RESPOND: Re-positionable Lotus Valve System - Post Market Evaluation of Real World Clinical Outcomes
Conditions: Aortic Valve Stenosis
Sponsor: Boston Scientific Corporation

 
 
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RESPOND: Repositionable Lotus Valve System – Post Market Evaluation of 
Real World Clinical Outcomes 
 
 
CLINICAL STUDY PROTOCOL 
 
Protocol Number: TP6461 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This protocol contains confidential information for use by the Investigators and their 
designated representatives participating in this clinical investigation. It should be held 
confidential and maintained in a secure location. 
Do not copy or distribute without written permission from Boston Scientific Corporation. 
 
 
 

 
 
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Contact Information 
Role 
Contact  
Sponsor 
Contacts 
Andrey Nersesov 
Senior Clinical Trial Manager 
Structural Heart – Interventional Cardiology  
Boston Scientific Structural Heart 
160 Knowles Drive 
Los Gatos, CA 95032 USA  
 
Blessie Concepcion 
Director, Clinical Trials 
Structural Heart – Interventional Cardiology 
Boston Scientific Structural Heart 
160 Knowles Drive 
Los Gatos, CA 95032 USA 
Coordinating 
Co-Principal 
Investigators 
Nicolas Van Mieghem, MD 
Department of Interventional Cardiology 
Thoraxcenter, Erasmus Medical Center 
's Gravendijkwal 230, Office Bd 171 
3000 CA Rotterdam, the Netherlands 
 
Volkmar Falk, MD, PhD 
University of Zürich 
Department of Cardiovascular Surgery 
Rämistrasse 100 
Zürich CH-8091, Switzerland
Date of Issue 
15 November 2013, Version AA 
Date(s) of 
Amendment(s) 
03 October 2014, Version AB 
08 April 2016, Version AC 

 
 
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2. Protocol Synopsis 
RESPOND: Repositionable Lotus Valve System – Post Market Evaluation of 
Real World Clinical Outcomes
Objective(s) 
To collect real world clinical and device performance outcomes data with 
the Lotus™ Valve System used in routine clinical practice for the 
treatment of severe calcific aortic stenosis. 
Indication(s) for 
Use  
The Lotus Valve System is indicated to improve aortic valve function for 
symptomatic subjects with severe calcific aortic stenosis (aortic valve 
area [AVA] of <1.0 cm2 or index of <0.6 cm2/m2) who are at high risk for 
standard surgical valve replacement.  
Test Device 
Commercially available Lotus Valve Systems. 
Study Design 
A prospective, open label, single arm, multi-center, observational post 
market study. Study cohorts include the main cohort of approximately 
1000 subjects and a second cohort of approximately 80 subjects.  
Planned 
Number of 
Subjects 
The main cohort of approximately 1000 real-world, prospective, 
consecutive subjects will be enrolled at up to 60 study centers in Europe, 
Asia Pacific and South America. 
An additional cohort of approximately 80 subjects will be enrolled at up 
to 8 study centers in Europe after enrollment in the main cohort is 
completed to assess center-driven implantation technique with the 
commercially available Lotus Valve System.  
NOTE: Consecutive is defined as a commitment by the participating investigators at 
each study center to enroll all consented patients admitted for transcatheter aortic valve 
implantation (TAVI) who are selected to receive a Lotus Valve. 
Study 
Population 
All subjects who are candidates for transcatheter aortic valve implantation 
(TAVI), signed the Informed Consent Form (ICF) and are selected to 
receive a Lotus Valve will be evaluated for enrollment in this study 
Definition of 
Enrollment 
A subject is considered enrolled upon obtaining a signed ICF from the 
subject or subject’s legally authorized representative (LAR) and an 
attempt to insert the Lotus Introducer sheath.  
Primary 
Endpoint 
Main cohort: All-cause mortality at 30 days and 1 year after the implant 
procedure. All-cause mortality at 30 days will be compared to a pre-
specified performance goal. 

 
 
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RESPOND: Repositionable Lotus Valve System – Post Market Evaluation of 
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Additional cohort: All-cause mortality at 30 days after the implant 
procedure. 
Secondary 
Endpoints 
The following secondary endpoints will be assessed according to current 
Valve Academic Research Consortium (VARC) guidelines: 
 Safety composite of all-cause mortality and disabling stroke at 30 
days and 1 year 
 In-hospital mortality 
 The VARC efficacy composite at 1 year, including all-cause mortality 
(after 30 days); all stroke (disabling and non-disabling); re-
hospitalization for valve-related symptoms or worsening congestive 
heart failure (NYHA class III or IV); and prosthetic valve-related 
dysfunction (mean aortic valve gradient ≥20 mmHg, effective orifice 
area (EOA) ≤0.9–1.1 cm2 and/or Doppler velocity index (DVI) <0.35 
m/s, AND/OR moderate or severe prosthetic valve aortic 
regurgitation) 
 Time related valve safety composite at 1 year, including structural 
valve deterioration (valve-related dysfunction requiring repeat 
procedure [TAVI or SAVR]); prosthetic valve endocarditis; prosthetic 
valve thrombosis; thromboembolic events (e.g. stroke) and VARC 
bleeding, unless clearly unrelated to valve therapy based on 
investigator assessment (e.g. trauma) 
 Clinical endpoints at 30 days defined according to current VARC 
guidelines: 
o Life-threatening bleeding 
o Acute kidney injury—Stage 2 or 3 (including renal 
replacement therapy) 
o Coronary artery obstruction requiring intervention 
o Major vascular complication 
o Valve-related dysfunction requiring repeat procedure (BAV, 
TAVI, or SAVR) 
o New conduction disturbances (LBBB, AVB, RBBB) and need 
for permanent pacemaker implantation 
 Grade of paravalvular aortic valve regurgitation pre-discharge as 
measured by transthoracic echocardiography (TTE) and assessed by 
an independent core laboratory. The moderate and severe paravalvular 
aortic regurgitation rate will be compared to a pre-specified 
performance goal. 
NOTE: Secondary endpoints will be assessed in the additional cohort of 80 patients 
through 30 day follow up.  

 
 
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Additional 
Measurements 
 The following events at discharge will be collected based on the 
current VARC definitionsa,b: 
o All-cause death (cardiovascular and non-cardiovascular) 
o Stroke: disabling and non-disabling  
o Myocardial infarction (MI): periprocedural (≤72 hours post 
index procedure) and spontaneous (>72 hours post index 
procedure) 
o Bleeding: life-threatening (or disabling), major and minor 
o Acute kidney injury (≤7 days post index procedure): based on 
the AKIN System Stage 3 (including renal replacement 
therapy), Stage 2, and Stage 1 
o Major and minor vascular complication 
o Repeat procedure for valve-related dysfunction (surgical or 
interventional therapy) 
o Hospitalization for valve-related symptoms or worsening 
congestive heart failure (NYHA class III or IV) 
o New permanent pacemaker implantation resulting from new or 
worsened conduction disturbances (including new left bundle 
branch block [LBBB] and third degree atrioventricular block) 
o New onset of atrial fibrillation or atrial flutter  
o Coronary obstruction (periprocedural) 
o Ventricular septal perforation (periprocedural) 
o Mitral apparatus damage (periprocedural) 
o Cardiac tamponade (periprocedural) 
o Prosthetic aortic valve malapposition, including valve 
migration, valve embolization, ectopic valve deployment, or 
transcatheter aortic valve (TAV)-in-TAV deployment 
o Prosthetic aortic valve thrombosis 
o Prosthetic aortic valve endocarditis 
 Device performance measured peri- and post-procedurally consisting 
of the following:  
o Successful vascular access, delivery and deployment of the 
Lotus Valve System, and successful retrieval of the delivery 
system 
o Successful repositioning (partial or complete resheathing of 
the Lotus Valve in the catheter and redeployment in a more 
accurate position within the aortic valve annulus) of the Lotus 

 
 
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Valve System if repositioning is attempted 
o Successful retrieval (complete resheathing of the Lotus Valve 
in the catheter and removal from the body) of the Lotus Valve 
System if retrieval is attempted 
o Grade of paravalvular aortic valve regurgitation 
 Physicians Preference Test (PPT), including device deficiencies, to 
measure device usability and ease of use peri-procedurally. 
 Prosthetic aortic valve performance as measured by transthoracic 
echocardiography (TTE) and assessed by an independent core 
laboratory, including effective orifice area, mean and peak aortic 
gradients, peak aortic velocity, and grade of aortic regurgitation, pre-
discharge and at 1 year. Site reported TTE measures will be collected 
at 30 days and annually from 2 through 5 year follow up per local 
standard of care for TAVI.  
 Health status as evaluated by EuroQoL (EQ-5D) Quality of Life 
questionnaire at baseline, 30 days, 1, 3 and 5 year follow up, during 
in-person clinic visit or via postal mail. 
 New York Heart Association (NYHA) functional classification at 
baseline, discharge, 30 days, 1 year and annually through 5 year 
follow up. 
a Kappetein AP, et al. J Am Coll Cardiol. 2012;60:1438-1454 
b Leon M, et al. J Am Coll Cardiol. 2011;57:253-269 
NOTE: Additional measurements will be assessed in the additional cohort of 80 patients 
through 30 day follow up. 
Safety 
Parameters 
 Any serious adverse event (SAE) that led to death, serious 
adverse device effect (SADE), adverse device effect (ADE), 
unanticipated serious adverse device effect (USADE), and 
VARC event regardless of seriousness and device relationship 
will be collected through complete subject follow up. 
 All-cause mortality and stroke events will be adjudicated by an 
independent Clinical Events Committee (CEC) through complete 
subject follow up. 
 Reporting of device deficiencies will follow applicable regional 
post-market safety surveillance requirements. 
Follow-up 
Schedule 
For the main cohort of 1000 subjects, follow up will occur at 30 days 
and 1, 2, 3, 4 and 5 years post index valve implantation for all 
enrolled subjects. Follow-up visit at 1 year post valve implantation 

 
 
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should be conducted via outpatient clinic visit. Follow up visits at 
30 days and 2 through 5 years may be conducted in person 
(preferred) or via telephone interview.  
For the additional cohort of 80 subjects, which is designed to 
evaluate center-driven implant technique, follow up will occur at 
30 days post index valve implantation for all enrolled subjects. 
Subjects who are not implanted with a Lotus Valve will be followed for 
safety through 30 days after the initial attempted index procedure. 
Statistical Methods  
Statistical 
Method for the 
Primary 
Endpoint  
(Main Cohort) 
All-cause mortality at 30 days post implant procedure is less than a 
performance goal (PG) of 14% (expected rate of 10% + testing margin of 
4%). A one-sample exact binominal test will be used to test the one-sided 
hypothesis: 
H0: Mortality30D ≥ PG 
H1: Mortality30D < PG  
where Mortality30D is the 30-day all-cause mortality rate for the Lotus 
Valve and PG is 14%. 
Sample Size 
Parameters 
(Main Cohort) 
 Expected 30-day all-cause mortality rate = 10%  
 Performance goal (PG) = 14% (expected rate of 10% + testing margin 
of 4%) 
 Test significance level () = 0.025 (1-sided) 
 Power (1 – ) > 95% 
 Planned enrollment of up to 1000 subjects 
 Two planned interim analyses on the primary endpoint at 30 days 
post-implant procedure will be performed on the first 250 and 500 
subjects enrolled. A final analysis will be performed on all enrolled 
subjects 
 The primary analysis population for the primary endpoint will be the 
subject population attempted or implanted with the Lotus Valve.    
Note:  The expected 30-day all-cause mortality rate is assumed to be 10% 
based on a literature review of studies evaluating the Medtronic 
CoreValve System and the Edwards Lifesciences SAPIEN Transcatheter 
Heart Valve System (FRANCE 2 registrya).  
Note: The alpha-level for the interim and final analyses is adjusted using 

 
 
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the Pocock alpha spending function (see Success Criteria below). 
a Gilard M, et al. N Engl J Med 2012;366:1705 
Statistical 
Method for the 
Secondary 
Endpoint 
(Main Cohort) 
Proportion of subjects with moderate/severe aortic regurgitation pre-
discharge as assessed by TTE post implant procedure is less than the PG 
of 16.5%. A one-sample exact binominal test will be used to test the one-
sided hypothesis: 
H0: ARpre-discharge ≥ PG 
H1: ARpre-discharge < PG 
where ARpre-discharge is the proportion of subjects with moderate/severe 
aortic regurgitation pre-discharge as assessed by TTE post implant 
procedure for the Lotus Valve and PG is 16.5%. 
Sample Size 
Parameters 
(Main Cohort) 
 Expected proportion of subjects with moderate/severe aortic 
regurgitation pre-discharge as assessed by TTE post implant 
procedure = 10%  
 Performance goal (PG) = 16.5% (based on FRANCE 2 registry) 
 Test significance level () = 0.025 (1-sided) 
 Power (1 – ) > 99% 
 Planned enrollment of up to 1000 subjects 
 Two planned interim analyses on the secondary endpoint prior to 
discharge from the hospital post- implant procedure will be 
performed on the first 250 and 500 subjects enrolled. A final analysis 
will be performed on all enrolled subjects 
 The primary analysis population for the secondary endpoint will be 
the subject population implanted with the Lotus Valve.    
Note:  The performance goal is set at 16.5% based on rates observed with 
Medtronic CoreValve System and the Edwards Lifesciences SAPIEN 
Transcatheter Heart Valve System (FRANCE 2 registry). 
Note: The alpha-level for the interim and final analyses is adjusted using 
the Pocock alpha spending function (see Success Criteria below). 
Success Criteria
(Main Cohort) 
Two interim analyses for the primary and secondary endpoints will be 
conducted on the first 250 and 500 subjects and a final analysis will be 
conducted on the planned 1000 subjects. The Pocock alpha spendinga 
function is used to adjust the alpha-level for each analysis: 0.00894, 
0.00895, and 0.01301, respectively. If the P value from the one-sample 

 
 
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exact binominal test is <alpha, the Lotus Valve will be concluded to have 
event rate < PG. This corresponds to the one-sided Clopper-Pearson 
upper (1-alpha)% confidence bound of the observed  event rate being 
< PG. 
The data of the additional cohort of approximately 80 subjects will be 
summarized using descriptive statistics and will not be pooled with the 
first cohort of 1,000 subjects in the data analysis. No statistical 
hypotheses will be tested in the additional cohort.  
 
a Kim K, DeMets DL. Biometrika 1987;74:149 
 
 

 
 
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3. Table of Contents 
1. 
TITLE PAGE  ........................................................................................................................ 1 
2. 
PROTOCOL SYNOPSIS .......................................................................................................... 3 
3. 
TABLE OF CONTENTS ........................................................................................................ 10 
3.1. Table of Figures ...................................................................................................... 13 
3.2. Table of Tables ....................................................................................................... 13 
4. 
INTRODUCTION ................................................................................................................. 14 
4.1. REPRISE I .............................................................................................................. 15 
4.1.1. 
Primary Endpoint ....................................................................................... 15 
4.1.2. 
Secondary Endpoints ................................................................................. 16 
4.1.3. 
Conclusion ................................................................................................. 16 
4.2. REPRISE II ............................................................................................................ 17 
4.2.1. 
Primary Endpoint ....................................................................................... 17 
4.2.1.1. 
Primary Device Performance Endpoint .................................... 17 
4.2.1.2. 
Primary Safety Endpoint ........................................................... 17 
4.2.2. 
Secondary Endpoints ................................................................................. 17 
4.2.3. 
Conclusion ................................................................................................. 19 
5. 
DEVICE DESCRIPTION ....................................................................................................... 19 
5.1. Lotus Valve System ................................................................................................ 19 
5.1.1. 
Lotus Valve ................................................................................................ 19 
5.1.2. 
Lotus Delivery System .............................................................................. 20 
5.2. Intended Use ........................................................................................................... 21 
5.3. Device Labeling ...................................................................................................... 21 
6. 
OBJECTIVES ...................................................................................................................... 22 
7. 
ENDPOINTS ........................................................................................................................ 22 
7.1. Primary Endpoint .................................................................................................. 22 
7.2. Secondary Endpoints ............................................................................................. 22 
7.3. Additional Measurements ..................................................................................... 23 
8. 
STUDY DESIGN .................................................................................................................. 24 
8.1. Justification for the Study Design ......................................................................... 25 

 
 
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9. 
SUBJECT SELECTION ......................................................................................................... 25 
10. SUBJECT ACCOUNTABILITY .............................................................................................. 25 
10.1. Point of Enrollment ................................................................................................ 25 
11. STUDY METHODS .............................................................................................................. 25 
11.1. Data Collection ....................................................................................................... 25 
11.2. Study Candidate Screening ................................................................................... 27 
11.3. Informed Consent .................................................................................................. 27 
11.4. Baseline ................................................................................................................... 27 
11.5. Index Procedure ..................................................................................................... 28 
11.6. Post-procedure / Prior to Hospital Discharge ..................................................... 28 
11.7. Follow-up ................................................................................................................ 29 
11.7.1. 30-Day Follow-up (30+7 days) ................................................................. 29 
11.7.2. Annual Follow-up (+45 days) .................................................................... 30 
11.8. Withdrawal and Replacement of Subjects ........................................................... 30 
11.9. Study Completion ................................................................................................... 31 
12. STATISTICAL CONSIDERATIONS ....................................................................................... 31 
12.1. Endpoints ................................................................................................................ 31 
12.1.1. Primary Endpoint ....................................................................................... 31 
12.1.1.1. Hypothesis................................................................................. 31 
12.1.1.2. Sample Size – Primary Endpoint .............................................. 31 
12.1.2. Secondary Endpoint ................................................................................... 32 
12.1.2.1. Hypothesis................................................................................. 32 
12.1.2.2. Sample Size – Secondary Endpoint .......................................... 32 
12.1.3. Statistical Methods ..................................................................................... 33 
12.2. General Statistical Methods .................................................................................. 33 
12.2.1. Analysis Sets .............................................................................................. 33 
12.2.2. Control of Systematic Error/Bias ............................................................... 33 
12.3. Data Analyses ......................................................................................................... 33 
12.3.1. Risk Adjusted Analysis.............................................................................. 33 
12.3.2. Interim Analyses ........................................................................................ 34 
12.3.3. Changes to Planned Analyses .................................................................... 34 
13. DATA MANAGEMENT ........................................................................................................ 34 
13.1. Data Collection, Processing, and Review ............................................................. 34 

 
 
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13.2. Record Retention .................................................................................................... 35 
13.3. Core Laboratory..................................................................................................... 35 
14. AMENDMENTS ................................................................................................................... 35 
15. DEVIATIONS ...................................................................................................................... 35 
16. COMPLIANCE ..................................................................................................................... 36 
16.1. Statement of Compliance ....................................................................................... 36 
16.2. Investigator Responsibilities ................................................................................. 36 
16.3. Institutional Review Board/ Ethics Committee ................................................... 36 
16.4. Sponsor Responsibilities ........................................................................................ 36 
16.5. Insurance ................................................................................................................. 37 
17. TRAINING .......................................................................................................................... 37 
18. MONITORING ..................................................................................................................... 37 
19. POTENTIAL RISKS AND BENEFITS .................................................................................... 38 
19.1. Potential Risks ........................................................................................................ 38 
19.2. Potential Benefits .................................................................................................... 38 
20. INFORMED CONSENT......................................................................................................... 38 
21. SAFETY REPORTING .......................................................................................................... 38 
21.1. Definitions and Classification ............................................................................... 38 
21.2. Relationship to Study Device(s) ............................................................................ 40 
21.3. Investigator Reporting Requirements .................................................................. 40 
21.4. Device Deficiencies ................................................................................................. 41 
22. COMMITTEES .................................................................................................................... 41 
22.1. Steering Committee ................................................................................................ 41 
22.2. Clinical Events Committee .................................................................................... 42 
23. SUSPENSION OR TERMINATION ........................................................................................ 42 
23.1. Criteria for Terminating the Study ...................................................................... 42 
23.2. Criteria for Suspending/Terminating a Study Center ........................................ 42 
24. PUBLICATION POLICY ....................................................................................................... 42 

 
 
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25. BIBLIOGRAPHY .................................................................................................................. 43 
26. ABBREVIATIONS AND DEFINITIONS .................................................................................. 47 
26.1. Abbreviations ......................................................................................................... 47 
26.2. Definitions ............................................................................................................... 49 
27. APPENDICES ...................................................................................................................... 62 
27.1. Changes in Protocol Versions ............................................................................... 62 
27.1.1. Protocol Version AA to Version AB ......................................................... 62 
 
 
3.1. Table of Figures 
Figure 5.1-1: Lotus™ Valve System ...................................................................................... 19 
Figure 5.1-2: Lotus Valve Implant .......................................................................................... 20 
Figure 5.1-3: Lotus Valve Delivery System – Handle ............................................................ 21 
 
 
3.2. Table of Tables 
Table 4-1: REPRISE I Primary Endpoint ............................................................................... 15 
Table 4-2: REPRISE I Secondary Endpoints.......................................................................... 16 
Table 4-3: REPRISE II Primary Device Performance Endpoint, As-Treated Analysis Set 
(N=60).................................................................................................................. 17 
Table 4-4: REPRISE II Secondary Endpoints, ITT Analysis Set (N=60) .............................. 18 
Table 11.1-1: Study Event Schedule ....................................................................................... 26 
Table 21.1-1: Adverse Event Definitions ............................................................................... 38 
Table 21.2-1: Criteria for Assessing Relationship of Study Device to Adverse Event .......... 40 
Table 21.3-1: Investigator Reporting Requirements ............................................................... 40 
Table 26.1-1: Abbreviations and Acronyms ........................................................................... 47 
Table 26.2-1: Definitions ........................................................................................................ 49 
Table 27.1-1: Table of Changes for Protocol Version AB (Compared to Protocol Version 
AA) ...................................................................................................................... 62 
 

 
 
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4. Introduction 
The incidence of aortic stenosis (AS) is increasing due to the aging of the world-wide 
population and the lack of drug therapies to prevent, halt, or effectively slow the stenotic 
process1,2. Nearly 5% of individuals >75 years of age have some degree of AS1,2. Once 
symptoms manifest, the prognosis is poor, especially when associated with congestive heart 
failure. Successful treatment of aortic valve obstruction can result in the improvement of 
symptoms, hemodynamic parameters, systolic function, and cardiac hypertrophy along with 
increased survival. 
Surgical aortic valve replacement (SAVR) remains the gold standard treatment for the 
management of subjects with severe AS. However, the operative risk is increased in elderly 
subjects, in subjects with concomitant coronary artery disease or severely reduced left 
ventricular (LV) function, and in subjects with associated comorbidities such as cerebral and 
peripheral vascular disease, renal failure, and respiratory dysfunction3-5. Percutaneous 
transluminal aortic valvuloplasty, which was introduced as an alternative to SAVR in elderly 
and/or high-risk subjects, can provide symptomatic relief and/or temporary improvement but 
does not provide definitive treatment in subjects with severe calcified AS. It is also 
associated with relatively high mortality and complication rates6. 
Transcatheter aortic valve implantation (TAVI) has recently emerged as an alternative to the 
surgical approach in the treatment of severe AS in subjects who are not suitable candidates 
for open-heart surgery7. This technology is generally restricted to subjects considered at 
prohibitive or high surgical risk. Evidence of the safety of the procedure using either a 
balloon expandable or a self-expanding bioprosthetic heart valve has rapidly accumulated 
through observational studies8-19, device-specific registries20-31, national registries32-38, and 
randomized controlled trials39-42. An expert consensus document on TAVI was recently 
published43. Standardized endpoint definitions were published by the Valve Academic 
Research Consortium (VARC) in 2011 and updated in 201244,45. 
The RESPOND study is designed to provide post-market surveillance information on the 
LotusTM Valve System after it has placed on the market of the European Economic Area and 
other regions worldwide. The study will collect clinical and device performance outcomes 
data for patients receiving the Lotus Valve System over 5 years in a real world setting.  
The Lotus Valve System consists of a pre-loaded, stent-mounted tissue valve prosthesis and 
catheter delivery system designed to enable predictable and precise placement of the valve 
during TAVI46. Early leaflet function during valve deployment and the presence of a 
radiopaque tantalum marker on the braided frame facilitates optimal initial positioning of the 
valve. If needed, the valve may be un-locked after being locked and partially or fully re-
sheathed for repositioning prior to final release or can be fully retrieved if during the 
procedure the decision is made not to implant. The valve also has a polycarbonate-based 
urethane outer seal (Adaptive™ Seal) designed to minimize paravalvular leakage. Additional 
device information can be found in Section 5. 

 
 
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The Lotus Valve is currently under study in the REPRISE Clinical Program to evaluate the 
safety and performance of the Lotus Valve System for TAVI in symptomatic subjects with 
severe calcific aortic stenosis who are considered high risk for surgical valve replacement.  
4.1. REPRISE I 
The REPRISE I clinical study is a prospective, single arm, multicenter feasibility study 
designed to assess the acute safety and performance of the Lotus Valve System in 
symptomatic subjects (N=11) with calcified stenotic aortic valves who were considered high 
risk for surgical valve replacement.  
4.1.1. Primary Endpoint 
The primary endpoint was clinical procedural success, defined as successful implantation of 
a Lotus Valve (per the Valve Academic Research Consortium [VARC] definitions) without 
in-hospital major adverse cardiovascular and cerebrovascular events (MACCE, defined as 
all-cause mortality, periprocedural myocardial infarction ≤72 hours after the index procedure, 
major stroke, urgent/emergent conversion to surgery or repeat procedure for valve-related 
dysfunction) through discharge or 7 days post-procedure, whichever came first.  Clinical 
follow-up will extend through 5 years.  
Table 4-1 summarizes primary endpoint data as adjudicated by a CEC. The primary endpoint 
was achieved in 9/11 subjects. The device was successfully implanted in all 11 subjects but 
there was a device failure in 1 subject based on not meeting one of four VARC-1 criteria44 
for device success. The Echocardiography Core Lab concluded that the device failure (mean 
aortic valve gradient >20 mmHg) resulted from a hyperdynamic state in the subject and noted 
that the prosthetic valve appeared to be functioning well. Ten (10) of 11 subjects had no in-
hospital MACCE; there were no deaths and 1 major stroke through discharge.  
Table 4-1: REPRISE I Primary Endpoint  
Variable 
REPRISE I (N=11) 
Clinical procedural success  
81.8% (9/11) 
 
Device success 
90.9% (10/11) 
 
 
Successful vascular access, delivery and deployment of the device and 
successful retrieval of the delivery system with correct position of the device 
in the proper anatomical location – at Procedure 
100% (11/11) 
 
 
Intended performance of the Lotus Valve (AVA >1.0 cm2 plus either a mean 
aortic valve gradient <20 mmHg or peak velocity <3m/sec, without moderate 
or severe prosthetic valve aortic regurgitation) – at Discharge 
90.9% (10/11) 
 
 
Only one valve implanted in the proper anatomical location – at Procedure 
100% (11/11) 
 
No in-hospital MACCE  through Discharge  
90.9% (10/11) 
 Numbers are % (count/sample size).  
 “Discharge” represents discharge from hospitalization or 7 days post-procedure, whichever comes first. 
Abbreviations: AVA= aortic valve area; MACCE=major adverse cardiovascular and cerebrovascular events 
  

 
 
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4.1.2. Secondary Endpoints 
Secondary endpoints include procedural device performance endpoints as determined by the 
investigator and echocardiography core lab analyses and are shown in Table 4-2. All attempts 
to reposition the Lotus Valve were successful (4/4) and retrieval of the valve was not 
required/attempted in any subject. Core lab adjudication of AR after valve placement 
indicated 2 cases of mild and 1 case of trivial paravalvular regurgitation; there was no 
paravalvular regurgitation in 8/11 cases. The single case of central/commissural regurgitation 
was considered trivial. Additional echocardiography data are presented below. 
Table 4-2: REPRISE I Secondary Endpoints 
Variable 
REPRISE I (N=11) 
Successful repositioning of the Lotus Valve System, if attempted   
100% (4/4) 
Successful retrieval of the Lotus Valve System, if attempted 
Not applicable 
Incidence of aortic valve regurgitation at Discharge (Core Lab determination) 
Central/commissural regurgitation 
9.1% (1/11) 
Trivial 
9.1% (1/11) 
  Mild 
0.0% (0/11) 
  Moderate 
0.0% (0/11) 
  Severe 
0.0% (0/11) 
Paravalvular regurgitation 
27.3% (3/11) 
Trivial 
9.1% (1/11) 
  Mild 
18.2% (2/11) 
  Moderate 
0.0% (0/11) 
  Severe 
0.0% (0/11) 
Numbers are % (count/sample size).  
“Discharge” represents discharge from hospitalization or 7 days post-procedure, whichever comes first. 
 
To date, data are available through 1 year47. There were no additional MACCE events 
beyond the primary endpoint. While all REPRISE I subjects were NYHA Class II (n=6) or 
Class III (n=5) at baseline, this distribution was significantly improved at 1 year (5 in Class I, 
6 in Class II, 0 in Class III; P=0.004). The mean aortic valve gradient was 15.4±4.6 mmHg 
for the cohort at 1 year, which was below the VARC criterion of 20 mmHg, and there was no 
moderate or severe paravalvular aortic regurgitation.  
4.1.3. Conclusion 
The results of the REPRISE I feasibility study support the acute safety and performance of 
the Lotus Valve System. 
 

 
 
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4.2. REPRISE II 
The REPRISE II clinical study is a prospective, single-arm, multicenter study designed to 
evaluate the safety and performance of the Lotus Valve System for TAVI in symptomatic 
subjects who have severe calcific aortic valve stenosis and who are at high risk for surgical 
aortic valve replacement (SAVR).   
A total of up to 120 subjects were enrolled in the main study at up to 15 centers Europe and 
Asia Pacific regions. Subsequently, up to 130 additional subjects will be enrolled at up to 21 
centers in the extended trial cohort in Europe and Asia Pacific regions. All subjects 
implanted will be followed at baseline, peri- and post-procedure, at discharge or 7 days post-
procedure (whichever comes first), 30 days, 3 months, 6 months, and then annually for up to 
5 years post-procedure.   
4.2.1. Primary Endpoint 
4.2.1.1. Primary Device Performance Endpoint 
Primary Device Performance Endpoint is mean aortic valve pressure gradient at 30 days post 
implant procedure as measured by echocardiography and assessed by an independent core 
laboratory.  
For the pre-specified interim analysis of the 60-subject cohort, the 30-day mean aortic valve 
pressure gradient was 11.28±5.23 mmHg with a one-sided 99.208% upper confidence bound 
of 13.09 (Table 4-3). The P value from the one-sample t-test was <0.0001, which is below 
the threshold value of 0.00792. Thus, the Lotus Valve was concluded to have a 30-day mean 
aortic pressure gradient <18 mmHg and the primary device performance endpoint was met48.  
Table 4-3: REPRISE II Primary Device Performance Endpoint, As-Treated Analysis 
Set (N=60) 
Measure 
REPRISE II 
(N=60)  
[95% 
Confidence 
Interval] 
One-sided Upper 
Confidence 
Bounda 
Performance 
Goal 
One-sided 
P valueb 
30-Day mean aortic 
valve pressure gradient 
11.28±5.23 (52)
(4.50, 31.00) 
[9.86, 12.70] 
13.09 
18.00 
<0.0001 
a: From t-test 
b: From one-sample t-test 
 
4.2.1.2. Primary Safety Endpoint 
Primary Safety Endpoint is all-cause mortality at 30 days post implant procedure. For the 60-
subject cohort, the primary safety endpoint, all-cause mortality at 30 days, was 1.7%. 
4.2.2. Secondary Endpoints 
Secondary endpoints are shown in Table 4-4. Successful vascular access, delivery and 
deployment of the Lotus Valve along with successful retrieval of the delivery system was 
achieved in all subjects (60/60). All attempts to reposition the Lotus Valve were successful 

 
 
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(16/16) as were all attempts to retrieve the Lotus Valve (4/4). The composite device success 
endpoint (VARC 2 definition45) was 54.5% (24/44). This low rate of success was driven by 
the low number of subjects meeting the indexed EOA criteria (>0.85 cm2/m2 [>0.7 cm2/m2 
for BMI ≥30 kg/m2]), which was 60.5% (26/43) in REPRISE II. This value is similar to what 
has been reported in the PARTNER Cohort A trial with the Edwards Lifesciences’ SAPIEN 
Transcatheter Heart Valve System (56%) and surgical valves (40%).49 Thus, the observed 
rate of device success with the Lotus Valve System (based on the VARC 2 definition) is 
consistent with what is expected from other transcatheter and surgical valves. Core lab 
assessment of paravalvular aortic regurgitation at 30 days indicated no severe regurgitation 
and 1 case of moderate regurgitation; in 79.2% (42/53) of subjects there was trace/trivial or 
no paravalvular regurgitation. At 30 days, mean EOA was 1.67±0.38 cm2. 
Table 4-4: REPRISE II Secondary Endpoints, ITT Analysis Set (N=60) 
Variable 
REPRISE II  
Device Performance  
 
Successful vascular access, delivery and deployment of the Lotus Valve System 
and successful retrieval of the delivery system 
100.0% (60/60) 
 
Successful repositioning (partial or complete resheathing of the Lotus Valve in the 
catheter and redeployment in a more accurate position within the aortic valve 
annulus) of the Lotus Valve System if repositioning is attempted 
100.0% (16/16) 
 
Successful retrieval (complete resheathing of the Lotus Valve in the catheter and 
removal from the body) of the Lotus Valve System if retrieval is attempted 
100.0% (4/4) 
Device Success (VARC 2 Definition)45 
54.5% (24/44) 
 
Absence of procedural mortality 
98.3% (59/60) 
 
Correct positioning of a single transcatheter valve in the proper anatomical location 
100.0% (60/60) 
 
Intended performance of the Lotus Valve (Discharge) a 
55.8% (24/43) 
 
Indexed effective orifice area >0.85 cm2/m2 [>0.7 cm2/m2 for BMI ≥30 kg/m2] 
60.5% (26/43) 
 
Mean aortic valve gradient <20 mmHg 
94.6% (53/56) 
 
Peak velocity <3m/sec 
94.6% (53/56) 
 
Without moderate or severe prosthetic valve aortic regurgitation 
96.4% (54/56) 
Aortic Regurgitation (30 Days) a 
  Central/commissural regurgitation 
 
None 
75.5% (40/53) 
 
Trace/Trivial 
17.0% (9/53) 
 
Mild 
7.5% (4/53) 
 
Moderate 
0.0% (0/53) 
 
Severe 
0.0% (0/53) 
 
Paravalvular regurgitation 
 
None 
71.7% (38/53) 
 
Trace/Trivial 
7.5% (4/53) 
 
Mild 
18.9% (10/53) 
 
Moderate 
1.9% (1/53) 
 
Severe 
0.0% (0/53) 
 
Combined central/commissural and paravalvular regurgitation 
 
None 
54.7% (29/53) 

 
 
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Table 4-4: REPRISE II Secondary Endpoints, ITT Analysis Set (N=60) 
Variable 
REPRISE II  
 
Trace/Trivial 
24.5% (13/53) 
 
Mild 
18.9% (10/53) 
 
Moderate 
1.9% (1/53) 
 
Severe 
0.0% (0/53) 
Effective orifice area at 30 days (cm2)a 
1.67±0.38 (39) 
(0.76, 2.85) 
Numbers are % (count/sample size) or mean±SD (n) (minimum, maximum). 
Note: “Discharge” represents discharge from hospitalization or 7 days post-procedure, whichever came first. 
a: Core lab determination 
Abbreviation: ITT=intent-to-treat; N/A=not applicable; VARC=Valve Academic Research Consortium; 
4.2.3. Conclusion 
Overall, the results from this study have demonstrated acceptable performance and safety of 
the Lotus Valve System. 
5. Device Description 
5.1. Lotus Valve System 
The Lotus Valve System (Figure 5.1-1) has two main parts: a bioprosthetic aortic valve 
implant and a catheter-based delivery system for introduction and delivery of the valve 
implant. The device is introduced percutaneously using conventional catheterization 
techniques. More detailed product information is contained in the Investigator Brochure and 
Directions for Use (DFU). 
 
Figure 5.1-1: Lotus™ Valve System 
 
5.1.1. Lotus Valve 
The Lotus Valve (Figure 5.1-2) consists of 3 bovine pericardial leaflets. The commissures of 
the leaflets are attached to the valve frame through portions of the locking components.  

 
 
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The valve frame is made of a single nitinol wire strand woven into a braid. The wire ends of 
this frame are encapsulated by a tantalum crimp that is used as a radiopaque marker, and 
which is located in the center of the frame height. The braided structure is designed to 
foreshorten and expand radially when delivered, and is then locked in this position using a 
post and buckle locking mechanism.  
The Adaptive™ Seal is made of a polycarbonate-based urethane and is located on the outside 
bottom half of the frame. This seal provides a barrier between the native annulus and the 
frame to help reduce paravalvular leakage. 
The valve is deployed in a beating heart and rapid pacing is not required during valve 
deployment. The valve begins to function early in the deployment process, providing 
stabilized hemodynamic functionality. 
 
 
 
Figure 5.1-2: Lotus Valve Implant 
 
The device is designed so that the radial strength of the frame produces a specified final “as-
deployed” diameter  when the valve is locked, regardless of the target annulus. The frame 
height in the deployed state is approximately 19 mm.  
5.1.2. Lotus Delivery System 
The Lotus Delivery System is made of the catheter and the handle. 
 The catheter is a sheath in which mandrels allowing the shortening, locking, unlocking, 
and elongation of the valve, as well as its releasing, connect from the handle to the valve.  
The catheter has a hydrophilic coating to facilitate the insertion. The tip of the catheter 
seats on the shoulder of a nosecone to provide a smooth transition.  
 The handle is shown in Figure 5.1-3. 
o The handle has 3 ports; 2 of the ports are for flushing purposes and one is the 
Guidewire Port. 

 
 
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o The Control Knob at the proximal end of the handle is the primary control used to 
deploy the valve. It operates both the sheathing/unsheathing function as well as the 
locking/unlocking function. 
 The sheathing/unsheathing capability allows the implant to be pulled into or 
pushed out of the outer catheter.   
 The locking function shortens the valve implant into the locked configuration; 
the unlocking function elongates the valve. 
 The Release Collar is used when the operator is ready to release the valve. A sliding 
door covers the collar to avoid inadvertent premature release. 
 
Figure 5.1-3: Lotus Valve Delivery System – Handle 
 
5.2. Intended Use 
The Lotus Valve System is intended to improve aortic valve function for symptomatic 
subjects with severe calcific aortic stenosis (aortic valve area [AVA] of <1.0 cm2 or AVA 
index of <0.6 cm2/m2) who are at high risk for standard surgical valve replacement.   
5.3. Device Labeling 
A basic description of the device and a comprehensive set of Directions for Use (DFU) are 
contained in each product package. 

 
 
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6. Objectives 
The primary objective of the RESPOND study is to collect real world clinical and device 
performance outcomes data with the Lotus Valve System used in routine clinical practice to 
demonstrate that the commercially available Lotus Valve System is a safe and effective 
treatment for patients with severe calcific aortic stenosis. 
7. Endpoints 
7.1. Primary Endpoints 
The primary endpoint for the main cohort of approximately 1000 subjects is all-cause 
mortality at 30 days and 1 year after the implant procedure. The primary endpoint will be 
evaluated on an intention-to-treat (ITT) basis (all subjects enrolled, whether or not a Lotus 
Valve is implanted). All-cause mortality at 30 days after the implant procedure will be 
compared to a pre-specified performance goal. 
The primary endpoint for the additional cohort of approximately 80 subjects is all-cause 
mortality at 30 days after the implant procedure. 
7.2. Secondary Endpoints   
The following secondary endpoints will be measured according to current VARC guidelines: 
 Safety composite of all-cause mortality and disabling stroke at 30 days and 1 year 
 In-hospital mortality 
 The VARC efficacy composite at 1 year, including all-cause mortality; all stroke 
(disabling and non-disabling); re-hospitalization for valve-related symptoms or 
worsening congestive heart failure (NYHA class III or IV); and prosthetic valve-related 
dysfunction (mean aortic valve gradient ≥20 mmHg, effective orifice area (EOA) ≤0.9–
1.1 cm2 and/or Doppler velocity index (DVI) <0.35 m/s, AND/OR moderate or severe 
prosthetic valve aortic regurgitation) 
 Time related valve safety composite at 1 year, including structural valve deterioration 
(valve-related dysfunction requiring repeat procedure [TAVI or SAVR]); prosthetic valve 
endocarditis; prosthetic valve thrombosis; thromboembolic events (e.g. stroke) and 
VARC bleeding, unless clearly unrelated to valve therapy based on investigator 
assessment (e.g. trauma) 
 Clinical endpoints at 30 days defined according to current VARC guidelines: 
o Life-threatening bleeding 
o Acute kidney injury—Stage 2 or 3 (including renal replacement therapy) 
o Coronary artery obstruction requiring intervention 
o Major vascular complication 
o Valve-related dysfunction requiring repeat procedure (BAV, TAVI, or SAVR) 
o New conduction disturbances (LBBB, AVB, RBBB) and need for permanent 
pacemaker implantation 

 
 
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 Grade of paravalvular aortic valve regurgitation pre-discharge as measured by 
transthoracic echocardiography (TTE) and assessed by an independent core laboratory. 
The moderate and severe paravalvular aortic regurgitation rate will be compared to a pre-
specified performance goal. 
NOTE: Secondary endpoints will be assessed in the additional cohort of 80 patients through 
30 day follow up. 
7.3. Additional Measurements 
Additional measurements will be collected as specified below: 
 The following events will be collected based on the current VARC definitions44,45: 
o All-cause death (cardiovascular and non-cardiovascular) 
o Stroke: disabling and non-disabling  
o Myocardial infarction (MI): periprocedural (≤72 hours post index procedure) and 
spontaneous (>72 hours post index procedure) 
o Bleeding: life-threatening (or disabling), major and minor 
o Acute kidney injury (≤7 days post index procedure): based on the AKIN System 
Stage 3 (including renal replacement therapy), Stage 2, and Stage 1 
o Major and minor vascular complication 
o Repeat procedure for valve-related dysfunction (surgical or interventional therapy) 
o Hospitalization for valve-related symptoms or worsening congestive heart failure 
(NYHA class III or IV) 
o New permanent pacemaker implantation resulting from new or worsened conduction 
disturbances (including new left bundle branch block [LBBB] and third degree 
atrioventricular block) 
o New onset of atrial fibrillation or atrial flutter  
o Coronary obstruction (periprocedural) 
o Ventricular septal perforation (periprocedural) 
o Mitral apparatus damage (periprocedural) 
o Cardiac tamponade (periprocedural) 
o Prosthetic aortic valve malapposition, including valve migration, valve embolization, 
ectopic valve deployment, or transcatheter aortic valve (TAV)-in-TAV deployment 
o Prosthetic aortic valve thrombosis 
o Prosthetic aortic valve endocarditis 
 Device performance measured peri- and post-procedurally consisting of the following:  
o Successful vascular access, delivery and deployment of the Lotus Valve System, and 
successful retrieval of the delivery system 
o Successful repositioning (partial or complete resheathing of the Lotus Valve in the 
catheter and redeployment in a more accurate position within the aortic valve 
annulus) of the Lotus Valve System if repositioning is attempted 

 
 
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o Successful retrieval (complete resheathing of the Lotus Valve in the catheter and 
removal from the body) of the Lotus Valve System if retrieval is attempted 
o Grade of paravalvular aortic valve regurgitation 
 Physicians Preference Test (PPT), including device deficiencies, to measure device 
usability and ease of use peri-procedurally.  
 Prosthetic aortic valve performance as measured by transthoracic echocardiography 
(TTE) and assessed by an independent core laboratory, including effective orifice area, 
mean and peak aortic gradients, peak aortic velocity, and grade of aortic regurgitation 
pre-discharge and at 1 year. Site reported TTE measures will be collected at 30 days and 
annually from 2 through 5 year follow up per local standard of care for TAVI.  
 Health status as evaluated by EuroQoL (EQ-5D) Quality of Life questionnaire at 
baseline, 30 days, 1, 3 and 5 year follow up, during in-person clinic visit or via postal 
mail. 
 New York Heart Association (NYHA) functional classification at baseline, procedure, 
discharge, 30 days, 1 year and annually through 5 year follow up. 
NOTE: Secondary endpoints will be assessed in the additional cohort of 80 patients through 
30 day follow up. 
8. Study Design 
The RESPOND study is a prospective, open label, single arm, multi-center, observational 
post market study designed to collect real world clinical and device performance outcomes 
data of the commercially available Lotus Valve used in routine clinical practice for the 
treatment of severe calcific aortic stenosis. The main cohort of approximately 1000 real-
world, prospective, consecutive subjects will be enrolled at up to 60 study centers in Europe, 
Asia Pacific and South America. An additional cohort of approximately 80 subjects will be 
enrolled after enrollment is complete in the main cohort at up to 8 centers in Europe. 
NOTE: Consecutive is defined as a commitment by the participating investigators at each 
study center to enroll all consented patients admitted for Transcatheter Aortic Valve 
Implantation (TAVI) who are selected to receive a Lotus Valve. 
All implanted subjects enrolled in the main cohort will be contacted for follow-up at 30 days, 
1, 2, 3, 4 and 5 years post index valve implantation. Follow-up visit at 1 year post valve 
implantation should be conducted via outpatient clinic visit. Follow-up visits at 30 days and 2 
through 5 years may be conducted in person (preferred) and via telephone interview. Subjects 
who are not implanted with a Lotus Valve will be followed for safety through 30 days after 
the initial attempted index procedure.  
The approximately 80 subjects enrolled in the additional cohort will be contacted for follow 
up at 30 days post valve implantation, at which point their participation in the study will be 
complete. 
Collection of safety events will include any serious adverse event (SAE) that led to death, 
adverse device effect (ADE), serious adverse device effect (SADE), unanticipated serious 

 
 
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adverse device effect (USADE), and all VARC events regardless of seriousness and device 
relationship through 5 year follow-up for the main cohort and through 30 days for the 
additional 80-subject cohort.  
The RESPOND study will be conducted in accordance with the International Standard 
ISO 14155: 2011; ethical principles that have their origins in the Declaration of Helsinki; the 
relevant parts of the International Conference on Harmonization (ICH) Guidelines for Good 
Clinical Practices (GCP); and pertinent individual country/state/local laws and regulations.  
8.1. Justification for the Study Design 
In order to support the stated objectives of this study (see Section 6), approximately 
1000 subjects will be enrolled in the study at up to 60 study centers in Europe, Asia Pacific 
and South America. Planned interim analyses of the primary and secondary endpoints will be 
performed on the first 250 and 500 enrolled subjects. A final analysis of the primary and 
secondary endpoints will be conducted on the main study cohort (N=1000). All implanted 
subjects will be followed for 5 years post index procedure. 
After enrollment in the main cohort is completed an additional cohort of approximately 80 
subjects will be enrolled in the study at up to 8 centers in Europe to assess center-driven 
implantation technique with the commercially available Lotus Valve System. Due to acute 
assessment of the implant technique, subjects enrolled in the additional cohort will be 
contacted for follow up at 30 days post valve implantation, at which point their participation 
in the study will be complete. 
9. Subject Selection  
All patients who are candidates for TAVI, signed the informed consent form and are selected 
to receive a Lotus Valve will be evaluated for enrollment in this study. 
10. Subject Accountability 
10.1. Point of Enrollment 
A subject is considered enrolled upon obtaining a signed Informed Consent Form (ICF) from 
the subject or subject’s legally authorized representative (LAR) and an attempt to insert the 
Lotus Introducer sheath.  
11. Study Methods 
11.1. Data Collection 
Table 11.1-1 below lists the schedule of observations and assessments planned during this 
study. Data collection at baseline, index procedure, discharge and each follow-up should be 
based on the study center’s standard of care for TAVI. 
 

 
 
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Table 11.1-1: Study Event Schedule 
Procedure/Assessment 
Baseline 
Index 
Procedure 
Post-
procedure/ 
Pre-
discharge 
Follow-up Visits 
30 Days1 
(± 7 Days) 
Office Visit 
or 
Telephone 
Interview 
1-5 Years1, 10 
(± 45 Days) 
Annual  
Office Visit 
or 
Telephone 
Interview 
Demographics, physical 
assessment, risk factors and 
medical history 
X 
 
 
 
 
NYHA Classification 
X 
 
X 
X 
X 
Risk assessment2 
X 
 
 
 
 
Frailty assessment3 
X 
 
 
 
 
CT angiogram of aortic 
structure and iliofemoral 
system4 
X 
 
 
 
 
Procedural cine-angiogram5 
 
X 
 
 
 
Heart rhythm6 
X 
X 
X 
X 
X 
Physician Preference Test 
 
X 
 
 
 
Antiplatelet and other 
cardiovascular medications 
X 
X 
X 
X 
X 
Transthoracic 
echocardiography (TTE)7 
X 
 
X 
X 
X 
QOL questionnaire8 
X 
 
 
X 
X 
SAE that led to death, 
ADE/SADE, USADE, device 
deficiency assessment and all 
VARC events9 
 
X 
X 
X 
X 
1 All follow-up dates will be calculated from the date of the index procedure. Follow-up visits may be conducted in person 
(preferred) and via telephone. Subjects with implant failures will be followed for safety through 30 days after the initial 
attempted index procedure. 
2 Consists of EuroSCORE 2011 or STS score. 
3 Frailty assessment at baseline, including nutritional assessment (body mass index), strength and balance (gait speed, 
maximal grip strength) and activities of daily living (Katz index) should be captured if performed according to local 
standard of care. 
4 Computed tomography (CT) angiogram of the aortic structure (from aortic annulus to the aortic distal bifurcation) and 
the iliofemoral bifurcation should be performed prior to the index procedure to evaluate the aortic valve anatomy, aortic 
root dimensions for device sizing and access assessment. CT angiogram should be performed according to the standard of 
care for TAVI. For the additional cohort of up to 80 subjects, baseline CT angiograms must be sent to the CT Core 
Laboratory for independent analysis.  
5 The procedural cine-angiogram should be submitted to Boston Scientific. 
6 Underlying heart rhythm, including data from the most recent pacemaker interrogation done by an 
electrophysiologist or in a device clinic per local standard of care for subjects who received a permanent pacemaker 
related to the index procedure. Pacemaker interrogation should also include assessment of pacer dependence. 
7 TTE should be performed at baseline, discharge, 30 days, 1 year and annually through 5 year follow up or per local 
standard of care for TAVI, if TTE frequency or requirements are different from study schedule. TTE performed at 
baseline, pre-discharge and 1 year after Lotus Valve implant must be sent to the Echocardiography Core Laboratory for 
independent analysis. 
8 The EQ-5D QOL questionnaire at baseline should be performed within 30 days of the index procedure. Additional 

 
 
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Table 11.1-1: Study Event Schedule 
Procedure/Assessment 
Baseline 
Index 
Procedure 
Post-
procedure/ 
Pre-
discharge 
Follow-up Visits 
30 Days1 
(± 7 Days) 
Office Visit 
or 
Telephone 
Interview 
1-5 Years1, 10 
(± 45 Days) 
Annual  
Office Visit 
or 
Telephone 
Interview 
surveys should be performed at 30 days, 1, 3 and 5 years post index procedure during office visits or via mail. 
9 Safety events will be monitored and reported to BSC from the time of enrollment through 5 year follow-up for the main 
cohort and through 30-day follow-up for the additional 80-subject cohort. For subjects who do not receive a Lotus Valve, 
events will be collected and reported through 30 days after the initial attempted index procedure. 
10 The additional cohort of up to 80 subjects will be followed through 30 days post implant procedure; 1-5 year follow up 
does not apply. 
Abbreviations: ADE=adverse device effect; CT=computerized tomography; ECG=electrocardiogram; NYHA=New 
York Heart Association; QOL=Quality of Life; SADE=serious adverse device effect; SAE=serious adverse event; 
TAVI=transcatheter aortic valve implantation; TTE=transthoracic echocardiography; USADE=unanticipated 
serious adverse device effect.
 
11.2. Study Candidate Screening 
Subjects will be evaluated for eligibility by the clinical site’s heart team per the local 
standard of practice. The heart team is generally comprised of interventional cardiologist, 
cardiac surgeon, cardiologist, echocardiographer, imaging specialist, anesthesiologist, nurse 
practitioner, etc. Assessment will be based on results from the Society of Thoracic Surgeons 
(STS) score (≥8%) and/or agreement by the heart team (including a cardiac surgeon’s 
documented evaluation) that the subject is at high operative risk of serious morbidity or 
mortality with surgical valve replacement.  The heart team (including an experienced cardiac 
surgeon's assessment) must also agree that the subject is likely to benefit from valve 
replacement.   
11.3. Informed Consent 
Written informed consent must be obtained for all qualified subjects who are potential study 
candidates prior to the subject’s index procedure.   
11.4. Baseline 
The following assessments should be completed prior to the index procedure, per local 
standard of care for TAVI. The study eCRFs identify the specific data points to be collected. 
 Confirmation of eligibility and contraindications per the DFU 
 Demographics, physical assessment, risk factors and medical history 
 New York Heart Association (NYHA) classification 
 Risk assessment, including EuroSCORE 2011 or STS score 
 The following frailty assessment 
o Nutritional assessment (body mass index) 

 
 
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o Strength and balance (gait speed, maximal grip strength, walking aid dependency)  
o Activities of daily living (Katz Index) 
 Angio CT scan of the aortic structure (from aortic annulus to the aortic distal bifurcation) 
and the iliofemoral bifurcation should be performed prior to the index procedure to 
evaluate the aortic valve anatomy, aortic root dimensions for device sizing and access 
assessment. For the additional cohort of up to 80 subjects , baseline CT angiograms must 
be sent to the CT Core Laboratory for independent analysis. 
 Underlying heart rhythm 
 Antiplatelet or other cardiovascular medications 
 Transthoracic Echocardiography (TTE), including assessment of effective orifice area, 
peak systolic and mean aortic valve gradient pressure, aortic regurgitation assessment, 
mitral regurgitation, LVEF, left ventricular end-diastolic and end-systolic diameter, TR 
jet velocity and LA volume. A baseline TTE for subjects implanted with a Lotus Valve 
must be sent to the Echocardiography Core Laboratory for independent analysis. 
 EQ-5D Quality of Life Questionnaire 
11.5. Index Procedure 
The preparation of the subject for the percutaneous procedure will be performed following 
standard techniques. Refer to the Lotus Valve System DFU for detailed instructions about 
preparation and placement of the Lotus Valve. 
It is recommended that a stiff guidewire (e.g., Safari) is used during the Lotus Valve implant 
procedure. 
11.6. Post-procedure / Prior to Hospital Discharge 
The subject may be discharged from the hospital when clinically stable, at the Investigator’s 
discretion per local standard of care. Prior to discharge from the hospital, the following data 
is to be collected: 
 Complete safety event assessment, including any SAE that led to death, ADE, SADE, 
USADE, device deficiency with associated treatment, and any VARC event regardless of 
seriousness and device relationship. 
 Per the expert consensus document on TAVI, antiplatelet therapy with aspirin and a 
thienopyridine is recommended to decrease the risk of thrombotic or thromboembolic 
complications if there are no contraindications to these medications43. Subjects should be 
treated with aspirin and clopidogrel for at least 1 month following valve implantation. 
Subsequent antiplatelet therapy should be at the investigator’s discretion, or in 
accordance with country-specific labeling for the medications. If oral anti-coagulation is 
indicated after valve implantation, antiplatelet therapy should consist of either aspirin or 
thienopyridine. Combination treatment with oral anti-coagulation and dual antiplatelet 
therapy after valve implantation should be avoided.  
 Underlying heart rhythm 
 NYHA classification 

 
 
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 TTE, including assessment of effective orifice area, peak systolic and mean aortic valve 
gradient pressure, aortic regurgitation assessment, mitral regurgitation, LVEF, left 
ventricular end-diastolic and end-systolic diameter, TR jet velocity and LA volume, per 
local standard of care. A pre-discharge TTE for subjects implanted with a Lotus Valve 
must be sent to the Echocardiography Core Laboratory for independent analysis. 
Prior to discharge, clinical staff should review the study follow-up visit schedule with the 
subject to maximize follow-up compliance. 
11.7. Follow-up 
All implanted subjects enrolled in the main cohort of 1000 subjects will be evaluated at 30 
days, 1, 2, 3, 4 and 5 years post index procedure. Follow-up visit at 1 year post valve 
implantation should be conducted via outpatient clinic visit. Follow-up visits at 30 days and 2 
through 5 years may be conducted in person (preferred) and via telephone interview. Subjects 
with no Lotus Valve implanted will be followed for safety through 30 days after the initial 
attempted index procedure.  
The additional cohort of approximately 80 subjects will be contacted for follow up at 30 days 
post valve implantation.  
It is important that the follow-up visit schedule be maintained as closely as possible for all 
subjects. Boston Scientific recognizes that subjects may not be able to return for all 
scheduled visits at precisely the date required, and therefore, a period of time in which each 
visit should be conducted is indicated in Table 11.1-1. Each follow-up visit must be 
performed by trained study personnel. Data from collected tests and images as well as 
medical assessments will be recorded in source documentation and captured in the eCRFs. 
In the event that study personnel learn of a subject’s hospitalization outside the study center, 
the center should make every effort to obtain copies of reports or results based on tests (e.g., 
echocardiogram) and/or procedures performed on the study subject.  
11.7.1. 30-Day Follow-up (30+7 days) 
All enrolled subjects must be evaluated 30 days after the index procedure. The 30-day 
follow-up visit may be conducted in person (preferred) or via telephone interview. During the 
30-day follow-up, the following assessments are to be collected:  
 Complete safety event assessment, including any SAE that led to death, ADE, SADE, 
USADE, device deficiencies with associated treatment, and any VARC events regardless 
of seriousness and device relationship. 
 All antiplatelet and other cardiovascular medications administered in accordance with 
society guidelines43 and local standard of care. Subjects should be treated with aspirin 
and clopidogrel for at least 1 month following valve implantation. Subsequent antiplatelet 
therapy should be at the investigator’s discretion, or in accordance with country-specific 
labeling for the medications. If oral anti-coagulation is indicated after valve implantation, 
antiplatelet therapy should consist of either aspirin or thienopyridine. Combination 

 
 
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treatment with oral anti-coagulation and dual antiplatelet therapy after valve implantation 
should be avoided. 
 Underlying heart rhythm, including assessment of pacemaker dependency for subjects 
who had a pacemaker implanted after the index procedure. 
 NYHA classification 
 TTE, including assessment of effective orifice area, peak systolic and mean aortic valve 
gradient pressure, aortic regurgitation assessment, mitral regurgitation, LVEF, left 
ventricular end-diastolic and end-systolic diameter, TR jet velocity and LA volume, per 
local standard of care. 
 EQ-5D Quality of Life Questionnaire during office visit or via mail. 
11.7.2. Annual Follow-up (+45 days) 
All implanted subjects enrolled in the main cohort of 1000 subjects will be evaluated at 1, 2, 
3, 4 and 5 years after the index procedure. Follow-up visit at 1 year post valve implantation 
should be conducted via outpatient clinic visit. Annual follow-up visits at 2 through 5 years 
may be conducted in person (preferred) or via telephone interview. During annual follow-up, 
the following assessments are to be collected:    
 Complete safety event assessment, including any SAE that led to death, ADE, SADE, 
USADE, device deficiencies with associated treatment, and any VARC events regardless 
of seriousness and device relationship. 
 All antiplatelet and other cardiovascular medications administered in accordance with 
society guidelines43 and local standard of care. 
 Underlying heart rhythm, including assessment of pacemaker dependency for subjects 
who had a pacemaker implanted after the index procedure.  
 NYHA classification 
 TTE, including assessment of effective orifice area, peak systolic and mean aortic valve 
gradient pressure, aortic regurgitation assessment, mitral regurgitation, LVEF, left 
ventricular end-diastolic and end-systolic diameter, TR jet velocity and LA volume, per 
local standard of care. A TTE performed 1 year after valve implantation must be sent to 
the Echocardiography Core Laboratory for independent analysis. 
 EQ-5D Quality of Life Questionnaire during office visit or via mail at 1 year, 3 year and 
5 year follow-up. 
11.8. Withdrawal and Replacement of Subjects 
Subjects may withdraw from the study at any time, with or without reason and without 
prejudice to further treatment. Withdrawn subjects will not undergo any additional study 
follow-up, nor will they be replaced. The reason for withdrawal will be recorded (if given) in 
all cases of withdrawal. The investigator may discontinue a subject from participation in the 
study if the investigator feels that the subject can no longer fully comply with the 
requirements of the study or if any of the study procedures are deemed potentially harmful to 
the subject. Data that have already been collected on withdrawn subjects will be retained and 
used for analysis but no new data will be collected after withdrawal.   

 
 
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11.9. Study Completion 
All implanted subjects enrolled in the main cohort of 1000 subjects will be followed for the 
duration of 5 years post index procedure. A subject’s participation in the study will conclude 
after completion of the 5 year follow-up visit. 
For subjects enrolled in the additional 80-subject cohort, participation in the study will 
conclude after completion of the 30-day follow-up visit. 
12. Statistical Considerations 
12.1. Endpoints 
12.1.1. Primary Endpoint (Main Cohort) 
The study is powered to assess one primary endpoint, which is all-cause mortality at 30 days 
post implant as assessed by an independent CEC. The null and alternative hypotheses for the 
primary device performance endpoint are as follows. 
H0: Mortality30D ≥ PG 
H1: Mortality30D < PG  
where Mortality30D is the 30-day all-cause mortality rate for the Lotus Valve and PG is 14%. 
A one-sample exact binominal test will be used to test the one-sided hypothesis. The all-
cause mortality at 1 year post implant will be summarized using descriptive statistics. 
12.1.1.1. Hypothesis (Main Cohort) 
All-cause mortality at 30 days post implant procedure is less than the PG of 14 % (expected 
rate of 10% + testing margin of 4%) 
12.1.1.2. Sample Size – Primary Endpoint (Main Cohort) 
The sample size calculation for the primary endpoint is based on the following assumptions: 
 Expected 30-day all-cause mortality rate = 10%  
 Performance goal (PG) = 14% (expected rate of 10% + testing margin of 4%) 
 Test significance level () = 0.025 (1-sided) 
 Power (1 – ) > 95% 
 Planned enrollment of up to 1000 subjects 
 Two planned interim analyses on the primary endpoint at 30 days post-implant procedure 
will be performed on the first 250 and 500 subjects enrolled. A final analysis will be 
performed on all enrolled subjects 
 The primary analysis population for the primary endpoint will be the subject population 
attempted or implanted with the Lotus Valve.    

 
 
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Note:  The expected 30-day all-cause mortality rate is assumed to be 10% based on a 
literature review of studies evaluating the Medtronic CoreValve System and the Edwards 
Lifesciences SAPIEN Transcatheter Heart Valve System (FRANCE 2 registry36).  
Note: The alpha-level for the interim and final analyses is adjusted using the Pocock alpha 
spending function50 (see Section 12.3.2). 
12.1.2. Secondary Endpoint (Main Cohort) 
The study is powered to assess one secondary endpoint, which is grade of paravalvular aortic 
valve regurgitation pre-discharge as assessed by TTE post valve implantation. The null and 
alternative hypotheses for the primary device performance endpoint are as follows. 
H0: ARpre-discharge ≥ PG 
H1: ARpre-discharge < PG 
where ARpre-discharge is the proportion of subjects with moderate/severe aortic regurgitation 
pre-dischage post implant procedure for the Lotus Valve and PG is 16.5%. 
A one-sample exact binominal test will be used to test the one-sided hypothesis. 
12.1.2.1. Hypothesis (Main Cohort) 
Proportion of subjects with moderate/severe aortic regurgitation pre-discharge as assessed by 
TTE post implant procedure is less than the PG of 16.5%. 
12.1.2.2. Sample Size – Secondary Endpoint (Main Cohort) 
The sample size calculation for the secondary endpoint is based on the following 
assumptions: 
 Expected proportion of subjects with moderate/severe aortic regurgitation pre-discharge 
as assessed by TTE post valve implantation = 10%  
 Performance goal (PG) = 16.5% (based on FRANCE 2 registry36) 
 Test significance level () = 0.025 (1-sided) 
 Power (1 – ) > 99% 
 Planned enrollment of up to 1000 subjects 
 Two planned interim analyses on the secondary endpoint prior to discharge from the 
hospital post-implant procedure will be performed on the first 250 and 500 subjects 
enrolled. A final analysis will be performed on all enrolled subjects. 
 The primary analysis population for the secondary endpoint will be the subject 
population implanted with the Lotus Valve.    
Note:  The performance goal is set at 16.5% based on rates observed with Medtronic 
CoreValve System and the Edwards Lifesciences SAPIEN Transcatheter Heart Valve System 
(FRANCE 2 registry). 
Note: The alpha-level for the interim and final analyses is adjusted using the Pocock alpha 
spending function (see Section 12.3.2). 

 
 
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12.1.3. Statistical Methods 
All subjects who are enrolled will be eligible for evaluation. Handling of dropouts and 
missing data will depend on their frequency and the nature of the outcome measure. The 
distribution of prognostic factors between subjects with and without data will be examined. 
Methods to eliminate or minimize bias will be implemented and described completely. 
Statistical models that account for censored data will be employed in appropriate 
circumstances (e.g., for time-to-event outcomes). Sensitivity analyses, including a tipping-
point analysis for the primary endpoint, will be conducted to assess the impact of different 
assumptions on interpretation of the results. Outlier values will be evaluated for their 
validity. Suspected invalid data will be queried and corrected in the database prior to 
statistical analysis. 
The data of the additional cohort of approximately 80 subjects will be summarized using 
descriptive statistics and will not be pooled with the first cohort of 1,000 subjects in the data 
analysis. No statistical hypotheses will be tested in the additional cohort. 
12.2. General Statistical Methods 
12.2.1. Analysis Sets 
The primary endpoint will be evaluated on an ITT basis (all subjects enrolled, whether or not 
a study device is implanted). For the ITT analysis, all subjects who sign the written ICF and 
are enrolled in the study will be included in the analysis sample, regardless of whether the 
study device was implanted. 
The primary analysis population for the secondary endpoint will be the subject population 
implanted with the Lotus Valve (as-treated subject population).  
12.2.2. Control of Systematic Error/Bias 
The selection of patients will be made from the Investigator’s usual case load. All subjects 
who have signed the ICF and are selected to receive a Lotus Valve will be enrolled in the 
study. The study center’s heart team assessments and imaging measurements before device 
placement will contribute to the determination of subject eligibility for the study.  
12.3. Data Analyses 
Baseline and outcome variables will be summarized using descriptive statistics for 
continuous variables (mean, standard deviation, number of observations, minimum and 
maximum) and discrete variables (percentage and count/sample).  
12.3.1. Risk Adjusted Analysis 
Risk adjusted clinical outcomes by valve size will be analyzed on the subject population 
implanted with the Lotus Valve (as-treated subject population). 

 
 
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12.3.2. Interim Analyses  
Two interim analyses for the primary and secondary endpoints will be conducted on the first 
250 and 500 subjects, and a final analysis will be conducted on the planned 1000 subjects of 
the main cohort. The Pocock alpha spending function50 is used to adjust the alpha-level for 
each analysis: 0.00894, 0.00895, and 0.01301, respectively. If the P value from the one-
sample exact binominal test is <alpha, the Lotus Valve will be concluded to have event rate < 
PG. This corresponds to the one-sided Clopper-Pearson upper (1-alpha)% confidence bound 
of the observed event rate being < PG. 
The two planned interim analyses are pre-specified to provide a formal hypothesis testing 
approach to examine the primary and secondary endpoints with the adjusted significance 
level.  There is no plan to stop the subject enrollment even if the null hypothesis is rejected at 
each of the two planned interim analyses. 
12.3.3. Changes to Planned Analyses 
Any changes to the planned statistical analyses will be documented in an amended Statistical 
Analysis Plan.  
13. Data Management 
13.1. Data Collection, Processing, and Review 
Subject data will be recorded in a limited access secure electronic data capture (EDC) 
system.  
The clinical database will reside on a production server hosted by Medidata. All changes 
made to the clinical data will be captured in an electronic audit trail and available for review 
by Boston Scientific Corporation (BSC) or its representative. The associated RAVE software 
and database have been designed to meet regulatory compliance for deployment as part of a 
validated system compliant with laws and regulations applicable to the conduct of clinical 
studies pertaining to the use of electronic records and signatures. Database backups are 
performed regularly. 
The Investigator provides his/her electronic signature on the appropriate electronic case 
report forms (eCRFs) in compliance with local regulations. A written signature on printouts 
of the eCRFs must also be provided if required by local regulation. Changes to data 
previously submitted to the sponsor require a new electronic signature by the Investigator 
acknowledging and approving the changes. 
Visual and/or electronic data review will be performed to identify possible data 
discrepancies. Manual and/or automatic queries will be created in the EDC system and will 
be issued to the site for appropriate response. Site staff will be responsible for resolving all 
queries in the database. 

 
 
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13.2. Record Retention 
The Investigator will maintain, at the study center, in original format all essential study 
documents and source documentation that support the data collected on the study subjects in 
compliance with ICH/GCP guidelines.  Documents must be retained for at least 2 years after 
the last approval of a marketing application or until at least 2 years have elapsed since the 
formal discontinuation of the clinical investigation of the product. These documents will be 
retained for a longer period of time by agreement with BSC or in compliance with other local 
regulations. It is BSC’s responsibility to inform the Investigator when these documents no 
longer need to be maintained. The Investigator will take measures to ensure that these 
essential documents are not accidentally damaged or destroyed. If for any reason the 
Investigator withdraws responsibility for maintaining these essential documents, custody 
must be transferred to an individual who will assume responsibility and BSC must receive 
written notification of this custodial change.  
13.3. Core Laboratory 
An independent Core Laboratory will review baseline, pre-discharge and 1 year follow up 
echocardiography images from all centers and every enrolled subject implanted with a Lotus 
Valve for qualitative and quantitative analysis. These analyses will minimize bias and 
inconsistencies by providing an independent interpretation of all measurements using 
standard techniques.  
An independent Core Laboratory will review baseline CT angiograms for the additional 
cohort of approximately 80 subjects that are implanted with a Lotus Valve to evaluate the 
aortic valve anatomy and aortic root dimensions for device sizing. These analyses will 
minimize bias and inconsistencies by providing an independent interpretation of all 
measurements using standard techniques. 
14. Amendments  
If a protocol revision is necessary which affects the rights, safety or welfare of the subject or 
scientific integrity of the data, an amendment is required. Appropriate approvals (e.g., 
IRB/EC) of the revised protocol must be obtained prior to implementation. 
15. Deviations 
All deviations from the protocol, with the reason for the deviation and the date of occurrence, 
must be documented and reported to the sponsor using the EDC CRF. Study centers may also 
be required to report deviations to the IRB/EC, per local guidelines and government 
regulations.  

 
 
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16. Compliance 
16.1. Statement of Compliance 
The RESPOND study will be conducted in accordance with the International Standard 
ISO 14155: 2011, ethical principles that have their origins in the Declaration of Helsinki, the 
relevant parts of the International Conference on Harmonization (ICH) Guidelines for Good 
Clinical Practices (GCP), and pertinent individual country laws and regulations. 
16.2. Investigator Responsibilities 
The Principal Investigator of an investigational center is responsible for ensuring that the 
study is conducted in accordance with the Clinical Study Agreement, the investigational 
plan/protocol, ISO 14155, ethical principles that have their origins in the Declaration of 
Helsinki, any conditions of approval imposed by the reviewing IRB/EC, and prevailing local 
and/or country laws and regulations, whichever affords the greater protection to the subject. 
16.3. Institutional Review Board/ Ethics Committee 
Prior to gaining Approval-to-Enroll status, the investigational center will provide to the 
sponsor documentation verifying that their IRB/EC is registered or that registration has been 
submitted to the appropriate agency, as applicable according to national/regulatory 
requirements.   
A copy of the written IRB/EC approval of the protocol (or permission to conduct the study) 
and ICF, must be received by the sponsor before recruitment of subjects into the study. Prior 
approval must also be obtained for other materials related to subject recruitment or which 
will be provided to the subject. 
Annual IRB/EC approval and renewals will be obtained throughout the duration of the study 
as required by local/country or IRB/EC requirements. Copies of the Investigator’s reports 
and the IRB/EC continuance of approval must be provided to the sponsor.  
16.4. Sponsor Responsibilities 
All information and data sent to BSC concerning subjects or their participation in this study 
will be considered confidential by BSC. Only authorized BSC personnel or a BSC 
representative including Contract Research Organization (CRO) will have access to these 
confidential records. Authorized regulatory personnel have the right to inspect and copy all 
records pertinent to this study. Study data collected during this study may be used by BSC 
for the purposes of this study, publication, and to support future research and/or other 
business purposes. All data used in the analysis and reporting of this study will be without 
identifiable reference to specific subject name. 
Boston Scientific will keep subjects’ health information confidential in accordance with all 
applicable laws and regulations.  Boston Scientific may use subjects’ health information to 
conduct this study, as well as for additional purposes, such as overseeing and improving the 
performance of its device, new medical research and proposals for developing new medical 

 
 
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products or procedures, and other business purposes. Information received during the study 
will not be used to market to subjects; subject names will not be placed on any mailing lists 
or sold to anyone for marketing purposes.  
16.5. Insurance  
Where required by local/country regulation, proof and type of insurance coverage, by BSC 
for subjects in the study will be obtained. 
17. Training 
Boston Scientific has established a structured training program for the physicians and staff 
(Heart Team) who will be involved in the peri-procedural care of the Lotus patients. This 
training program is designed to provide the physicians and staff with the information and 
experience necessary to control user-associated risks when the device is used in accordance 
with the DFU. Training records shall be maintained as evidence that physicians have 
received appropriate training. This training program includes proctored cases on site. 
Operators must complete the required training and proctorship (6-8 proctored cases), and 
perform a minimum of 2 independent cases using commercial Lotus Valve System prior to 
being authorized to participate in this study. 
18. Monitoring 
Monitoring visits to the clinical sites will be made periodically during the study, to ensure 
that all aspects of the current, approved protocol/amendment(s) are followed. 
Original source documents will be reviewed for verification of data in the electronic database 
for: 
• 
A random sample of 10% of subjects enrolled at each clinical site. 
• 
Subjects with ADE, SADE, USADE, VARC events, or device deficiencies 
associated with the Lotus Valve System implanted during the index procedure. 
• 
Subjects with CEC events (i.e. death and stroke). 
• 
Informed Consent for all enrolled and screen failure subjects at each clinical site. 
The Investigator/institution guarantees direct access to original source documents (including 
electronic medical records) by BSC personnel, their designees, and appropriate regulatory 
authorities. In the event that the original medical records cannot be obtained for a patient that 
is seen by a non-study physician at a non-study institution, photocopies of the original source 
documents should be made available for review. 
The study also may be subject to a quality assurance audit by BSC or its designees, as well as 
inspection by appropriate regulatory authorities. 

 
 
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19. Potential Risks and Benefits 
19.1. Potential Risks 
Adverse events potentially associated with transcatheter aortic valve implantation as well as 
additional risks related to the use of the Lotus Valve System are listed in the Directions for 
Use and Informed Consent Form.  
19.2. Potential Benefits 
Transcatheter aortic valve implantation may offer certain advantages when compared to 
surgical replacement of the stenotic native aortic valve, particularly in high risk subjects. 
These include the benefits of a minimally invasive procedure and a reduction in the risks 
related to open heart surgery. 
20. Informed Consent 
Subject participation in this clinical study is voluntary.  Informed Consent is required from 
all subjects or their legally authorized representative. The Investigator is responsible for 
ensuring that Informed Consent is obtained. 
The obtaining and documentation of Informed Consent must be in accordance with the 
principles of the Declaration of Helsinki, ISO 14155, any applicable national regulations, and 
local Ethics Committee and/or Regulatory authority body, as applicable. The ICF must be 
approved by the center’s IRB/EC.  
Boston Scientific will provide a study-specific template of the ICF to investigators 
participating in this study. The ICF template may be modified to meet the requirements of the 
investigative center’s IRB/EC.  Any modification requires approval from BSC prior to use of 
the form.  The ICF must be in a language understandable to the subject and if needed, BSC 
will assist the center in obtaining a written consent translation. Translated consent forms 
must also have IRB/EC approval prior to their use.  Privacy language shall be included in the 
body of the form or as a separate form as applicable.   
21. Safety Reporting 
21.1. Definitions and Classification 
Adverse event definitions are provided in Table 21.1-1. Administrative edits were made to 
combine definitions from ISO 14155-2011 and MEDDEV 2.7/3 12/2010. 
 
Table 21.1-1: Adverse Event Definitions 
Term 
Definition 
Adverse Device Effect (ADE) 
 
Adverse event related to the use of an investigational medical device 
NOTE 1: This definition includes any adverse event resulting from 

 
 
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Table 21.1-1: Adverse Event Definitions 
Term 
Definition 
Ref: ISO 14155-2011 
 
Ref: MEDDEV 2.7/3 12/2010 
insufficient or inadequate instructions for  use, the deployment, the 
implantation, the installation, the operation, or any malfunction of the 
investigational medical device. 
NOTE 2: This definition includes any event resulting from use error or 
from intentional misuse of the investigational medical device. 
Serious Adverse Event (SAE) 
Ref: ISO 14155:2011 
Adverse event that: 
Led to a death  
Led to serious deterioration in the health of the subject, that either resulted 
in: 
o 
a life-threatening illness or injury, or 
o 
a permanent impairment of a body structure or a body function, or 
o 
in-patient or prolonged hospitalization, or 
o 
medical or surgical intervention to prevent life- threatening illness 
or injury or permanent impairment to a body structure or a body 
function, 
o 
Led to foetal distress, foetal death or a congenital abnormality or 
birth defect 
Note: For the purpose of this study, only events that led to death will be 
reported as SAE. 
Serious Adverse Device Effect 
(SADE) 
 
Ref: ISO 14155-2011 
 
Ref: MEDDEV 2.7/3 12/2010
Adverse device effect that has resulted in any of the consequences 
characteristic of a serious adverse event. 
 
Unanticipated Serious Adverse 
Device Effect (USADE) 
 
Ref: ISO 14155-2011 
 
Ref: MEDDEV 2.7/3 12/2010 
Serious adverse device effect which by its nature, incidence, severity, or 
outcome has not been identified in the current version of the risk analysis 
report. 
NOTE 1: Anticipated serious adverse device effect (ASADE) is an effect 
which by its nature, incidence, severity or outcome has been identified in the 
risk analysis report. 
Device Deficiency 
 
Ref: ISO 14155-2011 
 
Ref: MEDDEV 2.7/3 12/2010 
A device deficiency is any inadequacy of a medical device with respect to its 
identity, quality, durability, reliability, safety or performance. 
NOTE 1: Device deficiencies include malfunctions, misuse or use errors, 
and inadequate labeling. 
 
Abbreviations: EC=Ethics Committee; IRB=Institutional Review Board 
 
Death should not be recorded as an event, but should only be reflected as an outcome of a 
specific SAE (see Table 21.1-1 for AE definitions).  
Any reportable safety event (see Section 8) experienced by the study subject from the point 
of enrollment in the study must be recorded in the eCRF. Collect any SAE that led to death 
and any VARC event regardless of seriousness and device relationship.  

 
 
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Refer to Section 19 for the known risks associated with the study device(s). 
21.2. Relationship to Study Device(s) 
The Investigator must assess the relationship of the event to the study device as related or 
unrelated. See criteria in Table 21.2-1. 
Table 21.2-1: Criteria for Assessing Relationship of Study Device to Adverse Event 
Classification 
Description 
Unrelated 
The adverse event is determined to be due to a concurrent illness or effect of another 
device/drug and is not related to the investigational product. 
Related 
 The adverse event is determined to be potentially related to the investigational 
product, and an alternative etiology is equally or less likely compared to the 
potential relationship to investigational product, or 
 There is a strong relationship to investigational product, or recurs on re-challenge, 
and another etiology is unlikely, or 
 There is no other reasonable medical explanation for the event. 
21.3. Investigator Reporting Requirements 
Event reporting on RESPOND study is limited to SAE that lead to death, ADE, SADE, 
USADE, device deficiencies and VARC events regardless of seriousness and device 
relationship. The communication requirements for reporting to BSC are as shown in Table 
21.3-1. 
Table 21.3-1: Investigator Reporting Requirements 
Event Classification 
Communication Method  
Communication Timeline  
Unanticipated Serious Adverse 
Device Effect (USADE) 
 
Complete AE eCRF page with all 
available new and updated information 
 Within 1 business day of first 
becoming aware of the event1. 
 Terminating at the end of the 
study 
Serious Adverse Event (SAE) 
that led to death, Serious 
Adverse Device Effects 
(SADE), and serious VARC 
events 
Complete AE eCRF page with all 
available new and updated information 
 Within 2 business days of first 
becoming aware of the event1 or 
as per local/regional regulations. 
 Reporting required through the 
end of the study 
Provide relevant source documentation 
(unidentified) for reported event 
 When documentation is 
available 
Adverse Device Effects and 
non-serious VARC events 
Complete AE eCRF page with all 
available new and updated information 
 As soon as possible after 
becoming aware of the 
information1 
 Reporting required through the 
end of the study 
Device Deficiencies (including 
but not limited to failures, 
Complete applicable CRF fields/forms 
with all available new and updated 
 Within 1 business day of first 
becoming aware of the event1

 
 
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Table 21.3-1: Investigator Reporting Requirements 
Event Classification 
Communication Method  
Communication Timeline  
malfunctions, and product 
nonconformities) 
Note:  Any Device Deficiency 
that might have led to a serious 
adverse device effect if a) 
suitable action had not been 
taken or b) intervention had 
not been made or c) if 
circumstances had been less 
fortunate is considered a 
reportable event. 
 
information. 
and as per local/regional 
regulations 
 Reporting required through the 
end of the study 
1 The “become aware date” for an event that requires reporting per the protocol is the date that study personnel 
listed on the Delegation of Authority Log identify or are notified of the event. Personnel may become aware via 
any of the following (inclusive but not limited to): 
 
Patient or patient’s caregiver 
 
Admission / visit with any study personnel 
 
Patient’s non-study physician, nurse or other medical personnel 
 
Medical record review 
 
Electronic medical record notification / alert, if applicable at institution 
Abbreviations: AE=adverse event; CRF=case report form; VARC=Valve Academic Research Consortium 
21.4. Device Deficiencies 
All device deficiencies (including but not limited to failures, malfunctions, use errors, 
product nonconformities, and labeling errors) will be documented and reported to BSC. If 
possible, the device(s) should be returned to BSC for analysis. Instructions for returning the 
device(s) will be provided. If it is not possible to return the device, the investigator should 
document why the device was not returned and the final disposition of the device. Device 
failures and malfunctions should also be documented in the subject’s medical record. 
Device deficiencies (including but not limited to failures, malfunctions, and product 
nonconformities) are not to be reported as events. However, if there is an event that results 
from a device failure or malfunction, that specific event would be recorded on the 
appropriate eCRF as outlined in Table 21.3-1. 
And, any Device Deficiency that might have led to a serious adverse device effect if a) 
suitable action had not been taken or b) intervention had not been made or c) if circumstances 
had been less fortunate is considered a reportable event. 
22. Committees 
22.1. Steering Committee 
A Steering Committee will be comprised of the sponsor’s clinical management, 
interventional cardiologists and cardiac surgeons, including the study co-principal 

 
 
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investigators, other investigators, and medical consultants experienced in TAVI. 
Responsibilities may include oversight of the overall conduct of the study with regard to 
protocol development, study progress, patient safety, overall data quality and integrity, and 
disseminating any study results through appropriate scientific sessions and publications. 
Steering Committee members may participate in the review and approval of all requests for 
data analysis, abstract and manuscript preparation and submission. 
 
22.2. Clinical Events Committee 
An independent medical reviewer (IMR) will review and adjudicate all-cause mortality and 
stroke events reported by study investigators. The IMR will review a safety event dossier, 
which may include copies of subject source documents provided by study sites, and 
adjudicate study endpoint related clinical events. The responsibilities, qualifications, 
membership, and procedures of the medical reviewer are outlined in the CEC charter. 
23. Suspension or Termination 
23.1. Criteria for Terminating the Study 
Boston Scientific reserves the right to terminate the study but intends to exercise this right 
only for valid scientific or administrative reasons and reasons related to protection of 
subjects. Investigators and associated IRBs/ECs will be notified in writing in the event of 
termination. 
23.2. Criteria for Suspending/Terminating a Study Center 
Boston Scientific reserves the right to suspend/terminate a study center at any time after the 
study initiation visit if no subjects have been enrolled or if the center has multiple and/or 
major protocol violations without justification or fails to follow remedial actions. 
24. Publication Policy 
In accordance with the Global SOP – Human Subject Data and Research Controls, BSC 
requires disclosure of its involvement as a sponsor or financial supporter in any publication 
or presentation relating to a BSC study or its results. In accordance with the Global SOP – 
Human Subject Data and Research Controls, BSC will submit study results for publication 
(regardless of study outcome) following the conclusion or termination of the study. Boston 
Scientific Corporation adheres to the Contributorship Criteria set forth in the Uniform 
Requirements of the International Committee of Medical Journal Editors (ICMJE; 
http://www.icmje.org). In order to ensure the public disclosure of study results in a timely 
manner, while maintaining an unbiased presentation of study outcomes, BSC personnel may 
assist authors and investigators in publication preparation provided the following guidelines 
are followed. 
 All authorship and contributorship requirements as described above must be followed. 

 
 
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 BSC involvement in the publication preparation and the BSC Publication Policy should 
be discussed with the Coordinating Principal Investigator(s) and/or Executive/Steering 
Committee at the onset of the project. 
 The First and Senior authors are the primary drivers of decisions regarding publication 
content, review, approval, and submission.  
25. Bibliography 
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Nkomo VT, Gardin JM, Skelton TN, Gottdiener JS, Scott CG, Enriquez-Sarano M. 
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Varadarajan P, Kapoor N, Bansal RC, Pai RG. Survival in elderly patients with severe 
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Leontyev S, Walther T, Borger MA, et al. Aortic valve replacement in octogenarians: 
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Brown JM, O'Brien SM, Wu C, Sikora JA, Griffith BP, Gammie JS. Isolated aortic 
valve replacement in North America comprising 108,687 patients in 10 years: changes 
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Hara H, Pedersen WR, Ladich E, et al. Percutaneous balloon aortic valvuloplasty 
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Thomas M. The global experience with percutaneous aortic valve replacement. JACC 
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Webb JG, Altwegg L, Boone RH, et al. Transcatheter aortic valve implantation: impact 
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Buchanan GL, Chieffo A, Montorfano M, et al. The role of sex on VARC outcomes 
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10. Gurvitch R, Toggweiler S, Willson AB, et al. Outcomes and complications of 
transcatheter aortic valve replacement using a balloon expandable valve according to the 
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11. Mussardo M, Latib A, Chieffo A, et al. Periprocedural and short-term outcomes of 
transfemoral transcatheter aortic valve implantation with the Sapien XT as compared 
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12. Schymik G, Schrofel H, Schymik JS, et al. Acute and late outcomes of transcatheter 
aortic valve implantation (TAVI) for the treatment of severe symptomatic aortic stenosis 
in patients at high- and low-surgical risk. Journal of Interventional Cardiology 2012. 
13. Seiffert M, Schnabel R, Conradi L, et al. Predictors and outcomes after transcatheter 
aortic valve implantation using different approaches according to the valve academic 
research consortium definitions. Catheter Cardiovasc Interv 2012:Epub before print. 
14. Tamburino C, Barbanti M, Capodanno D, et al. Comparison of complications and 
outcomes to one year of transcatheter aortic valve implantation versus surgical aortic 
valve replacement in patients with severe aortic stenosis. Am J Cardiol 2012;109:1487-
93. 
15. Bleiziffer S, Mazzitelli D, Opitz A, et al. Beyond the short-term: clinical outcome and 
valve performance 2 years after transcatheter aortic valve implantation in 227 patients. J 
Thorac Cardiovasc Surg 2012;143:310-7. 
16. Litzler PY, Borz B, Smail H, et al. Transapical aortic valve implantation in Rouen: four 
years' experience with the Edwards transcatheter prosthesis. Arch Cardiovasc Dis 
2012;105:141-5. 
17. Toggweiler S, Humphries KH, Lee M, et al. 5-Year Outcome After Transcatheter Aortic 
Valve Implantation. J Am Coll Cardiol 2012:Epub before print. 
18. Chieffo A, Buchanan GL, Van Mieghem NM, et al. Transcatheter Aortic Valve 
Implantation With the Edwards SAPIEN Versus the Medtronic CoreValve Revalving 
System Devices. A Multicenter Collaborative Study: The PRAGMATIC Plus Initiative 
(Pooled-RotterdAm-Milano-Toulouse In Collaboration). Journal of the American 
College of Cardiology 2013:Epub before print. 
19. Codner P, Assali A, Dvir D, et al. Two-Year Outcomes for Patients With Severe 
Symptomatic Aortic Stenosis Treated With Transcatheter Aortic Valve Implantation. 
Am J Cardiol 2013. 
20. Piazza N, Grube E, Gerckens U, et al. Procedural and 30-day outcomes following 
transcatheter aortic valve implantation using the third generation (18 Fr) CoreValve 
ReValving System: results from the multicentre, expanded evaluation registry 1-year 
following CE mark approval. EuroIntervention 2008;4:242-9. 
21. Rodes-Cabau J, Webb JG, Cheung A, et al. Transcatheter aortic valve implantation for 
the treatment of severe symptomatic aortic stenosis in patients at very high or 
prohibitive surgical risk: acute and late outcomes of the multicenter Canadian 
experience. J Am Coll Cardiol 2010;55:1080-90. 
22. Thomas M, Schymik G, Walther T, et al. Thirty-day results of the SAPIEN aortic 
Bioprosthesis European Outcome (SOURCE) Registry: A European registry of 
transcatheter aortic valve implantation using the Edwards SAPIEN valve. Circulation 
2010;122:62-9. 
23. Thomas M, Schymik G, Walther T, et al. One-year outcomes of Cohort 1 in the Edwards 
SAPIEN Aortic Bioprosthesis European Outcome (SOURCE) registry: The European 

 
 
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registry of transcatheter aortic valve implantation using the Edwards SAPIEN valve. 
Circulation 2011;124:425-33. 
24. Lefèvre T, Kappetein AP, Wolner E, et al. One year follow-up of the multi-centre 
European PARTNER transcatheter heart valve study. Eur Heart J 2011;32:148-57. 
25. Tamburino C, Capodanno D, Ramondo A, et al. Incidence and predictors of early and 
late mortality after transcatheter aortic valve implantation in 663 patients with severe 
aortic stenosis. Circulation 2011;123:299-308. 
26. Munoz-Garcia AJ, Hernandez-Garcia JM, Jimenez-Navarro MF, et al. Survival and 
predictive factors of mortality after 30 days in patients treated with percutaneous 
implantation of the CoreValve aortic prosthesis. Am Heart J 2012;163:288-94. 
27. Ussia GP, Barbanti M, Petronio AS, et al. Transcatheter aortic valve implantation: 3-
year outcomes of self-expanding CoreValve prosthesis. Eur Heart J 2012;33:969-76. 
28. Wendler O, Walther T, Schroefel H, et al. Transapical aortic valve implantation: mid-
term outcome from the SOURCE registry. European Journal of Cardio-Thoracic Surgery 
2012:Epub before print. 
29. Walther T, Kempfert J, Rastan A, et al. Transapical aortic valve implantation at 3 years. 
J Thorac Cardiovasc Surg 2012;143:326-31. 
30. Walther T, Thielmann M, Kempfert J, et al. PREVAIL TRANSAPICAL: multicentre 
trial of transcatheter aortic valve implantation using the newly designed bioprosthesis 
(SAPIEN-XT) and delivery system (ASCENDRA-II). Eur J Cardiothorac Surg 
2012;42:278-83; discussion 83. 
31. Rodes-Cabau J, Webb JG, Cheung A, et al. Long-Term Outcomes After Transcatheter 
Aortic Valve Implantation: Insights on Prognostic Factors and Valve Durability From 
the Canadian Multicenter Experience. J Am Coll Cardiol 2012;60:1864–75. 
32. Eltchaninoff H, Prat A, Gilard M, et al. Transcatheter aortic valve implantation: early 
results of the FRANCE (FRench Aortic National CoreValve and Edwards) registry. Eur 
Heart J 2011;32:191-7. 
33. Bosmans JM, Kefer J, De Bruyne B, et al. Procedural, 30-day and one year outcome 
following CoreValve or Edwards transcatheter aortic valve implantation: results of the 
Belgian national registry. Interact Cardiovasc Thorac Surg 2011;12:762-7. 
34. Zahn R, Gerckens U, Grube E, et al. Transcatheter aortic valve implantation: first results 
from a multi-centre real-world registry. Eur Heart J 2011;32:198-204. 
35. Moat NE, Ludman P, de Belder MA, et al. Long-term outcomes after transcatheter aortic 
valve implantation in high-risk patients with severe aortic stenosis: the U.K. TAVI 
(United Kingdom Transcatheter Aortic Valve Implantation) Registry. J Am Coll Cardiol 
2011;58:2130-8. 
36. Gilard M, Eltchaninoff H, Iung B, et al. Registry of transcatheter aortic-valve 
implantation in high-risk patients. N Engl J Med 2012;366:1705-15. 

 
 
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37. Spargias K, Toutouzas K, Chrissoheris M, et al. The ATHENS TAVR Registry of 
Newer Generation Transfemoral Aortic Valves: 30-Day Outcomes. Hellenic J Cardiol 
2013;54:18-24. 
38. Di Mario C, Eltchaninoff H, Moat N, et al. The 2011-12 pilot European Sentinel 
Registry of Transcatheter Aortic Valve Implantation: in-hospital results in 4,571 
patients. EuroIntervention 2012;8. 
39. Leon MB, Smith CR, Mack M, et al. Transcatheter aortic-valve implantation for aortic 
stenosis in patients who cannot undergo surgery. N Engl J Med 2010;363:1597-607. 
40. Smith CR, Leon MB, Mack MJ, et al. Transcatheter versus surgical aortic-valve 
replacement in high-risk patients. N Engl J Med 2011;364:2187-98. 
41. Makkar RR, Fontana GP, Jilaihawi H, et al. Transcatheter aortic-valve replacement for 
inoperable severe aortic stenosis. N Engl J Med 2012;366:1696-704. 
42. Kodali SK, Williams MR, Smith CR, et al. Two-year outcomes after transcatheter or 
surgical aortic-valve replacement. N Engl J Med 2012;366:1686-95. 
43. Holmes DR, Jr., Mack MJ, Kaul S, et al. 2012 ACCF/AATS/SCAI/STS Expert 
consensus document on transcatheter aortic valve replacement. J Am Coll Cardiol 
2012;59:1200-54. 
44. Leon MB, Piazza N, Nikolsky E, et al. Standardized endpoint definitions for 
Transcatheter Aortic Valve Implantation clinical trials: a consensus report from the 
Valve Academic Research Consortium. J Am Coll Cardiol 2011;57:253-69. 
45. Kappetein AP, Head SJ, Genereux P, et al. Updated standardized endpoint definitions 
for transcatheter aortic valve implantation: the valve academic research consortium-2 
consensus document. J Am Coll Cardiol 2012;60:1438-54. 
46. Meredith IT, Hood KL, Haratani N, Allocco DJ, Dawkins KD. The Lotus™ Valve: a 
next-generation transcatheter aortic valve replacement system. EuroIntervention 
2012;8:Q70-Q4. 
47. Meredith IT, Worthley SG, Whitbourn RJ, et al. First report of one-year outcomes of the 
REPRISE I feasibility study of the repositionable Lotus Aortic Valve Replacement 
System. In: EuroPCR. Paris; 2013. 
48. Meredith IT. Repositionable percutaneous replacement of a stenotic aortic valve through 
implantation of the Lotus Valve System: 30-day outcomes for the first 60 patients in the 
REPRISE II Study. In: EuroPCR. Paris; 2013. 
49. Pibarot P, Weissman N, Stewart W, et al. Reduced incidence of prosthesis-patient 
mismatch and its sequelae in transcatheter versus surgical valve replacement in high-risk 
patients with severe aortic stenosis: A PAR TNER Trial Cohort A analysis. Journal of 
the American College of Cardiology 2013;61:E1865. 
50. Kim K, DeMets DL. Design and analysis of group sequential tests based on the type I 
error spending rate function. Biometrika 1987;74:149-54. 

 
 
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51. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P. Acute renal failure - 
definition, outcome measures, animal models, fluid therapy and information technology 
needs: the Second International Consensus Conference of the Acute Dialysis Quality 
Initiative (ADQI) Group. Crit Care 2004;8:R204-12. 
52. Mehta RL, Kellum JA, Shah SV, et al. Acute Kidney Injury Network: report of an 
initiative to improve outcomes in acute kidney injury. Crit Care 2007;11:R31. 
53. Mehran R, Rao SV, Bhatt DL, et al. Standardized bleeding definitions for cardiovascular 
clinical trials: a consensus report from the Bleeding Academic Research Consortium. 
Circulation 2011;123:2736-47. 
54. Ndrepepa G, Schuster T, Hadamitzky M, et al. Validation of the Bleeding Academic 
Research Consortium definition of bleeding in patients with coronary artery disease 
undergoing percutaneous coronary intervention. Circulation 2012;125:1424-31. 
55. Durack DT, Lukes AS, Bright DK. New criteria for diagnosis of infective endocarditis: 
utilization of specific echocardiographic findings. Duke Endocarditis Service. Am J Med 
1994;96:200-9. 
56. Thygesen K, Alpert JS, White HD. Universal definition of myocardial infarction. Eur 
Heart J 2007;28:2525-38. 
57. Sharp AS, Michev I, Maisano F, et al. A new technique for vascular access management 
in transcatheter aortic valve implantation. Catheter Cardiovasc Interv 2010;75:784-93. 
58. Genereux P, Kodali S, Leon MB, et al. Clinical outcomes using a new crossover balloon 
occlusion technique for percutaneous closure after transfemoral aortic valve 
implantation. JACC Cardiovasc Interv 2011;4:861-7. 
 
26. Abbreviations and Definitions  
26.1. Abbreviations 
Abbreviations are shown in Table 26.1-1.   
Table 26.1-1: Abbreviations and Acronyms 
Abbreviation/Acronym 
Definition 
ACT 
activated clotting time 
ADE 
adverse device effect 
AE 
adverse event 
AKIN 
Acute Kidney Injury Network 
AO 
ascending aorta 
AR 
aortic regurgitation 
AS 
aortic stenosis 
AV 
Atrioventricular 
AVA 
aortic valve area 

 
 
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Table 26.1-1: Abbreviations and Acronyms 
Abbreviation/Acronym 
Definition 
AVR 
aortic valve replacement 
BARC 
Bleeding Academic Research Consortium 
BMI 
body mass index 
CBC 
complete blood count 
CPB 
cardiopulmonary bypass 
CRA 
clinical research associate  
CEC 
Clinical Events Committee 
CHF 
congestive heart failure 
CK 
creatine kinase 
CK-MB 
creatine kinase-myoglobin band, a fraction of creatine kinase 
CRC 
Case Review Committee 
CRO 
clinical research organization 
CT 
computed tomography 
CVA 
cerebrovascular accident 
DVI 
Doppler velocity index 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOA 
effective orifice area 
FCE 
field clinical engineer 
GCP 
Good Clinical Practices 
ICF 
Informed Consent form 
ICH 
International Conference on Harmonisation 
IEC/IRB 
Independent Ethics Committee/Institutional Review Board 
IFU 
Instructions for Use 
IMA 
internal mammary artery 
ISO 
International Organization For Standardization 
ITT 
intention to treat 
LA 
left atrial 
LBBB 
left bundle branch block 
LDH 
lactate dehydrogenase 
LV 
left ventricle 
LVEF 
left ventricular ejection fraction 
MACCE 
major adverse cardiovascular and cerebrovascular events 
MI 
myocardial infarction 
MR 
mitral regurgitation 
MRI 
magnetic resonance imaging 
mRS 
Modified Rankin Scale 
NIHSS 
National Institutes of Health Stroke Scale 
NYHA 
New York Heart Association classification 
PA 
pulmonary artery 
PPM 
permanent pacemaker 

 
 
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Table 26.1-1: Abbreviations and Acronyms 
Abbreviation/Acronym 
Definition 
QOL 
quality of life 
RBBB 
right bundle branch block 
SADE 
serious adverse device effect 
SAE 
serious adverse event 
SAVR 
surgical aortic valve replacement 
TAVR 
transcatheter aortic valve replacement 
TEE 
transesophageal Doppler echocardiography 
TIA 
transient ischemic attack 
TR 
tricuspid regurgitation 
TTE 
transthoracic Doppler echocardiography 
USADE 
unanticipated serious adverse device effect 
URL 
upper reference limit (defined as 99th percentile of normal reference range) 
VARC 
Valve Academic Research Consortium 
 
26.2. Definitions 
Terms are defined in Table 26.2-1.  
Table 26.2-1: Definitions 
Term 
Definition 
ACUTE KIDNEY 
INJURY (AKI) 
(AKIN  System51,52) 
Change in serum creatinine (up to 7 days) compared to baseline: 
 Stage 1: Increase in serum creatinine to 150–199% (1.5–1.99 × increase compared 
with baseline) OR increase of ≥0.3 mg/dl (≥26.4 mmol/L)  
 Stage 2: Increase in serum creatinine to 200–299% (2.0–2.99 × increase compared 
with baseline) 
 Stage 3: Increase in serum creatinine to ≥300% (>3 × increase compared with 
baseline) OR serum creatinine of ≥4.0 mg/dL (≥354 mmol/L) with an acute 
increase of at least 0.5 mg/dL (44 mmol/L) 
-OR-  
Based on urine output (up to 7 days): 
 Stage 1: <0.5 ml/kg per hour for >6 but <12 hours 
 Stage 2: <0.5 ml/kg per hour for >12 but <24 hours 
 Stage 3: <0.3 ml/kg per hour for ≥24 hours or anuria for ≥12 hours 
Note 1: Subjects receiving renal replacement therapy are considered to meet Stage 3 
criteria irrespective of other criteria. 
ACUTE VESSEL 
OCCLUSION 
The state of complete luminal obstruction with no antegrade blood flow 
ADVERSE DEVICE 
EFFECT (ADE) 
Adverse event related to the use of an investigational medical device 
Note 1: This definition includes adverse events resulting from insufficient or 
inadequate instructions for use, deployment, implantation, installation, or operation, 
or any malfunction of the investigational medical device.  
Note 2: This definition includes any event resulting from use error or from intentional 
misuse of the investigational medical device. 
AORTIC 
Intimal tear resulting in blood splitting the aortic media and producing a false lumen 

 
 
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Table 26.2-1: Definitions 
Term 
Definition 
DISSECTION 
that can progress in an antegrade or retrograde direction Aortic dissection is further 
classified using Stanford classification (Types A and B depending on whether 
ascending or descending aorta involved) or DeBakey classification (Types I, II and 
III) [see Figure below]. 
AORTIC 
REGURGITATION 
(AR) 
The leaking of the aortic valve that causes blood to flow in the reverse direction 
during ventricular diastole, from the aorta into the left ventricle. 
The echocardiographic findings in severe aortic regurgitation include the following. 
 An AR color jet dimension >60% of the left ventricular outflow tract diameter 
(may not be true if the jet is eccentric)  
 The pressure half-time of the regurgitant jet is <250 msec  
 Early termination of the mitral inflow (due to increase in LV pressure due to the 
AR)  
 Early diastolic flow reversal in the descending aorta.  
 
 Regurgitant volume >60 mL  
 Regurgitant fraction >55% 
ARRHYTHMIA 
Any variation from the normal rhythm of the heartbeat, including sinus arrhythmia, 
premature beat, heart block, atrial fibrillation, atrial flutter and tachycardia. Complete 
heart block, ventricular tachycardia and ventricular fibrillation are considered major 
arrhythmias. Data should be collected on any new arrhythmia resulting in 
hemodynamic instability or requiring therapy (therapy includes electrical/medical 
cardioversion or initiation of a new medication [oral anticoagulation, rhythm or rate 
controlling therapy]).  
New onset atrial fibrillation or atrial flutter (AF) is diagnosed as any arrhythmia 
within hospitalization that has the ECG characteristics of AF and lasts sufficiently 
long to be recorded on a 12-lead ECG, or at least 30 seconds on a rhythm strip.  
The therapeutic approach to new-onset AF (spontaneous conversion, electrical or 
medical cardioversion, initiation of oral anticoagulation, and rate or rhythm control 
medications) and any clinical consequences should be documented.   
Note: See also definitions for conductance disturbance and permanent pacemaker. 
BLEEDING44,45   
Life-threatening or Disabling Bleeding 
 Fatal bleeding (Bleeding Academic Research Consortium [BARC] type 553,54) 

 
 
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Table 26.2-1: Definitions 
Term 
Definition 
 Bleeding in a critical organ, such as intracranial, intraspinal, intraocular, or 
pericardial necessitating pericardiocentesis, or intramuscular with compartment 
syndrome (BARC type 3b and 3c)  
 Bleeding causing hypovolemic shock or severe hypotension requiring vasopressors 
or surgery (BARC type 3b)  
 Overt source of bleeding with drop in hemoglobin of ≥5 g/dL or whole blood or 
packed red blood cells (RBC) transfusion ≥4 units (BARC type 3b)* 
Major Bleeding (BARC type 3a) 
 Overt bleeding either associated with a drop in the hemoglobin level of at least 
3.0g/dL or requiring transfusion of 2 or 3 units of whole blood/RBC, or causing 
hospitalization or permanent injury, or requiring surgery AND does not meet 
criteria of life-threatening or disabling bleeding  
Minor Bleeding (BARC type 2 or 3a, depending on the severity) 
 Any bleeding worthy of clinical mention (e.g., access site hematoma) that does not 
qualify as life-threatening, disabling, or major 
* Given one unit of packed RBC typically will raise blood hemoglobin concentration 
by 1 g/dL, an estimated decrease in hemoglobin will be calculated. 
CARDIAC 
DECOMPENSATION 
Inability of the heart to maintain adequate circulation 
CARDIAC 
TAMPONADE 
Evidence of a new pericardial effusion associated with hemodynamic instability and 
clearly related to the TAVR procedure. Clinical syndrome caused by the 
accumulation of fluid in the pericardial space, resulting in reduced ventricular filling 
and subsequent hemodynamic compromise. 
CARDIOGENIC 
SHOCK 
An insufficient forward cardiac output to maintain adequate perfusion of vital organs 
to meet ongoing demands for oxygenation and metabolism. Cardiogenic shock is due 
to either inadequate left ventricular pump function (such as in congestive heart 
failure) or inadequate left ventricular filling (such as in cardiac tamponade). 
Cardiogenic shock is defined as sustained hypotension (>30 minutes) with evidence 
of tissue hypoperfusion including oliguria (<30 mL/h), cool extremities, cyanosis, and 
altered mental status. 
CEREBRAL 
INFARCTION 
Evidence of brain cell death from imaging studies or pathological examination. If 
there are clinical symptoms, then it is a stroke; otherwise, it is an asymptomatic 
cerebral infarction.  
CHRONIC RENAL 
INSUFFICIENCY 
Subject has chronic impairment of kidney function. 
CONDUCTION 
DISTURBANCES  
Implant-related new or worsened cardiac conduction disturbances include new or 
worsened first degree atrioventricular (AV) block, second degree AV block (Mobitz I 
or Mobitz II), third degree AV block, incomplete right bundle branch block (RBBB), 
RBBB, intraventricular conduction delay, left bundle branch block (LBBB), left 
anterior fascicular block, or left posterior fascicular block, including block requiring 
permanent pacemaker implant 
Note 1: High grade AV block is considered persistent if it is present every time the 
underlying rhythm is checked. 
Note 2: See also definitions for arrhythmia and permanent pacemaker. 
CONVERSION TO 
OPEN SURGERY 
Conversion to open sternotomy during the TAVR procedure secondary to any 
procedure-related complications 
CORONARY 
Angiographic or echocardiographic evidence of a new, partial or complete, 
obstruction of a coronary ostium, either by the valve prosthesis itself, the native 

 
 
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Term 
Definition 
OBSTRUCTION 
 
leaflets, calcifications, or dissection, occurring during or after the TAVR procedure. 
 
Mechanical coronary artery obstruction following TAVR or surgical AVR that 
typically occurs during the index procedure. Possible mechanisms for mechanical 
coronary obstruction include the following.  
 Impingement of the coronary ostia by the valve support structure in the setting of 
suboptimal valve positioning and/or ‘small aortic root’ anatomy  
 Embolization from calcium, thrombus, air, or endocarditis displacement of native 
aortic valve leaflets towards the coronary ostia during TAVR  
 Suture-related kinking or obstruction or cannulation related obstruction of the 
coronary ostia associated with surgical AVR 
The diagnosis of TAVR-associated coronary obstruction can be determined by 
imaging studies (coronary angiography, intravascular ultrasound, multi-slice CT 
angiography, or echocardiography), surgical exploration, or autopsy findings. Cardiac 
biomarker elevations and ECG changes indicating new ischemia provide 
corroborative evidence. 
DEATH  
 
All-cause Death 
Death from any cause after a valve intervention. 
Cardiovascular Death 
Any one of the following criteria is met. 
 Any death due to proximate cardiac cause (e.g., myocardial infarction, cardiac 
tamponade, worsening heart failure) 
 Sudden or unwitnessed death  
 Death of unknown cause 
 Death caused by noncoronary vascular conditions such as neurological events, 
pulmonary embolism, ruptured aortic aneurysm, dissecting aneurysm, or other 
vascular disease  
 All procedure-related deaths, including those related to a complication of the 
procedure or treatment for a complication of the procedure  
 All valve-related deaths including structural or nonstructural valve dysfunction or 
other valve-related adverse events  
Non-cardiovascular Death 
 Any death in which the primary cause of death is clearly related to another 
condition (e.g. trauma, cancer, suicide) 
DEVICE 
DEFICIENCY  
 
Inadequacy of a medical device with respect to its identity, quality, durability, 
reliability, safety or performance.  
Note 1: Device deficiencies include malfunctions, use errors, and inadequate labeling. 
DEVICE FAILURE 
A device failure is identified whenever the criteria for device success are not met.  

 
 
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Term 
Definition 
DEVICE 
MIGRATION 
Device migration is defined as an upward or downward displacement of the implanted 
valve from its original implant location, after initial correct positioning within the 
aortic annulus from its initial position, with or without consequences. This can be 
confirmed by X-ray, echocardiography, CT scan or MRI or valve migration 
demonstrated by direct assessment during open heart surgery or at autopsy. 
DEVICE RELATED 
COMPLICATIONS 
Complications associated with the device as it relates to delivery, placement, efficacy 
or durability; these may involve the implanted device or the delivery system.   
DEVICE SUCCESS 
Device Success as defined by VARC post-implant procedure. 
VARC 144 
 Successful vascular access, delivery and deployment of the device and successful 
retrieval of the delivery system 
 Correct position of the device in the proper anatomical location 
 Intended performance of the prosthetic heart valve (aortic valve area >1.2 cm2 and 
mean aortic valve gradient <20 mmHg or peak velocity <3 m/s, without moderate 
or severe prosthetic valve aortic regurgitation) 
 Only one valve implanted in the proper anatomical location 
VARC 245 
 Absence of procedural mortality 
 Correct positioning of a single transcatheter valve into the proper anatomical 
location 
 Intended performance of the Lotus Valve (indexed effective orifice area >0.85 
cm2/m2 [>0.7 cm2/m2 for BMI ≥30 kg/ m2] plus either a mean aortic valve gradient 
<20 mm Hg or a peak velocity <3m/sec, without moderate or severe prosthetic 
valve aortic regurgitation) 
ECTOPIC VALVE 
DEPLOYMENT 
Permanent deployment of the valve prosthesis in a location other than the aortic root. 
EMBOLISM 
Examples include a free flowing blood clot or lesion material that is located in the 
systemic or pulmonary circulation. Embolism may be manifested by a neurological 
event or a noncerebral embolic event. 
ENCEPHALOPATHY 
Altered mental state (e.g., seizures, delirium, confusion, hallucinations, dementia, 
coma, psychiatric episode, etc.) 
ENDOCARDITIS 
 
Infective endocarditis is diagnosed based on Duke criteria55 and necessitates the 
following.  
 Two major criteria -OR- 
 One major and three minor criteria -OR- 
 Five minor criteria 
Major Criteria 
 Positive blood culture for infective endocarditis  
o Typical microorganism consistent with infective endocarditis from 2 separate 
blood cultures, as noted below. 
 Viridans streptococci, Streptococcus bovis, or HACEK group (Haemophilus 
[Haemophilus parainfluenzae, Haemophilus aphrophilus, and Haemophilus 
paraphrophilus], Actinobacillus actinomycetemcomitans [Aggregatibacter 
actinomycetemcomitans], Cardiobacterium hominis, Eikenella corrodens, 
Kingella kingae -OR-  
 Community-acquired Staphylococcus aureus or enterococci, in the absence of 
a primary focus  

 
 
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Definition 
 
-OR-  
o Microorganisms consistent with infective endocarditis from persistently positive 
blood cultures defined as noted below. 
 Two (2) positive cultures of blood samples drawn >12 hours apart -OR-   
 All of 3 or a majority of 4 separate cultures of blood (with first and last 
sample drawn 1 hour apart)  
 Evidence of endocardial involvement 
o Positive echocardiogram for infective endocarditis defined as noted below. 
 Oscillating intracardiac mass on valve or supporting structures, in the path of 
regurgitant jets, or on implanted material in the absence of an alternative 
anatomic explanation -OR-   
 Abscess -OR-   
 New partial dehiscence of prosthetic valve  
 
-OR-  
o New valvular regurgitation (worsening or changing of preexisting murmur not 
sufficient) 
Minor Criteria 
 Predisposition: predisposing heart condition or intravenous drug use 
 Fever: temperature >38.0° C (100.4° F) 
 Vascular phenomena: major arterial emboli, septic pulmonary infarcts, mycotic 
aneurysm, intracranial hemorrhage, conjunctival hemorrhages, and Janeway 
lesions 
 Immunologic phenomena: glomerulonephritis, Osler's nodes, Roth spots, and 
rheumatoid factor 
 Microbiological evidence: positive blood culture but does not meet a major 
criterion as noted above or serological evidence of active infection with organism 
consistent with infective endocarditis 
 Echocardiographic findings: consistent with infective endocarditis but do not meet 
a major criterion as noted above  
Implanted valve endocarditis includes any infection involving an implanted valve. 
The diagnosis of operated valvular endocarditis is based on one of the following 
criteria.  
 Fulfillment of the Duke endocarditis criteria as defined above 
 Evidence of abscess, paravalvular leak, pus, or vegetation confirmed as secondary 
to infection by histological or bacteriologic studies during a re-operation 
 Findings of abscess, pus, or vegetation involving a repaired or replaced valve 
during an autopsy. 
EXPLANT 
Removal of the investigational valve implant for any reason. 
FRAILTY 
Slowness, weakness, exhaustion, wasting and malnutrition, poor endurance and 
inactivity, loss of independence.  
HEMOLYSIS 
 
Two plasma free hemoglobin values >40 mg/dL with the two readings taken within a 
single 48-hour period. If the second plasma free hemoglobin assessment is not 
performed within 48 hours following an initial determination of >40 mg/dL, this 
would qualify as an AE. 
HOSTILE CHEST 
Any of the following or other reasons that make redo operation through sternotomy or 
right anterior thoracotomy prohibitively hazardous: 
 Abnormal chest wall anatomy due to severe kyphoscoliosis or other skeletal 
abnormalities (including thoracoplasty, Potts’ disease) 

 
 
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Term 
Definition 
 Complications from prior surgery 
 Evidence of severe radiation damage (e.g. skin burns, bone destruction, muscle 
loss, lung fibrosis or esophageal stricture) 
 History of multiple recurrent pleural effusions causing internal adhesions 
INTERNAL 
MAMMARY 
ARTERY OR OTHER 
CRITICAL 
CONDUIT(S) 
CROSSING 
MIDLINE AND/OR 
ADHERENT TO 
POSTERIOR TABLE 
OF STERNUM 
A patent IMA graft that is adherent to the sternum such that injuring it during 
reoperation is likely. A patient may be considered extreme risk if any of the following 
are present:  
 The conduit(s) are radiographically indistinguishable from the posterior table of the 
sternum.  
 The conduit(s) are radiographically distinguishable from the posterior table of the 
sternum but lie within 2-3mm of the posterior table.  
INTRACRANIAL 
HEMORRHAGE 
Collection of blood between the brain and skull; subcategorized as epidural, subdural, 
and subarachnoid bleeds. 
LEFT BUNDLE 
BRANCH BLOCK 
(LBBB) 
The appearance of typical complete LBBB in the three KEY leads (I, V1, and V6) 
with the following diagnostic criteria [see Figure below].  
 The heart rhythm must be supraventricular in origin  
 QRS widening to at least 0.12 sec  
 An upright (monophasic) QRS complex in leads I and V6; the QRS may be 
notched, but there should not be any q wave in either lead I or lead V6. 
 A predominantly negative QRS complex in lead V1; there may or may not be an 
initial small r wave in lead V1, that is, lead V1 may show either a QS or RS 
complex. 
 
 
 
 
 
 
 
 
 
 
 
LIVER DISEASE 
(SEVERE) 
/CIRRHOSIS 
Any of the following: 
 Child-Pugh class C  
 MELD score ≥10 
 Portal-caval, spleno-renal, or transjugular intrahepatic portal shunt  
 Biopsy proven cirrhosis with portal hypertension or hepatocellular dysfunction 
MITRAL VALVE 
APPARATUS 
DAMAGE 
Angiographic or echocardiographic evidence of a new damage to the mitral valve 
apparatus (chordae papillary muscle, or leaflet) during or after the TAVR procedure. 
MYOCARDIAL 
INFARCTION (MI) 
 
Periprocedural MI (≤72 hours after the index procedure) 
 New ischemic symptoms (e.g., chest pain or shortness of breath) or new ischemic 
signs (e.g., ventricular arrhythmias, new or worsening heart failure, new ST-

 
 
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Definition 
segment changes, hemodynamic instability, new pathological Q waves in at least 
two contiguous leads, or imaging evidence of new loss of viable myocardium or 
new wall motion abnormality)  
 
-AND- 
 Elevated cardiac biomarkers (preferably CK-MB) within 72 h after the index 
procedure, consisting of at least one sample post-procedure with a peak value 
exceeding 15× upper reference limit (troponin) or 5× for CK-MB. If cardiac 
biomarkers are increased at baseline (>99th percentile), a further increase of at 
least 50% post-procedure is required AND the peak value must exceed the 
previously stated limit. 
Spontaneous MI (>72 hours after the index procedure) 
Any one of the following criteria applies. 
 Detection of rise and/or fall of cardiac biomarkers (preferably troponin) with at 
least one value above the 99th percentile URL, together with evidence of 
myocardial ischemia with at least one of the following 
o Symptoms of ischemia 
o ECG changes indicative of new ischemia [new ST-T changes or new LBBB] 
o New pathological Q waves in at least two contiguous leads 
o Imaging evidence of new loss of viable myocardium or new wall motion 
abnormality 
 Sudden, unexpected cardiac death, involving cardiac arrest, often with symptoms 
suggestive of myocardial ischemia, and accompanied by presumably new ST-
segment elevation, or new LBBB, and/or evidence of fresh thrombus by coronary 
angiography and/ or at autopsy, but death occurring before blood samples could be 
obtained, or at a time before the appearance of cardiac biomarkers in the blood. 
 Pathological findings of an acute myocardial infarction56. 
NEUROLOGICAL 
EVENT  
Any central, new neurological deficit, whether temporary or permanent and whether 
focal or global, that occurs after the subject emerges from anesthesia 
NEW YORK HEART 
ASSOCIATION 
CLASSIFICATION 
(NYHA) 
Classification system for defining cardiac disease and related functional limitations 
into four broad categorizations: 
 
Class I 
Subject with cardiac disease but without resulting limitations of 
physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain.
Class II 
Subjects with cardiac disease resulting in slight limitation of physical 
activity. They are comfortable at rest. Ordinary physical activity 
results in fatigue, palpitation, dyspnea, or anginal pain.
Class III 
Subjects with cardiac disease resulting in marked limitation of 
physical activity. They are comfortable at rest. Less than ordinary 
physical activity causes fatigue, palpitation, dyspnea, or anginal pain.
Class IV 
Subjects with cardiac disease resulting in inability to carry on any 
physical activity without discomfort. Symptoms of cardiac 
insufficiency or of the anginal syndrome may be present even at rest. 
If any physical activity is undertaken, discomfort is increased.
 
NONSTRUCTURAL 
DYSFUNCTION 
 
Any abnormality not intrinsic to the valve itself that results in stenosis or 
regurgitation of the operated valve or hemolysis. The term nonstructural dysfunction 
refers to problems (exclusive of thrombosis and infection) that do not directly involve 
valve components yet result in dysfunction of an operated valve, as diagnosed by re-

 
 
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Term 
Definition 
operation, autopsy, or clinical investigation. Nonstructural dysfunction includes the 
following. 
 Entrapment by pannus, tissue, or suture 
 Paravalvular leak 
 Inappropriate sizing or positioning 
 Residual leak or obstruction after valve implantation or repair 
 Clinically important intravascular hemolytic anemia 
 Development of aortic or pulmonic regurgitation as a result of technical errors 
 Dilatation of the sinotubular junction 
 Dilatation of the valve annulus after either valve replacement with stentless  
prostheses,  new onset of coronary ischemia from coronary ostial obstruction, or 
paravalvular aortic regurgitation  
PARAVALVULAR 
REGURGITATION  
 
Leakage due to a separation of the prosthetic valve from the annulus. Any evidence of 
leakage of blood around the device. Diagnosis of paravalvular regurgitation may be 
obtained from TEE/TTE, however, definitive diagnosis is obtained at re-operation, 
explant, or autopsy.  
PERMANENT 
PACEMAKER (PPM) 
IMPLANTATION  
Implantation of new PPM after the index procedure resulting from new or worsened 
conduction disturbances (including new left bundle branch block [LBBB] and third 
degree atrioventricular block)  
 Procedure-related: PPM is implanted in subjects with new onset or worsened 
conduction disturbances occurring post index procedure 
 Not related to procedure: PPM is implanted in subjects with known conduction 
disturbances that did not advance after the index procedure. 
Note: See also definitions for arrhythmia and conductance disturbance. 
PORCELAIN AORTA 
Heavy circumferential calcification of the entire ascending aorta extending to the arch 
such that aortic cross-clamping is not feasible 
PROCEDURE 
RELATED 
COMPLICATIONS 
Complications associated with any part of the vascular access procedure, associated 
treatments or necessary secondary interventions that do not necessarily involve the 
device.  This includes morbidity associated with either pre-medication, or anesthesia, 
or other adjunct to the surgical procedure.  Other technical errors including 
inappropriate subject selection, inappropriate operator techniques, measurements, or 
judgment that do not involve the device itself are also included.   
PROCEDURE-
RELATED EVENTS 
Events occurring during or as a direct result of the index procedure.  
REPEAT 
PROCEDURE FOR 
VALVE-RELATED 
DYSFUNCTION 
Any surgical or percutaneous interventional catheter procedure that repairs, otherwise 
alters or adjusts, or replaces a previously implanted valve. In addition to surgical re-
operations, enzymatic, balloon dilatation, interventional manipulation, repositioning, 
or retrieval, and other catheter-based interventions for valve-related complications are 
also considered reinterventions. Cardiac reinterventions will be categorized as repeat 
TAVR, valvuloplasty, or surgical AVR. 
 Conversion to open surgery 
 Conversion to open sternotomy during the TAVR procedure secondary to any 
procedure-related complications. 
 Unplanned use of CPB 
 Unplanned use of CPB for hemodynamic support at any time during the TAVR 
procedure. 
RESPIRATORY 
Inadequate ventilation or oxygenation 

 
 
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Table 26.2-1: Definitions 
Term 
Definition 
INSUFFICIENCY 
RESPIRATORY 
FAILURE 
The need for ventilatory support for >72 hours associated with an inability to wean 
from the respirator for any reason. 
RIGHT 
VENTRICULAR 
INSUFFICIENCY 
 Defined as sequelae of right ventricular failure including the following. 
o Significantly decreased right ventricular systolic and/or diastolic function 
o Tricuspid valvular regurgitation secondary to elevated pressure 
 Clinical symptoms to include the following. 
o Hepatic congestion 
o Ascites 
o Anasarca 
o Presence of “hepato-jugular reflux” 
o Edema 
Severe right ventricular dysfunction or severe pulmonary hypertension is primary or 
secondary pulmonary hypertension with PA systolic pressures greater than 2/3 of 
systemic pressure.  
SERIOUS ADVERSE 
EVENT (SAE) 
 
Adverse event that led to a death 
SERIOUS ADVERSE 
DEVICE EFFECT 
(SADE) 
Adverse device effect that has resulted in any of the consequences characteristic of a 
serious adverse event 
SOURCE DATA 
(per ISO 14155:2011) 
All information in original records of clinical findings, observations, or other 
activities in a clinical investigation, necessary for the reconstruction and evaluation of 
the clinical investigation 
SOURCE 
DOCUMENT 
(per ISO 14155:2011) 
Printed, optical or electronic document containing source data. Examples: Hospital 
records, laboratory notes, device accountability records, photograhic negatives, 
radiographs, records kept at the investigation center, at the laboratories and at the 
medico-technical departments involvced in the clinical investigation.  
STROKE44,45  
 
Stroke is defined as an acute episode of focal or global neurological dysfunction 
caused by brain, spinal cord, or retinal vascular injury as a result of hemorrhage or 
infarction  
Stroke Classification 
 Ischemic Stroke is defined as an acute episode of focal cerebral, spinal, or retinal 
dysfunction caused by an infarction of central nervous system tissue.  
 Hemorrhagic Stroke is defined as an acute episode of focal or global cerebral or 
spinal dysfunction caused by an intraparenchymal, intraventricular, or 
subarachnoid hemorrhage 
Note 1: The CEC will adjudicate ischemic versus hemorrhagic stroke. 
Note 2: A stroke may be classified as undetermined if there is insufficient information 
to allow categorization as ischemic or hemorrhagic 
Stroke Diagnostic Criteria  
 Rapid onset of a focal or global neurological deficit with at least one of the 
following: change in level of consciousness, hemiplegia, hemiparesis, numbness or 
sensory loss affecting one side of the body, dysphasia or aphasia, hemianopia, 
amaurosis fugax, or other neurological signs or symptoms consistent with stroke 
 Duration of a focal or global neurological deficit ≥24 h; OR <24 h, if  available 
neuroimaging documents a new hemorrhage or infarct; OR the neurological deficit 

 
 
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Table 26.2-1: Definitions 
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Definition 
results in death 
 No other readily identifiable nonstroke cause for the clinical presentation (e.g., 
brain tumor, trauma, infection, hypoglycemia, peripheral lesion, pharmacological 
influences), to be determined by or in conjunction with designated neurologist 
 Confirmation of the diagnosis by at least one of the following.  
o Neurology or neurosurgical specialist  
o Neuroimaging procedure (MRI or CT scan), but stroke may be diagnosed on 
clinical grounds alone 
Note 3: Subjects with non-focal global encephalopathy will not be reported as a 
stroke without unequivocal evidence based upon neuroimaging studies (CT scan or 
brain MRI).  
Stroke Definitions 
Diagnosis as above, preferably with positive neuroimaging study 
 Non-disabling: Modified Rankin Scale (mRS) score <2 at 90 days OR one that 
does not result in an increase of at least one mRS category from an individual’s 
pre-stroke baseline 
 Disabling: Modified Rankin Scale score ≥2 at 90 days AND an increase of at least 
one mRS category from an individual’s pre-stroke baseline  
Note 4: Modified Rankin Scale assessments should be made by qualified individuals 
according to a certification process.  
Note 5: Assessment of the mRS score should occur at all scheduled visits in a study; 
mRS also should be performed after a stroke and at 90 days after the onset of any 
stroke. 
STRUCTURAL 
VALVE 
DETERIORATION  
Component of time-related valve safety defined as follows. 
 Valve-related dysfunction: Mean aortic valve gradient ≥20 mmHg, EOA 
≤0.9-1.1 cm2, and/or DVI <0.35 AND/OR moderate or severe prosthetic valve 
regurgitation (per VARC definition) 
 Requiring repeat procedure (TAVR or SAVR). 
TAV-IN-TAV 
DEPLOYMENT 
An additional valve prosthesis is implanted within a previously implanted prosthesis 
because of suboptimal device position and/or function during or after the index 
procedure. 
TRANSIENT 
ISCHEMIC ATTACK 
(TIA) 
 Transient episode of focal neurological dysfunction caused by brain, spinal cord, or 
retinal ischemia, without acute infarction  
 Duration of a focal or global neurological deficit is <24 h  
 Neuroimaging does not demonstrate a new hemorrhage or infarct (if performed) 
Note: The difference between TIA and ischemic stroke is the presence of tissue 
damage or new sensory-motor deficit persisting >24 hours. By definition, TIA does 
not produce lasting disability. 
UNANTICIPATED 
SERIOUS ADVERSE 
DEVICE EFFECT 
(USADE) 
Serious adverse device effect which by its nature, incidence, severity, or outcome has 
not been identified in the current version of the risk analysis report  
Note: An anticipated serious adverse device effect (ASADE) is an effect which by its 
nature, incidence, severity, or outcome has been identified in the risk analysis report. 
UNPLANNED USE 
OF CPB 
Unplanned use of cardiopulmonary bypass (CPB) for hemodynamic support at any 
time during the TAVR procedure 
VALVE 
EMBOLIZATION 
The valve prosthesis moves during or after deployment such that it loses contact with 
the aortic annulus. 
VALVE 
Includes valve migration, valve embolization, ectopic valve deployment, or 

 
 
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Table 26.2-1: Definitions 
Term 
Definition 
MALAPPOSITION 
transcatheter aortic valve (TAV)-in-TAV deployment. 
VALVE MIGRATION 
After initial correct positioning the valve prosthesis moves upward or downward 
within the aortic annulus from its initial position, with or without consequences (e.g., 
regurgitation). 
VALVE-RELATED 
DYSFUNCTION 
Mean aortic valve gradient ≥20 mmHg, EOA ≤0.9-1.1 cm2, and/or DVI <0.35 
AND/OR moderate or severe prosthetic valve aortic regurgitation (per VARC 
definition) 
VALVE-RELATED 
SYMPTOMS/CHF 
REQUIRING 
HOSPITALIZATION 
The need for hospitalization associated with valve-related symptoms or worsening 
CHF (NYHA Class III or IV) is intended to serve as a basis for calculation of a “days 
alive outside the hospital” endpoint. Included are heart failure, angina, or syncope due 
to aortic valve disease requiring intervention or intensified medical management; 
clinical symptoms of CHF with objective signs including pulmonary edema, 
hypoperfusion, or documented volume overload AND administration of intravenous 
diuresis or inotropic therapy, performance of aortic valvuloplasty, institution of 
mechanical support (intra-aortic balloon pump or ventilation for pulmonary edema), 
or hemodialysis for volume overload; clear documentation of anginal symptoms AND 
no clinical evidence that angina was related to coronary artery disease or acute 
coronary syndrome; documented loss of consciousness not related to seizure or 
tachyarrhythmia. 
VALVE 
THROMBOSIS 
Any thrombus attached to or near an implanted valve that occludes part of the blood 
flow path, interferes with valve function, or is sufficiently large to warrant treatment. 
Note that valve-associated thrombus identified at autopsy in a patient whose cause of 
death was not valve-related or at operation for an unrelated indication should not be 
reported as valve thrombosis. 
VASCULAR 
ACCESS SITE AND 
ACCESS RELATED 
COMPLICATIONS 
Major Vascular Complications 
 Any aortic dissection, aortic rupture, annulus rupture, left ventricle perforation, or 
new apical aneurysm/pseudoaneurysm  
 Access site or access-related vascular injury (dissection, stenosis, perforation, 
rupture, arterio-venous fistula, pseudoaneurysm, hematoma, irreversible nerve 
injury, compartment syndrome, percutaneous closure device failure*) leading to 
death, life-threatening or major bleeding**, visceral ischaemia, or neurological 
impairment 
 Distal embolization (non-cerebral) from a vascular source requiring surgery or 
resulting in amputation or irreversible end-organ damage 
 The use of unplanned endovascular or surgical intervention associated with death, 
major bleeding, visceral ischaemia or neurological impairment 
 Any new ipsilateral lower extremity ischemia documented by patient symptoms, 
physical exam, and/or decreased or absent blood flow on lower extremity 
angiogram 
 Surgery for access site-related nerve injury 
 Permanent access site-related nerve injury 
Minor Vascular Complications 
 Access site or access-related vascular injury (dissection, stenosis, perforation, 
rupture, arterio-venous fistula, pseudoaneurysms , hematomas, percutaneous 
closure device failure*) not leading to death, life-threatening or major bleeding**, 
visceral ischaemia or neurological impairment 
 Distal embolization treated with embolectomy and/or thrombectomy and not 
resulting in amputation or irreversible end-organ damage 

 
 
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Table 26.2-1: Definitions 
Term 
Definition 
 Any unplanned endovascular stenting or unplanned surgical intervention not 
meeting the criteria for a major vascular complication 
 Vascular repair or the need for vascular repair (via surgery, ultrasound-guided 
compression, transcatheter embolization, or stent-graft) 
*Percutaneous Closure Device Failure 
Failure of a closure device to achieve hemostasis at the arteriotomy site leading to 
alternative treatment (other than manual compression or adjunctive endovascular 
ballooning) 
Note 1: Pre-planned surgical access or a planned endovascular approach to vascular 
closure (e.g., “pre-closure”)57,58 should be considered as part of the TAVR procedure 
and not as a complication, unless untoward clinical consequences are documented 
(e.g., bleeding complications, limb ischemia, distal embolization, or neurological 
impairment). 
Note 2: If unplanned percutaneous or surgical intervention does not lead to adverse 
outcomes this is not considered a major vascular complication.  
** Refers to VARC bleeding definitions44 
VENTRICULAR 
SEPTAL 
PERFORATION 
Angiographic or echocardiographic evidence of a new septal perforation during or 
after the TAVR procedure 
VESSEL 
PERFORATION 
Unexpected puncture of the vessel with evidence of extravasation into extraluminal 
surrounding tissue or space requiring treatment using interventional or surgical 
techniques 
Abbreviations: ADE=adverse device effect; AE=adverse event; AR=aortic regurgitation; AVA=aortic valve 
area; AVR= aortic valve replacement; CEC= Clinical Events Committee; CK= creatine kinase; CT=computed 
tomography; DVI=Doppler velocity index; ECG=electrocardiogram; EOA=effective orifice area; FEV= forced 
expiratory volume; LBBB=left bundle branch block; LV= left ventricle; MI=myocardial infarction; 
MRI=magnetic resonance imaging; NYHA=New York Heart Association; PPM=permanent pacemaker; 
RBC=red blood cell; SADE=serious adverse device effect; SAE=serious adverse event; TAVR =transcatheter 
aortic valve replacement; TEE=transesophageal Doppler echocardiography; TIA=transient ischemic attack; 
USADE= unanticipated serious adverse device effect; URL=upper reference limit (defined as 99th percentile of 
normal reference range); VARC=Valve Academic Research Consortium 
 
 
 

 
 
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27. Appendices 
27.1. Changes in Protocol Versions 
27.1.1. Protocol Version AA to Version AB 
Table 27.1-1 lists changes between protocol versions AA and AB. 
 
Table 27.1-1: Table of Changes for Protocol Version AB (Compared to Protocol 
Version AA) 
Section Modified 
Text as Written in  
Protocol Version AA 
Text as Written in  
Protocol Version AB 
Justification for 
Modification 
Page 2 Date of 
Amendment(s) 
N/A 
03 October 2014 
Date of protocol 
amendment 
Section 2 Protocol 
Synopsis & Section 
8.1 Justification for 
Study Design 
“…consecutive subjects will 
be enrolled at up to 50 study 
centers…” 
“…consecutive subjects will be 
enrolled at up to 60 study 
centers…” 
Number of centers 
increased to 60 
Section 27 
Appendices 
N/A 
Section 27 Appendices 
New section includes 
summary of changes in 
protocol versions