis in a location other than the aortic 
root. 
EMBOLISM 
Examples include a free-flowing blood clot or lesion material that is located in the 
systemic or pulmonary circulation. Embolism may be manifested by a 
neurological event or a noncerebral embolic event. 
ENCEPHALOPATHY 
Altered mental state (e.g., seizures, delirium, confusion, hallucinations, dementia, 
coma, psychiatric episode, etc.) 
ENDOCARDITIS 
Infective endocarditis is diagnosed based on Duke criteria45 and necessitates the 
following.  
• Two major criteria -OR- 
• One major and three minor criteria -OR- 
• Five minor criteria 
Major Criteria 
• Positive blood culture for infective endocarditis  
o Typical microorganism consistent with infective endocarditis from 2 
separate blood cultures, as noted below. 
 Viridans streptococci, Streptococcus bovis, or HACEK group 
(Haemophilus [Haemophilus parainfluenzae, Haemophilus aphrophilus, 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 64 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 65 of 76 
  
Table 25.2-1: Definitions 
Term 
Definition 
and Haemophilus paraphrophilus], Actinobacillus 
actinomycetemcomitans [Aggregatibacter actinomycetemcomitans], 
Cardiobacterium hominis, Eikenella corrodens, Kingella kingae -OR-  
 Community-acquired Staphylococcus aureus or enterococci, in the 
absence of a primary focus  
 
-OR-  
o Microorganisms consistent with infective endocarditis from persistently 
positive blood cultures defined as noted below. 
 Two (2) positive cultures of blood samples drawn >12 hours apart -OR-   
 All of 3 or a majority of 4 separate cultures of blood (with first and last 
sample drawn 1 hour apart)  
• Evidence of endocardial involvement 
o Positive echocardiogram for infective endocarditis defined as noted below. 
 Oscillating intracardiac mass on valve or supporting structures, in the path 
of regurgitant jets, or on implanted material in the absence of an 
alternative anatomic explanation -OR-   
 Abscess -OR-   
 New partial dehiscence of prosthetic valve  
 
-OR-  
o New valvular regurgitation (worsening or changing of preexisting murmur 
not sufficient) 
Minor Criteria 
• Predisposition: predisposing heart condition or intravenous drug use 
• Fever: temperature >38.0° C (100.4° F) 
• Vascular phenomena: major arterial emboli, septic pulmonary infarcts, mycotic 
aneurysm, intracranial hemorrhage, conjunctival hemorrhages, and Janeway 
lesions 
• Immunologic phenomena: glomerulonephritis, Osler's nodes, Roth spots, and 
rheumatoid factor 
• 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 infective endocarditis 
• Echocardiographic findings: consistent with infective endocarditis but do not 
meet a major criterion as noted above  
Implanted valve endocarditis includes any infection involving an implanted 
valve. The diagnosis of operated valvular endocarditis is based on one of the 
following criteria.  
• Fulfillment of the Duke endocarditis criteria as defined above 
• Evidence of abscess, paravalvular leak, pus, or vegetation confirmed as 
secondary to infection by histological or bacteriologic studies during a re-
operation 
• Findings of abscess, pus, or vegetation involving a repaired or replaced valve 
during an autopsy. 
EXPLANT 
Removal of an investigational valve implant for any reason. 
FRAILTY 
Slowness, weakness, exhaustion, wasting and malnutrition, poor endurance and 
inactivity, loss of independence.  
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 65 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 66 of 76 
  
Table 25.2-1: Definitions 
Term 
Definition 
GENERAL DATA 
PROTECTION 
REGULATION 
The General Data Protection Regulation (GDPR) is a legal framework that sets 
guidelines for the collection and processing of personal information of individuals 
within the European Union. 
HEMOLYSIS 
Two plasma free hemoglobin values >40 mg/dL with the two readings taken 
within a single 48-hour period. If the second plasma free hemoglobin assessment 
is not performed within 48 hours following an initial determination of >40 mg/dL, 
this would qualify as an AE. 
HOSPITALIZATION 
DUE TO VALVE-
RELATED 
SYMPTOMS/ 
WORSENING 
CONGESTIVE 
HEART FAILURE  
The need for hospitalization associated with valve-related symptoms or worsening 
CHF (NYHA Class III or IV) is intended to serve as a basis for calculation of a 
“days alive outside the hospital” endpoint. Included are heart failure, angina, or 
syncope due to aortic valve disease requiring intervention or intensified medical 
management; clinical symptoms of CHF with objective signs including pulmonary 
edema, hypoperfusion, or documented volume overload AND administration of 
intravenous diuresis or inotropic therapy, performance of aortic valvuloplasty, 
institution of mechanical support (intra-aortic balloon pump or ventilation for 
pulmonary edema), or hemodialysis for volume overload; clear documentation of 
anginal symptoms AND no clinical evidence that angina was related to coronary 
artery disease or acute coronary syndrome; documented loss of consciousness not 
related to seizure or tachyarrhythmia. 
HOSTILE CHEST 
Any of the following or other reasons that make redo operation through 
sternotomy or right anterior thoracotomy prohibitively hazardous: 
• Abnormal chest wall anatomy due to severe kyphoscoliosis or other skeletal 
abnormalities (including thoracoplasty, Potts’ disease) 
• Complications from prior surgery 
• Evidence of severe radiation damage (e.g. skin burns, bone destruction, muscle 
loss, lung fibrosis or esophageal stricture) 
• History of multiple recurrent pleural effusions causing internal adhesions 
INTERNAL 
MAMMARY 
ARTERY 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 
reoperation is likely. A patient may be considered extreme risk if any of the 
following are present:  
• The conduit(s) are radiographically indistinguishable from the posterior table of 
the sternum.  
• The conduit(s) are radiographically distinguishable from the posterior table of 
the sternum but lie within 2-3mm of the posterior table.  
INTRACRANIAL 
HEMORRHAGE 
Collection of blood between the brain and skull; subcategorized as epidural, 
subdural, and subarachnoid bleeds. 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 66 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 67 of 76 
  
Table 25.2-1: Definitions 
Term 
Definition 
LEFT BUNDLE 
BRANCH BLOCK 
(LBBB) 
The appearance of typical complete LBBB in the three KEY leads (I, V1, and V6) 
with the following diagnostic criteria [see Figure below].  
• The heart rhythm must be supraventricular in origin  
• QRS widening to at least 0.12 sec  
• An upright (monophasic) QRS complex in leads I and V6; the QRS may be 
notched, but there should not be any q wave in either lead I or lead V6. 
• A predominantly negative QRS complex in lead V1; there may or may not be 
an initial small r wave in lead V1, that is, lead V1 may show either a QS or RS 
complex. 
 
 
 
 
 
 
 
 
 
 
 
LIVER DISEASE 
(SEVERE) 
/CIRRHOSIS 
Any of the following: 
• Child-Pugh class C  
• MELD (Model for End-Stage Liver Disease) score ≥10 
• Portal-caval, spleno-renal, or transjugular intrahepatic portal shunt  
• Biopsy proven cirrhosis with portal hypertension or hepatocellular dysfunction 
MITRAL VALVE 
APPARATUS 
DAMAGE 
Angiographic or echocardiographic evidence of a new damage to the mitral valve 
apparatus (chordae papillary muscle, or leaflet) during or after the TAVR 
procedure. 
MYOCARDIAL 
INFARCTION (MI) 
Periprocedural MI (≤72 hours after the index procedure) 
• New ischemic symptoms (e.g., chest pain or shortness of breath) or new 
ischemic signs (e.g., ventricular arrhythmias, new or worsening heart failure, 
new ST-segment changes, hemodynamic instability, new pathological Q waves 
in at least two contiguous leads, or imaging evidence of new loss of viable 
myocardium or new wall motion abnormality)  
 
-AND- 
• Elevated cardiac biomarkers (preferably CK-MB) within 72 h after the index 
procedure, consisting of at least one sample post-procedure with a peak value 
exceeding 15× upper reference limit (troponin) or 5× for CK-MB. If cardiac 
biomarkers are increased at baseline (>99th percentile), a further increase of at 
least 50% post-procedure is required AND the peak value must exceed the 
previously stated limit. 
Spontaneous MI (>72 hours after the index procedure) 
Any one of the following criteria applies. 
• Detection of rise and/or fall of cardiac biomarkers (preferably troponin) with at 
least one value above the 99th percentile URL, together with evidence of 
myocardial ischemia with at least one of the following 
o Symptoms of ischemia 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 67 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 68 of 76 
  
Table 25.2-1: Definitions 
Term 
Definition 
o ECG changes indicative of new ischemia [new ST-T changes or new LBBB] 
o New pathological Q waves in at least two contiguous leads 
o Imaging evidence of new loss of viable myocardium or new wall motion 
abnormality 
• Sudden, unexpected cardiac death, involving cardiac arrest, often with 
symptoms suggestive of myocardial ischemia, and accompanied by presumably 
new ST-segment elevation, or new LBBB, and/or evidence of fresh thrombus 
by coronary angiography and/ or at autopsy, but death occurring before blood 
samples could be obtained, or at a time before the appearance of cardiac 
biomarkers in the blood. 
• Pathological findings of an acute myocardial infarction46. 
NEUROLOGICAL 
EVENT  
Any central, new neurological deficit, whether temporary or permanent and 
whether focal or global, that occurs after the subject emerges from anesthesia 
NEUROLOGY 
PROFESSIONAL 
Defined as a neurologist, neurology fellow, neurology physician assistant, or 
neurology nurse practitioner 
NEW YORK HEART 
ASSOCIATION 
CLASSIFICATION 
(NYHA) 
Classification system for defining cardiac disease and related functional 
limitations into four broad categorizations: 
 
Class I 
Subject with cardiac disease but without resulting limitations of 
physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain. 
Class II 
Subjects with cardiac disease resulting in slight limitation of 
physical activity. They are comfortable at rest. Ordinary physical 
activity results in fatigue, palpitation, dyspnea, or anginal pain. 
Class III 
Subjects with cardiac disease resulting in marked limitation of 
physical activity. They are comfortable at rest. Less than ordinary 
physical activity causes fatigue, palpitation, dyspnea, or anginal 
pain. 
Class IV 
Subjects with cardiac disease resulting in inability to carry on any 
physical activity without discomfort. Symptoms of cardiac 
insufficiency or of the anginal syndrome may be present even at 
rest. If any physical activity is undertaken, discomfort is 
increased. 
NONSTRUCTURAL 
DYSFUNCTION 
Any abnormality not intrinsic to the valve itself that results in stenosis or 
regurgitation of the operated valve or hemolysis. The term nonstructural 
dysfunction refers to problems (exclusive of thrombosis and infection) that do not 
directly involve valve components yet result in dysfunction of an operated valve, 
as diagnosed by re-operation, autopsy, or clinical investigation. Nonstructural 
dysfunction includes the following. 
• Entrapment by pannus, tissue, or suture 
• Paravalvular leak 
• Inappropriate sizing or positioning 
• Residual leak or obstruction after valve implantation or repair 
• Clinically important intravascular hemolytic anemia 
• Development of aortic or pulmonic regurgitation as a result of technical errors 
• Dilatation of the sinotubular junction 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 68 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 69 of 76 
  
Table 25.2-1: Definitions 
Term 
Definition 
• Dilatation of the valve annulus after either valve replacement with stentless 
prostheses, new onset of coronary ischemia from coronary ostial obstruction, or 
paravalvular aortic regurgitation  
PARAVALVULAR 
REGURGITATION / 
PARAVALVULAR 
LEAK  
Leakage due to a separation of the prosthetic valve from the annulus. Any 
evidence of leakage of blood around the device. Diagnosis of paravalvular 
regurgitation/paravalvular leak may be obtained from TEE/TTE, however, 
definitive diagnosis is obtained at re-operation, explant, or autopsy.  
PERMANENT 
PACEMAKER 
IMPLANTATION 
(PPI)  
Implantation of a new permanent pacemaker after the index procedure resulting 
from new or worsened conduction disturbances (including new left bundle branch 
block [LBBB] and third-degree atrioventricular block)  
• Procedure-related: Permanent pacemaker is implanted in subjects with new 
onset or worsened conduction disturbances occurring post index procedure 
• Not related to procedure: Permanent pacemaker is implanted in subjects with 
known conduction disturbances that did not advance after the index procedure. 
Note: See also definitions for arrhythmia and conductance disturbance. 
PORCELAIN AORTA 
Heavy circumferential calcification of the entire ascending aorta extending to the 
arch such that aortic cross-clamping is not feasible 
PROCEDURE 
RELATED 
COMPLICATIONS 
Complications associated with any part of the vascular access procedure, 
associated treatments or necessary secondary interventions that do not necessarily 
involve the device.  This includes morbidity associated with either pre-medication, 
or anesthesia, or other adjunct to the surgical procedure.  Other technical errors 
including inappropriate subject selection, inappropriate operator techniques, 
measurements, or judgment that do not involve the device itself are also included.   
PROCEDURE-
RELATED EVENTS 
Events occurring during or as a direct result of the index procedure.  
REPEAT 
PROCEDURE FOR 
VALVE-RELATED 
DYSFUNCTION 
Any surgical or percutaneous interventional catheter procedure that repairs, 
otherwise alters or adjusts, or replaces a previously implanted valve. In addition to 
surgical re-operations, balloon dilatation, interventional manipulation, 
repositioning, or retrieval, and other catheter-based interventions for valve-related 
complications are also considered reinterventions. Cardiac reinterventions will be 
categorized as repeat TAVR, valvuloplasty, or surgical AVR. 
REPOSITIONING OF 
A VALVE 
Any movement of the valve after the lead in phase (after the posts have entered 
the buckles) 
RESHEATHING OF A 
VALVE 
Full resheathing occurs when the top of the posts re-enter the Lotus catheter 
during repositioning. 
Partial resheathing occurs when the posts do not re-enter the Lotus catheter during 
repositioning. 
RESPIRATORY 
INSUFFICIENCY 
Inadequate ventilation or oxygenation 
RESPIRATORY 
FAILURE 
The need for ventilatory support for >72 hours associated with an inability to 
wean from the respirator for any reason. 
RIGHT 
VENTRICULAR 
INSUFFICIENCY 
• Defined as sequelae of right ventricular failure including the following. 
o Significantly decreased right ventricular systolic and/or diastolic function 
o Tricuspid valvular regurgitation secondary to elevated pressure 
• Clinical symptoms to include the following. 
o Hepatic congestion 
o Ascites 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 69 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 70 of 76 
  
Table 25.2-1: Definitions 
Term 
Definition 
o Anasarca 
o Presence of “hepato-jugular reflux” 
o Edema 
Severe right ventricular dysfunction or severe pulmonary hypertension is primary 
or secondary pulmonary hypertension with PA systolic pressures greater than 2/3 
of systemic pressure.  
SERIOUS ADVERSE 
EVENT (SAE) 
Ref: ISO 14155 
Ref: MEDDEV 2.7/3 
Note 1: This definition meets the reporting objectives and requirements of ISO 
14155 and MEDDEV 2.7/3. 
Adverse event that: 
• Led to death, 
• Led to serious deterioration in the health of the subject as defined by either: 
o a life-threatening illness or injury, or 
o a permanent impairment of a body structure or a body function, or 
o in-patient hospitalization or prolongation of existing hospitalization, or 
o medical or surgical intervention to prevent life-threatening illness or 
injury or permanent impairment to a body structure or a body function 
• Led to fetal distress, fetal death, or a congenital abnormality or birth defect. 
Note 2: Planned hospitalization for a pre-existing condition, or a procedure 
required by the clinical investigational plan, without a serious deterioration in 
health, is not considered a serious adverse event. 
SERIOUS ADVERSE 
DEVICE EFFECT 
(SADE) 
Ref: ISO 14155 
Ref: MEDDEV 2.7/3 
Adverse device effect that has resulted in any of the consequences characteristic 
of a serious adverse event 
SOURCE DATA 
(per ISO 14155:2011) 
All information in original records of clinical findings, observations, or other 
activities in a clinical investigation, necessary for the reconstruction and 
evaluation of the clinical investigation 
SOURCE 
DOCUMENT 
(per ISO 14155:2011) 
Printed, optical or electronic document containing source data. Examples: 
Hospital records, laboratory notes, device accountability records, photograhic 
negatives, radiographs, records kept at the investigation center, at the laboratories 
and at the medico-technical departments involvced in the clinical investigation.  
STROKE 
NeuroARC21 
 
Neurological Event 
Definitions 
Type 
Description 
Type 1 − Overt CNS Injury: Acutely Symptomatic Brain or Spinal Cord Injury 
Type 1.a 
Ischemic 
stroke 
Sudden onset of neurological signs or symptoms fitting a focal or 
multifocal vascular territory within the brain, spinal cord, or 
retina, that: 
1. Persist for ≥24 h or until death, with pathology or neuroimaging 
evidence that demonstrates either: 
a. CNS infarction in the corresponding vascular territory (with or 
without hemorrhage); or 
b. Absence of other apparent causes (including hemorrhage), even 
if no evidence of acute ischemia in the corresponding vascular 
territory is detected 
or 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 70 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 71 of 76 
  
Table 25.2-1: Definitions 
Term 
Definition 
2. Symptoms lasting <24 h, with pathology or neuroimaging 
confirmation of CNS infarction in the corresponding vascular 
territory. Note: When CNS infarction location does not match the 
transient symptoms, the event would be classified as covert CNS 
infarction (Type 2a) and a TIA (Type 3a), but not as an ischemic 
stroke. 
Signs and symptoms consistent with stroke typically include an 
acute onset of 1 of the following: focal weakness and/or 
numbness; impaired language production or comprehension; 
homonymous hemianopia or quadrantanopsia; diplopia; altitudinal 
monocular blindness; hemispatial neglect; dysarthria; vertigo; or 
ataxia. 
Type 2 − Covert CNS Injury: Acutely Asymptomatic Brain or Spinal Cord Injury 
Detected by Neuroimaging 
Type 2.a 
Covert CNS 
infarction 
Brain, spinal cord, or retinal cell death attributable to focal or 
multifocal ischemia, on the basis of neuroimaging or pathological 
evidence of CNS infarction, without a history of acute 
neurological symptoms consistent with the lesion location 
Subtype 
2.a.H 
Covert CNS 
infarction 
with 
hemorrhagic 
conversion 
Covert CNS infarction includes hemorrhagic conversions. These 
should be subclassified as Class A or B when CNS infarction is 
the primary mechanism and neuroimaging or pathology confirms a 
hemorrhagic conversion. 
Class A:  Petechial hemorrhage: Petechiae or confluent petechiae 
within the infarction or its margins, but without a space-
occupying effect 
Class B:  Confluent hemorrhage: Confluent hemorrhage 
originating from within the infarcted area with a space-
occupying effect 
Type 2.b 
Covert CNS 
hemorrhage 
Neuroimaging or pathological evidence of CNS hemorrhage 
within the brain parenchyma, subarachnoid space, ventricular 
system, spinal cord, or retina on neuroimaging that is not caused 
by trauma, without a history of acute neurological symptoms 
consistent with the bleeding location. 
Type 3 – Neurological Dysfunction (Acutely Symptomatic) Without CNS Injury 
Type 3.a  
Transient 
ischemic 
attack 
Transient focal neurological signs or symptoms (lasting <24 h) 
presumed to be due to focal brain, spinal cord, or retinal ischemia, 
but without evidence of acute infarction by neuroimaging or 
pathology (or in the absence of imaging). 
Type 3.b 
Delirium 
without 
CNS injury 
Transient nonfocal (global) neurological signs or symptoms 
(variable duration) without evidence of cell death by 
neuroimaging or pathology. 
Composite Neurological Endpointsa 
CNS 
infarction 
Any brain, spinal cord, or retinal infarction on the basis of 
imaging, pathology, or clinical symptoms persisting for ≥24 h 
(includes Types 1.a, 1.a.H, 1.d, 1.e, 2.a, 2.a.H) 
CNS 
hemorrhage 
Any brain, spinal cord, or retinal hemorrhage on the basis of 
imaging or pathology, not caused by trauma (includes Type 1.b, 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 71 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 72 of 76 
  
Table 25.2-1: Definitions 
Term 
Definition 
1.c, 2.b) 
a:  Neurological endpoints are not mutually exclusive; an individual subject may 
have >1 event. VARC–defined stroke includes all Type 1 events (stroke and 
symptomatic hypoxic-ischemic injury). American Stroke Association–defined 
stroke includes Type 1.a–d events (overt [focal only] CNS injury), and Type 
2.a and 2.a.H (covert CNS infarction). 
STROKE 
VARC16,22  
Stroke is defined as 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  
Stroke Classification 
• Ischemic Stroke is defined as an acute episode of focal cerebral, spinal, or 
retinal dysfunction caused by an infarction of central nervous system tissue.  
• Hemorrhagic Stroke is defined as an acute episode of focal or global cerebral or 
spinal dysfunction caused by an intraparenchymal, intraventricular, or 
subarachnoid hemorrhage 
Note 1: The CEC will adjudicate ischemic versus hemorrhagic stroke. 
Note 2: A stroke may be classified as undetermined if there is insufficient 
information to allow categorization as ischemic or hemorrhagic 
Stroke Diagnostic Criteria  
• Rapid onset of a focal or global neurological deficit with at least one of the 
following: change in level of consciousness, hemiplegia, hemiparesis, 
numbness or sensory loss affecting one side of the body, dysphasia or aphasia, 
hemianopia, amaurosis fugax, or other neurological signs or symptoms 
consistent with stroke 
• Duration of a focal or global neurological deficit ≥24 h; OR <24 h, if available 
neuroimaging documents a new hemorrhage or infarct; OR the neurological 
deficit results in death 
• No other readily identifiable nonstroke cause for the clinical presentation (e.g., 
brain tumor, trauma, infection, hypoglycemia, peripheral lesion, 
pharmacological influences), to be determined by or in conjunction with 
designated neurologist 
• Confirmation of the diagnosis by at least one of the following.  
o Neurology or neurosurgical specialist  
o Neuroimaging procedure (MRI or CT scan), but stroke may be diagnosed on 
clinical grounds alone 
Note 3: Subjects with non-focal global encephalopathy will not be reported as a 
stroke without unequivocal evidence based upon neuroimaging studies (CT scan 
or brain MRI).  
Stroke Definitions 
Diagnosis as above, preferably with positive neuroimaging study 
• Non-disabling: Modified Rankin Scale (mRS) score <2 at 90 days OR one that 
does not result in an increase of at least one mRS category from an individual’s 
pre-stroke baseline 
• Disabling: Modified Rankin Scale score ≥2 at 90 days AND an increase of at 
least one mRS category from an individual’s pre-stroke baseline  
Note 4: Modified Rankin Scale assessments should be made by qualified 
individuals according to a certification process.  
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 72 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 73 of 76 
  
Table 25.2-1: Definitions 
Term 
Definition 
Note 5: Assessment of the mRS score should occur at baseline; mRS also should 
be performed after a stroke and at 90 days after the onset of any stroke. 
STRUCTURAL 
VALVE 
DETERIORATION 
(SVD)  
Component of time-related valve safety defined as follows. 
• Valve-related dysfunction: Mean aortic valve gradient ≥20 mmHg, EOA 
≤0.9-1.1 cm2, and/or DVI <0.35 AND/OR moderate or severe prosthetic valve 
regurgitation (per VARC definition) 
• Requiring repeat procedure (TAVR or SAVR). 
Note: Additional outcomes may be measured per definitions set in the most 
current VARC guidelines (as released at the time of analysis). 
SURGICAL RISK47 
Surgical risk is determined by the Heart Team, including a center cardiac surgeon.  
Note: Input from the Heart Team regarding anatomic or functional factors not 
reflected in the Society of Thoracic Surgeons predicted risk of mortality (STS-
PROM) score may increase patient risk above the definitions provided below. 
Extreme Risk: Predicted operative mortality risk ≥15% at 30 days as determined 
by STS-PROM score  
High Risk: Predicted operative mortality risk ≥8% at 30 days as determined by 
STS-PROM score 
Intermediate Risk: Predicted operative mortality risk ≥3% and <8% at 30 days as 
determined by STS-PROM score 
Low Risk: Predicted operative mortality risk <3% at 30 days as determined by 
STS-PROM score 
TAV-IN-TAV 
DEPLOYMENT 
An additional valve prosthesis is implanted within a previously implanted 
prosthesis because of suboptimal device position and/or function during or after 
the index procedure. 
TRANSIENT 
ISCHEMIC ATTACK 
(TIA) 
• Transient episode of focal neurological dysfunction caused by brain, spinal 
cord, or retinal ischemia, without acute infarction  
• Duration of a focal or global neurological deficit is <24 h  
• Neuroimaging does not demonstrate a new hemorrhage or infarct (if performed) 
Note: The difference between TIA and ischemic stroke is the presence of tissue 
damage or new sensory-motor deficit persisting >24 hours. By definition, TIA 
does not produce lasting disability. 
UNANTICIPATED 
ADVERSE DEVICE 
EFFECT (UADE) 
 
Ref: 21 CFR Part 812 
Any serious adverse effect on health or safety or any life-threatening problem or 
death caused by, or associated with, a device, if that effect, problem, or death was 
not previously identified in nature, severity, or degree 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. 
UNANTICIPATED 
SERIOUS ADVERSE 
DEVICE EFFECT 
(USADE) 
Ref: ISO 14155 
Ref: MEDDEV 2.7/3 
Serious adverse device effect which by its nature, incidence, severity, or outcome 
has not been identified in the current version of the risk analysis report  
Note: An anticipated serious adverse device effect (ASADE) is an effect which by 
its nature, incidence, severity, or outcome has been identified in the risk analysis 
report. 
UNPLANNED USE 
OF CPB 
Unplanned use of cardiopulmonary bypass (CPB) for hemodynamic support at 
any time during the TAVR procedure 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 73 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 74 of 76 
  
Table 25.2-1: Definitions 
Term 
Definition 
VALVE 
EMBOLIZATION 
The valve prosthesis moves during or after deployment such that it loses contact 
with the aortic annulus. 
VALVE 
MALAPPOSITION 
Includes valve migration, valve embolization, ectopic valve deployment, or 
transcatheter aortic valve (TAV)-in-TAV deployment. 
VALVE MIGRATION 
After initial correct positioning the valve prosthesis moves upward or downward 
within the aortic annulus from its initial position, with or without consequences 
(e.g., regurgitation). 
VALVE-RELATED 
DYSFUNCTION 
Mean aortic valve gradient ≥20 mmHg, EOA ≤0.9-1.1 cm2, and/or DVI <0.35 
AND/OR moderate or severe prosthetic valve aortic regurgitation (per VARC 
definition) 
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. Note that valve-associated thrombus identified at autopsy in a patient 
whose cause of death was not valve-related or at operation for an unrelated 
indication should not be reported as valve thrombosis. 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 74 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 75 of 76 
  
Table 25.2-1: Definitions 
Term 
Definition 
VASCULAR ACCESS 
SITE AND ACCESS 
RELATED 
COMPLICATIONS 
Major Vascular Complications 
• Any aortic dissection, aortic rupture, annulus rupture, left ventricle perforation, 
or new apical aneurysm/pseudoaneurysm  
• 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 ischaemia, or 
neurological impairment 
• Distal embolization (non-cerebral) from a vascular source requiring surgery or 
resulting in amputation or irreversible end-organ damage 
• The use of unplanned endovascular or surgical intervention associated with 
death, major bleeding, visceral ischaemia or neurological impairment 
• Any new ipsilateral lower extremity ischemia documented by patient 
symptoms, physical exam, and/or decreased or absent blood flow on lower 
extremity angiogram 
• Surgery for access site-related nerve injury 
• Permanent access site-related nerve injury 
Minor Vascular Complications 
• Access site or access-related vascular injury (dissection, stenosis, perforation, 
rupture, arterio-venous fistula, pseudoaneurysms, hematomas, percutaneous 
closure device failure*) not leading to death, life-threatening or major 
bleeding**, visceral ischaemia or neurological impairment 
• Distal embolization treated with embolectomy and/or thrombectomy and not 
resulting in amputation or irreversible end-organ damage 
• Any unplanned endovascular stenting or unplanned surgical intervention not 
meeting the criteria for a major vascular complication 
• 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) 
Note 1: Pre-planned surgical access or a planned endovascular approach to 
vascular closure (e.g., “pre-closure”)48,49 should be considered as part of the 
TAVR procedure and not as a complication, unless untoward clinical 
consequences are documented (e.g., bleeding complications, limb ischemia, distal 
embolization, or neurological impairment). 
Note 2: If unplanned percutaneous or surgical intervention does not lead to 
adverse outcomes this is not considered a major vascular complication.  
** Refers to VARC bleeding definitions 
VENTRICULAR 
SEPTAL 
PERFORATION 
Angiographic or echocardiographic evidence of a new septal perforation during or 
after the TAVR procedure 
VESSEL 
PERFORATION 
Unexpected puncture of the vessel with evidence of extravasation into 
extraluminal surrounding tissue or space requiring treatment using interventional 
or surgical techniques 
Abbreviations: ADE=adverse device effect; AE=adverse event; AR=aortic regurgitation; AVA=aortic valve 
area; AVR= aortic valve replacement; CEC=Clinical Events Committee; CK=creatine kinase; CNS=central 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 75 of 76

Confidential  
 Form/Template 92120219_Rev/Ver C 
 
PROTECTED TAVR Study-Specific Protocol 
 
92365019 Rev/Ver B 
 
Page 76 of 76 
  
Table 25.2-1: Definitions 
Term 
Definition 
nervous system; CT=computed tomography; DVI=Doppler velocity index; ECG=electrocardiogram; 
EOA=effective orifice area; FEV=forced expiratory volume; GDPR=General Data Protection Regulation; 
LBBB=left bundle branch block; LV=left ventricle; MI=myocardial infarction; MRI=magnetic resonance 
imaging; NeuroARC=Neurologic Academic Research Consortium; NYHA=New York Heart Association; 
PPI=permanent pacemaker implant; RBC=red blood cell; SADE=serious adverse device effect; SAE=serious 
adverse event; SVD=structural valve deterioration; TAVR =transcatheter aortic valve replacement; 
TEE=transesophageal Doppler echocardiography; TIA=transient ischemic attack; USADE= unanticipated 
serious adverse device effect; URL=upper reference limit (defined as 99th percentile of normal reference 
range); VARC=Valve Academic Research Consortium 
 
Released
92365019 B.3
PROTECTED TAVR Study-Specific Protocol
Boston Scientific Confidential. Unauthorized use is prohibited.
Page 76 of 76