A Randomized Evaluation of the TriGuard Embolic Deflection Device to Reduce the Impact of Cerebral Embolic Lesions After Transcatheter Aortic Valve Implantation
Phase: NA
Conditions: Symptomatic Aortic Stenosis
Sponsor: Keystone Heart



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Table of Contents 
1.0 
DOCUMENT CONTROL .................................................................................................................................... 4 
1.1 VERSION HISTORY ........................................................................................................................................................... 4 
1.2 PROTOCOL APPROVAL PAGE ............................................................................................................................................. 7 
1.3 INVESTIGATOR SIGNATURE PAGE ....................................................................................................................................... 8 
2.0 
PROTOCOL SYNOPSIS ...................................................................................................................................... 9 
3.0 
STUDY CONTACTS .......................................................................................................................................... 28 
4.0 
INTRODUCTION .............................................................................................................................................. 33 
4.1 BACKGROUND .............................................................................................................................................................. 33 
4.2 RATIONALE .................................................................................................................................................................. 39 
4.3 DEVICE DESCRIPTION ..................................................................................................................................................... 39 
5.0 
STUDY DESIGN ............................................................................................................................................... 45 
5.1 STUDY DESIGN CHANGE AND RATIONALE .......................................................................................................................... 45 
5.2 STUDY DESIGN OVERVIEW .............................................................................................................................................. 45 
5.3 STUDY OBJECTIVES ........................................................................................................................................................ 47 
5.4 STUDY ENDPOINTS ........................................................................................................................................................ 47 
6.0 
STUDY CONDUCT ........................................................................................................................................... 53 
6.1 ENROLLMENT CRITERIA .................................................................................................................................................. 53 
6.2 SUBJECT ENROLLMENT ................................................................................................................................................... 54 
6.3 BLINDING .................................................................................................................................................................... 56 
7.0 
STUDY PROCEDURES ...................................................................................................................................... 58 
7.1 STUDY SCHEDULE OF PROCEDURES AND ASSESSMENTS ........................................................................................................ 58 
7.2 SCREENING / BASELINE .................................................................................................................................................. 60 
7.3 CONCOMITANT THERAPIES ............................................................................................................................................. 62 
7.4 TAVI PROCEDURE......................................................................................................................................................... 63 
7.5 POST-PROCEDURE FOLLOW-UP ........................................................................................................................................ 63 
7.6 ONE-MONTH FOLLOW-UP (CLINIC VISIT) ........................................................................................................................... 64 
7.7 THREE-MONTH FOLLOW-UP ............................................................................................................................................ 65 
8.0 
DEVICE ACCOUNTABILITY ............................................................................................................................... 66 
9.0 
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, AND END-POINTS POTENTIALLY MEETING END-POINT 
CRITERIA ...................................................................................................................................................................... 66 
9.1 ADVERSE EVENTS (AE) .................................................................................................................................................. 66 
9.2 SERIOUS ADVERSE EVENTS (SAE) .................................................................................................................................... 67 
9.3 ADVERSE DEVICE EFFECT (ADE) ...................................................................................................................................... 67 
9.4 SERIOUS ADVERSE DEVICE EFFECT (SADE) ........................................................................................................................ 67 
9.5 UNANTICIPATED ADVERSE DEVICE EFFECT (UADE) ............................................................................................................. 67 
9.6 DEVICE DEFICIENCIES, MALFUNCTIONS, AND USE ERROR...................................................................................................... 68 
9.7 END-POINTS POTENTIALLY MEETING END-POINT CRITERIA ................................................................................................... 68 
9.8 DOCUMENTATION ......................................................................................................................................................... 68 
9.9 REPORTING.................................................................................................................................................................. 70 
9.10 EXPECTED ADVERSE EVENTS ......................................................................................................................................... 72 
10.0 
RISK/BENEFIT ANALYSIS ................................................................................................................................. 73 
10.1 POTENTIAL RISKS AND DISCOMFORTS .......................................................................................................................... 73 
10.2 METHODS TO MINIMIZE RISKS ...................................................................................................................................... 73 
10.3 POTENTIAL BENEFITS ................................................................................................................................................... 73 
11.0 
STUDY COMMITTEES ...................................................................................................................................... 74 
11.1 PATIENT REVIEW COMMITTEE (PRC) ............................................................................................................................. 74 

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11.2 CLINICAL EVENTS COMMITTEE (CEC) ............................................................................................................................. 74 
11.3 DATA AND SAFETY MONITORING BOARD (DSMB) ........................................................................................................... 75 
12.0 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN .................................................................................... 75 
12.1 GENERAL ANALYSIS DEFINITIONS ................................................................................................................................... 75 
12.2 SAMPLE SIZE CALCULATION .......................................................................................................................................... 76 
12.3 ANALYSIS POPULATIONS .............................................................................................................................................. 85 
12.4 METHOD OF ANALYSIS AND REPORTING .......................................................................................................................... 86 
13.0 
PUBLICATION POLICY ..................................................................................................................................... 96 
14.0 
DATA COLLECTION AND MONITORING .......................................................................................................... 97 
14.1 DATA COLLECTION AND MONITORING ............................................................................................................................ 97 
14.2 SOURCE DOCUMENTATION AND VERIFICATION ................................................................................................................. 98 
14.3 RECORD RETENTION .................................................................................................................................................... 98 
15.0 
ETHICAL AND REGULATORY CONSIDERATIONS .............................................................................................. 98 
15.1 APPLICABLE REGULATIONS ........................................................................................................................................... 98 
15.2 INSTITUTIONAL REVIEW BOARD / MEDICAL ETHICS COMMITTEE .......................................................................................... 98 
15.3 REGULATORY APPROVAL .............................................................................................................................................. 99 
15.4 TRIAL REGISTRATION ................................................................................................................................................... 99 
15.5 RECORDS AND REPORTS ............................................................................................................................................... 99 
15.6 PROTOCOL AMENDMENTS .......................................................................................................................................... 101 
15.7 INFORMED CONSENT ................................................................................................................................................. 102 
15.8 TERMINATION OF THE STUDY ...................................................................................................................................... 102 
15.9 AUDITING ............................................................................................................................................................... 103 
15.10 PATIENT PRIVACY ................................................................................................................................................... 103 
16.0 
APPENDICES ................................................................................................................................................. 104 
16.1 APPENDIX I: DEFINITIONS ........................................................................................................................................... 104 
16.2 APPENDIX II: ACRONYMS ........................................................................................................................................... 122 
16.3 APPENDIX III: DECLARATION OF HELSINKI ...................................................................................................................... 126 
16.4 APPENDIX IV: REFERENCES ......................................................................................................................................... 129 
16.5 APPENDIX V: STRUCTURED INTERVIEW FOR THE MODIFIED RANKIN SCALE ........................................................................... 137 
16.6 APPENDIX VI: NIH STROKE SCALE ............................................................................................................................... 138 
16.7 APPENDIX VII: NEUROPSYCHOLOGICAL TEST BATTERY ..................................................................................................... 147 
16.8 APPENDIX VIII: ANGIOGRAPHIC IMAGING ACQUISITION GUIDELINES .................................................................................. 168 
16.9 APPENDIX IX: MAGNETIC RESONANCE IMAGING ACQUISITION PROTOCOL ........................................................................... 170 
16.10 APPENDIX X: CT ANGIOGRAPHY IMAGING ACQUISITION GUIDELINES ............................................................................... 182 
16.11 APPENDIX XI: SF-36 HEALTH SURVEY ........................................................................................................................ 190 
 
 
 

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1.0 Document Control 
1.1 Version History 
Version 
Description 
1.0 
April 7, 2014 
Original version submitted to FDA 
2.0 
December 1, 2014 
Revised based on FDA Study Design Considerations 
3.0 
May 11, 2015 
Revised based on FDA Study Design Considerations 
4.0 
July 6, 2015 
Revised based on FDA Study Design Considerations 
5.0 
December 14, 
2015 
Updated description of device packaging; clarification of device 
regulatory status; clarification of CT imaging acquisition; minor 
additions to OUS adverse event reporting procedures; minor 
administrative changes. 
6.0 
September 28, 
2016 
Addition of quality of life assessment and supplemental neurocognitive 
assessment; addition of CT core laboratory for evaluation of anatomic 
eligibility criteria; clarification of data to be captured from post-
procedure echocardiography performed as part of the standard of care; 
minor changes to study eligibility criteria (exclusion timeframe of prior 
stroke or TIA, range of concomitant vascular disease that would 
preclude delivery sheath access); clarification of protocol requirements 
for study-specific training for neurologists performing assessments; 
minor administrative changes. 
7.0 
January 13, 2017 
Primary efficacy endpoint revised to include more clinically meaningful 
threshold and evaluation time point for MoCA worsening; hypothesis-
driven secondary safety endpoints revised to add CNS infarction and 
total volume of cerebral ischemic lesions and omit stroke/TIA; 
additional prespecified exploratory analyses of primary and secondary 
efficacy endpoints; added NeuroARC-defined neurological events and 
“General Safety” composite to secondary safety endpoints; As Treated 
population modified to include all subjects exposed to the risks of the 
investigational device or procedure; mITT analysis population removed; 
revised assessment window for post-procedure NIHSS, mRS, and 
neuropsychological assessments to match post-procedure DW-MRI 
window; added frailty assessment at baseline and 90 days; added 
assessment of NYHA functional capacity, height, and weight at 
screening/baseline; eliminated select unnecessary blood chemistry 
tests from post-procedure assessment; updated device description to 
reflect changes to compatible commercially-available introducer 
sheaths; eliminated blinding of DSMC members based on DSMC 
request; updated Study Contacts; updated listing of investigators and 
investigational sites; minor administrative changes. 
8.0 
March 1, 2017 
Reverted previous change to blinding of DSMC members (made in 
Version 7.0) based on FDA recommendation with DSMC agreement. 
DSMC members will be blinded to treatment allocation per protocol. 

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The DSMC reserves the right to request unblinding if deemed 
necessary to protect subject rights, welfare, or well-being. 
9.0 
May 19, 2017 
Increased total sample size from up to 375 subjects (285 randomized, 
90 roll-in) to up to 495 subjects (405 randomized, 90 roll-in). This 
prospective increase in the number of allowable randomized subjects 
is intended to prevent a delay in further enrollment if the interim analysis 
determines that additional subjects are required to ensure adequate 
study power. Anticipated study timelines revised; additional minor 
administrative changes. 
10.0 
June 20, 2017 
Revised total sample size to 445 subjects (355 randomized, 90 roll-in) 
in response to FDA feedback. The revised number of allowable 
randomized subjects will be sufficient to prevent a delay in further 
enrollment if the interim analysis determines that additional subjects are 
required to ensure adequate study power. 
11.0 
December 6, 
2017- DSMB 
submission 
January 22, 2018- 
FDA submission 
Protocol amendments due to incorporation of a next iteration device 
and following FDA feedback and DSMB comments on current protocol 
version. 
Changes include: 
Trial design- Addition of Phase II of the trial, incorporating a redesigned 
device (TriGUARD 3) into the intervention arm and maintaining blinded 
data from the previous REFLECT trial 
Total number of expected subjects was updated to 533 including control 
patients from phase I. 
Randomization will be stratified by implanted valve type (Medtronic vs. 
Edwards). No single valve type will be implanted in more than 
approximately 70% of randomized patients (phase II). 
Event rate assumptions and sample size calculations- updated to 
reflect current RCT data and inclusion of controls from Phase I. 
Primary endpoint was updated- a new Tier 3 was added- Freedom from 
any MRI lesions to incorporate a meaningful clinical endpoint into the 
current hierarchy. 
MoCA assessment was excluded from this protocol as current data 
show inconclusive evidence concerning the validity and utility of this 
endpoint. 
90 days clinical visit was changed to a telephone call to assess death 
and stroke to reflect that the Cerebral Embolic Protection Device 
(CEPD) is a peri-procedural device and should demonstrate its efficacy 
early. Assessment up to 30 days post procedure will ensure a correct 
balance between significant clinical efficacy and diminishing noise from 
other events such as atrial fibrillation. 
Other updates including fewer exclusion criteria due to next iteration 
device design, Cardiac biomarkers measurements only when clinically 
indicated and updated antiplatelet treatment recommendations to 
reflect current standard of care. 

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12.0 
July 20, 2018 
Post FDA- 
submission 
response 
Protocol amendments following FDA feedback including: 
Event rate assumptions and sample size calculations- while event rates 
remained unchanged from the previous version, clarifications were 
added in regard to MRI findings and the comparison of lesion sizes 
between patients and to the FS methodology. 
Primary endpoints analysis detailed and clarified. Secondary sensitivity 
analyses added. 
Adaptive design added. 
Revised Statistical Code. 
Power calculations were updated following a revised statistical code 
Study Contacts updated 
Minor grammatical and format modifications 
13.0 
November 1, 2018 
Post FDA 
Feedback on 
Version 12.0 
Protocol amendments following FDA feedback, including: 
In Phase II, the primary efficacy endpoint and hypothesis-driven 
secondary endpoint comparisons will be one-sided with the level of 
significance set at 0.025. Text was corrected to reflect a one-sided 
analysis. 
Further clarifications to the adaptive design plan per FDA request. 
Revised total Phase II sample size to 345 subjects (295 randomized, 
40-50 roll-in), from 275 subjects (225 randomized, 40-50 roll-in). The 
revised number of allowable randomized subjects will be sufficient to 
prevent a delay in further enrollment if the interim analysis determines 
that additional subjects are required to ensure adequate study power. 

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1.3 Investigator Signature Page 
Study title: 
The REFLECT Trial 
A randomized evaluation of the TriGuard™ HDH Cerebral 
Embolic Protection Device and the TriGUARD™ 3 Cerebral 
Embolic Protection Device to reduce the impact of cerebral 
embolic lesions after transcatheter aortic valve implantation 
Protocol version: 
13.0    
Protocol date: 
November 1, 2018 
Investigator’s Responsibility 
Prior to participation in the REFLECT Trial, as the site principal investigator, I understand 
that I must obtain written approval from my Institutional Review Board/Ethics Committee. 
This approval must include my name and a copy must be provided to Keystone Heart Ltd. 
(or designee), along with the approved Patient Information and Consent Form prior to the 
first enrollment at my study site.   
As the site Principal Investigator, I must also: 
1. Conduct the study in accordance with the study protocol, the signed Clinical 
Investigation Agreement, applicable laws, 21 CFR Part 812 and other applicable 
United States Food and Drug Administration (FDA) regulations, any conditions of 
approval imposed by the FDA or IRB/EC, local regulations where applicable, 
International Conference on Harmonization (ICH) Good Clinical Practice guidelines, 
and the Declaration of Helsinki, and ensure that all study personnel are appropriately 
trained prior to any study activities. 
2. Ensure that the study is not commenced until all approvals have been obtained. 
3. Supervise all use of the TriGuard HDH Cerebral Embolic Protection Device and 
TriGUARD 3 Cerebral Embolic Protection Device at my institution. 
4. Ensure that written informed consent is obtained from each subject prior to any data 
collection, using the most recent Institutional Review Board/Ethics Committee 
approved Patient Information and Consent Form. 
5. Provide all required data and reports and agree to source document verification of 
study data with patient’s medical records by Keystone Heart Ltd. (or designee) and 
any regulatory authorities. 
6. Allow Keystone Heart Ltd. personnel or its designees, as well as regulatory 
representatives, to inspect and copy any documents pertaining to this clinical 
investigation according to national data protection laws.  
Investigator Signature  
I have read and understand the contents of the REFLECT Trial protocol and agree to abide 
by the requirements set forth in this document.  
 
__________________________  
 
__________________________  
Investigator Name (print)  
 
 
Investigative Site (print) 
 
__________________________  
 
___________________________ 
                      
Investigator Signature                                         Date 
 

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2.0 Protocol Synopsis 
Title: 
The REFLECT Trial 
A Randomized Evaluation oF the TriGuard™ HDH Cerebral Embolic 
Protection Device and the TriGUARD™ 3 Cerebral Embolic Protection 
Device to reduce the impact of cerebral embolic LEsions after transCatheter 
aortic valve implanTation 
Study device: 
The Keystone Heart TriGuard™ HDH Cerebral Embolic Protection Device 
(CEPD) and TriGUARD™ 3 CEPD systems are aortic embolism protection 
devices intended to reduce the amount of embolic material that may enter 
the carotid, subclavian, and vertebral arteries during transcatheter heart 
valve implantation. 
TriGuard HDH 
The TriGuard HDH consists of a temporary, sterile, single use, biocompatible 
filter, introduced transfemorally through a 9F sheath to the aortic arch. Under 
fluoroscopic guidance, the device is positioned in the aortic arch to cover all 
3 major cerebral arteries (innominate, left carotid, and subclavian arteries), 
and is held in position by an atraumatic stabilizer in the innominate artery. 
Once the device is in position, emboli and particulate matter are diverted 
away from the cerebral circulation and downstream to the descending aorta, 
where they are either harmless or can be treated effectively. 
The TriGuard HDH has received CE Mark and was commercially available 
in Europe and Israel during phase I. Use of the device at European and 
Israeli sites in the REFLECT study was in accordance with its market 
approved use.  
In the United States, the TriGuard HDH was for investigational use only. The 
device has received IDE approval for use in the REFLECT study (Phase I).  
TriGUARD 3 
The TriGUARD 3 consists of a temporary, retrievable, sterile, single use, 
biocompatible filter, introduced transfemorally through an 8F sheath to the 
aortic arch. The TriGUARD 3 CEPD filter includes a self-stabilizing frame 
design, a reduced pore size filter mesh, and a redesigned delivery system 
intended for improved ease of use. Under fluoroscopic guidance, the device 
is positioned in the aortic arch to cover all major cerebral arteries (covering 
the innominate, left carotid, and left subclavian arteries), and is held in 
position by the device’s circumferential pressure and the support of the nitinol 
shaft (external communicating device) in the aortic arch without the need for 
a stabilizer in the inominate artery. Once the device is in position, emboli and 
particulate matter are diverted away from the cerebral circulation and 
downstream to the descending aorta, where they are either harmless or can 
be treated effectively. 
The TriGUARD 3 device is for investigational use only. 
Objective: 
To assess the safety and efficacy of the TriGuard HDH and TriGUARD 3 
cerebral embolic protection devices in patients undergoing transcatheter 

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aortic valve implantation/replacement (TAVI1), in comparison with a control 
group of patients undergoing unprotected TAVI.  
Study 
design2: 
This prospective, single-blind, three arm, randomized, (2 device: 1 control), 
multicenter safety and efficacy trial is designed to enroll up to 603 total 
subjects in two consecutive phases: Phase I enrolled 258 subjects (including 
54 Roll-Ins) and utilized the TriGuard HDH and Phase II will enroll up to 345 
subjects (including 40-50 Roll-Ins) and will utilize the TriGUARD 3 (Figure 3b 
shows the patient flow/disposition).  
Phase I 
In phase I, a total of 204 evaluable subjects and 54 roll-in subjects were 
enrolled at 26 total investigational sites in the United States, Europe, and 
Israel, of which 20 sites were in the United States. A minimum of 50% of 
subjects were planned to be enrolled at US sites, and no single site was 
permitted to enroll more than 20% of all subjects. 
Subjects with indications for TAVI and who met study eligibility criteria were 
randomized 2:1 (stratified by study site) to one of two treatment arms: 
• Intervention (Phase 1 Cohort) – TAVI with the TriGuard HDH CEPD 
• Control – standard unprotected TAVI 
At sites where the investigator did not have prior experience with the 
TriGuard device (minimum of 2 prior cases), up to 3 roll-in subjects were 
enrolled. Roll-in subjects were not randomized, but underwent TAVI with the 
TriGuard HDH device. These cases were proctored by a Sponsor 
representative. Investigational sites with ≥2 prior TriGuard cases were 
allowed to enroll 1 roll-in subject at the discretion of the site principal 
investigator. 
All subjects were to be followed clinically in-hospital and at 30 and 90 days, 
and to undergo diffusion-weighted MR imaging 2 to 5 days post-procedure, 
and neurologic and neuropsychological testing pre-procedure, post-
procedure (2-5 days post-procedure), and at 30 and 90 days. 
The initial randomized cohort expected to enroll up to 285 subjects.  
Note: Enrollment in Phase I has been halted after enrolling a total of 258 
subjects (54 roll-ins and 204 randomized subjects including 63 controls) 
based on the recommendation of the Data Monitoring Committee following a 
review of interim 30-day data on 90 subjects at the prespecified interim 
analysis time point. A next iteration device designed for increased efficacy, 
ease of use, and improved safety will be tested in Phase II (below). 
                                            
 
1 Throughout the protocol, the term TAVI will be used to signify TAVI in OUS and TAVR in US. 
2 REFLECT Version 10.0 intended to enroll up to 355 subjects and up to 90 roll-ins. Enrollment in this cohort 
(termed Phase I in this protocol version) was halted based on the recommmendation of the independent DSMB 
following interim data review at the prespecified interim analysis timepoint, as well as availability of the 
redesigned TriGuard 3 system, after 204 subjects were randomized and 54 roll-ins were enrolled. 

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Phase II 
In Phase II, up to 295 randomized subjects and 40-50 roll-in subjects will be 
enrolled at up to 25 sites in the United States (inclusive of sites enrolling 
subjects in Phase I). No single site will be permitted to enroll more than 20% 
of all randomized subjects in Phase II. 
Subjects with indications for TAVI and who meet study eligibility criteria will 
be randomized 2:1 (stratified by study site) to one of two treatment arms: 
• Intervention – TAVI with the TriGUARD 3 CEPD 
• Control – standard unprotected TAVI. 
Randomization will be stratified by implanted valve type (Medtronic vs. 
Edwards). 
No single valve type will be implanted in more than approximately 70% of 
randomized patients (phase II). 
Roll-in subjects (a minimum of 2 and a maximum of 3 Roll-ins per-site) will 
not be randomized, but will undergo TAVI with the TriGUARD 3 device. 
These cases will be proctored by a Sponsor representative. 
All subjects will be followed clinically in-hospital and at 30 days, undergo 
diffusion-weighted MR imaging 2 to 5 days post-procedure, and undergo 
neurologic (NIHSS) testing pre-procedure, post-procedure (2-5 days post-
procedure), and at 30 days. A follow-up phone-call to assess the occurrence 
of death or stroke will be done at 90 days. 
The initial randomized cohort will consist of up to 225 subjects. After at least 
50% of the initial randomized cohort (approximately 112 subjects) have 
reached the 30 day primary efficacy endpoint evaluation time point, a sample 
size reestimation will be performed in case the conditional power of the trial 
(assessed by the independent biostatistician) is >40% but <80%, subject to 
approval by the Sponsor. If this analysis determines that more than 225 
randomized subjects will be required to ensure adequate study power, 
enrollment may continue until the required number of subjects have been 
enrolled, or until the total subject limit for the study has been reached 
(whichever occurs first). 
Primary 
safety 
endpoint: 
Combined safety endpoint (modified VARC 2 defined1) at 30 days, defined 
as a composite of death, stroke, life-threatening or disabling bleeding, acute 
kidney injury (stage 2 or 3), coronary artery obstruction requiring intervention, 
major vascular complication, and valve-related dysfunction requiring repeat 
procedure. 
Primary 
efficacy 
endpoint: 
(Phase II): 
 
Hierarchical composite efficacy endpoint, determined by pair-wise 
comparisons among all subjects according to the following pre-specified 
hierarchy of adverse outcomes: 
• All-cause mortality and/or any stroke (fatal and non-fatal, disabling or 
non-disabling) [evaluated at 30 days] 
o If both had a death/stroke a time to event analysis by days will 
determine a win 

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o If both patients had a stroke at the same day the comparison 
moves to the next tier 
• NIHSS worsening (increase from baseline) [evaluated at 2 to 5 days 
post-procedure] 
• Freedom from any cerebral ischemic lesions detected by diffusion-
weighted magnetic resonance imaging (DW-MRI) 2 to 5 days post-
procedure 
• Total volume of cerebral ischemic lesions detected by diffusion-
weighted magnetic resonance imaging (DW-MRI) 2 to 5 days post-
procedure 
Each subject in the intervention group will be compared with each and every 
subject from the control group based on the above hierarchy according to the 
Finkelstein-Schoenfeld method.2 For example, if Subject A dies or has stroke 
and Subject B survives free of stroke to 30 days, Subject B wins (score +1) 
and Subject A loses (score -1). If both subjects die or have a stroke, the 
patient with the later event will be the winner. If both have death/stroke on 
same day it is equilibrium (score 0). If both subjects are alive and have a 
stroke on the same day, the comparison moves to the next tier of the 
hierarchy (NIHSS worsening). If both subjects survive free of stroke to 30 
days, the comparison also moves to the next tier of the hierarchy. After all 
between-subject comparisons have been performed, scores are summed to 
obtain a cumulative score for each subject, and outcomes between treatment 
groups are then compared. 
Secondary 
endpoints:  
 
 
 
 
 
 
 
 
 
 
 
 
SECONDARY SAFETY ENDPOINTS 
The following safety endpoints will be evaluated in-hospital and at 30 days. 
Overall event rates will be reported by treatment group. In the Intervention 
and Roll-In groups, all safety endpoints will be adjudicated for their 
relationship to the investigational device and/or the investigational procedure 
by an independent Clinical Events Committee. 
In-hospital procedural safety, defined as the composite of the following 
Major Adverse Cardiovascular and Cerebrovascular Events (MACCE): 
• All-cause mortality 
• All stroke (disabling and non-disabling) 
• Life-threatening (or disabling) bleeding 
• Acute kidney injury – Stage 2 or 3 (including renal replacement 
therapy) 
• Major vascular complications 
TAVI device success (VARC), evaluated in-hospital, defined as: 
• Absence of procedural mortality AND 
• Correct positioning of a single prosthetic heart valve into the proper 
anatomical location AND 

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• Intended performance of the prosthetic heart valve (no prosthesis-
patient mismatch (VARC-defined) and mean aortic valve gradient 
<20 mm Hg or peak velocity <3 m/s, AND no moderate or severe 
prosthetic valve regurgitation (VARC-defined) (site-reported) 
General Safety, defined as the composite of the following adverse events: 
• All-cause mortality 
• All stroke (disabling and non-disabling) 
• Acute kidney injury – Stage 3 (including renal replacement therapy) 
Mortality: [evaluated in-hospital and at 30 and 90 days] 
• All-cause mortality 
o Cardiovascular mortality 
 Neurologic event related mortality 
o Non-cardiovascular mortality 
Myocardial infarction:  
• Peri-procedural MI (≤72 hours after the index procedure) 
• Spontaneous MI (>72 hours after the index procedure) 
Neurological Events (component and composite): 
• Stroke (VARC-2 defined) [evaluated in-hospital and at 30 and 90 
days] 
o Ischemic stroke 
o Hemorrhagic stroke 
o Undetermined 
• Disabling Stroke (VARC-2 defined) [evaluated in-hospital and at 
30 and 90 days] 
• Non-disabling stroke (VARC-2 defined) [evaluated in-hospital 
and at 30 and 90 days] 
• Transient ischemic attack (TIA) (VARC-2 defined) 
• Overt CNS Injury (NeuroARC3 defined Type 1) [evaluated in-
hospital and at 30 and 90 days] 
• Covert CNS Injury (NeuroARC defined Type 2) 
• Neurological dysfunction without CNS injury (NeuroARC defined 
Type 3) 
• CNS infarction (NeuroARC defined composite neurological 
endpoint) 
• CNS hemorrhage (NeuroARC defined composite neurological 
endpoint) 
Bleeding Complications: 

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• Life-threatening bleeding (VARC-2) 
• Major bleeding 
• Minor bleeding 
Acute Kidney Injury (AKIN Classification): 
• Stage 2 
• Stage 3 
Vascular Complications: 
• Major vascular complications 
• Major vascular complications related to TriGUARD 3 
SECONDARY EFFICACY ENDPOINTS 
Hypothesis-driven Secondary Endpoints (Phase II) 
For the following secondary endpoints, a test for superiority of each 
intervention group to the control group will be performed. To address the 
issue of multiple tests among these secondary endpoints, sequential testing 
is planned. Secondary endpoints will be formally tested if and only if the 
primary study hypotheses are confirmed. The secondary endpoints will be 
tested individually, in the order in which they are listed as follows: 
• All stroke [evaluated at 7 days in the eITT population] 
• NIHSS worsening, defined as any NIHSS score increase from 
baseline [evaluated at 2 to 5 days post-procedure in the efficacy 
Intention to Treat (eITT) analysis population]. A sensitivity analysis will 
further compare >2 points NIHSS worsening [evaluated at 2-5 days 
post-procedure in the efficacy Intention to Treat (eITT) analysis 
population] 
• Composite of all-cause mortality and all stroke [evaluated at 7 
days in the eITT population] 
• CNS Infarction (NeuroARC defined) [evaluated at 30 days in the eITT 
analysis population] 
• Total volume of cerebral ischemic lesions detected by DW-MRI, 
[evaluated 2 to 5 days post-procedure in the efficacy Intention to Treat 
(eITT) analysis population]  
The above endpoints will be tested by this pre-specified sequence, until the 
first non-significant difference is found between the two treatment groups. 
After that, other treatment comparisons will be examined in an exploratory 
manner. 
Phase I: Hierarchical composite efficacy endpoint, determined by pair-
wise comparisons among all subjects according to the following pre-specified 
hierarchy of adverse outcomes: 
• All-cause mortality or any stroke (disabling or non-disabling) 
[evaluated at 30 days] 

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• NIHSS worsening (increase from baseline) [evaluated at 2-5 days 
post-procedure] or Montreal Cognitive Assessment worsening 
(decrease of 3 or more points from baseline) [evaluated at 30 days] 
• Total volume of cerebral ischemic lesions detected by diffusion-
weighted magnetic resonance imaging (DW-MRI) 2 to 5 days post-
procedure 
Each subject in the intervention group will be compared with each and every 
subject from the control group based on the above hierarchy according to the 
Finkelstein-Schoenfeld method.2 For example, if Subject A dies or has stroke 
and Subject B survives free of stroke to 30 days, Subject B wins (score +1) 
and Subject A loses (score -1). If both subjects die or have a stroke, it is 
equilibrium (score 0). If both subjects survive free of stroke to 30 days, the 
comparison moves to the next tier of the hierarchy.  
After all between-subject comparisons have been performed, scores are 
summed to obtain a cumulative score for each subject, and outcomes 
between treatment groups are then compared. 
Imaging Efficacy Endpoints (Phase I and II) 
• Presence of cerebral ischemic lesions detected by DW-MRI, 
evaluated 2 to 5 days post-procedure  
• Number of cerebral ischemic lesions detected by DW-MRI, 
evaluated 2 to 5 days post-procedure  
• Per-patient average single cerebral ischemic lesion volume 
detected by DW-MRI, evaluated 2 to 5 days post-procedure 
• Single cerebral ischemic lesion volume (lesion-level analysis) 
detected by DW-MRI, evaluated 2 to 5 days post-procedure 
• Total volume of cerebral ischemic lesions detected by DW-MRI, 
evaluated 2 to 5 days post-procedure   
Neurologic Efficacy Endpoints (Phase I and II) 
• NIHSS worsening, defined as an NIHSS score increase from 
baseline [baseline score compared with score evaluated at 2-5 
days post-procedure and at 30 days] 
• New neurologic impairment, defined as NIHSS worsening from 
baseline accompanied by the presence of cerebral ischemic 
lesions [evaluated at 2-5 days post-procedure and at 30 days]  
 
SECONDARY PERFORMANCE ENDPOINTS 
The following performance endpoints will be evaluated post-procedure in the 
Intervention group (Roll-Ins excluded) (TriGuard HDH and TriGUARD 3 
reported individually): 
• Successful device deployment, defined as ability to access the 
aortic arch with the TriGuard HDH or TriGUARD 3 delivery catheter 
and deploy the device from the delivery catheter into the aortic arch 

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• Device positioning, defined as ability to position the TriGuard 
HDH or TriGUARD 3 device in the aortic arch to cover all major 
cerebral arteries, with proper positioning maintained (verified by 
fluoroscopy) until the following time points: 
o Final deployment of the first prosthetic valve 
o Final procedure (after any additional post-dilatation or 
additional valve implantations have been completed, and 
the TAVR delivery system has been removed) 
Extent of cerebral artery coverage will be reported as: 
o Complete (coverage of all 3 cerebral artery branches) 
o Partial (coverage of 1-2 cerebral artery branches) 
o None 
Note: Maintenance of device positioning to each time point and 
extent of cerebral artery coverage will be evaluated by the 
Angiographic Core Laboratory.   
• Device interference, defined as interaction of the TriGuard HDH 
or TriGUARD 3 device with the TAVI system leading to: 
o Inability to advance or manipulate the TAVI delivery system 
or valve prosthesis, OR 
o Inability to deploy the TAVI valve prosthesis, OR 
o Inability to retrieve the valve prosthesis or delivery system  
• Successful device retrieval, defined as ability to retrieve the 
TriGuard HDH or TriGUARD 3 CEPD. 
• Technical success, defined as successful device deployment, 
device positioning, and successful device retrieval in the absence 
of device interference  
• Procedure success, defined as technical success in the absence 
of any investigational device-related or investigational procedure-
related in-hospital procedural safety events 
Other 
measures: 
The following additional measures will also be reported (TriGuard HDH and 
TriGUARD 3 reported individually): 
o Device deployment time − Time elapsed between insertion of the 
TriGuard HDH or TriGUARD 3 device into the groin access point and 
successful device deployment [evaluated post-procedure] 
o Total procedural time − Time elapsed between first arterial access 
and removal of the last catheter from the arterial access sheath 
[evaluated post-procedure] 
o Total fluoroscopy time [evaluated post-procedure] 
o Total contrast utilization [evaluated post-procedure] 

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o Health-related quality of life, as measured by the SF-36 Health 
Survey [evaluated at baseline and at 30 days, Phase I only].  
Patient 
population: 
The study will enroll up to 603 subjects (499 randomized subjects and up to 
104 roll-in subjects) meeting approved indications for transcatheter aortic 
valve implantation. Of these, up to 295 will be randomized in Phase II, with 
an additional 40-50 roll in patients. 
Patient 
Follow-Up: 
Phase I: All subjects were followed clinically in-hospital and at 30 and 90 
days, underwent diffusion-weighted MR imaging 2 to 5 days post-procedure, 
and underwent neurologic and neuropsychological testing pre-procedure, 
post-procedure (2-5 days post-procedure), and at 30 and 90 days. 
Phase II: All subjects will be followed clinically in-hospital and at 30 days, 
undergo diffusion-weighted MR imaging 2 to 5 days post-procedure, and 
undergo neurologic testing pre-procedure, post-procedure (2-5 days post-
procedure), and at 30 days. 90 days phone-call follow-up will assess the 
occurrence of death and/or stroke. 
Study 
Committees: 
Patient Review Committee 
A Patient Review Committee (PRC) will evaluate each potentially eligible 
subject (Includes confirmation that subject meets selected anatomic eligibility 
criteria based on imaging analysis by an independent CT core laboratory). 
All subjects must be approved by the PRC prior to enrollment in the trial.  
Clinical Events Committee 
An independent Clinical Events Committee (CEC) will adjudicate all site-
reported cardiovascular adverse events and all site-reported adverse events 
potentially meeting endpoint criteria, in an ongoing fashion during the trial. In 
the Intervention and Roll-In groups, relationship to the investigational device 
or investigational procedure will also be adjudicated.  
Data and Safety Monitoring Board 
An independent Data and Safety Monitoring Board (DSMB) will be 
responsible for the oversight and safety monitoring of the study. The DSMB 
will advise the Sponsor regarding the continuing safety of the trial subjects 
and those yet to be recruited to the trial, as well as the continuing validity and 
scientific merit of the trial. 
Antiplatelet 
Therapy: 
Selection and dosing of antiplatelet therapy will be performed according to 
physician standard practice, in accordance with local standards of care and 
published guidelines for TAVI procedures. Each site is encouraged to commit 
to a consistent antiplatelet regimen to be applied to all subjects enrolled in 
the trial, independent of treatment group.  
The investigators recommend (but do not require) the following antiplatelet 
regimen, and further recommend that all subjects receive dual anti-platelet 
therapy for a minimum of 6 months in the absence of contraindications:  
• ASA 75-100 mg maintenance dose indefinitely, and  
• Clopidogrel 75 mg daily maintenance dose 

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• If the patient is on warfarin therapy prior to the procedure the 
following is recommended: 
o Discontinue warfarin three days prior to the procedure  
o Confirm that the INR is <1.8 prior to the procedure 
o Clopidogrel 75 mg for 3 days or ASA 75-100 mg prior to the 
procedure 
• If the patient is on warfarin therapy post-procedure 
      it is recommended that the patient is prescribed either daily aspirin 
(75-100 mg) or daily clopidogrel (75 mg)  
Minimum recommended maintenance dosages can be higher based on 
physician’s discretion. 
Inclusion 
criteria: 
Subjects must meet ALL of the following criteria: 
General Inclusion Criteria 
1. The patient is a male or non-pregnant female ≥18 years of age 
2. The patient meets indications for TAVI  
3. The patient is willing to comply with protocol-specified follow-up 
evaluations 
4. The patient, or legally authorized representative, has been informed of 
the nature of the study, agrees to its provisions and has provided written 
informed consent, approved by the appropriate Institutional Review 
Board (IRB) or Ethics Committee (EC).  
Exclusion 
criteria: 
Potential subjects will be excluded if ANY of the following criteria apply: 
General Exclusion Criteria 
1. Patients undergoing TAVI via the trans-apical, trans-axillary, trans-
subclavian, or trans-aortic route (applicable to Phase II) 
2. Patients undergoing TAVI via the trans-apical approach due to friable or 
mobile atherosclerotic plaque in the aortic arch (Phase I only) 
3. Patients with a previously implanted prosthetic aortic valve (i.e., planned 
valve-in-valve TAVI) 
4. Pregnant or nursing subjects and those who plan pregnancy in the 
period up to 1 year following index procedure. Female subjects of child-
bearing potential must have a negative pregnancy test done within 14 
days prior to index procedure per site standard test 
5. Patients with known diagnosis of acute myocardial infarction (AMI) within 
72 hours preceding the index procedure (according to definition) or AMI 
>72 hours preceding the index procedure, in whom CK and CK-MB have 
not returned to within normal limits at the time of procedure, or patients 
who are currently experiencing clinical symptoms consistent with new-
onset AMI, such as nitrate-unresponsive prolonged chest pain 
6. Patients with a history of bleeding diathesis or coagulopathy or patients 
in whom anti-platelet and/or anticoagulant therapy is contraindicated, 

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patients who will refuse transfusion, or patients with an active peptic 
ulcer or history of upper gastrointestinal (GI) bleeding within the prior 3 
months  
7. Patients with known mental or physical illness or known history of 
substance abuse that may cause non-compliance with the protocol, 
confound the data interpretation, or is associated with a life expectancy 
of less than one year 
8. Patients with severe allergy or known hypersensitivity or contraindication 
to aspirin, heparin/bivalirudin, clopidogrel, nitinol, stainless steel alloy, 
and/or contrast sensitivity that cannot be adequately pre-medicated 
9. Patients with a history of a stroke or transient ischemic attack (TIA) within 
the prior 6 months 
10. Patients with renal failure (estimated Glomerular Filtration Rate [eGFR] 
<30 mL/min calculated from serum creatinine by the Cockcroft-Gault 
formula or MDRD- Modification of Diet in Renal Disease formula) 
11. Patients with hepatic failure (Child-Pugh class C)  
12. Patients with hypercoagulable states that cannot be corrected by 
additional peri-procedural heparin  
13. Patients presenting with cardiogenic shock at the time of the index 
procedure 
14. Patients with severe peripheral arterial, abdominal aortic, or thoracic 
aortic disease that precludes delivery sheath vascular access 
15. Patients in whom the aortic arch (Phase I and II), innominate artery 
ostium (Phase I only), or proximal innominate artery (Phase I only) are 
heavily calcified, severely atheromatous, or severely tortuous  
16. Patients with an innominate artery ostium diameter <10 mm or >25 mm 
(Phase I only) 
17. Patients with a transverse aortic diameter >43 mm (Phase I only) 
18. Patients with anatomic irregularities of the innominate artery that could 
prevent positioning of the TriGuard upper stabilizer and compromise 
stability of the device (Phase I only) 
19. Patients with any other condition that would prevent adherence to the 
TriGuard HDH (Phase I) or TriGUARD 3 (Phase II) Instructions for Use 
20. Patients with contraindication to cerebral MRI 
21. Patients who have a planned treatment with any other investigational 
device or procedure during the study period 
22. Patients planned to undergo any other cardiac surgical or interventional 
procedure (e.g., concurrent coronary revascularization) during the TAVI 
procedure or within 10 days prior to the TAVI procedure. NOTE: 
Diagnostic cardiac catheterization is permitted within 10 days prior to the 
TAVI procedure.  

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Blinding 
This is a single-blind study. The following individuals will be blinded to the 
subject’s treatment allocation: 
• Subject and his/her family members 
• Site personnel administering neurological evaluations (NIHSS or mRS 
and/or neuropsychological test battery in Phase I); these individuals 
will also be blinded to DW-MRI results 
• Members of the Data and Safety Monitoring Board 
• MRI Core Laboratory personnel performing imaging analysis 
Un-blinding will occur only after the database has been locked for the 
analysis of the primary endpoint or to protect subject rights, welfare, or well-
being at the request of the DSMB. 
Analysis 
Plan: 
Primary Endpoint Analysis 
Primary Safety Endpoint Analysis 
(Phase I and II3 reported individually) 
The primary safety hypothesis is that the rate of the VARC 2 Combined 
Safety Endpoint (defined as the composite of death, stroke, life-threatening 
or disabling bleeding, AKI [Stage 2/3], coronary artery obstruction requiring 
intervention, major vascular complication, and valve-related dysfunction 
requiring repeat procedure) at 30 days in the group undergoing TAVI with 
either protection device system (Intervention groups) is significantly less in 
each device group (TriGuard HDH and TriGUARD 3) compared separately 
to the Performance Goal (PG). 
The PG has been determined based on published literature reporting the 
VARC-2 combined safety endpoint in patients undergoing TAVI with 
Medtronic or Edwards Valves. Based on an expected event rate of 25% and 
a relative non-inferiority delta of 37.5% (absolute delta 9.4%), the PG will be 
set at 34.4% (25% + 9.4%). A sample size of 179 evaluable subjects in the 
intervention group will provide 85% power to demonstrate that the 
intervention group event rate is significantly less than the PG at the 
alpha=0.05 level. After accounting for a potential 5% loss to clinical follow-
up at 30 days (including subjects who do not meet As Treated population 
criteria), the total required intervention group sample size is 190 subjects in 
each Phase. For Phase II, the 150 subjects randomized to the TriGUARD 3 
and 40-50 roll-ins will constitute the primary safety population. 
The primary analysis population for the primary safety endpoint will be the 
As Treated (AT) population. The AT population is defined by the treatment 
actually received, regardless of the assigned treatment. In the AT population, 
subjects in whom vascular access in the contralateral femoral artery has 
been established for the intended deployment of the TriGuard HDH or 
TriGUARD 3 device will be assigned to the Intervention group, and subjects 
                                            
 
3 Safety power calculation was done for TriGUARD 3 independently. 

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in whom the TAVI procedure is initiated (but no vascular access for intended 
deployment of the TriGuard HDH or TriGUARD 3 is established) will be 
assigned to the Control group. As a secondary analysis, the primary safety 
endpoint will be evaluated in the Intention To Treat (ITT) population of 
evaluable subjects (Roll-In patients are excluded). 
 
Primary Efficacy Endpoint Analysis 
Phase II: 
The primary efficacy hypothesis is that TAVI with the TriGUARD 3 system is 
superior to standard (unprotected) TAVI for the primary hierarchical 
composite efficacy endpoint of all-cause mortality or any stroke at 30 days 
(Tier 1), NIHSS worsening 2-5 days post-procedure (Tier 2), freedom from 
any cerebral ischemic lesions detected by diffusion-weighted magnetic 
resonance imaging (DW-MRI) 2 to 5 days post-procedure (Tier 3), and total 
volume of post-procedure cerebral ischemic lesions detected by DW-MRI 
(Tier 4). In tier 1 death/stroke will be analyzed as time to event by days.  
Each subject in the intervention group of phase II will be compared with every 
control subject (from phases I and II) based on the pre-specified hierarchy of 
adverse outcomes according to the Finkelstein-Schoenfeld method.2 For 
example, if Subject A dies or has stroke and Subject B survives free of stroke 
to 30 days, Subject B wins (score +1) and Subject A loses (score -1). If both 
subjects die or have a stroke on the same day, it is equilibrium (score 0, 
otherwise the patient with the later (by at least a day) death/stroke will be the 
winner. If both patients had a stroke on the same day the comparison will 
move to the next tier of the hierarchy.  
If neither subject experiences a Tier 1 event, the comparison moves to the 
next tier of the hierarchy. After all between-subject comparisons have been 
performed, scores are summed to obtain a cumulative score for each subject, 
and outcomes between treatment groups are then compared by the chi-
square test. 
Based on published clinical data from randomized controlled trials of subjects 
undergoing TAVI4-7 as well as data from the DEFLECT III randomized trial of 
TriGuard HDH vs. unprotected TAVI8 and the recent SENTINEL9 trial we 
assume the following hierarchical event rates: 
Assumed Event Rates Phase II 
  
Assumed 
Control Rates 
Assumed 
TriGUARD 3 Rates 
Death or Stroke 
11% 
6% 
Worsening NIHSS 
9% 
6% 
Freedom from MRI Findings 
(Lesion Volume 0 mm3) 
11% 
27% 
Lesion Volume (mm3) 
 
 
>0-50 
7% 
19% 
>50-150 
33% 
7.5% 
> 150 
48% 
46% 

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15% Missing in MRI Follow-up and 5% missing for all other parameters 
Type I Error = 5% 
Among subjects who reach third tier of the comparison hierarchy, we assume 
a 15% loss to DW-MRI follow-up (due to contraindications to post-procedure 
DW-MRI [e.g., pacemaker implantation] or subject non-compliance). 
Given these assumptions, the initial randomized cohort sample size of 225 
subjects (2:1 randomization with 150 Intervention and 75 new control 
patients) will provide a power of >80% to demonstrate superiority (1-sided 
α=0.025) of the intervention group over the control group for the primary 
efficacy endpoint. Notably, in several simulations, considering different 
distributions for lesion volume and different distributions for death/ stroke, the 
study power remained greater than 80%. Adding the 63 control subjects 
already enrolled in REFLECT phase I for a total of 138 control subjects would 
increase the power to at least 92% to demonstrate superiority of the primary 
efficacy endpoint; poolability of the Phase I and Phase II control subjects will 
be assessed at the time of the primary analysis and the results will determine 
the control population used for the primary analysis of the primary efficacy 
endpoint. 5% loss to clinical follow up at 30 days is included.  
As a primary efficacy analysis, the primary efficacy endpoint will be evaluated 
in the efficacy Intention to Treat (eITT) population. The eITT population is 
defined as: 
• Subjects who are enrolled in the trial and randomized to a treatment 
group, regardless of treatment actually received AND 
• Who do not have conversion to surgery or prolonged cardiac arrest 
(>3 minutes) prior to the post-procedure DW-MRI 
Selection of the eITT population as the primary analysis population for the 
primary efficacy endpoint ensures that, should a small number of subjects 
experience an adverse event due to circumstances unrelated to procedural 
neuroprotection (i.e., conversion to surgery or prolonged cardiac arrest prior 
to the post-procedure DW-MRI), the study will remain powered to detect a 
clinically-meaningful treatment effect, particularly regarding the volume of 
subclinical cerebral ischemic lesions on DW-MRI. 
If the primary endpoint is met in the primary (eITT) analysis population, 
sequential testing of the primary efficacy hypothesis will be conducted in the 
Intention to Treat (ITT) analysis population of evaluable subjects (Roll-In 
patients are excluded). As a secondary analysis, the primary efficacy 
endpoint and its components will be evaluated in the Intention To Treat (ITT) 
analysis population of evaluable subjects (Roll-In patients are excluded). The 
ITT population is defined as all subjects who are enrolled the study, by 
assigned treatment, regardless of the treatment actually received. An 
additional analysis will also be performed in the Per Treatment (PT) 
Population. 
The PT population is defined as subjects in the Intervention group in whom 
device positioning is maintained until final procedure with complete cerebral 
coverage, and all Control group subjects. An additional analysis of the 

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primary efficacy endpoint with adjustment for pre-existing cerebral lesion 
volume will also be performed in the primary eITT analysis population. 
Secondary Endpoints Analysis (Phase I) 
The efficacy hypothesis for phase I was that TAVI with the TriGuard HDH 
system is superior to standard (unprotected) TAVI for the phase I hierarchical 
composite efficacy endpoint of all-cause mortality or any stroke at 30 days 
(Tier 1), NIHSS worsening 2-5 days post-procedure or MoCA worsening at 
30 days (Tier 2), and total volume of post-procedure cerebral ischemic 
lesions detected by DW-MRI (Tier 3).  
Each subject in the intervention group was to be compared with every subject 
from the control group based on the pre-specified hierarchy of adverse 
outcomes according to the Finkelstein-Schoenfeld method2. For example, if 
Subject A dies or has stroke and Subject B survives free of stroke to 30 days, 
Subject B wins (score +1) and Subject A loses (score -1). If both subjects die 
or have a stroke, it is equilibrium (score 0). If neither subject experiences a 
Tier 1 event, the comparison moves to the next tier of the hierarchy. After all 
between-subject comparisons have been performed, scores were to be 
summed to obtain a cumulative score for each subject, then outcomes 
between treatment (TriGuard HDH and control) groups were to be compared 
by the Mann-Whitney test. 
Based on published clinical data from randomized controlled trials of subjects 
undergoing TAVI as well as data from the DEFLECT III randomized trial of 
TriGuard vs. unprotected TAVI, we assumed the following hierarchical event 
rates: 
Event  
Intervention 
Control 
Death or stroke 
7% 
8% 
NIHSS or MoCA worsening 
10% 
15% 
Total Lesion Volume 
70 mm3 
100 mm3 
In addition, among subjects who reach Tier 3 of the comparison hierarchy, 
we assume a 20% loss to DW-MRI follow-up (due to contraindications to 
post-procedure DW-MRI [e.g., pacemaker implantation] or subject non-
compliance). 
Given these assumptions, a sample size of 270 evaluable subjects (180 
Intervention and 90 Control) would provide >90% power to demonstrate 
superiority (2-sided α=0.049) of the Intervention group to the Control group 
for the primary efficacy endpoint. Therefore, the total sample size of the initial 
randomized cohort of 285 subjects (190 Intervention and 95 Control) will 
provide sufficient power to evaluate the primary efficacy endpoint, even in 
the event that up to 5% of trial subjects do not meet criteria for inclusion in 
the primary efficacy analysis population** 
** Enrollment in this cohort (termed Phase I in this protocol version) was 
halted after 204 subjects were randomized and 54 roll-ins were enrolled). 

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Secondary Safety Endpoints 
All secondary safety endpoints will be reported by treatment group in the AT 
population of evaluable subjects using appropriate descriptive statistics 
(sample size, mean, standard deviation, median, minimum, and maximum 
for continuous characteristics; counts and percentages of patients for 
dichotomous characteristics). No formal hypothesis testing will be performed, 
and there is no plan to adjust alpha to account for multiple testing of 
exploratory secondary endpoints. 
The AT analysis will be considered primary. As a secondary analysis, all 
secondary safety endpoints will be evaluated in the ITT population of 
evaluable subjects.  
For safety endpoints occurring in the Intervention and Roll-In groups, 
relationship to the investigational device/investigational procedure (as 
determined by an independent Clinical Events Committee) will also be 
reported.  
Secondary Efficacy Endpoints 
Imaging Efficacy Endpoints 
All secondary imaging efficacy endpoints will be reported by treatment group 
in the eITT population of evaluable subjects (Roll-In subjects are excluded) 
with interpretable DW-MRI data using descriptive statistics. 
No formal hypothesis testing will be performed, and there is no plan to adjust 
alpha to account for multiple testing of exploratory secondary endpoints. 
Statistics for continuous variables will include mean, median, quartiles, 
standard deviation, minimum, maximum, and sample size for each treatment 
group. Binary variables will be summarized using frequencies, percentages, 
and sample size for each treatment group. 
The analysis of the eITT population of subjects with available DW-MRI data 
will be considered primary. As a secondary analysis, all secondary imaging 
efficacy endpoints will be evaluated in the ITT population of evaluable 
subjects. An additional analysis will also be performed in the PT population. 
An additional analysis of secondary imaging efficacy endpoints with 
adjustment for pre-existing cerebral lesion volume will also be performed in 
the primary eITT analysis population. 
Neurologic Efficacy Endpoints 
All secondary neurologic efficacy endpoints will be reported by treatment 
group in the eITT Population of evaluable subjects (Roll-In subjects are 
excluded) using descriptive statistics. No formal hypothesis testing will be 
performed, and there is no plan to adjust alpha to account for multiple testing 
of exploratory secondary endpoints. Statistics for continuous variables will 
include mean, median, quartiles, standard deviation, minimum, maximum, 
and sample size for each treatment group. Binary variables will be 
summarized using frequencies, percentages, and sample size for each 
treatment group 

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The analysis of the eITT population will be considered primary. As a 
secondary analysis, all secondary neurologic and cognitive efficacy 
endpoints will be evaluated in the ITT population of evaluable subjects. An 
additional analysis will also be performed in the PT population. An additional 
analysis of secondary neurologic and cognitive efficacy endpoints with 
adjustment for pre-existing cerebral lesion volume will also be performed in 
the primary eITT analysis population. 
Secondary Performance Endpoints 
All secondary performance endpoints will be reported by treatment group in 
the ITT population of evaluable subjects (Roll-In subjects are excluded) using 
appropriate descriptive statistics (sample size, mean, standard deviation, 
median, minimum, maximum for continuous characteristics; counts and 
percentages of patients for dichotomous characteristics). No formal 
hypothesis testing will be performed, and there is no plan to adjust alpha to 
account for multiple testing of exploratory secondary endpoints. 
The ITT analysis will be considered primary. As an additional analysis, all 
secondary performance endpoints will be evaluated in the AT population of 
evaluable subjects.  
Other Measures 
Other Measures will be reported by treatment group in the ITT population of 
evaluable subjects (Roll-In subjects are excluded) using descriptive 
statistics. No formal hypothesis testing will be performed. 
The ITT analysis will be considered primary. As a secondary analysis, Other 
Measures will be evaluated in the AT population of evaluable subjects. An 
additional analysis will also be performed in the PT population. 
Subgroup Analyses 
Subgroup analyses will be performed for all primary and secondary 
endpoints in their respective primary analysis populations for the following 
subgroups, and results will be reported by treatment group using descriptive 
statistics: 
• Subjects with paroxysmal or persistent atrial fibrillation (AF) at 
baseline 
• Subjects by valve prosthesis type (Edwards vs. Medtronic)  
Roll-In Population Analysis 
The Phase II Roll-In population will be pooled with the Phase II intervention 
group for the primary analysis of the primary safety endpoint. The Roll-In 
patient population will also be used for a separate analysis of all primary and 
secondary endpoints and other measures. Additional analyses will evaluate 
primary and secondary endpoints in the pooled population of Roll-In Subjects 
plus Evaluable Subjects. 
Analysis Timing and Adjustment 
Interim Analysis (Phase I only) 
The assumptions for powering the primary efficacy endpoint were based on 
neurologic, cognitive, and imaging data from a limited number of subjects in 

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the DEFLECT III Trial. Due to uncertainty regarding the primary efficacy 
endpoint, an unblinded interim analysis was planned to be conducted to re-
evaluate the sample size required to demonstrate superiority of the 
Intervention group to the Control group.  
The unblinded interim analysis was to be conducted when 90 subjects total 
(approximately 60 Intervention group subjects and 30 Control group 
subjects) who meet the eITT population definition have completed the 30-
day follow-up visit. At the interim analysis, the trial sample size would have 
been re-calculated, if necessary, to ensure 80% conditional power to 
demonstrate superiority (overall 2-sided α=0.05) of the Intervention group to 
the control group for the primary efficacy endpoint, taking into account the 
interim unblinded results, according to the eITT population definition (there 
was to be no imputation of missing data in this interim analysis; i.e., missing 
data will be excluded). The conditional power and sample size re-calculation 
for the final analysis was planned to be ascertained by computer simulations 
and by established methodology outlined in Chen, DeMets and Lan.10 
Specifically, at the interim stage, Monte Carlo simulations were to be used to 
assess the conditional power of achieving a significant Mann-Whitney test by 
the end of the study, conditioned on the distribution of the observed interim 
data. If the conditional power was found to be 50% - 80% (the “promising 
zone” according to Chen, DeMets and Lan), the plan was to use simulations 
to ascertain the increase in sample size that is required to yield 80% 
conditional power for the Mann-Whitney test. If the interim analysis 
determined that more than 285 randomized subjects will be required to 
ensure adequate study power, enrollment would have continued until the 
required number of subjects have been enrolled, or until the total subject limit 
for the study has been reached (whichever occured first). If the conditional 
power was found to be <50% or >80%, the study would have proceeded as 
is without a sample size adjustment (i.e., only the initial randomized cohort 
of 285 subjects would have been enrolled).  
There was no intention to stop the study for overwhelming efficacy at the 
interim analysis. However, as a precautionary measure and to be 
conservative (due to the presence of an unblinded interim analysis), the 
O’Brien Fleming alpha spending method was to be used to calculate an alpha 
penalty for the final analysis regardless of whether a sample size increase is 
needed (final analysis two-sided alpha = 0.049). 
Note: Enrollment in Phase I (TriGuard HDH CEPD) has been halted after 
enrolling a total of 258 subjects (54 roll-ins and 204 randomized subjects 
including 63 controls) based on a recommendation of the DSMB following 
data review at the prespecified interm analysis time point. A next iteration 
device (TriGUARD 3) designed for increased efficacy, ease of use, and 
improved safety will be tested in Phase II. 
Adaptive Design (Phase II) 
Once at least 50% of the Phase II cohort has been enrolled and has reached 
the 30 day primary efficacy endpoint evaluation time point, the independent 
unblinded statistician will perform a conditional power analysis. If the trial, 
based on the results at that point is either ≤ 40% powered to achieve success 

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in meeting the primary endpoint or is ≥80% powered to achieve the primary 
endpoint, no sample size reestimation will be required. If the conditional 
power of the study is >40% but <80% the independent unblinded statistician 
will recommend a sample size reestimation, subject to approval by the 
Sponsor.  
Promising zone computation 
After the trial has enrolled 50% of the originally planned sample size of the 
initial randomized cohort (approximately 112 subjects), an independent 
statistician will estimate all 4 levels of the Finkelstein-Schoenfeld hierarchy 
for device and control, and use these estimates to re-calculate the trial’s 
power given the originally planned 225 Phase II patients.   
If the trial power is between >40% and <80%, the trial will be considered 
promising and the trial will readjust the sample size to attain 80% power. If 
on the other hand the power falls to ≤ 40% or to ≥ 80%, the sample size will 
not be adjusted. 
Conditional power computation 
The conditional power will estimate all four Finkelstein-Schoenfeld levels and 
use these estimates to simulate future enrolled patients. The power 
simulation will follow exactly the same algorithm as used to power the original 
Phase II study with updated estimates of effect size. 
Alpha spending and controlling type I error 
Since the study leadership and sponsor do not conduct any formal statistical 
hypothesis test, this design will not incur any alpha penalty or affect the 
overall type I error. As detailed by Mehta and Pocock11 and based on the 
work of Chen10 as long as the sample size reestimation occurs only when 
the conditional power falls in the promising zone, no additional alpha spend 
is required and the overall type I error is preserved.   
Anticipated 
timelines: 
Phase I 
Initial Enrollment: 
Last Enrollment: 
30 days follow-up: 
90 days follow-up: 
Phase II 
Initial Phase II Enrollment: 
Last Enrollment: 
30 days follow-up: 
90 days follow-up: 
 
June 2016 
July 2017 
September 2017 
November 2017 
 
June 2018 
December 2018 
January 2019 
March 2019 

REFLECT – US IDE Trial [CIP-09 (v13.0)] 
 
   
 
 
 
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3.0 Study Contacts 
Sponsor 
Keystone Heart Ltd. 
Keystone Heart, Ltd.   
3000 Bayport Drive, Suite 980   
Tampa, FL 33607 USA 
 
Keystone Heart Research and Development Ltd. 
15 Halamish St.  
P.O. Box 3170 
Caesarea Business Park 3088900 
Israel 
Contacts: 
M. Pauliina Margolis, MD, PhD 
Chief Medical Officer 
Tel: 305.972.8447 
email: pauliina.margolis@keystoneheart.com  
Ron Nitzan, PhD 
Vice President, Regulatory and Quality Affairs 
Tel: +972 4 615 8005 
Fax: +972 4 615 8099 
email: ron.nitzan@keystoneheart.com 
  
Study Chairman 
Jeffrey W. Moses, MD 
Director, Cardiovascular Interventions 
New York Presbyterian Hospital/ Columbia 
University Medical Center 
161 Fort Washington Ave., 5th Fl. 
New York, NY 10032 USA 
Tel:  (212) 342-3601 
email: jm2456@cumc.columbia.edu  
 
Principal Investigator 
Tamim M. Nazif, MD 
Director of Clinical Services for the Structural 
Heart & Valve Center, Director of Clinical 
Research for the Center for Interventional 
Vascular Therapy, New York Presbyterian 
Hospital/ Columbia University Medical Center 
161 Fort Washington Ave., 5th Fl. 
New York, NY 10032 USA 
Tel:  (212) 342-0444 
email: tmn31@cumc.columbia.edu 

REFLECT – US IDE Trial [CIP-09 (v13.0)] 
 
   
 
 
 
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US Co-Principal Investigator 
Alexandra J. Lansky, MD 
Associate Professor of Cardiology 
Director, Yale Cardiovascular Research Group 
Co-Director, Yale Valve Program 
Yale University School of Medicine 
135 College Street, Suite 101 
New Haven CT 06510 USA 
Tel: (212) 737-2142 
email: alexandra.lansky@yale.edu  
US Co-Principal Investigator 
 
Rajendra Makkar, MD 
Director, Interventional Cardiology and Cardiac 
Catheterization Laboratory 
Co-Director, Interventional Cardiology Research 
Program 
Cedars-Sinai Medical Center 
127 S. San Vicente Blvd, Advanced Health 
Sciences Pavilion, Third Floor, A3600 
Los Angeles, CA 90048 USA 
Tel: (310) 423-3871 
Email: raj.makkar@cshs.org  
EU Co-Principal Investigator / 
Coordinating Investigator 
(Phase I) 
Andreas Baumbach, MD 
Chair for Device Innovation 
Queen Mary University London 
Consultant Cardiologist and Director of 
Interventional Research 
Barts Heart Centre, St. Bartholomew’s Hospital 
West Smithfield 
London EC1A 7BE UK 
email: a.baumbach@qmul.ac.uk  
  
EU Co-Principal Investigator / 
Coordinating Investigator 
(Phase I) 
Joachim Schofer, MD 
Medical Director, Medical Care Center  
Hamburg University Cardiovascular Center  
Wördemanns Weg 25-27 
Hamburg 22527, DE 
Tel: +49 (040) 889009-0 
email: schofer@herz-hh.de  

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Regulatory, Angiographic Core 
Laboratory, Clinical Events 
Committee, Data Safety Monitoring 
Committee 
(phase I) 
 
 
Yale Cardiovascular Research Group 
Yale University School of Medicine 
135 College Street, Suite 101 
New Haven CT 06510 USA 
Contacts:  
Alexandra J. Lansky, MD 
Director 
Tel: (203) 737-2142 
Fax: (203) 737-7457 
email: alexandra.lansky@yale.edu 
Louise Gambone, RN 
Director of Operations 
Tel: (203) 737-3427 
Fax:(203) 737-7457 
e-mail: louise.gambone@yale.edu 
Angiographic Core Laboratory, 
(Phase II) 
Cardiovascular Research Foundation 
Clinical Trials Center 
1700 Broadway, 9th Floor 
New York, NY 10019 
Tel: (646) 434-4500 
Fax: (646) 434-4711 
e-mail: info@crf.org 
 
Contacts: 
Ivana Jankovic, MD 
Director, Core Lab Operations 
Tel: (646) 434-4388 
Fax: (646) 434-471 
e-mail: ijankovic@crf.org 
Clinical Events Committee, 
Biostatistics 
(Phase II) 
 
Cardiovascular Research Foundation 
Clinical Trials Center 
1700 Broadway, 9th Floor 
New York, NY 10019 
Tel: (646) 434-4500 
Fax: (646) 434-4711 
e-mail: info@crf.org 
Data Safety Monitoring Committee 
(Phase II) 
Yale Cardiovascular Research Group 
Yale University School of Medicine 
135 College Street, Suite 101 
New Haven CT 06510 USA 
Contacts: 
Louise Gambone, RN 
Director of Operations 
Tel: (203) 737-3427 
Fax:(203) 737-7457 
e-mail: louise.gambone@yale.edu 

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MRI 
Core 
Laboratory, 
CT 
Core 
Laboratory, Monitoring (US), Data 
Management 
Global Institute for Research, LLC 
14701 Village Square Place, Suite B 
Midlothian, VA 23112 USA  
 
Contacts: 
Szilard Voros, MD  
Chief Medical Officer 
email: szilard.voros@globalifr.com  
Bradley Brown, MS, MBA 
Chief Executive Officer 
Tel: +1 804 638 8598 
Fax: +1 804 884 3885 
email: brad.brown@globalifr.com  
  
Monitoring (OUS) (Phase I) 
genae N.V. 
Europaallee 41 
8021 Zürich, Switzerland  
Tel: +32 3 290 0306 
Fax: +32 3 290 0307 
 
Contact: 
Evert Verbraak, PhD 
Director, Operations 
email: evert.verbraak@genae.com 
Biostatistics (Phase I) 
CardioMed Device Consultants, LLC 
5523 Research Park Drive, Suite 205 
Baltimore, MD 21228 USA  
 
Contact: 
Victor Novack, MD, PhD 
Tel: (410) 674-2060 
Fax: (410) 674-2133 
Email: vnovack@cardiomedllc.com  
  
Biostatistics (Phase II) 
Cardiovascular Research Foundation 
Clinical Trials Center 
CRF Imaging Core Labs 
1700 Broadway, 9th Floor 
New York, NY 10019, USA 
 
Contact: 
Thomas McAndrew, PhD 
Tel: (646) 434-4570 
Fax: (646) 434-4711 
e-mail: tmcandrew@crf.org 
 

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Patient Review Committee 
Cedars Sinai Medical Center Heart Institute 
CT Core Laboratory 
127 S San Vicente Blvd 
Advanced Health Sciences Pavilion, 3rd Floor 
Los Angeles, CA 90058 USA 
 
Contact: 
Rahul P. Sharma, MD 
Email: Rahul.Sharma@cshs.org  
 
 
 
 
 

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4.0 Introduction 
4.1 Background 
4.1.1 Periprocedural Stroke 
Stroke is a dreaded complication of endovascular procedures due to its association with an 
extreme morbidity and mortality burden.12, 13 Periprocedural stroke rates increase with the 
complexity of cardiac surgery, ranging from 1-5% for coronary artery bypass graft surgery 
(CABG) or isolated aortic valve replacement to as high as 7.4% for combined CABG and 
valve surgery and 9.7% for multiple valve surgery.14 Periprocedural stroke during catheter-
based cardiovascular procedures is also a major concern. While stroke after left heart 
catheterization or percutaneous coronary intervention (PCI) is rare (<0.5%),15 it is associated 
with significant morbidity and an in-hospital mortality rate of 25% to 30%.16, 17 
Cerebral microembolism is the primary mechanism of periprocedural stroke during catheter-
based interventions, and is primarily caused by embolization of aortic plaque dislodged during 
retrograde instrumentation of the aortic arch.18 In particular, retrograde catheterization with 
crossing of the aortic valve has been associated with focal diffusion-imaging abnormalities 
suggesting cerebral embolic events in 22% of patients, in addition to a 3% rate of clinical 
neurological deficits.19  
Given the frequency and dire implications of periprocedural stroke, methods to reduce 
cerebral embolism during cardiac interventions are sorely needed. 
4.1.2 Transcatheter Aortic Valve Implantation and Cerebral Injury 
4.1.2.1.1 TAVI and Periprocedural Stroke 
Transcatheter aortic valve implantation (TAVI) has emerged as an important alternative to 
surgical aortic valve replacement (SAVR) for high-risk and moderate-risk patients with aortic 
stenosis, offering overall less morbidity, similar mortality and significantly reduced recovery 
time.4, 20-22 However, periprocedural neurological injury remains an important limitation of 
TAVI. In high-risk surgical candidates in the randomized PARTNER trial, TAVI was 
associated with an approximately two-fold increased risk of stroke or TIA (5.5% vs. 2.4%, 
p=0.04) compared with SAVR at 30 days.4 In inoperable subjects, stroke or TIA occurred in 
6.7% of TAVI patients at 30 days, with 5.0% of subjects suffering a major stroke.5 A meta-
analysis of 10,037 published TAVI patients found an overall 30-day stroke rate of 3.3±1.8%, 
with the majority being major strokes (2.9±1.8%).23 In this study, stroke was associated with 
a more than 3.5-fold increase in 30-day mortality (25.5±21.9% vs. 6.9±4.2%). 
In the more recent PARTNER 2 trial, the rates of any stroke in moderate risk patients with 
AS after TAVI were similar to the rates after SAVR: 5.5% vs. 6.1% at 30 days and as high as 
9.5% vs. 8.9% at 2 years, for TAVI and SAVR respectively.22 
The timing of stroke after TAVI follows a bimodal distribution. The risk of stroke during an 
early high-peaking hazard phase (within 2 days of the procedure) is primarily procedure-
related (TAVI versus SAVR).24 More than 50% of strokes in TAVI patients occur during this 
early phase. During a later constant hazard phase (1 to 12 months post-procedure), patient 
factors including generalized heavy atherosclerotic burden, recent cerebral ischemic event, 
and higher NYHA class appear to be the primary determinants of risk. 
As during other types of cardiac procedures, periprocedural stroke during TAVI is generally 
ischemic and embolic.25 TAVI patients have several high-risk features that make cerebral 
embolization particularly common. First, the prevalence of severe aortic atherosclerosis 
increases across grades of AS, which when combined with the large-caliber catheters 

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34
necessary for TAVI, make dislodgement of aortic debris more likely.26 Second, disruption of 
aortic valvular and annular calcification during TAVI is an additional source of embolic 
material; procedural transcranial Doppler monitoring indicates that the valve itself is the 
primary source of cerebral emboli following TAVI, and that most emboli are composed of 
debris dislodged during direct manipulation of the calcified aortic valve and crushing of the 
leaflets and aortic annulus during implantation.27  
4.1.3 TAVI and Silent Cerebral Ischemia 
In addition to clinical stroke, there is increasing recognition of the importance of subclinical 
manifestations of periprocedural cerebral embolization in cardiac procedures in general and 
TAVI in particular.28-30 A growing body of evidence indicates that clinically silent cerebral 
ischemia is common after TAVI and may have an important impact on clinical and 
neurocognitive outcomes.  
Diffusion-weighted magnetic resonance imaging (DW-MRI) is a highly sensitive and specific 
technique to visualize acute ischemia.31 Acute ischemia presents on DW-MRI as a 
hyperintense area against the dark background of normal tissue, allowing detection of even 
small lesions. MRI-based methods have greater sensitivity to detect cerebral infarcts, 
particularly small lesions, compared with computed tomography (CT) due to stronger field 
magnets, thinner slices, and different pulse sequences.32 DW-MRI has an average sensitivity 
of 94% and specificity of 97% in detecting stroke in humans.33 It has been used extensively 
as a surrogate for cerebral embolization after catheter-based and surgical cardiovascular 
interventions.31, 34 In addition, standardized endpoint definitions for TAVI trials (VARC-2)  
include MRI or computed tomographic neuroimaging as an important supplement to the 
clinical diagnosis of stroke and TIA, as well as a requisite for diagnosing stroke in patients 
with non-focal global encephalopathy.35  
Several small studies (Tables 1-4) have reported DW-MRI data after unprotected TAVI. Foci 
of restricted cerebral perfusion on DW-MRI (cerebral ischemic lesions) are present in 
approximately 77% of patients (reported range 58% to 93%) after TAVI (Table 1). Most 
patients have multiple lesions (mean 4.6) (Table 2), distributed bilaterally in a pattern 
suggesting cerebral embolization. Several studies have reported the volume of single (Table 
3) and total per-patient (Tables 4 and 5) lesion volumes after TAVI, with wide variance
between studies; the relative degree to which this variation is attributable to methodological 
and patient-level differences in the extent of affected cerebral tissue is unclear.  
Table 1. Reported Incidence of Ischemic Lesions on Post-TAVI DW-MRI
Study 
Sample Size (N) 
Subjects with 
Lesions (n) 
Proportion with 
Lesions (n/N) 
Arnold 201036 
25 
17 
68% 
Astarci 201337†* 
44 
41 
93% 
Fairbairn 201238 
31 
24 
77% 
Ghanem 201339† 
39 
28 
72% 
Kahlert 201040 * 
32 
27 
84% 
Knipp 201341 
12 
7 
58% 
Rodes-Cabau 201120* 
60 
41 
68% 
Uddin 201342 
45 
37 
82% 
Average 
36 
28 
75% 
Weighted Mean 
-- 
-- 
77% 
† Multiple publications with overlapping data. Data from the most recent (and largest) reports are provided. 
* Data from studies reporting separate results from multiple study arms were pooled.

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Table 2. Reported Number of Ischemic Lesions on Post-TAVI DW-MRI 
Study 
N 
Lesion Count 
Range (min, 
max) 
Mean 
SD 
Median IQR [25-75] 
Astarci 201337†* 
44 
-- 
7.9 
-- 
-- 
-- 
Fairbairn 201238 
31 
-- 
4.2 
6.5 
2 
1-5 
Ghanem 201043‡ 
22 
0, 19 
3.4 
5.1 
1.5 
0.25-4 
Kahlert 201040* 
32 
0, 19 
3.6 
-- 
-- 
-- 
Knipp 201341 
12 
0, 5 
1.8 
1.9 
1.5 
-- 
Onsea 201244 
20 
-- 
7.2 
-- 
-- 
-- 
Rodes-Cabau 201120* 
60 
1, 36 
4.2 
-- 
3 
2-8 
Average 31.5 
0, 20 
4.6 
-- 
2 
1-6 
† Multiple publications with overlapping data. Data from the most recent (and largest) report is provided. 
* Data from studies reporting separate results from multiple study arms were pooled. 
‡Multiple publications with overlapping data. Data from the first report were used because patient-level 
data was provided, allowing calculation of SD, median, and IQR. 
 
Table 3. Reported Single-lesion Volume on Post-TAVI DW-MRI 
Study 
N 
Per Lesion Volume (cm3) 
Range (min, max) 
Mean 
SD 
Median IQR [25-75] 
Astarci 201337†* 
44 
-- 
0.17 
-- 
-- 
-- 
Fairbairn 201238 
31 
-- 
0.49 
-- 
-- 
-- 
Ghanem 201043‡ 
22 
0, 11.7 
0.76 
2.47 
0.15 
0.025-0.33 
Kahlert 201040* 
32 
0.059, 0.094 
0.075 
-- 
-- 
-- 
Knipp 201341 
12 
0.015, 1.21 
0.172 
0.283 
-- 
-- 
Average 28.2 
0.025, 4.33 
0.334 
-- 
0.15 
-- 
† Multiple publications with overlapping data. Data from the most recent (and largest) report is provided. 
* Data from studies reporting separate results from multiple study arms were pooled. 
‡Multiple publications with overlapping data. Data from the first report were used because patient-level 
data was provided, allowing calculation of SD, median, and IQR. 
 
Table 4. Reported Total Lesion Volume (Per-Subject) on Post-TAVI DW-MRI 
Study 
N 
Per Patient Lesion Volume (cm3) 
Range (min, max) 
Mean 
SD** Median 
IQR [25-75] 
Astarci 201337†* 
44 
-- 
1.65 
-- 
-- 
-- 
Fairbairn 201238 
31 
-- 
2.05 
3.50 
-- 
-- 
Ghanem 201043‡ 
22 
0, 70.3 
4.3 
14.9 
0.30 
0.025-1.23 
Uddin 201342 
45 
-- 
1.74 
2.8 
-- 
-- 
Average 
36 
-- 
2.44 
5.5 
-- 
-- 
Weighted Average 
-- 
-- 
2.18 
4.5 
-- 
-- 
† Multiple publications with overlapping data. Data from the most recent (and largest) report is provided. 
* Data from studies reporting separate results from multiple study arms were pooled. 
‡Multiple publications with overlapping data. Data from the first report were used because patient-level data 
was provided, allowing calculation of SD, median, and IQR for per-patient total lesion volume. 
** Average and weighted average Standard Deviations calculated using SD per unit method 
 

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Table 5. Reported Total Lesion Volume (Per-Subject) on Post-TAVI DW-MRI - Excluding 
Subjects Who Experienced a Stroke 
Study 
N 
Per Patient Lesion Volume (cm3) 
Range (min, max) Mean SD** Median 
IQR [25-75] 
Astarci 201337†* 
44 
-- 
1.65 
-- 
-- 
-- 
Fairbairn 201238¥ 
29 
-- 
1.1 
1.1 
-- 
-- 
Ghanem 201043‡¥ 
21 
0, 7.8 
1.16 
2.08 
0.30 
0-1.00 
Uddin 201342 
45 
-- 
1.74 
2.8 
-- 
-- 
Average 
35 
-- 
1.41 
2.07 
-- 
-- 
Weighted Average 
-- 
-- 
1.49 
2.18 
-- 
-- 
† Multiple publications with overlapping data. Data from the most recent (and largest) report is provided. 
* Data from studies reporting separate results from multiple study arms were pooled. 
‡Multiple publications with overlapping data. Data from the first report were used because patient-level data 
was provided, allowing calculation of SD, median, and IQR for per-patient total lesion volume. 
** Average and weighted average Standard Deviations calculated using SD per unit method 
¥ Strokes excluded where possible (1 subject with a major stroke [Ghanem 2010] and 2 subjects 
with unspecified stroke [Fairbairn 2012]) 
The clinical significance of asymptomatic DW-MRI lesions is incompletely characterized. 
However, in population-based studies the presence of clinically silent brain infarcts has been 
associated with frailty, declines in physical function, reduced cognitive ability, depressive 
symptoms, and an increased risk of subsequent stroke or TIA.32, 45, 46 Several studies have 
found an association between DW-MRI lesions and neuropsychological deficits after 
conventional valve surgery,47, 48 and DW-MRI lesions have also been associated with 
chemical markers of neuronal damage that in turn correlate with postoperative cognitive 
deficits and embolic stroke.49  
Thus far, small studies of DW-MRI lesions after TAVI have failed to detect an association 
between post-procedural ischemic lesions and risk of future neurological events36, 50, 51 or 
measurable impairments of neurocognitive function (using the Mini Mental State 
Examination).20, 40, 43, 52 However, concerns remain about the potential impact of even 
transient and asymptomatic ischemic lesions on long-term cognitive outcomes and other 
neurological syndromes.33, 53-57  
DW-MRI studies examining neurocognitive outcomes after TAVI have been exploratory (not 
powered to detect clinically meaningful neurocognitive changes) and lack long term follow-
up. Furthermore, while routine clinical examination can reliably detect focal neurological 
abnormalities and deficits, more subtle evidence of global neurological dysfunction such as 
cognitive decline, memory and mood disturbances, reduction of psychomotor speed, and 
personality changes require specific testing for diagnosis and may be missed. The MMSE, 
the most frequently used cognitive test in these studies, is relatively insensitive to mild 
cognitive impairment and declines in non-memory domains.58 These issues are likely to 
receive increased attention as the indications for TAVI are expanded to younger populations 
with increased life expectancy.  
4.1.4 Stroke Assessment- National Institute of Health Stroke Scale- 
NIHSS 
The NIHSS was first derived by Brott et al. to assess stroke severity in a naloxone trial59 and 
later modified and utilized in a tPA trial by the NINDS60. While the scale has been shown to 
have prognostic implications61-64, the timing of conducting the NIHSS assessment and the 
number of points considered as ‘true worsening’ differs between trials65-71. Previous Cerebral 

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Embolic Protection Device (CEPD) trials (DEFLECT III8, EMBOL-X72, MISTRAL-C73, and 
CLEAN-TAVI74) have used a cut-off of 1 point (See below).  
4.1.5 Prevention of Periprocedural Cerebral Embolism 
The devastating consequences of periprocedural stroke during TAVI, as well as concern 
regarding potential long-term neurocognitive sequelae of subclinical cerebral embolic events, 
have prompted investigation into methods to minimize or prevent periprocedural cerebral 
embolism during cardiac surgery and endovascular interventions. Because atheromatous 
and calcific embolic are substantial contributors to cerebral embolism during TAVI, a 
mechanical means of preventing such material from reaching the cerebral circulation could 
be an effective approach. Because approximately 50% of TAVI-related neurological events 
are directly procedure-related,23 such devices could have a meaningful impact on stroke and 
other cerebral embolic events in TAVI patients. 
The DEFLECT I Trial (NCT01448421) of the first-generation TriGuard cerebral embolic 
protection device (CEPD) (from which the TriGuard HDH device and the TriGUARD 3 device 
used in the present study were developed) demonstrated good procedural success and 
safety, as well as a reduction in total per-patient cerebral ischemic lesion volume after TAVI 
with embolic protection compared with a historical control of unprotected TAVI.75  
Table 6. Comparison of Post-TAVI DW-MRI Lesion Data for TAVI Without vs. With Embolic 
Protection 
Parameter 
Unprotected TAVI 
Historical Average 
TAVI with Embolic 
Protection 
Incidence of lesions 
[proportion of patients] 
77% 
78.6% 
Number of lesions 
[mean (range)] 
4.6 (0-36) 
5.1±6.1 (0-28) 
Single lesion volume 
[mean (range)] 
0.33 (0.075 – 0.76) 
0.13±0.13 (0 – 0.47) 
Total lesion volume 
[mean (range)] 
2.18±4.5 (1.65 – 4.3) cm3 
0.77±0.96 (0 – 3.94) cm3 
Results of the DEFLECT I trial of the first-generation TriGuard device (n=28 subjects with paired DW-
MRI) compared with Historical Average (Tables 1-4 above) 
 
Thus far, several randomized control trials have addressed the issue of embolic protection 
device during TAVI.  
The DEFLECT III trial8 included 85 patients and evaluated the efficacy of the TriGuard HDH 
device. Complete cerebral vessel coverage was achieved in 89% of subjects. Device use 
was associated with greater freedom from ischemic brain lesions and a shift towards smaller 
lesion volumes compared to controls. Clinically, device protection afforded better 
neurocognitive function and numerically lower rates of death and stroke. 
The EMBOL-X trial72 included 30 patients, with half of the patients randomized to protection 
with the EMBOL-X device (self-expandable mesh placed in the aorta). Protected patients had 
fewer lesions and the authors reported statistically significant smaller lesion volumes in the 
supply region of the MCA. No mortality was observed in this trial in both groups. 
Mistral- C73 included 55 patients with 1:1 randomization to protection with the SENTINEL 
device (2 cone shaped filters placed into the brachiocephalic trunk and the left common 
carotid artery). Patients with SENTINEL protection had numerically fewer lesions and a 

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smaller total lesion volume. Neurocognitive deterioration was present in 4% of patients with 
device protection and 27% of patients without (p=0.017). Mortality was also reduced in the 
device arm (not statistically significant). 
CLEAN-TAVI74 published in 2016 included 100 patients with 50 patients randomized to 
device protection with Claret (2 cone shaped filters described above). The trial showed a 
statistically significant reduction in the number of lesions and total lesion volume in the device 
arm. Stroke rates were similar between groups and one death occurred in the control group. 
Finally, the recently published SENTINEL trial9 included 119 controls and 242 device patients 
(including 123 safety patients). Patients in the device arm had smaller lesion volumes and a 
lower number of lesions. Stroke rates were reduced in the device arm but no difference was 
noted in neurocognitive function between groups. 
* MRI and other clinical results in the trials above were not statistically significant unless 
otherwise mentioned. 
Major trials and their MRI findings are summarized in table 6a. A comparison of the different 
clinical endpoints assessed in these trials is presented in table 6b. 
Table 6a. MRI findings in RCTs using device protection in TAVI. 
Trial* 
N 
Percent of patients 
with MRI lesions 
Median Number 
of MRI lesions 
Median Total Lesion 
Volume (mm^3)*** 
Device 
Control 
Device Control 
Device 
Control 
DEFLECT III8 2015 
85 
78.8% 
88.46% 
7 
4 
100.9**** 
110**** 
EMBOL-X72 2015 
30 
57.14% 
68.75% 
1.28** 
2** 
-- 
-- 
MISTRAL-C73 2016 
65 
72.73% 
86.67% 
-- 
-- 
95 
197 
CLEAN TAVI74 2016 
100 97.96% 
97.78% 
5 
10 
205 
472 
SENTINEL9 2017 
363 
-- 
-- 
3 
5 
294 
309.8 
* Based on published results where available. CLEAN-TAVI results of number of lesions and volume were 
statistically significant. 
** Unclear calculation methodology in the paper. 
*** Total lesion volume in all territories 
**** Results by per treatment. 
Table 6b. Clinical endpoints in RCTs using device protection in TAVI 
Trial 
N 
Death at 30 days 
Stroke at 30 
days 
Any worsening 
NIHSS 
Device 
Control 
Device 
Control 
Device 
Control 
DEFLECT III8 2015 
85 
2.17% 
5.13% 
4.35% 
5.13% 
3.8%* 
4.5%* 
EMBOL-X72 2015 
30 
0% 
0% 
-- 
-- 
3.8%* 
4.5%* 
MISTRAL-C73 2016 
65 
3.12% 
9.09% 
0% 
6.06% 
0%** 
5%** 
CLEAN TAVI74 2016 
100 
0% 
2% 
8% 
8% 
17.9%* 
22.5%* 
SENTINEL9 2017 
363 
1.28% 
1.8% 
5.63% 
9.09% 
-- 
-- 
* At 30 days 
** At discharge, data from presentation at TCT 2015, not presented in published paper.   

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4.1.6 Study Population- Minorities 
CEPD trials enrolled patients referred for TAVI, hence patient demographics are similar to 
current TAVI enrollment practices. Table 6c summarizes the distribution of age and sex in 
current CEPD trials. Racial disparities in TAVI have been previously reported76. Race was 
not reported in the above-mentioned CEPD trials but is expected to reflect rates similar to 
TAVI trials. In this trial sites will be encouraged to enroll minorities. 
Table 6c. Sex and age distribution in current CEPD trials. 
Trial 
N 
Age (years) 
mean+SD or median (IQR) 
Female N(%) 
Device 
Control 
Device 
Control 
DEFLECT III8 2015 
85 
82.5+6.5 
82.3+6.0 
56.5%** 
48.7%** 
EMBOL-X72 2015 
30 
81.0+5.0 
82.1+4.1 
10 (71.4%) 
8 (50.0%) 
MISTRAL-C73 2016 
65 
82 (79-84) 
82 (77-86) 
15 (47%) 
16 (49%) 
CLEAN TAVI74 2016 
100 
80.0+5.1 
79.3+4.1 
29 (58%) 
28 (56%) 
SENTINEL9 2017 
240* 
85.0 (78.4-89.4) 83.1 (77.2-87.2) 
58 (48.7%) 
63 (52%) 
* Safety population not included 
** N not reported 
4.2 Rationale  
The incidence of stroke and subclinical cerebral ischemic lesions, and their association with 
post-procedural neurological deficits, indicate that methods to prevent or reduce cerebral 
embolization are vital to optimizing TAVI procedures and improving the outcomes of patients 
with severe aortic stenosis. The first-generation TriGuard device has been demonstrated to 
safely reduce the total cerebral ischemic lesion volume after TAVI compared with historical 
controls. This prospective, randomized trial will provide more comprehensive evaluation of 
the safety and efficacy of the TriGuard HDH and TriGUARD 3 devices compared with a 
concurrent active control of unprotected TAVI.  
By employing standardized image acquisition and analysis parameters and detailed 
neurological testing, the REFLECT trial will also advance the understanding of subclinical 
neurological events and their relationship with neurocognitive function in patients undergoing 
cardiovascular interventions. 
4.3 Device Description 
The following is a summary description of the Investigational Devices. For additional 
information, please refer to the Instructions for Use.  
4.3.1 Devices Summary 
4.3.1.1.1 Phase I- TriGuard HDH 
The Keystone Heart TriGuard HDH CEPD (Figure 1) is a temporary, sterile, single use, 
biocompatible filter, introduced transfemorally through a 9F sheath to the aortic arch. Under 
fluoroscopic guidance, the device is positioned in the aortic arch to cover all 3 major cerebral 
arteries (innominate, left carotid, and subclavian arteries), and is held in position by an 
atraumatic stabilizer in the innominate artery (Figure 2). Once the device is in position, emboli 
and particulate matter are diverted away from the cerebral circulation and downstream to the 
descending aorta, where they are either harmless or can be treated effectively.  

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Figure 1. The TriGuard HDH CEPD 
 
Figure 2.  TriGuard HDH device positioning in the aortic arch. 
The TriGuard HDH CEPD is available in a single size, and is composed of a structural nitinol 
frame, lower stabilizer legs that push it towards the upper wall of the aortic arch, an upper 
stabilizer that protrudes into the innominate artery ostium, and a nitinol mesh. The frame 
includes 4 radiopaque markers to increase CEPD visualization under fluoroscopy, and ends 
in a 60 mm tail comprised of braided nitinol wires with a Duraskin™-coated coil on top of it. 
A connector with 180° of rotational freedom connects the CEPD frame to the delivery tether.  
The CEPD filter consists of a thin and durable nitinol mesh (nominal pore size 130 X 250 µm) 
attached to the frame, allowing maximal blood flow while diverting clinically significant emboli 
toward the descending aorta. The CEPD is heparin coated to reduce thrombogenicity and 
increase lubricity. The chemical and physical properties of this immobilized, biocompatible, 
hydrophilic, ultrathin polymeric coating reduce the likelihood of blood component adherence 
and activation, reducing the formation of thrombi or emboli. 
The CEPD filter unit is connected to a delivery tether that serves for pushing, maintaining and 
retrieving the filter from the aortic arch. In addition to the filter, the TriGuard System includes 
a delivery subsystem for crimping and loading the device into commercially-available 7F and 

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9F sheaths (please refer to the TriGuard HDH Instructions for Use for a listing of compatible 
introducer sheaths).  
Device deployment is accomplished by pre-loading (crimping) the CEPD through the 
dedicated crimper into the distal end of a commercially-available 7F sheath delivery system. 
Under fluoroscopy, the 7F sheath is pushed via a commercially-available 9F sheath delivery 
system, already inserted through a femoral artery access site. The device is then de-
sheathed into the 9F introducer and the 7F introducer is removed. 
4.3.1.1.2 Phase II- TriGUARD 3 CEPD 
The Keystone Heart TriGUARD 3 CEPD (Figures 1a, 1b and 2a) is a temporary, retrievable, 
sterile, single use, biocompatible filter, introduced transfemorally through an 8F sheath to the 
aortic arch. Under fluoroscopic guidance, the device is positioned in the aortic arch (Figure 
2a) to cover all 3 major cerebral arteries (covering the innominate, left carotid, and left 
subclavian arteries), and is held in position by the device’s circumferential pressure and the 
support of the nitinol shaft (external communicating device) in the aortic arch. Once the device 
is in position, emboli and particulate matter are diverted away from the cerebral circulation 
and downstream to the descending aorta, where they are either harmless or can be treated 
effectively. 
The TriGUARD 3 CEPD is available in a single size, and is composed of a structural nitinol 
frame that pushes it towards the upper wall of the aortic arch, and a Polymer mesh. The 
frame is radiopaque to increase device visualization under fluoroscopy. A nitinol connector 
connects the device frame to the delivery system. 
The CEPD filter consists of a thin and durable Polymer mesh (nominal pore size 115 X 145 
µm) attached to the frame, allowing maximal blood flow while diverting clinically significant 
emboli toward the descending aorta. The filter is heparin coated to reduce thrombogenicity 
and increase lubricity. The chemical and physical properties of this immobilized, 
biocompatible, hydrophilic, ultrathin polymeric coating reduce the likelihood of blood 
component adherence and activation, reducing the formation of thrombi or emboli. 
The CEPD filter unit is connected to a delivery system that serves for pushing, maintaining 
and retrieving the filter from the aortic arch. In addition to the filter, the TriGUARD 3 System 
includes a delivery subsystem for crimping and loading the device into a commercially 
available 8F braided sheath.  
Device deployment is accomplished by pre-loading (crimping) the CEPD through the 
dedicated crimper into the distal end of the 8F delivery system. Under fluoroscopy, the 8F 
sheath is advanced over the wire already inserted through a femoral artery access site. The 
device is then de-sheathed and exposed to the blood stream. 
 
 

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Figure 1a. The TriGUARD 3 CEPD 
 
 
Figure 1b.  TriGUARD 3 system overview.  
 
Figure 2a. TriGUARD 3 device positioned in the aortic arch 

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4.3.2 Regulatory Status 
The TriGuard HDH has received CE Mark and is commercially available in Europe and Israel. 
Use of the device at European and Israeli sites in the REFLECT study is in accordance with 
its market approved use.  
In the United States, the TriGuard HDH and the TriGUARD 3 are for investigational use only.  
4.3.3 Device Packaging 
4.3.3.1.1 Phase I- TriGuard HDH 
The device is supplied pre-assembled in a single rigid inner blister tray (Figure 3) containing 
the TriGuard HDH CEPD, a 9F delivery sheath extension (including a loading tube with a 
double hemostasis valve), a crimper (to load the CEPD into the delivery system), and 
Instructions for Use. The inner blister tray is placed in a sterility barrier consisting of a 
thermoformed blister tray with a Tyvek lid, which is placed in a cardboard box. The entire 
package is sterilized using Gamma irradiation. 
 
Figure 3. The TriGuard HDH System 
 
4.3.3.1.2 Phase II- TriGUARD 3 
The device is supplied pre-assembled in a single rigid blister tray (Figure 3a) containing the 
TriGUARD 3 CEPD filter, a crimper (to load the filter into the delivery system), and 
Instructions for Use. The inner blister tray is placed in a sterility barrier consisting of a 
thermoformed sealed Tyvek pouch, which is placed in a cardboard box. The entire package 
is sterilized using EtO. 
 
 
 

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Figure 3a. TriGUARD 3 System Packaging 
  
 
4.3.4 Comparison between Device Generations 
The TriGuard HDH device and the TriGUARD 3 device share the same basic principles of 
operation and intended use and are manufactured under the same Quality System. Design 
changes between the TriGuard HDH and TriGUARD 3 are expected to improve device safety, 
effectiveness, performance, and ease of use (Table 6d) and will be tested in Phase II.  
In comparison with TriGuard HDH system, the TriGUARD 3 system includes the following 
design changes: 
• A simplified self-positioning, self-stabilizing frame design that utilizes circumferential 
pressure and the support of the nitinol delivery shaft to improve vessel wall apposition 
and eliminate the need for dedicated stabilizer elements in the innominate artery and 
aortic arch, improving device safety, particle deflection efficacy, and ease of 
deployment and positioning. In addition, the revised device design permits the use of 
cerebral protection in a broader anatomic subset of patients because it is not limited 
by aortic arch or innominate artery ostium diameter or the presence of calcification, 
atheroma, or tortuosity in the innominate artery.  
• Reduced filter mesh pore size (115 × 145 µm vs. 130 × 250 µm) for deflection of 
smaller particles, achieved via a different mesh material (Polymer vs. nitinol);  
• An increased filter area of 68.3 cm2 vs. 20.9 cm2. 
• A frame that is fully visible via fluoroscopy (eliminating the need for radiopaque marker 
bands) for improved monitoring during deployment and positioning; and 
• A refined delivery subsystem that reduces the delivery profile (8 F vs. 9 F) expected 
to improve safety, reduce the number of procedural steps required for deployment, 
and allow over-the-wire introduction and positioning for better ease of use. 
 
Table 6d. Comparison between devices 
TriGuard HDH 
TriGUARD 3 
Nitinol frame with upper and lower 
stabilizers 
Self-positioning, self-stabilizing nitinol 
frame, fully visible via fluoroscopy 
Nitinol mesh (pore size 130 x 250 µm) 
Polymer mesh (pore size 115 x 145 µm) 
Filter area = 20.9 cm2 
Filter area = 68.3 cm2 
9 Fr delivery 
8 Fr OTW delivery 
 

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4.3.5 Intended Use  
The Keystone Heart TriGuard™ HDH and TriGUARD 3 are aortic CEPDs designed to reduce 
the amount of embolic material that may enter the cerebral blood circulation during 
transcatheter heart valve replacement or implantation. 
5.0 Study Design 
5.1 Study Design Change and Rationale 
REFLECT Version 10.0 was a prospective, single-blind, randomized, multicenter safety and 
efficacy trial. The study was intended to enroll up to 355 subjects and up to 90 roll-ins. 
Enrollment in this cohort (termed Phase I in this protocol version) was halted after 204 
subjects were randomized and 54 roll-ins were enrolled) based on a recommendation of the 
DSMB following interim data review at the prespecified interm analysis timepoint. A next 
iteration device (TriGUARD 3) designed for increased efficacy, ease of use, and improved 
safety will be tested in Phase II.  
5.1.1 Rationale for Phase II  
This amendment to the protocol is intended to allow the evaluation of the TriGUARD 3. This 
next iteration of the device will be the only manufactured and available TriGuard device.  
The proposed modifications to the ongoing REFLECT trial will allow a scientifically valid 
evaluation of the safety, effectiveness, and performance of the TriGUARD 3 device by 
leveraging the engagement of existing US sites and operators who are familiar with the prior 
generation device, as well as blinded clinical data already collected from Phase I control 
patients. This approach will minimize the total number of study subjects exposed to any risks 
associated with the investigational device, maximize the value of the contributions of subjects 
already enrolled in the trial, and potentially speed market availability of the TriGUARD 3 
device.  
Analysis will include poolability assessment and data validity of the old controls with the new 
ones and between sites in US and OUS as detailed in the SAP. 
5.2 Study Design Overview 
This study is a prospective, single-blind, three arm, randomized (2 device: 1 control), 
multicenter safety and efficacy trial designed to enroll up to 603 evaluable subjects in two 
consecutive phases: Phase I, which evaluated the TriGuard HDH device enrolled 258 
subjects (including 54 Roll-Ins) prior to enrollment suspension at the recommendation of the 
independent DSMB following an interim data review at the prespecified interim analysis time 
point. Phase II will enroll up to 345 subjects (including up to 50 Roll-Ins) and will utilize the 
TriGUARD 3 (Figure 3b shows the patient flow/disposition). 

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Figure 3b. REFLECT Phase I and Phase II Trial Design (Note: The depicted Phase II design reflects the 
sample size of the initial randomized cohort, not including a possible adaptive design sample size increase)
Phase I: 
In phase 1, a total of 204 evaluable subjects and 54 roll-in subjects were enrolled at 26 total 
investigational sites in the United States, Europe, and Israel, including 20 sites in the United 
States. A minimum of 50% of subjects were planned to be enrolled at US sites, and no single 
site was permitted to enroll more than 20% of all subjects. 
Subjects with indications for TAVI and who meet study eligibility criteria were randomized 2:1 
(stratified by study site) to one of two treatment arms: 
•
Intervention (Phase I Cohort) – TAVI with the TriGuard HDH CEPD
•
Control – standard unprotected TAVI
At sites where the investigator did not have prior experience with the TriGuard device 
(minimum of 2 prior cases), up to 3 roll-in subjects were enrolled. Roll-in subjects were not 
randomized, but underwent TAVI with the TriGuard HDH device. These cases were proctored 
by a Sponsor representative. Investigational sites with ≥2 prior TriGuard cases were allowed 
to enroll 1 roll-in subject at the discretion of the site principal investigator. 
All subjects were to be followed clinically in-hospital and at 30 and 90 days, undergo diffusion-
weighted MR imaging 2 to 5 days post-procedure, and undergo neurologic and 
neuropsychological testing pre-procedure, post-procedure (2-5 days post-procedure), and at 
30 and 90 days.  
The initial randomized cohort was planned to enroll up to 285 subjects. 
Note: Enrollment in Phase I has been halted after enrolling a total of 258 subjects (54 roll-ins 
and 204 randomized subjects including 63 controls) based on a recommendation of the 
DSMB following interim data review at the prespecified interm analysis timepoint. A new 
generation device designed for increased efficacy, ease of use, and improved safety which 
will be tested in Phase II (below). 
Phase II 
In Phase II, up to 295 randomized subjects and 40-50 roll-in subjects will be enrolled at up to 
25 sites in the United States (inclusive of sites enrolling subjects in Phase I). No single site 
will be permitted to enroll more than 20% of all randomized subjects in Phase II. 

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Subjects with indications for TAVI and who meet study eligibility criteria will be randomized 
2:1 (stratified by study site) to one of two treatment arms: 
• Intervention – TAVI with the TriGUARD 3 CEPD 
• Control – standard unprotected TAVI. 
Randomization will be stratified by implanted valve type (Medtronic vs. Edwards). 
No single valve type will be implanted in more than approximately 70% of randomized 
patients (phase II). 
Roll-in subjects (a minimum of 2 and a maximum of 3 Roll-ins per-site) will not be randomized, 
but will undergo TAVI with the TriGUARD 3 device. These cases will be proctored by a 
Sponsor representative. 
All subjects will be followed clinically in-hospital and at 30 days, undergo diffusion-weighted 
MR imaging 2 to 5 days post-procedure, and undergo neurologic (NIHSS) testing pre-
procedure, post-procedure (2-5 days post-procedure), and at 30 days. A follow-up phone-call 
to assess the occurrence of death or stroke will be done at 90 days.   
The initial randomized cohort will consist of up to 225 subjects. After at least 50% of the initial 
randomized cohort (approximately 112 subjects) have reached the 30 day primary efficacy 
endpoint evaluation time point, a sample size re-estimation will be performed in case the 
conditional power of the trial (assessed by the independent biostatistician) is >40% but <80%, 
subject to approval by the Sponsor. If this analysis determines that more than 225 
randomized subjects will be required to ensure adequate study power, enrollment may 
continue until the required number of subjects have been enrolled, or until the total subject 
limit for the study has been reached (whichever occurs first). 
5.3 Study Objectives 
The objective of the REFLECT trial is to evaluate the safety and efficacy of the TriGuard HDH 
and TriGUARD 3 CEPDs in patients TAVI, in comparison with an active control group of 
patients undergoing unprotected TAVI.  
The study will also report additional secondary safety, efficacy, and performance endpoints 
evaluating the TriGuard HDH and TriGUARD 3 in patients undergoing transcatheter aortic 
valve implantation (TAVI) in comparison with patients undergoing unprotected TAVI. Other 
measures related to the effect of embolic protection on TAVI procedural time and radiation 
exposure will also be collected.  
5.4 Study Endpoints 
5.4.1 Primary Endpoints 
5.4.1.1.1 Primary Safety Endpoint 
The primary safety endpoint of the study is combined safety at 30 days, defined according 
to modified VARC-2 1 (“TAVI early safety”) as the composite of: 
• All-cause mortality 
• All stroke (disabling and non-disabling) 
• Life-threatening or disabling bleeding 
• Acute kidney injury – Stage 2 or 3 (including renal replacement therapy) 
• Coronary artery obstruction requiring intervention 

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• Major vascular complication 
• Valve-related dysfunction requiring repeat procedure (BAV, TAVI, or SAVR) 
 
5.4.1.1.2 Primary Efficacy Endpoint- Phase II 
The primary efficacy endpoint of the study is the hierarchical composite efficacy endpoint, 
determined by pair-wise comparisons among all subjects according to the following pre-
specified hierarchy of adverse outcomes: 
• All-cause mortality and/or any stroke (fatal and non-fatal, disabling or non-disabling) 
[evaluated at 30 days] 
o If both had a death/stroke, a time to event analysis by days will determine a win 
o If both patients had a stroke at the same day the comparison moves to the next 
tier 
• NIHSS worsening (increase from baseline) [evaluated at 2 to 5 days post-procedure]  
• Freedom from any cerebral ischemic lesions detected by diffusion-weighted magnetic 
resonance imaging (DW-MRI) 2 to 5 days post-procedure 
• Total volume of cerebral ischemic lesions detected by diffusion-weighted magnetic 
resonance imaging (DW-MRI) 2 to 5 days post-procedure. 
Each subject in the intervention group will be compared with each and every subject from 
the control group based on the above hierarchy according to the Finkelstein-Schoenfeld 
method.2 For example, if Subject A dies or has stroke and Subject B survives free of 
stroke to 30 days, Subject B wins (score +1) and Subject A loses (score -1). If both 
subjects die or both have a stroke on the same day, it is equilibrium (score 0). If both 
subjects survive free of stroke to 30 days, the comparison moves to the next tier of the 
hierarchy. A lack of an event is given a +1 score. An event which is less severe than the 
comparison gets a 0 score (for example death vs. stroke) 
After all between-subject comparisons have been performed, scores are summed to 
obtain a cumulative score for each subject, and outcomes between treatment groups are 
then compared. 
5.4.2 Secondary Endpoints 
5.4.2.1.1 Hypothesis-driven secondary endpoints 
For the following secondary endpoints, a test for superiority of each intervention group to the 
control group will be performed. To address the issue of multiple tests among these 
secondary endpoints, sequential testing is planned. Secondary endpoints will be formally 
tested if and only if the primary study hypotheses are confirmed. The secondary endpoints 
will be tested individually, in the order in which they are listed as follows: 
• All stroke [evaluated at 7 days in the eITT population] 
• NIHSS worsening, defined as any NIHSS score increase from baseline [evaluated at 
2 to 5 days post-procedure in the efficacy Intention to Treat (eITT) analysis population]. 
A sensitivity analysis will further compare >2 points NIHSS worsening [evaluated at 2-
5 days post-procedure in the efficacy Intention to Treat (eITT) analysis population] 
• Composite of all-cause mortality and all stroke [evaluated at 7 days in the eITT 
population] 

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• CNS Infarction (NeuroARC defined) [evaluated at 30 days in the eITT analysis 
population] 
• Total volume of cerebral ischemic lesions detected by DW-MRI, [evaluated 2 to 5 
days post-procedure in the efficacy Intention to Treat (eITT) analysis population]  
The above endpoints will be tested by this pre-specified sequence, until the first non-
significant difference is found between the two treatment groups. After that, other treatment 
comparisons will be examined in an exploratory manner. 
 
5.4.2.1.2 Secondary Safety Endpoints  
The following safety endpoints will be evaluated in-hospital and at 30 days. Overall event 
rates will be reported by treatment group. In the Intervention and Roll-In groups, all safety 
endpoints will be adjudicated for their relationship to the investigational device and/or the 
investigational procedure by an independent Clinical Events Committee (§11.1): 
• In-hospital procedural safety, defined as the composite of the 
following Major Adverse Cardiovascular and Cerebrovascular 
Events (MACCE): 
• All-cause mortality 
• All stroke (disabling and non-disabling) 
• Life threatening (or disabling) bleeding 
• Acute kidney injury – Stage 2 or 3 (including renal replacement 
therapy) 
• Major vascular complications 
• TAVI device success (VARC), evaluated in-hospital, defined as: 
• Absence of procedural mortality AND 
• Correct positioning of a single prosthetic heart valve into the 
proper anatomical location AND 
• Intended performance of the prosthetic heart valve (no 
prosthesis-patient mismatch (VARC-defined) and mean aortic 
valve gradient <20 mm Hg or peak velocity <3 m/s, AND no 
moderate or severe prosthetic valve regurgitation (VARC-
defined) (site-reported) 
• General safety, defined as the composite of the following adverse 
events (each VARC-2 defined): 
• All-cause mortality  
• All stroke (disabling and non-disabling) 
• Acute kidney injury – Stage 3 (including renal replacement 
therapy) 
• Mortality [evaluated in-hospital and at 30 and 90 days]: 
• All-cause mortality 
o Cardiovascular mortality 

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 Neurologic event related mortality 
o Non-cardiovascular mortality 
• Myocardial infarction:  
• Peri-procedural MI (≤72 hours after the index procedure) 
• Spontaneous MI (>72 hours after the index procedure) 
• Neurological Events (component and composite): 
• Stroke (VARC-2 defined) [evaluated in-hospital and at 30 and 
90 days] 
o Ischemic stroke 
o Hemorrhagic stroke 
o Undetermined 
• Disabling Stroke (VARC-2 defined) [evaluated in-hospital and 
at 30 and 90 days] 
• Non-disabling stroke (VARC-2 defined) [evaluated in-hospital 
and at 30 and 90 days] 
• Transient ischemic attack (TIA) (VARC-2 defined) 
• Overt CNS Injury (NeuroARC defined Type 1) [evaluated in-
hospital and at 30 and 90 days] 
• Covert CNS Injury (NeuroARC defined Type 2) 
• Neurological dysfunction without CNS injury (NeuroARC defined 
Type 3) 
• CNS infarction (NeuroARC defined composite neurological 
endpoint) 
• CNS hemorrhage (NeuroARC defined composite neurological 
endpoint) 
• Bleeding Complications: 
• Life-threatening bleeding (VARC-2) 
• Major bleeding 
• Minor bleeding 
• Acute Kidney Injury (AKIN Classification): 
• Stage 2 
• Stage 3 
• Vascular Complications: 
• Major vascular complications 
• Major vascular complications related to device 
 

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5.4.2.1.3 Secondary Efficacy Endpoints 
5.4.2.1.4 Phase I: Hierarchical composite efficacy endpoint, determined by 
pair-wise comparisons among all subjects according to the following pre-
specified hierarchy of adverse outcomes: 
• All-cause mortality or any stroke (disabling or non-disabling) 
[evaluated at 30 days] 
• NIHSS worsening (increase from baseline) [evaluated at 2-5 days 
post-procedure] or Montreal Cognitive Assessment worsening 
(decrease of 3 or more points from baseline) [evaluated at 30 days] 
• Total volume of cerebral ischemic lesions detected by diffusion-
weighted magnetic resonance imaging (DW-MRI) 2 to 5 days post-
procedure 
Each subject in the intervention group will be compared with each and 
every subject from the control group based on the above hierarchy 
according to the Finkelstein-Schoenfeld method.2 For example, if Subject 
A dies or has stroke and Subject B survives free of stroke to 30 days, 
Subject B wins (score +1) and Subject A loses (score -1). If both subjects 
die or have a stroke, it is equilibrium (score 0). If both subjects survive free 
of stroke to 30 days, the comparison moves to the next tier of the hierarchy.  
After all between-subject comparisons have been performed, scores are 
summed to obtain a cumulative score for each subject, and outcomes 
between treatment groups are then compared. 
5.4.2.1.5 Imaging Efficacy Endpoints (Phase I and Phase II): 
• Presence of cerebral ischemic lesions detected by DW-MRI, 
evaluated 2 to 5 days post-procedure  
• Number of cerebral ischemic lesions detected by DW-MRI, 
evaluated 2 to 5 days post-procedure  
• Per-patient average single cerebral ischemic lesion volume 
detected by DW-MRI, evaluated 2 to 5 days post-procedure  
• Single cerebral ischemic lesion volume (lesion-level analysis) 
detected by DW-MRI, evaluated at 2 to 5 days post-procedure 
• Total volume of cerebral ischemic lesions detected by DW-MRI, 
evaluated 2 to 5 days post-procedure   
5.4.2.1.6 Neurologic Efficacy Endpoints (Phase I and Phase II): 
• NIHSS worsening, defined as an NIHSS score increase from 
baseline [baseline score compared with score evaluated at 2-5 days 
post-procedure and at 30 days] 
• New neurologic impairment, defined as an NIHSS score increase 
from baseline accompanied by the presence of cerebral ischemic 
lesions [evaluated at 2-5 days post-procedure and at 30 days]  
 

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5.4.2.1.7 Secondary Performance Endpoints 
The following performance endpoints will be evaluated post-procedure in 
the Intervention group (Roll-Ins excluded). TriGuard HDH and TriGUARD 3 
reported individually: 
• Successful device deployment, defined as ability to access the aortic 
arch with the TriGuard HDH or TriGUARD 3 delivery catheter and 
deploy the device from the delivery catheter into the aortic arch 
• Successful device positioning, defined as ability to position the 
TriGuard HDH or TriGUARD 3 device in the aortic arch to cover all 
major cerebral arteries, with proper positioning maintained (verified 
by fluoroscopy) until the following time points: 
o Final deployment of the first prosthetic valve 
o Final procedure (after any additional post-dilatation or additional 
valve implantations have been completed, and the TAVR delivery 
system has been removed) 
• Extent of cerebral artery coverage will be reported as: 
o Complete (coverage of all 3 cerebral artery branches) 
o Partial (coverage of 1-2 cerebral artery branches) 
o None 
Note: Maintenance of device positioning to each time point and extent of 
cerebral artery coverage will be evaluated by the Angiographic Core 
Laboratory.  
• Device interference, defined as interaction of the TriGuard HDH or 
TriGUARD 3 device with the TAVI system leading to: 
o Inability to advance or manipulate the TAVI delivery system or 
valve prosthesis, OR 
o Inability to deploy the TAVI valve prosthesis, OR 
o Inability to retrieve the valve prosthesis or delivery system  
• Successful device retrieval, defined as ability to retrieve the 
TriGuard HDH or TriGUARD 3 CEPD. 
• Technical success, defined as successful device deployment, 
device positioning, and successful device retrieval in the absence of 
device interference  
• Procedure success, defined as technical success in the absence of 
any investigational device-related or investigational procedure-
related in-hospital procedural safety events 
5.4.3 Other Measures 
The following additional measures will also be evaluated (TriGuard HDH and TriGUARD 3 
reported individually): 

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5.4.3.1.1 Device deployment time − Time elapsed between insertion of the 
TriGuard HDH or TriGUARD 3 device into the groin access point and successful 
device deployment [evaluated post-procedure] 
5.4.3.1.2 Total procedural time − Time elapsed between first arterial access 
and removal of the last catheter from the arterial access sheath [evaluated post-
procedure] 
5.4.3.1.3 Total fluoroscopy time [evaluated post-procedure] 
5.4.3.1.4 Total contrast utilization [evaluated post-procedure] 
6.0 Study Conduct 
6.1 Enrollment Criteria 
6.1.1 General Inclusion Criteria 
Subjects must meet ALL of the following criteria to be eligible for enrollment into the study: 
6.1.1.1.1 The patient is a male or non-pregnant female ≥18 years of age 
6.1.1.1.2 The patient meets indications for TAVI  
6.1.1.1.3 The patient is willing to comply with protocol-specified follow-up 
evaluations 
6.1.1.1.4 The patient, or legally authorized representative, has been informed 
of the nature of the study, agrees to its provisions and has provided written 
informed consent, approved by the appropriate Institutional Review Board (IRB) 
or Ethics Committee (EC)  
6.1.2 General Exclusion Criteria 
Potential subjects will be excluded if ANY of the following criteria apply: 
6.1.2.1.1 Patients undergoing TAVI via the trans- apical, trans -axillary, trans-
subclavian, or trans-aortic route (applicable to Phase II) 
6.1.2.1.2 Patients undergoing TAVI via the transapical approach due to friable 
or mobile atherosclerotic plaque in the aortic arch (Phase I only) 
6.1.2.1.3 Patients with a previously implanted prosthetic aortic valve (i.e., 
planned valve-in-valve TAVI) 
6.1.2.1.4 Pregnant or nursing subjects and those who plan pregnancy in the 
period up to 1 year following index procedure. Female subjects of child-bearing 
potential must have a negative pregnancy test done within 14 days prior to 
index procedure per site standard test. 
6.1.2.1.5 Patients with known diagnosis of acute myocardial infarction (AMI) 
within 72 hours preceding the index procedure (according to definition) or AMI 
>72 hours preceding the index procedure, in whom CK and CK-MB have not 
returned to within normal limits at the time of procedure, or patients who are 
currently experiencing clinical symptoms consistent with new-onset AMI, such 
as nitrate-unresponsive prolonged chest pain. 
6.1.2.1.6 Patients with a history of bleeding diathesis or coagulopathy or 
patients in whom anti-platelet and/or anticoagulant therapy is contraindicated, 
patients who will refuse transfusion, or patients with an active peptic ulcer or 
history of upper gastrointestinal (GI) bleeding within the prior 3 months. 

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6.1.2.1.7 Patients with known mental or physical illness or known history of 
substance abuse that may cause non-compliance with the protocol, confound 
the data interpretation, or is associated with a life expectancy of less than one 
year 
6.1.2.1.8 Patients with severe allergy to heparin or known hypersensitivity or 
contraindication to aspirin, heparin/bivalirudin, clopidogrel, nitinol, stainless 
steel alloy, and/or contrast sensitivity that cannot be adequately pre-medicated 
6.1.2.1.9 Patients with a history of a stroke or transient ischemic attack (TIA) 
within the prior 6 months 
6.1.2.1.10 Patients with renal failure (estimated Glomerular Filtration Rate 
[eGFR] <30 mL/min, calculated from serum creatinine by the Cockcroft-Gault 
formula or MDRD- Modification of Diet in Renal Disease formula) 
6.1.2.1.11 Patients with hepatic failure (Child-Pugh class C)  
6.1.2.1.12 Patients with hypercoagulable states that cannot be corrected by 
additional periprocedural heparin  
6.1.2.1.13 Patients presenting with cardiogenic shock at the time of the index 
procedure 
6.1.2.1.14 Patients with severe peripheral arterial, abdominal aortic, or thoracic 
aortic disease that precludes delivery sheath vascular access 
6.1.2.1.15 Patients in whom the aortic arch (Phase I and II), innominate artery 
ostium (Phase I only), or proximal innominate artery (Phase I only) are heavily 
calcified, severely atheromatous, or severely tortuous 
6.1.2.1.16 Patients with an innominate artery ostium diameter <10 mm or >25 
mm (Phase I only) 
6.1.2.1.17 Patients with a transverse aortic diameter >43 mm (Phase I only) 
6.1.2.1.18 Patients with anatomic irregularities of the innominate artery that 
could prevent positioning of the TriGuard upper stabilizer and compromise 
stability of the device (Phase I only) 
6.1.2.1.19 Patients with any other condition that would prevent adherence to 
the TriGuard HDH (Phase I) or TriGUARD 3 (Phase II) Instructions for Use 
6.1.2.1.20 Patients with contraindication to cerebral MRI 
6.1.2.1.21 Patients who have a planned treatment with any other investigational 
device or procedure during the study period 
6.1.2.1.22 Patients planned to undergo any other cardiac surgical or 
interventional procedure during the TAVI procedure (e.g., concurrent coronary 
revascularization) or within 10 days prior to the TAVI procedure. NOTE: 
Diagnostic cardiac catheterization is permitted within 10 days prior to the TAVI 
procedure. 
6.2 Subject Enrollment 
6.2.1 Screening and Enrollment 
Patients meeting indications for TAVI will be pre-screened for study eligibility by a member 
of the research team, including a review of the patient’s medical history and any existing 
diagnostic imaging testing that has been performed as a part of the patient’s normal medical 
care.  

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Based on the results of pre-screening, potentially eligible patients will be asked to provide 
written informed consent. Informed consent must be documented prior to the performance of 
any study-specific screening procedures or assessments. Following receipt of informed 
consent, a baseline screening assessment will be conducted to verify eligibility; the required 
documentation must also be provided to the Patient Review Committee (§11.1) to determine 
anatomic eligibility for the trial. 
The patient will be considered enrolled in the study when all the following criteria have been 
met: 
• The patient has provided written informed consent 
• Baseline screening has been conducted and: 
o The Patient Review Committee has determined that the patient meets the 
evaluated anatomic eligibility criteria (based on imaging analysis by 
independent CT core laboratory) AND 
o The investigator has determined that the patient meets all applicable remaining 
inclusion and no exclusion criteria 
• The point of enrollment has been reached: 
o For evaluable subjects (Intervention and Control groups), the point of 
enrollment is the moment of randomization. Randomization will occur: 
 Within 72 hours prior to the scheduled initiation of the TAVI procedure 
AND 
 After the investigator has confirmed the subject meets all anatomic 
eligibility criteria 
o For Roll-In subjects, the point of enrollment is the introduction of the TriGuard 
HDH or TriGUARD 3 device into the bloodstream. 
A screening log will be completed to document the enrollment and subject number, or reason 
for non-enrollment of subjects screened but not enrolled in the study. All enrolled subjects 
are required to complete all assigned follow-up assessments. No single site was permitted to 
enroll more than 20% of the total number of evaluable subjects (i.e., no single site may enroll 
more than 57 evaluable subjects in the initial randomized cohort [in addition to any roll-in 
subjects] in Phase I, and no more than 45 randomized subjects in the initial randomized 
cohort [in addition to any roll-in subjects] in Phase II.  
Randomization will be stratified by implanted valve type (Medtronic vs. Edwards). 
No single valve type will be implanted in more than approximately 70% of randomized 
patients (phase II). 
After at least 50% of the patients in the initial randomized cohort (approximately 112 subjects) 
have reached the 30 day primary efficacy endpoint evaluation time point, a sample size 
reestimation will be performed in case the conditional power of the trial (assessed by the 
independent biostatistician) is >40% but <80%, subject to approval by the Sponsor. If this 
analysis determines that more than 225 randomized subjects will be required to ensure 
adequate study power, enrollment may continue until the required number of subjects have 
been enrolled, or until the total subject limit for the study has been reached (whichever occurs 
first). 

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6.2.2 Roll-In Subjects 
Sites will enroll a minimum of 2 and a maximum of 3 Roll-In subjects. Roll-In subjects will not 
be randomized to a treatment arm, but will undergo TAVI with the TriGUARD 3 CEPD and 
will undergo all protocol-specified follow-ups. These cases will be proctored by a Sponsor 
representative. 
For the purposes of analysis, a subject is considered enrolled in the Roll-In phase of the study 
when: 
• The patient has been judged to meet all inclusion and no exclusion criteria (including 
approval by the PRC), and has signed a Patient Informed Consent form 
• The TriGuard HDH or TriGUARD 3 device has been introduced into the patient’s 
bloodstream  
6.2.3 Withdrawal and Replacement of Patients 
Subjects can withdraw from the study at any time; the reason(s) for withdrawal (if given) will 
be documented. All data available at the time of withdrawal (if any) will be used for analysis. 
There will be no further follow-up (per this study protocol) on a subject who has withdrawn. 
Subjects who withdraw from the study will not be replaced. The withdrawal of a subject can 
be initiated by the Investigator if he/she determines it is in the best interest of the patient. 
6.2.4 Protocol Deviations 
All deviations from the requirements of this Clinical Investigation Plan will be considered 
protocol deviations.  
A major protocol deviation is a protocol deviation that may affect the scientific soundness of 
the protocol or the rights, safety, or welfare of the patients. Major protocol deviations require 
urgent reporting to the Study Monitor and the Institutional Review Board/ Ethics Committee.  
Patient-level deviations are those that occur in direct association with a specific study patient. 
These include, but are not limited to, deviations from informed consent procedures, 
inclusion/exclusion criteria, protocol-specified procedures and assessments, and device 
handling and usage. 
Site-level deviations are those that occur at the study center but are not directly related to a 
study specific patient. All efforts should be made to avoid any protocol deviation.  
6.3 Blinding  
This is a single-blind study. The following individuals will be blinded to the subject’s treatment 
allocation: 
• Subject and his/her family members 
• Site personnel administering neurological evaluations (NIHSS and mRS); these 
individuals will also be blinded to DW-MRI results 
• Members of the Data Safety Monitoring Committee 
• MRI Core Laboratory personnel performing imaging analysis 
Un-blinding will occur only after the database has been locked for the analysis of the primary 
endpoint or to protect subject rights, welfare, or well-being at the request of the DSMB. The 
circumstances under which the DSMB may request unblinding to treatment allocation will be 
outlined in the DSMB charter prior to the onset of the trial.   

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If a site investigator determines it is necessary to reveal treatment allocation to the subject 
as a result of complication or injury, he or she is requested to notify the Sponsor.  
 
 

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7.0 Study Procedures 
7.1 Study Schedule of Procedures and Assessments 
Table 7. Study Schedule of Procedures and Assessments- Phase I (TriGuard HDH) 
 
 
 
Screening/ 
Baseline 
Procedure 
(day 0) 
Post-Procedure 
/ Pre-Discharge 
30-day 
Follow-up 
(30 ± 7 days) 
90-day 
Follow-up 
(90 ± 14 days) 
Written Informed Consent 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
Physical Examination1 
X 
 
X 
X 
X 
Review of Eligibility Criteria2 
X 
X 
 
 
 
Clinical Frailty Scale 
X 
 
 
 
X 
12-lead ECG3 
X 
 
X 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
Pregnancy Test4 
X 
 
 
 
 
Hematology/Chemistry5 
X 
 
X 
 
 
Cardiac Enzymes6 
X 
 
X 
 
 
CT Imaging7 
X 
 
 
 
 
Cerebral DW-MRI8 
 
 
X 
 
 
NIH Stroke Scale9 
X 
 
X 
X 
X 
Modified Rankin Scale9 
X 
 
X 
X 
X 
Neuropsychological test 
battery10 
X 
 
X 
X 
X 
SF-36 Health Survey11 
X 
 
 
X 
X 
TAVI 
 
X 
 
 
 
Echocardiography (SOC)12 
 
 
X 
 
 
TriGuard HDH deployment 
 
X 
 
 
 
Adverse Events 
 
X 
X 
X 
X 
1 Physical examination to include heart rate, blood pressure, and ischemic / anginal status (CCS or silent 
ischemia). The screening/baseline assessment must also include NYHA functional capacity, height, and 
weight. 
2 If the full screening/baseline review of eligibility criteria is conducted before the day of enrollment, the 
following repeat review of selected eligibility criteria should be performed on the day of enrollment and 
randomization (§6.2.1) to confirm study eligibility, using the most recent available laboratory values and 
clinical assessments: 1.) Ensure that the subject has not had symptoms or chemistry results indicating acute 
myocardial infarction (§6.1.2.1.5); 2.) Ensure that the most recent eGFR remains ≥30 (§6.1.2.1.10); 3.) 
Ensure that there are no signs of cardiogenic shock or severe hypotension (systolic blood pressure <90 mm 
Hg) (§6.1.2.1.13); and 4.) Review the planned approach for TAVI, as certain approaches will make the 
subject ineligible for the study (§6.1.2.1.1, §6.1.2.1.2) 
3 Screening/baseline ECG may be performed up to 30 days prior to procedure, as long as there have been 
no intervening signs or symptoms of myocardial ischemia (in which case the ECG should be performed 
within 24 hours prior to enrollment). The post-procedure ECG must be performed within 24 hours of the 
procedure or prior to hospital discharge (whichever occurs first).  
4 Female patients of childbearing potential must have a pregnancy test within 14 days prior to the procedure 
5 Hematology and chemistry within 14 days prior to the procedure are defined in §7.2. 
6 For the screening/baseline assessment, cardiac enzymes (CK), isoenzymes CK-MB or troponins obtained 
up to 14 days prior to the procedure (or on current admission) are acceptable, provided there has been no 
intervening episode of myocardial ischemia (in which case cardiac enzymes should be confirmed within 24 
hours prior to enrollment). Post-procedure, CK/CKMB or troponin (preferably CKMB isoenzyme) will be 
measured at 12-24 hours post-procedure, at 24±3 hours after the first measurement, and again at 72±6 
hours post-procedure or at discharge (whichever occurs first). If cardiac biomarkers are elevated, they should 
be repeated daily until values show a decline.  

R E F L E C T – U S I D E Tri al [ CI P -0 9 ( v 1 3. 0)]   
 
    
  
  
 
K e y st o n e H e art Lt d.  
5 9  
 
7  M ulti -sli c e C T a n gi o gr a p h y of t h e l eft h e art,  a ort a, gr e at v e s s el s a n d p eri p h er al a c c e s s v e s s el s p erf or m e d 
u p t o 1 y e ar pri or t o pr o c e d ur e  s h o ul d b e s u b mitt e d f or r e vi e w .  
8  D W -M RI m u st b e p erf or m e d 2 t o 5 d a y s ( ≥4 8 t o < 1 4 4 h o ur s) p o st -pr o c e d ur e.  
9  T h e NI H S S a n d m R S (i n a d diti o n t o t h e n e ur o p s y c h ol o gi c al t e st b att er y) m u st b e p erf or m e d 2 t o 5 d a y s 
( ≥4 8 t o < 1 4 4 h o ur s) p o st-pr o c e d ur e  b y  a n e ur ol o gi st  or a cli ni c al d e si g n e e ( e. g.  n e ur ol o g y f ell o w). A f ull 
n e ur ol o gi c al e v al u ati o n s h o ul d b e p erf or m e d b y a n e ur ol o gi st i n all p ati e nt s i n w h o m a str o k e or TI A i s 
s u s p e ct e d o n t h e b a si s of t h e NI H S S, m R S, or ot h er si g n s or s y m pt o m s.  
1 0  A bri ef p a p er -a n d -p e n cil n e ur o p s y c h ol o gi c al t e st b att er y ( § 1 6. 7 ), will b e a d mi ni st er e d u p t o 3 0 d a y s pri or t o 
pr o c e d ur e, 2 t o 5 d a y s ( ≥4 8 t o < 1 4 4 h o ur s) p o st -pr o c e d ur e , a n d at t h e 3 0- a n d 9 0 -d a y cli ni c vi sit s .  
1 1  T h e S h ort F or m 3 6 H e alt h S ur v e y ( S F -3 6) ( §1 6. 1 1 ) will b e a d mi ni st er e d u p t o 3 0 d a y s pri or t o pr o c e d ur e 
a n d at t h e 3 0 - a n d 9 0 -d a y cli ni c vi sit s.  W h e n a d mi ni st er e d d uri n g a vi sit t h at i n cl u d e s ot h er a s s e s s m e nt s, t h e 
S F -3 6 s h o ul d b e p erf or m e d fir st.   
1 2  If e c h o c ar di o gr a p h y (tr a n st h or a ci c or tr a n s e s o p h a g e al) w a s p erf or m e d aft er T A V R pr o st h e si s i m pl a nt ati o n 
a s p art of t h e st a n d ar d of c ar e, t h e r el e v a nt p ar a m et er s (i n cl u di n g m e a n a orti c v al v e gr a di e nt, p e a k v el o cit y, 
a n d d e gr e e of pr o st h eti c a orti c v al v e r e g ur git ati o n) m u st b e c a pt ur e d o n t h e e C R F f or e v al u ati o n i n -h o s pit al 
T A VI d e v i c e s u c c e s s ( §). 
 
T a bl e 7 a.  St u d y S c h e d ul e of Pr o c e d ur e s a n d A s s e s s m e nt s - P h a s e II  ( Tri G U A R D 3 ) 
 
 
 
S cr e e ni n g/  
B a s eli n e  
Pr o c e d ur e  
( d a y 0) 
P o st -
Pr o c e d ur e  
3 0 -d a y 
F oll o w -u p  
( 3 0 ± 7 d a y s) 
9 0 -d a y 
F oll o w -u p  
( 9 0 ± 1 4 d a y s)  
Writt e n I nf or m e d C o n s e nt  
X  
 
 
 
 
M e di c al Hi st or y  
X  
 
 
 
 
P h y si c al E x a mi n ati o n 1  
X  
 
X  
X  
 
R e vi e w of Eli gi bilit y Crit eri a 2  
X  
X  
 
 
 
Cli ni c al Fr ailt y S c al e  
X  
 
 
 
 
1 2 -l e a d E C G3  
X  
 
X  
 
 
C o n c o mit a nt M e di c ati o n s  
X  
X  
X  
X  
 
Pr e g n a n c y T e st 4  
X  
 
 
 
 
H e m at ol o g y/ C h e mi str y 5  
X  
 
X  
 
 
C ar di a c E n z y m e s 6  
X 6 
 
X 6 
 
 
C T I m a gi n g 7  
X  
 
 
 
 
C er e br al D W -M RI
8  
 
 
X  
 
 
NI H Str o k e S c al e 9  
X  
 
X  
X  
 
M o difi e d R a n ki n S c al e
9  
X  
 
X  
X  
 
T A VI  
 
X  
 
 
 
E c h o c ar di o gr a p h y ( S O C) 1 0  
 
 
X  
 
 
D e vi c e  d e pl o y m e nt  
 
X  
 
 
 
A d v er s e E v e nt s  
 
X  
X  
X  
 
P h o n e c all t o a s s e s s m ort alit y/ Str o k e  
 
 
 
 
X   
1  P h y si c al  e x a mi n ati o n  t o  i n cl u d e  h e art  r at e,  bl o o d  pr e s s ur e,  a n d  i s c h e mi c/ a n gi n al  st at u s  ( C C S  or  sil e nt 
i s c h e mi a). T h e s cr e e ni n g/ b a s eli n e a s s e s s m e nt m u st al s o i n cl u d e N Y H A f u n cti o n al c a p a cit y, h ei g ht, a n d w ei g ht. 
2  If t h e f ull s cr e e ni n g/ b a s eli n e r e vi e w of eli gi bilit y crit eri a i s c o n d u ct e d b ef or e t h e d a y of e nr oll m e nt, t h e f oll o wi n g 
r e p e at r e vi e w of s el e ct e d eli gi bilit y crit eri a s h o ul d b e p erf or m e d o n t h e d a y of e nr oll m e nt a n d r a n d o mi z ati o n 
( §6. 2. 1 ) t o c o nfir m st u d y eli gi bilit y, u si n g t h e m o st r e c e nt a v ail a bl e l a b or at or y v al u e s a n d cli ni c al a s s e s s m e nt s: 
1) E n s ur e t h at t h e s u bj e ct h a s n ot h a d s y m pt o m s or c h e mi str y r e s ult s i n di c ati n g a c ut e m y o c ar di al i nf ar cti o n 
( §6. 1. 2. 1. 5 ); 2) E n s ur e t h at t h e m o st r e c e nt e G F R r e m ai n s ≥3 0 ( §6. 1. 2. 1. 1 0 ); 3) E n s ur e t h at t h er e ar e n o si g n s 
of c ar di o g e ni c s h o c k ( §6. 1. 2. 1. 1 3 ); a n d 4) R e vi e w t h e pl a n n e d a p pr o a c h f or T A VI, a s c ertai n a p pr o a c h e s will 
m a k e t h e s u bj e ct i n eli gi bl e f or t h e st u d y ( §6. 1. 2. 1. 1 ) 
3  S cr e e ni n g/ b a s eli n e E C G m a y b e p erf or m e d u p t o 3 0 d a y s pri or t o pr o c e d ur e, a s l o n g a s t h er e h a v e b e e n n o 
i nt er v e ni n g si g n s or s y m pt o m s of m y o c ar di al i s c h e mi a (i n w hi c h c a s e t h e E C G s h o ul d b e p erf or m e d wit hi n 2 4 
h o ur s pri or t o e nr oll m e nt). T h e p o st -pr o c e d ur e E C G m u st b e p erf or m e d wit hi n 2 4 h o ur s of t h e pr o c e d ur e or 
pri or t o h o s pit al di s c h ar g e ( w hi c h e v er o c c ur s fir st).  

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4 Female patients of childbearing potential must have a pregnancy test within 14 days prior to the procedure 
5 Hematology and chemistry within 14 days prior to the procedure are defined in §7.2. 
6 For the screening/baseline assessment, cardiac enzymes (CK), isoenzymes CK-MB or troponins obtained 
up to 14 days prior to the procedure (or on current admission) are acceptable, provided there has been no 
intervening episode of myocardial ischemia (in which case cardiac enzymes should be confirmed within 24 
hours prior to enrollment). Post-procedure CK/CKMB or troponin (preferably CKMB isoenzyme) will be 
measured post procedure when clinically indicated. If cardiac biomarkers are elevated, they should be 
repeated per local standard of care.  
7 Multi-slice CT angiography of the left heart, aorta, great vessels and peripheral access vessels performed 
up to 1 year prior to procedure should be submitted for review.  
8 DW-MRI must be performed 2 to 5 days (≥48 to <144 hours) post-procedure. 
9 The NIHSS and mRS must be performed 2 to 5 days (≥48 to <144 hours) post-procedure by a neurologist or 
a clinical designee (e.g. neurology fellow). A full neurological evaluation should be performed by a neurologist 
in all patients in whom a stroke or TIA is suspected on the basis of the NIHSS, mRS, or other signs or 
symptoms. 
10 If echocardiography (transthoracic or transesophageal) was performed after TAVI prosthesis implantation 
as part of the standard of care, the relevant parameters (including mean aortic valve gradient, peak velocity, 
and degree of prosthetic aortic valve regurgitation) must be captured on the eCRF for evaluation in-hospital 
TAVI device success. 
 
 
7.2 Screening / Baseline 
The following tests and examinations must be performed prior to the procedure to verify 
eligibility and to collect baseline study data: 
• Relevant medical history and patient demographic information, including STS Risk 
Score and EuroSCORE II risk evaluations 
• Physical examination including ischemic / anginal status (CCS or silent ischemia), 
NYHA functional capacity, heart rate, blood pressure, height, and weight  
• Frailty assessment with the Clinical Frailty Scale 
• Concomitant medication documentation 
• Review of the study eligibility criteria (inclusion and exclusion). NOTE: If the full 
screening/baseline review of eligibility criteria is conducted before the day of 
enrollment, the following repeat review of selected eligibility criteria should be 
performed on the day of enrollment and randomization (§6.2.1) to confirm study 
eligibility, using the most recent available laboratory values and clinical assessments:  
o Ensure that the subject has not had symptoms or chemistry results indicating 
acute myocardial infarction (§6.1.2.1.5) 
o Ensure that the most recent eGFR remains ≥30 (§6.1.2.1.10) 
o Ensure that there are no signs of cardiogenic shock (§6.1.2.1.13) 
o Review the planned approach for TAVI, as certain approaches will make the 
subject ineligible for the study (§6.1.2.1.1, §6.1.2.1.2) 
• Routine laboratory tests including:  
o Hematology - hemoglobin, hematocrit, platelet count, white blood cell count 
within 14 days prior to the procedure  

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o Chemistry - creatinine, ALT/serum glutamic-pyruvic transaminase (SGPT), and 
AST/serum glutamic-oxaloacetic acid transaminase (SGOT) within 14 days 
prior to the procedure,  
o Cardiac enzymes (CK), isoenzymes CK-MB or troponins should be obtained 
when clinically indicated (for example if there is a suspected ischemic event).  
o Female patients of childbearing potential must also have a pregnancy test 
within 14 days prior to the procedure.  
• At the investigator’s discretion and according to site standard practice, subjects 
requiring warfarin therapy may undergo a pre-procedure Coagulation Panel including 
prothrombin time, partial thromboplastin time (PTT) and International Normalized 
Ratio (INR) to ensure compliance with the concomitant therapy recommendations 
(§7.3). 
• A 12-lead electrocardiogram. An ECG performed within 30 days prior to the procedure 
may be used as the baseline ECG provided there have been no signs or symptoms of 
myocardial ischemia between the time of the ECG and enrollment (in which case the 
ECG should be performed within 24 hours prior to enrollment). 
• CT imaging (standard and contrast-enhanced angiography preferred) of the left heart, 
aorta, great vessels, and peripheral access vessels performed up to 1 year prior to the 
procedure should be submitted for review.  
• NIH Stroke Scale (NIHSS) up to 14 days prior to procedure. Neurologic status 
evaluation using the NIH stroke scale shall also be performed 2-5 days post-procedure 
and during each follow-up assessment. The examination must be performed by a 
neurologist, or a clinical designee (e.g. neurology fellow). 
• Modified Rankin Scale (mRS) up to 14 days prior to procedure. The mRS will also be 
performed 2-5 days post-procedure and during each follow-up assessment. The 
assessment must be performed by a neurologist or a clinical designee (e.g. neurology 
fellow).  
• A full neurological evaluation should be performed by a neurologist in all patients in 
whom a stroke or TIA is suspected on the basis of the NIHSS, mRS, or other signs or 
symptoms.  
• A neuropsychological test battery (§16.7) will be administered up to 30 days prior to 
procedure by a qualified individual, and will be re-administered 2-5 days post-
procedure and at 30 and 90 days. The test battery includes: (Phase I only) 
o Montreal Cognitive Assessment (MoCA) - A cognitive screening instrument that 
includes tasks that assess attention and concentration, executive functions, 
memory, language, visuoconstructional abilities, abstraction, calculations, and 
orientation.  It takes approximately 10 minutes to administer and is available in 
several languages. 
o Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) 
- A comprehensive, but brief, neuropsychological battery that includes 
assessment of immediate memory, visuospatial/constructional abilities, 
language, attention, and delayed memory. The RBANS is available in many 
different languages and typically takes less than 30 minutes to administer. 
Alternate forms of the tests are used for repeat testing. 

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o Trail Making Test Parts A & B. These tests evaluate attention, psychomotor 
speed, and mental flexibility. In Part A, the subject connects 25 encircled 
numbers in ascending order as quickly as possible. In Part B, the subject 
connects encircled numbers and letters in ascending order, alternating between 
the two (i.e., 1-A-2-B-etc.). The total administration time is less than 10 minutes.  
• The Short Form 36 Health Survey (SF-36v2) will be administered up to 30 days prior 
to procedure, and will be re-administered at 30. The SF-36 is a 36-item questionnaire 
that measures health-related quality of life across 8 physical and mental domains. It is 
available in many different languages and takes approximately 10 minutes to 
administer. When administered during a visit that includes other assessments, the SF-
36 should be performed first (Phase I only). 
7.3 Concomitant Therapies 
Selection and dosing of procedural and post-procedural concomitant therapies, including 
antiplatelet and anticoagulant therapies, will be performed according to physician standard 
practice, in accordance with local standards of care and published guidelines. Each site is 
encouraged to commit to a consistent antiplatelet regimen to be applied to all subjects 
enrolled in the trial, independent of treatment group. 
The investigators recommend (but do not require) that all subjects receive the medication 
regimen listed below (Table 8). All medications administered should be recorded in the 
patient’s medical record and the CRF. 
Table 8: Concomitant Medications  
Timing  
Medication  
Recommended Doses 
Prior to 
Procedure  
IV Heparin or low molecular 
weight heparin or bivalirudin 
Per routine hospital practice  
During 
Procedure  
IV Heparin or low molecular 
weight heparin or bivalirudin 
Per routine hospital practice. It is 
recommended to maintain an ACT > 250 
seconds.† 
Post 
Procedure* 
Acetylsalicylic acid (ASA)  
75-100 mg QD indefinitely 
Clopidogrel 
 
75 mg QD for a minimum of 6 months or 
longer based on local guidelines. 
†Peak and nadir intraprocedural ACT measurements must be recorded in the CRF for all subjects. 
*Note for patients receiving warfarin therapy: 
• 
If the patient is on warfarin therapy prior to the procedure, the following is recommended: 
o Discontinue warfarin three days prior to the procedure  
o Confirm that the INR is <1.8 prior to the procedure 
o ASA 75-100 mg or clopidogrel 75 mg for 3 days prior to the procedure 
• 
If the patient is on warfarin therapy post-procedure, it is recommended that the patient is 
prescribed either daily aspirin (75-100 mg) or daily clopidogrel (75 mg).  
Minimum recommended maintenance dosages can be higher based on physician’s 
discretion. 
 

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7.4 TAVI Procedure 
TAVI will be performed according to standard institutional practice under local or general 
anesthesia and via the transfemoral approach at the discretion of the investigator.  
In subjects in the Intervention or Roll-in Groups, the TriGuard HDH or TriGUARD 3 device 
will be advanced and deployed across the aortic arch to cover the ostia of the 3 major vessel 
takeoffs (innominate, left carotid and subclavian arteries) at the initiation of the TAVI 
procedure and withdrawn at the completion of the procedure. Please refer to the TriGuard 
HDH or TriGUARD 3 Instructions For Use for additional information. 
Device coverage and positioning must be verified by fluoroscopy (a steep left anterior oblique 
[LAO] view is recommended), with particular attention paid to 1.) Device coverage after initial 
deployment, 2.) Device positioning after final deployment of the first prosthetic valve, and 3.) 
Device positioning after the procedure is complete (i.e., after any additional post-dilatation or 
additional valve implantations have been completed, and the TAVR delivery system has been 
removed). All imaging should be forwarded to the Angiographic Core Laboratory for analysis. 
For additional details, please refer to the Angiographic Imaging Acquisition Guidelines 
(§16.8). 
7.5 Post-procedure Follow-up 
The procedure is considered complete once the last guiding catheter has been removed from 
the patient and the patient is off the table. Thereafter, if a guiding catheter is re-introduced, 
this is considered a repeat intervention, which must be documented.   
The post-procedure follow up will consist of: 
• Physical examination including ischemic / anginal status (CCS or silent ischemia), 
heart rate, and blood pressure  
• Documentation of any adverse events/ serious adverse events occurring since the 
point of enrollment  
• Current concomitant medications documentation, including antiplatelet and 
anticoagulant therapy 
• Routine laboratory tests including:  
o Hematology - hemoglobin, hematocrit, platelet count, white blood cell count 
o Chemistry - creatinine. Serum creatinine should be measured within 48 hours 
post-procedure in all subjects. Subjects with elevated serum creatinine (≥1.5x 
baseline OR >0.3 mg/dL [>26.4 mmol/L]) should have continued assessments 
to 7 days post-procedure or until discharge (whichever occurs first) to assess 
acute kidney injury. 
o Cardiac enzymes: CK/CKMB or Troponin (preferably CKMB isoenzyme) will be 
measured when clinically indicated. If cardiac biomarkers are elevated, they 
should be repeated per local standard of care.   
• A 12-lead ECG, to be completed within 24 hours post-procedure or prior to hospital 
discharge (whichever occurs first) 
• If echocardiography (transthoracic or transesophageal) was performed after TAVR 
prosthesis implantation as part of the standard of care, the relevant parameters 
(including mean aortic valve gradient, peak velocity, and degree of prosthetic aortic 

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v a l v e  r e g ur git ati o n)  m u st  b e  c a pt ur e d  o n  t h e  e C R F  f or  e v al u ati o n  i n-h o s pit al  T A VI 
d e vi c e s u c c e s s ( § ) 
•  Diff u si o n -w ei g ht e d M RI of t h e br ai n 2 t o 5 d a y s ( ≥4 8 t o < 1 4 4 h o ur s) p o st -pr o c e d ur e  
•  NI H Str o k e S c al e ( NI H S S) . N e ur ol o gi c st at u s  e v al u ati o n u si n g t h e NI H str o k e s c al e 
s h all b e p erf or m e d 2 t o 5 d a y s ( ≥4 8 t o < 1 4 4 h o ur s) p o st -pr o c e d ur e  a n d d u ri n g e a c h 
f oll o w-u p  a s s e s s m e nt. T h e  e x a mi n ati o n  m u st  b e p erf or m e d b y a  n e ur ol o gi st  or a 
cli ni c al d e si g n e e ( e. g. n e ur ol o g y f ell o w). 
•  M o difi e d R a n ki n S c al e  ( m R S) s h all b e p erf or m e d 2 t o 5 d a y s ( ≥4 8 t o < 1 4 4 h o ur s) p o st -
pr o c e d ur e  a n d  d uri n g  e a c h  f oll o w -u p  a s s e s s m e nt.  T h e  a s s e s s m e nt  m u st  b e 
p erf or m e d b y  a n e ur ol o gi st or a cli ni c al d e si g n e e ( e. g.  n e ur ol o g y f ell o w). 
•  A f ull n e ur ol o gi c al e v al u ati o n s h o ul d b e  p erf or m e d b y a n e ur ol o gi st i n all p ati e nt s i n 
w h o m a str o k e or TI A i s s u s p e ct e d o n t h e b a si s of t h e NI H S S, m R S, or ot h er si g n s or 
s y m pt o m s.  
•  A n e ur o p s y c h ol o gi c al  t e st b att er y ( §1 6. 7 ) will b e a d mi ni st er e d 2 t o 5 d a y s ( ≥4 8 t o <1 4 4 
h o ur s)  p o st -pr o c e d ur e  b y  a  q u alifi e d  i n di vi d u al.  T h e  t e st  b att er y  i n cl u d e s:  ( P h a s e  I 
o nl y) . 
o  M o ntr e al C o g niti v e A s s e s s m e nt ( M o C A)  
o  R e p e at a bl e B att er y f or t h e A s s e s s m e nt of N e ur o p s y c h ol o gi c al St at u s ( R B A N S)  
o  Tr ail  Ma ki n g T e st P art s A a n d B  
Pri or t o h o s pit al di s c h ar g e, r e s e ar c h st aff s h o ul d al s o r e vi e w t h e f oll o w -u p r e q uir e m e nt s wit h 
t h e s u bj e ct t o h el p e n s ur e t h at t h e p ati e nt r et ur n s t o t h e cli ni c f or t h e o n e-m o nt h f oll o w -u p 
vi sit. T el e p h o n e n u m b er s s h o ul d b e o bt ai n e d fr o m t h e p ati e nt t o e n s ur e t h e a bilit y t o c o nt a ct 
hi m or h er at  t h e  r e q uir e d  ti m e. T h e s e p h o n e  n u m b er s  s h o ul d  i n cl u d e  all h o m e  n u m b er s, 
w or k n u m b er s a n d pri m ar y p h y si ci a n n u m b er s. A p h o n e n u m b er of a r el ati v e or fri e n d s h o ul d 
al s o b e r e q u e st e d.   
N ot e: All cli ni c all y si g nifi c a nt a d v er s e e v e nt s  s h o ul d b e c ar ef ull y d o c u m e nt e d b y t h e r e s e ar c h 
st aff  u si n g  t h e a d v er s e  e v e nt  d at a f or m s.  A n y  cli ni c all y -i n di c at e d n e ur oi m a gi n g  s h o ul d b e 
f or w ar d e d t o t h e M RI C or e L a b or at or y.  
7. 6  O n e -m o nt h F oll o w -u p ( Cli ni c Vi sit)  
All s u bj e ct s  will  r et ur n  t o  t h e  cli ni c  at  3 0  d a y s  ( ±  7  d a y s)  p o st -pr o c e d ur e  f or  a  cli ni c al 
e v al u ati o n.  
T h e 3 0 d a y f oll o w -u p vi sit will c o n si st of t h e f oll o wi n g a s s e s s m e nt s:  
•  P h y si c al e x a mi n ati o n  
•  D o c u m e nt ati o n  of  a n y  a d v er s e  e v e nt s/  s eri o u s  a d v er s e  e v e nt s  o c c urri n g  si n c e  t h e 
pr e vi o u s e v al u ati o n  
•  C urr e n t  c o n c o mit a nt  
m e di c ati o n  d o c u m e nt ati o n,  i n cl u di n g  a nti pl at el et  a n d 
a nti c o a g ul a nt t h er a p y  
•  NI H Str o k e S c al e ( NI H S S):  N e ur ol o gi c st at u s e v al u ati o n u si n g t h e NI H str o k e s c al e 
m u st b e p erf or m e d b y a n e ur ol o gi st or a cli ni c al d e si g n e e (e. g.  ne ur ol o g y f ell o w). 
•  M o difi e d  R a n ki n  S c al e  ( m R S) m u st  b e  p erf or m e d  b y 
a n e ur ol o gi st  or a  cli ni c al  
d e si g n e e ( e. g.  ne ur ol o g y f ell o w). 

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• A full neurological evaluation should be performed by a neurologist in all patients in 
whom a stroke or TIA is suspected on the basis of the NIHSS, mRS, or other signs or 
symptoms.  
• A neuropsychological test battery (§16.7), to be administered by a qualified individual. 
The test battery includes: (Phase I only) 
o Montreal Cognitive Assessment (MoCA) 
o Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) 
o Trail Making Test Parts A and B 
• The Short Form 36 Health Survey (SF-36) (Phase I only) 
Prior to concluding the visit, research staff should also review the follow-up requirements with 
the subject to help ensure that the patient can be contacted by telephone at the three-month 
follow-up time point.  
Note: All clinically significant adverse events should be carefully documented by the research 
staff using the adverse event data forms. Any clinically-indicated neuroimaging should be 
forwarded to the MRI Core Laboratory. 
7.7 Three-month Follow-up  
7.7.1 Phase I: 
All subjects in Phase I were expected to return to the clinic at 90 days (± 14 days) post-
procedure for a clinical evaluation.  
The 90 day follow-up visit consisted of the following assessments: 
• Physical examination including ischemic / anginal status (CCS or silent ischemia), 
heart rate, and blood pressure  
• Frailty assessment with the Clinical Frailty Scale 
• Documentation of any adverse events/ serious adverse events occurring since the 
previous evaluation 
• Current 
concomitant 
medication 
documentation, 
including 
antiplatelet 
and 
anticoagulant therapy 
• NIH Stroke Scale (NIHSS): Neurologic status evaluation using the NIH stroke scale 
must be performed by a neurologist or a clinical designee (e.g. neurology fellow). 
• Modified Rankin Scale (mRS) must be performed by a neurologist or a clinical 
designee (e.g. neurology fellow). 
• A full neurological evaluation should be performed by a neurologist in all patients in 
whom a stroke or TIA is suspected on the basis of the NIHSS, mRS, or other signs or 
symptoms.  
• A neuropsychological test battery (§16.7), to be administered by a qualified individual. 
The test battery includes: 
o Montreal Cognitive Assessment (MoCA) 
o Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) 
o Trail Making Test Parts A and B 

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• The Short Form 36 Health Survey (SF-36) 
Note: All clinically significant adverse events should be carefully documented by the research 
staff using the adverse event data forms. Any clinically-indicated neuroimaging should be 
forwarded to the MRI Core Laboratory. 
7.7.2 Phase II: 
In Phase II, a telephone contact at 90 days (± 14 days) post-procedure will establish: 
• Mortality 
• Stroke 
If death or stroke is reported, source documentation will be requested from treating facility 
to enable CEC adjudication of cause of death (cardiovascular [subclassified and 
neurologic-event related] or non-cardiovascular) and stroke classification according to the 
protocol-specified definitions. 
8.0 Device Accountability 
The Site Principal Investigator is responsible for device accountability at his/her trial site and 
must maintain associated trial records according to 21 CFR Part 812.140 (§15.5.2). The 
investigator may assign the responsibility for device accountability to an appropriate study 
staff member, but remains the final responsible person. 
The investigator will maintain device use/disposition records that document device delivery 
to the trial site, the inventory at the site, administration to each patient as well as any device 
that was opened but not used. These records must include dates, quantities, batch/serial 
numbers, expiration dates, and the unique code numbers assigned to the trial patients. The 
investigator must maintain records that adequately document which device was used (or 
exposed to the circulation) of each subject and any device malfunctions. 
At the trial closeout visit, the Investigator must return to the Sponsor any unused devices and 
a copy of the completed device inventory. The Investigator’s copy of the device reconciliation 
records must document all device usage (including devices that were opened but not used) 
and any unused devices that have been returned to the sponsor. 
9.0 Adverse Events, Serious Adverse Events, and End-points 
Potentially Meeting End-point Criteria 
In this study, patients should be encouraged to report adverse events (AEs) spontaneously 
or in response to general, non-directed questioning. Any time during the study, the patient 
may volunteer information that resembles an adverse event (AE). If it is determined that a 
clinically significant AE has occurred, the investigator should obtain all the information 
required to complete the AE CRFs. Non-clinically-significant adverse events will not be 
required post discharge from the initial study procedure. 
9.1 Adverse Events (AE) 
An adverse event is any untoward medical occurrence, unintended disease or injury or any 
untoward clinical signs (including an abnormal laboratory finding) in subjects, users or other 
persons, whether or not related to the study device.  

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NOTE: This definition includes events related to the study device or to the procedures 
involved, but does not imply that there is a relationship between the adverse event and the 
study device.  
Pre-Existing Conditions: 
Pre-existing medical conditions or a repeat of symptoms reported prior to the TAVR 
procedure will not be recorded as an AE. Pre-existing conditions that worsen during a study 
are to be considered adverse events. For users or other persons, this classification is 
restricted to events related to the study device. 
9.2 Serious Adverse Events (SAE) 
A serious adverse event is an adverse event that: 
1. Led to a death 
2. Led to a serious deterioration in the health of the subject that: 
a. Resulted in a life-threatening illness or injury 
b. Resulted in a permanent impairment of a body structure or a body function 
c. Required in-patient hospitalization or prolongation of existing hospitalization 
d. Resulted in medical or surgical intervention to prevent life-threatening illness or 
injury or permanent impairment to body structure or a body function. 
3. Led to fetal distress, fetal death or a congenital abnormality or birth defect. 
9.3 Adverse Device Effect (ADE) 
An adverse device effect is an adverse event related to the use of a medical device. This 
includes: 
• Any adverse event resulting from insufficiencies or inadequacies in the Instructions for 
Use, the deployment, the implantation, the installation, the operation, or any 
malfunction of the medical device 
• Any event that is a result of a use error or intentional misuse 
9.4 Serious Adverse Device Effect (SADE) 
A serious adverse device effect is an adverse device effect that has resulted in any of the 
consequences characteristic of a serious adverse event.  
9.5 Unanticipated Adverse Device Effect (UADE) 
An unanticipated adverse device effect is any serious adverse effect on the 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. 
NOTE: An anticipated serious adverse device effect (ASADE) is a serious adverse device 
effect which by its nature, incidence, severity, or outcome has been identified in the 
investigational plan or application (including a supplementary plan or application).  

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9.6 Device Deficiencies, Malfunctions, and Use Error 
Investigators are instructed to report all possible device deficiencies, malfunctions, misuse or 
use error observed during the course of the trial. These incidents will be documented in the 
case report form provided as follows: 
• Device deficiency: Inadequacy of a medical device related to its identity, quality, 
durability, reliability, safety or performance. NOTE: Device deficiencies include 
malfunction, use error, and inadequate labeling. They may or may not affect device 
performance or lead to an adverse event. 
• Device malfunction: Failure of an investigational medical device to perform in 
accordance with its intended purpose when used in accordance with the Instructions 
for Use or protocol. NOTE: A device malfunction occurs when the device is used in 
compliance with the Instructions for Use, but does not perform as described in the 
Instructions for Use. 
• Use error: Act or omission of an act that results in a different medical device response 
than intended by the manufacturer or expected by the user. NOTE 1: Use error 
includes slips, lapses and mistakes. NOTE 2: An unexpected physiological response 
of the patient does not itself constitute a use error. 
• Device misuse: Any use of the investigational device by an investigator that is 
contradictory to the application described in the Instructions for Use will be categorized 
as device misuse. This is a form of Use Error. 
9.7 End-points Potentially Meeting End-point Criteria 
Investigators are instructed to report all cardiovascular events and all adverse events 
potentially meeting end-point criteria. These events will be documented in the case report 
form as SAEs and be assessed by the medical monitor. Events classified as potential end-
points will then be sent to CEC adjudication (§11.2). 
9.8 Documentation 
Adverse events must be listed on the appropriate CRF. All AEs will be characterized by the 
following criteria:  
• Intensity or Severity 
• Relatedness 
• Outcome 
• Treatment or Action Taken 
9.8.1 Intensity or Severity 
The following categories of the intensity of an adverse event are to be used:  
Mild 
Awareness of a sign or symptom that does not interfere with the 
patient’s usual activity or is transient, resolved without treatment 
and with no sequelae. 
Moderate 
Interferes with the patient’s usual activity and/or requires 
symptomatic treatment. 
Severe 
Symptom(s) causing severe discomfort and significant impact of 
the patient’s usual activity and requires treatment. 

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9.8.2 Relatedness 
The investigator will use the following definitions to assess the relationship to the device: 
Not related 
 
The cause of the AE is known and the event is not related to 
any aspect of study participation. 
Unlikely to be 
related 
There is little or no temporal relationship to the study device 
and/or a more likely alternative etiology exists. 
Possibly 
related 
There is a reasonable possibility that the event may have been 
caused by study participation.  
The AE has a timely relationship to the study procedure(s); 
however, follows no known pattern of response, and an 
alternative cause seems more likely or there is significant 
uncertainty about the cause of the event.  
Probably 
related 
It is likely that the event was caused by study participation. 
The AE has a timely relationship to the study procedure(s) 
and follows a known pattern of response; a potential 
alternative cause, however, may explain the event. 
Related 
A related event has a strong temporal relationship and an 
alternative cause is unlikely. 
 
If the relationship between any adverse event and the use of the investigational medical 
device is considered to be possibly or probably related, that event will be classified as an 
ADE or SADE. 
 
9.8.3 Outcome 
The clinical outcome of the AE or SAE will be characterized as follows: 
Death 
The SAE CRF must be completed for this outcome 
Recovered without 
sequelae 
The patient returned to baseline status 
Ongoing 
Patient did not recover and symptoms continue; 
Recovered with 
sequelae 
The patient has recovered but with clinical sequelae 
from the event 
Unknown 
The patient outcome is unknown 
 
 
9.8.4 Treatment or Action Taken 
The treatment or action taken after the occurrence of an AE or SAE will be reported as: 

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Interventional 
Treatment 
Surgical, percutaneous or other procedure 
Medical Treatment 
Medication dose reduction/interruption or 
discontinuation, or medication initiated for event 
None 
No action is taken 
9.9 Reporting  
9.9.1 General Adverse Event Reporting Procedures 
Investigators are required to keep records on “all relevant observations, including records 
concerning adverse device effects (whether anticipated or unanticipated)” according to 21 
CFR 812.140. Adverse event collection will occur from the point of study enrollment to study 
closure. All new or worsening (from baseline) clinically significant adverse events will be 
captured on the AE CRF through the 90-day follow-up telephone visit. Non-clinically-
significant adverse events will not be required post discharge from the initial study procedure. 
It is the responsibility of the Investigator to assess the subject for adverse events and, if it is 
determined that a clinically significant AE has occurred, to capture the required adverse event 
information on the AE CRF. Independent monitoring will be conducted (§14.1) to review 
source documentation and verify the complete and accurate capturing of adverse events.  
The general procedure for investigators reporting any adverse event is as follows: 
• If an adverse event occurs, complete all sections of the Adverse Event CRF 
• Each unique event/diagnosis must be documented separately 
• Documented pre-existing conditions are not considered to be reportable AEs unless 
there is a change in the nature or severity of the condition 
• The AE CRF must be reviewed by the investigator 
For adverse events not meeting the criteria for an SAE or (potential) UADE, the sponsor 
recommends that the Investigator notify the sponsor within 10 working days of first learning 
of the AE using the electronic data capture (EDC) CRF. If necessary, the Investigator may 
be requested to provide de-identified copies of source documentation (e.g., physician/nurse 
notes or summaries) regarding the event. 
The Investigator must also notify the responsible IRB/EC regarding new and significant safety 
information and any events identified by Keystone Heart Ltd. that require expedited FDA or 
other regulatory authority reporting as serious, unexpected, and related to the investigational 
device. It is the responsibility of the investigator to ensure site-specific IRB/EC reporting 
requirement are met. 
The sponsor is responsible for reporting SAEs and device deficiencies to regulatory 
authorities in line with applicable regulatory requirements and for reviewing the risk analysis, 
determining the need for corrective or preventative action, and informing investigators and 
regulatory authorities accordingly. 
9.9.2 Serious Adverse Events 
Keystone Heart Ltd. recommends that the Investigator notify the sponsor within 3 working 
days of first learning of any SAE using the EDC CRF. All cardiovascular events and all 
adverse events potentially meeting endpoint criteria will be considered an SAE (even if they 
do not result in death or prolong the hospitalization) and should be reported as well (see also 
section 11.2). If necessary, the Investigator may be requested to provide copies of de-

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identified source documentation (e.g., physician/nurse notes or summaries) regarding the 
event. The sponsor will conduct an evaluation of the event and, if it is determined by the 
sponsor to be a UADE, it will be reported as described in the following section. 
At EU sites (phase I), Serious Adverse Device Effects (SADEs) must be reported to genae, 
N.V. within 48 hours of knowledge if required by local or national regulations. Contact details 
are as follows: 
genae, N.V. 
Justitiestraat 6B 
2018 Antwerp, Belgium 
Tel: +32 3 290 0306 
Fax: +32 3 290 0307 
It is the responsibility of each Investigator to report all serious adverse events and/or serious 
adverse device effects and device deficiencies that could have led to a serious adverse 
device effect to the IRB/EC, according to national regulations and IRB/EC requirements. If 
required by national regulations, the Investigator may also be required to report SAEs to the 
regulatory authority. 
European investigators (phase I) who become aware of an event must report the event to 
genae and to the Sponsor. While there is no legal requirement within the Medical Device 
Directives obliging users to have an active role in the medical devices vigilance system, user 
involvement is critical to successful post market surveillance by 1.) Ensuring that suspected 
incidents are communicated to manufacturers, and 2.) Making the proper implementation of 
field safety corrective actions possible.  
9.9.3 Unanticipated Adverse Device Effects 
Investigators must report any (potential) unanticipated adverse device effects to the sponsor 
and their IRB as soon as possible but no later than within 5 working days after the investigator 
first learns of the event [21 CFR 812.150]. UADEs should be reported immediately via 
telephone (contact details follow) as well as on the eCRF.  
Sponsor contact (US):  
M. Pauliina Margolis, MD, PhD 
Chief Medical Officer 
Tel: 305.972.8447 
email: pauliina.margolis@keystoneheart.com  
 
Sponsor contact (OUS): 
Ron Nitzan, PhD 
Vice President, Regulatory and Quality Affairs 
Tel: +972 4 615 8005 
Fax: +972 4 615 8099 
email: ron.nitzan@keystoneheart.com  
Investigators should consider the device labeling and the listing of expected adverse events 
(§9.10) in determining whether an event may qualify as “unanticipated.” 
If an event is determined by Keystone Heart Ltd. to be a UADE, the sponsor will report the 
event to the FDA, relevant competent authorities and the European Databank on Medical 
Devices (Eudamed) if necessary (in accordance with MEDDEV 2.12-1), and to all 
investigators to enable reporting to their respective IRB/EC. The sponsor will provide this 
notification within 10 days after first receiving notice of the effect [21 CFR 812.150].  

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If the sponsor and the DSMB determine that the event presents an unreasonable risk to the 
participating subjects, the sponsor must terminate all investigations or parts of investigations 
presenting the risk in the clinical trial not more than 5 working days after making that 
determination, and not more than 15 working days after the sponsor first received notice of 
the effect [21 CFR 812.26]. Follow-up visits for enrolled subjects will continue according to 
the schedule of assessments. 
9.10 Expected Adverse Events 
As with any endovascular intervention, TAVI involves some risks and possible complications. 
The following anticipated events have been identified as possible complications of TAVI 
procedures: 
• Acute cardiovascular surgery (need for) 
• Acute coronary artery occlusion 
• Acute myocardial infarction 
• Acute neurological events such as stroke, transient ischemic attack (TIA), and 
encephalopathy 
• Allergic reaction to contrast, antiplatelet therapy or device component materials 
• Angina pectoris 
• Anesthesia reactions 
• Aneurysm or pseudoaneurysm 
• Arteriovenous fistula 
• Ascending or descending aorta trauma 
• Atrial or ventricular arrhythmias or fibrillation or sustained heart palpitations requiring 
therapy 
• Bleeding complications such as hematoma and hemorrhage 
• Blood loss requiring transfusion 
• Bowel ischemia 
• Coronary artery or other vascular injury, dissection, or perforation (which may require 
repair)  
• Embolism (air, tissue, device, or thrombus) 
• Fever 
• Femoral nerve damage 
• Hemodynamic changes  
• Hypertension or hypotension (sustained requiring therapy) 
• Infection, including endocarditis and septicemia 
• Pain (at the femoral puncture site, abdominal, back, or other) 
• Percutaneous coronary intervention (need for)  
• Peripheral ischemia, peripheral nerve damage 

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• Pulmonary edema 
• Pyrogenic reaction 
• Renal complications, injury, or failure 
• Unstable angina 
• Vascular complications which may require vessel repair 
• Vessel spasm (sustained, not responding to therapy) 
In addition to the risks listed above, the potential risks specifically associated with the 
TriGuard HDH or TriGUARD 3 procedure include, but may not be limited to, the following: 
• Dissection of the innominate artery by improper manipulations, disruption or migration 
of the TriGuard HDH CEPD filter due to passage of other instrumentation, e.g.: 
balloon, stent, catheter, wire 
• Blue toe syndrome or blue discoloration of a toe 
• Femoral bleeding at the access site 
• Local trauma to the aortic wall due to device migration 
10.0 Risk/Benefit Analysis 
10.1 Potential Risks and Discomforts 
Enrollment in the trial involves exposure to some risks. Most risks of trial participation 
are not materially different than those encountered by an individual undergoing TAVI 
outside the context of the trial (§9.10). However, the use of the TriGuard HDH or 
TriGUARD 3 embolic protection devices may involve exposure to additional risks (§9.10) 
as well as other potential risks of an unknown nature.  
10.2 Methods to Minimize Risks 
The clinical investigation plan is specifically designed to manage and minimize risks through 
careful subject selection, thorough training of investigators, adherence to pre-determined 
time points to assess subject clinical status, and regular clinical monitoring visits by Sponsor-
appointment monitoring personnel. A dedicated contract research organization has been 
included in the study team to ensure high quality follow-up and minimize potential drop out. 
In addition, an independent Data Safety Monitoring Committee will monitor the safety of 
subjects throughout the trial.  
10.3 Potential Benefits 
The targeted trial population (subjects with severe symptomatic AS meeting indications 
for TAVI) has been demonstrated to be at risk for stroke and other neurological 
complications during and after the procedure. The study intervention has the potential 
to benefit subjects by preventing or reducing cerebral embolization during the TAVI 
procedure, limiting subsequent cerebral ischemia. Potential risks and benefits will be 
evaluated on an individual basis and discussed with each patient prior to enrollment in 
the study. 

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11.0 Study Committees 
11.1 Patient Review Committee (PRC) 
The PRC will ensure appropriate and consistent application of selected anatomic eligibility 
criteria to all potentially eligible subjects at all study sites. The PRC will consist of at least one 
imaging specialist, two interventional cardiologists, and a Sponsor representative (non-voting 
role). 
Following initial pre-screening for study eligibility by the research team and documentation of 
informed consent, the following information will be submitted to the PRC for review for each 
potentially eligible subject: 
• A completed Screening Worksheet 
• The results of independent core laboratory analysis of CT imaging (standard and 
contrast-enhanced angiography preferred) of the left heart, aorta, great vessels, and 
peripheral access vessels performed up to 1 year prior to procedure.  
The PRC will meet regularly during the enrollment phase to determine whether potential 
candidates meet selected applicable anatomic eligibility criteria (§6.1.2.1.15, §6.1.2.1.16, 
§6.1.2.1.17, §6.1.2.1.18, §6.1.2.1.19). PRC responsibilities, membership, meeting 
frequencies, and procedures will be outlined in the PRC charter prior to the onset of the trial. 
11.2 Clinical Events Committee (CEC) 
The CEC will be responsible for adjudicating all site-reported cardiovascular events and all 
adverse events potentially meeting endpoint criteria, in an ongoing fashion during the trial. In 
order to fully capture all endpoints, events potentially meeting end-point criteria will be 
considered an SAE (even if they do not result in death or prolong the hospitalization) and 
sent to the medical monitor for further assessment. Events appropriately classified 
as potential endpoints by the medical monitor will be sent to CEC for adjudication. 
Events potentially meeting end-point criteria and therefore defined as SAE for this 
purpose include: 
• Death 
• Stroke/TIA or any other Neurological Dysfunction (NeuroARC definitions) 
• MI or Coronary artery obstruction requiring intervention 
• Bleeding (including life-threatening or disabling bleeding, Major and Minor bleeding) 
• Acute kidney injury (stage 2 or 3 or requiring dialysis) 
• Major vascular complications 
• Valve-related dysfunction requiring repeat procedure 
The CEC will include at least one interventional cardiologist with relevant clinical experience 
and one neurologist with experience in clinical trials involving stroke who are otherwise 
independent of the Sponsor or the conduct of the study. Members will not have scientific, 
financial or other conflicts of interest related to Keystone Heart Ltd. or the Investigators. The 
CEC will operate and conduct all meetings and event reviews independent of the Sponsor 
unless specific expert knowledge regarding the characteristics or function of the study device 
is requested by the CEC from the Sponsor.  

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The CEC will meet regularly throughout the study to adjudicate events in an ongoing and 
timely fashion. The adjudication process, event definitions and required source document 
materials for each types of event will be pre-specified in the CEC Charter prior to the onset 
of the trial. The adjudication process will include CEC member review of copies of all relevant 
medical records and imaging studies associated with an event reporting. All adjudication 
decisions will be made by the CEC in an independent fashion based upon review of all 
available medical evidence associated with an event. 
11.3 Data and Safety Monitoring Board (DSMB) 
The Data Safety Monitoring Committee (DSMB) is responsible for the oversight and safety 
monitoring of the study. The DSMB advises the Sponsor regarding the continuing safety of 
the trial subjects and those yet to be recruited to the trial, as well as the continuing validity 
and scientific merit of the trial. The DSMB will be composed of members are leading experts 
in cardiovascular medicine, vascular neurology (with experience in clinical trials involving 
stroke), and biostatistics who are not participating in the trial and have no affiliation with the 
sponsor. 
During the enrollment phase of the trial, the DSMB will review accumulating safety data to 
monitor for the incidence of serious adverse events that would warrant modification or 
termination of the trial according to a pre-specified safety monitoring plan. Any DSMB 
recommendations for study modification or termination prompted by concerns regarding 
subject safety or issues relating to data monitoring or quality control will be submitted in 
writing to the Sponsor for consideration and final decision. However, if the DSMB at any time 
determines that a potential serious risk exists to subjects in this trial, the DSMB chairman will 
immediately notify the Sponsor. 
The DSMB will meet at regular intervals to review the safety data. DSMB responsibilities, 
membership, meeting frequencies, and procedures will be outlined in the DSMB charter prior 
to the onset of the trial. The circumstances under which the DSMB may request unblinding 
to treatment allocation will also be outlined in the charter.   
12.0 Statistical Considerations and Analysis Plan 
12.1 General Analysis Definitions 
Analysis will be conducted using SAS (version 9.3 or greater), unless otherwise noted. 
Descriptive statistics for continuous variables will include mean, median, standard deviation, 
quartiles, minimum, maximum, and sample size for each treatment group. Binary variables 
will be summarized using frequencies, percentages, and sample size for each treatment 
group. For time-to-event data, Kaplan-Meier estimates at the indicated time points will be 
displayed graphically. Further clarifications regarding endpoint criteria assessment and 
analysis between subjects will be provided in the Statistical Analysis Plan (SAP). 
12.1.1 Adaptive Design 
Once at least 50% of the initial randomized Phase II cohort has been enrolled and has 
reached the 30 day primary efficacy endpoint evaluation time point, the independent 
unblinded statistician will perform a conditional power analysis. If the trial, based on the 
results at that point is either ≤40% powered to achieve success in meeting the primary 
efficacy endpoint or is ≥80% powered to achieve the primary efficacy endpoint no sample 
size reestimation will be required. If the conditional power of the study is >40% but <80% the 
independent unblinded statistician will recommend a sample size reestimation, subject to 
approval by the Sponsor. If this analysis determines that more than 225 randomized subjects 

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will be required to ensure adequate study power, enrollment may continue until the required 
number of subjects have been enrolled, or until the total subject limit for the study has been 
reached (whichever occurs first). 
Promising zone computation 
After the trial has enrolled 50% of the originally planned sample size of the initial randomized 
cohort (112 patients), an independent statistician will estimate all 4 levels of the Finkelstein-
Schoenfeld hierarchy for device and control, and use these estimates to re-calculate the trial’s 
power given the originally planned 225 Phase II patients.   
If the trial power is between >40% and <80%, the trial will be considered promising and the 
trial will readjust the sample size to attain 80% power. If on the other hand the power falls to 
≤ 40% or ≥ 80%, the sample size will not be adjusted. 
Conditional power computation 
The conditional power will estimate all four Finkelstein-Schoenfeld levels and use these 
estimates to simulate future enrolled patients. The power simulation will follow exactly the 
same algorithm as used to power the original Phase II study with updated estimates of effect 
size. 
Alpha spending and controlling type I error 
Since the study leadership and sponsor do not conduct any formal statistical hypothesis test, 
this design will not incur any alpha penalty or affect the overall type I error. As detailed by 
Mehta and Pocock11 and based on the work of Chen10 as long as the sample size 
reestimation occurs only when the conditional power falls in the promising zone, no additional 
alpha spend is required and the overall type I error is preserved.   
 
12.2 Sample Size Calculation 
 
12.2.1 Hypotheses 
12.2.1.1.1 Primary Safety Hypothesis (Phase I and Phase II reported 
individually) 
The primary safety hypothesis is that the rate of the primary safety endpoint (a composite of 
death, stroke, life-threatening of disabling bleeding, AKI [Stage 2 OR 3], coronary artery 
obstruction requiring intervention, major vascular complication, and valve-related dysfunction 
requiring repeat procedure) in the group undergoing TAVI with either protection device 
system (Intervention Groups) at 30 days will be less in each device group (TriGuard HDH 
and TriGUARD 3) compared separately to a performance goal (PG) of 34.4%.  
Specifically, the primary safety analysis will assess if the Intervention group’s safety event 
rate is significantly less than the PG of 34.4% using a one-sample z-test of proportions.  The 
formal null and alternative hypotheses to be tested are: 
 
H0: π ≥ 0.344 
 
H1: π < 0.344 
where π is the true safety event rate for the Intervention arm.  
The primary hypothesis test will be carried out by comparing the upper bound of the one-
sided 95% confidence interval of the primary safety endpoint event rate in the intervention 
arm to the PG. With the planned evaluable sample size of 179 subjects and a one-sided 
alpha of 0.05, the critical value for rejection of the null hypothesis is 28.5%: if the primary 

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safety endpoint occurs in 28.5% or less of intervention group subjects, the performance goal 
will be met. 
After accounting for a potential 5% loss to clinical follow-up at 30 days (including subjects 
who do not meet As Treated population criteria), the total required intervention group sample 
size is 190 subjects in each Phase. For Phase II 150 subjects randomized to the TriGUARD 
3 and the 40-50 roll-ins will constitute the primary safety population. 
Trial success depends on both primary endpoints being met in their primary analysis 
populations; i.e., the primary safety endpoint must be met in the primary (AT) population and 
the primary efficacy endpoint must be met in the primary (eITT) population in order for the 
trial to be declared a success. Because both primary endpoints (safety and efficacy) must be 
met (i.e., both H0 must be rejected) for the trial to be declared a success, no adjustment to 
alpha for multiple endpoints is required for the two primary study endpoints. 
12.2.1.1.2 Primary Efficacy Hypothesis 
The primary hypothesis is that TAVI with the TriGUARD 3 system is superior to standard 
(unprotected) TAVI for the primary hierarchical composite efficacy endpoint of all-cause 
mortality or any stroke at 30 days (Tier 1), NIHSS worsening from baseline assessed at 2-5 
days post-procedure (Tier 2), freedom from any cerebral ischemic lesions detected by 
diffusion-weighted magnetic resonance imaging (DW-MRI) 2 to 5 days post-procedure (Tier 
3), and total volume of post-procedure cerebral ischemic lesions detected by DW-MRI (Tier 
4).  
Specifically, the primary efficacy hypotheses are: 
H0: The hierarchical composite of death/stroke, NIHSS worsening, freedom from 
any lesions detected by DW-MRI, and larger total lesion volumes is not different 
between Intervention and Control groups 
H1:  The hierarchical composite of death/stroke, NIHSS worsening, freedom from 
any lesions detected by DW-MRI, and larger total lesion volumes is lower in the 
Intervention group than in the Control group 
The null hypothesis will be tested at the final analysis at a one-sided 0.025 level of 
significance. The null hypothesis will be tested using the chi-square test according to the 
method described in Finkelstein-Schoenfeld2 and Pocock77. 
12.2.1.1.3 Hypothesis-driven Secondary Endpoints 
In order to control alpha at 0.025 level overall, the secondary endpoints will be tested if and 
only if the primary study endpoints are met. Secondary testing will be conducted sequentially 
beginning with all stroke, followed by NIHSS worsening, followed by the composite of all-
cause mortality and all stroke, followed by CNS Infarction, followed by total volume of cerebral 
ischemic lesions.  
• All stroke [evaluated at 7 days in the eITT analysis population] 
The hypothesis is that the event rate for all stroke in the Intervention Group at 7 days will be 
lower than the Control Group at 7 days.  
The formal null and alternative hypotheses to be tested are: 
 
H0: πSTRK-I = πSTRK-C 
 
H1: πSTRK-I < πSTRK-C 

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where πSTRK-I is the true rate of all stroke in the Intervention arm and πSTRK-C is the true rate 
of all stroke in the Control arm. 
The null hypothesis will be tested at a one-sided 0.025 level of significance using a two-
sample z-test of proportions. 
• NIHSS worsening, defined as an NIHSS score increase from 
baseline [evaluated at 2-5 days post-procedure in the efficacy 
Intention to Treat (eITT) analysis population] 
The hypothesis is that the rate of the patients with worsening NIHSS score in the Intervention 
Group at post-procedure (2-5 days post-procedure) will be lower than the Control Group at 
post-procedure (2-5 days post-procedure).  
The formal null and alternative hypotheses to be tested are: 
 
H0: πNIHSS-I = πNIHSS-C 
 
H1: πNIHSS-I < πNIHSS-C 
where πNIHSS-I is the true rate of worsening NIHSS scores in the Intervention arm and πNIHSS-
C is the true rate of worsening NIHSS scores in the Control arm. 
The null hypothesis will be tested at a one-sided 0.025 level of significance using a two-
sample z-test of proportions. 
• Composite of all-cause mortality and all stroke [evaluated at 7 
days in the eITT analysis population] 
The hypothesis is that the event rate for the composite of all-cause mortality and all stroke in 
the Intervention Group at 7 days will be lower than the Control Group at 7 days.  
The formal null and alternative hypotheses to be tested are: 
 
H0: πCOMP-I = πCOMP-C 
 
H1: πCOMP-I < πCOMP-C 
where πCOMP-I is the true rate of the composite of all-cause death and all stroke in the 
Intervention arm and πCOMP-C is the true rate of the composite of all-cause death and all stroke 
in the Control arm. 
The null hypothesis will be tested at a one-sided 0.025 level of significance using a two-
sample z-test of proportions. 
• CNS infarction (NeuroARC defined) [evaluated at 30 days in the 
eITT analysis population] 
The hypothesis is that the event rate for CNS infarction in the Intervention Group at 30 days 
will be lower than the Control Group at 30 days.  
The formal null and alternative hypotheses to be tested are: 
 
H0: πCNS-I = πCNS-C 
 
H1: πCNS-I < πCNS-C 
where πCNS-I is the true rate of CNS infarction in the Intervention arm and πCNS-C is the true 
rate of CNS infarction in the Control arm. 
The null hypothesis will be tested at a one-sided 0.025 level of significance using a two-
sample z-test of proportions. 

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• Total volume of cerebral ischemic lesions detected by DW-MRI, 
[evaluated 2 to 5 days post-procedure in the efficacy Intention to 
Treat (eITT) analysis population]  
The hypothesis is that the total volume of cerebral ischemic lesions in the Intervention Group 
will be lower than the Control Group.  
The formal null and alternative hypotheses to be tested are: 
 
H0: πTLV-I = πTLV-C 
 
H1: πTLV-I < πTLV-C 
where πTLV-I is the true total volume of cerebral ischemic lesions in the Intervention arm and 
πTLV-C is the true total volume of cerebral ischemic lesions in the Control arm. 
The null hypothesis will be tested at a one-sided 0.025 level of significance using the two-
sample z-test. 
12.2.2 Expected Control Primary Safety Endpoint Event Rate  
An expected event rate for the control group was determined based on published data from 
subjects undergoing unprotected TAVI.  
A search of bibliographic scientific databases (PubMed and EMBASE) was undertaken to 
identify studies reporting VARC combined safety outcomes using the following search 
parameters: 
• Language = English, species = humans 
• Publication date January 2011 (publication of original VARC definitions) to present 
• Keywords included: Valve Academic Research Consortium or VARC; aortic valve; and 
percutaneous, transcatheter, transluminal, transarterial, transfemoral, or transapical 
Results were evaluated according to the following selection criteria: 
• Peer-reviewed publications only. Abstracts, case reports, conference presentations, 
editorials, and expert opinions were excluded.  
• Reported using VARC or VARC-2 definitions (explicitly mentioned in text), and 
reported VARC combined safety endpoint or the VARC-2 early safety endpoint at 30 
days 
• N≥20 (studies reporting outcomes in fewer than 20 TAVI subjects were excluded) 
• Patients with severe AS undergoing TAVI with Medtronic or Edwards valves. Studies 
reporting outcomes exclusively in valve-in valve or subjects undergoing TAVI via any 
approach other than transfemoral or transapical (e.g., transaxillary, transsubclavian, 
direct aortic) were excluded. When larger cohorts included these subjects, the results 
in these subjects were excluded when data allowed; otherwise they were included.  
• Publications with overlapping data were identified where possible, and the most recent 
procedural timeframe (or largest N) was used and the other(s) discarded. 
Additional relevant studies were identified through a manual search of secondary sources, 
including the bibliographies of initially identified articles and review articles and 
commentaries. 
Although the primary safety endpoint is the VARC-21 early safety endpoint, which differs from 
the original VARC definition78, studies reporting either composite endpoint were collected and 

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evaluated to inform determination of the PG. Based on differences between the definitions 
(see Table 9 below), we would expect the VARC-2 event rate to be slightly higher based on 
the addition of all stroke and Stage 2 acute kidney injury; however, more published data 
according to the earlier VARC definitions is likely available. 
 
Table 9. Comparison of VARC and VARC-2 Early Safety Endpoint Components 
VARC78 
Combined Safety Endpoint (at 30 days) 
VARC-21 
Early Safety (at 30 days) 
• 
All-cause mortality 
• 
Major stroke 
• 
Life-threatening (or disabling) bleeding 
• 
Acute kidney injury – Stage 3 
(including renal replacement therapy) 
• 
Coronary artery obstruction requiring 
intervention 
• 
Major vascular complication 
• 
Repeat procedure for valve-related 
dysfunction (surgical or interventional 
therapy) 
• 
Peri-procedural MI 
• 
All-cause mortality 
• 
All stroke (disabling and non-disabling) 
• 
Life-threatening bleeding 
• 
Acute kidney injury – Stage 2 or 3 
(including renal replacement therapy) 
• 
Coronary artery obstruction requiring 
intervention 
• 
Major vascular complication 
• 
Valve-related dysfunction requiring repeat 
procedure (BAV, TAVI, or SAVR) 
Note: Bold text indicates differences between the two definitions. This table represents an overall 
comparison; details of individual component definitions have also changed between consensus documents. 
The literature search and sift identified a total of 19 studies reporting the original VARC 
combined safety endpoint and 6 studies reporting the VARC-2 early safety endpoint (Table 
10 below).  
Table 10. Published Combined Safety Event Rates at 30 days after Unprotected TAVI 
Study 
N 
Event Rate (%) 
VARC 1 Combined Safety 
 
 
Abdel-Wahab 201279 
70 
13.0 
Buchanan 201180 
305 
38.2 
D’Ascenzo 201381 
377 
28.9 
Dubois 201382 
73 
29.0 
van der Boon 201483 
882 
26.6 
Eltchaninoff 201284 
190 
16.3 
Gurvitch 201185 
310 
18.4 
Hammerer 201286 
50 
18.0 
Hayashida 201287 
260 
17.3 
van der Boon 201388 
298 
23.5 
Scherner 201289 
150 
28.0 
Seiffert 201390 
326 
21.2 
Stahli 201191 
130 
20.8 
Ussia 201292 
181 
25.8 

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Wenaweser 201193 
256 
29.3 
Yamamoto 201394 
415 
16.4 
Abramowitz 201495 
249 
6.8 
Greif 201496 
461 
12.6 
Sabate 201397 
1416 
14.0 
Simple mean 
337 
23.8 
Weighted mean 
-- 
20.4 
VARC 2  Early Safety 
 
 
D’Onofrio 201398 
774 
21.7 
Tarantini 201399 
250 
21.2 
Chopard 2014100 
3928 
40.4 
Conradi 2013101 
100 
19.0 
Magri 2013102 
330 
30.9 
Seco 2014103 
32 
21.9 
Simple mean 
902 
25.9 
Weighted mean 
-- 
35.8 
The above studies represent the best estimation of the expected event rate in the population 
of subjects with severe AS undergoing TAVI via the transfemoral or transapical route with 
Edwards or Medtronic valve systems. The average event rate in studies reporting outcomes 
according to the VARC-2 definition (the primary safety endpoint for the REFLECT Trial) was 
25.9%; among studies reporting the slightly more circumscribed VARC 1 definition, the 
average event rate was 23.8%. Therefore, the expected event rate of the primary safety 
endpoint in the Control group was estimated at 25%.  
12.2.3 Expected Primary Efficacy Endpoint Event Rate 
Occurrence of the components of the primary hierarchical composite efficacy endpoint was 
estimated based on published literature and special consideration of data from the DEFLECT 
III randomized controlled trial of the TriGuard device:  
For Tier 1 of the hierarchy, an expected event rate of all-cause mortality or stroke (disabling 
and non-disabling) at 30 days was estimated based on published data from randomized 
controlled trials of subjects undergoing unprotected TAVI (Table 11).  
Table 11. Composite of all-cause mortality and any stroke (30 days) in unprotected TAVI 
RCTs  
Trial 
N 
Composite 
Component 
Death + 
All Stroke 
Death + 
Disabling 
Stroke 
Death 
 All 
Stroke 
All stroke 
or TIA 
Disabling 
/ Major 
Stroke 
Non-
disabling 
/ Minor 
Stroke 
TIA 
PARTNER 1A 
(High Risk)4* 
348 
7.8% (27) 
6.9% (24) 
3.4% (12) 
4.6% (16) 
5.5%(19) 
3.8% (13) 
0.9% (3) 
0.9% (3) 
PARTNER 1B 
(Inoperable)5 
179 
10.1% (18) 
8.4% (15) 
5.0% (9) 
6.7% (12) 
6.7% (12) 
5.0% (9) 
1.7% (3) 
0% (0) 

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In addition, we took into account randomized control trials of subjects randomized to TAVI 
with vs. without protection device (table 11a). 
 
 
 
 
Table 11a. Rates of death and Stroke at 30 days in RCTs of protection devices. 
Trial* 
N 
Death at 30 days 
Stroke at 30 days 
Device 
Control 
Device 
Control 
DEFLECT III8 2015 
85 
2.17% 
5.13% 
4.35% 
5.13% 
EMBOL-X72 2015 
30 
0% 
0% 
-- 
-- 
MISTRAL-C73 2016 
65 
3.12% 
9.09% 
0% 
6.06% 
CLEAN TAVI74 2016 
100 
0% 
2% 
8% 
8% 
SENTINEL9 2017 
363 
1.28% 
1.8% 
5.63% 
9.09% 
Simple mean 
 
1.32% 
3.6% 
3.6% 
5.66% 
Weighted mean 
 
1.33% 
3.21% 
5.09% 
7.25% 
Meta-analytic mean* 
 
1.6% 
3.83% 
5.09% 
7.26% 
* Embol-X excluded 
A recently published letter104 presented a meta-analysis of the above trials for the primary 
end point of death and stroke at longest follow-up available, showed rates of 6% vs 10% for 
device vs. control respectively.  
Based on the above, and considering SENTINEL being the most recent trial (with up to 9% 
stroke rate and 1.8% death rate in the controls), we conservatively estimate an ~11% rate of 
all-cause mortality or stroke at 30 days in subjects undergoing unprotected TAVI and a 50% 
reduction yielding a ~6% assumed event rate in the protected group.  
CoreValve 
High Risk6* 
390 
6.9% (27) 
5.9% (23) 
3.3% (13) 
4.9% (19) 
5.9% (23) 
3.9% (15) 
1.0% (4) 
0.8% (3) 
CoreValve 
Extreme 
Risk7* 
489 
11.5% (56) 
9.8% (48) 
8.4% (41) 
4.0% (19) 
4.5% (22) 
2.3% (11) 
1.9% (9) 
0.6% (3) 
Simple average 
9.1% 
Weighted average 
9.1% 
Meta-analytic 
average 
8.8% 
NOTE: Italics indicates that the event rate is not directly reported, but the given percentage represents a best estimate based on 
component event rates; for the composite of death and all stroke, it is assumed that no subject with a non-disabling stroke also 
experienced a death or disabling stroke within the 30-day timeframe (with the exception of CoreValve Extreme, in which data 
indicates that 1 subject experienced both a major and a minor stroke). 
*Percentages given are Kaplan Meier estimates, and therefore do not equal the number of subjects experiencing an event 
divided by the total number of subjects 

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The remaining component event rates (Tiers 2-4) are estimated based on data from the 
above mentioned trials, which employed identical NIHSS assessments and DW-MRI analysis 
methodology. 
We conservatively expect 9% of controls and 6% of device group patients to have any NIHSS 
worsening (table 6b).  
Among subjects who survived free of stroke to 30 days, and who did not experience NIHSS 
worsening at the post-procedure (2-5 days post-procedure) assessment (Tier 3 of the 
hierarchy), we expect 11% of controls and 27% of device group patients to be free of any 
lesions on MRI. These assumptions are based on the above trials and more specifically on 
the published results of DEFLECT III8 (Per Treatment) which used a similar device with full 
cerebral protection (as opposed to SENTINEL) and the same MRI assessment modality as 
planned in this trial (see also table 6a). 
Among patients surviving without stroke at 30 days, and who did not experience NIHSS 
worsening, and who had MRI lesions on DW-MRI (final 4th Tier) we expect the rates of lesion 
volumes categorized by size in pre-specified set ranges of >0-50 mm3, >50-150 mm3 and 
above 150 mm3 to be 7%, 33%, and 48% in the controls, respectively, and 19%, 7.5% and 
46% in the device arm, respectively. Expected rates were adapted from DEFLECT III (Per 
Treatment), the only published study thus far to incorporate such volume subdivisions.8 
All tiers and their respective assumed rates are presented in table 11b. 
 
 
Table 11b. Assumed event rates 
  
Assumed 
Control Rates 
Assumed 
TriGUARD 3 Rates 
Death or Stroke 
11% 
6% 
Worsening NIHSS 
9% 
6% 
Freedom from MRI Findings 
(Lesion Volume 0 mm3) 
11% 
27% 
Lesion Volume (mm3) 
>0-50 
7% 
19% 
>50-150 
33% 
7.5% 
> 150 
48% 
46% 
15% Missing in MRI Follow-up and 5% missing for all other parameters 
Type I Error = 5% 
 
The primary analysis population for the primary endpoint is the efficacy Intention to Treat 
(eITT) population (§12.3.1), which excludes subjects with conversion to surgery or prolonged 
cardiac arrest prior to the post-procedure DW-MRI. Selection of this population as the primary 
analysis population for the efficacy endpoint ensures that, should a small number of subjects 
experience an adverse endpoint event due to circumstances unrelated to procedural 
neuroprotection, the study will remain powered to detect a clinically-meaningful treatment 
effect, particularly regarding the volume of subclinical cerebral ischemic lesions on DW-MRI.  
12.2.4 Sample Size Estimation 
12.2.4.1.1 Primary Safety Endpoint 

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The primary safety endpoint is combined safety (VARC-2 defined as a composite of death, 
stroke, life-threatening or disabling bleeding, acute kidney injury [Stage 2 or 3], coronary 
artery obstruction requiring intervention, major vascular complication, and valve-related 
dysfunction requiring repeat procedure), evaluated at 30 days. 
Based on published literature of patients undergoing unprotected TAVI (§12.2.2), establishing 
the expected Control event rate of 25%, and a 37.5% relative margin (absolute delta 9.4%), 
a Performance Goal (PG) has been has been set at 34.4% (25% + 9.4%). The primary safety 
analysis will assess if the Intervention group’s safety event rate is significantly less than the 
PG of 34.4%. 
A sample size of 179 evaluable subjects in the intervention group will provide 85% power to 
determine whether the intervention group meets the PG at the one-sided alpha=0.05 level 
when using a one-sample z-test of proportions. After accounting for a potential 5% loss to 
clinical follow-up or dropout from the primary analysis population (As Treated) at 30 days, the 
total required sample size is 190 subjects in each intervention group. Therefore, the initial 
randomized sample size of 190 subjects in each intervention group in each phase will have 
sufficient power to determine whether the intervention meets the safety PG. For Phase II 150 
subjects randomized to the TriGUARD 3 and 40- 50 roll-ins will constitute the primary safety 
population. 
12.2.4.1.2 Primary Efficacy Endpoint 
Sample size for assessing superiority of Intervention over Control with respect to the 
hierarchical composite primary efficacy endpoint was estimated using the following 
assumptions: 
• All-cause mortality or any stroke at 30 days will occur in ~11% of Control subjects 
and ~6% of Intervention subjects (5% absolute reduction, ~45% relative reduction) 
• Among subjects without all-cause mortality or any stroke to 30 days, NIHSS 
worsening 2-5 days post-procedure will occur in 9% of Control subjects and 6% of 
Intervention subjects (3% absolute reduction, 33.3% relative reduction)  
• Among subjects without all-cause mortality or any stroke to 30 days and without 
NIHSS worsening 2-5 days post-procedure, MRI findings will occur in 89% of Control 
subjects and in 73% of intervention subjects (16% absolute reduction, 17.9% relative 
reduction). 
• Among subjects without all-cause mortality or any stroke to 30 days, without NIHSS 
worsening 2-5 days post procedure, but with MRI findings, lesion volumes can be 
divided into 3 out of 4 subsets- 0 mm3, >0-50 mm3, >50-150 mm3 and >150 mm3 . 
For these volume subsets, we expect rates of 11%, 7%, 33% and 48%, respectively, 
in the control group and 27%, 19%, 7.5%, and 46%, respectively, in the intervention 
group. 
• For sample size calculations a relative reduction of 30% is expected in each lesion 
volume subset, based on the comparison of total lesion volumes between device and 
control groups in DEFLECT I, MISTRAL C73 SENTINEL9 and CLEAN-TAVI74.  
• The smallest detectable difference in MRI is a single voxel. In addition, inter-rater 
mean differences between two independent observers was 15% or ~5 voxels (40.5 
mm3) in the KSH Methodology/Reproducibility Study (data on file). Accordingly, a 
meaningful difference to declare a win/lose between MRI lesion volumes was set at 
a 15% relative difference or a 50 mm3 absolute difference.  

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• Loss to post-procedure DW-MRI follow-up is expected to occur in 15% of all subjects 
(due to contraindications to post-procedure DW-MRI [e.g., pacemaker implantation] 
or subject non-compliance) 
• Loss to follow-up for all other reasons is expected to be 5%. 
• Overall α (one-sided)=0.025; (see §12.4.2) 
To determine the required sample size, calculations were performed by simulating 5000 
samples on SAS software postulating the above parameters; mortality and stroke rates and 
proportions of patients with NIHSS worsening, any MRI lesions and volumes divided to 
subsets were simulated by a random binary function. 
An evaluable sample size of 225 subjects (2:1 randomization with 150 in the Intervention 
group and 75 new Control subjects) is sufficient to demonstrate superiority of the Intervention 
group to the Control group for the primary efficacy endpoint when pair-wise comparisons are 
made between subjects using the Finkelstein-Schoenfeld method,2 and outcomes between 
treatment groups are compared by the chi-square test.  
Therefore, the initial randomized cohort sample size of 225 subjects (150 in the Intervention 
group and 75 new control subjects) will have >80% power to demonstrate superiority of the 
Intervention group for the primary efficacy endpoint (one sided α=0.025). Notably, in several 
simulations, considering different distributions for lesion volume and different distributions for 
death/ stroke, the study power remained greater than 80%. 
Adding the 63 control subjects already enrolled in REFLECT Phase I for a total of 138 control 
subjects would increase the power to at least 92% to demonstrate superiority of the primary 
efficacy endpoint. 5% loss to follow up is included. 
12.3 Analysis Populations 
12.3.1 Efficacy Intention to Treat (eITT) Analysis Population 
The efficacy Intention to Treat (eITT) analysis population is defined as: 
• Subjects who are enrolled in the trial and randomized to a treatment group, regardless 
of treatment actually received AND 
• Who do not have conversion to surgery or prolonged cardiac arrest (>3 minutes) prior 
to the post-procedure DW-MRI 
The eITT population of evaluable (i.e., not Roll-In) subjects will be used for the primary 
analysis of the primary efficacy endpoint, the primary analysis of the secondary hypothesis-
driven endpoints, and the primary analysis of all secondary neurologic efficacy endpoints. 
12.3.2 Intention to Treat Analysis Population 
The Intention To Treat (ITT) analysis population is defined as all subjects enrolled in the 
study, by assigned treatment, regardless of the treatment actually received. 
The ITT population of evaluable (i.e., not Roll-In) subjects will be used for the primary analysis 
of secondary performance endpoints and Other Measures. The ITT population will also be 
used for a secondary analysis of the primary and secondary efficacy endpoints and the 
primary and secondary safety endpoints.  
12.3.3 As Treated Analysis Population 
The As Treated (AT) analysis population is defined by the treatment actually received, rather 
than the treatment assigned. In the AT population, subjects in whom vascular access in the 

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contralateral femoral artery has been established for the intended deployment of the TriGuard 
HDH or TriGUARD 3 device will be analyzed as part of the Intervention group, and subjects 
in whom the TAVI procedure is initiated (but no vascular access for intended deployment of 
the TriGuard HDH or TriGUARD 3 is established) will be analyzed as part of the Control 
group. 
The AT population will be used for the primary analysis of all primary and secondary safety 
endpoints. The AT population will also be used as the secondary analysis population for the 
secondary performance endpoints and Other Measures.  
12.3.4 Per Treatment Population 
The Per Treatment (PT) analysis population is defined as subjects in the Intervention group 
in whom device positioning is maintained until final procedure with complete cerebral 
coverage, and all Control group subjects.  
The PT population will be used for an additional analysis of the primary and secondary 
efficacy endpoints and other measures. 
12.3.5 Roll-In Patient Population 
The Roll-In (RI) patient population is defined as all subjects who undergo TAVI with the 
TriGuard HDH or TriGUARD 3 prior to enrollment of the first evaluable subject at each 
investigational site. Each investigational site without prior experience with the TriGuard 
device (minimum of 2 prior cases) will enroll a minimum of 2 RI subjects. RI subjects will not 
be randomized to a treatment arm, but will undergo TAVI with the embolic protection device 
and will undergo all protocol-specified follow-ups.  
For the purposes of analysis, a subject is considered enrolled in the Roll-In phase of the study 
when: 
• The patient has been judged to meet all inclusion and no exclusion criteria, and has 
signed a Patient Informed Consent form 
• The TriGuard HDH of TriGUARD 3 device has been introduced into the patient’s 
bloodstream  
The RI patient population will be used for a separate analysis of all primary and secondary 
endpoints and Other Measures. Additional analyses will evaluate primary and secondary 
endpoints in the pooled population of RI Subjects plus Evaluable Subjects.   
12.4 Method of Analysis and Reporting  
12.4.1 Baseline Characteristics 
The following data will be summarized using descriptive statistics and presented by treatment 
group for eITT (Roll-In subjects are excluded), ITT (Roll-In subjects are excluded), AT (Roll-
In subjects are excluded), PT (Roll-In subjects are excluded), and Roll-In analysis sets. 
Descriptive statistics for continuous variables will include mean, median, standard deviation, 
minimum, maximum, and sample size for each treatment group. Binary variables will be 
summarized using frequencies, percentages, and sample size for each treatment group.  
• Baseline demographics  
• Baseline comorbidities, risk factors and medical history  
• Cardiac risk factors, angina status and cardiac history  
• Procedural characteristics  

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• Device details 
12.4.2 Primary Safety Endpoint 
The primary safety hypothesis is that the rate of the Combined Safety Endpoint (defined 
according to VARC 2 as the composite of death, stroke, life-threatening or disabling bleeding, 
AKI [Stage 2/3], coronary artery obstruction requiring intervention, major vascular 
complication, and valve-related dysfunction requiring repeat procedure) at 30 days in the 
group undergoing TAVI with the TriGuard HDH or TriGUARD 3 system (Intervention group) 
is significantly less than the Performance Goal (PG). The following analysis will be carried 
out in the AT (primary analysis population) and ITT populations including Roll-ins. 
The primary safety analysis will assess if the Intervention group’s safety endpoint rate is 
significantly less than 34.4% using a one-sample z-test of proportions. Specifically, the null 
and alternative hypotheses to be tested are: 
H0: π ≥ 0.344 
H1: π < 0.344 
where π is the true, unknown, safety event rate for the Intervention arm.    
The number and percentage of patients in each group experiencing the safety endpoint rate 
will be presented for each treatment; in addition, one-sided 95% confidence intervals of the 
percentage will be presented, based on the normal approximation to the binomial distribution. 
For the intervention group, the above null hypothesis will be carried out at a one-sided 0.05 
level of significance using the one-sample z-test of proportions. Only AT and ITT patients 
who experienced a safety endpoint or had at least 23 days (30 days minus the allowable 7 
day visit window) of follow-up will be included in the analyses. 
As a secondary analysis, to account for any missing data in the primary endpoint (caused by 
not experiencing the safety endpoint AND prematurely withdrawing from the study before 23 
days of follow-up), a tipping point analysis will be conducted. Here the above safety null 
hypothesis will be repeatedly tested, first assuming 0 patients with missing data failed (i.e., 
experienced the safety event), then assuming 1 patient with missing data experienced the 
safety event, then assuming 2 patients with missing data experienced the safety event, etc. 
Of interest is the “tipping” point, i.e., the number of Intervention missing data subjects who 
must be imputed as failures in order for the safety null hypothesis to no longer be rejected. 
In addition, in the final analysis, assessments of study-center and of region effect on the 
primary safety endpoint will be carried out on the interventional group within the AT population 
using logistic regressions. A 0.15 level of significance will be used to assess the significance 
of each of the study center and region effects on the safety endpoint. A non-significant result 
for each of study centers and regions will support the pooling of patients across study centers 
and across regions for the primary safety analysis. A significant result will require further 
inspection of the by-center and by-region results to assess if poolability is appropriate. Note 
that centers with less than 5 subjects will be pooled with other centers by closest geographic 
region; this pooling will be carried out prior to the unblinding.  
In addition, a logistic regression to assess the consistency of the primary safety endpoint rate 
across the following categories will also be performed on the interventional arm (separately 
for Phase I and Phase II) within the AT population: 
• Subject gender (male versus female) 
• Valve prosthesis type (Edwards vs. Medtronic) 

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• Operative risk (by Society of Thoracic Surgeons [STS] Risk Score) 
• Type and duration of antiplatelet therapy: 
o Pre- and peri-procedural therapy: 
 Protocol-recommended antiplatelet therapy vs. other 
o Maintenance therapy:   
 Dual antiplatelet therapy (DAPT) to 90 days vs.  
 Monotherapy (aspirin or clopidogrel) to 90 days vs. 
 Warfarin with antiplatelet therapy to 90 days vs. 
 Other  
As above, a 0.15 level of significance will be used to assess the significance of the difference 
of the primary safety endpoint rate across the subgroups of each factor.  
12.4.3 Primary Efficacy Endpoint 
The primary hypothesis is that TAVI with the TriGuard HDH or TriGUARD 3 system is superior 
to standard (unprotected) TAVI for the primary hierarchical composite efficacy endpoint of all-
cause mortality or any stroke at 30 days (Tier 1), followed by NIHSS worsening (increase 
from baseline) 2-5 days post-procedure (Tier 2), followed by any ischemic cerebral findings 
on DW-MRI (Tier 3), followed by total volume of post-procedure cerebral ischemic lesions 
detected by DW-MRI divided into preset subdivisions (Tier 4). Poolability of the Phase I and 
Phase II control subjects will be assessed at the time of the primary analysis and the results 
will determine the control population used for the primary analysis of the primary efficacy 
endpoint as detailed in the SAP. 
The analytic approach is based on the statistical method described by Finkelstein and 
Schoenfeld.2 A similar approach was used in PARTNER Trial (Cohort B) where the co-
primary end point was hierarchical composite of the time to death from any cause or the time 
to the first occurrence of repeat hospitalization (after the index procedure) due to valve-
related or procedure related clinical deterioration.105 In addition, this approach was further 
explored and recommended for cardiovascular trials by Pocock et al.77 
In brief, we propose the following analysis methodology:  
Each subject in the intervention group is compared with each and every subject from the 
control group based on the following prespecified hierarchy: 
• All-cause mortality or any stroke (disabling or non-disabling) [evaluated at 30 days] 
o If both had a death/stroke a time to event analysis by days will determine a win 
o If both patients had a stroke at the same day the comparison moves to the next 
tier 
• NIHSS worsening (increase from baseline) [evaluated at post-procedure (2 to 5 days post-
procedure)]  
• Freedom from any cerebral ischemic lesions detected by diffusion-weighted magnetic 
resonance imaging (DW-MRI) 2 to 5 days post-procedure 
• Total volume of cerebral ischemic lesions detected by diffusion-weighted magnetic 
resonance imaging (DW-MRI) 2 to 5 days post-procedure 
For example: 

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• If Subject A has stroke and Subject B survives free of stroke or death to 30 days, 
Subject B wins (score +1) and Subject A loses (score -1). 
• If Subject A and Subject B both have death/stroke,  time to event by day will determine 
a win. 
• If both had a stroke on same day, the comparison moves on to the next tier. 
• Assuming neither experiences a stroke or death before 30 days, if Subject A 
experiences NIHSS worsening, and Subject B does not experience NIHSS 
worsening, Subject A loses (score -1) and Subject B wins (score +1). In case both 
have NIHSS worsening the patient with the lesser worsening wins. 
• Assuming neither subject experiences a stroke or death before 30 days or NIHSS 
worsening from baseline, if Subject A has no cerebral ischemic lesions on DW-MRI 
and Subject B has a cerebral ischemic lesion on DW-MRI, Subject A wins (score +1) 
and Subject B loses (Score -1).  
• Assuming neither subject experiences a stroke or death before 30 days, NIHSS 
worsening from baseline or freedom from DW-MRI cerebral ischemic lesions, if 
Subject A has a total cerebral ischemic lesion volume of 50 mm3 and Subject B has 
a total cerebral ischemic lesion volume of 100 mm3, Subject A wins (score +1) and 
Subject B loses (Score -1).  
An illustration of this algorithm is provided in Figure 4 below.  
 
 

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Figure 4. Algorithm of assigning scores by the Finkelstein and Schoenfeld method (Note: 
each patient from the intervention group is compared with each and every patient from the 
control group) 
 
 
 
Subject A 
Subject B 
Subject A: death or stroke  
Subject B: no death or stroke   
Subject A: no death 
or stroke 
Subject B: no death 
or stroke  
Subject A: stroke on same 
day  
Subject B: stroke on same 
day 
 
Subject A: death or 
stroke on same day 
Subject B:  death or 
stroke on same day 
Subject A gets -1 
Subject B gets +1 
Subject A gets 0 
Subject B gets 0 
(Equilibrium) 
Subject A gets 0 
Subject B gets 0 
(Equilibrium) 
Subject A: NIHSS worsening  
Subject B: no NIHSS 
worsening 
Subject A: no 
worsening 
Subject B: no 
worsening 
Subject A: no worsening  
Subject B: NIHSS 
worsening 
 
Subject A: NIHSS 
worsening  
Subject B: NIHSS 
worsening 
Subject A gets -1 
Subject B gets +1 
Subject A gets 0 
Subject B gets 0 
Compare: 
Freedom from any new lesions 
Subject A gets +1 
Subject B gets -1 
Subject A: New lesion 
Subject B: no lesions 
Subject A: MRI lesions 
Subject B: MRI lesions 
Subject A: no lesions 
Subject B: New lesion 
Subject A: no lesions 
Subject B: no lesions 
Subject A gets -1 
Subject B gets +1 
Subject A gets 0 
Subject B gets 0 
Subject A gets +1 
Subject B gets -1 
Compare: 
 Death or stroke 
Compare: 
Total lesion volume 
Subject A volume 
>  
Subject B volume 
One or both values 
is missing. 
Subject A volume 
<  
Subject B volume 
Subject A volume 
= 
Subject B volume 
Subject A gets -1 
Subject B gets +1 
Subject A gets 0 
Subject B gets 0 
Subject A – no 
score assigned 
Subject B – no 
score assigned  
Subject A gets +1 
Subject B gets -1 
Compare: 
   NIHSS worsening 

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After all between-subject comparisons have been performed, scores are summed to obtain 
a cumulative score for each subject, and outcomes between treatment groups are then 
compared by chi-square test.  
This analytic approach does not result in a natural point-estimate (e.g., proportion, mean, 
median, time-to-event); however, Pocock et al. provided a computational framework for the 
test statistic called “win ratio". In brief, it is calculated as a proportion of "wins" for each group 
out of the total number of the pairwise comparisons. 
No imputation of missing DW-MRI data will be performed for the primary analysis. However, 
in order to assess the sensitivity of results to missing DW-MRI data, multiple imputations with 
the linear regression approach will be used as the secondary sensitivity analysis. This 
assessment is necessary because the rate of permanent pacemaker implantation (causing 
loss to DW-MRI follow-up) may vary according to patient clinical characteristics and 
prosthesis type.106 Specifically, missing total volume of cerebral ischemic lesions on post-
procedure diffusion-weighted MRI will be imputed via multiple imputation linear regression 
(10 imputed data sets will be created). The covariates used for the imputation model will be 
treatment group, age at time of enrollment, body mass index, race, smoking status, creatinine 
level, hyperlipidemia, hypertension, aortic arch disease burden, porcelain aorta, aortic valve 
area at baseline, procedure time, country, valve type, balloon post dilatation, arch type, and 
level of calcification. This creation of the 10 datasets will be carried out using PROC MI in 
SAS. For each data set, the above-mentioned chi-square test will be carried out on the 
primary endpoint and one overall chi-square result will be generated from the 10 datasets. 
For each patient with missing TLV, the crux of multiple imputation is to estimate TLV from 
patients with non-missing TLV who have similar baseline characteristics as the patient with 
missing TLV. Thus, in essence, TLV for high risk patients with missing TLV due to pacemaker 
will theoretically be estimated from patients with similar high risk profiles who do not have 
pacemakers. 
The assumptions for powering the primary efficacy endpoint are based on neurologic, and 
imaging data from a limited number of subjects in the above mentioned RCTs (§12.2.2). In 
Phase I due to uncertainty regarding the primary efficacy endpoint, an unblinded interim 
analysis was planned to be conducted to re-evaluate the sample size required to demonstrate 
superiority of the Intervention group to the Control group. The unblinded interim analysis was 
planned to be conducted when 90 subjects total who meet the eITT population definition have 
completed the 30-day follow-up visit. This interim analysis was to be inspected by an 
independent data safety and monitoring Board (DSMB) and the unblinded results will not be 
made privy to the sponsor, investigator, or any REFLECT team member, even in the event 
of a DSMB recommendation of an increase in sample size (i.e., the sponsor will not be made 
privy to the reason for any DSMB recommendation of an increase in sample size). If the 
interim analysis would have determined that more than 285 randomized subjects will be 
required to ensure adequate study power, enrollment would have continued (contingent on 
DSMB recommendation and prior FDA approval, and at the Sponsor’s discretion) until the 
required number of subjects would have been enrolled, or until the total subject limit for the 
study has been reached (whichever occurs first). 
Specifically,  at the interim analysis in Phase I, the trial sample size was to be re-calculated, 
if necessary, to ensure 80% conditional power to demonstrate superiority (overall 2-sided 
α=0.05) of the Intervention group to the control group for the primary efficacy endpoint, 
conditioned on the interim unblinded results and loss to DW-MRI follow-up, according to the 
eITT population definition (there will be no imputation of missing data in this interim analysis; 
i.e., missing data will be excluded; also, sample size can only be increased at this interim 

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stage; it will not be decreased beyond what is currently planned). The conditional power and 
sample size re-calculation for the final analysis were to be ascertained by computer 
simulations and by established methodology outlined in Chen, DeMets and Lan.10 i.e., at the 
interim stage, we were to use Monte Carlo simulations to assess the conditional power of 
achieving a significant Mann-Whitney test by the end of the study, conditioned on the 
distribution of the observed interim data. If the conditional power is 50% - 80% (the “promising 
zone” according to Chen, DeMets and Lan), we were to use simulations to ascertain the 
increase in sample size required to yield 80% conditional power for the Mann-Whitney test. 
If the conditional power was determined to be <50% or >80%, the study was to proceed as 
is without a sample size adjustment (i.e., only the initial randomized cohort of 225 subjects 
were to be enrolled). The above-mentioned computer simulations were to be carried out 
assuming the distribution of TLV data follows a negative binomial distribution within each 
treatment group. The intent of this analysis was to ensure adequate power to detect a 
clinically meaningful treatment effect at the end of the study by providing the option to 
increase the sample size if necessary.  
There was no intention to stop the study for overwhelming efficacy at the interim analysis. 
However, as a precautionary measure and to be conservative (due to the presence of an 
unblinded interim analysis), the O’Brien Fleming alpha spending method was to be used to 
calculate an alpha penalty for the final analysis regardless of whether a sample size increase 
is needed (final analysis two-sided alpha = 0.049). 
NOTE: A revised adaptive design has been developed for Phase II of the study to inform a 
potential sample size increase based on interim conditional power; for details, please refer to 
§12.1.1. 
In the final analysis, assessment of treatment-by-study-center and treatment-by-region on 
the primary efficacy endpoint will be carried out on the eITT population using quantile 
regression. Total score obtained for each subject using the proposed approach (Finkelstein 
and Schoenfeld) will be the model dependent variable. The following two models will be built: 
1.) Model inclusive of treatment, study center, and treatment-by-study center interaction, and 
2.) Treatment region (US versus OUS, Phase I only), and treatment-by-region interaction. A 
0.15 level of significance will be used to assess the significance of each of the study center 
and region effects on the efficacy endpoint. A non-significant result for each of study center 
and region will support the pooling of patients across study centers and across regions for 
the primary efficacy analysis. A significant result will require further inspection of the by-center 
and by-region results to assess if poolability is appropriate. Note that centers with less than 
5 subjects will be pooled with other centers by closest geographic region; this pooling will be 
carried out prior to the unblinding. 
Additionally, an assessment of treatment-by-study-center and treatment-by-region on each 
component of the primary efficacy endpoint will be carried out on the eITT population using 
analysis of variance on the cube root transformation for total lesion volume data and logistic 
regression for death/stroke and NIHSS worsening, with effects for 1.) Treatment, study 
center, and treatment-by-study center interaction, and 2.) Treatment, region (US versus OUS, 
Phase I only), and treatment-by-region interaction. As above, a 0.15 level of significance will 
be used to assess the significance of the interaction; a non-significant interaction or an 
interaction that is significant but only quantitative (and not qualitative) in nature will support 
the pooling of patients across study centers and across regions for the primary analysis; and 
centers with less than 5 subjects will be pooled with other centers by closest geographic 
region, with pooling carried out prior to the unblinding.  

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In addition, the above analysis will be repeated in the eITT population (separately in Phase I 
and Phase II analysis sets) to assess the consistency of treatment effects on each component 
of the primary efficacy endpoint across the following variables: 
• Subject gender (male versus female) 
• Valve prosthesis type (Edwards vs. Medtronic) 
• Operative risk (by Society of Thoracic Surgeons [STS] Risk Score) 
• Type and duration of antiplatelet therapy: 
o Pre- and peri-procedural therapy: 
 Protocol-recommended antiplatelet therapy vs. other 
o Maintenance therapy:   
 Dual antiplatelet therapy (DAPT) to 90 days vs.  
 Monotherapy (aspirin or clopidogrel) to 90 days vs. 
 Warfarin with antiplatelet therapy to 90 days vs. 
 Other  
As above, analysis of variance on the cube root transformation for total lesion volume data 
and logistic regression for death/stroke and NIHSS worsening will be used, and a 0.15 level 
of significance will be used to assess the significance of the interaction. 
If the primary efficacy endpoint is met in the primary (eITT) analysis population, sequential 
testing of the primary efficacy hypothesis will be conducted in the ITT analysis population of 
evaluable subjects (Roll-In patients are excluded.) As a secondary analysis, the primary 
efficacy endpoint and its components will be evaluated in the ITT analysis population of 
evaluable subjects (Roll-In patients are excluded). As an additional analysis, the primary 
efficacy endpoint will be evaluated in the PT population of subjects with available data.  
An additional analysis of the primary efficacy endpoint will also be performed in the primary 
eITT analysis population with adjustment for pre-existing cerebral lesion volumes. The 
adjustment will be performed using a quantile regression with the resultant score being the 
dependent variable and group and the pre-existing cerebral lesion volumes will be 
independent. Specifically, the PROC QUANTREG procedure will be used to model the 
median of the score with QUANTILE=0.5 option. 
12.4.4 Hypothesis-driven Secondary Endpoints 
For the following secondary endpoints, a test for superiority of each intervention group to the 
control group will be performed. To address the issue of multiple tests among these 
secondary endpoints, sequential testing is planned. Secondary endpoints will be formally 
tested if and only if the primary study hypotheses are confirmed. The secondary endpoints 
will be tested individually, in the order in which they are listed as follows: 
• All stroke [evaluated at 7 days in the eITT population] 
• NIHSS worsening, defined as any NIHSS score increase from baseline [evaluated at 
2 to 5 days post-procedure in the efficacy Intention to Treat (eITT) analysis population]. 
A sensitivity analysis will further compare >2 points NIHSS worsening [evaluated at 2-
5 days post-procedure in the efficacy Intention to Treat (eITT) analysis population] 

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•  C o m p o sit e of all -c a u s e m ort alit y a n d all str o k e [ e v al u at e d at 7 d a y s i n t h e eI T T 
p o p ul ati o n]  
•  C N S  I nf ar cti o n  ( N e ur o A R C  d efi n e d)  [ e v al u at e d  at  3 0  d a y s  i n  t h e  eI T T a n al y si s 
p o p ul ati o n]  
•  T ot al v ol u m e of c er e br al i s c h e mi c l e si o n s  d et e ct e d b y D W -M RI, [ e v al u at e d 2 t o 5 
d a y s p o st -pr o c e d ur e i n t h e effi c a c y I nt e nti o n t o Tr e at ( eI T T) a n al y si s p o p ul ati o n]  
T h e  a b o v e  e n d p oi nt s  will  b e  t e st e d  b y  t hi s  pr e -s p e cifi e d  s e q u e n c e,  u nt il  t h e  fir st  n o n-
si g nifi c a nt diff er e n c e i s f o u n d b et w e e n t h e t w o tr e at m e nt gr o u p s. Aft er t h at, ot h er tr e at m e nt 
c o m p ari s o n s will b e e x a mi n e d i n a n e x pl or at or y m a n n er.  
1 2. 4. 5  E x pl or at or y S e c o n d ar y E n d p oi nt s  
1 2. 4. 5. 1. 1  S e c o n d ar y S af et y E n d p oi nt s  
All s e c o n d ar y s af et y e n d p oi nt s , i n cl u di n g t h e c o m p o n e nt s of t h e pri m ar y s af et y e n d p oi nt will 
b e r e p ort e d b y tr e at m e nt gr o u p i n t h e A T p o p ul ati o n of e v al u a bl e s u bj e ct s u si n g a p pr o pri at e 
d e s cri pti v e st ati sti c s  ( s a m pl e si z e, m e a n, st a n d ar d d e vi ati o n, m e di a n, mi ni m u m, m a xi m u m 
f or  c o nti n u o u s c h ar a ct eri sti c s;  c o u nt s  a n d  p er c e nt a g e s  of  p ati e nt s  f or  di c h ot o m o u s 
c h ar a ct eri sti c s) . N o f or m al h y p ot h e si s t e sti n g will b e p erf or m e d, a n d t h er e i s n o pl a n t o a dj u st 
al p h a t o a c c o u nt f or m ulti pl e t e sti n g of e x pl or at or y s e c o n d ar y e n d p oi nt s . 
T h e A T a n al y si s will b e c o n si d er e d pri m ar y. A s a s e c o n d ar y a n al y si s, all s e c o n d ar y s af et y 
a n d p erf or m a n c e e n d p oi nt s will b e e v al u at e d i n t h e I T T p o p ul ati o n of e v al u a bl e s u bj e ct s.  
F or  s af et y  e n d p oi nt s  o c c urri n g  i n  t h e  I nt er v e nti o n  a n d  R oll -I n  gr o u p s,  r el ati o n s hi p  t o  t h e 
in v e sti g ati o n al d e vi c e/i n v e sti g ati o n al pr o c e d ur e ( a s d et er mi n e d b y a n i n d e p e n d e nt Cli ni c al 
E v e nt s C o m mitt e e [ § 1 1. 1 ]) will al s o b e r e p ort e d.  
1 2. 4. 5. 1. 2  S e c o n d ar y Effi c a c y E n d p oi nt s  
•  I m a gi n g Effi c a c y E n d p oi nt s 
All  s e c o n d ar y i m a gi n g effi c a c y  e n d p oi nt s  will  b e  r e p ort e d  b y  tr e at m e nt  gr o u p  i n  t h e eI T T  
P o p ul ati o n of s u bj e ct s wit h a v ail a bl e d at a  u si n g d e s cri pti v e st ati sti c s. N o f or m al h y p ot h e si s 
t e sti n g will b e p erf or m e d, a n d t h er e i s n o pl a n t o a dj u st al p h a t o a c c o u nt f or m ulti pl e t e sti n g 
of  e x pl or at or y  s e c o n d ar y  e n d p oi nt s . St ati sti c s  f or  c o nti n u o u s  v ari a bl e s  will  i n cl u d e  m e a n, 
m e di a n, st a n d ar d d e vi ati o n, mi ni m u m, m a xi m u m, a n d s a m pl e si z e f or e a c h tr e at m e nt gr o u p. 
Bi n ar y  v ari a bl e s  will  b e  s u m m ari z e d  u si n g  fr e q u e n ci e s,  p er c e nt a g e s,  a n d s a m pl e  si z e  f or 
e a c h tr e at m e nt gr o u p . 
T h e eI T T  a n al y si s will b e c o n si d er e d pri m ar y. A s a s e c o n d ar y a n al y si s, all s e c o n d ar y i m a gi n g 
effi c a c y e n d p oi nt s will b e e v al u at e d i n t h e I T T p o p ul ati o n of e v al u a bl e s u bj e ct s. A n a d diti o n al 
a n al y si s will al s o b e p erf or m e d i n t h e P T p o p ul ati o n.   
A n  a d diti o n al  a n al y si s  of  s e c o n d ar y  i m a gi n g  effi c a c y  e n d p oi nt s wit h  a dj u st m e nt  f or  pr e -
e xi sti n g c er e br al l e si o n v ol u m e wil l al s o b e p erf or m e d i n t h e pri m ar y eI T T a n al y si s p o p ul ati o n. 
T h e s e  e n d p oi nt s  i n cl u d e  pr e s e n c e  of  c er e br al  i s c h e mi c  l e si o n s  ( §), n u m b er  of  c er e br al 
i s c h e mi c  l e si o n s ( §), p er -p ati e nt  a v er a g e  si n gl e  c er e br al  i s c h e mi c  l e si o n  v ol u m e  ( §), 
si n gl e c er e br al i s c h e mi c l e si o n v ol u m e ( §), a n d tot a l v ol u m e of c er e br al i s c h e mi c l e si o n s 
( §), w hi c h  v ar y  b y  t h eir  di stri b uti o n  fr o m  bi n ar y  ( a s  i n  " pr e s e n c e  of  c er e br al  i s c h e mi c 
l e si o n s") t o P oi s s o n, or p o s si bl y n e g ati v e bi n o mi al i n ot h er s. T h e c h oi c e of a s p e cifi c m o d el 
u s e d f or a dj u st m e nt will t h er ef or e d e p e n d o n t h e a ct u al di stri b uti o n of t h e d e p e n d e nt v ari a bl e 
(l o gi sti c, l o g-li n e ar, P oi s s o n, n e g ati v e bi n o mi al or q u a ntil e). T h e m o d el s will i n cl u d e t h e st u d y 
gr o u p a n d pr e -e xi sti n g c er e br al l e si o n v ol u m e a s i n d e p e n d e nt v ari a bl e s. 

R E F L E C T – U S I D E Tri al [ CI P -0 9 ( v 1 3. 0)]   
 
    
  
  
 
K e y st o n e H e art Lt d.  
9 5  
 
•  N e ur ol o gi c Effi c a c y E n d p oi nt s  
All s e c o n d ar y n e ur ol o gi c effi c a c y e n d p oi nt s will b e r e p ort e d b y tr e at m e nt gr o u p i n t h e eI T T 
P o p ul ati o n of e v al u a bl e s u bj e ct s ( R oll -I n s u bj e ct s ar e e x cl u d e d) u si n g d e s cri pti v e st ati sti c s. 
N o f or m al h y p ot h e si s t e sti n g will b e p erf or m e d, a n d t h er e i s n o pl a n t o a dj u st al p h a t o a c c o u nt 
f or m ulti pl e t e sti n g of e x pl or at or y s e c o n d ar y e n d p oi nt s. St ati sti c s f or c o nti n u o u s v ari a bl e s will 
i n cl u d e m e a n, m e di a n, q u artil e s, st a n d ar d d e vi ati o n, mi ni m u m, m a xi m u m, a n d s a m pl e si z e 
f or  e a c h  tr e at m e nt  gr o u p.  Bi n ar y  v ari a bl e s  will  b e  s u m m ari z e d  u si n g  fr e q u e n ci e s, 
p er c e nt a g e s, a n d s a m pl e si z e f or e a c h tr e at m e nt gr o u p . 
T h e a n al y si s of t h e eI T T p o p ul ati o n will b e c o n si d er e d pri m ar y. A s a s e c o n d ar y a n al y si s, all 
s e c o n d ar y n e ur ol o gi c a n d c o g niti v e effi c a c y e n d p oi nt s will b e e v al u at e d i n t h e I T T p o p ul ati o n 
of e v al u a bl e s u bj e ct s. A n a d diti o n al a n al y si s will al s o b e p erf or m e d i n t h e P T p o p ul ati o n.  
A n  a d diti o n al  a n al y si s  of  s e c o n d ar y  n e ur ol o gi c  a n d  c o g niti v e  effi c a c y  e n d p oi nt s wit h 
a dj u st m e nt f or pr e -e xi s ti n g c er e br al l e si o n v ol u m e will al s o b e p erf or m e d i n t h e pri m ar y eI T T 
a n al y si s  p o p ul ati o n.  A s  i n  s e c o n d ar y  i m a gi n g  effi c a c y  e n d p oi nt s,  t h e  di stri b uti o n  of  t h e 
n e ur ol o gi c e n d p oi nt s (i n cl u di n g NI H S S w or s e ni n g  [ §], a n d n e w n e ur ol o gi c i m p air m e nt  [ §]) 
v ari e s. T h e m o d el s, t h er ef or e, will b e c h o s e n b a s e d o n t h e a ct u al di stri b uti o n of d e p e n d e nt 
v ari a bl e (l o gi sti c, l o g-li n e ar, p oi s s o n, n e g ati v e bi n o mi al or q u a ntil e), wit h st u d y gr o u p v ari a bl e 
a n d c er e br al l e si o n v ol u m e a s i n d e p e n d e nt v ari a bl e.  
1 2. 4. 5. 1. 3  S e c o n d ar y P erf or m a n c e E n d p oi nt s  
All  s e c o n d ar y  p erf or m a n c e  e n d p oi nt s  will  b e  r e p ort e d  b y  tr e at m e nt  gr o u p  i n  t h e  I T T 
p o p ul ati o n  of  e v al u a bl e  s u bj e ct s  ( RI  s u bj e ct s  ar e  e x cl u d e d)  u si n g  a p pr o pri at e  d e s c ri pti v e 
st ati sti c s  ( s a m pl e  si z e,  m e a n,  st a n d ar d  d e vi ati o n,  m e di a n,  mi ni m u m,  m a xi m u m  f or 
c o nti n u o u s  c h ar a ct eri sti c s;  c o u nt s  a n d  p er c e nt a g e s  of  p ati e nt s  f or  di c h ot o m o u s 
c h ar a ct eri sti c s). N o f or m al h y p ot h e si s t e sti n g will b e p erf or m e d, a n d t h er e i s n o pl a n t o  a dj u st 
al p h a t o a c c o u nt f or m ulti pl e t e sti n g of e x pl or at or y s e c o n d ar y e n d p oi nt s . 
T h e I T T a n al y si s will b e c o n si d er e d pri m ar y. A s a s e c o n d ar y a n al y si s, all s e c o n d ar y s af et y 
a n d p erf or m a n c e e n d p oi nt s will b e e v al u at e d i n t h e A T p o p ul ati o n of e v al u a bl e s u bj e ct s.  
1 2. 4. 6  Ot h er M e a s ur e s  
Ot h er  M e a s ur e s  will  b e  r e p ort e d  b y  tr e at m e nt  gr o u p  i n  t h e  I T T  p o p ul ati o n  of  e v al u a bl e 
s u bj e ct s ( RI  s u bj e ct s ar e e x cl u d e d) u si n g d e s cri pti v e st ati sti c s. N o f or m al h y p ot h e si s t e sti n g 
will b e p erf or m e d.  
T h e I T T a n al y si s will b e c o n si d er e d  pri m ar y. A s a s e c o n d ar y a n al y si s, Ot h er M e a s ur e s will 
b e e v al u at e d i n t h e A T  p o p ul ati o n of e v al u a bl e s u bj e ct s. A n a d diti o n al a n al y si s will al s o b e 
p erf or m e d i n t h e P T p o p ul ati o n.  
1 2. 4. 7  S u b gr o u p A n al y s e s  
S u b gr o u p  a n al y s e s  will  b e  p erf or m e d  f or  all  pri m ar y  a n d  s e c o n d ar y  e n d p oi nt s  i n  t h eir 
r e s p e cti v e  pri m ar y  a n al y si s  p o p ul ati o n s  f or  t h e  f oll o wi n g  s u b gr o u p s,  a n d  r e s ult s  will  b e 
r e p ort e d b y tr e at m e nt gr o u p u si n g d e s cri pti v e st ati sti c s: 
•  S u bj e ct s wit h p ar o x y s m al or p er si st e nt atri al fi brill ati o n ( A F) at b a s eli n e  
•  S u bj e c t s b y v al v e pr o st h e si s t y p e ( E d w ar d s v s. M e dtr o ni c)  
1 2. 4. 8  R oll -I n P o p ul ati o n A n al y si s 
T h e P h a s e II R oll -I n p o p ul ati o n will b e p o ol e d wit h t h e P h a s e II i nt er v e nti o n gr o u p f or t h e 
pri m ar y a n al y si s of t h e pri m ar y s af et y e n d p oi nt.  T h e R oll -I n p ati e nt p o p ul ati o n will al s o b e 

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used for a separate analysis of all primary and secondary endpoints and other measures. 
Additional analyses will evaluate primary and secondary endpoints in the pooled population 
of Roll-In Subjects plus Evaluable Subjects. The results of all analyses will be reported using 
descriptive statistics. 
12.4.9 Additional Analyses 
The following data will be summarized using descriptive statistics presented by treatment 
group:  
• Subject enrollment and data compliance by site and visit (data compliance at each 
visit is percent of patients whose data forms have been collected and entered divided 
by the percent of patients whose forms should have been collected and entered) (ITT, 
eITT, PT, and AT populations) 
• Frequency (number and percent of patients) with each type of concomitant medication 
(AT population) 
• Frequency (number and percent of patients) with each site-reported Treatment 
Emergent AE overall and by MedDRA system organ class and preferred term (a 
treatment emergent AE is an AE that started or worsened during or after the index 
procedure) (AT population) 
• Frequency (number and percent of patients) with each site-reported Treatment 
Emergent Serious AE overall and by MedDRA system organ class and preferred term 
(AT population) 
• Frequency (number and percent of patients) with each site-reported Treatment 
Emergent AE or SAE, by CEC-adjudicated relationship to the investigational device or 
procedure (AT population) 
• Protocol deviations (number and percentage of patients with each deviation type) (ITT 
population) 
• Kaplan-Meier plots for MACCE and TAVI early safety through 30 days (AT Population; 
patients without an event will be censored at 30 days or day of withdrawal, whichever 
is earlier) 
• Detailed listings on primary and secondary endpoints, site-reported AE as well as 
protocol deviations 
13.0 Publication Policy 
The Sponsor and the Principal Investigators are committed to the publication and widespread 
dissemination of the results of the study in the scientific community.  This study represents a 
joint effort between the Sponsor and the Principal Investigators; as such, the parties agree 
that the recommendation of any party concerning manuscript or text shall be taken into 
consideration in the preparation of final scientific documents for publication or presentation.  
All parties agree that the Investigators will prepare publications and/or presentations. The 
number of authors will be determined according to the rules of the addressed scientific journal 
and by decision of the investigators. Abstracts and articles shall be submitted to the Sponsor 
in advance of their publication. An agreement on the final form of abstracts and articles shall 
be obtained within an appropriate time frame of 60 days. In the event that diverging opinions 
on presentation of the data cannot be reconciled, the executive operation committee 

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consisting of one representative of the trial management team, the Sponsor and the Principal 
Investigators (or designated substitutes) will make a final decision.  
Any and all information supplied or obtained during this study by or on behalf of any party 
involved in the study (in whatever form) shall be treated as confidential, shall not be disclosed 
to any third party unless with the prior written consent of the Sponsor in each case. Any 
documents, papers, drawings or other materials which are released or created by any party 
involved in this study are and shall remain at all times the property of the Sponsor excluding 
publications which are approved in writing by the Sponsor. Such materials shall not be 
reproduced in any form without the prior written consent of the Sponsor and must be returned 
to the Sponsor immediately upon request, or upon completion of the evaluation of such 
materials, whichever is the earlier. 
All clinical data or any other information gathered during or after this Study related to the 
Study, people involved, or materials involved will be considered confidential. Confidential 
information will remain confidential for a period of 36 months following the study completion. 
14.0 Data Collection and Monitoring 
14.1 Data Collection and Monitoring 
All required data for this study will be collected on standardized Case Report Forms (CRFs) 
using an electronic data capture system (EDC). The investigator (or designated hospital staff) 
will assure primary data collection based on source-documented hospital chart reviews. 
Independent monitoring will be performed to ensure that the investigator and his/her study 
team conduct the clinical investigation in accordance with contract specifications, this 
protocol, the Declaration of Helsinki, ICH-GCP, ISO 14155, 21 CFR Part 812, and other 
applicable FDA and local regulations, and to ensure adequate protection of the rights and 
safety of subjects and the quality and integrity of the resulting data. Submitted trial data will 
be verified against patient charts and other sources containing original records of patient 
data. Source document verification will occur in accordance with the pre-specified Monitoring 
Plan.  
Progress of the trial will be monitored by: 
• On-site review, as deemed appropriate by the sponsor 
• Telephone communications between site personnel (e.g., Site Investigator, Trial 
Coordinator) and trial monitors 
• Review of CRFs and associated clinical records 
• Review of regulatory documents 
Responsible entities for monitoring in the US and EU respectively are listed in §3.0.   
If a monitor becomes aware that an Investigator is not complying with the requirements 
mentioned above, the sponsor will be notified by the monitor. The sponsor will evaluate the 
non-compliance and if necessary, immediately either secure compliance or discontinue 
shipments of the investigational device to the Investigator and terminate the Investigator’s 
participation in continued enrolment in the investigation. The Investigator will be required to 
return all unused devices to the sponsor.  

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14.2 Source Documentation and Verification 
Auditors, monitors, IRBs/ECs, the study sponsor, and the FDA and other regulatory 
authorities will have access to the medical records related to this study. Original or certified 
copies of all relevant clinical findings, observations, and other activities throughout the clinical 
investigation must be recorded and maintained in the medical file of each enrolled patient (no 
source documentation will be recorded directly on the CRF). At a minimum, the following 
must be included in each patient’s file: 
• Sufficient medical history and current physical condition, including any medication(s) 
the patient is taking at the time of the procedure to assess the patient’s eligibility; 
• The medical file should reveal the patient’s participation in this study, including 
documentation of written informed consent; 
• Dated report of the investigational procedure including medication, material usage, 
and complications, if applicable; 
• Dated reports of the discharge and follow-up assessments; 
• Dated results of required laboratory tests; 
• Any adverse event(s), the resultant action or treatment, and outcome, if applicable; 
and 
• In the case of withdrawal of patient consent, the reason and patient status at time of 
withdrawal. 
The investigator will permit study-related monitoring, audits, IRB/EC review, and FDA and 
other applicable regulatory authority inspections by allowing direct access to the source data. 
In case of electronic source data, periodic access will be allowed for full safety review. The 
review will be specific to study subjects and the records that would contain potential safety 
data. Dated print-outs are acceptable for preliminary review of safety information. Print-outs 
will not be limited to cardiac data only, but should include all available data related to the 
identified patient(s). 
14.3 Record Retention 
Sponsor and investigator will maintain records related to this study for 7 years (or longer 
according to local requirements) after the end of this study. 
15.0 Ethical and Regulatory Considerations 
15.1 Applicable Regulations 
This trial will be conducted in compliance with the protocol, the sponsor’s standard operating 
procedures and/or guidelines, FDA regulations, local regulations where applicable, ICH GCP 
guidelines, the Declaration of Helsinki, Annex X of the European Medical Devices Directive, 
and EN/ISO 14155:2011. 
15.2 Institutional Review Board / Medical Ethics Committee 
This trial will be conducted in accordance with 21 CFR 56 Institutional Review Boards. The 
investigator will assure that an appropriately constituted Institutional Review Board (IRB) or 
Ethics Committee (EC) complies with the requirements of the International Conference on 
Harmonization Guideline. Prior to initiation of the study, the investigator will forward copies 

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of the protocol, Investigators Brochure, informed consent form and all other appendices to be 
used for the study to the IRB/EC for its review and approval. A copy of the written IRB/EC 
approval must be provided to the Sponsor (or designee) and should include the following: 
• A statement of IRB/EC approval for the proposed study at the institution; 
• The date the study was approved and the duration of approval (if applicable); 
• Identification of the approved documents including version dates and/or other 
references. At a minimum, the following documents should be listed: 
o Study protocol  
o Patient information and consent form 
o Any additional written information to be provided to the patient 
• A listing of any conditions attached to the approval (if applicable); 
• Identification of the approved primary investigator; 
• The signature of the IRB/EC chairperson; 
• Acknowledgement of the sub-Investigators. 
Any amendments to the protocol, as well as possible associated information and consent 
form changes, will be submitted to the IRB/EC and written approval obtained prior to 
implementation. Substantive changes will be submitted to the FDA for approval prior to 
implementation, and the FDA will be notified of any changes not requiring approval according 
to applicable guidelines. 
15.3 Regulatory Approval 
The Sponsor is responsible for notifying the study to the FDA and any other relevant 
authorities (as applicable) according to regulatory requirements. Investigators may not 
commence enrollment of subjects until they have met any local IRB/EC and hospital 
management requirements and have received confirmation from the Sponsor that the 
appropriate regulatory approvals have been obtained. 
15.4 Trial Registration 
This trial meets the definition of an “applicable clinical trial” according to Section 801 of the 
Food and Drug Administration Amendments Act. The Sponsor affirms that it will serve as the 
Responsible Party and fulfill all requirements regarding trial registration, the provision of 
clinical trial information, and results reporting through the ClinicalTrials.gov registry data 
bank.  
Clinical trial information will be submitted no more than 21 days after the first subject is 
enrolled in the trial, and results information will be submitted no later than 1 year after 
completion of the trial or no later than 30 days after the device is approved, licensed, or 
cleared by the FDA.  
15.5 Records and Reports 
15.5.1 Responsibilities of the Sponsor 
The Sponsor must maintain the following records: 
• All essential correspondence related to the clinical trial 
• Signed Investigator Agreement 

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• Curriculum vitae for each Investigator 
• Records of device shipment and disposition (shipping receipts, material destruct 
records, etc.) 
• Adverse event information 
• Complaint documentation 
• All data forms prepared and signed by the Investigators and received source 
documentation and core lab reports 
• Clinical Investigation Plan (CIP) and any amendments 
• Investigators Brochure / Report of Prior Investigations  
• Site monitoring reports 
• Financial disclosure information 
The Sponsor is responsible for the preparation of, the accuracy of the data contained in, and 
the review and submission of the reports listed in Table 12.  
Table 12. Sponsor Reporting Responsibilities 
Report 
Submit To 
Description 
(confirmed) UADE 
IRB/EC, Investigators, 
FDA, Other 
Regulatory (as 
applicable) 
Sponsor will report on any confirmed UADE 
within 10 working days of notice receipt [21 
CFR 812.150] 
Withdrawal of IRB/EC approval 
IRB/EC, Investigators, 
FDA, Other 
Regulatory (as 
applicable) 
Notification, when appropriate, will be made 
with 5 working days of notice receipt. 
Withdrawal of FDA/other 
regulatory approval 
IRB/EC, Investigators 
Notification, when appropriate, will be made 
with 5 working days of notice receipt. 
Current investigator list 
FDA 
Sponsor will submit a list of the names and 
addresses of all investigators at 6 month 
intervals, beginning 6 months after FDA IDE 
approval. 
Progress report 
IRB/EC, Investigators, 
FDA 
Annual 
Recall and device disposition 
IRB/EC, Investigators, 
FDA 
Notification and explanation will be made 
within 30 days of the Sponsor’s request that 
an Investigator return, repair, or otherwise 
dispose of any devices. 
Final Report 
IRB/EC, Investigators, 
FDA, Notified Bodies 
and Other Regulatory 
(as applicable) 
Notification will be made within 30 working 
days of trial completion or termination. A final 
report will be submitted within 6 months of trial 
completion or termination. 
Failure to obtain Informed 
Consent 
FDA 
Notification will be made within 5 working days 
after Sponsor’s receipt of notification that 
Informed Consent was not obtained. 
Emergency deviation from Clinical 
Investigation Plan (CIP) 
FDA 
Notification will be made within 5 working days 
after Sponsor’s receipt of notification that an 
emergency deviation from the CIP was made 
to protect the life or physical well-being of a 
subject. 

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15.5.2 Responsibilities of the Investigator 
Each Site Investigator is responsible for the preparation, review, signature, and retention of 
the records below: 
• All essential correspondence related to the clinical trial 
• Device use/disposition records 
• Records of each subject’s case history and exposure to the device. Case histories 
include the CRFs and supporting data (source documentation). 
• Signed Investigator Agreement 
• Curriculum vitae  
• Clinical Investigation Plan (CIP) and any amendments 
The investigator is responsible for the preparation, review, signature, and submission of the 
reports listed in Table 13. These are also subject to inspection by regulatory authorities and 
must be retained as specified in the CIP. The investigator may delegate responsibility for 
record maintenance to a member of his/her study team, but remains the ultimate responsible 
person. 
Table 13. Investigator Reporting Responsibilities 
Report 
Submit To 
Description 
(potential) UADE 
Sponsor, IRB/EC 
Submit immediately via EDC CRF and via 
telephone. UADE must be submitted as soon 
as possible, but no later than 5 working days 
after first learning of the event. 
SAE 
Sponsor 
Submit within 3 working days of first learning 
of the event (via EDC CRF). 
SADE 
Sponsor 
Within 48 hours (if required by local or national 
regulations; otherwise, report as SAE) 
Withdrawal of IRB/EC approval 
Sponsor 
Submit within 5 working days. 
Failure to obtain Informed 
Consent 
Sponsor, IRB/EC 
Submit within 5 working days of subject 
exposure to device. 
Emergency deviation from CIP 
Sponsor, IRB/EC 
Submit within 5 working days. 
Planned deviation from CIP 
Sponsor, IRB/EC, 
FDA 
If the deviation affects the scientific soundness 
of the trial or the rights, safety, or welfare or 
the subject, and is not an emergency, prior 
approval must be obtained from the Sponsor, 
the IRB/EC, and the FDA. 
Other deviation from CIP 
Sponsor 
Uncontrollable deviations (e.g., loss to follow-
up) or deviations that do not affect the 
scientific soundness of the trial or the rights, 
safety, or welfare of the subject, and that are 
not an emergency, should be submitted as 
identified by the site or the Sponsor (or 
designee). 
15.6 Protocol Amendments 
Any protocol amendments will be approved by the Sponsor, the Principal Investigator, the 
IRB/EC and any necessary regulatory body before it can be implemented. Substantive 
changes will be submitted to the FDA for approval prior to implementation, and the FDA will 
be notified of any changes not requiring approval according to applicable guidelines. 

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15.7 Informed Consent 
The background of the proposed study and the benefits and risks of the procedures and study 
must be explained to the patient in accordance with 21 CFR Part 50. The patient must sign 
the consent form prior to enrollment. This form or a modification based on local IRB/EC 
recommendations must be presented to and signed by all enrolled patients and signed by the 
principal investigator, sub-investigator or designated research staff in accordance with 
approving IRB/EC guidelines. 
Prior to obtaining informed consent, information should be given in a language and at a level 
of complexity understandable to the subject in both oral and written form by the investigator 
or assigned designee. Patients should not be coerced, persuaded, or unduly influenced to 
participate or remain in the trial. A subject or his/her legal representative must be given ample 
time and opportunity to inquire about details of the trial and all questions about the trial should 
be answered to the satisfaction of the subject or the representative. 
Prior to participation in the trial, the written informed consent form should be signed and 
personally dated by the subject or his/her legal representative, and by the person who 
conducted the informed consent discussion (investigator or designee). If the subject or his/her 
legal representative is unable to read the consent form, a witness should be present during 
the entire informed consent discussion. After the informed consent form is read to the subject 
and signed by the subject or his/her legal representative, the witness should also sign the 
consent form, attesting that informed consent was freely given by the subject or his/her legal 
representative. For non-English speaking subjects, the written informed consent should be 
translated into the subject’s native language, or a short form (including the elements of 
informed consent translated into the subject’s native language) should be used. The informed 
consent process should be documented in each subject’s medical record.   
The subject or his/her legal representative must receive a copy of the signed and dated 
informed consent form. 
The Investigator shall inform the subject of any new significant findings occurring during the 
clinical investigation, including the need for additional medical care that may be required, that 
may be relevant to the subject and his/her willingness to continue participation in the study. 
The consent form should be updated or amended whenever such new information becomes 
available and updated consent shall be recorded. 
15.8 Termination of the Study 
Keystone Heart Ltd. reserves the right to terminate the study but intends only to exercise this 
right for valid scientific or administrative reasons and reasons related to protection of patients. 
Possible reasons for early trial termination include: 
• Unanticipated Adverse Device Effects (UADEs) present an unreasonable risk to 
patients 
• Recommendation from the DSMB 
If the trial is terminated early, the Sponsor will provide a written statement to the Investigators 
to enable notification of the IRBs/ECs. The Sponsor will also inform the FDA and the relevant 
Competent Authority (where required). In the case of early termination of trial enrollment, 
follow-up visits will continue for all enrolled subjects. 
The Sponsor may terminate an investigator’s or site’s participation in the study if there is 
evidence of an investigator’s failure to maintain adequate clinical standards or evidence of 
an investigator or staff’s failure to comply with the protocol. Should investigator or site 

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participation be considered for termination, the Sponsor (or designee) will ensure appropriate 
follow-up for any subjects enrolled, including transferal to the supervision of an approved 
investigator and approval of transfer of subject oversight and follow-up by the appropriate 
IRB/EC. Notification of study site suspension or termination will occur no later than five (5) 
working days after the Sponsor makes the determination. A suspended or terminated study 
site may not be reinitiated without approval of the reviewing IRB/EC. The investigator should 
notify the IRB/EC in writing as soon as possible but no later than within 10 days if the 
premature termination is related to safety or compliance issues. The same procedure will be 
applied to the Competent Authority where required. 
15.9 Auditing 
As a quality assurance measure, the site may be audited during the course of the ongoing 
clinical trial as well as following completion of the trial. The purpose of an audit is to provide 
an independent evaluation separate from routine monitoring or quality control functions of 
trial conduct and protocol and GCP compliance. The audit may be conducted by Keystone 
Heart Ltd personnel (or designee), the FDA, or another regulatory body. Please notify the 
Sponsor if the FDA or another regulatory body requests an audit. The site investigator and/or 
institution shall permit Keystone Heart Ltd. and regulatory bodies direct access to source data 
and documents.  
15.10 Patient Privacy 
Keystone Heart Ltd affirms and upholds the principle of patient confidentiality. Throughout 
this study, all data forwarded to Keystone Heart Ltd. or its designee will only be identified by 
a study-specific subject identification number. “Protected Health Information” will be 
maintained in compliance with the Health Insurance Portability and Accountability Act of 1996 
(HIPAA), and all personal data of EU individuals will be protected in compliance with the EU-
US Privacy Shield Principles (12.7.2016). 
The investigator agrees that representatives of Keystone Heart Ltd., the contract research 
organizations and regulatory authorities may inspect included patients’ records to verify trial 
data, provide the data are treated as confidential and that the subject’s privacy is guaranteed.  
 
 

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16.0 Appendices 
16.1 Appendix I: Definitions 
Acute cardiovascular 
surgery 
An immediate transfer from the catheterization lab to the 
operative room during the initial treatment phase due to the 
need for emergency coronary artery bypass graft surgery, 
cardiac 
valve 
surgery, 
or 
other 
vascular 
surgical 
intervention.   
Access related 
Any adverse clinical consequence possibly associated with 
any of the access sites used during the procedure. 
Access site 
Any location (arterial or venous) traversed by a guide-wire, 
a catheter or a sheath, including the left ventricular (LV) 
apex and the aorta. 
Acute Kidney Injury 
(AKI), 
[AKIN classification] 
Change in serum creatinine (up to 7 days) compared with 
baseline:35 
•
Stage 1:
o
Increase in serum creatinine to 150–199%
(1.5–1.99 × increase compared with
baseline) OR increase of ≥0.3 mg/dL (≥26.4
mmol/L) OR
o
Urine output <0.5 ml/kg per hour for >6 but
<12 hours
•
Stage 2:
o
Increase in serum creatinine to 200–299%
(2.0–2.99 × increase compared with
baseline) OR
o
Urine output <0.5 ml/kg per hour for >12 but
<24 hours
•
Stage 3:
o
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
o
Urine output <0.3 ml/kg per hour for ≥24
hours OR
o
Anuria for >12 hours
o
[Patients receiving renal replacement therapy
are considered to meet Stage 3 criteria
irrespective of other criteria]
Adverse Event (AE) 
An adverse event is any untoward medical occurrence, 
unintended disease or injury or any untoward clinical signs 

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(including an abnormal laboratory finding) in subjects, users 
or other persons whether or not related to the investigational 
medical device.   
NOTE: This definition includes events related to the 
investigational medical device or to the procedures involved 
but does not imply that there is a relationship between the 
adverse event and the device under investigation.  
Pre-Existing Conditions: 
Pre-existing medical conditions or a repeat of symptoms 
reported prior to the TAVR procedure will not be recorded 
as an AE. Pre-existing conditions that worsen during a study 
are to be considered adverse events. For users or other 
persons this classification is restricted to events related to 
the investigational medical device. 
Adverse Device Effect 
(ADE) 
An adverse device effect is an adverse event related to the 
use of a medical device. This includes: 
• Any adverse event resulting from insufficiencies or 
inadequacies in the instructions for use, the 
deployment, the implantation, the installation, the 
operation, or any malfunction of the medical device 
• Any event that is a result of a use error or intentional 
misuse 
Anticipated Serious 
Adverse Device Effect 
(ASADE) 
An anticipated serious adverse device effect is a serious 
adverse device effect which by its nature, incidence, 
severity, 
or 
outcome 
has 
been 
identified 
in 
the 
investigational 
plan 
or 
application 
(including 
a 
supplementary plan or application).  
As Treated (AT) 
Population 
The AT population is defined by the treatment actually 
received, regardless of the assigned treatment. In the AT 
population, all subjects in whom vascular access in the 
contralateral femoral artery has been established for the 
intended deployment of the TriGuard HDH or TriGUARD 3 
device will be assigned to the intervention group, and 
subjects in whom the TAVI procedure is initiated (but no 
vascular access for intended deployment of the TriGuard 
HDH or TriGUARD 3 is established) will be assigned to the 
control group. 
Bleeding  
Life-threatening or disabling bleeding:35   
• Fatal bleeding (BARC type 5) OR 
• Bleeding in a critical organ, such as intracranial, 
intraspinal, intraocular, or pericardial necessitating 
pericardiocentesis, or intramuscular with 
compartment syndrome (BARC type 3b and 3c) OR 

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• Bleeding causing hypovolemic shock or severe 
hypotension requiring vasopressors or surgery 
(BARC type 3b) OR 
• Overt source of bleeding with drop in hemoglobin of 
≥5 g/dL or whole blood or packed red blood cells 
(RBCs) transfusion ≥4 units [Given that one unit of 
packed RBC typically will raise hemoglobin 
concentration by 1 g/dL, an estimated decrease in 
hemoglobin will be calculated] (BARC type 3b) 
Major bleeding (BARC type 3a): 
• Overt bleeding either associated with a drop in the 
hemoglobin level of at least 3.0 g/dL or requiring 
transfusion of 2 or 3 units of whole blood/RBC, or 
causing hospitalization or permanent injury, or 
requiring surgery AND 
• 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 
Cardiac tamponade 
Evidence of a new pericardial effusion associated with 
hemodynamic instability and clearly related to the TAVI 
procedure35 
CCS (Canadian 
Cardiovascular Society) 
classification 
Class I:  Ordinary physical activity, such as walking and 
climbing stairs, does not cause angina. Angina with 
strenuous, rapid, or prolonged exertion at work or 
recreation. 
Class II: Slight limitation of ordinary activity. Walking or 
climbing stairs rapidly, walking up hill, walking or 
stair climbing after meals, in cold, in wind, or when 
under emotional stress or during the first few hours 
after awakening may cause pain. Walking more 
than two blocks on the level and climbing more 
than one flight of stairs at a normal pace and in 
normal conditions. 
Class III: Marked limitation of ordinary physical activity. 
Walking one-two blocks on a level and climbing 
one flight of stairs at normal pace results in angina. 
Class IV: Inability to carry on any physical activity without 
discomfort. Anginal syndrome may be present at 
rest. 

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Child-Pugh score 
A scoring system used to assess the prognosis of chronic 
liver disease.107 Scoring and interpretation as below: 
Scoring 
Measure 
1 point 
2 points 
3 points 
Total bilirubin, μmol/l (mg/dl) 
<34 (<2) 
34-50 (2-3) 
>50 (>3) 
Serum albumin, g/dl 
>3.5 
2.8-3.5 
<2.8 
PT INR 
<1.7 
1.71-2.30 
> 2.30 
Ascites 
None 
Mild 
Moderate to Severe 
Hepatic encephalopathy 
None 
Grade I-II (or suppressed 
with medication) 
Grade III-IV (or 
refractory) 
Interpretation 
Points 
Class 
One year survival 
Two year survival 
5-6 
A 
100% 
85% 
7-9 
B 
81% 
57% 
10-15 
C 
45% 
35% 
 
Clinical Frailty Scale 
A measure of frailty based on clinical judgement, scored 
according to the following categories108: 
1. Very Fit – People who are robust, active, energetic, and 
motivated. These people commonly exercise regularly. 
They are among the fittest for their age.  
2. Well – People who have no active disease symptoms but 
are less fit than Category 1. Often, they exercise or are very 
active occasionally, e.g., seasonally. 
3. Managing Well – People whose medical problems are 
well controlled, but are not regulatory active beyond routine 
walking. 
4. Vulnerable – While not dependent on others for daily 
help, often symptoms limit activities. A common complaint is 
being “slowed up,” and/or being tired during the day.  
5. Mildly Frail – These people often have more evident 
slowing, and need help in high order independent activities 
of daily living (finances, transportation, heavy housework, 
medications). Typically, mild frailty progressively impairs 
shopping and walking outside alone, meal preparation, and 
housework.  
6. Moderately Frail – People need help with all outside 
activities and with keeping house. Inside, they often have 
problems with stairs and need help with bathing, and might 
need minimal assistance (cuing, standby) with dressing.  
7. Severely Frail – Completely dependent for personal care, 
from whatever cause (physical or cognitive). Even so, they 
seem stable and not at high risk of dying (within ~6 months).  
8. 
Very 
Severely 
Frail 
– 
Completely 
dependent, 
approaching the end of life. Typically, they could not recover 
even from a minor illness.  

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9. Terminally Ill – Approaching the end of life. The category 
applies to people with a life expectancy < 6 months, who are 
not otherwise evidently frail. 
Based on the above categories, subjects also will be 
classified as Not Frail (Category 1-3), Mildly Frail (Category 
4-5), and Moderately-to-Severely Frail (Category 6-9). 
CNS hemorrhage 
NeuroARC defined3 as any brain, spinal cord, or retinal 
hemorrhage on the basis of imaging or pathology, not 
caused by trauma (includes symptomatic intracerebral 
hemorrhage 
[Type 
1.b], 
symptomatic 
subarachnoid 
hemorrhage [Type 1.c], and covert CNS hemorrhage [Type 
2.b]) 
CNS infarction 
NeuroARC defined3 as any brain, spinal cord, or retinal 
infarction on the basis of imaging, pathology, or clinical 
symptoms persisting for ≥24 h (includes ischemic stroke 
[Type 1.a], ischemic stroke with hemorrhagic conversion 
[Type 1.a.H], stroke not otherwise specified [Type 1.d], 
symptomatic hypoxic-ischemic injury [Type 1.e], covert CNS 
infarction [Type 2.a], and covert CNS infarction with 
hemorrhagic conversion [Type 2.a.H]) 
Cockcroft-Gault formula 
A proxy for Glomerular Filtration Rate in which creatinine 
clearance is estimated from age, weight, and serum 
creatinine by the formula: 
 
in which weight is recorded in kg and creatinine in mg/dL, 
and which is valid for male patients. If the patient is female, 
the result should be multiplied by 0.85. 
Combined safety 
endpoint 
Equivalent to the VARC-2 definition of “early safety (at 30 
days)”,1 defined as the composite of: 
• All-cause mortality 
• All stroke (disabling and non-disabling) 
• Life-threatening bleeding 
• Acute kidney injury – Stage 2 or 3 (including renal 
replacement therapy) 
• Coronary artery obstruction requiring intervention 
• Major vascular complication 
• Valve-related dysfunction requiring repeat procedure 
(BAV, TAVI, or SAVR) 
Covert CNS injury 
Acutely asymptomatic brain or spinal cord injury detected 
by neuroimaging (NeuroARC Type 2), including3: 
Type 2.a Covert CNS infarction 

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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 or hematoma originating from within 
the infarcted area with 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 
Device deployment time 
Time elapsed between insertion of the TriGuard HDH or 
TriGUARD 3 device into the groin access point and 
successful device deployment 
Device deficiency 
Inadequacy of a medical device related to its identity, 
quality, durability, reliability, safety or performance.  
NOTE: Device deficiencies include malfunction, use error, 
and inadequate labeling. They may or may not affect device 
performance or lead to an adverse event. 
Device interference 
Interaction of the TriGuard device with the TAVI system 
leading to: 
o Inability to advance or manipulate the TAVI delivery 
system or valve prosthesis, OR 
o Inability to deploy the TAVI valve prosthesis, OR 
o Inability to retrieve the valve prosthesis or delivery 
system  

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Device malfunction 
Failure of an investigational medical device to perform in 
accordance with its intended purpose when used in 
accordance with the Instructions for Use or protocol. 
NOTE: A device malfunction occurs when the device is used 
in compliance with the Instructions for Use, but does not 
perform as described in the Instructions for Use. 
Device misuse 
Any use of the investigational device by an investigator that 
is contradictory to the application described in the 
Instructions for Use will be categorized as device misuse. 
This is a form of Use Error. 
Device positioning 
Ability to position the TriGuard HDH or TriGUARD 3 device 
in the aortic arch to cover all major cerebral arteries, with 
proper positioning maintained (verified by fluoroscopy) until 
the following time points: 
o Final deployment of the first prosthetic valve 
o Final procedure (after any additional post-dilatation 
or 
additional 
valve 
implantations 
have 
been 
completed, and the TAVR delivery system has been 
removed) 
Extent of cerebral artery coverage will be reported as: 
o Complete (coverage of all 3 cerebral artery branches) 
o Partial (coverage of 1-2 cerebral artery branches) 
o None  
Note: Maintenance of device positioning to each time point 
and extent of cerebral coverage will be evaluated separately 
by the Angiographic Core Laboratory.  
Efficacy Intention to Treat 
(eITT) population 
The eITT analysis population is defined as:  
• Subjects who are enrolled in the trial and 
randomized to a treatment group, regardless of 
treatment actually received AND 
• Who do not have conversion to surgery or prolonged 
cardiac arrest (>3 minutes) prior to the post-
procedure DW-MRI 
Encephalopathy 
Altered mental state (e.g., seizures, delirium, confusion, 
hallucinations, dementia, coma, psychiatric episode, etc.) 
Evaluable 
Evaluable subjects are those who are enrolled in the 
randomized portion of the trial (i.e., not Roll-In subjects) 
General safety 
Defined as the composite of the following adverse events 
(each VARC-2 defined): 
• All-cause mortality 
• All stroke (disabling and non-disabling) 

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• Acute kidney injury – Stage 3 (including renal 
replacement therapy) 
Hepatic failure 
Child-Pugh Class C (see definition for classification scoring) 
In-hospital procedural 
safety 
The 
composite 
of 
the 
following 
Major 
Adverse 
Cardiovascular and Cerebrovascular events (MACCE): 
• All-cause mortality 
• All stroke (disabling and non-disabling) 
• Life threatening (or disabling) bleeding 
• Acute kidney injury – Stage 2 or 3 (including renal 
replacement therapy) 
• Major vascular complications 
Intention to treat (ITT) 
The principle of including outcomes of all subjects in the 
analysis who are randomized into the study, regardless of 
the treatment actually received. The ITT analysis population 
is defined as all subjects enrolled in the study, by assigned 
treatment, regardless of the treatment actually received. 
Intracranial hemorrhage 
Collection of blood between the brain and skull. 
Subcategorized as epidural, subdural, and subarachnoid 
bleeds. 
Modification of Diet in 
Renal Disease (MDRD) 
A proxy for Glomerular Filtration Rate in which creatinine 
clearance is estimated from age, serum creatinine, gender 
and race by the formula: 
 GFR (mL/min/1.73 m2) = 175 × (Scr)-1.154 × (Age)-0.203 
× (0.742 if female) × (1.212 if African American) 
Modified RANKIN Score 
(mRS) 
 
 
A commonly used scale for measuring stroke functional 
outcome.109 See §16.5 for the standardized interview.  The 
scale runs from 0 to 6.  The scores and descriptions are:  
0. No symptoms at all 
1. No significant disability despite symptoms; able to 
carry out all usual duties and activities 
2. Slight disability; unable to carry out all previous 
activities, but able to look after own affairs without 
assistance 
3. Moderate disability; requiring some help, but able to 
walk without assistance 
4. Moderately severe disability; unable to walk without 
assistance and unable to attend to own bodily needs 
without assistance 
5. Severe disability; bedridden, incontinent and 
requiring constant nursing care and attention 

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6. Dead 
Montreal Cognitive 
Assessment (MoCA) 
worsening 
A MoCA score decrease of 3 or more points from baseline 
to follow-up. 
Mortality 
All-cause mortality35 
Cardiovascular mortality 
Any of the following criteria: 
• Death due to proximate cardiac cause (e.g. 
myocardial infarction, cardiac tamponade, 
worsening heart failure) 
• Death caused by non-coronary vascular conditions 
such as neurological events, pulmonary  embolism, 
ruptured aortic aneurysm, dissecting aneurysm, or 
other vascular disease 
• All procedure-related deaths, including those related 
to a complication of the procedure or treatment for a 
complication of the procedure 
• All valve-related deaths including structural or 
nonstructural valve dysfunction or other valve-
related adverse events 
• Sudden or unwitnessed death 
• Death of unknown cause 
Non-cardiovascular mortality 
Any death in which the primary cause of death is clearly 
related to another condition (e.g. trauma, cancer, suicide) 
Myocardial infarction (MI) Peri-procedural MI (≤72 h after the index procedure):35  
• New ischemic symptoms (e.g. chest pain or 
shortness of breath), or new ischemic signs (e.g. 
ventricular arrhythmias, new or worsening heart 
failure, new ST-segment changes, hemodynamic 
instability, new pathological Q waves in at least two 
contiguous leads, imaging evidence of new loss of 
viable myocardium or new wall motion abnormality) 
AND 
• Elevated cardiac biomarkers (preferably CK-MB) 
within 72 h after the index procedure consisting of at 
least one sample post-procedure with a peak value 
exceeding 15x upper reference limit for troponin or 
5x for CK-MB. If cardiac biomarkers are increased 
at baseline (>99th percentile), a further increase of at 
least 50% post-procedure is required AND the peak 
value must exceed the previously stated limit.  

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Spontaneous MI (>72 h after the index procedure). Any one 
of the following criteria: 
• Detection of rise and/or fall of cardiac biomarkers 
(preferably troponin) with at least one value above 
the 99th percentile URL, together with evidence of 
myocardial ischemia with at least one of the 
following: 
o Symptoms of ischemia 
o ECG changes indicative of new ischemia 
[new ST-T changes or new left bundle branch 
block (LBBB)] 
o New pathological Q waves in at least two 
contiguous leads 
o Imaging evidence of new loss of viable 
myocardium or new wall motion abnormality 
• Sudden, unexpected cardiac death, involving 
cardiac arrest, often with symptoms suggestive of 
myocardial ischemia, and accompanied by 
presumably new ST elevation, or new LBBB, and/or 
evidence of fresh thrombus by coronary 
angiography and/or at autopsy, but death occurring 
before blood samples could be obtained, or at a 
time before the appearance of cardiac biomarkers in 
the blood. 
• Pathological findings of an acute myocardial 
infarction. 
National Institute of 
Health Stroke Scale 
(NIHSS) 
A commonly-used scale to assess stroke. See §16.6 
Neurologic dysfunction 
without CNS injury 
Acutely symptomatic (NeuroARC Type 3) without CNS 
injury, including:3 
Type 3.a TIA 
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 
Neurological events 
See “stroke (VARC-2 defined)”, “Overt CNS Injury”, “Covert 
CNS Injury”, “Neurological dysfunction without CNS injury”, 
“CNS infarction”, and “CNS hemorrhage”  

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New neurologic 
impairment 
NIHSS worsening at post-procedure (2-5 days post-
procedure) accompanied by the presence of cerebral 
ischemic lesions. 
NIHSS worsening 
An NIHSS score increase from baseline to follow-up. 
NYHA (New York Heart 
Association) functional 
capacity 
Classified as110:  
Class I. Patients with cardiac disease but without resulting 
limitation of physical activity. Ordinary physical activity does 
not cause undue fatigue, palpitation, dyspnea, or anginal 
pain. 
Class II. Patients 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. Patients with cardiac disease resulting in marked 
limitation of physical activity. They are comfortable at rest. 
Less than ordinary activity causes fatigue, palpitation, 
dyspnea, or anginal pain. 
Class IV. Patients with cardiac disease resulting in inability 
to carry on any physical activity without discomfort. 
Symptoms of heart failure or the anginal syndrome may be 
present even at rest. If any physical activity is undertaken, 
discomfort is increased. 
Overt CNS Injury 
Acutely symptomatic brain or spinal cord injury (NeuroARC 
Type 1), including3: 
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 
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 

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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. 
Subtype 1.a.H Ischemic stroke with hemorrhagic 
conversion 
Ischemic stroke includes hemorrhagic conversions. 
These should be subclassified as Class A or B when 
ischemic stroke is the primary mechanism and 
pathology or neuroimaging 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 or hematoma originating from within 
the infarcted area with space-occupying effect  
Type 1.b Symptomatic intracerebral hemorrhage 
Rapidly developing neurological signs or symptoms (focal 
or global) caused by an intraparenchymal, intraventricular, 
spinal cord, or retinal collection of blood, not caused by 
trauma 
Type 1.c Symptomatic subarachnoid hemorrhage 
Rapidly developing neurological signs or symptoms (focal 
or global) and/or headache caused by bleeding into the 
subarachnoid space, not caused by trauma 
Type 1.d Stroke, not otherwise specified 
An episode of acute focal neurological signs or symptoms 
and/or headache presumed to be caused by CNS ischemia 
or CNS hemorrhage, persisting ≥24 h or until death, but 
without sufficient evidence to be classified as either (i.e., 
no neuroimaging performed) 
Type 1.e Symptomatic hypoxic-ischemic injury 
Nonfocal (global) neurological signs or symptoms due to 
diffuse brain, spinal cord, or retinal cell death (confirmed by 
pathology or neuroimaging) in a nonvascular distribution, 
attributable to hypotension and/or hypoxia 
Per Treatment (PT) 
population 
The PT population is defined as subjects in the Intervention 
group in whom device positioning is maintained until final 

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procedure with complete cerebral coverage, and all Control 
group subjects. 
Procedure success 
Technical success in the absence of any investigational 
device-related or investigational procedure-related in-
hospital procedural safety events. 

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Prosthetic Valve 
Dysfunction 
Defined according to VARC criteria in the table below:35 
Prosthetic Valve Dysfunction 
Prosthetic aortic valve stenosis* 
 
Normal 
Mild Stenosis 
Moderate/Severe Stenosis 
Quantitative Parameters (Flow-dependent)† 
Peak velocity 
<3 m/s 
3-4 m/s 
>4 m/s 
Mean gradient 
<20 mmHg 
20-40 mmHg 
>40 mmHg 
Quantitative Parameters (Flow-independent)  
Doppler velocity index‡ 
>0.35 
0.35-0.25 
<0.25 
Effective orifice area¶ 
>1.1 cm2 
1.1-0.8 cm2 
<0.8 cm2 
Effective orifice area§ 
>0.9 cm2 
0.9-0.6 cm2 
<0.6 cm2 
Prosthesis-patient mismatch (PPM) 
 
Insignificant 
Moderate 
Severe 
Indexed effective orifice area** 
>0.85 cm2/m2 
0.85-0.65 cm2/m2 
<0.65 cm2/m2 
Indexed effective orifice area†† 
>0.70 cm2/m2 
0.90-0.60 cm2/m2 
<0.60 cm2/m2 
Prosthetic aortic valve regurgitation 
 
Mild 
Moderate 
Severe 
Semi-quantitative Parameters 
Diastolic flow reversal in the descending 
aorta—PW  
Absent or brief early 
diastolic 
Intermediate 
Prominent, holodiastolic 
Circumferential extent of prosthetic valve 
paravalvular regurgitation (%)¶¶ 
<10 
10-29 
≥30 
Quantitative Parameters‡ 
Regurgitant volume (ml/beat) 
<30 
30-59 
≥60 
Regurgitant fraction (%) 
<30 
30-49 
≥50 
EROA (cm2)  
0.10 
0.10-0.29 
≥0.30 
*In conditions of normal or near normal stroke volume (50–70 mL) 
†These parameters are more affected by flow, including concomitant aortic regurgitation 
‡For LVOT >2.5 cm, significant stenosis criteria is <0.20 
¶Use in setting of BSA ≥1.6 cm2 (note: dependent on the size of the valve and the size of the native annulus) 
§Use in setting of BSA <1.6 cm2 
**Use in setting of BMI <30 kg/cm2 
††Use in setting of BMI ≥30 kg/cm2 
¶¶Not well-validated and may overestimate severity compared to quantitative Doppler 
 
Serious Adverse Device 
Effect (SADE) 
A serious adverse device effect is an adverse device effect 
that has resulted in any of the consequences characteristic 
of a serious adverse event.  

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Serious Adverse Event 
(SAE) 
A serious adverse event is an adverse event that: 
1. Led to a death 
2. Led to a serious deterioration in the health of the 
subject that: 
a. Resulted in a life-threatening illness or injury 
b. Resulted in a permanent impairment of a body 
structure or a body function 
c. Required 
in-patient 
hospitalization 
or 
prolongation of existing hospitalization 
d. Resulted in medical or surgical intervention to 
prevent life-threatening illness or injury or 
permanent impairment to body structure or a 
body function 
3. Led to fetal distress, fetal death or a congenital 
abnormality or birth defect. 
Stroke (VARC-2 defined) 
Diagnostic criteria: 
• Acute episode of a focal or global neurological 
deficit with at least one of the following: change in 
level of consciousness, hemiplegia, hemiparesis, 
numbness or sensory loss affecting one side of the 
body, dysphasia or aphasia, hemianopia, amaurosis 
fugax, or other neurological signs or symptoms 
consistent with stroke 
• Stroke: duration of a focal or global neurological 
deficit ≥24 h; OR <24 h if available neuroimaging 
documents a new hemorrhage or infarct; OR the 
neurological deficit results in death 
• TIA: duration of a focal or global neurological deficit 
<24 h, any variable neuroimaging does not 
demonstrate a new hemorrhage or infarct 
• No other readily identifiable non-stroke cause for the 
clinical presentation (e.g. brain tumor, trauma, 
infection, hypoglycemia, peripheral lesion, 
pharmacological influences), to be determined by or 
in conjunction with designated neurologist (Patients 
with non-focal global encephalopathy will not be 
reported as a stroke without unequivocal evidence 
of cerebral infarction based upon neuroimaging 
studies [CT scan or brain MRI]). 
• Confirmation of the diagnosis by at least one of the 
following: 
o Neurologist or neurosurgical specialist 

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o Neuroimaging procedure (CT scan or brain 
MRI), but stroke may be diagnosed on clinical 
grounds alone 
Stroke classification: 
• Ischemic – An acute episode of focal cerebral, 
spinal, or retinal dysfunction caused by infarction of 
central nervous system tissue 
• Hemorrhagic – An acute episode of focal or global 
cerebral or spinal dysfunction caused by 
intraparenchymal, intraventricular, or subarachnoid 
hemorrhage 
• A stroke may be classified as undetermined if there 
is insufficient information to allow categorization as 
ischemic or hemorrhagic 
Stroke definitions (Modified Rankin Scale assessments 
should be made by qualified individuals according to a 
certification process): 
• Disabling stroke –  a mRS score of 2 or more at 90 
days and an increase of at least one mRS category 
from an individual’s pre-stroke baseline 
• Non-disabling stroke – a mRS score of less than 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 
Successful device 
deployment 
Ability to access the aortic arch with the TriGuard HDH or 
TriGUARD 3 delivery catheter and deploy the device from 
the delivery catheter into the aortic arch. 
Successful device 
retrieval 
Ability to retrieve the TriGuard device and remove the 
TriGuard CEPD. 
TAVI device success 
Equivalent to the VARC definition111 of “device success” for 
transcatheter aortic valves. Defined as: 
• Absence of procedural mortality AND 
• Correct positioning of a single prosthetic heart valve into 
the proper anatomical location AND 
• Intended performance of the prosthetic heart valve (no 
prosthesis-patient mismatch (VARC-defined) and mean 
aortic valve gradient <20 mm Hg or peak velocity <3 
m/s, AND no moderate or severe prosthetic valve 
regurgitation (VARC-defined) 
Technical success 
Successful TriGuard HDH or TriGUARD 3 device 
deployment, device positioning, and successful device 
retrieval in the absence of device interference 

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Total procedural time 
Time elapsed between first arterial access and removal of 
the last catheter from the arterial access sheath 
Unanticipated Adverse 
Device Effect (UADE) 
An unanticipated adverse device effect is any serious 
adverse effect on the 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. 
NOTE: An anticipated serious adverse device effect 
(ASADE) is a serious adverse device effect which by its 
nature, incidence, severity, or outcome has been identified 
in the investigational plan or application (including a 
supplementary plan or application).   
Use Error 
Act or omission of an act that results in a different medical 
device response than intended by the manufacturer or 
expected by the user.  
NOTE 1: Use error includes slips, lapses and mistakes. 
NOTE 2: An unexpected physiological response of the 
patient does not itself constitute a use error. 
 
Vascular access site and 
access-related 
complications 
Major Vascular Complications:35   
• Any aortic dissection, aortic rupture, annulus rupture, 
left ventricle perforation, or new apical 
aneurysm/pseudo-aneurysm OR 
• Access site or access-related vascular injury 
(dissection, stenosis, perforation, rupture, arterio-
venous fistula, pseudoaneurysm, hematoma, 
irreversible nerve injury, compartment syndrome, 
percutaneous closure device failure) leading to death, 
life-threatening or major bleeding, visceral ischemia or 
neurological impairment OR 
• Distal embolization (non-cerebral) from a vascular 
source requiring surgery or resulting in amputation or 
irreversible end-organ damage OR 
• The use of unplanned endovascular or surgical 
intervention associated with death, major bleeding, 
visceral ischemia or neurological impairment OR 
• Any new ipsilateral lower extremity ischemia 
documented by patient symptoms, physical exam, 
and/or decreased or absent blood flow on lower 
extremity angiogram OR 
• Surgery for access site-related nerve injury OR 

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• Permanent access site-related nerve injury 
Minor vascular complications: 
• Access site or access-related vascular injury 
(dissection, stenosis, perforation, rupture, arterio-
venous fistula, pseudoaneurysms, hematomas, 
percutaneous closure device failure) not leading to 
death, life-threatening or major bleeding, visceral 
ischemia or neurological impairment OR 
• Distal embolization treated with embolectomy and/or 
thrombectomy and not resulting in amputation or 
irreversible end-organ damage OR 
• Any unplanned endovascular stenting or unplanned 
surgical intervention not meeting the criteria for a major 
vascular complication OR 
• Vascular repair or the need for vascular repair (via 
surgery, ultrasound-guided compression, transcatheter 
embolization, or stent-graft) 
 
 
 
 

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16.2 Appendix II: Acronyms 
AE  
adverse event 
ADE  
adverse device effect 
AF 
atrial fibrillation 
ALT/SGPT 
alanine transaminase / serum glutamic pyruvic transaminase 
AKI  
acute kidney injury 
AMI  
acute myocardial infarction 
ANOVA 
analysis of variance 
AS 
aortic stenosis 
ASA  
acetylsalicylic acid 
ASADE 
anticipated serious adverse device effect 
AST/SGOT 
Aspartate transaminase / serum glutamic oxaloacetic 
transaminase 
AT 
As treated  
BARC 
Bleeding Academic Research Consortium 
BAV 
balloon aortic valvuloplasty 
BUN 
blood urea nitrogen 
CABG 
coronary artery bypass graft surgery 
CCS 
Canadian Cardiovascular Society 
CEC 
clinical events committee 
CEPD 
Cerebral Embolic Protection Device 
CI 
confidence interval 
CIP 
clinical investigation plan 
CK 
creatine kinase 
CK-MB 
creatine kinase-MB fraction 
CNS 
central nervous system 
CRF 
case report form 

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CT  
computed tomography 
DAPT  
dual antiplatelet therapy 
DICOM  
Digital Imaging and Communications in Medicine 
DSMB 
data and safety monitoring Board (Interchangeable with 
DSMC) 
DW-MRI  
diffusion-weighted magnetic resonance imaging 
EC  
Ethics Committee 
ECG  
electrocardiogram 
EDC 
electronic data capture (system) 
EDD/EPD 
embolic deflection device/embolic protection device (see also 
CEPD) 
eGFR 
estimated Glomerular Filtration Rate 
eITT 
efficacy Intention to Treat 
EU  
European Union 
F 
french (catheter scale system) 
FDA 
U.S. Food and Drug Administration 
GCP  
good clinical practices 
GI  
gastrointestinal 
ICH 
International Conference on Harmonization 
INR 
international normalized ratio 
IQR 
interquartile range 
IRB  
Institutional Review Board 
ISO 
International Organization for Standardization 
ITT  
intention to treat 
IV  
intravenous 
LAO 
left anterior oblique 
LBBB  
left bundle branch block 

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LV  
left ventricle/left ventricular 
MACCE  
major adverse cardiovascular and cerebrovascular events 
MDRD 
Modification of Diet in Renal Disease 
MI  
myocardial infarction 
MoCA 
Montreal Cognitive Assessment 
MRI  
magnetic resonance imaging 
mRS 
modified Rankin Scale 
NeuroARC 
Neurologic Academic Research Consortium 
NIHSS  
National Institutes of Health Stroke Scale 
NYHA  
New York Heart Association 
OPC  
objective performance criterion 
PCI  
percutaneous coronary intervention 
PP  
per protocol 
PPM 
prosthesis-patient mismatch 
PT 
per treatment 
PTT 
partial thromboplastin time 
QD  
quaque die (daily) 
RBANS 
Repeatable Battery for the Assessment of 
Neuropsychological Status 
RBC  
red blood cells 
RI 
roll-in 
SADE  
serious adverse device effect 
SAE  
serious adverse event 
SAVR  
surgical aortic valve replacement 
SD 
standard deviation 
SF-36 
Short Form 36 Health Survey 
SOC 
standard of care 

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STS 
Society of Thoracic Surgeons 
TAVI  
transcatheter aortic valve implantation 
TEE  
transesophageal echocardiography 
TIA  
transient ischemic attack 
UADE  
unanticipated adverse device effect 
URL  
upper reference limit 
US 
United States 
VARC  
Valve Academic Research Consortium 
WBC 
white blood cell 
 
 
 

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16.3 Appendix III: Declaration of Helsinki 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
and the 52nd WMA General Assembly, Edinburgh, Scotland, October 2000  
Note of Clarification on Paragraph 29 added by the WMA General Assembly, Washington 2002 
Note of Clarification on Paragraph 30 added by the WMA General Assembly, Tokyo 2004 
A. INTRODUCTION 
1.
The World Medical Association has developed the Declaration of Helsinki as a statement of ethical
principles to provide guidance to physicians and other participants in medical research involving
human subjects. Medical research involving human subjects includes research on identifiable
human material or identifiable data.
2.
It is the duty of the physician to promote and safeguard the health of the people. The physician's
knowledge and conscience are dedicated to the fulfillment of this duty.
3.
The Declaration of Geneva of the World Medical Association binds the physician with the words,
"The health of my patient will be my first consideration," and the International Code of Medical
Ethics declares that, "A physician shall act only in the patient's interest when providing medical care
which might have the effect of weakening the physical and mental condition of the patient."
4.
Medical progress is based on research which ultimately must rest in part on experimentation
involving human subjects.
5.
In medical research on human subjects, considerations related to the well-being of the human
subject should take precedence over the interests of science and society.
6.
The primary purpose of medical research involving human subjects is to improve prophylactic,
diagnostic and therapeutic procedures and the understanding of the etiology and pathogenesis of
disease. Even the best proven prophylactic, diagnostic, and therapeutic methods must continuously
be challenged through research for their effectiveness, efficiency, accessibility and quality.
7.
In current medical practice and in medical research, most prophylactic, diagnostic and therapeutic
procedures involve risks and burdens.
8.
Medical research is subject to ethical standards that promote respect for all human beings and
protect their health and rights. Some research populations are vulnerable and need special
protection. The particular needs of the economically and medically disadvantaged must be
recognized. Special attention is also required for those who cannot give or refuse consent for
themselves, for those who may be subject to giving consent under duress, for those who will not
benefit personally from the research and for those for whom the research is combined with care.
9.
Research Investigators should be aware of the ethical, legal and regulatory requirements for
research on human subjects in their own countries as well as applicable international requirements.
No national ethical, legal or regulatory requirement should be allowed to reduce or eliminate any of
the protections for human subjects set forth in this Declaration.
B. BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH 
10.
It is the duty of the physician in medical research to protect the life, health, privacy, and dignity of
the human subject.
11.
Medical research involving human subjects must conform to generally accepted scientific principles,
be based on a thorough knowledge of the scientific literature, other relevant sources of information,
and on adequate laboratory and, where appropriate, animal experimentation.
12.
Appropriate caution must be exercised in the conduct of research which may affect the environment,
and the welfare of animals used for research must be respected.

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13. 
The design and performance of each experimental procedure involving human subjects should be 
clearly formulated in an experimental protocol. This protocol should be submitted for consideration, 
comment, guidance, and where appropriate, approval to a specially appointed ethical review 
committee, which must be independent of the investigator, the sponsor or any other kind of undue 
influence. This independent committee should be in conformity with the laws and regulations of the 
country in which the research experiment is performed. The committee has the right to monitor 
ongoing trials. The researcher has the obligation to provide monitoring information to the committee, 
especially any serious adverse events. The researcher should also submit to the committee, for 
review, information regarding funding, sponsors, institutional affiliations, other potential conflicts of 
interest and incentives for subjects.  
14. 
The research protocol should always contain a statement of the ethical considerations involved and 
should indicate that there is compliance with the principles enunciated in this Declaration.  
15. 
Medical research involving human subjects should be conducted only by scientifically qualified 
persons and under the supervision of a clinically competent medical person. The responsibility for 
the human subject must always rest with a medically qualified person and never rest on the subject 
of the research, even though the subject has given consent.  
16. 
Every medical research project involving human subjects should be preceded by careful 
assessment of predictable risks and burdens in comparison with foreseeable benefits to the subject 
or to others. This does not preclude the participation of healthy volunteers in medical research. The 
design of all studies should be publicly available. 
17. 
Physicians should abstain from engaging in research projects involving human subjects unless they 
are confident that the risks involved have been adequately assessed and can be satisfactorily 
managed. Physicians should cease any investigation if the risks are found to outweigh the potential 
benefits or if there is conclusive proof of positive and beneficial results.  
18. 
Medical research involving human subjects should only be conducted if the importance of the 
objective outweighs the inherent risks and burdens to the subject. This is especially important when 
the human subjects are healthy volunteers.  
19. 
Medical research is only justified if there is a reasonable likelihood that the populations in which the 
research is carried out stand to benefit from the results of the research.  
20. 
The subjects must be volunteers and informed participants in the research project. 
21. 
The right of research subjects to safeguard their integrity must always be respected. Every 
precaution should be taken to respect the privacy of the subject, the confidentiality of the patient's 
information and to minimize the impact of the study on the subject's physical and mental integrity 
and on the personality of the subject. 
22. 
In any research on human beings, each potential subject must be adequately informed of the aims, 
methods, sources of funding, any possible conflicts of interest, institutional affiliations of the 
researcher, the anticipated benefits and potential risks of the study and the discomfort it may entail. 
The subject should be informed of the right to abstain from participation in the study or to withdraw 
consent to participate at any time without reprisal. After ensuring that the subject has understood 
the information, the physician should then obtain the subject's freely-given informed consent, 
preferably in writing. If the consent cannot be obtained in writing, the non-written consent must be 
formally documented and witnessed.  
23. 
When obtaining informed consent for the research project the physician should be particularly 
cautious if the subject is in a dependent relationship with the physician or may consent under 
duress. In that case the informed consent should be obtained by a well-informed physician who is 
not engaged in the investigation and who is completely independent of this relationship. 
24. 
For a research subject who is legally incompetent, physically or mentally incapable of giving consent 
or is a legally incompetent minor, the investigator must obtain informed consent from the legally 
authorized representative in accordance with applicable law. These groups should not be included 
in research unless the research is necessary to promote the health of the population represented 
and this research cannot instead be performed on legally competent persons. 
25. 
When a subject deemed legally incompetent, such as a minor child, is able to give assent to 
decisions about participation in research, the investigator must obtain that assent in addition to the 
consent of the legally authorized representative.  

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26. 
Research on individuals from whom it is not possible to obtain consent, including proxy or advance 
consent, should be done only if the physical/mental condition that prevents obtaining informed 
consent is a necessary characteristic of the research population. The specific reasons for involving 
research subjects with a condition that renders them unable to give informed consent should be 
stated in the experimental protocol for consideration and approval of the review committee. The 
protocol should state that consent to remain in the research should be obtained as soon as possible 
from the individual or a legally authorized surrogate. 
27. 
Both authors and publishers have ethical obligations. In publication of the results of research, the 
investigators are obliged to preserve the accuracy of the results. Negative as well as positive results 
should be published or otherwise publicly available. Sources of funding, institutional affiliations and 
any possible conflicts of interest should be declared in the publication. Reports of experimentation 
not in accordance with the principles laid down in this Declaration should not be accepted for 
publication.  
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH MEDICAL CARE 
a. 
The physician may combine medical research with medical care, only to the extent that the research 
is justified by its potential prophylactic, diagnostic or therapeutic value. When medical research is 
combined with medical care, additional standards apply to protect the patients who are research 
subjects. 
b. 
The benefits, risks, burdens and effectiveness of a new method should be tested against those of 
the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use 
of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic 
method exists. See footnote  
c. 
At the conclusion of the study, every patient entered into the study should be assured of access to 
the best proven prophylactic, diagnostic and therapeutic methods identified by the study. See 
footnote 
d. 
The physician should fully inform the patient which aspects of the care are related to the research. 
The refusal of a patient to participate in a study must never interfere with the patient-physician 
relationship. 
e. 
In the treatment of a patient, where proven prophylactic, diagnostic and therapeutic methods do not 
exist or have been ineffective, the physician, with informed consent from the patient, must be free 
to use unproven or new prophylactic, diagnostic and therapeutic measures, if in the physician's 
judgment it offers hope of saving life, re-establishing health or alleviating suffering. Where possible, 
these measures should be made the object of research, designed to evaluate their safety and 
efficacy. In all cases, new information should be recorded and, where appropriate, published. The 
other relevant guidelines of this Declaration should be followed.  
Note: Note of clarification on paragraph 29 of the WMA Declaration of Helsinki 
The WMA hereby reaffirms its position that extreme care must be taken in making use of a placebo-controlled 
trial and that in general this methodology should only be used in the absence of existing proven therapy. 
However, a placebo-controlled trial may be ethically acceptable, even if proven therapy is available, under the 
following circumstances: 
• 
Where for compelling and scientifically sound methodological reasons its use is necessary to determine 
the efficacy or safety of a prophylactic, diagnostic or therapeutic method; or  
• 
Where a prophylactic, diagnostic or therapeutic method is being investigated for a minor condition and 
the patients who receive placebo will not be subject to any additional risk of serious or irreversible harm.  
All other provisions of the Declaration of Helsinki must be adhered to, especially the need for appropriate ethical 
and scientific review. 

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16.4 Appendix IV: References 
1.
Kappetein AP, Head SJ, Genereux P, Piazza N, van Mieghem NM, Blackstone EH, Brott
TG, Cohen DJ, Cutlip DE, van Es GA, Hahn RT, Kirtane AJ, Krucoff MW, Kodali S, Mack MJ, 
Mehran R, Rodes-Cabau J, Vranckx P, Webb JG, Windecker S, Serruys PW and Leon MB. 
Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve 
Academic Research Consortium-2 consensus document. J Thorac Cardiovasc Surg. 2013;145:6-
23. 
2.
Finkelstein DM and Schoenfeld DA. Combining mortality and longitudinal measures in
clinical trials. Statistics in medicine. 1999;18:1341-54. 
3.
Lansky AJ, Messé SR, Brickman AM, Dwyer MG, van der Worp HB, Lazar RM, Pietras CG,
Abrams KJ, McFadden E, Petersen NH, Browndyke JN, Prendergast B, Ng VG, Cutlip DE, Kapadia 
S, Krucoff MW, Linke A, Moy CS, Schofer J, van Es GA, Virmani R, Popma JJ, Parides MK, Kodali 
S, Bilello M, Zivadinov R, Akar J, Furie KL, Gress D, Voros S, Moses J, Greer D, Forrest JK, 
Holmes D, Kappetein AP, Mack M and Baumbach A. Proposed standardized neurological endpoints 
for cardiovascular clinical trials: an Academic Research Consortium initiative. J Am Coll Cardiol. 
2017;(in press). 
4.
Smith CR, Leon MB, Mack MJ, Miller DC, Moses JW, Svensson LG, Tuzcu EM, Webb JG,
Fontana GP, Makkar RR, Williams M, Dewey T, Kapadia S, Babaliaros V, Thourani VH, Corso P, 
Pichard AD, Bavaria JE, Herrmann HC, Akin JJ, Anderson WN, Wang D and Pocock SJ. 
Transcatheter versus Surgical Aortic-Valve Replacement in High-Risk Patients. N Engl J Med. 
2011;364:2187-98. 
5.
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definitions by the Valve Academic Research Consortium (VARC). J Invasive Cardiol. 2011;23:307-
12. 
92. 
Ussia GP, Barbanti M, Petronio AS, Tarantini G, Ettori F, Colombo A, Violini R, Ramondo A, 
Santoro G, Klugmann S, Bedogni F, Maisano F, Marzocchi A, Poli A, De Carlo M, Napodano M, 
Fiorina C, De Marco F, Antoniucci D, de Cillis E, Capodanno D and Tamburino C. Transcatheter 
aortic valve implantation: 3-year outcomes of self-expanding CoreValve prosthesis. Eur Heart J. 
2012. 
93. 
Wenaweser P, Pilgrim T, Guerios E, Stortecky S, Huber C, Khattab AA, Kadner A, 
Buellesfeld L, Gloekler S, Meier B, Carrel T and Windecker S. Impact of coronary artery disease 
and percutaneous coronary intervention on outcomes in patients with severe aortic stenosis 
undergoing transcatheter aortic valve implantation. EuroIntervention. 2011;7:541-8. 
94. 
Yamamoto M, Hayashida K, Mouillet G, Chevalier B, Meguro K, Watanabe Y, Dubois-Rande 
JL, Morice MC, Lefevre T and Teiger E. Renal function-based contrast dosing predicts acute kidney 
injury following transcatheter aortic valve implantation. JACC Cardiovasc Interv. 2013;6:479-86. 

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95. 
Abramowitz Y, Banai S, Katz G, Steinvil A, Arbel Y, Havakuk O, Halkin A, Ben-Gal Y, Keren 
G and Finkelstein A. Comparison of early and late outcomes of TAVI alone compared to TAVI plus 
PCI in aortic stenosis patients with and without coronary artery disease. Catheter Cardiovasc Interv. 
2014;83:649-54. 
96. 
Greif M, Lange P, Nabauer M, Schwarz F, Becker C, Schmitz C, Pohl T, D'Anastasi M, 
Boekstegers P, Massberg S and Kupatt C. Transcutaneous aortic valve replacement with the 
Edwards SAPIEN XT and Medtronic CoreValve prosthesis under fluoroscopic guidance and local 
anaesthesia only. Heart. 2014;100:691-5. 
97. 
Sabate M, Canovas S, Garcia E, Hernandez Antolin R, Maroto L, Hernandez JM, Alonso 
Briales JH, Munoz Garcia AJ, Gutierrez-Ibanes E and Rodriguez-Roda J. In-hospital and Mid-term 
Predictors of Mortality After Transcatheter Aortic Valve Implantation: Data From the TAVI National 
Registry 2010-2011. Revista espanola de cardiologia (English ed). 2013;66:949-58. 
98. 
D'Onofrio A, Salizzoni S, Agrifoglio M, Cota L, Luzi G, Tartara PM, Cresce GD, Aiello M, 
Savini C, Cassese M, Cerillo A, Punta G, Cioni M, Gabbieri D, Zanchettin C, Agostinelli A, Mazzaro 
E, Di Gregorio O, Gatti G, Faggian G, Filippini C, Rinaldi M and Gerosa G. Medium term outcomes 
of transapical aortic valve implantation: results from the italian registry of trans-apical aortic valve 
implantation. Ann Thorac Surg. 2013;96:830-6. 
99. 
Tarantini G, Gasparetto V, Napodano M, Frigo AC, Fraccaro C, Buja P, D'Onofrio A, 
D'Amico G, Barioli A, Baritussio A, Facchin M, Dariol G, Isabella G, Gerosa G and Iliceto S. 
Transcatheter aortic valve implantation and bleeding: Focus on Valve Academic Research 
Consortium-2 classification. Int J Cardiol. 2013. 
100. 
Chopard R, Meneveau N, Chocron S, Gilard M, Laskar M, Eltchaninoff H, Iung B, Leprince 
P, Teiger E, Chevreul K, Prat A, Lievre M, Leguerrier A, Donzeau-Gouge P, Fajadet J and Schiele 
F. Impact of chronic obstructive pulmonary disease on Valve Academic Research Consortium-
defined outcomes after transcatheter aortic valve implantation (from the FRANCE 2 Registry). Am J 
Cardiol. 2014;113:1543-9. 
101. 
Conradi L, Seiffert M, Schirmer J, Koschyk D, Blankenberg S, Reichenspurner H, Diemert P 
and Treede H. Transapical transcatheter aortic valve implantation without prior balloon aortic 
valvuloplasty: feasible and safe. Eur J Cardiothorac Surg. 2013. 
102. 
Magri CJ, Chieffo A, Durante A, Latib A, Montorfano M, Maisano F, Cioni M, Agricola E, 
Covello RD, Gerli C, Franco A, Spagnolo P, Alfieri O and Colombo A. Impact of mean platelet 
volume on combined safety endpoint and vascular and bleeding complications following 
percutaneous transfemoral transcatheter aortic valve implantation. BioMed research international. 
2013;2013:645265. 
103. 
Seco M, Martinez G, Bannon PG, Cartwright BL, Adams M, Ng M, Wilson MK and Vallely 
MP. Transapical aortic valve implantation-an Australian experience. Heart Lung Circ. 2014;23:462-
8. 
104. 
Giustino G, Sorrentino S, Mehran R, Faggioni M and Dangas G. Cerebral Embolic Protection 
During TAVR: A Clinical Event Meta-Analysis. Journal of the American College of Cardiology. 
2017;69:465-466. 
105. 
Makkar RR, Fontana GP, Jilaihawi H, Kapadia S, Pichard AD, Douglas PS, Thourani VH, 
Babaliaros VC, Webb JG, Herrmann HC, Bavaria JE, Kodali S, Brown DL, Bowers B, Dewey TM, 
Svensson LG, Tuzcu M, Moses JW, Williams MR, Siegel RJ, Akin JJ, Anderson WN, Pocock S, 
Smith CR and Leon MB. Transcatheter Aortic-Valve Replacement for Inoperable Severe Aortic 
Stenosis. New England Journal of Medicine. 2012;366:1696-1704. 
106. 
Siontis GC, Juni P, Pilgrim T, Stortecky S, Bullesfeld L, Meier B, Wenaweser P and 
Windecker S. Predictors of permanent pacemaker implantation in patients with severe aortic 
stenosis undergoing TAVR: a meta-analysis. J Am Coll Cardiol. 2014;64:129-40. 
107. 
Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC and Williams R. Transection of the 
oesophagus for bleeding oesophageal varices. The British journal of surgery. 1973;60:646-9. 
108. 
Rockwood K, Song X, MacKnight C, Bergman H, Hogan DB, McDowell I and Mitnitski A. A 
global clinical measure of fitness and frailty in elderly people. CMAJ : Canadian Medical Association 
journal = journal de l'Association medicale canadienne. 2005;173:489-95. 
109. 
van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ and van Gijn J. Interobserver 
agreement for the assessment of handicap in stroke patients. Stroke. 1988;19:604-7. 

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110. 
The Criteria Committee of the New York Heart Association. Nomenclature and criteria for 
diagnosis of diseases of the heart and great vessels. 9th ed. Boston, MA: Little, Brown & Co.; 1994. 
pp. 253-256. 
111. 
Kappetein AP, Head SJ, Genereux P, Piazza N, van Mieghem NM, Blackstone EH, Brott 
TG, Cohen DJ, Cutlip DE, van Es GA, Hahn RT, Kirtane AJ, Krucoff MW, Kodali S, Mack MJ, 
Mehran R, Rodes-Cabau J, Vranckx P, Webb JG, Windecker S, Serruys PW and Leon MB. 
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. 
 
 
 
 
 
 
 
 
 
 
 
 

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137
16.5 Appendix V: Structured Interview for the Modified Rankin 
Scale 
Modified Rankin Scale 
Structured Interview for the 
Modified Rankin Scale 
5=Severe disability: 
bedridden, incontinent, and 
requiring constant nursing 
care and attention 
5=Severe disability; someone needs to be available at all times; 
care may be provided by either a trained or untrained caregiver.  
Question: Does the person require constant care? 
4=Moderately severe 
disability: 
unable to walk without 
assistance, and unable to 
attend to own bodily needs 
without assistance 
4=Moderately severe disability; need for assistance with some basic 
activities of daily living (ADL), but not requiring constant care. 
Question: Is assistance essential for eating, using the toilet, daily 
hygiene, or walking? 
3=Moderate disability: 
requiring some help, but 
able to walk without 
assistance 
3=Moderate disability; need for assistance with some instrumental 
ADL but not basic ADL.  
Question: Is assistance essential for preparing a simple meal, doing 
household chores, looking after money, shopping, or traveling 
locally? 
2=Slight disability: 
unable to carry out all 
previous activities but able 
to look after own affairs 
without assistance 
2=Slight disability; limitations in participation in usual social roles, 
but independent for ADL.  
Questions: Has there been a change in the person’s ability to work 
or look after others if these were roles before stroke? Has there 
been a change in the person’s ability to participate in previous social 
and leisure activities? Has the person had problems with 
relationships or become isolated? 
1=No significant disability 
despite symptoms: 
able to carry out all usual 
duties and activities 
1=No significant disability; symptoms present but not other 
limitations.  
Question: Does the person have difficulty reading or writing, 
difficulty speaking or finding the right word, problems with balance 
or coordination, visual problems, numbness (face, arms, legs, 
hands, feet), loss of movement (face, arms, legs, hands, feet), 
difficulty with swallowing, or other symptom resulting from stroke? 
0=No symptoms at all 
0=No symptoms at all; no limitations and no symptoms 
Sources: 
Modified Rankin Scale: van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. Inter-observer 
agreement for the assessment of handicap in stroke patients. Stroke. 1988;19:604-607. 
Structured Interview: Wilson JRL, Hareendran A, Grant M, Baird T, Schulz UGR, Muir KW, Bone I. Improving 
the assessment of outcomes in stroke: Use of a structured interview to assign grades on the Modified Rankin 
Scale. Stroke. 2002;33:2243-2246. 

REFLECT – US IDE Trial [CIP-09 (v13.0)] 
Keystone Heart Ltd. 
138
16.6 Appendix VI: NIH Stroke Scale  
Note: Additional copies of the NIH Stroke Scale are available on the Internet at the following 
web sites: 
•
http://www.ninds.nih.gov/disorders/stroke/strokescales.htm
•
http://stroke.nih.gov/resources/scale.htm
You may also call the US National Institute of Neurological Disorders and Stroke (NINDS) 
Brain Resources and Information Network at (800) 352-9424 to order hard copies. The NIH 
Stroke Scale is in the Public domain and may be copied and distributed without restriction.  

Patient Identification. ___ ___-___ ___ ___-___ ___ ___ 
     Pt. Date of Birth ___ ___/___ ___/___ ___ 
Hospital ________________________(___ ___-___ ___) 
Date of Exam ___ ___/___ ___/___ ___ 
Interval: [ ] Baseline 
[ ] 2 hours post treatment    [ ] 24 hours post onset of symptoms ±20 minutes    [ ] 7-10 days          
[ ] 3 months [ ] Other ________________________________(___ ___) 
Time: ___ ___:___ ___   [ ]am   [ ]pm 
Person Administering Scale _____________________________________  
Administer stroke scale items in the order listed.  Record performance in each category after each subscale exam.  Do not go 
back and change scores.  Follow directions provided for each exam technique.  Scores should reflect what the patient does, not 
what the clinician thinks the patient can do.  The clinician should record answers while administering the exam and work quickly. 
Except where indicated, the patient should not be coached (i.e., repeated requests to patient to make a special effort). 
Instructions 
  Scale Definition 
Score 
1a.  Level of Consciousness: The investigator must choose a 
response if a full evaluation is prevented by such obstacles as an 
endotracheal tube, language barrier, orotracheal trauma/bandages.  A 
3 is scored only if the patient makes no movement (other than reflexive 
posturing) in response to noxious stimulation. 
 0 =    Alert; keenly responsive. 
 1 = Not alert; but arousable by minor stimulation to obey, 
answer, or respond. 
 2 = Not alert; requires repeated stimulation to attend, or is 
obtunded and requires strong or painful stimulation to 
make movements (not stereotyped). 
 3 = Responds only with reflex motor or autonomic effects or 
totally unresponsive, flaccid, and areflexic. 
______ 
1b.  LOC Questions:  The patient is asked the month and his/her age. 
The answer must be correct - there is no partial credit for being close.  
Aphasic and stuporous patients who do not comprehend the questions 
will score 2.  Patients unable to speak because of endotracheal 
intubation, orotracheal trauma, severe dysarthria from any cause, 
language barrier, or any other problem not secondary to aphasia are 
given a 1.  It is important that only the initial answer be graded and that 
the examiner not "help" the patient with verbal or non-verbal cues. 
 0 = 
Answers both questions correctly. 
 1 = 
Answers one question correctly. 
 2 = 
Answers neither question correctly.  
______ 
1c.  LOC Commands:  The patient is asked to open and close the 
eyes and then to grip and release the non-paretic hand.  Substitute 
another one step command if the hands cannot be used.  Credit is 
given if an unequivocal attempt is made but not completed due to 
weakness.  If the patient does not respond to command, the task 
should be demonstrated to him or her (pantomime), and the result 
scored (i.e., follows none, one or two commands).  Patients with 
trauma, amputation, or other physical impediments should be given 
suitable one-step commands.  Only the first attempt is scored. 
 0 = Performs both tasks correctly. 
 1 = Performs one task correctly. 
 2 = Performs neither task correctly. 
______ 
2.
Best Gaze:  Only horizontal eye movements will be tested.
Voluntary or reflexive (oculocephalic) eye movements will be scored, 
but caloric testing is not done.  If the patient has a conjugate 
deviation of the eyes that can be overcome by voluntary or reflexive 
activity, the score will be 1.  If a patient has an isolated peripheral 
nerve paresis (CN III, IV or VI), score a 1.  Gaze is testable in all 
aphasic patients.  Patients with ocular trauma, bandages, pre-existing 
blindness, or other disorder of visual acuity or fields should be tested 
with reflexive movements, and a choice made by the investigator. 
Establishing eye contact and then moving about the patient from side 
to side will occasionally clarify the presence of a partial gaze palsy. 
 
 0 = Normal. 
 1 = Partial gaze palsy; gaze is abnormal in one or both eyes, 
but forced deviation or total gaze paresis is not present. 
 2 = Forced deviation, or total gaze paresis not overcome by the 
oculocephalic maneuver. 
______ 
Rev 10/1/2003 

Patient Identification. ___ ___-___ ___ ___-___ ___ ___ 
     Pt. Date of Birth ___ ___/___ ___/___ ___ 
Hospital ________________________(___ ___-___ ___) 
Date of Exam ___ ___/___ ___/___ ___ 
Interval: [ ] Baseline 
[ ] 2 hours post treatment    [ ] 24 hours post onset of symptoms ±20 minutes    [ ] 7-10 days          
[ ] 3 months [ ] Other ________________________________(___ ___) 
3. Visual:  Visual fields (upper and lower quadrants) are tested by
confrontation, using finger counting or visual threat, as appropriate. 
Patients may be encouraged, but if they look at the side of the 
moving fingers appropriately, this can be scored as normal.  If there is 
unilateral blindness or enucleation, visual fields in the remaining eye 
are scored.  Score 1 only if a clear-cut asymmetry, including 
quadrantanopia, is found.  If patient is blind from any cause, score 3. 
Double simultaneous stimulation is performed at this point.  If there is 
extinction, patient receives a 1, and the results are used to respond to 
item 11. 
 0 = No visual loss. 
 1 = Partial hemianopia. 
 2 = Complete hemianopia. 
 3 = Bilateral hemianopia (blind including cortical blindness). 
______ 
4. Facial Palsy:  Ask – or use pantomime to encourage – the patient
to show teeth or raise eyebrows and close eyes.  Score symmetry of 
grimace in response to noxious stimuli in the poorly responsive or 
non-comprehending patient.  If facial trauma/bandages, orotracheal 
tube, tape or other physical barriers obscure the face, these should 
be removed to the extent possible. 
 0 = Normal symmetrical movements. 
 1 = Minor paralysis (flattened nasolabial fold, asymmetry on 
smiling). 
 2 = Partial paralysis (total or near-total paralysis of lower 
face). 
 3 = Complete paralysis of one or both sides (absence of 
facial movement in the upper and lower face). 
______ 
5. Motor Arm:  The limb is placed in the appropriate position: extend
the arms (palms down) 90 degrees (if sitting) or 45 degrees (if 
supine).  Drift is scored if the arm falls before 10 seconds.  The 
aphasic patient is encouraged using urgency in the voice and 
pantomime, but not noxious stimulation.  Each limb is tested in turn, 
beginning with the non-paretic arm.  Only in the case of amputation or 
joint fusion at the shoulder, the examiner should record the score as 
untestable (UN), and clearly write the explanation for this choice. 
  0 =  No drift; limb holds 90 (or 45) degrees for full 10 seconds. 
  1 =  Drift; limb holds 90 (or 45) degrees, but drifts down before 
full 10 seconds; does not hit bed or other support. 
  2 =  Some effort against gravity; limb cannot get to or 
maintain (if cued) 90 (or 45) degrees, drifts down to bed, 
but has some effort against gravity. 
  3 =  No effort against gravity; limb falls. 
  4 =  No movement. 
  UN = Amputation or joint fusion, explain:  _____________________ 
 5a.  Left Arm 
 
 5b.  Right Arm  
______ 
______ 
6. Motor Leg:  The limb is placed in the appropriate position:  hold
the leg at 30 degrees (always tested supine).  Drift is scored if the leg 
falls before 5 seconds.  The aphasic patient is encouraged using 
urgency in the voice and pantomime, but not noxious stimulation. 
Each limb is tested in turn, beginning with the non-paretic leg.  Only 
in the case of amputation or joint fusion at the hip, the examiner 
should record the score as untestable (UN), and clearly write the 
explanation for this choice. 
  0 =  No drift; leg holds 30-degree position for full 5 seconds. 
  1 =  Drift; leg falls by the end of the 5-second period but does 
not hit bed.    
  2 =  Some effort against gravity; leg falls to bed by 5 
seconds, but has some effort against gravity. 
  3 =  No effort against gravity; leg falls to bed immediately. 
  4 =  No movement. 
  UN = Amputation or joint fusion, explain: ________________ 
6a.  Left Leg 
6b.  Right Leg 
______ 
Rev 10/1/2003 

 
 
 
 
Patient Identification. ___ ___-___ ___ ___-___ ___ ___ 
 
     Pt. Date of Birth ___ ___/___ ___/___ ___ 
 
Hospital ________________________(___ ___-___ ___) 
 
Date of Exam ___ ___/___ ___/___ ___ 
 
           
 
Interval: [ ] Baseline 
[ ] 2 hours post treatment    [ ] 24 hours post onset of symptoms ±20 minutes    [ ] 7-10 days          
 
[ ] 3 months [ ] Other ________________________________(___ ___) 
 
______ 
7.  Limb Ataxia:  This item is aimed at finding evidence of a unilateral 
cerebellar lesion.  Test with eyes open.  In case of visual defect, 
ensure testing is done in intact visual field.  The finger-nose-finger 
and heel-shin tests are performed on both sides, and ataxia is scored 
only if present out of proportion to weakness.  Ataxia is absent in the 
patient who cannot understand or is paralyzed.  Only in the case of 
amputation or joint fusion, the examiner should record the score as 
untestable (UN), and clearly write the explanation for this choice.  In 
case of blindness, test by having the patient touch nose from 
extended arm position. 
 0 = Absent. 
 
 1 = Present in one limb. 
 
 2 = Present in two limbs. 
 
 UN = Amputation or joint fusion, explain:  ________________ 
  
 
 
 
______ 
 
 
 
 
8.  Sensory:  Sensation or grimace to pinprick when tested, or 
withdrawal from noxious stimulus in the obtunded or aphasic patient.  
Only sensory loss attributed to stroke is scored as abnormal and the 
examiner should test as many body areas (arms [not hands], legs, 
trunk, face) as needed to accurately check for hemisensory loss.  A 
score of 2, “severe or total sensory loss,” should only be given when 
a severe or total loss of sensation can be clearly demonstrated.  
Stuporous and aphasic patients will, therefore, probably score 1 or 0. 
The patient with brainstem stroke who has bilateral loss of sensation 
is scored 2.  If the patient does not respond and is quadriplegic, score 
2.  Patients in a coma (item 1a=3) are automatically given a 2 on this 
item. 
 0 = Normal; no sensory loss. 
 
 1 = Mild-to-moderate sensory loss; patient feels pinprick is 
less sharp or is dull on the affected side; or there is a 
loss of superficial pain with pinprick, but patient is aware 
of being touched. 
 
 2 = Severe to total sensory loss; patient is not aware of 
being touched in the face, arm, and leg. 
 
 
 
 
 
______ 
9.  Best Language:  A great deal of information about comprehension 
will be obtained during the preceding sections of the examination.  
For this scale item, the patient is asked to describe what is happening 
in the attached picture, to name the items on the attached naming 
sheet 
and 
to 
read 
from 
the 
attached 
list 
of 
sentences.  
Comprehension is judged from responses here, as well as to all of 
the commands in the preceding general neurological exam.  If visual 
loss interferes with the tests, ask the patient to identify objects placed 
in the hand, repeat, and produce speech.  The intubated patient 
should be asked to write. The patient in a coma (item 1a=3) will 
automatically score 3 on this item.  The examiner must choose a 
score for the patient with stupor or limited cooperation, but a score of 
3 should be used only if the patient is mute and follows no one-step 
commands. 
 0 = No aphasia; normal. 
 
 1 =  Mild-to-moderate aphasia; some obvious loss of fluency 
or facility of comprehension, without significant 
limitation on ideas expressed or form of expression.  
Reduction of speech and/or comprehension, however, 
makes conversation about provided materials difficult 
or impossible.  For example, in conversation about 
provided materials, examiner can identify picture or 
naming card content from patient’s response. 
 
 2 = Severe aphasia; all communication is through fragmentary 
expression; great need for inference, questioning, and guessing 
by the listener.  Range of information that can be exchanged is 
limited; listener carries burden of communication.  Examiner 
cannot identify materials provided from patient response. 
 
 3 = Mute, global aphasia; no usable speech or auditory 
comprehension. 
 
 
 
 
 
 
 
 
 
______ 
10.  Dysarthria: If patient is thought to be normal, an adequate 
sample of speech must be obtained by asking patient to read or 
repeat words from the attached list.  If the patient has severe 
aphasia, the clarity of articulation of spontaneous speech can be 
rated.  Only if the patient is intubated or has other physical barriers to 
producing speech, the examiner should record the score as 
untestable (UN), and clearly write an explanation for this choice.  Do 
not tell the patient why he or she is being tested. 
 0 = Normal. 
 1 = Mild-to-moderate dysarthria; patient slurs at least some 
words and, at worst, can be understood with some 
difficulty. 
 2 = Severe dysarthria; patient's speech is so slurred as to be 
unintelligible in the absence of or out of proportion to 
any dysphasia, or is mute/anarthric. 
UN = Intubated or other physical barrier, 
explain:_____________________________ 
 
 
 
______ 
 
Rev 10/1/2003 

Patient Identification. ___ ___-___ ___ ___-___ ___ ___ 
     Pt. Date of Birth ___ ___/___ ___/___ ___ 
Hospital ________________________(___ ___-___ ___) 
Date of Exam ___ ___/___ ___/___ ___ 
Interval: [ ] Baseline 
[ ] 2 hours post treatment    [ ] 24 hours post onset of symptoms ±20 minutes    [ ] 7-10 days          
[ ] 3 months [ ] Other ________________________________(___ ___) 
11.
Extinction and Inattention (formerly Neglect):  Sufficient
information to identify neglect may be obtained during the prior 
testing.  If the patient has a severe visual loss preventing visual 
double simultaneous stimulation, and the cutaneous stimuli are 
normal, the score is normal.  If the patient has aphasia but does 
appear to attend to both sides, the score is normal.  The presence of 
visual spatial neglect or anosagnosia may also be taken as evidence 
of abnormality.  Since the abnormality is scored only if present, the 
item is never untestable.   
 0 = No abnormality. 
 1 = Visual, tactile, auditory, spatial, or personal inattention 
or extinction to bilateral simultaneous stimulation in one 
of the sensory modalities. 
 2 = Profound hemi-inattention or extinction to more than 
one modality; does not recognize own hand or orients 
to only one side of space. 
______ 
______ 
______ 
Rev 10/1/2003 

You know how. 
Down to earth. 
I got home from work. 
Near the table in the dining 
room. 
They heard him speak on the 
radio last night. 

MAMA 
TIP – TOP 
FIFTY – FIFTY 
THANKS 
HUCKLEBERRY 
BASEBALL PLAYER 

REFLECT – US IDE Trial [CIP-09 (v13.0)] 
Keystone Heart Ltd. 
147
16.7 Appendix VII: Neuropsychological Test Battery 
Note:  Instructions and score sheet forms for the components of the Neuropsychological 
Test Battery are provided below. Please refer to the Neuropsychological Battery Manual of 
Operations for additional information. 
The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) is 
administered as a component of the Neuropsychological Test Battery. The RBANS test is 
copyright NCS Pearson, Inc., and is licensed for use in this trial; authorized copies, 
alternate versions, and translations will be provided as required. It is provided below for 
informational purposes. 
The Trail Making Tests Parts A and B are administered as a component of the 
Neuropsychological Test Battery. The test forms are in the public domain and are provided 
below for informational purposes. Administration instructions are licensed for use in this trial 
and will be provided as required, along with additional test forms.  

-
Name------------------ Age ___ Sex ___ Education Level ____ _ 
Examiner __________________ Date ofTesting _____ Ethnicity _____ _ 
---
--
-
,-
• 
-
-
-1 
Immediate · Visuospatial/ 1 
l 
1 
Att t• 
1 
Delayed 
. 
anguage 
1 
en ron 
1 
Memory 
1 
__ _ _ __ 
1 
_ 
Memory 
, 
Index Score 
Confidence 
Interval 
__ % 
Percentile 
Percentile 
Total Scale 
Index Score 
Rank 
Index Score 
160 
>99.9 
160 
155 
>99.9 
155 
150 
>99.9 
150 
145 
99.9 
145 
140 
99.6 
140 
135 
99 
135 
130 
98 
130 
125 
95 
125 
120 
91 
120 
115 
84 
115 
110 
75 
110 
105 
63 
105 
100 
50 
100 
95 
37 
95 
90 
25 
90 
85 
16 
85 
80 
9 
80 
75 
5 
75 
70 
2 
70 
65 
65 
60 
0.4 
60 
55 
0.1 
55 
50 
<0.1 
50 
45 
<0.1 
45 
40 
<0.1 
40 
Observations: 
PEARSON 
Copyright© 1998, 2012 NCS Pearson, Inc. All rights reserved. 
0 
7 8 9 10 11 12 A 8 C D E 
Product Number 0158007212 

List Learning 
Trial1 
Say I am going to read you a list of words. I want you to listen carefully and, when I finish, repeat back as 
many words as you can. You don't have to say them in the same order that I do-just repeat back as 
many words as you can remember, in any order. Okay? 
Trials 2-4 
Say I am going to read the list again. When I finish, repeat back as many words as you can, even if you have 
already said them before. Okay? 
Record responses in order. 
Scoring: l point for each word correctly recalled on each trial. 
List 
Market 
Package 
Elbow 
Apple 
Story 
Carpet 
Bubble 
Highway 
Saddle 
Powder 
Number 
Correct 
Triall 
Trial2 
+ 
Trial3 
Trial4 
+ 
+ 
-
Total Triall 
Total Trial 2 
Total Trial 3 
Total Trial4 
Total Score 
Range=0-40 
PEARSON 
PsychCorp is an imprint of Pearson Clinical Assessment. 
Pearson Executive Office 5601 Green Valley Drive Bloomington, MN 55437 
800.627.7271 www.PsychCorp.com 
Copyright© 1998, 2012 NCS Pearson, Inc. All rights reserved. 
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Pearson, the PSI logo, PsychCorp, and RBANS are trademarks in ti"e U.S. and/or other countries of Pearson Education, 
Inc., or its affiliate(s). 
The Line Orientation portion of the RBANS is adapted from "The Judgment of Line Orientation" by Dr. Arthur Benton, 
under license from and reprinted with permission of Psychological Assessment Resources, Inc. 
Printed in the United States of America. 

Story I'V1emory 
Triall 
Say 1 am going to read you a short story. I'd like you to listen carefully and, when I finish, repeat back as much 
of the story as you can remember. Try and use the same wording, if you can. Okay? 
Read the story below, then say Now repeat back as much of that story as you can. 
Trial2 
Say I am going to read that same story again. When I finish, I want you to again repeat back as much of the 
story as you can remember. Try to repeat it as exactly as you can. 
Read the story below, then say Now repeat back as much of that story as you can. 
Scoring: l point for verbatim recall of bold, italic words or alternatives, shown below in color within parentheses. Record intrusions or variations in 
the Responses column. 
Trial1 
Trial2 
Item Score 
Story 
Trial1 Responses 
Score 
Trial 2 Responses 
Score 
(0-2) 
(0 or 1) 
(0 or 1) 
1. On Tuesday, 
2.May 
3. Fourth, 
4. in Cleveland, Ohio, 
5. a3alarm 
6. fire broke out. 
7. Two 
8. hotels 
9. and a restaurant 
10. were destroyed 
11. before the firefighters (firemen) 
12. were able to extinguish it 
(put it out). 
Total Score 
(Trial1 + Trial2) 
Range=0-24 
·-

Figure Copy 
• 
Time 
4 minutes 
Fold this page back and present the Figure Copy Drawing Page along with 
stimulus. Ask the examinee to 
make an exact copy of the figure. Tell the examinee that he or she is being timed, but that the score is based only 
on the exactness of his or her copy. 
Scoring: l point for correctness and completeness (drawing), and l point for proper placement. See Appendix lin Stimulus Booklet A for complete 
scoring criteria and scoring examples. 
Item 
Drawing Placemen 
Score 
(Oorl) 
(Oorl) 
(0, 1, or2) 
l. rectangle 
2. diagonal cross 
3. horizontal line 
4. circle 
5. 3 small circles 
6. square 
7. curving line 
8. outside cross 
9. triangle 
-
10. arrow 
Total Score 
Range=0-20 
Figure Copy Criteria 
(Fold back for use.) 
Scoring Criteria 
Drawing: lines are unbroken and straight; angles 90 degrees; top/bottom lines 25% longer than sides 
Placement: not rotated more than 15 degrees 
Drawing: lines are unbroken and straight and should approximately bisect each other 
Placement: ends of lines should meet comers of the rectangle without significant overlap or measurable 
distance between the ends of the lines and the comers 
Drawing: line is unbroken and straight; should not exceed 1/2 the length of the rectangle 
Placement: should bisect left side of the rectangle at approximately a right angle and intersect the 
diagonal cross 
Drawing: round, unbroken and closed; diameter should be approximately 1/4-1/3 height of rectangle 
Placement: placed in appropriate segment; not touching any other part of figure 
Drawing: round, unbroken and closed; equal size; triangular arrangement; not touching each other 
Placement: in appropriate segment; not touching figure; triangle formed not rotated more than 15 degrees 
Drawing: must be closed; 90 degree angles; lines straight and unbroken; height is 1/4-1/3 height of rectangle 
Placement: in appropriate segment; not touching any other part of figure; not rotated more than 15 degrees 
Drawing: 2 curved segments are approximately equal in length and symmetrical; correct direction of curves 
Placement: ends of line touch diagonal; do not touch comer of rectangle or intersection of diagonal lines 
Drawing: vertical line of the outside cross is parallel to side of rectangle; > 1/2 the heifht of rectangle; 
horizontal line crosses vertical at 90 degree angle and is between 20-50% of length o vertical line 
Placement: horizontal line of outside cross touches rectangle higher than 2/3 the height of rectangle, but 
below top; does not penetrate the rectangle 
Drawing: angle formed by 2 sides of triangle is between 60-100 degrees; sides are straight, unbroken 
and meet in a point; distance on vertical side of rectangle subsumed by triangle is approximately 50% of the 
height of vertical side 
Placement: roughly centered on the left vertical side of the rectangle 
Drawing: straight and unbroken; lines forming arrow are approximately equal in length and not more than 
l/3 length of staff 
Placement: must protrude from appropriate comer of rectangle such that staff appears to be continuation 
of diagonal cross 

Figure Copy Dra\\Jing Page 
(Fold back for use.) 

line Orientation 
• 
Time Limit: 20 seconds/item 
Present the sample item, and say These two lines down here (indicate) match two of the lines on top. Can you tell 
me the numbers, or point to the lines that they match? Correct any errors and make sure the examinee understands 
the task. Continue with Items 1-10. 
Scoring: l point for each line correctly identified. 
Item 
Responses 
Correct 
Score 
Responses 
(0, l, or 2) 
6. 
1,6 
1. 
7. 
3,10 
2. 
4, 11 
8. 
5,8 
3. 
6,9 
9. 
1, 3 
10. 
11,13 
5. 
Total Score 
Range=0-20 
Picture Naming 
Timelimit:20seconds/item 
Ask the examinee to name each picture. Give the semantic cue only if the picture is obviously misperceived. 
Scoring: l point for each item that is correctly named spontaneously or following semantic cue. 
Item 
Semantic Cue 
Responses 
Score 
(0 or l) 
l. chair 
a piece of furniture 
2. pencil 
used for writing 
3. well 
you get water from it 
4. giraffe 
an animal 
5. sailboat 
used on the water (if "boat," query "what kind") 
6. cannon 
a weapon, used in war 
7. pliers 
a tool 
8. trumpet 
a musical instrument ("comet" okay) 
9. clothespin 
used to hold laundry on a line 
10. kite 
its flown in the air 
Total Score 
Range=0-10 

Semantic Fluency 
Time Limit: 60 seconds 
Say Now I'd like you to tell me the names of all of the different kinds of fruits and vegetables that 
you can think of. I'll give you one minute to come up with as many as you can. Ready? 
Scoring: l point for each correct response. 
l. 
11. 
2. 
12. 
3. 
13. 
4. 
14. 
5. 
15. 
6. 
16. 
7. 
17. 
8. 
18. 
9. 
19. 
10. 
20. 
Digit Span 
21. 
22. 
23. 
24. 
25. 
26. 
27. 
28. 
29. 
30. 
31. --------
32. --------
33. --------
34. --------
35. --------
36. --------
37. --------
38. --------
39. --------
40. --------
Total Score D 
Range=0-40 
Say I am going to say some numbers, and I want you to repeat them after me. Okay? 
Read the numbers at the rate of 1 per second. Only read the second string in each set if the first string was failed. 
Discontinue after failure of both strings in any set. 
Scoring: 2 points for the first string correct, l point for the second string correct, and 0 points for both strings failed. 
Item First String 
String Score Second String 
String Score Item Score 
(0 or 2) 
(0 or l) 
(0-2) 
l. 
4-9 
5-3 
2. 
8-3-5 
2-4-1 
3. 
7-2-4-6 
1-6-3-8 
4. 
5-3-9-2-4 
3-8-4-9-1 
5. 
6-4-2-9-3-5 
9-1-5-3-7-6 
6. 
2-8-5-1-9-3-7 
5-3-1-7-4-9-2 
7. 
8-3-7-9-5-2-4-1 
9-5-1-4-2-7-3-8 
8. 
1-5-9-2-3-8-7-4-6 
5-1-9-7-6-2-3-6-5 
Total Score 
Range=0-16 

II Coding 
Time Limit: 90 seconds 
Say Look at these boxes (indicate key). For each one of these marks there is a number that goes with it. Down 
here there are marks, but no numbers. I want you to fill in the number that goes with each mark. 
Demonstrate the first three. Say Now I would like you to fill in the rest of these boxes up to the double lines 
(indicate) for practice. Correct any errors as they are made. Make sure that the examinee understands the task and 
has correctly completed the sample items before you begin timing. 
Say Now 1 would like you to continue to fill in the numbers that match the marks. Go as quickly as you can 
without skipping any. When you reach the end of the line, go on to the next one. Ready? Go ahead. 
Redirect the examinee to the task if he or she becomes distracted. If the examinee is unable to comprehend the 
task, the subtest score is 0. 
Scoring: l point for each item correctly coded within 90 seconds (do not score the sample items). 
Note: Familiarize yourself with these instructions before administering this subtest. 
Total Score 
Range=0-89 

Q ListRecan 
Say Do you remember the list of words that I read to you in the beginning? Tell me as many of those words as 
you can remember now. 
Scoring: l point for each word correctly recalled. 
List 
Response 
Score 
(Do not read.) 
(0 or 1) 
Market 
Package 
Elbow 
Apple 
Story 
•. 
Carpet 
Bubble 
Highway 
Saddle 
Powder 
Total Score 
Range=0-10 
II!J List Recognition 
Say I'm going to read you some words. Some of these words were on that list, and some of them weren't. I want 
you to tell me which words were on the list. For each word, ask Was 
on the list? 
Scoring: l point for each word correctly identified. Circle the letter corresponding to examinees response (y =yes, n =no); bold, capitalized (Y, N) 
letter indicates correct response. 
List 
Circle One 
List 
Circle One 
List 
Circle One 
List 
Circle One 
1. Apple 
y 
n 
6. sailor 
y 
N 
11. Bubble 
y 
n 
16. Saddle 
y 
n 
2. honey 
y 
N 
7. velvet 
y 
N 
12. prairie 
y 
N 
17. Powder 
y 
n 
3. Market 
y 
n 
8. Carpet 
y 
n 
13. Highway 
y 
n 
18. angel 
y 
N 
4. Story 
y 
n 
9. valley 
y 
N 
14. oyster 
y 
N 
19. Package 
y 
n 
5. fabric 
y 
N 
10. Elbow 
y 
n 
15. student 
y 
N 
20. meadow 
y 
N 
Total Score 
Range=0-20 

m Story Recall 
Say Do you remember that story about a fire that I read to you earlier? Tell me as many details from the 
story as you can remember now. 
Scoring: 1 point for each verbatim recall of bold, italic words or alternatives, shown below in color within parentheses. Record intrusions or variations 
in the Responses column. 
Story (Do not read.) 
Responses 
Item Score 
(0 or l) 
1. On Tuesday, 
2. May 
3. Fourth, 
4. in Cleveland, Ohio, 
5. a3alarm 
6. fire broke out. 
7. Two 
' 
8. hotels 
9. and a restaurant 
10. were destroyed 
11. before the firefighters (firemen) 
12. were able to extinguish it (put it out). 
Total Score 
Range=0-12 

m Figure Recall 
Say Do you remember that figure that I had you copy? I want you to draw as much of it as you can remember now. 
If you remember a part, but you're not sure where it goes, put it anywhere. Try to draw as much of it as you can. 
Now, present the Figure Recall Drawing Page. 
Scoring: l point for correctness and completeness (drawing), and l point for proper placement. See Appendix lin Stimulus Booklet A for complete 
scoring criteria and scoring examples. 
Item 
Drawing Placement 
Score 
(Oar l) 
(0 or l) 
(0, 1, or2) 
l. rectangle 
2. diagonal cross 
3. horizontal line 
4. circle 
5. 3 small circles 
6. square 
7. curving line 
8. outside cross 
9. triangle 
10. arrow 
Total Score 
Range=0-20 
Figure Recall Criteria 
(Fold back for use.) 
Scoring Criteria 
Drawing: lines are unbroken and straight; angles 90 degrees; top/bottom lines 25% longer than sides 
Placement: not rotated more than 15 degrees 
Drawing: lines are unbroken and straight and should approximately bisect each other 
Placement: ends of lines should meet comers of the rectangle without significant overlap or measurable 
distance between the ends of the lines and the comers 
Drawing: line is unbroken and straight; should not exceed 1/2 the length of the rectangle 
Placement: should bisect left side of the rectangle at approximately a right angle and intersect the diagonal cross 
Drawing: round, unbroken and closed; diameter should be approximately l/4-1/3 height of rectangle 
Placement: placed in appropriate segment; not touching any other part of figure 
Drawing: round, unbroken and closed; equal size; triangular arrangement; not touching each other 
Placement: in appropriate segment; not touching figure; triangle formed not rotated more than 15 degrees 
Drawing: must be closed; 90 degree angles; lines straight and unbroken; height is l/4-1/3 height of rectangle 
Placement: in appropriate segment; not touching any other part of figure; not rotated more than 15 degrees 
Drawing: 2 curved segments are approximately equal in length and symmetrical; correct direction of curves 
Placement: ends of line touch diagonal; do not touch comer of rectangle or intersection of diagonal lines 
Drawing: vertical line of the outside cross is parallel to side of rectangle; > 112 the heifht of rectangle; 
horizontal line crosses vertical at 90 degree angle and is between 20-50% of length o vertical line 
Placement: horizontal line of outside cross touches rectangle higher than 2/3 the height of rectangle, but 
below top; does not penetrate the rectangle 
Drawing: angle formed by 2 sides of triangle is between 60-100 degrees; sides are straight, unbroken 
and meet in a point; distance on vertical side of rectangle subsumed by triangle is approximately 50% of the 
height of vertical side 
Placement: roughly centered on the left vertical side of the rectangle 
Drawing: straight and unbroken; lines forming arrow are approximately equal in length and not more than 
1/3 length of staff 
Placement: must protrude from appropriate comer of rectangle such that staff appears to be continuation 
of diagonal cross 

Figure Recall Drawing Page 
(Fold back for use.) 

Score Conversion Page 
Total 
Score 
I. 
Immediate Memory 
1. List Learning 
2. Story Memory 
11. 
(+) 
3. Figure Copy 
1-------1 > 
4. Line Orientation 
Ill. Language 
5. Picture Naming 
> 
6. Semantic Fluency 
IV. Attention 
(+) 
7. Digit Span 
> 
8. Coding 
·Merri-C:rv- c •· 
' 
,::, -
" 
-
-. 
.. 
. - _. 
... : ·-· 
-
r·------------• . 
I 
I 
9. List Recall 
I 
I 
1 0. List Recognition D 
I 
I 
I 
I 
11. Story Recall 
I 
I 
,. ___________ -4 
I 
I 
I 
I 
I 
I 
I 
I 
12. Figure Recall 
Sum of Total Scores for 
10
1 
Subtests 9 + 11 + 12 = 
Note. Use Appendix 2 in the 
Stimulus Booklet to convert 
Total Scores to Index Scores 
and Sum of Index Scores to 
Total Scale. Subtest scaled 
scores and cumulative per-
centages are also available. 
(=) 
Sum of Index Scores D 
(light-colored boxes) 
TOTAL SCALE D 
. -
-
.. 
:----, 
. ·' '. . 
l ' ' 
D 
D 

Supplemental Discrepancy Analysis Page 
Index Differences 
Statistical 
Frequency of 
Score 1-Score 2 
Score 1 
Score 2 
Difference 
Significance 
Difference in 
Standardization 
--Level 
Sample 
Immediate Memory-Visuospatiai/Constructional 
Immediate Memory-Attention 
Immediate Memory-Language 
Immediate Memory-Delayed Memory 
Immediate Memory-Total Scale 
Visuospatiai/Constructionai-Attention 
Visuospatiai/Constructionai-Language 
Visuospatiai/Constructionai-Delayed Memory 
Visuospatiai/Constructional-Total Scale 
Attention-Language 
Attention-Delayed Memory 
Attention-Total Scale 
Language-Delayed Memory 
Language-Total Scale 
Delayed Memory-Total Scale 

c 
-
_j 'V 
+ j_ 
1-
-
1 
2 
3 
4 
5 
6 
7 
8 
9 
SAMPLE. ________ 
_ 
-
1- c 
+ _j j_ 
'V -
1-
A 
+ 
-
-
j_ 
'V 1-
-
c + _j 
j_ c + _j 
-
1-
A 
-
'V c _j + j_ -
A 
1- c 
-
-
+ c 1-
_j -
1- + A 
c _j j_ + 1-
-
c + 1-
A -
j_ _j c -
+ v 
j_ A 
·-
-
A 
-
_j 1- + 'V j_ _j A 
v 
j_ c _j 
-
+ c _j 
- c + j_ 'V _j A 
-
-
-

I

REFLECT – US IDE Trial [CIP-09 (v13.0)] 
Keystone Heart Ltd. 
168
16.8 Appendix VIII: Angiographic Imaging Acquisition Guidelines 
REFLECT TRIAL 
Angiographic Acquisition Guidelines 
 All angiograms should be obtained paying strict attention to the following features: 
1. Acquire all standard procedural fluoroscopic/angiograms in DICOM format at the
highest magnification which will still incorporate the entire segment of the aortic arch
and the ostia of the 3 major cerebral vessel takeoffs (innominate, left carotid and left
subclavian).
2. All images should have subject identifiers removed prior to uploading images to the
web-based image transfer system. Imaging studies should be appropriately labeled
with Study Name, site ID, subject ID and date that the imaging study was performed.
3. Submit the best LAO projection for assessment of the Aortic Arch and the 3 major
cerebral vessel takeoffs (innominate, left carotid and left subclavian). If renal
dysfunction or other clinical concerns limit contrast administration, angiography of the
innominate artery alone is sufficient. All subsequent fluoroscopic/angiographic images
should be taken using the same LAO projection that was used for the initial
assessment.
4. Submit fluoroscopic images using the initial arch projection to document proper device
positioning at the following recommended time points:
•
After deployment of the TriGuard™ HDH or TriGUARD 3, angiography of the
device and the entire arch is strongly recommended and can be done during or
after pigtail placement.
•
Tracking of the TAVR delivery system to the aortic annulus
•
Final deployment of the first prosthetic valve
•
Removal of the TAVR delivery system (after any additional post-dilatation or
additional valve implantations have been completed)
•
If the position of the TriGuard™ HDH or TriGUARD 3 is perceived to have
changed during the procedure, repeat arch assessment with contrast is strongly
recommended.
5. Provide a plain, non-contrast image of any device complication or malfunction
observed during the procedure.
PLEASE TRY TO INCLUDE IN YOUR SUBMISSION: 
1. Cath Lab Procedure Log or Technician’s Worksheet Form (Please keep a copy of
the original). This may be scanned and emailed to the Angiographic Core Laboratory
contact at the email address below:
Phase I: Ecaterina Cristea, MD 
Yale Angiographic Core Laboratory 
ecaterina.cristea@yale.edu  
Phase II: Ivana Jankovic, MD 
CRF Core Lab Operations 
ijankovic@crf.org  

REFLECT – US IDE Trial [CIP-09 (v13.0)] 
Keystone Heart Ltd. 
169
2. Procedural films. Angiographic and fluoroscopic imaging studies will be uploaded by
the site to a web-based imaging media transfer system (Intelemage®, LLC,
Cincinnati, OH USA).
Phase I: Yale Angiographic Core Lab Contact: 
Ecaterina Cristea, MD 
YALE CARDIOVASCULAR RESEARCH GROUP 
REFLECT TRIAL  
Yale Angiographic Core Laboratory 
Yale University School of Medicine 
135 College Street, Suite 101 
New Haven, CT 06510 
(203) 737-2275 (Office) 
(203) 737-7457 (Office Fax) 
ecaterina.cristea@yale.edu  
Phase II: Cardiovascular Research Foundation Core Lab Contact: 
Ivana Jankovic, MD 
Director, Core Lab Operations 
Cardiovascular Research Foundation 
Clinical Trials Center 
1700 Broadway, 9th Floor 
New York, NY 10019 
Tel: (646) 434-4388 
Fax: (646) 434-4711 
ijankovic@crf.org   

REFLECT – US IDE Trial [CIP-09 (v13.0)] 
Keystone Heart Ltd. 
170
16.9 Appendix IX: Magnetic Resonance Imaging Acquisition 
Protocol 

REFLECT – US IDE Trial [CIP-09 (v13.0)] 
Keystone Heart Ltd. 
182
16.10 Appendix X: CT Angiography Imaging Acquisition Guidelines 

CTA Acquisition Guidelines (CIP-09-2 ver 03)   Confidential
Page 2 
The REFLECT Trial
Computed Tomography (CT) Angiography 
Acquisition Guidelines 
These acquisition guidelines are confidential and proprietary and
meant to accompany the Keystone Heart REFLECT Clinical
Investigational Plan. Any copying or distribution of this document
outside of the purposes of the REFLECT Study are prohibited
without the express permission of Keystone Heart Ltd.

CTA Acquisition Guidelines (CIP-09-2 ver 03)   Confidential  
  Page 3 
 
Table of Contents 
1.0 BACKGROUND 
4 
2.0 EQUIPMENT 
4 
3.0 SCANS 
4 
4.0 SCANNING PROCEDURES 
4 
4.1 STEP 1: PATIENT PREPARATION 
4 
4.2 STEP 2: CHEST TOPOGRAM 
5 
4.3 STEP 3: PROSPECTIVE ECG-GATED NON-CONTRAST SCAN OF AORTIC ROOT 
5 
4.4 STEP 4: ECG-GATED CONTRAST ENHANCED SCAN OF THE AORTIC ROOT AND 
THORACIC AORTA, AND NON-ECG GATED CONTRAST ENHANCED SCAN OF 
ABDOMINAL AORTA AND PERIPHERAL VESSELS 
5 
4.4.1 EXAMPLE CONTRAST ENHANCED SCAN ACQUISITION PROCEDURE 
6 
4.4.2 EXAMPLE POST-PROCESSING PROCEDURE 
6 
4.5 STEP 5: SUBMISSION OF CT DATA 
6 
 
 
 
 
 
 
 
 
 
 
 

CTA Acquisition Guidelines (CIP-09-2 ver 03)   Confidential
Page 4 
1.0 Background
Cardiac Multi-Detector Computed Tomographic Angiography (Cardiac MDCT Angiography)
is intended to evaluate aortic valve anatomy, aortic root dimensions for prosthetic valve
sizing, and assessment of the aorta and peripheral vessels for anatomy and disease burden.
The CT scan results will be used for assessment of the aortic arch for compliance with
positioning of Keystone Heart TriGuard™ as well as planning the best fluoroscopy angle for 
the procedure. Assessment of the ileo-femoral arteries will indicate if the peripheral arteries
anatomy can accommodate the TriGuard delivery system.
2.0 Equipment 
•
Multi-detector CT scanner (64-slice minimum) with ECG-gating capability.
o
The scans submitted for analysis of the aortic root should be ECG-gated; non-
gated scans in areas with cardiac motion lead to measurement inaccuracy and
therefore incomplete information for device selection.
o
Abdominal aorta and peripheral vessel image acquisition may be non-gated.
•
Dual-source scanner preferred due to enhanced temporal resolution and reduced
motion artifacts.
3.0 Scans 
1) Chest Topogram.
2) Prospective ECG-gated non-contrast scan of aortic root and thoracic aorta.
3) Retrospective ECG-gated contrast enhanced scan of the aortic root and thoracic aorta,
immediately followed by non ECG-gated contrast enhanced scan of the abdominal
aorta and peripheral vessels.*
*If CT scanner is incapable of sequential ECG-gated to non-ECG gated scan, the contrast
enhanced CT study can be performed using retrospective ECG-gating in its entirety.
4.0 Scanning Procedures
The optimal scan is similar to a coronary calcium score scan followed by a CT coronary
angiogram / aortogram. The aim is to first evaluate the degree of calcification in the aortic
valve, and then to obtain adequate contrast in the following regions of interest: endo-luminal
surface for visualization of left heart, aorta, and peripheral access vessels (i.e., femoral
arteries). Temporal resolution should be optimized to reduce motion artifact. Spatial
resolution should be as high as possible (goal is smallest isotropic voxel size).
4.1
Step 1: Patient Preparation
•
Administer medication per institution standard practice for CT scanning.
•
Attach ECG electrodes for gating of scan. Verify quality of ECG tracing on scanner
console.
•
Prepare intravenous line for administration of contrast media.
•
Assess heart rate variability during breath-hold.

CTA Acquisition Guidelines (CIP-09-2 ver 03)   Confidential
Page 5 
4.2
Step 2: Chest Topogram
•
A chest topogram can be used to plan subsequent imaging.
Figure CTA-1: Example image of chest topogram
4.3
Step 3: Prospective ECG-gated non-contrast scan of aortic root
The aim of this scan is to quantify the extent of calcium in the aortic valve and aorta,
equivalent to scans calculating a coronary calcium score (e.g. Agatston score).
1. The submitted scan should cover the area from the temporal-mandibular-joint (TMJ)
to the diaphragm to encompass the entire heart, aortic arch and thoracic aorta.
2. Prospective ECG-gating with sequential slice acquisition is preferred.
3. Scan at peak voltage of 120kVp with tube current of 140-150 mAs tube current.
4. Slice thickness 2.5-3.0 mm with a pitch of 1.
4.4 
Step 4: ECG-gated contrast enhanced scan of the aortic root and thoracic
aorta, and non-ECG gated contrast enhanced scan of abdominal aorta and
peripheral vessels
The aim of this scan is to assess the anatomy of the aortic root, aortic arch and cerebral
vessels, thoracic / abdominal aorta, and peripheral vessels (please refer to Table 1 below for
suggested parameters).

CTA Acquisition Guidelines (CIP-09-2 ver 03)   Confidential
Page 6 
1. The optimal scan would include the area from the temporal-mandibular-joint (TMJ) to
the mid-thigh, using dynamic 4D acquisition and retrospective ECG-gating from the
TMJ to the diaphragm (to evaluate the aortic root, aortic arch, cerebral vessels and
thoracic aorta), followed by a non-ECG-gated scan from the diaphragm to the mid-
thigh (to evaluate the abdominal aorta and peripheral vessels). If a sequential ECG-
gated/non-ECG gated study is not available, the entire study could be performed using
retrospective ECG-gating.
2. Detector collimation is 0.4-0.625mm.
3. Slice thickness is ≤ 0.8mm.
4. Peak voltage of 120kVp with tube current from 350-550 mAs per scanner protocol for
patient body mass index.
4.4.1 Example Contrast Enhanced Scan Acquisition Procedure
•
Prepare iodinated contrast injection apparatus (suggested scan parameters are
provided in Table 1).
•
Ensure availability of immediate treatments in case of contrast allergy.
•
Set up scan parameters.
•
Instruct patient to lie still during scan, even if they experience warmth or tingling due
to the injection of contrast.
•
Initiate contrast injection.
•
When contrast reaches threshold at bolus-tracking location, instruct patient to hold
breath at end-inspiration, then initiate main scan.
•
At completion of scan, verify scan is of adequate quality.
•
Record amount of contrast given.
•
Record heart rate average and range.
•
Record dose-length-product
4.4.2 Example Post-processing Procedure
•
Verify heart rate ECG triggers are at consistent place in cardiac cycle, edit if
necessary. Additional editing/removal of arrhythmias may be performed.
•
Reconstruct at multiple phases (20 preferred, increments of 5-10%), with ≤0.8mm
slice thickness. If the system has the capability, also reconstruct a “best systolic” and
“best diastolic” phase.
4.5 
Step 5: Submission of CT data
All available CT data should be sent electronically to the data center (Core Laboratory).
•
Data should be stored in DICOM 3.0 format, not DICOMDAT.
•
Submitted images must have patient identifiers (protected health information (PHI)
such as name, date of birth, medical record number) removed at time of image
transfer to the data center.
•
Please use the following during anonymization:

CTA Acquisition Guidelines (CIP-09-2 ver 03)   Confidential
Page 7 
o
Modality = CT
o
“Body Part Examined” contains the value = CHEST
o
“Protocol Name” contains any of the values = PWI, Brain, Neuro, Perf,
Low Grade
o
“Series Description” contains any of the values = CHEST TOPOGRAM,
ECG NON CONTRAST AORTIC ROOT, ECG CONTRAST AORTIC ROOT,
ECG CONTRAST THORATIC AORTA, NON ECG CONTRAST ABDOMINAL
AORTA NON ECG CONTRAST PERIPHERAL VESSELS.
•
Submitted imaging studies should be labeled as follows: CCSCTC-SNR
CC- is the region ID which will be assigned in two letter format (US or UK).
SC- is the site ID which will be assigned in two number format (01, 02, etc.).
TC- is the internal ID which will be assigned in two number format (for REFLECT the
number is 09).
SNR- is the subject number which will be assigned in three number format (001, 002,
etc.)
•
Please provide all the following images if available:
o
Chest Topogram
o
ECG-gated non-contrast scan of aortic root and aortic arch
o
ECG-gated contrast enhanced scan of aortic root and thoracic aorta,
immediately followed by non-ECG-gated contrast scan of abdominal aorta and
peripheral vessels
Instructions for submission of CT imaging data will be reviewed with each site during CT
Protocol Training sessions. Images will be sent via electronic transfer using the transfer
solution. 
Instructions will be provided during site set-up.  Reference the transfer solutions Site User
Guide and/or the  Quick Reference Sheet for specific instructions regarding the electronic
transfer of CT images.

CTA Acquisition Guidelines (CIP-09-2 ver 03)   Confidential
Page 8 
Table 1. Suggested Scan Parameters for contrast enhanced scan of aortic root, aorta and
peripheral vessels
Dual-Source CT
Single-Source CT
IV injection with iodine
contrast
100-120 (320 mg/ml or higher)
Injection Rate
4-5 mL/s
Bolus tracking, delay
Delay time calculated using protocol for current scanner
(bolus tracking, etc.) with triggered by contrast
concentration >100 HU in the high descending aorta
ECG Leads
Required
ECG-gating
Retrospective ECG-gating from TMJ to diaphragm;
then non-ECG-gating from diaphragm to mid-thigh
Scan direction
Cranial-caudal
Scan coverage
From above the temporal mandibular joint to the mid-thigh
Detector collimation
0.4-0.625 mm
Pitch
0.2-0.43 adapted to the
heart rate
0.2 adapted to heart rate
Dose modulation
Modulation between 30% and 80% of the cardiac cycle
Slice thickness
0.8mm
Slice overlap
0.4mm
Reconstruction kernel
B25 Smooth++
Medium Smooth
Post-processing
Use retrospective ECG gating reconstruction algorithm that
minimizes motion artifact. Reconstruct at multiple phases
(20 preferred, increments of 5-10%). Reconstructed slice
thickness 0.4-0.6 mm.

REFLECT – US IDE Trial [CIP-09 (v13.0)] 
Keystone Heart Ltd. 
190
16.11 Appendix XI: SF-36 Health Survey 
The Short Form Short Form 36 Health Survey (SF-36v2) is copyright Medical Outcomes Trust 
and Quality Metric Incorporated, and is licensed for use in this trial; authorized copies, 
alternate versions, and translations will be provided as required. A sample form is provided 
below for informational purposes. 

SF-36v2® Health Survey  1992, 1996, 2000 Medical Outcomes Trust and QualityMetric Incorporated.  All rights reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
(SF-36v2® Health Survey Acute, United States (English)) 
Your Health and Well-Being 
This survey asks for your views about your health.  This information will help 
keep track of how you feel and how well you are able to do your usual activities. 
Thank you for completing this survey! 
For each of the following questions, please mark an 
 in the one box that best 
describes your answer. 
1.
In general, would you say your health is:
Excellent 
Very good 
Good 
Fair 
Poor 
 
 
 
 

  
 1 
  
 2 
  
 3 
  
 4 
  
 5 
2.
Compared to one week ago, how would you rate your health in general
now? 
Much better 
now than one 
week ago 
Somewhat 
better  
now than one 
week ago 
About the 
same as one 
week ago 
Somewhat 
worse  
now than one 
week ago 
Much worse 
now than one 
week ago 
 
 
 
 

  
 1 
  
 2 
  
 3 
  
 4 
  
 5 

 
SF-36v2® Health Survey  1992, 1996, 2000 Medical Outcomes Trust and QualityMetric Incorporated.  All rights reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
(SF-36v2® Health Survey Acute, United States (English)) 
3. The following questions are about activities you might do during a typical 
day.  Does your health now limit you in these activities?  If so, how much?  
 
 
 
Yes,  
limited  
a lot 
Yes, 
limited  
a little 
No, not 
limited  
at all 
 
   
a Vigorous activities, such as running, lifting  
heavy objects, participating in strenuous sports ...................... 
 1 ............. 
 2 ............. 
 3 
 
b Moderate activities, such as moving a table, pushing  
a vacuum cleaner, bowling, or playing golf............................. 
 1 ............. 
 2 ............. 
 3 
 
c Lifting or carrying groceries .................................................... 
 1 ............. 
 2 ............. 
 3 
 
d Climbing several flights of stairs ............................................. 
 1 ............. 
 2 ............. 
 3 
 
e Climbing one flight of stairs .................................................... 
 1 ............. 
 2 ............. 
 3 
 
f Bending, kneeling, or stooping ................................................ 
 1 ............. 
 2 ............. 
 3 
 
g Walking more than a mile ........................................................ 
 1 ............. 
 2 ............. 
 3 
 
h Walking several hundred yards ............................................... 
 1 ............. 
 2 ............. 
 3 
 
i Walking one hundred yards ..................................................... 
 1 ............. 
 2 ............. 
 3 
 
j Bathing or dressing yourself .................................................... 
 1 ............. 
 2 ............. 
 3 

SF-36v2® Health Survey  1992, 1996, 2000 Medical Outcomes Trust and QualityMetric Incorporated.  All rights reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
(SF-36v2® Health Survey Acute, United States (English)) 
4.
During the past week, how much of the time have you had any of the
following problems with your work or other regular daily activities as a
result of your physical health?
All of 
the time 
Most of 
the time 
Some of 
the time 
A little of 
the time 
None of 
the time 
    
a Cut down on the amount of 
time you spent on work or 
other activities .................................. 
 1 ..............
 2 .............. 
 3 .............. 
 4 ............. 
5
b Accomplished less than you 
would like ........................................ 
 1 ..............
 2 .............. 
 3 .............. 
 4 ............. 
5
c Were limited in the kind of 
work or other activities .................... 
 1 ..............
 2 .............. 
 3 .............. 
 4 ............. 
5
d Had difficulty performing the 
work or other activities (for 
example, it took extra effort) ........... 
 1 ..............
 2 .............. 
 3 .............. 
 4 ............. 
5
5.
During the past week, how much of the time have you had any of the
following problems with your work or other regular daily activities as a
result of any emotional problems (such as feeling depressed or anxious)?
All of 
the time 
Most of 
the time 
Some of 
the time 
A little of 
the time 
None of 
the time 
    
a Cut down on the amount of 
time you spent on work or 
other activities .................................. 
 1 ..............
 2 .............. 
 3 .............. 
 4 ............. 
5
b Accomplished less than you 
would like ........................................ 
 1 ..............
 2 .............. 
 3 .............. 
 4 ............. 
5
c Did work or other activities 
less carefully than usual ................... 
 1 ..............
 2 .............. 
 3 .............. 
 4 ............. 
5

 
SF-36v2® Health Survey  1992, 1996, 2000 Medical Outcomes Trust and QualityMetric Incorporated.  All rights reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
(SF-36v2® Health Survey Acute, United States (English)) 
6. During the past week, to what extent has your physical health or emotional 
problems interfered with your normal social activities with family, friends, 
neighbors, or groups? 
Not at all 
Slightly 
Moderately 
Quite a bit 
Extremely 
 
 
 
 
 
  
 1 
  
 2 
  
 3 
  
 4 
  
 5 
 
 
 
 
 
7. How much bodily pain have you had during the past week? 
None 
Very mild 
Mild 
Moderate 
Severe 
Very severe 
      
  
 1 
  
 2 
  
 3 
  
 4 
  
 5 
  
 6 
 
 
 
 
 
8. During the past week, how much did pain interfere with your normal work 
(including both work outside the home and housework)? 
Not at all 
A little bit 
Moderately 
Quite a bit 
Extremely 
 
 
 
 
 
  
 1 
  
 2 
  
 3 
  
 4 
  
 5 

 
SF-36v2® Health Survey  1992, 1996, 2000 Medical Outcomes Trust and QualityMetric Incorporated.  All rights reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
(SF-36v2® Health Survey Acute, United States (English)) 
9. These questions are about how you feel and how things have been with you 
during the past week.  For each question, please give the one answer that 
comes closest to the way you have been feeling.  How much of the time 
during the past week… 
 
 
10. During the past week, how much of the time has your physical health or 
emotional problems interfered with your social activities (like visiting with 
friends, relatives, etc.)? 
All of  
the time 
Most of  
the time 
Some of  
the time 
A little of  
the time 
None of 
the time 
 
 
 
 
 
  
 1 
  
 2 
  
 3 
  
 4 
  
 5 
 
 
 
All of  
the time 
Most of  
the time 
Some of  
the time 
A little of  
the time 
None of 
the time 
     
 
a Did you feel full of life? ..................
 1 ..............
 2 ..............
 3 ..............
 4 ..............
 5 
 
b Have you been very nervous? ..........
 1 .............. 
 2 ..............
 3 ..............
 4 ..............
 5 
 
c Have you felt so down in the  
dumps that nothing could  
cheer you up? ...................................
 1 ..............
 2 ..............
 3 ..............
 4 ..............
 5 
 
d Have you felt calm and  
peaceful? ..........................................
 1 .............. 
 2 ..............
 3 ..............
 4 ..............
 5 
 
e Did you have a lot of energy? ..........
 1 ..............
 2 ..............
 3 ..............
 4 ..............
 5 
 
f Have you felt downhearted   
and depressed? .................................
 1 .............. 
 2 ..............
 3 ..............
 4 ..............
 5 
 
g Did you feel worn out? ....................
 1 .............. 
 2 ..............
 3 ..............
 4 ..............
 5 
 
h Have you been happy? .....................
 1 .............. 
 2 ..............
 3 ..............
 4 ..............
 5 
 
i Did you feel tired? ...........................
 1 ..............
 2 ..............
 3 ..............
 4 ..............
 5 

SF-36v2® Health Survey  1992, 1996, 2000 Medical Outcomes Trust and QualityMetric Incorporated.  All rights reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
(SF-36v2® Health Survey Acute, United States (English)) 
11.
How TRUE or FALSE is each of the following statements for you?
Definitely 
true 
Mostly 
true 
Don’t 
know 
Mostly 
false 
Definitely 
false 




a I seem to get sick a little 
easier than other people .................. 
 1 ..............
 2 ............. 
 3............... 
 4 .............. 
 5 
b I am as healthy as 
anybody I know .............................. 
 1 ..............
 2 ............. 
 3............... 
 4 .............. 
 5 
c I expect my health to 
get worse ......................................... 
 1 ..............
 2 ............. 
 3............... 
 4 .............. 
 5 
d My health is excellent ..................... 
 1 ..............
 2 ............. 
 3............... 
 4 .............. 
 5 
Thank you for completing these questions!