REPRISE II: REpositionable Percutaneous Replacement of Stenotic Aortic Valve Through Implantation of Lotus™ Valve System - Evaluation of Safety and Performance
Phase: NA
Conditions: Transcatheter Aortic Valve Replacement
Sponsor: Boston Scientific Corporation

Confidential 
 
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CONSENT OF BOSTON SCIENTIFIC CORP. 
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REPRISE II:  REpositionable Percutaneous Replacement of Stenotic 
Aortic Valve through Implantation of Lotus™ Valve System – Evaluation of 
Safety and Performance 
 
CLINICAL PROTOCOL  
Protocol Number: TP3687  
 
 
Sponsor: 
Boston Scientific Structural Heart a Division of Boston Scientific 
Corporation   
160 Knowles Drive 
Los Gatos, CA 95032 USA 
International Representative 
Boston Scientific International SA 
European Headquarters, Paris 
55 Av. des Champs Pierreux, TSA 51101 
92729 Nanterre Cedex, France 
Australian Representative 
Boston Scientific Pty. Ltd. 
Suite 5.01, Level 5  
247 Coward Street 
Mascot, NSW 2020, Australia  
 
 
 
 
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  
Clinical 
Contacts 
Stijn Bollen 
Clinical Trial Manager – Interventional Cardiology 
Boston Scientific 
Green Square, Lambroekstraat 5D 
1831 Diegem, Belgium 
Blessie Concepcion 
Director, Clinical Trials, Structural Heart – Interventional Cardiology 
Boston Scientific Structural Heart 
160 Knowles Drive 
Los Gatos, CA 95032 USA 
Anne Cornaille 
Senior Clinical Trial Manager – Interventional Cardiology  
Boston Scientific, Parc Val Saint Quentin 
2 Rue René Caudron, Bâtiment H 
78960 Voisins-le-Bretonneux, France 
Coordinating 
Principal 
Investigator 
Professor Ian T. Meredith, AM, MBBS, PhD 
Director, MonashHeart, Southern Health 
Executive Director, Monash Cardiovascular Research Centre 
Monash Medical Centre 
246 Clayton Road 
Clayton, Victoria 3168, Australia 
 
Original Release: 05-June-2012 
Current Version: 12-March-2013 
 
Revision History 
Revision Number 
Release Date 
Reason for Change 
AB 
07-Aug-2012 
See Table 27.1-1 
AC 
13-Aug-2012 
See Table 27.1-2 
AD 
05-Sept-2012 
See Table 27.1-3 
AE 
20-Dec-2012 
See Table 27.1-4 
AF 
12-Mar-2013 
See Table 27.1-5 
 

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2. Protocol Synopsis 
REPRISE II: Repositionable Percutaneous Replacement of Stenotic Aortic Valve 
through Implantation of Lotus™ Valve System – Evaluation of Safety and Performance 
Objective(s) 
To evaluate the safety and performance of the Lotus™ Valve System for 
transcatheter aortic valve replacement (TAVR) in symptomatic subjects 
with severe calcific aortic stenosis who are considered high risk for surgical 
valve replacement. 
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 index of <0.6 cm2/m2) who are at high risk for 
standard surgical valve replacement. 
Test Device 
The Lotus Valve System consisting of two main components: 
 
- a bioprosthetic bovine pericardial aortic valve 
 
- a delivery system. 
Device Sizes 
The sizes of the Lotus Valve used in this study will include the 23 mm 
diameter size suitable for subjects with aortic annulus diameter between 
≥20 mm and ≤23 mm, and the 27 mm diameter size suitable for aortic 
annulus diameter between ≥23 mm and ≤27 mm. 
Note: The commercially approved Lotus Introducer Set will be used as an 
accessory to the Lotus Valve System during the procedure. The Lotus 
Introducer provided for use with the 23 mm valve will be suitable for use in 
subjects with femoral artery lumen diameter ≥6.0 mm, and the Lotus 
Introducer provided for use with the 27 mm valve will be suitable for use in 
subjects with femoral artery lumen diameter ≥6.5 mm. 
Comparator 
For the device performance primary endpoint, a performance goal (PG) 
based on the 30-day mean aortic valve pressure gradient derived from 
published literature will be used as the comparator for analysis.   
For the primary safety endpoint, a performance goal (PG) based on 30-day 
all-cause mortality data derived from published literature will be used as 
the comparator for analysis. 
Study Design 
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 TAVR in symptomatic subjects who have severe calcific aortic 
valve stenosis and who are at high risk for surgical aortic valve replacement 

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REPRISE II: Repositionable Percutaneous Replacement of Stenotic Aortic Valve 
through Implantation of Lotus™ Valve System – Evaluation of Safety and Performance 
(SAVR).   
A total of up to 120 subjects will be enrolled in the main study at up to 15 
centers. Subsequently, up to 130 additional subjects will be enrolled at up 
to 21 centers in the extended trial cohort. The statistical hypotheses for the 
main trial cohort and the combined (main + extended) cohorts are described 
below.    
The REPRISE II 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 Harmonisation (ICH) Guidelines for Good Clinical 
Practices (GCP); and pertinent individual country/state/local laws and 
regulations. 
Planned 
Number of 
Subjects 
A total enrollment of up to 120 subjects is planned for the main study. 
Subsequently, up to 130 additional subjects (250 subjects in total) will be 
enrolled in the extended trial cohort. 
Planned 
Number of 
Centers / 
Countries 
The main study will enroll subjects at up to 15 centers in these possible 
countries: Australia, France, Germany and United Kingdom. 
The extended trial cohort will enroll subjects at up to 21 centers in 
Australia and European countries. 
Primary 
Endpoints 
Primary Device Performance Endpoint: Mean aortic valve pressure gradient 
at 30 days post implant procedure as measured by echocardiography and 
assessed by an independent core laboratory  
Primary Safety Endpoint:  All-cause mortality at 30 days post implant 
procedure 
Secondary 
Endpoints 
• Effective orifice area at 30 days as measured by echocardiography and 
assessed by an independent core laboratory 
• Device Performance endpoints peri- and post-procedure:  
o Successful vascular access, delivery and deployment of the Lotus 
Valve System, and successful retrieval of the delivery system 
o Successful repositioning of the Lotus Valve System if repositioning is 
attempted 
o Successful retrieval of the Lotus Valve System if retrieval is 
attempted 

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REPRISE II: Repositionable Percutaneous Replacement of Stenotic Aortic Valve 
through Implantation of Lotus™ Valve System – Evaluation of Safety and Performance 
o Grade of aortic valve regurgitation: paravalvular, central and 
combined 
• Device Success based on the Valve Academic Research Consortium 
definitions  (VARC)a, b  
Note: At least 1 echocardiogram must be obtained before discharge or 
7 days (whichever comes first); if multiple echocardiographic studies are 
performed prior to discharge and within 7 days of the procedure, the latest 
study performed will be used for analysis. 
a:  Kappetein AP, et al. J Am Coll Cardiol. 2012;60:1438 
b:  Leon MB, et al. J Am Coll Cardiol. 2011;57:253 
Additional 
Measurements 
Additional measurements based on the VARCa,b endpoints and definitions 
(see Table 26.2-1 for definitions) will be collected peri- and post-procedure, 
at discharge or 7 days post-procedure (whichever comes first), 30 days, 
3 months, 6 months, and 1, 2, 3, 4, and 5 years post index procedure, unless 
otherwise specified below.  
• Safety endpoints adjudicated by an independent Clinical Events 
Committee (CEC): 
o Mortality: all-cause, cardiovascular, and non-cardiovascular 
o Stroke: disabling and non-disabling  
o Composite of all-cause mortality and disabling stroke 
o Myocardial infarction (MI): periprocedural (≤72 hours post index 
procedure) and spontaneous (>72 hours post index procedure) 
o Bleeding: life-threatening (or disabling) and major 
o Acute kidney injury (≤7 days post index procedure): based on the 
AKIN System Stage 3 (including renal replacement therapy) or 
Stage 2 
o Major 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  

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REPRISE II: Repositionable Percutaneous Replacement of Stenotic Aortic Valve 
through Implantation of Lotus™ Valve System – Evaluation of Safety and Performance 
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 
• 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 
• Functional status as evaluated by the following: 
o 5-m gait speed test (at 1 year compared to baseline)  
o New York Heart Association (NYHA) classification 
• Neurological status as determined by the following: 
o National Institutes of Health Stroke Scale (NIHSS) at discharge and 
1 year  
o Modified Rankin Scale (mRS) 
• Health status as evaluated by SF-12 and EQ-5D Quality of Life 
questionnaires at baseline; 1 and 6 months; and 1, 3, and 5 years 
Note 1: The VARC safety composite at 30 days will be reported; this 
includes all-cause mortality, all  stroke, life-threatening bleeding, acute 
kidney injury Stage 2 or 3 (including renal replacement therapy), coronary 
artery obstruction requiring intervention, , major vascular complication, 
and repeat procedure for valve-related dysfunction (surgical or 
interventional therapy).  
Note 2: The VARC efficacy composite at 1 year will be reported. This 
includes all-cause mortality (after 30 days); all stroke; requiring 
hospitalization for valve-related symptoms or worsening congestive heart 
failure (NYHA class III or IV); and prosthetic heart valve dysfunction 
(mean aortic valve gradient ≥20 mm Hg, effective orifice area ≤0.9-1.1 
cm2,and/or Doppler velocity index (DVI) <0.35 AND/OR moderate or 
severe prosthetic valve aortic regurgitation [per VARC definition]). 
Note 3: Time-related valve safety composite will be reported. This includes 

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REPRISE II: Repositionable Percutaneous Replacement of Stenotic Aortic Valve 
through Implantation of Lotus™ Valve System – Evaluation of Safety and Performance 
structural valve deterioration (valve-related dysfunction requiring repeat 
procedure [TAVR 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).  
Note 4: A total enrollment of up to 120 subjects is planned for the main 
study.  Subsequently, up to 130 additional subjects will be enrolled for the 
extended trial cohort. In the main study, for subjects diagnosed with a 
neurological event (e.g., stroke, transient ischemic attack), a neurological 
physical exam, NIHSS assessment, and mRS must be performed after the 
event; mRS must also be administered at 90 days post-neurological event.  
In the extended trial cohort, for subjects diagnosed with a neurological 
event, NIHSS assessment and mRS must be performed after the event; 
mRS must also be administered at 90 days post-neurological event; the 
neurological physical exam is not required in the extended trial cohort. 
a:  Kappetein AP, et al. J Am Coll Cardiol. 2012;60:1438 
b:  Leon MB, et al. J Am Coll Cardiol. 2011;57:253 
Follow-up 
Schedule 
All subjects implanted with the Lotus Valve will be assessed 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.  Subjects who are not implanted with the Lotus 
Valve at the time of the procedure will be followed for safety through 
30 days. 
Study 
Duration 
Subjects implanted with the Lotus Valve will be followed for up to 5 years 
after the procedure. 
Adjunctive 
Pharmacologic 
Therapy 
Anticoagulant Therapy 
Anticoagulant therapy (e.g., unfractionated heparin) per local standard of 
care must be administered during the implant procedure, with a 
recommended target activated clotting time of ≥250 seconds during the 
index procedure. 
Anti-Platelet Therapy 
Subjects must be treated with aspirin and a thienopyridine prior to 
implantation of the Lotus Valve and for at least 1 month following valve 
implantation. Per society guidelinesc, antiplatelet therapy with aspirin and 
clopidogreld is recommended after TAVR to decrease the risk of 
thrombotic or thromboembolic complications if there are no 

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REPRISE II: Repositionable Percutaneous Replacement of Stenotic Aortic Valve 
through Implantation of Lotus™ Valve System – Evaluation of Safety and Performance 
contraindications to these medications. 
Aspirin 
A loading dose of aspirin (recommended dose of 75–325 mg) is required 
for subjects who have not been taking aspirin for 72 hours at the time of 
the index procedure. The loading dose must be administered prior to the 
implant procedure or immediately after. Subjects who have been taking 
aspirin daily for 72 hours at the time of the index procedure do not require 
a loading dose. 
After the Lotus Valve implant procedure, aspirin (recommended dose of 
≥75 mg daily) must be given for at least 1 month. It is recommended that 
daily aspirin be given indefinitely thereafter as per local standard of care. 
Aspirin doses may be adjusted to the closest approximation based on local 
tablet formulation availability. 
Clopidogreld 
A loading dose of clopidogrel (recommended dose of ≥300 mg) is required 
for subjects who have not been taking clopidogrel for 72 hours at the time 
of the index procedure.  The loading dose must be administered prior to the 
implant procedure or immediately after. 
After the Lotus valve implant procedure, clopidogrel (recommended dose 
of 75 mg daily) is required for at least 1 month. 
Note 1: If the study-specific dosages and durations for antiplatelet 
medications conflict with country-specific labeling for the medications, the 
country-specific labeling should take precedence. 
Note 2: If a subject requires chronic anticoagulation (e.g., warfarin, 
dabigatran, etc.), either clopidogreld or aspirin is required prior to and after 
implant procedure in addition to the anticoagulant therapy (but both aspirin 
and clopidogrel are not required). 
c:  Holmes, D. R., et al. J Am Coll Cardiol. 2012;59:1200. 
d:  An alternative P2Y12 inhibitor may be prescribed if subject is allergic to 
or intolerant of clopidogrel. 
Inclusion 
Criteria 
IC1.  Subject is ≥70 years of age 
IC2.  Subject has documented calcific native aortic valve stenosis with an 
initial aortic valve area (AVA) of <1.0 cm2 (or AVA index of 
<0.6 cm2/m2) and either a mean pressure gradient >40 mm Hg or a jet 
velocity >4 m/s, as measured by echocardiography 
IC3.  Subject has a documented aortic annulus size between ≥20 and 
≤27 mm based on pre-procedure diagnostic imaging 

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REPRISE II: Repositionable Percutaneous Replacement of Stenotic Aortic Valve 
through Implantation of Lotus™ Valve System – Evaluation of Safety and Performance 
IC4.  Symptomatic aortic valve stenosis with NYHA Functional Class ≥ II 
IC5.  Subject is considered high risk for surgical valve replacement based 
on at least one of the following: 
a. Society of Thoracic Surgeons (STS) score ≥8%, AND/OR 
b. Agreement by the heart team (which must include an in-person 
evaluation by an experienced cardiac surgeon) that subject is at 
high operative risk of serious morbidity or mortality with surgical 
valve replacement  
IC6.  Heart team (which must include an experienced cardiac surgeon) 
assessment that the subject is likely to benefit from valve 
replacement.  
IC7.  Subject (or legal representative) understands the study requirements 
and the treatment procedures, and provides written informed consent. 
IC8.  Subject, family member, and/or legal representative agree(s) and 
subject is capable of returning to the study hospital for all required 
scheduled follow up visits. 
Exclusion 
Criteria 
EC1.  Subject has a congenital unicuspid or bicuspid aortic valve. 
EC2.  Subject with an acute myocardial infarction within 30 days of the 
index procedure (defined as Q-wave MI or non–Q-wave MI with 
total CK elevation ≥ twice normal in the presence of CK-MB 
elevation and/or troponin elevation). 
EC3.  Subject has had a cerebrovascular accident or transient ischemic 
attack within the past 6 months, or has any permanent neurologic 
defect prior to study enrollment. 
EC4.  Subject is on dialysis or has serum creatinine level >3.0 mg/dL or 
265 µmol/L.  
EC5.  Subject has a pre-existing prosthetic heart valve (aortic or mitral) or a 
prosthetic ring in any position. 
EC6.  Subject has ≥3+ mitral regurgitation, ≥3+ aortic regurgitation or ≥3+ 
tricuspid regurgitation (i.e., subject cannot have more than moderate 
mitral, aortic or tricuspid regurgitation). 
EC7.  Subject has a need for emergency surgery for any reason. 
EC8.  Subject has a history of endocarditis within 12 months of index 
procedure or evidence of an active systemic infection or sepsis. 
EC9.  Subject has echocardiographic evidence of intra-cardiac mass, 
thrombus or vegetation. 

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REPRISE II: Repositionable Percutaneous Replacement of Stenotic Aortic Valve 
through Implantation of Lotus™ Valve System – Evaluation of Safety and Performance 
EC10.  Subject has Hgb <9 g/dL, platelet count <50,000 cells/mm3 or 
>700,000 cells/mm3, or white blood cell count <1,000 cells/mm3. 
EC11.  Subject requires chronic anticoagulation therapy (e.g., warfarin, 
dabigatran, etc.) and cannot tolerate concomitant therapy with either 
aspirin or clopidogreld.  
  
 
Note: Subjects who require chronic anticoagulation must be able to 
be treated additionally with either aspirin or clopidogreld. 
EC12.  Subject has active peptic ulcer disease or gastrointestinal bleed 
within the past 3 months, other bleeding diathesis or coagulopathy 
or will refuse transfusions. 
EC13.  Subject has known hypersensitivity to contrast agents that cannot be 
adequately pre-medicated, or has known hypersensitivity to aspirin, 
all thienopyridines, heparin, nickel, tantalum, titanium, or 
polyurethanes. 
EC14.  Subject has a life expectancy of less than 12 months due to non-
cardiac, co-morbid conditions based on the assessment of the 
investigator at the time of enrollment. 
EC15.  Subject has hypertrophic obstructive cardiomyopathy. 
EC16.  Subject has any therapeutic invasive cardiac procedure (including 
balloon aortic valvuloplasty) within 30 days prior to the index 
procedure (except for pacemaker implantation which is allowed).  
EC17.  Subject has untreated coronary artery disease, which in the opinion 
of the treating physician is clinically significant and requires 
revascularization. 
EC18.  Subject has documented left ventricular ejection fraction <30%. 
EC19.  Subject is in cardiogenic shock or has hemodynamic instability 
requiring inotropic support or mechanical support devices. 
EC20.  Subject has severe peripheral vascular disease (including aneurysm 
defined as maximal luminal diameter >5 cm or with documented 
presence of thrombus, marked tortuosity, narrowing of the 
abdominal aorta, severe unfolding of the thoracic aorta or thick 
[>5 mm], protruding or ulcerated atheroma in the aortic arch) or 
symptomatic carotid or vertebral disease.  
EC21.  Femoral artery lumen of <6.0 mm for subjects requiring 23 mm 
valve size or <6.5 mm for subjects requiring 27 mm valve size, or 
severe iliofemoral tortuosity or calcification that would prevent safe 
placement of the introducer sheath. 

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REPRISE II: Repositionable Percutaneous Replacement of Stenotic Aortic Valve 
through Implantation of Lotus™ Valve System – Evaluation of Safety and Performance 
EC22.  Current problems with substance abuse (e.g., alcohol, etc.). 
EC23.  Subject is participating in another investigational drug or device 
study that has not reached its primary endpoint. 
EC24.  Subject has untreated conduction system disorder (e.g., Type II 
second degree atrioventricular block) that in the opinion of the 
treating physician is clinically significant and requires a pacemaker 
implantation.   
d:  An alternative P2Y12 inhibitor may be prescribed if subject is allergic to 
or intolerant of clopidogrel. 
Statistical Methods – Main Trial Cohort (N=120) 
Primary 
Statistical 
Hypothesis 
Mean aortic valve pressure gradient at 30 days post implant procedure is 
less than the performance goal (PG) of 18 mmHg 
Statistical Test 
Method 
A one-sample t-test will be used to test the one-sided hypothesis: 
H0: Gradient30D ≥ PG 
H1: Gradient30D < PG  
where Gradient30D is the 30-day mean aortic valve pressure gradient for the 
Lotus Valve and PG is 18 mmHg. 
Sample Size 
Parameters 
• Expected 30-day mean pressure gradient from Lotus Valve ≤15 mmHg 
• Expected standard deviation = 7 mmHg  
• PG = 18 mmHg 
• Test significance level () = 0.025 (1-sided) 
• Power ≥ 80% 
• Evaluable number of subjects = Minimum of 49 subjects 
• Expected rate of attrition = 15% (9 subjects) 
• Planned enrollment of up to 120 subjects  
• Two planned interim analyses will be performed on the first 40 and 60 
subjects enrolled based on the primary endpoint at 30 days post-implant 
procedure  
• A final analysis will be performed on all subjects enrolled in the main 
trial cohort (120 subjects) 
• The primary analysis population for the primary endpoint will be the 

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REPRISE II: Repositionable Percutaneous Replacement of Stenotic Aortic Valve 
through Implantation of Lotus™ Valve System – Evaluation of Safety and Performance 
subject population implanted with the Lotus Valve.    
Note 1: The expected 30-day mean aortic valve pressure gradient is 
assumed to be ≤15 mmHg based on a literature review of studies 
evaluating the Medtronic CoreValve System and the Edwards Lifesciences 
SAPIEN Transcatheter Heart Valve System. 
Note 2: The alpha-level for the interim and final analyses of the main trial 
cohort is adjusted using the Pocock alpha spending function (see Success 
Criteria below). 
Success 
Criteria 
Two interim analyses will be conducted on the first 40 and 60 subjects and 
a final analysis will be conducted on the fully enrolled main trial cohort 
(N=120). The Pocock alpha spending function is used to adjust the alpha-
level for each analysis: 0.01123, 0.00792, and 0.01305, respectively. If the 
P value from the one-sample t-test is <alpha, the Lotus Valve will be 
concluded to have a 30-day mean aortic valve pressure gradient <18 mm 
Hg. This corresponds to the one-sided upper (1-alpha)% confidence bound 
of the observed 30-day mean aortic valve pressure gradient being 
<18 mmHg.  
Statistical Methods – Combined Main and Extended Trial Cohort (N=250) 
Primary 
Statistical 
Hypothesis  
All-cause mortality at 30 days post implant procedure is less than the PG of 
16 % (expected rate of 9.8% + testing margin of 6.2%) 
Statistical Test 
Method 
A one-sample z-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 16%. 

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REPRISE II: Repositionable Percutaneous Replacement of Stenotic Aortic Valve 
through Implantation of Lotus™ Valve System – Evaluation of Safety and Performance 
Sample Size 
Parameters 
• Expected 30-day all-cause mortality rate = 9.8%  
• Performance goal (PG) = 16 % (expected rate of 9.8% + testing margin 
of 6.2%) 
• Test significance level () = 0.025 (1-sided) 
• Power (1 – ) = 80% 
• Expected rate of attrition = 2% 
• Planned enrollment of up to 250 subjects (main trial cohort enrollment 
of 120 subjects plus extended trial cohort enrollment of 130 subjects) 
Note:  The expected 30-day all-cause mortality rate is assumed to be 9.8% 
based on a literature review of studies evaluating the Medtronic CoreValve 
System and the Edwards Lifesciences SAPIEN Transcatheter Heart Valve 
System. 
Success 
Criteria 
If the P value from the one-sample z-test is <0.025, it will be concluded 
that the primary safety endpoint for the Lotus Valve is less than the PG. 
This corresponds to the one-sided upper 97.5% confidence bound of the 
observed 30 day mortality rate being <16 %. 

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3. Table of Contents 
1. 
TITLE PAGE  ........................................................................................................................ 1 
2. 
PROTOCOL SYNOPSIS .......................................................................................................... 3 
3. 
TABLE OF CONTENTS ........................................................................................................ 14 
3.1. Table of Figures ...................................................................................................... 18 
3.2. Table of Tables ....................................................................................................... 18 
4. 
INTRODUCTION ................................................................................................................. 20 
4.1. Justification for the Use of the Investigational Device in Human Subjects ...... 20 
4.1.1. 
Treatments for Aortic Stenosis .................................................................. 20 
4.1.2. 
REPRISE I Study ....................................................................................... 22 
4.2. Justification for the Study Design ......................................................................... 23 
5. 
DEVICE DESCRIPTION ....................................................................................................... 24 
5.1. Lotus Valve System ................................................................................................ 24 
5.1.1. 
Lotus Valve ................................................................................................ 25 
5.1.2. 
Lotus Delivery System .............................................................................. 25 
5.2. Intended Use ........................................................................................................... 27 
5.3. Device Labeling ...................................................................................................... 27 
6. 
OBJECTIVES ...................................................................................................................... 27 
7. 
ENDPOINTS ........................................................................................................................ 27 
7.1. Primary Endpoints ................................................................................................. 27 
7.2. Secondary Endpoints ............................................................................................. 28 
7.3. Additional Measurements ..................................................................................... 28 
8. 
DESIGN .............................................................................................................................. 30 
8.1. Scale and Duration ................................................................................................. 30 
8.2. Treatment Assignment........................................................................................... 31 
8.2.1. 
Treatment ................................................................................................... 31 
8.3. Study Design Justification ..................................................................................... 31 
9. 
SUBJECT SELECTION ......................................................................................................... 31 

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9.1. Study Population and Eligibility ........................................................................... 31 
9.2. Inclusion Criteria ................................................................................................... 32 
9.3. Exclusion Criteria .................................................................................................. 32 
10. SUBJECT ACCOUNTABILITY .............................................................................................. 34 
10.1. Point of Enrollment ................................................................................................ 34 
10.2. Withdrawal ............................................................................................................. 34 
11. STUDY METHODS .............................................................................................................. 34 
11.1. Data Collection ....................................................................................................... 34 
11.2. Study Candidate Screening ................................................................................... 45 
11.3. Informed Consent .................................................................................................. 45 
11.4. Screening Assessments ........................................................................................... 46 
11.5. Baseline Assessments ............................................................................................. 48 
11.6. Preprocedure Medications .................................................................................... 50 
11.7. Index Procedure ..................................................................................................... 50 
11.7.1. Percutaneous Procedure for Delivering the Lotus Device ......................... 50 
11.7.2. Valvuloplasty ............................................................................................. 50 
11.7.3. Preparing and Using the Lotus Valve System ........................................... 51 
11.8. Post-Procedure ....................................................................................................... 53 
11.9. Prior to Discharge or 7 Days Post-Procedure (Whichever Comes First) ......... 53 
11.10. 
Follow-up .................................................................................................. 54 
11.10.1. 30-Day Follow-up (307 Days) ................................................................. 55 
11.10.2. 3-Month Follow-up (9014 Days) ............................................................. 55 
11.10.3. 6-Month (18030 Days) Follow-up ........................................................... 56 
11.10.4. 12-Month (36545 Days) Follow-up ......................................................... 56 
11.10.5. Annual Follow-up (45 Days) ................................................................... 57 
11.10.6. Management of Missed or Late Visits ....................................................... 58 
11.10.7. Procedure for Determining when a Subject is Lost to Follow-up ............. 58 
11.10.8. Withdrawal and Replacement of Subjects ................................................. 58 
11.10.9. Explant Procedure ...................................................................................... 59 
11.11. 
Study Completion .................................................................................... 59 
11.12. 
Source Documents ................................................................................... 59 

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12. STATISTICAL CONSIDERATIONS ....................................................................................... 59 
12.1. Endpoints ................................................................................................................ 59 
12.1.1. Primary Endpoints ..................................................................................... 59 
12.1.1.1. Primary Device Performance Endpoint .................................... 59 
12.1.1.2. Sample Size – Primary Device Performance Endpoint ............ 60 
12.1.1.3. Primary Safety Endpoint ........................................................... 61 
12.1.1.4. Statistical Methods .................................................................... 62 
12.1.2. Post-procedure Endpoints and Measurements ........................................... 62 
12.2. General Statistical Methods .................................................................................. 62 
12.2.1. Analysis Sets .............................................................................................. 62 
12.2.2. Control of Systematic Error/Bias ............................................................... 63 
12.3. Data Analyses ......................................................................................................... 63 
12.3.1. Other Endpoints/Measurements ................................................................. 63 
12.3.2. Interim Analyses ........................................................................................ 63 
12.3.3. Justification of Pooling .............................................................................. 63 
12.3.4. Multivariable Analyses .............................................................................. 64 
12.3.5. Other Analyses ........................................................................................... 64 
12.3.6. Changes to Planned Analyses .................................................................... 64 
13. DATA MANAGEMENT ........................................................................................................ 64 
13.1. Data Collection, Processing, and Review ............................................................. 64 
13.2. Data Retention ........................................................................................................ 65 
13.3. Core Laboratories .................................................................................................. 65 
13.3.1. Transthoracic Echocardiography (TTE) Core Laboratory ........................ 65 
13.3.2. CT and Rotational X-Ray Angiography Core Laboratory ........................ 65 
13.3.3. Electrocardiography (ECG) Core Laboratory ........................................... 65 
13.3.4. Histopathology Core Laboratory ............................................................... 66 
14. AMENDMENTS ................................................................................................................... 66 
15. DEVIATIONS ...................................................................................................................... 66 
16. DEVICE ACCOUNTABILITY ............................................................................................... 66 
17. COMPLIANCE ..................................................................................................................... 67 
17.1. Statement of Compliance ....................................................................................... 67 
17.2. Investigator Responsibilities ................................................................................. 68 
17.2.1. Delegation of Responsibility ..................................................................... 69 

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17.3. Institutional Review Board/ Ethics Committee ................................................... 70 
17.4. Sponsor Responsibilities ........................................................................................ 70 
17.4.1. Training ...................................................................................................... 70 
17.4.2. Role of Boston Scientific Corporation Representatives ............................ 72 
17.5. Insurance ................................................................................................................. 72 
18. MONITORING ..................................................................................................................... 72 
19. POTENTIAL RISKS AND BENEFITS .................................................................................... 73 
19.1. Risks Associated with Transcatheter Aortic Valve Implantation Procedure 
and Lotus Valve System......................................................................................... 73 
19.2. Risk Minimization Actions .................................................................................... 74 
19.3. Anticipated Benefits ............................................................................................... 76 
19.3.1. Potential Benefits to the TAVR Procedure ................................................ 76 
19.3.2. Potential Benefit Using the Lotus Valve System ...................................... 76 
19.4. Risk to Benefit Rationale ....................................................................................... 76 
20. INFORMED CONSENT......................................................................................................... 77 
21. SAFETY REPORTING .......................................................................................................... 78 
21.1. Definitions and Classification ............................................................................... 78 
21.2. Relationship to Study Device(s) ............................................................................ 80 
21.3. Investigator Reporting Requirements .................................................................. 81 
21.4. Boston Scientific Device Deficiencies .................................................................... 82 
21.5. Reporting to Regulatory Authorities / IRBs / ECs / Investigators .................... 82 
22. COMMITTEES .................................................................................................................... 83 
22.1. Safety Monitoring Process ..................................................................................... 83 
22.1.1. Clinical Events Committee ........................................................................ 83 
22.1.2. Data Monitoring Committee ...................................................................... 83 
22.2. Case Review Committee ........................................................................................ 83 
22.3. Steering Committee ................................................................................................ 84 
23. SUSPENSION OR TERMINATION ........................................................................................ 84 
23.1 Premature Termination of the Study ................................................................... 84 
23.1.1 
Criteria for Premature Termination of the Study ....................................... 84 

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23.2 Termination of Study Participation by the Investigator or Withdrawal of 
IRB/EC Approval ................................................................................................... 84 
23.3 Requirements for Documentation and Subject Follow-up ................................. 85 
23.4 Criteria for Suspending/Terminating a Study Center ........................................ 85 
24. PUBLICATION POLICY ....................................................................................................... 85 
25. BIBLIOGRAPHY .................................................................................................................. 86 
26. ABBREVIATIONS AND DEFINITIONS .................................................................................. 91 
26.1. Abbreviations ......................................................................................................... 91 
26.2. Definitions ............................................................................................................... 93 
27. APPENDICES .................................................................................................................... 106 
27.1. Changes in Protocol Versions ............................................................................. 106 
27.1.1. Protocol Version AA to Version AB ....................................................... 106 
27.1.2. Protocol Version AB to Version AC ....................................................... 106 
27.1.3. Protocol Version AC to Version AD ....................................................... 106 
27.1.4. Protocol Version AD to Version AE ....................................................... 106 
27.1.5. Protocol Version AE to Version AF ........................................................ 106 
 
3.1. Table of Figures 
Figure 5.1-1: Lotus™ Valve System ...................................................................................... 24 
Figure 5.1-2: Lotus Valve Implant .......................................................................................... 25 
Figure 5.1-3: Lotus Valve Delivery System – Handle ............................................................ 26 
Figure 11.1-1: REPRISE II Study Design – Main Trial Cohort ............................................. 35 
Figure 11.1-2: REPRISE II Study Design – Extended Trial Cohort ...................................... 40 
Figure 11.4-1: Assessment Considerations for Lotus Valve Size Selection ........................... 48 
 
3.2. Table of Tables 
Table 4.1-1: Events from Peri-Operative to 30 Days (Transfemoral Approach) ................... 21 
Table 9.2-1: Inclusion Criteria ................................................................................................ 32 
Table 9.3-1: Exclusion Criteria ............................................................................................... 32 

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Table 11.1-1: Study Event Schedule – Main Trial Cohort ..................................................... 36 
Table 11.1-2: Study Event Schedule – Extended Trial Cohort ............................................... 41 
Table 21.1-1: Adverse Event Definitions ............................................................................... 78 
Table 21.2-1: Criteria for Assessing Relationship of Study Device to Adverse Event .......... 81 
Table 21.3-1: Investigator Reporting Requirements ............................................................... 81 
Table 26.1-1: Abbreviations and Acronyms ........................................................................... 91 
Table 26.2-1: Definitions ........................................................................................................ 93 
Table 27.1-1: Table of Changes for REPRISE II Protocol Version AB (Compared to 
REPRISE II Protocol Version AA) ................................................................... 107 
Table 27.1-2: Table of Changes for REPRISE II Protocol Version AC (Compared to 
REPRISE II Protocol Version AB) .................................................................... 126 
Table 27.1-3: Table of Changes for REPRISE II Protocol Version AD (Compared to 
REPRISE II Protocol Version AC) .................................................................... 127 
Table 27.1-4: Table of Changes for REPRISE II Protocol Version AE (Compared to 
REPRISE II Protocol Version AD) ................................................................... 128 
Table 27.1-5: Table of Changes for REPRISE II Protocol Version AF (Compared to 
REPRISE II Protocol Version AE) .................................................................... 129 
 
 

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4. Introduction 
This protocol specifies procedures and contains information relevant to the clinical 
evaluation of the Lotus™ Valve System, a transfemoral aortic valve replacement device 
designed and manufactured by  Boston Scientific Structural Heart a Division of Boston 
Scientific Corporation. 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 transcatheter aortic valve replacement (TAVR). 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 resheathed 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 polyurethane outer seal (Adaptive™ Seal) designed to 
minimize paravalvular leakage. Additional device information can be found in Section 5.  
4.1. Justification for the Use of the Investigational Device in Human Subjects 
4.1.1. Treatments for Aortic Stenosis  
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 replacement 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 
studies8-15, device-specific registries16-22, national registries23-26, and randomized controlled 

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trials27,28. Through 2-year follow-up in the PARTNER US IDE trial there have been 
significant reductions in mortality and repeat hospitalization rates compared to standard 
medical therapy in subjects unsuitable for SAVR29, and similar mortality rates compared to 
surgical valve replacement in high-surgical-risk subjects30. An expert consensus document on 
TAVR was recently published31. 
Table 4.1-1 summarizes the peri-operative event rates through 30 days post-procedure from 
several TAVR studies that enrolled similar subjects as those planned for this study, as well as 
the results from the inoperable (Cohort B) and high risk (Cohort A) subjects with severe 
aortic stenosis enrolled in PARTNER 27,28. A more detailed summary of the available 
literature is presented in the Investigator Brochure. 
Table 4.1-1: Events from Peri-Operative to 30 Days (Transfemoral Approach) 
Study  
Device/N 
Death 
MI 
Major 
Stroke 
Bleeding 
Acute 
Kidney 
Injury 
Vascular 
Compli-
cations 
Webb, et al. 
200632 
EW/18 
11% 
0% 
0% 
N/A 
N/A 
N/A 
Webb, et al. 
200733 
EW/50 
12% 
2% 
4% 
N/A 
N/A 
N/A 
Webb, et al. 
20098 
EW/113a 
8% 
N/A 
5.3% 
11.6% 
4.4% 
8% 
Osten, et al. 
20109 
EW/16 
6% 
0% 
6% 
13% 
0% 
13% 
Rodés-Cabau,  
et al. 201017 
EW/168a 
9.5% 
0.6% 
3.0% 
N/A 
N/A 
N/A 
Thomas, et al. 
201018 
EW/463a 
6.3% 
N/A 
2.4% 
9.9%  
1.3%  
22.9% 
Leon, et al. 
201027 
EW/267b 
5% 
0% 
5% 
16.8% 
1.1% 
16.2%c 
30.7% 
Smith, et al. 
201128 
EW/244a,d 
3.4% 
0% 
3.8% 
9.3% 
2.9% 
14%c 
22.7% 
Lefèvre, et al. 
201120 
EW/55 
8.2% 
3.3% 
3.3% 
23.5% 
0% 
28.4% 
Grube, et al. 
200634 
CV/25 
20% 
0% 
4% 
N/A 
N/A 
N/A 
Grube, et al. 
200735 
CV/86 
12% 
1% 
10% 
N/A 
N/A 
N/A 
Piazza, et al. 
200816 
CV/646 
8% 
0.6% 
1.9%e  
N/A 
N/A 
1.2% 
Baan, et al. 
201036 
CV/30 
20% 
0% 
0% 
N/A 
N/A 
N/A 
Munoz-Garcia, 
et al. 201222 
CV/133f 
4.5% 
0.8% 
1.5% 
N/A 
N/A 
2.2%c 
Bullesfeld, et al. 
201112 
CV/72b,d,g 
18.1% 
5.6% 
8.3%e  
N/A 
N/A 
N/A 
Buchanan, et al. 
CV, 
4.7% 
1.3% 
1.0% 
33.1% 
10.2%h 
15.7%c 

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Table 4.1-1: Events from Peri-Operative to 30 Days (Transfemoral Approach) 
Study  
Device/N 
Death 
MI 
Major 
Stroke 
Bleeding 
Acute 
Kidney 
Injury 
Vascular 
Compli-
cations 
201111 
EW/305 
Moat, et al. 
201125 
CV, 
EW/599 
5.5% 
1.0% 
4.0%i 
N/A 
N/A 
6.2% 
Stohr, et al. 
201110 
CV/73a 
EW/82j 
12%k  
N/A 
1.0% 
N/A 
4.0% 
N/A 
Zahn, et al. 
201124 
CV, 
EW/697l 
12.4% 
0.3% 
2.8%e  
N/A 
N/A 
17.1%m  
Bosmans, et al. 
201137 
CV/133a 
EW/99a 
8% (CV); 
6% (EW) 
N/A 
5%e,n 
N/A 
6%n,o  
N/A 
Tamburino,  
et al. 201213 
CV, 
EW/218p 
6.9% 
0.0% 
2.3% 
5.5% 
N/A 
N/A 
Gilard, et al. 
201226 
CV, 
EW/2361a 
8.5% 
0.8% 
2.2% 
1.2%q 
N/A 
5.5%c 
a:  Transfemoral approach population only 
b:  Inoperable subjects 
c:  Major 
d:  High risk subjects 
e: All stroke 
f:  Femoral access in 90.9% of cases 
g: Femoral access in 98% of cases 
h:  Stage 3 
i:   In hospital 
j: Apical access only 
k: Includes apical and transfemoral 
l: 92.4% transfemoral and 3.2% subclavian; 84% of all procedures were CV 
m: Groin problem with need of transfusion 
n: All subjects 
o:  Dialysis 
p:  Femoral access in 97.2% of cases 
q: Life-threatening bleeding 
Abbreviations: CV=CoreValve; EW=Edwards; MI=myocardial infarction; N/A=not available 
 
4.1.2. REPRISE I Study 
The aforementioned results notwithstanding, TAVR with early generation devices has been 
associated with increased stroke risk versus surgical valve replacement28,30. Cerebrovascular 
accidents and vascular complications associated with TAVR have been significant predictors 
of mortality38,39. The paravalvular regurgitation more commonly seen with TAVR compared 
to surgery has also been accompanied by higher early and late mortality21,30,40. While careful 
subject selection may serve to mitigate these risks41-43, device design improvements such as 
seen with the Lotus Valve System (Section 5.1) may enable more precise placement, 

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minimize or eliminate paravalvular regurgitation, and obviate the need for valve-in-valve 
repeat intervention.  
The prospective, single arm, multicenter REPRISE I (REpositionable Percutaneous 
Replacement of Stenotic Aortic Valve through Implantation of Lotus™ Valve SystEm) 
feasibility study (N=11) assessed the acute safety and performance of the Lotus Valve 
System in symptomatic subjects with calcified stenotic aortic valves who were considered 
high risk for surgical valve replacement. The primary endpoint was clinical procedural 
success, defined as successful implantation of a Lotus Valve (per the Valve Academic 
Research Consortium [VARC] definitions44) 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.  
The primary endpoint was achieved in 9/11 subjects45. 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 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. 
Paravalvular regurgitation at discharge TTE was mild in 2 subjects, trivial in 1 subject, and 
absent in the other 8 subjects; these outcomes compare favorably with published 
data16,24,27,28,46.  
To date, data are available through 6 months47. 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 6 months (6 in 
Class I, 4 in Class II, 1 in Class III; P=0.004). The mean aortic valve gradient was 13.9±3.8 
mmHg for the cohort at 6 months, which was below the VARC criterion of 20 mmHg, and 
there was no moderate or severe paravalvular aortic regurgitation. The results of the 
REPRISE I feasibility study support the acute safety and performance of the Lotus Valve 
System. 
4.2. Justification for the Study Design 
As noted above, the Lotus Valve System potentially provides a number of performance and 
safety features beyond that of earlier TAVR devices. These include a pre-loaded delivery 
system, early leaflet function to maintain hemodynamic stability during valve deployment, an 
enhanced ability to place the valve correctly at the first attempt using the radiopaque marker 
to aid in valve positioning, the capacity to reposition the device if the initial deployment is 
considered to be suboptimal, the ability to retrieve the device if during the procedure the 
decision is made not to implant, and the aforementioned outer seal designed to minimize 
paravalvular leakage. The anticipated risks and benefits associated both with the Lotus Valve 
System and with participation in this clinical investigation are summarized in the Investigator 

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Brochure and in Section 19 of this document. The conclusion of this risk-benefit analysis 
demonstrates that the known risks associated with the procedure and the specific use of the 
Lotus Valve System have been mitigated to acceptable limits and are comparable to that 
associated with existing transcatheter aortic valves. It was also concluded that the 
aforementioned design features may improve procedural safety. The available sponsor-
provided training program and proctorship for physicians further mitigates the risk. The 
result is a procedure with residual subject risk comparable to that of currently available 
transcatheter aortic valves and significant potential benefit compared with other alternatives.  
It is therefore determined that: 
• All applicable risks have been addressed through appropriate testing and any residual 
risks are acceptable when weighed against the potential benefits to the subject. 
• The potential benefits of the use of the device out-weigh the risks. 
   
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 via the femoral artery using conventional 
catheterization techniques. Femoral access using the surgical cut-down approach can also be 
performed to gain access into the aortic vessel. More detailed product information is 
contained in the Investigator Brochure and Instructions for Use (IFU). 
 
Figure 5.1-1: Lotus™ Valve System 
 

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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.  
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 polyurethane/polycarbonate blend 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 (23 mm or 27 mm) when the valve is locked, regardless of the target 
annulus. The frame height of both valve sizes 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.  
Nitinol Frame
Bovine Pericardium
Adaptive Seal
Locking Mechanism

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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. 
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 
 

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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 
The study Manual of Operations includes the IFU for the Lotus Valve System. Study devices 
are labeled on the top and one side (one label wraps around the top and side) of the outer 
carton and on the sterile pouch. Packaging will include peelable, self-adhesive labels for each 
unit shipped. The labeling will include the following information. 
• Product Name 
• Part/Reference number  
• Lot number (matches the lot number on the handle) 
• Valve size 
• Expiration (use by) date (labeled as month/year, device not to be used after the last day of 
the indicated month) 
• Temperature storage requirements 
The following statement appears on the label.  
CAUTION:  Exclusively for Clinical Investigations. 
Device labeling will be provided in local language(s) as per respective national regulations. 
 
6. Objectives 
The objective of the REPRISE II study is to evaluate the safety and performance of the 
Lotus™ Valve System for transcatheter aortic valve replacement (TAVR) in symptomatic 
subjects with severe calcific aortic stenosis who are considered high risk for surgical valve 
replacement.   
 
7. Endpoints 
7.1. Primary Endpoints 
The primary device performance endpoint is the mean aortic valve pressure gradient at 
30 days post implant as measured by echocardiography and assessed by an independent core 
laboratory. The primary analysis population will be the subject population implanted with the 

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Lotus Valve. Outcomes in this as-treated subject population in the main trial cohort (N=120) 
will be compared to a performance goal (PG; see Section 12.1.1.1).  
The primary safety endpoint is all-cause mortality at 30 days after the implant procedure. The 
primary safety endpoint will be evaluated on an intention-to-treat (ITT) basis (all subjects 
enrolled, whether or not a study device is implanted). Outcomes in the combined main and 
extended trial cohort (N=250) will be compared to a PG (see Section 12.1.1.3). 
7.2. Secondary Endpoints   
Secondary endpoints are listed below and will be evaluated on an ITT basis. Definitions can 
be found in Table 26.2-1. 
• Effective orifice area at 30 days as measured by echocardiography and assessed by an 
independent core laboratory 
• Device performance endpoints peri- and post-procedure:  
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 
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 aortic valve regurgitation: paravalvular, central and combined  
• Device Success post implant procedure based on the VARC definitions 44,48  
Note: At least 1 echocardiogram must be obtained before discharge or 7 days (whichever 
comes first); if multiple echocardiographic studies are performed prior to discharge and 
within 7 days of the procedure, the latest study performed will be used for analysis. 
7.3. Additional Measurements 
Additional measurements based on the VARC endpoints and definitions (see references 44,48 
and Table 26.2-1 in the Appendix for definitions) will be collected peri- and post-procedure, 
at discharge or 7 days post-procedure (whichever comes first), 30 days, 3 months, 6 months, 
and 1, 2, 3, 4, and 5 years post index procedure, unless otherwise specified below. Data will 
be evaluated on an ITT basis. 
• Safety endpoints adjudicated by an independent Clinical Events Committee (CEC): 
o Mortality: all-cause, cardiovascular, and non-cardiovascular 
o Stroke: disabling and non-disabling 
o Composite of all-cause mortality and disabling stroke 
o Myocardial infarction (MI): periprocedural ≤ 72 hours post index procedure) and 
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o Bleeding: life-threatening (or disabling) and major 
o Acute kidney injury (≤7 days post index procedure): based on AKIN System49,50 Stage 
3 (including renal replacement therapy) or Stage 2 
o Major 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 left bundle branch block [LBBB] and third degree 
atrioventricular block)  
o New onset of atrial fibrillation and 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 
• 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 
• Functional status as evaluated by the following: 
o 5-m gait speed test51 (at 1 year compared to baseline)  
o New York Heart Association (NYHA) classification 
• Neurological status as determined by the following: 
o National Institutes of Health Stroke Scale (NIHSS) at discharge and 1 year  
o Modified Rankin Scale (mRS) 
• Health status as evaluated by SF-12 and EQ-5D Quality of Life (QOL) questionnaires52,53 
at baseline; 1 and 6 months; and 1, 3, and 5 years 
Note 1: The VARC safety composite at 30 days will be reported. This includes all-cause 
mortality, all stroke, life-threatening bleeding, acute kidney injury Stage 2 or 3, coronary 
artery obstruction requiring intervention, major vascular complication, and repeat procedure 
for valve-related dysfunction.  
Note 2: The VARC efficacy composite at 1 year will be reported. This includes all-cause 
mortality (after 30 days), all stroke, requiring hospitalization for valve-related symptoms or 
worsening congestive heart failure (NYHA class III or IV), and prosthetic heart valve 

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dysfunction (mean aortic valve gradient ≥20 mm Hg, effective orifice area ≤0.9-1.1 cm2 
and/or Doppler velocity index [DVI] <0.35, AND/OR moderate or severe prosthetic valve 
aortic regurgitation [per VARC definition]) . 
Note 3: Time-related valve safety composite will be reported.  This includes structural valve 
deterioration (valve-related dysfunction requiring repeat procedure [TAVR 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).  
Note 4: In the main trial cohort (N=120), for subjects diagnosed with a neurological event 
(e.g., stroke, transient ischemic attack), a neurological physical exam, NIHSS assessment, 
and mRS must be performed after the event; mRS must also be administered at 90 days post-
neurological event (see Table 11.1-1).  Among the 130 subjects subsequently enrolled 
(extended trial cohort), for subjects diagnosed with a neurological event, NIHSS assessment 
and mRS must be performed after the event; mRS must also be administered at 90 days post-
neurological event; the neurological physical exam is not required (see Table 11.1-2). 
Note 5: The VARC clinical efficacy composite includes the need for hospitalization 
associated with valve-related symptoms or worsening congestive heart failure (CHF) as a 
basis for calculation of a “days alive outside the hospital” endpoint. This includes 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.  
 
8. Design 
8.1. Scale and Duration 
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 TAVR in symptomatic 
subjects who have severe calcific aortic valve stenosis and who are at high risk for surgical 
valve replacement.   
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.  Subjects who do not have the Lotus Valve 
implanted will be assessed through 30 days post procedure for safety/adverse events.   

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The REPRISE II 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 Harmonisation (ICH) Guidelines for Good 
Clinical Practices (GCP); and pertinent individual country/state/local laws and regulations. 
See Section 11 below for additional information on study design and data collection.   
8.2. Treatment Assignment 
Screening materials from eligible subjects who are identified by the investigators as having 
met the inclusion and exclusion criteria (see below Table 9.2-1 and Table 9.3-1, respectively) 
and who provide written informed consent, will be reviewed by a Case Review Committee 
(CRC, see Section 22.2) to assess and confirm suitability of subjects for enrollment. In all 
enrolled subjects an attempt will be made to implant a single Lotus Valve.  
8.2.1. Treatment  
The test device is the Lotus Valve System, which consists of a bioprosthetic bovine 
pericardial aortic valve and a delivery system. The commercially available Lotus Introducer 
Set is used as an accessory in the procedure. See Section 5 for a detailed description and 
information on device sizes. 
8.3. Study Design Justification  
In order to support the stated objectives of this study (see Section 6) while also limiting the 
potential exposure of study subjects to risk, a total of 120 subjects will be enrolled in the 
main trial cohort at up to 15 centers in these possible countries: Australia, France, Germany 
and United Kingdom.  Planned interim analyses based on the primary endpoint at 30 days 
post-implant procedure will be performed on the first 40 and 60 enrolled subjects and a final 
analysis will be conducted on the main trial  cohort (N=120). Subsequently, up to 130 
additional subjects will be enrolled at up to 21 centers in Australia and European countries 
and a statistically powered analysis based on the primary safety endpoint will be performed 
on the combined main and extended trial cohort (250 subjects). In addition to the risk-benefit 
analysis noted in Section 4.2 (see also Section 19), ongoing dynamic data safety monitoring 
will be performed throughout the trial to minimize risk to subjects. All implanted subjects 
will be followed for 5 years post index procedure. 
 
9. Subject Selection  
9.1. Study Population and Eligibility  
The study will include subjects presenting with symptomatic, calcific aortic valve stenosis 
who are considered at high risk for surgical valve replacement. Prior to being eligible for the 
REPRISE II study, a subject must meet all of the inclusion criteria (Section 9.2) and none of 

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the exclusion criteria (Section 9.3). All subjects will then be reviewed by the CRC to confirm 
eligibility and suitability for enrollment in the study. 
9.2. Inclusion Criteria 
Subjects who meet all of the following criteria (see Table 9.2-1) may be given consideration 
for inclusion in this clinical investigation, provided no exclusion criterion (see Section 9.3) is 
met.  
Table 9.2-1: Inclusion Criteria 
Inclusion 
Criteria 
IC1. 
Subject is ≥70 years of age 
IC2. 
Subject has documented calcific native aortic valve stenosis with an initial aortic 
valve area (AVA) of <1.0 cm2 (or AVA index of <0.6 cm2/m2) and either a mean 
pressure gradient >40 mm Hg or a jet velocity >4 m/s, as measured by 
echocardiography. 
IC3. 
Subject has a documented aortic annulus size between ≥20 and ≤27 mm based on 
pre-procedure diagnostic imaging 
IC4. 
Subject has symptomatic aortic valve stenosis with NYHA Functional Class ≥ II. 
IC5. 
Subject is considered high risk for surgical valve replacement based on at least one 
of the following: 
–  STS score ≥8%, and/or 
–  Agreement by the heart team (which must include an in-person evaluation by an 
experienced cardiac surgeon) that subject is at high operative risk of serious 
morbidity or mortality with surgical valve replacement. 
IC6. 
Heart team (which must include an experienced cardiac surgeon) assessment that 
the subject is likely to benefit from valve replacement 
IC7. 
Subject (or legal representative) understands the study requirements and the 
treatment procedures, and provides written informed consent. 
IC8. 
Subject, family member and/or legal representative agree(s) and subject is capable 
of returning to the study hospital for all required scheduled follow up visits. 
Abbreviations: AVA=aortic valve area; NYHA=New York Heart Association; STS= Society of Thoracic 
Surgeons 
 
9.3. Exclusion Criteria 
Subjects who meet any one of the following criteria (Table 9.3-1) will be excluded from this 
clinical study. 
Table 9.3-1: Exclusion Criteria 
Exclusion 
Criteria 
EC1. 
Subject has a congenital unicuspid or bicuspid aortic valve. 
EC2. 
Subject with an acute myocardial infarction within 30 days of the index procedure 
(defined as Q-wave MI or non–Q-wave MI with total CK elevation ≥ twice normal 

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Table 9.3-1: Exclusion Criteria 
in the presence of CK-MB elevation and/or troponin level elevation). 
EC3. 
Subject has had a cerebrovascular accident or transient ischemic attack within the 
past 6 months, or has any permanent neurologic defect prior to study enrollment. 
EC4. 
Subject is on dialysis or has serum creatinine level >3.0 mg/dL or 265 µml/L.  
EC5. 
Subject has a pre-existing prosthetic heart valve (aortic or mitral) or a prosthetic ring 
in any position. 
EC6. 
Subject has ≥3+ mitral regurgitation, ≥3+ aortic regurgitation or ≥3+ tricuspid 
regurgitation (i.e., subject cannot have more than moderate mitral, aortic or tricuspid 
regurgitation). 
EC7. 
Subject has a need for emergency surgery for any reason. 
EC8. 
Subject has a history of endocarditis within 12 months of index procedure or 
evidence of an active systemic infection or sepsis. 
EC9. 
Subject has echocardiographic evidence of intra-cardiac mass, thrombus or 
vegetation. 
EC10. Subject has Hgb <9 g/dL, platelet count <50,000 cells/mm3 or >700,000 cells/mm3, 
or white blood cell count <1,000 cells/mm3. 
EC11. Subject is receiving chronic (≥72 hours) anticoagulation therapy (e.g., warfarin, 
dabigatran, etc.), and cannot tolerate concomitant therapy with aspirin or clopidogrel 
(subjects who require chronic anticoagulation must additionally be able to be treated 
with either aspirin or clopidogrel).* 
EC12. Subject has active peptic ulcer disease or gastrointestinal bleed within the past 
3 months, other bleeding diathesis or coagulopathy or will refuse transfusions. 
EC13. Subject has known hypersensitivity to contrast agents that cannot be adequately pre-
medicated, or has known hypersensitivity to aspirin, all thienopyridines, heparin, 
nickel, titanium, or polyurethanes. 
EC14. Subject has a life expectancy of less than 12 months due to non-cardiac, co-morbid 
conditions based on the assessment of the investigator at the time of enrollment. 
EC15. Subject has hypertrophic obstructive cardiomyopathy. 
EC16. Subject has any therapeutic invasive cardiac procedure (including balloon aortic 
valvuloplasty) within 30 days prior to the index procedure (except for pacemaker 
implantation which is allowed).  
EC17. Subject has untreated coronary artery disease, which in the opinion of the treating 
physician, is clinically significant and requires revascularization. 
EC18. Subject has documented left ventricular ejection fraction <30%. 
EC19. Subject is in cardiogenic shock or has hemodynamic instability requiring inotropic 
support or mechanical support devices. 
EC20. Subject has severe peripheral vascular disease (including aneurysm defined as 
maximal luminal diameter >5 cm or with documented presence of thrombus, marked 
tortuosity, narrowing of the abdominal aorta, severe unfolding of the thoracic aorta 
or thick [>5 mm] protruding or ulcerated atheroma in the aortic arch) or symptomatic 
carotid or vertebral disease.  
EC21. Femoral artery lumen of <6.0 mm for subjects requiring 23 mm valve size or 
<6.5 mm for subjects requiring 27 mm valve size, or severe iliofemoral tortuosity or 
calcification that would prevent safe placement of the introducer sheath. 
EC22. Current problems with substance abuse (e.g., alcohol, etc.). 

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Table 9.3-1: Exclusion Criteria 
EC23. Subject is participating in another investigational drug or device study that has not 
reached its primary endpoint. 
EC24. Subject has untreated conduction system disorder (e.g., Type II second degree 
atrioventricular block) that in the opinion of the treating physician is clinically 
significant and requires a pacemaker implantation.  
*  An alternative P2Y12 inhibitor (e.g., ticlopidine) may be prescribed if subject is allergic to or intolerant of 
clopidogrel. 
Abbreviation: AV= atrioventricular; CK=creatine kinase; MI=myocardial infarction 
 
10. Subject Accountability 
10.1. Point of Enrollment 
Subjects confirmed eligible for the study by the CRC (see Section 22.2) and who provided 
written informed consent are considered enrolled in the study as soon as an attempt is made 
to insert the Lotus Valve System into the subject’s femoral artery.    
10.2. Withdrawal 
All subjects enrolled in the clinical study (including those withdrawn from the clinical study 
or lost to follow-up) shall be accounted for and documented. If a subject withdraws from the 
clinical investigation, the reason(s) shall be reported. If such withdrawal is due to problems 
related to investigational device safety or performance, the investigator shall ask for the 
subject’s permission to follow his/her status/condition outside of the clinical study.   
11. Study Methods 
11.1. Data Collection 
The study event schedules are shown diagrammatically and discussed in Figure 11.1-1 and 
Table 11.1-1 for the main trial cohort (N=120) and in Figure 11.1-2 and Table 11.1-2 for the 
subsequently enrolled 130 additional subjects (extended trial cohort).   

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Figure 11.1-1: REPRISE II Study Design – Main Trial Cohort 
1m
(30d)
3m
(90d)
6m
(180d)
1yr
(365d)
2yr
(730d)
3yr
(1095d)
QOL
Survey
QOL
Survey
Electrocardiogram (ECG)
Modified Rankin Scale (mRS)
Transthoracic Doppler Echocardiography (TTE) 
mRS
QOL
Survey
Case 
Review 
Committee
Clinical Follow-up
Discharge 
or 7days
Index 
Procedure 
4yr
(1190d)
5yr
(1555d)
1 Day
Subject
Enrollment*
Clinical 
Assessment
Baseline
Clinical &
Anatomic 
Eligibility Criteria 
Assessment
Subject 
eligibility
confirmed
N=120
Subject 
meets
criteria
QOL
Survey
QOL
Survey
Annual Imaging  (Rotational X-ray)
Informed Consent
Frailty
Labs
Labs
NIHSS
Neurological
Physical
Exam
ECG
TTE
CT assessment
of aortic structure
CT angiogram or
invasive angiogram
of iliofemoral system
Coronary
Angiogram
TEE
(Recommended)
QOL
Survey
Antiplatelet
& CV Meds
Antiplatelet
& CV Meds
Antiplatelet & Other Cardiovascular Medications
Neurological
Physical
Exam
Neurological
Physical
Exam
Adverse Event Assessment
NYHA Classification
NYHA
Heart
Rhythm
Medical Hx; 
Risk Assessments 
by Heart Team 
NIHSS
NIHSS
ECG
Gait 
Speed
Procedural 
Cine-
Angiography
* Subjects  are considered enrolled as soon as an attempt is made to insert the Lotus Valve System into the subject’s femoral artery

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Table 11.1-1: Study Event Schedule – Main Trial Cohort 
Assessment 
Screeninga 
Baselineb 
Procedure 
 
Within 1 
Day Post-
procedure 
 Prior to 
Discharge 
or 7 Days 
Post-
Procedure 
30 Daysc 
(±7 Days) 
Office 
Visit 
3 Monthsc 
(±14 Days)  
Office 
Visit 
6 Monthsc 
(±30 Days)  
Office 
Visit 
12 Monthsc 
(±45 Days)  
Office  
Visit 
24–60  
Monthsc 
[Annual] 
(±45 Days)  
Office Visit 
Signed Informed 
Consent Formd 
X 
 
 
 
 
 
 
 
 
 
Demographics and 
medical history, 
including cardiac, 
neurological, renal (e.g., 
creatinine) and 
peripheral disease  
X 
 
 
 
 
 
 
 
 
 
NYHA Classification 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Neurological physical 
exame 
 
X 
 
 
X 
 
 
 
X 
 
NIHSSe 
 
X 
 
 
X 
 
 
 
X 
 
Modified Rankin Scalee  
 
X 
 
 
X 
X 
X 
X 
X 
X 
12-lead ECGf 
X 
X 
Xf 
X 
X 
X 
X 
X 
X 
 
Laboratory testsg 
 
X 
 
X 
 
X 
 
 
 
 
Risk assessmentsh  
X 
 
 
 
 
 
 
 
 
 
Frailty, disability and 
comorbidityi 
 
X 
 
 
 
 
 
 
X 
 
Antiplatelet and other 
cardiovascular 
medications 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
TTEj 
X 
 
 
 
X 
X 
X 
X 
X 
X 
TEEk 
 
 
X 
 
 
 
 
 
 
 
Coronary angiograml 
X 
 
 
 
 
 
 
 
 
 
CT angiogram of aortic 
structurem 
X 
 
 
 
 
 
 
 
 
 

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Table 11.1-1: Study Event Schedule – Main Trial Cohort 
Assessment 
Screeninga 
Baselineb 
Procedure 
 
Within 1 
Day Post-
procedure 
 Prior to 
Discharge 
or 7 Days 
Post-
Procedure 
30 Daysc 
(±7 Days) 
Office 
Visit 
3 Monthsc 
(±14 Days)  
Office 
Visit 
6 Monthsc 
(±30 Days)  
Office 
Visit 
12 Monthsc 
(±45 Days)  
Office  
Visit 
24–60  
Monthsc 
[Annual] 
(±45 Days)  
Office Visit 
CT angiogram or 
invasive angiogram of 
iliofemoral systemn 
X 
 
 
 
 
 
 
 
 
 
Annual imaging 
(rotational X-ray)o 
 
 
 
 
 
 
 
 
X 
X 
QOL surveysp 
 
X 
 
 
 
X 
 
X 
X 
Xq 
Procedural cine-
angiography (including 
post-deployment 
aortogram)r 
 
 
X 
 
 
 
 
 
 
 
AE and ADE 
assessmentss 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Device deficiencies, 
SAE, SADE, USADE, 
and CEC event 
assessmentt 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
a: It is recommended that screening occur no later than 10 days prior to the index procedure (unless otherwise specified); results from these assessments should be 
submitted to the CRC at least 10 days prior to the planned procedure to allow for adequate scheduling of subject review at a CRC meeting. 
b: Within 30 days prior to index procedure (unless otherwise specified) 
c: All follow-up dates will be calculated from the date of the index procedure.  Visits must be an office/clinical visit, but may be done in-hospital should the subject be 
admitted at the time. Subjects who are enrolled but do not receive a Lotus Valve will be followed for 30 days to assess for safety but do not need to have protocol 
required TTE, ECG, or laboratory tests or complete quality of life questionnaires. 
d:  Study-specific consent includes screening consent to perform required assessments that will be evaluated by the CRC to confirm subject eligibility. If the study 
Informed Consent Form is modified during the course of the study, study subjects will be re-consented as necessary.  
e:   Neurological physical examination must be performed by a neurologist or neurology fellow. NIHSS and mRS must be performed by certified personnel (external 
certification for NIHSS; internal or external certification for mRS). The assessors should be independent (not involved with the care of study subjects). For subjects 
diagnosed with a neurological event (e.g., stroke, transient ischemic attack), a neurological physical exam, mRS, and NIHSS must be performed after the event; mRS 
must also be administered at 90 days post-neurological event.   
f:  All baseline and post-procedure 12-lead ECGs must be performed according to the ECG Core Laboratory guidelines (see study Manual of Operations).  Heart rhythm 

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Table 11.1-1: Study Event Schedule – Main Trial Cohort 
Assessment 
Screeninga 
Baselineb 
Procedure 
 
Within 1 
Day Post-
procedure 
 Prior to 
Discharge 
or 7 Days 
Post-
Procedure 
30 Daysc 
(±7 Days) 
Office 
Visit 
3 Monthsc 
(±14 Days)  
Office 
Visit 
6 Monthsc 
(±30 Days)  
Office 
Visit 
12 Monthsc 
(±45 Days)  
Office  
Visit 
24–60  
Monthsc 
[Annual] 
(±45 Days)  
Office Visit 
strip must be obtained between balloon aortic valvuloplasty and before Lotus Valve insertion. 
g:  Laboratory tests at baseline include CBC, platelet count, LDH, haptoglobin, serum creatinine, and cardiac enzymes. Cardiac enzymes (CK is required, CK-MB or 
troponin if CK is elevated) must be collected twice at intervals per standard of care within 6-24 hours post-procedure. Acute kidney injury (AKI) should be assessed 
through discharge/7 days based on the AKIN system. At 30 days, laboratory tests include LDH and haptoglobin. 
h:  Consists of STS score (2.73), euroSCORE 2011, and heart team assessment including an in-person evaluation by a cardiac surgeon.  
i:   Frailty, disability and comorbidity risk assessments must also be captured at baseline: nutritional assessment (albumin, body mass index), cognitive function (Mini-
Cognitive Assessment for Dementia), strength and balance (use of wheelchair, gait speed to walk 5 meters, number of falls in the past 6 months, maximal grip 
strength), activities of daily living (Katz Index), and comorbidity (Charlson Index); at 1 year, gait speed to walk 5 meters must be assessed again.   
j:  Transthoracic echocardiogram (TTE) is required, including assessment of effective orifice area, peak systolic and mean aortic valve gradient pressure, aortic 
regurgitation assessment, and LVEF. Screening TTE must be performed within 60 days prior to the index procedure. At least 1 echocardiogram must be obtained 
before discharge or 7 days (whichever comes first); if multiple echocardiographic studies are performed prior to discharge and within 7 days of the procedure, the 
latest study performed will be used for analysis.  All TTEs must be performed according to the Echocardiography Core Laboratory procedure guidelines (see study 
Manual of Operations).   
k: TEE is recommended but not required during the implant procedure. 
l:  A coronary angiogram must be performed within 365 days prior to the index procedure. If there is concern regarding the current extent of coronary artery disease or 
aortic stenosis, the Case Review Committee may recommend a repeat study closer to the time of enrollment.     
m: Computed tomography (CT) angiogram of the entire aortic structure, including the aortic root (from superior to the aortic arch to inferior to the cardiac apex) and from 
descending to abdominal aorta, must be performed within 180 days prior to the index procedure (and should be performed within 90 days if possible) to evaluate the 
aortic valve anatomy and aortic root dimensions for device sizing. CT angiogram must be performed according to the CT Core Laboratory procedure guidelines (see 
study Manual of Operations). It must be sent to the Core Laboratory for detailed measurements and analyses in advance of the CRC meeting where results will be 
reviewed to confirm subject’s eligibility. 
n:  Either a CT angiogram or invasive angiogram of iliofemoral system must be performed within 180 days prior to the index procedure (and should be performed within 
90 days if possible) for complete visualization of the iliac and femoral arteries to assess  for dimensions, tortuosity and calcification. CT angiogram of the iliofemoral 
system should be performed per the procedure guidelines (see study Manual of Operations) and sent to the CT Core Laboratory with the screening CT angiogram of 
the aortic structure.  
o: Annual imaging using rotational x-ray angiography to assess for structural valve frame integrity must be performed. Please refer to the Imaging Core Laboratory 
procedure guidelines (see study Manual of Operations). Results must be forwarded to the CT/X-Ray Core Laboratory for analysis. If additional imaging is performed 
(e.g., cardiac CT or MRI scan), data may be provided for analysis.  
p: Includes the SF-12 and EQ-5D QOL questionnaires. Baseline QOLs should be performed within 30 days prior to the index procedure. 

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Table 11.1-1: Study Event Schedule – Main Trial Cohort 
Assessment 
Screeninga 
Baselineb 
Procedure 
 
Within 1 
Day Post-
procedure 
 Prior to 
Discharge 
or 7 Days 
Post-
Procedure 
30 Daysc 
(±7 Days) 
Office 
Visit 
3 Monthsc 
(±14 Days)  
Office 
Visit 
6 Monthsc 
(±30 Days)  
Office 
Visit 
12 Monthsc 
(±45 Days)  
Office  
Visit 
24–60  
Monthsc 
[Annual] 
(±45 Days)  
Office Visit 
q:  QOL survey at 36 and 60 months. 
r: Procedural cine-angiogram including the final post-deployment aortogram of the ascending aorta should be sent to the CT/X-Ray Core Laboratory for analysis. 
s: AEs and ADEs will be monitored and collected from the time of enrollment through 12-month follow-up. For subjects who do not receive the study device, AEs will 
be monitored through 30-day follow-up.  
t:  Device deficiencies (for the Lotus Valve System), SAEs, SADEs, USADEs, and CEC events will be monitored and reported to Boston Scientific for all enrolled 
subjects from the time of enrollment through termination of the study. For subjects who do not receive the study device, the mentioned events will be monitored 
through 30 days post-index procedure. Please refer to Section 7.3 for a list of CEC events and Table 26.2-1 for definitions of these events, which specify data required 
for CEC adjudication.   
Abbreviations: AE=adverse event; ADE=adverse device effect; AKI=acute kidney injury; CBC=complete blood count; CEC=Clinical Events Committee; 
CK-MB=creatine kinase-myoglobin band; CRC=Case Review Committee; CT=computed tomography; ECG=electrocardiogram; LDH=lactate dehydrogenase; LV=left 
ventricle; MRI=magnetic resonance imaging; mRS=modified Rankin Scale; NIHSS=National Institutes of Health Stroke Scale; NYHA=New York Heart Association; 
QOL=Quality of Life; SAE=serious adverse event; SADE=serious adverse device effect; STS=Society of Thoracic Surgery; TEE=transesophageal Doppler 
echocardiography; TTE=transthoracic Doppler echocardiography; USADE=unanticipated serious adverse device effect 
 
 
 
 

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Figure 11.1-2: REPRISE II Study Design – Extended Trial Cohort 
1m
(30d)
3m
(90d)
6m
(180d)
1yr
(365d)
2yr
(730d)
3yr
(1095d)
QOL
Survey
QOL
Survey
Electrocardiogram (ECG)
Modified Rankin Scale (mRS)
Transthoracic Doppler Echocardiography (TTE) 
mRS
QOL
Survey
Case 
Review 
Committee
Clinical Follow-up
Discharge 
or 7days
Index 
Procedure 
4yr
(1190d)
5yr
(1555d)
1 Day
Subject
Enrollment*
Clinical 
Assessment
Baseline
Clinical &
Anatomic 
Eligibility Criteria 
Assessment
Subject 
eligibility
confirmed
N=130
Subject 
meets
criteria
QOL
Survey
QOL
Survey
Informed Consent
Frailty
Labs
Labs
NIHSS
ECG
TTE
CT assessment
of aortic structure
CT angiogram or
invasive angiogram
of iliofemoral system
Coronary
Angiogram
TEE
(Recommended)
QOL
Survey
Antiplatelet
& CV Meds
Antiplatelet
& CV Meds
Antiplatelet & Other Cardiovascular Medications
Adverse Event Assessment
NYHA Classification
NYHA
Heart
Rhythm
Medical Hx; 
Risk Assessments 
by Heart Team 
NIHSS
NIHSS
ECG
Gait 
Speed
Procedural 
Cine-
Angiography
* Subjects  are considered enrolled as soon as an attempt is made to insert the Lotus Valve System into the subject’s femoral artery

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Table 11.1-2: Study Event Schedule – Extended Trial Cohort 
Assessment 
Screeninga 
Baselineb 
Procedure 
 
Within 1 
Day Post-
procedure 
 Prior to 
Discharge 
or 7 Days 
Post-
Procedure 
30 Daysc 
(±7 Days) 
Office 
Visit 
3 Monthsc 
(±14 Days)  
Office 
Visit 
6 Monthsc 
(±30 Days)  
Office 
Visit 
12 Monthsc 
(±45 Days)  
Office  
Visit 
24–60  
Monthsc 
[Annual] 
(±45 Days)  
Office Visit 
Signed Informed 
Consent Formd 
X 
 
 
 
 
 
 
 
 
 
Demographics and 
medical history, 
including cardiac, 
neurological, renal (e.g., 
creatinine) and 
peripheral disease  
X 
 
 
 
 
 
 
 
 
 
NYHA Classification 
X 
 
 
 
X 
X 
X 
X 
X 
X 
NIHSSe 
 
X 
 
 
X 
 
 
 
X 
 
Modified Rankin Scalee  
 
X 
 
 
X 
X 
X 
X 
X 
X 
12-lead ECGf 
X 
Xf 
X 
X 
X 
X 
X 
X 
 
Laboratory testsg 
 
X 
 
X 
 
X 
 
 
 
 
Risk assessmentsh  
X 
 
 
 
 
 
 
 
 
 
Frailty, disability and 
comorbidityi 
X 
 
 
 
 
 
 
X 
 
Antiplatelet and other 
cardiovascular 
medications 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
TTEj 
X 
 
 
 
X 
X 
X 
X 
X 
X 
TEEk 
 
 
X 
 
 
 
 
 
 
 
Coronary angiograml 
X 
 
 
 
 
 
 
 
 
 
CT angiogram of aortic 
structurem 
X 
 
 
 
 
 
 
 
 
 
CT angiogram or 
invasive angiogram of 
iliofemoral systemn 
X 
 
 
 
 
 
 
 
 
 
QOL surveyso 
 
X 
 
 
 
X 
 
X 
X 
Xp 

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Table 11.1-2: Study Event Schedule – Extended Trial Cohort 
Assessment 
Screeninga 
Baselineb 
Procedure 
 
Within 1 
Day Post-
procedure 
 Prior to 
Discharge 
or 7 Days 
Post-
Procedure 
30 Daysc 
(±7 Days) 
Office 
Visit 
3 Monthsc 
(±14 Days)  
Office 
Visit 
6 Monthsc 
(±30 Days)  
Office 
Visit 
12 Monthsc 
(±45 Days)  
Office  
Visit 
24–60  
Monthsc 
[Annual] 
(±45 Days)  
Office Visit 
Procedural cine-
angiography (including 
post-deployment 
aortogram and 
rotational angiogram)q 
 
 
X 
 
 
 
 
 
 
 
AE and ADE 
assessmentsr 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Device deficiencies, 
SAE, SADE, USADE, 
and CEC event 
assessments 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
a: It is recommended that screening occur no later than 10 days prior to the index procedure (unless otherwise specified); results from these assessments should be 
submitted to the CRC at least 10 days prior to the planned procedure to allow for adequate scheduling of subject review at a CRC meeting. 
b: Within 30 days prior to index procedure (unless otherwise specified) 
c: All follow-up dates will be calculated from the date of the index procedure.  Visits must be an office/clinical visit, but may be done in-hospital should the subject be 
admitted at the time. Subjects who are enrolled but do not receive a Lotus Valve will be followed for 30 days to assess for safety but do not need to have protocol 
required TTE, ECG, or laboratory tests or complete quality of life questionnaires. 
d:  Study-specific consent includes screening consent to perform required assessments that will be evaluated by the CRC to confirm subject eligibility. If the study 
Informed Consent Form is modified during the course of the study, study subjects will be re-consented as necessary.  
e:   NIHSS and mRS must be performed by certified personnel (external certification for NIHSS; internal or external certification for mRS). The assessors should be 
independent (not involved with the care of study subjects). For subjects diagnosed with a neurological event (e.g., stroke, transient ischemic attack), mRS, and NIHSS 
must be performed after the event; mRS must also be administered at 90 days post-neurological event.   
f:  All pre-(screening or baseline) and post-procedure 12-lead ECGs must be performed according to the ECG Core Laboratory guidelines (see study Manual of 
Operations).  Heart rhythm strip must be obtained between balloon aortic valvuloplasty and before Lotus Valve insertion. 
g:  Laboratory tests at baseline include CBC, platelet count, LDH, haptoglobin, serum creatinine, and cardiac enzymes. Cardiac enzymes (CK is required, CK-MB or 
troponin if CK is elevated) must be collected twice at intervals per standard of care within 6-24 hours post-procedure. Acute kidney injury (AKI) should be assessed 
through discharge/7 days based on the AKIN system. At 30 days, laboratory tests include LDH and haptoglobin. 
h:  Consists of STS score 2.73, euroSCORE 2011, and heart team assessment including an in-person evaluation by a cardiac surgeon.  
i:   Frailty, disability and comorbidity risk assessments must also be captured prior to the implant procedure: nutritional assessment (albumin, body mass index), cognitive 

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Table 11.1-2: Study Event Schedule – Extended Trial Cohort 
Assessment 
Screeninga 
Baselineb 
Procedure 
 
Within 1 
Day Post-
procedure 
 Prior to 
Discharge 
or 7 Days 
Post-
Procedure 
30 Daysc 
(±7 Days) 
Office 
Visit 
3 Monthsc 
(±14 Days)  
Office 
Visit 
6 Monthsc 
(±30 Days)  
Office 
Visit 
12 Monthsc 
(±45 Days)  
Office  
Visit 
24–60  
Monthsc 
[Annual] 
(±45 Days)  
Office Visit 
function (Mini-Cognitive Assessment for Dementia), strength and balance (use of wheelchair, gait speed to walk 5 meters, number of falls in the past 6 months, 
maximal grip strength), activities of daily living (Katz Index), and comorbidity (Charlson Index); at 1 year, gait speed to walk 5 meters must be assessed again.   
j:  Transthoracic echocardiogram (TTE) is required, including assessment of effective orifice area, peak systolic and mean aortic valve gradient pressure, aortic 
regurgitation assessment, and LVEF. Screening TTE must be performed within 60 days prior to the index procedure. At least 1 echocardiogram must be obtained 
before discharge or 7 days (whichever comes first); if multiple echocardiographic studies are performed prior to discharge and within 7 days of the procedure, the 
latest study performed will be used for analysis.  All TTEs must be performed according to the Echocardiography Core Laboratory procedure guidelines (see study 
Manual of Operations).   
k: TEE is recommended but not required during the implant procedure. 
l:  A coronary angiogram must be performed within 365 days prior to the index procedure. If there is concern regarding the current extent of coronary artery disease or 
aortic stenosis, the CRC may recommend a repeat study closer to the time of enrollment.     
m: CT angiogram of the entire aortic structure, including the aortic root (from superior to the aortic arch to inferior to the cardiac apex) and from descending to abdominal 
aorta, must be performed within 180 days prior to the index procedure (and should be performed within 90 days if possible) to evaluate the aortic valve anatomy and 
aortic root dimensions for device sizing. CT angiogram must meet the CT Core Laboratory procedure guidelines (see study Manual of Operations). It must be sent to 
the Core Laboratory for detailed measurements and analyses in advance of the CRC meeting where results will be reviewed to confirm subject’s eligibility. 
n:  Either a CT angiogram or invasive angiogram of iliofemoral system must be performed within 180 days prior to the index procedure (and should be performed within 
90 days if possible) for complete visualization of the iliac and femoral arteries to assess  for dimensions, tortuosity and calcification. CT angiogram of the iliofemoral 
system should be performed per the procedure guidelines (see study Manual of Operations) and sent to the CT Core Laboratory with the screening CT angiogram of 
the aortic structure.  
o: Includes the SF-12 and EQ-5D QOL questionnaires. Baseline QOLs should be performed within 30 days prior to the index procedure. 
p:  QOL survey at 36 and 60 months. 
q: Procedural cine-angiogram including the final post-deployment aortogram of the ascending aorta (including recommended rotational angiogram of the valve frame) 
should be sent to the CT/X-Ray Angio Core Laboratory for analysis. 
r: AEs and ADEs will be monitored and collected from the time of enrollment through 12-month follow-up. For subjects who do not receive the study device, AEs will 
be monitored through 30-day follow-up.  
s:  Device deficiencies (for the Lotus Valve System), SAEs, SADEs, USADEs, and CEC events will be monitored and reported to Boston Scientific  for all enrolled 
subjects from the time of enrollment through termination of the study. For subjects who do not receive the study device, the mentioned events will be monitored 
through 30 days post-index procedure. Please refer to Section 7.3 for a list of CEC events and Table 26.2-1 for definitions of these events, which specify data required 
for CEC adjudication.   
Abbreviations: AE=adverse event; ADE=adverse device effect; AKI=acute kidney injury; CBC=complete blood count; CEC=Clinical Events Committee; 

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Table 11.1-2: Study Event Schedule – Extended Trial Cohort 
Assessment 
Screeninga 
Baselineb 
Procedure 
 
Within 1 
Day Post-
procedure 
 Prior to 
Discharge 
or 7 Days 
Post-
Procedure 
30 Daysc 
(±7 Days) 
Office 
Visit 
3 Monthsc 
(±14 Days)  
Office 
Visit 
6 Monthsc 
(±30 Days)  
Office 
Visit 
12 Monthsc 
(±45 Days)  
Office  
Visit 
24–60  
Monthsc 
[Annual] 
(±45 Days)  
Office Visit 
CK-MB=creatine kinase-myoglobin band; CRC=Case Review Committee; CT=computed tomography; ECG=electrocardiogram; LDH=lactate dehydrogenase; LV=left 
ventricle; mRS=modified Rankin Scale; NIHSS=National Institutes of Health Stroke Scale; NYHA=New York Heart Association; QOL=Quality of Life; SAE=serious 
adverse event; SADE=serious adverse device effect; STS=Society of Thoracic Surgery; TEE=transesophageal Doppler echocardiography; TTE=transthoracic Doppler 
echocardiography; USADE=unanticipated serious adverse device effect 

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11.2. Study Candidate Screening 
Subjects will be evaluated for eligibility by the center heart team (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.   
Clinical assessment and evaluation as well as all collected tests and images (e.g., 
echocardiography, computerized tomography [CT], angiography) performed in preparation 
for TAVR will be reviewed by the CRC (see Section 8.2 and Section 22.2). The CRC will be 
comprised of the Study Principal Investigator (PI) and other investigators experienced with 
TAVR along with the Sponsor to review and confirm subject eligibility for enrollment. 
11.3. Informed Consent 
Informed consent (see Section 20) must be obtained from a potential subject prior to 
conducting any preoperative assessments that are not part of the local routine preparation and 
evaluation of a subject for TAVR, even if the subject’s eligibility has not yet been completely 
determined.   
The Investigator/designee, who has been trained on the protocol, will explain the nature and 
scope of the study, potential risks and benefits of participation, and answer questions for the 
subject. If the subject agrees to participate, the Informed Consent form (ICF) must be signed 
and personally dated by the subject or his/her legally authorized representative. The 
Investigator/designee must also sign the ICF prior to subject enrollment. Any additional 
persons required by the center’s Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) to sign the ICF must also comply. Study personnel should explain to the 
subject that even if the subject agrees to participate in the study and signs the ICF, the heart 
team and/or the CRC may determine that the subject is not a suitable candidate for the study 
and/or TAVR procedure. 
If during the course of the preoperative evaluations, the subject is found not to be eligible for 
inclusion in the study, the subject should be notified. Reason for ineligibility will be 
accounted for as “screening failure” and will be documented as such in the screening module. 
If the subject has signed the ICF, but is found not eligible for inclusion in the study prior to 
or during the procedure, the subject should receive the appropriate treatment as identified by 
the clinical investigator. Information regarding the screening failure will be captured on the 
screening module and subject will be included in the “screening cohort” accountability. 

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11.4. Screening Assessments 
The following screening tests and procedures must be performed and submitted to the Case 
Review Committee for evaluation to confirm a subject’s eligibility into the study.  These 
assessments should be completed no later than 10 days prior to the planned procedure, unless 
otherwise specified below. The results from these assessments should be submitted to the 
CRC at least 10 days prior to the planned procedure to allow for adequate scheduling of 
subject review at a CRC meeting. It is planned that the CRC meeting will take place at least 
weekly to ensure timely review and confirmation of subject eligibility. This will 
accommodate a second review before the planned procedure should this be needed.  
Sites will be trained on the screening process as detailed in the REPRISE II Training Plan 
(see Section 17.4.1). Specific data points will be collected in the REPRISE II electronic Case 
Report Forms (eCRFs) as shown below.  
• Clinical assessments  
o Demographics including age and gender 
o Medical history (general medical; cardiac [including previous cardiac surgery]; 
neurological, renal (including creatinine) and peripheral disease; and other medical 
conditions)   
o Physical examination including weight and height 
o NYHA classification  
o Risk assessments: STS Score (2.73),  euroSCORE 2011, heart team assessment 
including an in-person evaluation by a cardiac surgeon, and any frailty assessments  
o Current antiplatelet and other cardiovascular medications 
o 12-lead electrocardiogram (ECG) 
• Imaging assessments  
o Within 60 days prior to the procedure, TTE (2-D, M-Mode, and color) must be 
carried out. The evaluation should include 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, 
tricuspid regurgitation (TR) jet velocity, and left atrial (LA) volume. Other 
echocardiographic measurements include, but are not limited to, aortic valve 
diameter, left ventricular outflow tract, diameter, Sinus of Valsalva diameter, annulus 
to ventricular apex length, mitral hinge point to apex length. TTEs must be performed 
according to the Echocardiography Core Laboratory procedure guidelines (see study 
Manual of Operations).  All TTEs for enrolled subjects must be sent to the 
Echocardiography Core Laboratory for independent analyses.  
o A coronary angiogram must be performed within 365 days prior to the index 
procedure. If there is concern regarding the current extent of coronary artery disease 
or aortic stenosis, the Case Review Committee may recommend a repeat study closer 
to the time of enrollment. An aortogram and hemodynamics including simultaneous 
ascending aorta and left ventricle pressure measurements should be performed.  

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o A CT angiogram of the entire aortic structure, including the aortic root (from superior 
to the aortic arch to inferior to the cardiac apex) and from the descending to the 
abdominal aorta, must be performed 180 days prior to the index procedure and should 
be performed within 90 days, if possible, to evaluate the aortic valve anatomy and 
aortic root dimensions to determine eligibility and device sizing. It must meet the CT 
Core Laboratory procedure guidelines (see study Manual of Operations) and 
forwarded in advance to the Core Laboratory for detailed measurements and 
independent analyses, which will be reviewed by the CRC to confirm subject’s 
eligibility. 
o Either a CT or invasive angiogram of the iliofemoral system must be performed 
within 180 days prior to the index procedure (and should be performed within 90 days 
if possible) for complete visualization of the iliac and femoral arteries to assess for 
dimensions, tortuosity and calcification. The CT angiogram of the iliofemoral system 
should be performed per the procedure guidelines (see study Manual of Operations) 
and sent to the CT Core Laboratory with the screening CT angiogram of the aortic 
structure for independent measurements and review by the CRC to confirm subject’s 
eligibility.  
o Figure 11.4-1 shows a list of assessment considerations dependent upon a subject’s 
anatomy in order to determine which Lotus Valve size should be implanted for those 
subjects who might be a candidate for either valve size.  

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Figure 11.4-1: Assessment Considerations for Lotus Valve Size Selection 
 
11.5. Baseline Assessments 
The following assessments must be completed within 30 days prior to the index procedure, 
unless otherwise specified below. The REPRISE II electronic eCRFs identify the specific 
data points to be collected. 
• Confirmation of eligibility criteria 
• Neurological physical examination required in the main trial cohort, which must be 
performed by a neurologist or neurology fellow (see Table 11.1-1); assessors should be 
independent (not involved with the care of study subjects). A neurological physical 
examination is not required in the extended trial cohort (see Table 11.1-2). 
Small
Assessment 
Consideration
Large
<6.5mm
Femoral Size
≥6.5 mm
Smaller
Subject Size 
(ht/wt/BMI)
Larger
Very Heavy
Calcification
Moderate
Smaller
Sinus Dimension
Larger
Smaller
Left Ventricular 
Outflow Tract
Larger
Borderline
Coronary Height
Adequate
Lesser
Eccentricity
Greater
20
23
27

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• NIH Stroke Scale (NIHSS), which must be performed by certified personnel (external 
certification); assessors should be independent (not involved with the care of study 
subjects)  
• Modified Rankin Scale score, which must be performed by certified personnel (external 
or internal certification); assessors should be independent (not involved with the care of 
study subjects). 
• Laboratory tests 
o Complete blood count (CBC) with platelets 
o LDH 
o Haptoglobin  
o Serum creatinine 
o Cardiac enzymes (CK is required, CKMB or troponin if CK is elevated) 
• The following frailty, disability, and comorbidity assessments at screening and/or 
baseline will be collected prospectively in the REPRISE II study.  
o Nutritional assessment  
▪ Albumin  
▪ Body Mass Index from the physical exam 
o Cognitive function: Mini-Cognitive Assessment for Dementia54,55 where a subject is 
instructed to listen carefully to and recall three unrelated words (1 point for each 
recalled word) and to draw a clock with hands specific to a time given (2 points for a 
normal clock and no points for an abnormal clock).     
o Strength and balance  
▪ Use of wheelchair 
▪ Gait speed as measured by a stopwatch for a subject to walk 5 meters (3 measures 
averaged)56-58  
▪ Number of falls in the past 6 months 
▪ Maximal grip strength (kg) in the dominant hand (3 measures averaged), using a 
Jamar hand-held dynamometer59  
o Activities of daily living: Katz Index55,60 is based on an evaluation of the functional 
independence or dependence of a subject in bathing, dressing, going to toilet, 
transferring, continence, and feeding. A point is assigned for independence in each of 
the 6 functions, and 0 points if there is any dependence in these 6 categories. 
o Comorbidity: Charlson Index contains 19 categories of comorbidity and assigns a 
weighted value to each subject’s comorbidity based on the risk of 1-year 
mortality55,61. 
• 12-lead electrocardiogram (ECG) at screening and/or baseline must be performed 
according to the ECG Core Laboratory guidelines (see study Manual of Operations) and 
forwarded to Core Laboratory for analysis.   
• Quality Of Life (QOL) Surveys: SF-12 and EQ-5D QOL Questionnaires52,53 must be 
administered to the subject within 30 days prior to the procedure. 

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11.6. Preprocedure Medications 
• Antiplatelet Therapy: 
Subjects must be treated with aspirin and a thienopyridine prior to implantation of the 
Lotus Valve.  
 
Aspirin 
 
A loading dose of aspirin (recommended dose of 75–325 mg) is required for subjects who 
have not been taking aspirin for 72 hours at the time of the index procedure. The 
loading dose must be administered prior to the implant procedure or immediately after. 
Subjects who have been taking aspirin daily for 72 hours at the time of the index 
procedure do not require a loading dose. 
 
Clopidogrel 
A loading dose of clopidogrel (recommended dose of ≥300 mg) is required for subjects 
who have not been taking clopidogrel for 72 hours at the time of the index procedure.  
The loading dose must be administered prior to the implant procedure or immediately 
after. 
Note 1: An alternative P2Y12 inhibitor (e.g., ticlopidine) may be prescribed as an 
alternative if subject is allergic to or intolerant of clopidogrel.  
Note 2: If the study-specific dosages and durations for antiplatelet medications conflict 
with country-specific labeling for the medications, the country-specific labeling should 
take precedence. 
Note 3: If a subject requires chronic anticoagulation (e.g., warfarin, dabigatran, etc.), 
either clopidogrel or aspirin is required prior to implant procedure (but both aspirin and 
clopidogrel are not required). 
• Anticoagulant therapy (e.g., unfractionated heparin) must be administered per local 
standard of care during the implant procedure, with a recommended target activated 
clotting time (ACT) of ≥250 seconds during the implantation procedure. 
• Additionally, the subject should be given prophylactic antibiotic therapy according to the 
local practice. The choice of antibiotic drug is left to the investigator’s discretion. 
11.7. Index Procedure 
11.7.1. Percutaneous Procedure for Delivering the Lotus Device 
The preparation of the subject for the percutaneous procedure will be performed following 
standard techniques. The Lotus Introducer is then prepared and introduced into the subject’s 
femoral artery, as described in the Lotus Introducer IFU. 
11.7.2. Valvuloplasty 
A balloon valvuloplasty on the native valve following standard techniques must be 
performed with an adequately sized valvuloplasty balloon (avoid oversizing). In the event of 

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a significant waist  and the subject is hemodynamically stable, balloon valvuloplasty should 
be repeated as needed to achieve a resulting aortic annulus in which a valvuloplasty balloon 
can be fully inflated with no significant waist. If a significant waist remains after repeated 
valvuloplasty, it is strongly recommended that appropriate valve size be reconsidered or, if 
annulus size is within the lower measurement of the annulus size, that the Lotus Valve not be 
implanted. The subject should be treated according to the Investigator’s discretion and 
standard of care. If the subject is not implanted with the Lotus Valve, then the subject will be 
followed for 30 days post-procedure.  
Careful attention should be paid to the position of the guidewire throughout the procedure. 
Prior to introduction of the Lotus Valve System, the subject’s hemodynamic status and heart 
rhythm must be assessed, and a heart rhythm strip should be obtained.  
Information on the balloon valvuloplasty, including number of inflations, should be 
documented in the source data and will be captured in the eCRFs. 
Note: If the subject becomes hemodynamically unstable after the valvuloplasty for reasons 
unrelated to the aortic valve annulus and/or leaflets, the Lotus Valve implantation should be 
interrupted until the subject is stable.  
11.7.3. Preparing and Using the Lotus Valve System 
The Lotus Valve implantation procedure requires two operators: First and Second Operators. 
Both operators must comply with the IFU and must be adequately trained and certified by 
Boston Scientific personnel in accordance with the training plan before performing the 
procedure.  
The Lotus Valve System must be prepared in accordance with the IFU.   
Prior to insertion of the Lotus Valve catheter into the Lotus Introducer, the recommended 
target ACT of ≥250 seconds should be confirmed, with additional anticoagulant boluses (e.g., 
heparin) administered if needed.  
The following summarizes the Lotus Valve System procedure. 
1) The Lotus catheter is inserted in the Lotus Introducer and carefully advanced through 
the aorta and the aortic arch under fluoroscopy. 
2) The catheter is then advanced slowly through the aortic annulus until the marker is 
appropriately positioned within the native aortic leaflets.  
3) The valve is then deployed in the desired position.  
4) Prior to the release of the Lotus Valve, assessment of its position and function is 
performed using contrast media and/or TEE. 
5) If the position of the valve is deemed too aortic or too ventricular, the valve is then 
partially or completely resheathed inside the catheter, with a repositioning made by 
either pulling or pushing the catheter carefully, using the radiopaque marker as a guide. 
6) Once repositioning is complete, the Lotus Valve is redeployed while maintaining the 
position of the marker.  

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7) Once the Lotus Valve position is deemed satisfactory, the release process is then 
initiated until the Lotus Valve is detached from the catheter.  
8) The nosecone is then reseated on the catheter and the system is pulled back to the aorta 
and out of the body through the introducer. 
9) A final post-deployment aortogram of the ascending aorta (including recommended 
rotational angiography of the valve frame) should be performed and forwarded to the 
Core Laboratory with the procedural cine-angiogram for analysis. 
10) The Lotus Introducer is then removed.  
11) The femoral access is then closed according to standard practice. 
Labels from the devices used during the procedure (e.g., the Lotus Valve System, Lotus 
Introducer) should be retained so that they can be affixed in the appropriate source 
documents and reported in the eCRFs.   
During the procedure, designated site study personnel must capture necessary information on 
acute device/delivery system performance and procedure. The following information will be 
collected during the procedure. 
• Date of procedure 
• Specifics of device type (such as size [23 mm vs. 27 mm] and model [if the Lotus Valve 
is not implanted]) 
• Time of first vascular puncture (femoral) and time of vascular closure (skin-to-skin time) 
• Lotus Introducer insertion and removal time 
• Descriptive information on balloon valve annuloplasty (e.g., size of balloon, number of 
balloon inflations) 
• Any devices used and adjunctive procedures performed during implant procedure  
• Heart rhythm after balloon valvuloplasty with rhythm strip 
• Lotus Valve catheter insertion and removal time 
• Descriptive information on Lotus Valve implantation procedure and information on valve 
repositioning (if performed) 
• Adverse event (AE) assessment and associated treatment (including AE, serious adverse 
event [SAE], serious adverse device effect [SADE], unanticipated serious adverse device 
effect [USADE], adverse device effect [ADE] and Clinical Events Committee [CEC] 
events; see Section 21. 
• Device deficiencies assessment (for the Lotus Valve System) 
Note: All Lotus Valve implantation procedures will be performed with the support/presence 
of trained Boston Scientific personnel.    

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11.8. Post-Procedure 
The following are to be performed post-procedure. 
• Per society guidelines, 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 medications31. Subjects must be treated with 
aspirin and clopidogrel for at least 1 month following valve implantation. If the study-
specific dosages and durations for antiplatelet medications conflict with country-specific 
labeling for the medications, the country-specific labeling should take precedence.  
 
o After the Lotus Valve implant procedure, aspirin (recommended dose of ≥75 mg 
daily) must be given for at least 1 month. It is recommended that daily aspirin be 
given indefinitely thereafter as per local standard of care. Aspirin doses may be 
adjusted to the closest approximation based on local tablet formulation availability. 
o After the Lotus valve implant procedure, clopidogrel (recommended dose of 75 mg 
daily) is required for at least 1 month. 
Note: An alternative P2Y12 inhibitor (e.g., ticlopidine) may be prescribed as an 
alternative if subject is allergic to or intolerant of clopidogrel.  
o If the subject requires chronic anticoagulation (e.g., warfarin, dabigatran, etc.), either 
clopidogrel or aspirin is required in addition to the anticoagulant therapy post-
procedure (but both aspirin and clopidogrel are not required). 
• Prophylactic antibiotic regimen should be completed as per local practice. 
• Additional medications may be used at the investigator’s discretion. 
• It is recommended that the subject’s heart rhythm be monitored using telemetry for at 
least 48 hours after the index procedure.       
• 12-lead ECG must be completed within 24 hours post-procedure per the ECG Core 
Laboratory guidelines (see study Manual of Operations) and must be forwarded to the 
Core Laboratory for analysis.   
• Cardiac enzymes (CK is required, CK-MB or troponin if CK is elevated) must be 
collected twice at intervals per standard of care within 6-24 hours post-procedure. 
11.9. Prior to Discharge or 7 Days Post-Procedure (Whichever Comes First) 
Subjects must be evaluated prior to discharge or 7 days post-procedure (whichever comes 
first) based on the assessments below. The REPRISE II eCRFs identify the specific data 
points to be collected. 
• Physical examination including weight and height  
• NYHA classification 
• Neurological physical examination required in the main trial cohort, which must be 
performed by a neurologist or neurology fellow; assessors should be independent (not 

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involved with the care of study subjects; see Table 11.1-1). A neurological physical 
examination is not required in the extended trial cohort (see Table 11.1-2). 
• NIHSS, which must be performed by certified personnel (external certification); 
assessors should be independent (not involved with the care of study subjects).  
• Modified Rankin Scale score, which must be performed by certified personnel (external 
or internal certification); assessors should be independent (not involved with the care of 
study subjects). 
• 12-lead ECG per the Core Laboratory guidelines (see study Manual of Operations) and 
must be forwarded for analysis.   
• 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 
the Echocardiography Core Laboratory procedure guidelines (see study Manual of 
Operations).  All TTEs for enrolled subjects must be sent to the Echocardiography Core 
Laboratory for independent analyses.  
Note: At least 1 echocardiogram must be obtained before discharge or 7 days (whichever 
comes first); if multiple echocardiographic studies are performed prior to discharge and 
within 7 days of the procedure, the latest study performed will be used for analysis.   
• Current antiplatelet, anticoagulant (if applicable), and other cardiovascular medications 
• Complete adverse event (AE, SAE, SADE, USADE, ADE, and CEC events) and device 
deficiencies assessment (with associated treatment) 
11.10. Follow-up 
All implanted subjects will be evaluated at 30 days, 3 months, 6 months, 12 months, 24 
months, 36 months, 48 months, and 60 months post index procedure. Subjects who do not 
have the Lotus Valve implanted will be assessed through 30 days post procedure for 
safety/adverse events. Physical clinic visits or follow-up visits are scheduled for appointed 
times after the date of the procedure. It is important that this 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 is allowed is indicated in Table 11.1-1. Studies not completed will be 
considered missed visits. Visits completed outside these windows will be recorded as 
protocol deviations. After 6 months, visits will be scheduled on an annual basis from 1 
through 5 years. Each follow-up visit must be performed by study personnel; data from the 
required tests and images as well as medical assessments will be recorded in source 
documentation and captured in the eCRFs. The determination of specified study endpoints 
and measurements such as valve function and CEC events will require data from images and 
tests as outlined in the event definitions (Table 26.2-1).    

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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.  
11.10.1. 30-Day Follow-up (307 Days)  
All enrolled subjects must be evaluated 30 days after the index procedure. During the 30-day 
follow-up, the following assessments must be completed. The REPRISE II eCRFs identify 
the specific data points to be collected. 
• Physical examination including weight and height  
• NYHA classification  
• Modified Rankin Scale score, which must be performed by certified personnel (external 
or internal certification); assessors should be independent (not involved with the care of 
study subjects). 
• Laboratory tests, including LDH and haptoglobin 
• 12-lead ECG per the Core Laboratory guidelines (see study Manual of Operations) and 
must be forwarded to the Core Laboratory for analysis. 
• Current antiplatelet, anticoagulant (if applicable), and other cardiovascular medications 
• 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.  TTE 
must be performed per the Echocardiography Core Laboratory procedure guidelines (see 
study Manual of Operations).  All TTEs for enrolled subjects must be sent to the 
Echocardiography Core Laboratory for independent analyses.  
• Quality of Life Surveys: SF-12 and EQ-5D Quality of Life Questionnaire 
• Complete adverse event (AE, SAE, SADE, USADE, ADE, and CEC events) and device 
deficiencies assessment (with associated treatment) 
11.10.2. 3-Month Follow-up (9014 Days)  
All implanted subjects must be evaluated 3 months after the index procedure. During the 
3 month follow-up, the following assessments must be completed. The REPRISE II eCRFs 
identify the specific data points to be collected. 
• Physical examination including weight and height  
• NYHA classification  
• Modified Rankin Scale score, which must be performed by certified personnel (external 
or internal certification); assessors should be independent (not involved with the care of 
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• 12-lead ECG per the Core Laboratory guidelines (see study Manual of Operations) and 
must be forwarded for analysis.  
• Current antiplatelet, anticoagulant (if applicable), and other cardiovascular medications 
• 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 
the Echocardiography Core Laboratory procedure guidelines (see study Manual of 
Operations).  All TTEs for implanted subjects must be sent to the Echocardiography Core 
Laboratory for independent analyses.  
• Complete adverse event (AE, SAE, SADE, USADE, ADE and CEC events) and device 
deficiencies assessment (with associated treatment) 
11.10.3. 6-Month (18030 Days) Follow-up  
All implanted subjects must be evaluated at 6 months after the index procedure. During the 
6-month follow-up, the following assessments must be completed. The REPRISE II eCRFs 
identify the specific data points to be collected. 
• Physical examination including weight and height  
• NYHA classification  
• Modified Rankin Scale score, which must be performed by certified personnel (external 
or internal certification); assessors should be independent (not involved with the care of 
study subjects). 
• 12-lead ECG per the Core Laboratory guidelines (see study Manual of Operations) and 
must be forwarded for analysis 
• Current antiplatelet, anticoagulant (if applicable), and other cardiovascular medications 
• 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 
the Echocardiography Core Laboratory procedure guidelines (see study Manual of 
Operations).  It must be sent to the Core Laboratory for independent analysis.  
• Complete adverse event (AE, SAE, SADE, USADE, ADE and CEC events) and device 
deficiencies assessment (with associated treatment) 
• Quality of Life Surveys: SF-12 and EQ-5D Quality of Life Questionnaires 
11.10.4. 12-Month (36545 Days) Follow-up 
All implanted subjects must be evaluated at 12 months after the index procedure. During the 
12-month follow-up, the following assessments must be completed. The REPRISE II eCRFs 
identify the specific data points to be collected. 

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• Physical examination including weight and height  
• NYHA classification  
• Modified Rankin Scale score, which must be performed by certified personnel (external 
or internal certification); assessors should be independent (not involved with the care of 
study subjects).   
• Neurological physical examination required in the main trial cohort, which must be 
performed by a neurologist or neurology fellow (see Table 11.1-1); assessors should be 
independent (not involved with the care of study subjects). A neurological physical exam 
is not required in the extended trial cohort (see Table 11.1-2). 
• NIHSS, which must be performed by certified personnel (external certification); 
assessors should be independent (not involved with the care of study subjects). 
• Gait speed to walk 5 meters  
• Rotational x-ray angiography to assess for structural valve frame integrity per the 
Imaging Core Laboratory procedure guidelines (see study Manual of Operations) is 
required in the main trial cohort.  It must be forwarded to the Core Laboratory for 
analysis. Rotational x-ray angiography is not required in the extended trial cohort. 
• 12-lead ECG per the Core Laboratory Guidelines (see study Manual of Operations) and 
must be forwarded for analysis  
• Current antiplatelet, anticoagulant (if applicable), and other cardiovascular medications 
• 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 
the Echocardiography Core Laboratory procedure guidelines (see study Manual of 
Operations).  It must be forwarded to the Core Laboratory for independent analysis.  
• Complete adverse event (AE, SAE, SADE, USADE, ADE and CEC events) and device 
deficiencies assessment (with associated treatment) 
• Quality of Life Surveys: SF-12 and EQ-5D Quality of Life Questionnaires 
11.10.5. Annual Follow-up (45 Days) 
All enrolled subjects implanted with a Lotus Valve must be evaluated at 24, 36, 48, and 60 
months after the index procedure. During the annual follow-up, the following assessments 
must be completed. The REPRISE II eCRFs identify the specific data points to be collected. 
• Physical examination including weight and height  
• NYHA classification  
• Modified Rankin Scale score, which must be performed by certified personnel (external 
or internal certification); assessors should be independent (not involved with the care of 
study subjects). 

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• Current antiplatelet, anticoagulant (if applicable), and other cardiovascular medications 
• 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 
the Echocardiography Core Laboratory procedure guidelines. All TTEs must be 
forwarded to the Core Laboratory for independent analyses.  
• Rotational x-ray angiography to assess for structural valve frame integrity per the 
Imaging Core Laboratory procedure guidelines (see study Manual of Operations) is 
required in the main trial cohort.  It must be forwarded to the Core Laboratory for 
analysis. If additional imaging is performed (e.g., cardiac CT or MRI scan), data may 
also be provided for analysis. Rotational x-ray angiography is not required in the 
extended trial cohort. 
 
• Complete serious adverse event (SAE, SADE, USADE, and CEC events) and device 
deficiencies assessment (with associated treatment). 
• Quality of Life Surveys: SF-12 and EQ-5D Quality of Life Questionnaires at 3 years and 
5 years 
11.10.6. Management of Missed or Late Visits 
Missed or late visits will be recorded as protocol deviations and will be reviewed as such by 
the sponsor or designee on a regular basis in accordance with the applicable standard 
operating procedures.  
11.10.7. Procedure for Determining when a Subject is Lost to Follow-up    
A subject will be considered “lost to follow-up” and terminated from the study when all of 
the following criteria have been met. 
• Failure to complete 2 consecutive visits without due cause (after 30 days) 
• Documentation of 3 unsuccessful attempts, one of which must be in written 
communication, by the Investigator or his/her designee to contact the subject or next of 
kin 
• A letter from the Investigator to Sponsor reporting subject as lost to follow up 
11.10.8. 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 

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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.   
11.10.9. Explant Procedure 
If a Lotus Valve is explanted during conventional scheduled or emergent surgical valve 
replacement or during an autopsy, if possible, the explanted valve should be sent to an 
independent histopathology core laboratory for macroscopic and microscopic analyses. 
Please refer to the study Manual of Operations for recommendations on the explant 
procedure and shipment of the explanted valve.  
Information on the explant procedure must be documented in source notes and captured in 
the Explant Form of the eCRFs. 
11.11. Study Completion 
All subjects will be evaluated at 30 days, 3 months, 6 months, 12 months, 24 months, 
36 months, 48 months, and 60 months post index procedure. All visits are office visits. A 
subject’s participation in the study will be considered complete after the 60-month visit. 
11.12. Source Documents 
It is preferable that original source documents (see Table 26.2-1 for definition) are 
maintained. Where copies of the original source document as well as printouts of original 
electronic source documents are retained, these should be signed and dated by a member of 
the investigation center team with a statement that it is a true reproduction of the original 
source document.  
 
12. Statistical Considerations 
12.1. Endpoints 
12.1.1. Primary Endpoints 
12.1.1.1. Primary Device Performance Endpoint  
The study is powered to assess the primary device performance endpoint, which is the mean 
aortic valve pressure gradient at 30 days post implant as measured by TTE and assessed by 
an independent core laboratory. The null and alternative hypotheses for the primary device 
performance endpoint are as follows. 
H0: Gradient30D ≥ PG 
H1: Gradient30D < PG  
where Gradient30D is the 30-day mean aortic valve pressure gradient for the Lotus Valve and 
PG is the performance goal (18 mm Hg).  

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Testing will be done for the primary device performance endpoint as described in the 
statistical analysis plan. A one-sample t-test will be used. 
For the one-sample t-test, the test statistic is 
X
D
s
PG
x
t
−
=
30
, 
where 
D
x30  is the sample 30-day mean aortic valve pressure gradient, 
PG  is the performance goal,  
(
)








−
−
=

1
1
2
30
N
x
x
N
s
D
x
 is the sample standard error, 
x  is the 30-day mean aortic valve pressure gradient per subject, and 
N  is the sample size. 
The degrees of freedom used in this test is 
1
−
N
. 
Two interim analyses will be conducted on the first 40 and 60 subjects and a final analysis 
will be conducted on the main trial cohort (N=120). The alpha-level for the interim and final 
analyses is adjusted using the Pocock alpha spending function method for unequal 
information time intervals62; they are 0.01123, 0.00792, and 0.01305, respectively. If the 
P value from the one-sample t-test is <alpha, the Lotus Valve will be concluded to have a 
30-day mean aortic valve pressure gradient <18 mm Hg. This corresponds to the one-sided 
upper (1–alpha)% confidence bound of the observed 30-day mean aortic valve pressure 
gradient being <18 mm Hg.  
A sensitivity analysis (tipping-point analysis) will be performed to assess the impact of 
subjects with inadequate follow-up (i.e., missing data) on the primary device performance 
endpoint and to assess the robustness of the conclusion of the primary analysis. 
12.1.1.2. Sample Size – Primary Device Performance Endpoint  
The sample size calculation for the primary device performance endpoint is based on the 
following assumptions. 
• Expected 30-day mean pressure gradient from Lotus Valve ≤ 15 mm Hg (based on the 
aforementioned literature review23,32,34,44,46,63  
• Expected standard deviation = 7 mm Hg  
• Performance goal (PG) = 18 mm Hg 
• Test significance level () = 0.025 (1-sided) 
• Power (1 – ) ≥ 80% 
• Evaluable number of subjects = Minimum of 49 subjects 
• Expected rate of attrition = 15% (9 subjects) 

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Given the above assumptions, the planned enrollment will be up to 120 subjects. Two 
planned interim analyses based on the primary device performance endpoint at 30 days post-
implant procedure will be performed on the first 40 and 60 enrolled subjects. Enrollment of a 
total of 120 subjects is planned to meet regulatory requirements. A final analysis will be 
carried out on the fully enrolled main trial cohort.  
12.1.1.3. Primary Safety Endpoint 
 
Subsequent to the enrollment of the main trial cohort for device performance assessment (see 
Section 12.1.1.2), up to 130 more subjects will be enrolled in the extended trial cohort to 
perform a statistically powered assessment of the primary safety endpoint. The null and 
alternative hypotheses for the primary safety 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 the 
performance goal. 
Testing will be done for the primary safety endpoint as described in the statistical analysis 
plan. A one-sample z-test will be used, the z-test statistic is 
p
D
s
PG
P
z
−
=
30
, 
where  
P30D is the sample 30-day all-cause mortality rate, 
PG is the performance goal,  
N
P
P
s
D
D
p
)
1(
30
30
−
=
 is the sample standard error, 
N is the sample size. 
A sensitivity analysis (tipping-point analysis) will be performed to assess the impact of 
subjects with inadequate follow-up (i.e., missing data) on the primary safety endpoint and to 
assess the robustness of the conclusion of the primary analysis. 
The sample size calculation for the primary safety endpoint is based on the following 
assumptions. 
• Expected 30-day all-cause mortality rate = 9.8%  
• Performance goal (PG) = 16 % (expected rate of 9.8% + testing margin of 6.2%) 
• Test significance level () = 0.025 (1-sided) 
• Power (1 – ) = 80% 
• Expected rate of attrition = 2% 

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If the P value from the one-sample z-test is <0.025, it will be concluded that the primary 
safety endpoint for the Lotus Valve is less than the PG. This corresponds to the one-sided 
upper 97.5% confidence bound of the observed 30-day mortality rate being <16 %. 
The expected rate of 9.8% for 30-day all-cause mortality is based on a literature review8-13,16-
18,20,22,24-28,32-37. Given the above assumptions, 233 subjects will be required. In order to 
account for a 5% expected rate of attrition, a total of 250 subjects is required for the planned 
hypothesis testing.     
12.1.1.4. 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. 
12.1.2. Post-procedure Endpoints and Measurements 
Post-procedure information will be collected at regularly scheduled follow-up examinations 
as detailed in the clinical study schedule (Table 11.1-1 and Table 11.1-2) and will be 
summarized using descriptive statistics for continuous variables (e.g., mean, standard 
deviation, n, minimum, maximum) and frequency tables or proportions for discrete variables. 
No inferences are planned on the additional endpoints and, therefore, alpha-adjustments for 
multiple comparisons will not be used. The Kaplan-Meier product-limit method will be used 
to determine rates for time-to-event endpoints. Adverse event and SAE rates will be reported.  
12.2. General Statistical Methods 
All statistical analyses will be performed using the SAS System software, version 9.2 or later 
(Copyright© 2000 SAS Institute Inc., SAS Campus Drive, Cary, North Carolina 27513, USA. 
All rights reserved).  
 
All statistical analyses will be conducted according to applicable Standard Operating 
Procedures, Work Instructions, and the study-specific Statistical Analysis Plan.  
12.2.1. Analysis Sets 
The primary analysis population for the primary device performance endpoint will be the 
subject population implanted with the Lotus Valve (as-treated subject population.  

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The primary safety 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. 
12.2.2. Control of Systematic Error/Bias 
All subjects who have met the inclusion/exclusion criteria,  received a positive 
recommendation from the CRC, and signed the informed consent form will be eligible for 
enrollment in the study. The center’s heart team  assessments and imaging measurements 
before device placement will contribute to the determination of subject eligibility for the 
study.  
To control for inter-observer variability, an Echocardiography Core Laboratory will 
independently analyze echocardiography images collected for each subject during the study. 
Echocardiographic data obtained from the core laboratory will be used for analyses. 
Similarly, an Electrocardiography Core Laboratory will independently analyze protocol-
required 12-lead ECGs performed for each subject. Data obtained from the ECG core 
laboratory will be used for analyses. 
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). See Section 12.1.1 for a 
discussion on analysis of primary endpoints. 
12.3.1. Other Endpoints/Measurements  
Other endpoints not driven by statistical hypotheses are listed in Section 7.2 and Section 7.3. 
12.3.2. Interim Analyses  
12.3.3. There are 2 planned interim analyses for CE Mark dossier submission purposes. 
They will be based on the primary device performance endpoint at 30 days post-
implant procedure and will be performed on the first 40 and 60 enrolled 
subjects. The final analysis of the primary device performance endpoint will be 
conducted on the fully enrolled main trial cohort (N=120). The Pocock alpha 
spending function method for unequal information time intervals62 is used to 
adjust the alpha-level for each analysis: 0.01123, 0.00792, and 0.01305, 
respectively.  Justification of Pooling 
The analyses will be presented using data pooled across institutions as well as by center for 
the primary device performance endpoint and the primary safety endpoint. 
Assessments of the poolability of subjects across centers will be made using the Chi-square 
test to determine if there is a relationship between the center and the primary safety endpoint, 

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and analysis of variance (ANOVA) to test for differences in the means of the primary device 
performance endpoint across centers. If the P value for the Chi-square test or ANOVA is 
≥0.15, the data can be pooled across that center. In the analysis to justify pooling across 
centers, the centers with fewer than 5 subjects enrolled in the study will be combined into 
“virtual centers” based on geographic region so that “virtual centers” have ≥5 subjects in the 
study but no more than the largest enrolling center. 
12.3.4. Multivariable Analyses 
Univariate and multivariate analyses will be performed to assess the effect of potential 
predictors on the primary endpoint of mean aortic valve pressure gradient at 30 days post 
implant, as described in the statistical analysis plan. 
12.3.5. Other Analyses 
Exploratory univariate and multivariate analyses will be performed to assess the effect of 
potential predictors on the primary safety endpoint of all-cause mortality at 30 days post 
implant plus additional safety endpoints as described in the statistical analysis plan. 
12.3.6. Changes to Planned Analyses 
Any changes to the planned statistical analyses made prior to performing the analyses will be 
documented in an amended statistical analysis plan approved before performing the analyses. 
Changes from the planned statistical methods after performing the analyses will be 
documented in the clinical study report along with a reason for the deviation. 
 
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 or its representative. The associated RAVE software and database have 
been designed to meet regulatory compliance for deployment as part of a validated system 
compliant with laws and regulations applicable to the conduct of clinical studies pertaining to 
the use of electronic records and signatures. Database backups are performed regularly. 
The Investigator provides his/her electronic signature on the appropriate eCRFs in 
compliance with local regulations. A written signature on printouts of the eCRFs must also 
be provided if required by local regulation. Changes to data previously submitted to the 
sponsor require a new electronic signature by the Investigator acknowledging and approving 
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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 center for appropriate response. Center staff will be responsible for resolving 
all queries in the database. 
13.2. Data Retention 
The Investigator will maintain at the investigative 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 Boston Scientific or in compliance 
with other local regulations. It is Boston Scientific’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 Boston 
Scientific must receive written notification of this custodial change.  
13.3. Core Laboratories 
13.3.1. Transthoracic Echocardiography (TTE) Core Laboratory 
An independent Core Laboratory will review echocardiography images from all centers and 
every subject enrolled in this study for qualitative and quantitative analysis. These analyses 
will minimize bias and inconsistencies by providing an independent interpretation of all 
measurements using standard techniques. The TTE procedure guideline is provided by the 
core laboratory in the study Manual of Operations. 
13.3.2. CT and Rotational X-Ray Angiography Core Laboratory 
An independent Core Laboratory will centrally assess all of the CT and rotational X-ray 
angiography data in this study to reduce variability. These analyses will minimize bias and 
inconsistencies by providing an independent interpretation of all measurements using 
standard techniques. The screening CT Angiogram procedure guidelines and annual imaging 
acquisition protocol are provided by the core laboratory in the study Manual of Operations. 
13.3.3. Electrocardiography (ECG) Core Laboratory 
All 12-lead ECGs performed at each of the required protocol visits will be sent to an ECG 
core laboratory (see study Manual of Operations) for independent analyses. These analyses 
will minimize bias and will provide consistent interpretation of the ECGs.  

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13.3.4. Histopathology Core Laboratory 
If a Lotus Valve is explanted during conventional scheduled or emergent surgical valve 
replacement or during an autopsy, please refer to the study Manual of Operations for 
recommendations on the explant procedure and shipment of the explanted valve to an 
independent histopathology laboratory for analyses. 
 
14. Amendments  
If a protocol revision is necessary which affects the rights, safety or welfare of the subjects or 
scientific integrity of the data, an amendment is required. Appropriate approvals (e.g., 
IRB/EC/FDA/CA) of the revised protocol must be obtained prior to implementation. 
 
15. Deviations 
An Investigator must not make any changes or deviate from this protocol, except to protect 
the life and physical well-being of a subject in an emergency. An investigator shall notify the 
sponsor and the reviewing IRB/EC of any deviation from the investigational plan to protect 
the life or physical well-being of a subject in an emergency, and those deviations which 
affect the scientific integrity of the clinical investigation. Such notice shall be given as soon 
as possible, but no later than 5 working days after the emergency occurred, or per prevailing 
local requirements, if sooner than 5 working days.  
All deviations from the investigational plan, with the reason for the deviation and the date of 
occurrence, must be documented and reported to the sponsor using the EDC CRF.  Centers 
may also be required to report deviations to the IRB/EC, per local guidelines and government 
regulations.  
Deviations will be reviewed and evaluated on an ongoing basis and, as necessary, appropriate 
corrective and preventive actions (including notification, center re-training, or 
discontinuation) will be put into place by the sponsor. 
 
16. Device Accountability 
The Lotus Valve System and Lotus Introducer will be provided by the Sponsor to the clinical 
centers. This will occur only after the center has been initiated and all regulatory approvals as 
well as required documentation have been collected from the center. 
The devices shall be securely maintained, controlled, and used only in this clinical study. 
Additionally, the study personnel must follow the instructions related to the storage of the 

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devices as noted in the IFU. Device Accountability Logs will be provided to the centers and 
will be used to track subjects and device allocations during the study.  
The sponsor shall keep records to document the physical location of all investigational 
devices from shipment of investigational devices to the investigation centers until return or 
disposal. 
Records shall be kept at each study center to document the physical location and conditions 
of storage of all investigational devices. Centers must not dispose of any devices for any 
reason at the center unless instructed to do so by Boston Scientific. Any device that is 
disposed of at the center must be recorded in the Device Accountability Log. The PI must 
document the reasons for any discrepancy noted in device accountability. 
The principal investigator or an authorized designee shall keep records documenting the 
receipt, use, return and disposal of the investigational devices, which shall include the 
following; this will be verified by Boston Scientific personnel or its designee. 
• Date of receipt 
• Identification of each investigational device (Part/Reference and Lot numbers, valve size) 
• Expiry date, as applicable 
• Date of use 
• Subject identification 
• Date on which the investigational device was returned/explanted from subject, if 
applicable 
• Date of return of unused, expired, or malfunctioning investigational devices, if applicable 
Written procedures may be required by national regulations. 
Once the Investigator and Center are notified in writing by Boston Scientific that subject 
enrollment is complete, all unused devices must be returned to Boston Scientific or its 
designee. A copy of the Device Accountability Logs must also be provided to Boston 
Scientific. 
 
17. Compliance 
17.1. Statement of Compliance 
The REPRISE II 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 Harmonisation (ICH) Guidelines for Good 
Clinical Practices (GCP); and pertinent individual country/state/local laws and regulations. 

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17.2. 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/or regulations, whichever affords the greater protection to the 
subject. 
The Principal Investigator’s responsibilities include, but are not limited to, the following.  
• Prior to beginning the study, sign the Investigator Agreement and Protocol Signature 
page documenting his/her agreement to conduct the study in accordance with the 
protocol. 
• Provide his/her qualifications and experience to assume responsibility for the proper 
conduct of the study and that of key members of the center team through up-to-date 
curriculum vitae or other relevant documentation and disclose potential conflicts of 
interest, including financial, that may interfere with the conduct of the clinical study or 
interpretation of results. 
• Complete all Lotus Valve training requirements as detailed in the REPRISE II Training 
Plan (see Section 17.4.1) 
• Make no changes in or deviate from this protocol, except to protect the life and physical 
well-being of a subject in an emergency; document and explain any deviation from the 
approved protocol that occurred during the course of the clinical investigation. 
• Create and maintain source documents throughout the clinical study and ensure their 
availability with direct access during monitoring visits or audits; ensure that all clinical-
investigation-related records are retained per requirements. 
• Ensure the accuracy, completeness, legibility, and timeliness of the data reported to the 
sponsor in the CRFs and in all required reports. 
• Record, report, and assess (seriousness and relationship to the device/procedure) every 
adverse event and observed device deficiency. 
• Report to Boston Scientific, per the protocol requirements, all SAEs and device 
deficiencies that could have led to a SADE. 
• Report to the IRB/EC and regulatory authorities any SAEs and device deficiencies that 
could have led to a SADE, if required by the national regulations or this protocol or by 
the IRB/EC, and supply Boston Scientific with any additional requested information 
related to the safety reporting of a particular event. 
• Maintain the device accountability records and control of the device, ensuring that the 
investigational device is used only by authorized/designated users and in accordance with 
this protocol and instructions/directions for use. 

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• Allow the sponsor to perform monitoring and auditing activities, and be accessible to the 
monitor and respond to questions during monitoring visits. 
• Allow and support regulatory authorities and the IRB/EC when performing auditing 
activities. 
• Ensure that informed consent is obtained in accordance with this protocol and local 
IRB/EC requirements. 
• Provide adequate medical care to a subject during and after a subject’s participation in a 
clinical study in the case of adverse events, as described in the ICF. 
• Inform the subject of the nature and possible cause of any adverse events experienced. 
• Inform the subject of any new significant findings occurring during the clinical 
investigation, including the need for additional medical care that may be required. 
• Provide the subject with well-defined procedures for possible emergency situations 
related to the clinical study, and make the necessary arrangements for emergency 
treatment as needed. 
• Ensure that clinical medical records are clearly marked to indicate that the subject is 
enrolled in this clinical study. 
• Ensure that, if appropriate, subjects enrolled in the clinical investigation are provided 
with some means of showing their participation in the clinical investigation, together with 
identification and compliance information for concomitant treatment measures (contact 
address and telephone numbers shall be provided). 
• Inform, with the subject’s approval or when required by national regulations, the 
subject’s personal physician about the subject’s participation in the clinical investigation. 
• Make all reasonable efforts to ascertain the reason(s) for a subject’s premature 
withdrawal from clinical investigation while fully respecting the subject’s rights. 
• Ensure that an adequate investigation center team and facilities exist and are maintained 
and documented during the clinical investigation. 
• Ensure that maintenance and calibration of the equipment relevant for the assessment of 
the clinical investigation is appropriately performed and documented, where applicable. 
17.2.1. Delegation of Responsibility 
When specific tasks are delegated by an investigator, included but not limited to conducting 
the informed consent process, the investigator is responsible for providing appropriate 
training and adequate supervision of those to whom tasks are delegated. The investigator is 
accountable for regulatory violations resulting from failure to adequately supervise the 
conduct of the clinical study.  

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17.3. 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 and/or competent authority approval of the protocol (or 
permission to conduct the study) and Informed Consent Form, must be received by the 
sponsor before recruitment of subjects into the study and shipment of investigational 
product/equipment. 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.  
17.4. Sponsor Responsibilities 
All information and data sent to Boston Scientific and its authorized designee concerning 
subjects or their participation in this study will be considered confidential by Boston 
Scientific. Only authorized Boston Scientific personnel, representative or designee 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 Boston Scientific for the purposes of this study, publication, and to support future 
research and/or other business purposes. Data used in the analysis and reporting of this study 
will not be identified by specific subject name. 
Note: Boston Scientific may utilize a contract research organization (CRO) or other 
contractors to act as its representative for carrying out designated tasks.  
Boston Scientific Corporation will keep subjects’ health information confidential in 
accordance with all applicable laws and regulations.  Boston Scientific Corporation may use 
subjects’ health information to conduct this research, 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 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.  
17.4.1. Training  
The Sponsor is responsible for providing Investigators with the information and training they 
need to conduct the study properly and in accordance with the Training Plan. Study-specific 
training and education is required for all site staff with roles in this trial. The Sponsor is 
responsible for maintaining documentation of attendance at each of the training sessions 
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In compliance with the initial requirements for training TAVR physicians in the latest Draft 
ISO 5840 Part 3 Annex O, Boston Scientific has developed a Training Plan that includes the 
following elements for implanting investigators. 
• Review of subject selection and screening, with a detailed review of imaging 
requirements for implanting the device such as fluoroscopy, CT, and TTE  
• Detailed description of all the Lotus Valve components 
• Detailed description of the step-by step Lotus Valve procedure, with a complete review 
of the IFU including the indications for use, subject selection, contra-indications, 
precautions, warning, potential adverse events, pre-procedure set-up, sizing the valve, 
implant procedure, and post-procedure subject care  
• Hands-on bench top demonstration of the valve and delivery system in a simulated model 
• Use of the device in a simulation system 
• A clinical training program for the proctors 
• Cases review either via a taped case or library of previous cases, or by observing a Lotus 
Valve implantation 
• The Training Phases will include the following. 
o Phase I – Device Demonstration: An initial introduction to the Lotus Valve device 
description and quick demonstration of the Step-by-Step Procedure using a simulation 
bench model ideally in the catheter lab, under fluoroscopy. 
o Phase II – Online Training: Following introduction to the device, the Operators 
(First and Second) as well as the site personnel who will be involved in the subject 
screening and selection will be given access to on-line training modules at the Lotus 
University training web-site. The online training includes modules that describe the 
subject selection process, the CRC roles and responsibilities, the device description 
and Step-by-Step procedure training.  
o Phase III – Formal Training: Hands-on (in-service) training using standard Lotus 
Valve components to practice the implantation procedure in a bench simulation 
model and/or a computer-based simulation (when available). During the bench model 
training, up to five procedures will be performed by the operators, initially guided by 
the Boston Scientific trainers (including Field Clinical Engineers [FCE]), with the last 
procedure being evaluated for the operators’ certification.   
o Phase IV – Refresher Training: This training represents the last step of the hands-
on training, with the purpose of providing more hands-on practice using the Lotus 
Valve System on the simulation bench model before the actual Lotus Valve implant 
procedures. Up to three practice procedures will be performed, with very minimal or 
no guidance from the Boston Scientific trainers in the catheter lab of the 
investigational site and under fluoroscopy. At the end of this training, the First and 
Second Operators will be provided with the official certification.  TAVR investigators 

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with prior experience successfully implanting the Lotus Valve System may only need 
to complete this phase of the training plan.  
• Case Observation: Prior to performing the first case, each investigator should be required 
to observe at least two Lotus Valve implantation procedures, performed by an 
experienced Lotus Valve implanter. The case observation may occur either via 
broadcasting, in the format of taped case, or in the catheter lab where the procedure is 
conducted, depending on the Operators and the administration of the center where the 
case is taking place. 
• Proctoring: The investigator and co-investigators as well as the scrub team will be 
proctored by an experienced TAVR physician on a minimum of four Lotus Valve 
implantation procedures. These are to be performed in the investigator’s institution with 
his staff. If the proctor or investigators (First Operator and Second Operator) are not 
satisfied that these initial proctored procedures are sufficient preparation, then subsequent 
proctoring sessions may be added as needed.   
17.4.2. Role of Boston Scientific Corporation Representatives 
Boston Scientific personnel (including FCEs) will provide training and technical support to 
the investigator and other health care personnel (collectively HCP) as needed during implant 
and testing required by the protocol. Support may include addressing HCP questions or 
providing clarifications to HCPs concerning the operation of Boston Scientific 
equipment/devices. In addition, Boston Scientific personnel may perform certain activities to 
ensure study quality. These activities may include the following. 
• Observing testing or medical procedures to provide information relevant to protocol 
compliance 
• Reviewing collected data and study documentation for completeness and accuracy. 
17.5. Insurance  
Where required by local/country regulation, proof and type of insurance coverage by Boston 
Scientific for subjects in the study will be obtained. 
 
18. Monitoring 
Monitoring will be performed during the study according to the monitoring plan to assess 
continued compliance with the protocol and applicable regulations. In addition, the monitor 
verifies that study records are adequately maintained, that data are reported in a satisfactory 
manner with respect to timeliness, adequacy, and accuracy, and that the Investigator 
continues to have sufficient staff and facilities to conduct the study safely and effectively. 
The Investigator/institution guarantees direct access to original source documents by Boston 
Scientific personnel, their designees, and appropriate regulatory authorities. 

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The study may also be subject to a quality assurance audit by Boston Scientific or its 
designees, as well as inspection by appropriate regulatory authorities. It is important that the 
Investigator and relevant study personnel are available during on-site monitoring visits or 
audits and that sufficient time is devoted to the process. 
 
19. Potential Risks and Benefits 
Risks to clinical subjects associated with their participation in this clinical investigation, 
arising from the clinical procedures set out in the study protocol, have been identified from 
prior studies conducted by Boston Scientific and review of relevant literature, most recently 
from the Edwards Lifesciences’ Placement of Aortic Transcatheter Valves (PARTNER) 
Trial27,28.   
Benefits to subjects anticipated to arise from the use of the investigational device have also 
been identified. These clinical risks and benefits are summarized below, with an assessment 
of the balance of risks and benefits to subjects.   
19.1. Risks Associated with Transcatheter Aortic Valve Implantation Procedure and Lotus 
Valve System  
Adverse events (in alphabetical order) potentially associated with transcatheter aortic valve 
implantation as well as additional risks related to the use of the Lotus Valve System are listed 
below. 
• Allergic reaction (including to medications, anesthesia, contrast, or device materials) 
• Angina   
• Arrhythmia or new conduction system injury (including need for pacemaker insertion) 
• AV fistula 
• Bleeding or hemorrhage 
• Cardiac arrest  
• Cerebrovascular accident, stroke or transient ischemic attack 
• Coronary obstruction 
• Death  
• Device misplacement or migration 
• Endocarditis  
• Emboli (including air, tissue, thrombus or device materials)  
• Fever 
• Heart failure 

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• Hemolysis and/or hemolytic anemia 
• Hematoma or lymphatic problems at the access sites 
• Hemodynamic instability or shock 
• Hypertension/hypotension  
• Infection (local and/or systemic) 
• Myocardial infarction 
• Myocardial or valvular injury (including perforation or rupture) 
• Neurologic deficits 
• Pain 
• Pericardial effusion or tamponade 
• Pseudoaneurysm 
• Renal insufficiency or failure 
• Respiratory insufficiency or failure 
• Valve dysfunction, deterioration or failure 
• Valvular stenosis or regurgitation (central or paravalvular) 
• Valve thrombosis 
• Vessel injury (including spasm, trauma, dissection, perforation or rupture).  
As a result of these complications, the subject may require medical, percutaneous or surgical 
intervention, including re-operation and replacement of the Lotus Valve. Such complications 
can be fatal.   
 As the Lotus valve is an investigational device, uncertainty remains over risks of 
experiencing some or all of the complications listed above. There may be risks that are 
unknown at this time. 
19.2. Risk Minimization Actions 
Additional risks may exist. Risks can be minimized through compliance with this protocol, 
performing procedures in the appropriate hospital environment, adherence to subject 
selection criteria, close monitoring of the subject's physiologic status during research 
procedures and/or follow-ups and by promptly supplying Boston Scientific with all pertinent 
information required by this protocol. 
• Boston Scientific Corporation will employ measures throughout the course of this 
investigation consistent with the best practices and lessons learned from other ongoing 
TAVR trials and commercial use to minimize risk for subjects choosing to participate. 
All efforts will be made to minimize risks by selecting investigators who are experienced 
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• Risk mitigation will be accomplished through the following actions. 
o Clearly defining the inclusion/exclusion criteria to ensure only appropriate subjects 
are enrolled  
o Confirmation of eligible subjects by a Case Review Committee, including 
experienced investigators in TAVR 
o Ensuring that treatment and follow-up of the subject are consistent with current 
medical practices 
o Selection of investigators who are experienced and skilled in TAVR procedures 
o Completion of training and proctorship provided by the Sponsor  
o Performing all procedures in accordance with the IFU, including the preparation of 
the valve and delivery system 
o Dynamic safety review processes, including assessment by the Data Monitoring 
Committee (DMC, Section 22.1) and CEC (Section 22.1) adjudication of specified 
events as recommended by VARC44. 
In addition to its repositioning and self-centering features designed to facilitate optimal 
positioning, the Lotus Valve System provides physicians with control throughout the 
procedure by allowing them to pause, assess, lock, un-lock, incrementally reverse, resheath 
and, if needed, retrieve the valve prior to final release. The assessment of the need for such 
maneuvers is facilitated by early leaflet function during valve deployment. These features 
allow the physician to place the valve correctly at the first attempt, the capacity to reposition 
the device if the initial deployment is considered to be suboptimal, and the capability of 
retrieving the device if during the procedure the decision is made not to implant. The valve’s 
outer seal is also designed to minimize paravalvular leakage. 
Anticoagulation medication (e.g., heparin) will be administered during the procedure to 
reduce the risk of embolism and stroke. Additionally, post-procedure anti-platelet therapy is 
recommended to minimize any risk of thrombus formation, stroke, or transient ischemic 
attack (TIA). Neurological assessments will be performed at each required follow-up visit to 
identify any change in the neurological status of the subjects as recommended by VARC44,48. 
Cardiac enzyme measurements as well as ECGs post-procedure will be performed to detect 
periprocedural MI.  
Subjects will be carefully monitored during the procedure, hospitalization, and throughout 
the follow-up period. Serial echocardiograms and electrocardiograms will be used to evaluate 
valve and general cardiac function. Any abnormal rhythm will be assessed and, if needed, the 
implantation of a permanent pacemaker will be performed. Annual imaging will also be 
performed to assess for structural valve frame integrity. 
Subjects who are converted to standard surgical aortic valve replacement will be carefully 
monitored in a method appropriate for their surgical procedure.   
Data will be monitored as they are submitted to Boston Scientific. Qualified employees of 
Boston Scientific, or a designee under contract, will conduct monitoring visits at the 

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initiation of the study and at interim intervals described in the monitoring plan throughout the 
course of the study to evaluate protocol compliance and determine if there are any issues that 
could affect the safety or welfare of any subject in the study. 
19.3. Anticipated Benefits 
19.3.1. Potential Benefits to the TAVR Procedure 
Transcatheter aortic valve replacement (TAVR) may offer certain advantages when 
compared to surgical replacement of the stenotic native aortic valve, particularly in high risk 
subjects. Known benefits associated with TAVR, as described in the scientific literature (see 
summary in Section 4 of this document and details in Sections 2 and 3 of the investigator 
brochure), potentially include the following. 
• Minimally invasive procedure and reduced risks related to open heart surgery 
• Shorter stay in the intensive care unit and overall hospital stay 
• Reduced blood loss 
• More rapid recovery 
• Reduced need for general anesthesia and associated risks 
• Opportunity to receive a new aortic prosthesis in spite of having been refused surgery 
or being of high surgical risk profile 
19.3.2. Potential Benefit Using the Lotus Valve System 
Potential benefits that may be associated specifically with use of the Lotus™ Valve System 
compared to other TAVR systems include the following. 
• Pre-loaded delivery system minimizing time required and potential issues with 
preparing the device  
• Accurate valve placement due to the ability to reposition the valve during deployment 
• Device is minimally obstructive to the blood flow and maintains hemodynamic 
stability through the annulus during delivery because there is no balloon or other 
obstructive device required for deployment and due to early valve leaflet function 
• Reduced or obviated need for valve-in-valve repeat intervention 
• Reduced incidence of paravalvular aortic regurgitation due to the Adaptive Seal 
19.4. Risk to Benefit Rationale 
Review of the aforementioned clinical benefits versus risks takes into account the known 
risks/benefits that have been identified in the published literature on other TAVR devices. 
The estimation of risk also includes prior limited clinical experience with the predicate Sadra 
Medical TAVR products. When used according to the IFU, all known risks associated with 
the TAVR procedure and the specific use of the Lotus Valve System are mitigated to 
acceptable limits comparable to existing TAVR devices. The design features of full 
repositioning and retrievability may improve TAVR procedural safety. 

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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 prior to the use of any investigational devices, 
study-required procedures and/or testing, or data collection.  
The obtaining and documentation of Informed Consent must be in accordance with the 
principles of the Declaration of Helsinki; the relevant parts of ISO 14155: 2011and the ICH 
guidelines for GCP; 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, 
or central IRB, if applicable. 
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 Boston Scientific 
prior to use of the form. The ICF must be in a language understandable to the subject and if 
needed, Boston Scientific 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.   
The process of obtaining Informed Consent shall: 
• be conducted by the Principal Investigator or designee authorized to conduct the process,  
• include a description of all aspects of the clinical study that are relevant to the subject’s 
decision to participate throughout the clinical study, 
• avoid any coercion of or undue influence of subjects to participate, 
• not waive or appear to waive subject’s legal rights, 
• use native language that is non-technical and understandable to the subject or his/her 
legal representative, 
• provide ample time for the subject to consider participation and ask questions if 
necessary, 
• ensure important new information is provided to new and existing subjects throughout the 
clinical study. 
The ICF shall always be signed and personally dated by the subject or legal representative 
and by the investigator or an authorized designee responsible for conducting the informed 
consent process. If a legal representative signs, the subject shall be asked to provide informed 
consent for continued participation as soon as his/her medical condition allows. The original 
signed ICF will be retained by the center and a copy of the signed and dated document and 
any other written information must be given to the person signing the form.  

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Failure to obtain subject consent will be reported by Boston Scientific to the applicable 
regulatory body according to their requirements. Any violations of the informed consent 
process must be reported as deviations to the sponsor and local regulatory authorities (e.g. 
IRB/EC), as appropriate. 
If new information becomes available that can significantly affect a subject's future health 
and medical care, that information shall be provided to the affected subject(s) in written form 
via a revised ICF or, in some situations, enrolled subjects may be requested to sign and date 
an addendum to the ICF. In addition to new significant information during the course of a 
study, other situations may necessitate revision of the ICF, such as if there are amendments 
to the protocol, a change in Principal Investigator, administrative changes, or following 
annual review by the IRB/EC. The new version of the ICF must be approved by the IRB/EC. 
Boston Scientific Corporation approval is required if changes to the revised ICF are 
requested by the center’s IRB/EC. The IRB/EC will determine the subject population to be 
re-consented. 
 
21. Safety Reporting 
21.1. Definitions and Classification 
Adverse event definitions are provided in Table 21.1-1. 
Table 21.1-1: Adverse Event Definitions 
Term 
Definitiona 
Adverse Event (AE) 
Ref: ISO 14155:2011 
Any untoward medical occurrence, unintended disease or injury or 
untoward clinical signs (including abnormal laboratory findings) in 
subjects, users or other persons, whether or not related to the 
investigational medical device 
Note 1: This definition includes events related to the investigational 
medical device or the comparator. 
Note 2: This definition includes events related to the procedures involved. 
Note 3: For users or other persons, this definition is restricted to events 
related to investigational medical devices. 
Adverse Device Effect (ADE) 
Ref: ISO 14155:2011 
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. 
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 

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Table 21.1-1: Adverse Event Definitions 
Term 
Definitiona 
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, 
• 
Led to foetal distress, foetal death or a congenital abnormality or birth 
defect 
Note: Planned hospitalization for a pre-existing condition, or a procedure 
required by the protocol, without serious deterioration in health, is not 
considered a serious adverse event. 
Serious Adverse Device Effect 
(SADE) 
Ref: ISO 14155:2011 
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 
Serious adverse device effect which by its nature, incidence, severity or 
outcome has not been identified in the current version of the risk analysis 
report  
Note: Anticipated serious adverse device effect (ASADE) is an effect 
which by its nature, incidence, severity or outcome has been identified in 
the risk analysis report. 
Device Deficiency 
Ref: ISO 14155:2011 
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, use errors, and 
inadequate labeling. 
Note 2: All device deficiencies that could have led to a SADE if a) suitable 
action had not been taken or b) if intervention had not been made or c) if 
circumstances had been less fortunate shall be reported as required by the 
local IRB/EC, national regulations, or the protocol.  
a: Other definitions may apply per local reporting requirements. 
 
Underlying diseases are not reported as AEs unless there is an increase in severity or 
frequency during the course of the investigation. Death should not be recorded as an AE, but 
should only be reflected as an outcome of a specific SAE (see Table 21.1-1 for AE 
definitions).  
In-patient hospitalization is defined as the subject being admitted to the hospital, with the 
following exceptions. 
• A hospitalization that is uncomplicated and elective/planned (i.e., planned prior to 
enrollment) does not have to be reported as an SAE. 
• If complications or AEs occur during an elective/planned (i.e., planned prior to 
enrollment) hospitalization after enrollment, the complications and AEs must be reported 
as AEs or SAEs if they meet the protocol-specified definitions.  
Any AE experienced by the study subject beginning from the time of Lotus Introducer sheath 
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Refer to Section 19 for the known risks associated with the study device(s). 
Based on the VARC44,48 recommendations and definitions, the adverse events and/or safety 
endpoints requiring adjudication by the CEC include but are not limited to the following. 
• Mortality: all-cause, cardiovascular, and non-cardiovascular  
• Neurologic event: disabling or non-disabling stroke, and TIAs 
• Myocardial infarction (MI): periprocedural (≤72 hours post index procedure) and 
spontaneous (>72 hours post index procedure) 
• Bleeding events: life-threatening (or disabling), major and minor 
• Acute kidney injury (≤7 days post index procedure): based on AKIN System49,50 Stage 3 
(including renal replacement therapy), Stage 2, and Stage 1  
• Vascular complications: major and minor 
• Repeat procedure for valve-related dysfunction (surgical or interventional therapy)  
• Hospitalization for valve-related symptoms or worsening congestive heart failure (NYHA 
class III or IV) 
• New permanent pacemaker implantation resulting from new or worsened conduction 
disturbances (including new left bundle branch block [LBBB] and third degree 
atrioventricular block) 
• New onset of atrial fibrillation or atrial flutter  
• Coronary obstruction (periprocedural) 
• Ventricular septal perforation (periprocedural) 
• Mitral apparatus damage (periprocedural) 
• Cardiac tamponade (periprocedural) 
• Prosthetic aortic valve malapposition, including valve migration, valve embolization, 
ectopic valve deployment, or transcatheter aortic valve (TAV)-in-TAV deployment 
• Prosthetic aortic valve thrombosis 
• Prosthetic aortic valve endocarditis 
Details on the CEC events and procedures are outlined in the CEC charter.  Tests and images 
required to adjudicate these events are specified in the event definitions (see Table 26.2-1). 
21.2. Relationship to Study Device(s) 
The Investigator must assess the relationship of the AE to the study device as related or 
unrelated. See criteria in Table 21.2-1. 
 

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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. 
• There is a strong relationship to investigational product, or recurs on re-challenge, 
and another etiology is unlikely. 
• There is no other reasonable medical explanation for the event. 
 
21.3. Investigator Reporting Requirements 
The communication requirements for reporting to Boston Scientific 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 electronic case report 
form (eCRF) page with all available 
new and updated information 
• Within 1 business day of first 
becoming aware of the event 
• Beginning from time of Lotus 
Introducer sheath insertion for 
all subjects 
• Terminating at the end of the 
study  
Provide copies of all relevant source 
documents requested by Boston 
Scientific  
• As soon as possible after 
reporting the event 
Serious Adverse Event (SAE) 
including Serious Adverse 
Device Effects (SADE) 
  
Complete AE eCRF page with all 
available new and updated information 
• Within 2 business days of first 
becoming aware of the event or 
as per local/regional regulations. 
• Beginning from time of Lotus 
Introducer sheath insertion for 
all subjects 
• Reporting required through the 
end of the study 
Provide all relevant source 
documentation (unidentified) for 
reported event 
• When documentation is 
available 
Adverse Event (AE) 
Complete AE eCRF page, which 
contains such information as date of 
AE, treatment of AE resolution, 
assessment of seriousness and 
relationship to the device 
• Review with CRA during next 
monitoring visit  
• Beginning from time of Lotus 
Introducer sheath insertion for 
all subjects 
• Reporting required through 

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Table 21.3-1: Investigator Reporting Requirements 
Event Classification 
Communication Method  
Communication Timeline  
12 months  
Device Deficiencies, Failures, 
Malfunctions, and Product 
Nonconformities 
Complete applicable CRF fields/pages 
with all available new and updated 
information. 
• Within 1 business day of first 
becoming aware of the event and 
as per local/regional regulations 
• Beginning from time of Lotus 
Introducer sheath insertion for 
all subjects 
• Reporting required through the 
end of the study 
Abbreviations: AE=adverse event; CRA=clinical research associate; eCRF=electronic case report form; 
SADE=serious adverse device effect; SAE=serious adverse event’ USADE=unanticipated serious adverse 
device effect   
 
21.4. Boston Scientific Device Deficiencies 
All Lotus Valve System device deficiencies (including but not limited to failures, 
malfunctions, use errors, product nonconformities, and labeling errors) must be documented 
on the appropriate eCRF and, if possible, the device should be returned to Boston Scientific 
for analysis. Instructions for returning the investigational device will be provided in the study 
Manual of Operations. 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 
deficiencies should also be documented in the subject’s medical record.  
Device deficiencies and other device issues should not be reported as AEs. Instead, they 
should be reported on the appropriate eCRF. If an AE results from a device deficiency or 
other device issue, the AE must be reported on the appropriate eCRF. 
Device deficiencies that did not lead to an AE but could have led to a SAE if a) suitable 
action had not been taken, or b) intervention had not been made, or c) circumstances had 
been less fortunate must be reported as described in Table 21.3-1. 
21.5. Reporting to Regulatory Authorities / IRBs / ECs / Investigators 
Boston Scientific Corporation will notify all participating study centers if 
SAEs/SADEs/Device Deficiencies occur which imply a possible increase in the anticipated 
risk of the procedure or use of the device or if the occurrence of certain SAEs/SADEs 
requires changes to the protocol or the conduct of the study in order to further minimize the 
unanticipated risks. 
Boston Scientific Corporation is responsible for reporting AE information to all participating 
investigators and regulatory authorities as applicable according to local reporting 
requirements.  

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The PI is responsible for informing the IRB/EC, and regulatory authorities of SADEs, SAEs, 
Device Deficiencies and/or other CEC events as applicable according to local reporting 
requirements. A copy of the Investigator’s reports and other relevant reports (if applicable) to 
the IRB/IEC must be provided to Boston Scientific in accordance with local requirements. 
 
22. Committees 
22.1. Safety Monitoring Process 
To promote early detection of safety issues, the CEC and DMC (see below) will provide 
evaluations of safety events. Success of this program requires dynamic collection of 
unmonitored data as soon as the event is reported. This is expedited through Boston 
Scientific’s Global Safety Office, which is responsible for coordinating the collection of 
information for the subject dossier from the centers and core laboratories. During regularly 
scheduled monitoring visits, clinical research monitors will support the dynamic reporting 
process through their review of source document information. 
22.1.1. Clinical Events Committee  
A CEC will be used in this study. A CEC is an independent group of individuals with 
pertinent expertise, including cardiovascular interventional therapy, cardiovascular surgery, 
and neurology, which reviews and adjudicates important endpoints and relevant adverse 
events reported by study investigators. The CEC will review a safety event dossier, which 
may include copies of subject source documents provided by study sites, and adjudicate 
study endpoint related clinical events. The responsibilities, qualifications, membership, and 
committee procedures of the CEC are outlined in the CEC charter. 
22.1.2. Data Monitoring Committee 
The DMC is responsible for the oversight review of all AEs. The DMC will include leading 
experts in cardiovascular interventional therapy, cardiovascular surgery, and biostatistics 
who are not participating in the study and who have no affiliation with Boston Scientific. 
During the course of the study, the DMC will review accumulating safety data to monitor the 
incidence of CEC events and other trends that would warrant modification or termination of 
the study. Responsibilities, qualifications, membership, and committee procedures are 
outlined in the DMC Charter. 
22.2. Case Review Committee 
A CRC will be comprised of interventional cardiologists and cardiac surgeons, including the 
Study PI, Country PIs, other investigators, Proctors and Medical Consultants experienced in 
TAVR for their clinical/medical expertise; and the Sponsor for technical expertise on the 
Lotus Valve System requirements. This committee will be responsible for the review of 

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subject screening data to confirm eligibility given the high surgical risk subject population 
being studied and to ensure consistency of subjects enrolled across study sites.  
22.3. Steering Committee 
A Steering Committee consisting of Sponsor Clinical Management, the Study Coordinating 
PI, Lead Country PIs, and other investigators experienced in TAVR will be convened. 
Responsibilities may include oversight of the overall conduct of the study with regard to 
protocol development, study progress, subject safety, overall data quality and integrity, as 
well as disseminating any study results through appropriate scientific sessions and 
publications. Steering Committee members may participate in the review and approval of all 
requests for data analysis, abstract and manuscript preparation and submission.  
 
23. Suspension or Termination 
23.1 Premature Termination of the Study 
Boston Scientific Corporation reserves the right to terminate the study at any stage but 
intends to exercise this right only for valid scientific or administrative reasons and reasons 
related to protection of subjects.  Investigators, associated IRBs/ECs, and regulatory 
authorities, as applicable, will be notified in writing in the event of study termination. 
23.1.1 Criteria for Premature Termination of the Study 
Possible reasons for premature study termination include, but are not limited to, the 
following. 
• The occurrence of unanticipated adverse device effects that present a significant or 
unreasonable risk to subjects enrolled in the study. 
• An enrollment rate far below expectation that prejudices the conclusion of the study.  
• A decision on the part of Boston Scientific to suspend or discontinue development of the 
device. 
23.2 Termination of Study Participation by the Investigator or Withdrawal of IRB/EC 
Approval 
Any investigator or IRB/EC in the REPRISE II study may discontinue participation in the 
study or withdrawal approval of the study, respectively, with suitable written notice to 
Boston Scientific. Investigators, associated IRBs/ECs, and regulatory authorities, as 
applicable, will be notified in writing in the event of these occurrences. 

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23.3 Requirements for Documentation and Subject Follow-up 
In the event of premature study termination a written statement as to why the premature 
termination has occurred will be provided to all participating centers by Boston Scientific. 
The IRB/EC and regulatory authorities, as applicable, will be notified. Detailed information 
on how enrolled subjects will be managed thereafter will be provided.  
In the event an IRB/EC terminates participation in the study, participating investigators, 
associated IRBs/ECs, and regulatory authorities, as applicable, will be notified in writing. 
Detailed information on how enrolled subjects will be managed thereafter will be provided 
by Boston Scientific. 
In the event an investigator terminates participation in the study, study responsibility will be 
transferred to a co-investigator, if possible. In the event there are no opportunities to transfer 
investigator responsibility; detailed information on how enrolled subjects will be managed 
thereafter will be provided by Boston Scientific. The investigator must return all documents 
and investigational product to Boston Scientific, unless this action would jeopardize the 
rights, safety, or welfare of the subjects. 
23.4 Criteria for Suspending/Terminating a Study Center 
Boston Scientific Corporation reserves the right to stop the inclusion of subjects at a study 
center at any time after the study initiation visit if no subjects have been enrolled or if the 
center has multiple or severe protocol violations/noncompliance without justification and/or 
fails to follow remedial actions. 
In the event of termination of investigator participation, all study devices and testing 
equipment, as applicable, will be returned to Boston Scientific unless this action would 
jeopardize the rights, safety or well-being of the subjects. The IRB/EC and regulatory 
authorities, as applicable, should be notified. All subjects enrolled in the study at the center 
will continue to be followed per this protocol. The Principal Investigator at the center must 
make provision for these follow-up visits unless Boston Scientific notifies the investigational 
center otherwise. 
 
24. Publication Policy 
In accordance with the Corporate Policy on the Conduct of Human Subject Research, Boston 
Scientific requires disclosure of its involvement as a sponsor or financial supporter in any 
publication or presentation relating to a Boston Scientific study or its results. In accordance 
with the Corporate Policy for the Conduct of Human Subject Research, Boston Scientific 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 

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outcomes, Boston Scientific 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. 
• Boston Scientific involvement in the publication preparation and the Boston Scientific 
Publication Policy should be discussed with the Coordinating Principal Investigator(s) 
and/or 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.  
 
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Varadarajan P, Kapoor N, Bansal RC, Pai RG. Survival in elderly patients with severe 
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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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Osten MD, Feindel C, Greutmann M, et al. Transcatheter aortic valve implantation for 
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10. Stohr R, Dohmen G, Herpertz R, et al. Thirty-day outcome after transcatheter aortic 
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11. Buchanan GL, Chieffo A, Montorfano M, et al. The role of sex on VARC outcomes 
following transcatheter aortic valve implantation with both Edwards SAPIEN and 
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12. Buellesfeld L, Gerckens U, Schuler G, et al. 2-year follow-up of patients undergoing 
transcatheter aortic valve implantation using a self-expanding valve prosthesis. J Am 
Coll Cardiol 2011;57:1650-7. 
13. Tamburino C, Barbanti M, Capodanno D, et al. Comparison of complications and 
outcomes to one year of transcatheter aortic valve implantation versus surgical aortic 
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14. Buellesfeld L, Stortecky S, Heg D, et al. Impact of permanent pacemaker implantation 
on clinical outcome among patients undergoing transcatheter aortic valve implantation. J 
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15. Jilaihawi H, Chakravarty T, Weiss RE, Fontana GP, Forrester J, Makkar RR. Meta-
analysis of complications in aortic valve replacement: comparison of Medtronic-
Corevalve, Edwards-Sapien and surgical aortic valve replacement in 8,536 patients. 
Catheter Cardiovasc Interv 2012;80:128-38. 
16. 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. 
17. 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. 
18. 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. 
19. 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 
registry of transcatheter aortic valve implantation using the Edwards SAPIEN valve. 
Circulation 2011;124:425-33. 
20. Lefevre 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. 
21. 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 
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22. 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. 
23. 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. 
24. 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. 
25. 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. 
26. 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. 
27. 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. 
28. 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. 
29. 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. 
30. 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. 
31. 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. 
32. Webb JG, Chandavimol M, Thompson CR, et al. Percutaneous aortic valve implantation 
retrograde from the femoral artery. Circulation 2006;113:842-50. 
33. Webb JG, Pasupati S, Humphries K, et al. Percutaneous transarterial aortic valve 
replacement in selected high-risk patients with aortic stenosis. Circulation 
2007;116:755-63. 
34. Grube E, Laborde JC, Gerckens U, et al. Percutaneous implantation of the CoreValve 
self-expanding valve prosthesis in high-risk patients with aortic valve disease: the 
Siegburg first-in-man study. Circulation 2006;114:1616-24. 
35. Grube E, Schuler G, Buellesfeld L, et al. Percutaneous aortic valve replacement for 
severe aortic stenosis in high-risk patients using the second- and current third-generation 
self-expanding CoreValve prosthesis: device success and 30-day clinical outcome. J Am 
Coll Cardiol 2007;50:69-76. 
36. Baan J, Yong ZY, Koch KT, et al. Percutaneous implantation of the CoreValve aortic 
valve prosthesis in patients at high risk or rejected for surgical valve replacement: 

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Clinical evaluation and feasibility of the procedure in the first 30 patients in the AMC-
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following CoreValve or Edwards transcatheter aortic valve implantation: results of the 
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38. Stortecky S, Windecker S, Pilgrim T, et al. Cerebrovascular accidents complicating 
transcatheter aortic valve implantation: frequency, timing and impact on outcomes. 
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39. Lange R, Bleiziffer S, Piazza N, et al. Incidence and treatment of procedural 
cardiovascular complications associated with trans-arterial and trans-apical 
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41. Buellesfeld L, Wenaweser P, Gerckens U, et al. Transcatheter aortic valve implantation: 
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42. Piazza N, Lange R, Martucci G, Serruys PW. Patient selection for transcatheter aortic 
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43. van Mieghem NM, Head SJ, van der Boon RM, et al. The SURTAVI model: proposal 
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44. Leon MB, Piazza N, Nikolsky E, et al. Standardized endpoint definitions for 
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46. Chodor P, Wilczek K, Przybylski R, et al. Immediate and 6-month outcomes of 
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aortic stenosis. Kardiol Pol 2010;68:1124-31. 
47. Meredith IT. The repositionable Lotus Aortic Valve Replacement System: six-month 
outcomes in the REPRISE I feasibility study. In: ACC. San Francisco, CA USA  2013. 
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for transcatheter aortic valve implantation: the valve academic research consortium-2 
consensus document. J Am Coll Cardiol 2012;60:1438-54. 

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57. Studenski S, Perera S, Patel K, et al. Gait speed and survival in older adults. JAMA 
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58. Afilalo J, Mottillo S, Eisenberg MJ, et al. Addition of frailty and disability to cardiac 
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59. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype. 
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63. Ye J, Cheung A, Lichtenstein SV, et al. Transapical transcatheter aortic valve 
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64. Mehran R, Rao SV, Bhatt DL, et al. Standardized bleeding definitions for cardiovascular 
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66. Durack DT, Lukes AS, Bright DK. New criteria for diagnosis of infective endocarditis: 
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67. Thygesen K, Alpert JS, White HD. Universal definition of myocardial infarction. Eur 
Heart J 2007;28:2525-38. 
68. 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. 
69. 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 
AVR 
aortic valve replacement 
BARC 
Bleeding Academic Research Consortium 
BMI 
body mass index 
CBC 
complete blood count 
CPB 
cardiopulmonary bypass 
CRA 
clinical research associate  

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Table 26.1-1: Abbreviations and Acronyms 
Abbreviation/Acronym 
Definition 
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 
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 

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Table 26.1-1: Abbreviations and Acronyms 
Abbreviation/Acronym 
Definition 
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.  See Table 26.1-1for abbreviations. 
Table 26.2-1: Definitions 
Term 
Definition 
ACUTE KIDNEY 
INJURY (AKI) 
(AKIN  System49,50) 
Change in serum creatinine (up to 7 days) compared to baseline: 
• Stage 1: Increase in serum creatinine to 150–199% (1.5–1.99 × increase compared 
with baseline) OR increase of ≥0.3 mg/dl (≥26.4 mmol/L)  
• Stage 2: Increase in serum creatinine to 200–299% (2.0–2.99 × increase compared 
with baseline) 
• Stage 3: Increase in serum creatinine to ≥300% (>3 × increase compared with 
baseline) OR serum creatinine of ≥4.0 mg/dL (≥354 mmol/L) with an acute 
increase of at least 0.5 mg/dL (44 mmol/L) 
-OR-  
Based on urine output (up to 7 days): 
• Stage 1: <0.5 ml/kg per hour for >6 but <12 hours 
• Stage 2: <0.5 ml/kg per hour for >12 but <24 hours 
• Stage 3: <0.3 ml/kg per hour for ≥24 hours or anuria for ≥12 hours 
Note 1: Subjects receiving renal replacement therapy are considered to meet Stage 3 
criteria irrespective of other criteria. 
ACUTE VESSEL 
OCCLUSION 
The state of complete luminal obstruction with no antegrade blood flow 
ADVERSE EVENT 
(AE) 
Any untoward medical occurrence, unintended disease or injury or untoward clinical 
signs (including abnormal laboratory findings) in subjects, users or other persons, 
whether or not related to the investigational medical device. 
Note 1: This definition includes events related to the investigational medical device or 
the comparator. 
Note 2: This definition includes events related to the procedures involved. 
Note 3: For users or other persons, this definition is restricted to events related to 
investigational medical devices. 
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. 

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Table 26.2-1: Definitions 
Term 
Definition 
AORTIC 
DISSECTION 
Intimal tear resulting in blood splitting the aortic media and producing a false lumen 
that can progress in an antegrade or retrograde direction Aortic dissection is further 
classified using Stanford classification (Types A and B depending on whether 
ascending or descending aorta involved) or DeBakey classification (Types I, II and 
III) [see Figure below]. 
 
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. 
BLEEDING44,48   
Life-threatening or Disabling Bleeding 

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Table 26.2-1: Definitions 
Term 
Definition 
• Fatal bleeding (Bleeding Academic Research Consortium [BARC] type 564,65) 
• 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 

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Table 26.2-1: Definitions 
Term 
Definition 
CORONARY 
OBSTRUCTION 
 
Angiographic or echocardiographic evidence of a new, partial or complete, 
obstruction of a coronary ostium, either by the valve prosthesis itself, the native 
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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Table 26.2-1: Definitions 
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 1 44 
• 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 2 48 
• 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 criteria66 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 

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Table 26.2-1: Definitions 
Term 
Definition 
a primary focus  
 
-OR-  
o Microorganisms consistent with infective endocarditis from persistently positive 
blood cultures defined as noted below. 
▪ Two (2) positive cultures of blood samples drawn >12 hours apart -OR-   
▪ All of 3 or a majority of 4 separate cultures of blood (with first and last 
sample drawn 1 hour apart)  
• Evidence of endocardial involvement 
o Positive echocardiogram for infective endocarditis defined as noted below. 
▪ Oscillating intracardiac mass on valve or supporting structures, in the path of 
regurgitant jets, or on implanted material in the absence of an alternative 
anatomic explanation -OR-   
▪ Abscess -OR-   
▪ New partial dehiscence of prosthetic valve  
 
-OR-  
o New valvular regurgitation (worsening or changing of preexisting murmur not 
sufficient) 
Minor Criteria 
• Predisposition: predisposing heart condition or intravenous drug use 
• Fever: temperature >38.0° C (100.4° F) 
• Vascular phenomena: major arterial emboli, septic pulmonary infarcts, mycotic 
aneurysm, intracranial hemorrhage, conjunctival hemorrhages, and Janeway 
lesions 
• Immunologic phenomena: glomerulonephritis, Osler's nodes, Roth spots, and 
rheumatoid factor 
• Microbiological evidence: positive blood culture but does not meet a major 
criterion as noted above or serological evidence of active infection with organism 
consistent with infective endocarditis 
• Echocardiographic findings: consistent with infective endocarditis but do not meet 
a major criterion as noted above  
Implanted valve endocarditis includes any infection involving an implanted valve. 
The diagnosis of operated valvular endocarditis is based on one of the following 
criteria.  
• Fulfillment of the Duke endocarditis criteria as defined above 
• Evidence of abscess, paravalvular leak, pus, or vegetation confirmed as secondary 
to infection by histological or bacteriologic studies during a re-operation 
• Findings of abscess, pus, or vegetation involving a repaired or replaced valve 
during an autopsy. 
EXPLANT 
Removal of 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: 

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Table 26.2-1: Definitions 
Term 
Definition 
• Abnormal chest wall anatomy due to severe kyphoscoliosis or other skeletal 
abnormalities (including thoracoplasty, Potts’ disease) 
• Complications from prior surgery 
• Evidence of severe radiation damage (e.g. skin burns, bone destruction, muscle 
loss, lung fibrosis or esophageal stricture) 
• History of multiple recurrent pleural effusions causing internal adhesions 
INTERNAL 
MAMMARY 
ARTERY OR OTHER 
CRITICAL 
CONDUIT(S) 
CROSSING 
MIDLINE AND/OR 
ADHERENT TO 
POSTERIOR TABLE 
OF STERNUM 
A patent IMA graft that is adherent to the sternum such that injuring it during 
reoperation is likely. A patient may be considered extreme risk if any of the following 
are present:  
• The conduit(s) are radiographically indistinguishable from the posterior table of the 
sternum.  
• The conduit(s) are radiographically distinguishable from the posterior table of the 
sternum but lie within 2-3mm of the posterior table.  
INTRACRANIAL 
HEMORRHAGE 
Collection of blood between the brain and skull; subcategorized as epidural, subdural, 
and subarachnoid bleeds. 
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 
Periprocedural MI (≤72 hours after the index procedure) 

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Table 26.2-1: Definitions 
Term 
Definition 
INFARCTION (MI) 
 
• New ischemic symptoms (e.g., chest pain or shortness of breath) or new ischemic 
signs (e.g., ventricular arrhythmias, new or worsening heart failure, new ST-
segment changes, hemodynamic instability, new pathological Q waves in at least 
two contiguous leads, or imaging evidence of new loss of viable myocardium or 
new wall motion abnormality)  
 
-AND- 
• Elevated cardiac biomarkers (preferably CK-MB) within 72 h after the index 
procedure, consisting of at least one sample post-procedure with a peak value 
exceeding 15× upper reference limit (troponin) or 5× for CK-MB. If cardiac 
biomarkers are increased at baseline (>99th percentile), a further increase of at 
least 50% post-procedure is required AND the peak value must exceed the 
previously stated limit. 
Spontaneous MI (>72 hours after the index procedure) 
Any one of the following criteria applies. 
• Detection of rise and/or fall of cardiac biomarkers (preferably troponin) with at 
least one value above the 99th percentile URL, together with evidence of 
myocardial ischemia with at least one of the following 
o Symptoms of ischemia 
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 infarction67. 
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 
Any abnormality not intrinsic to the valve itself that results in stenosis or 
regurgitation of the operated valve or hemolysis. The term nonstructural dysfunction 

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Table 26.2-1: Definitions 
Term 
Definition 
DYSFUNCTION 
 
refers to problems (exclusive of thrombosis and infection) that do not directly involve 
valve components yet result in dysfunction of an operated valve, as diagnosed by re-
operation, autopsy, or clinical investigation. Nonstructural dysfunction includes the 
following. 
• Entrapment by pannus, tissue, or suture 
• Paravalvular leak 
• Inappropriate sizing or positioning 
• Residual leak or obstruction after valve implantation or repair 
• Clinically important intravascular hemolytic anemia 
• Development of aortic or pulmonic regurgitation as a result of technical errors 
• Dilatation of the sinotubular junction 
• 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 

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Table 26.2-1: Definitions 
Term 
Definition 
procedure. 
RESPIRATORY 
INSUFFICIENCY 
Inadequate ventilation or oxygenation 
RESPIRATORY 
FAILURE 
The need for ventilatory support for >72 hours associated with an inability to wean 
from the respirator for any reason. 
RIGHT 
VENTRICULAR 
INSUFFICIENCY 
• Defined as sequelae of right ventricular failure including the following. 
o Significantly decreased right ventricular systolic and/or diastolic function 
o Tricuspid valvular regurgitation secondary to elevated pressure 
• Clinical symptoms to include the following. 
o Hepatic congestion 
o Ascites 
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 resulted in the following. 
• Led to a death 
• Led to serious deterioration in the health of the subject, that resulted in one or more 
of the following. 
o Life-threatening illness or injury 
o Permanent impairment of a body structure or a body function 
o In-patient or prolonged hospitalization 
o Medical or surgical intervention to prevent life- threatening illness or injury or 
permanent impairment to a body structure or a body function, 
• Led to fetal distress, fetal death or a congenital abnormality or birth defect 
Note 1: Planned hospitalization for a pre-existing condition, or a procedure required 
by the protocol, without serious deterioration in health, is not considered a serious 
adverse event. 
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.  
STROKE44,48  
 
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.  

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Table 26.2-1: Definitions 
Term 
Definition 
• Hemorrhagic Stroke is defined as an acute episode of focal or global cerebral or 
spinal dysfunction caused by an intraparenchymal, intraventricular, or 
subarachnoid hemorrhage 
Note 1: The CEC will adjudicate ischemic versus hemorrhagic stroke. 
Note 2: A stroke may be classified as undetermined if there is insufficient information 
to allow categorization as ischemic or hemorrhagic 
Stroke Diagnostic Criteria  
• Rapid onset of a focal or global neurological deficit with at least one of the 
following: change in level of consciousness, hemiplegia, hemiparesis, numbness or 
sensory loss affecting one side of the body, dysphasia or aphasia, hemianopia, 
amaurosis fugax, or other neurological signs or symptoms consistent with stroke 
• Duration of a focal or global neurological deficit ≥24 h; OR <24 h, if  available 
neuroimaging documents a new hemorrhage or infarct; OR the neurological deficit 
results in death 
• No other readily identifiable nonstroke cause for the clinical presentation (e.g., 
brain tumor, trauma, infection, hypoglycemia, peripheral lesion, pharmacological 
influences), to be determined by or in conjunction with designated neurologist 
• Confirmation of the diagnosis by at least one of the following.  
o Neurology or neurosurgical specialist  
o Neuroimaging procedure (MRI or CT scan), but stroke may be diagnosed on 
clinical grounds alone 
Note 3: Subjects with non-focal global encephalopathy will not be reported as a 
stroke without unequivocal evidence based upon neuroimaging studies (CT scan or 
brain MRI).  
Stroke Definitions 
Diagnosis as above, preferably with positive neuroimaging study 
• Non-disabling: Modified Rankin Scale (mRS) score <2 at 90 days OR one that 
does not result in an increase of at least one mRS category from an individual’s 
pre-stroke baseline 
• Disabling: Modified Rankin Scale score ≥2 at 90 days AND an increase of at least 
one mRS category from an individual’s pre-stroke baseline  
Note 4: Modified Rankin Scale assessments should be made by qualified individuals 
according to a certification process.  
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  

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Table 26.2-1: Definitions 
Term 
Definition 
• 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 
MALAPPOSITION 
Includes valve migration, valve embolization, ectopic valve deployment, or 
transcatheter aortic valve (TAV)-in-TAV deployment. 
VALVE MIGRATION 
After initial correct positioning the valve prosthesis moves upward or downward 
within the aortic annulus from its initial position, with or without consequences (e.g., 
regurgitation). 
VALVE-RELATED 
DYSFUNCTION 
Mean aortic valve gradient ≥20 mmHg, EOA ≤0.9-1.1 cm2, and/or DVI <0.35 
AND/OR moderate or severe prosthetic valve aortic regurgitation (per VARC 
definition) 
VALVE-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, 

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Table 26.2-1: Definitions 
Term 
Definition 
major bleeding, visceral ischaemia or neurological impairment 
• Any new ipsilateral lower extremity ischemia documented by patient symptoms, 
physical exam, and/or decreased or absent blood flow on lower extremity 
angiogram 
• Surgery for access site-related nerve injury 
• Permanent access site-related nerve injury 
Minor Vascular Complications 
• Access site or access-related vascular injury (dissection, stenosis, perforation, 
rupture, arterio-venous fistula, pseudoaneurysms , hematomas, percutaneous 
closure device failure*) not leading to death, life-threatening or major bleeding**, 
visceral ischaemia or neurological impairment 
• Distal embolization treated with embolectomy and/or thrombectomy and not 
resulting in amputation or irreversible end-organ damage 
• Any unplanned endovascular stenting or unplanned surgical intervention not 
meeting the criteria for a major vascular complication 
• Vascular repair or the need for vascular repair (via surgery, ultrasound-guided 
compression, transcatheter embolization, or stent-graft) 
*Percutaneous Closure Device Failure 
Failure of a closure device to achieve hemostasis at the arteriotomy site leading to 
alternative treatment (other than manual compression or adjunctive endovascular 
ballooning) 
Note 1: Pre-planned surgical access or a planned endovascular approach to vascular 
closure (e.g., “pre-closure”)68,69 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 
27.1.2. Protocol Version AB to Version AC 
Table 27.1-2 lists changes between protocol versions AB and AC. 
27.1.3. Protocol Version AC to Version AD 
Table 27.1-3 lists changes between protocol versions AC and AD. 
27.1.4. Protocol Version AD to Version AE 
Table 27.1-4 lists changes between protocol versions AD and AE. 
27.1.5. Protocol Version AE to Version AF 
Table 27.1-5 lists changes between protocol versions AE and AF. 

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Table 27.1-1: Table of Changes for REPRISE II Protocol Version AB (Compared to REPRISE II Protocol Version AA) 
Section 
Modified 
Text as Written in  
REPRISE II Protocol Version AA 
Text as Written in  
REPRISE II Protocol Version AB 
Justification for 
Modification 
Page 2 
Original Release: 05-June-2012 
Current Version: 07-August-2012 
Revision History 
Revision 
Number 
Release Date 
Reason for Change 
AB 
07-Aug-2012 
See Appendix 1 
Protocol updated 
based on VARC 2 
manuscript 
specifications 
2. Protocol 
Synopsis 
Additional 
Measurements 
Additional measurements based on the VARCa,b endpoints and 
definitions (see Table 17.2-1 in the Appendix for definitions)… 
Additional measurements based on the VARCa,b endpoints and 
definitions (see Table 26.2-1for definitions)… 
Corrected table 
number 
Mortality: all-cause, cardiovascular, and procedure-related 
Mortality: all-cause, cardiovascular, and non-cardiovascular 
Updated per VARC-2 
manuscript 
Composite of all-cause mortality and stroke 
Composite of all-cause mortality and disabling stroke 
Acute kidney injury (≤72 hours post index procedure): based on 
the modified RIFLE Stage 3… 
Acute kidney injury (≤72 hours post index procedure): based on 
the AKIN System Stage 3… 
Failure of current therapy for aortic stenosis: requiring 
hospitalization for valve-related symptoms or worsening 
congestive heart failure, NYHA class III or IV 
Hospitalization for valve-related symptoms or worsening 
congestive heart failure (NYHA class III or IV) 
New permanent pacemaker implantation resulting from new 
conduction… 
New permanent pacemaker implantation resulting from new or 
worsened conduction… 
Functional status as evaluated by the New York Heart 
Association (NYHA) classification and Modified Rankin Scale 
 
• Functional status as evaluated by the following: 
o  5-m gait speed test (at 1 year compared to baseline)  
o  New York Heart Association (NYHA) classification and 
Modified Rankin Scale 
• Neurological status as determined by the following: 
o  National Institutes of Health Stroke Scale (NIHSS) at 
discharge and 1 year  
o  Modified Rankin Scale (mRS) 
Updated per VARC-2 
manuscript and  for 
clarity 
Note 1: … all-cause mortality, disabling stroke, life-
threatening/disabling bleeding, acute kidney injury Stage 3 
(including renal replacement therapy), periprocedural MI, major 
… 
Note 1: … all-cause mortality, all  stroke, life-threatening 
bleeding, acute kidney injury Stage 2 or 3 (including renal 
replacement therapy), coronary artery obstruction requiring 
intervention, major … 
Updated per VARC-2 
manuscript 

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Table 27.1-1: Table of Changes for REPRISE II Protocol Version AB (Compared to REPRISE II Protocol Version AA) 
Section 
Modified 
Text as Written in  
REPRISE II Protocol Version AA 
Text as Written in  
REPRISE II Protocol Version AB 
Justification for 
Modification 
Note 2: … mortality (after 30 days); disabling stroke; failure … 
prosthetic heart valve dysfunction (indexed effective orifice area 
<0.85 cm2,/m2 [≤0.7 cm2/m2 for BMI ≥30 kg/m2] and either a 
mean aortic valve gradient ≥20 mm Hg or a peak velocity 
≥3m/sec, OR moderate or severe prosthetic valve aortic 
regurgitation). 
Note 2: … mortality (after 30 days); all stroke; failure … 
prosthetic heart valve dysfunction (mean aortic valve gradient 
≥20 mm Hg, effective orifice area ≤0.9-1.1 cm2, and/or Doppler 
velocity index (DVI) <0.35 AND/OR moderate or severe 
prosthetic valve aortic regurgitation [per VARC definition]). 
Note 3: ... bleeding (unless clearly unrelated to valve therapy). 
Note 3: ... bleeding (unless clearly unrelated to valve therapy 
based on investigator assessment). 
Note 4: For subjects diagnosed with a neurological event (e.g., 
stroke, transient ischemic attack), a neurological physical exam, 
NIHSS assessment, and mRS must be performed after the event; 
mRS must also be administered at 90 days post-neurological 
event.   
a: Serruys P, et al. (2012) VARC Clinical Research Updates: 
Important Changes from VARC-2. Transcatheter Valve 
Therapeutics, Seattle, USA. 
a: Serruys P, et al. (2012) VARC Clinical Research Updates: 
Important Changes from VARC-2. Transcatheter Valve 
Therapeutics, Seattle, USA (manuscript pending publication). 
2. Protocol 
Synopsis 
Adjunctive 
Pharmacologic 
Therapy 
Anticoagulant therapy (e.g., unfractionated heparin) per local 
standard of care must be administered prior to the implant… 
Anticoagulant therapy (e.g., unfractionated heparin) per local 
standard of care must be administered during the implant… 
Per TAVR guideline 
recommendations 
Aspirin 
The loading dose... implant procedure. 
Clopidogrel 
The loading dose... implant procedure. 
 
c: Holmes, D. R., et al. J Am Coll Cardiol. 2012;59:1200 
Aspirin 
The loading dose… implant procedure or immediately after. 
Clopidogreld 
The loading dose... implant procedure or immediately after 
c:  Holmes, D. R., et al. J Am Coll Cardiol. 2012;59:1200 
d:  An alternative P2Y12 inhibitor may be prescribed if subject is 
allergic to or intolerant of clopidogrel. 
Updated for clarity 
and to allow use of 
alternative P2Y12 
inhibitors 
2. Protocol 
Synopsis 
Exclusion 
Criteria 
EC 11. …either aspirin or clopidogrel/ticlopidine. 
 
EC 11. …either aspirin or clopidogreld 
d:  An alternative P2Y12 inhibitor may be prescribed if subject is 
allergic to or intolerant of clopidogrel. 
3. Table of 
Contents 
Table of Contents 
- 8.3 Justification for the Study Design 
Table of Contents 
- 8.3Study Design  Justification 
- Section 27. Appendices 
Updated for clarity: 
Sections 4.2 and 8.3 
had the same title 
Updated to reflect 

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Table 27.1-1: Table of Changes for REPRISE II Protocol Version AB (Compared to REPRISE II Protocol Version AA) 
Section 
Modified 
Text as Written in  
REPRISE II Protocol Version AA 
Text as Written in  
REPRISE II Protocol Version AB 
Justification for 
Modification 
addition of appendix 
with table of changes. 
4.1 
Justification… 
Table 4.1-1 references 
Table 4.1-1 MACCE column 
Table 4.1-1 Title 
Table 4.1-1 updated with additional  references 
Table 4.1-1: replaced MACCE column with “Vascular 
Complications” column 
Table 4.1-1 Title: Removed “MACCE” 
Added newer 
references  
Use of individual 
measurements rather 
than the composite 
MACCE to better 
compare across 
studies  
5.1.1 Lotus 
valve 
The maximum height of both valve sizes in the deployed state is 
19 mm. 
The frame height of both valve sizes in the deployed state is 
approximately 19 mm. 
Updated for clarity 
7.3 Additional 
Measurements 
Additional measurements … and Table 17.2-1 in the Appendix 
for definitions… 
Additional measurements … and Table 26.2-1 in the Appendix 
for definitions… 
Corrected table 
number 
Mortality: all-cause, cardiovascular, and procedure-related  
Mortality: all-cause, cardiovascular, and non-cardiovascular 
Updated per VARC-2 
manuscript 
Composite of all-cause mortality and stroke 
Composite of all-cause mortality and disabling stroke 
Acute kidney injury (≤72 hours post index procedure): based on 
the modified RIFLE Stage… 
Acute kidney injury (≤72 hours post index procedure): based on 
the AKIN System Stage… 
Failure of current therapy for aortic stenosis: requiring 
hospitalizations for valve-related symptoms or worsening 
congestive heart failure NYHA class III or IV 
Hospitalization for valve-related symptoms or worsening 
congestive heart failure (NYHA class III or IV) 
New permanent pacemaker implantation resulting from new 
conduction… 
New permanent pacemaker implantation resulting from new or 
worsened conduction… 
Functional status as evaluated by the New York Heart 
Association (NYHA) classification and Modified Rankin Scale 
 
• Functional status as evaluated by the following: 
o 5-m gait speed test35 (at 1 year compared to baseline)  
o New York Heart Association (NYHA) classification 
• Neurological status as determined by the following: 
o National Institutes of Health Stroke Scale (NIHSS) at 
discharge and 1 year  
o Modified Rankin Scale (mRS) 
Updated per VARC-2 
manuscript and to 
add clarity 

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Table 27.1-1: Table of Changes for REPRISE II Protocol Version AB (Compared to REPRISE II Protocol Version AA) 
Section 
Modified 
Text as Written in  
REPRISE II Protocol Version AA 
Text as Written in  
REPRISE II Protocol Version AB 
Justification for 
Modification 
Note 1: The VARC safety composite at 30 days (including all-
cause mortality, disabling stroke, life-threatening/disabling 
bleeding, acute kidney injury, peri-procedural MI, major 
vascular complication, and repeat procedure for valve-related 
dysfunction) will be reported.  
Note 1: The VARC safety composite at 30 days will be reported. 
This includes all-cause mortality, all stroke, life-threatening 
bleeding, acute kidney injury Stage 2 or 3, coronary artery 
obstruction requiring intervention, major vascular complication, 
and repeat procedure for valve-related dysfunction.  
Note 2: The VARC efficacy composite at 1 year (including all-
cause mortality [after 30 days], disabling stroke, failure of 
current therapy for aortic stenosis [requiring hospitalizations for 
valve-related symptoms or worsening congestive heart failure, 
NYHA class III or IV], and prosthetic heart valve dysfunction 
[indexed effective orifice area <0.85 cm2/m2 (≤0.7 cm2/m2 for 
BMI≥30 kg/m2) and either a mean aortic valve gradient 
≥20 mm Hg or a peak velocity ≥3m/sec, OR moderate or severe 
prosthetic valve aortic regurgitation]) will be reported.  
Note 2: The VARC efficacy composite at 1 year will be reported. 
This includes all-cause mortality (after 30 days), all stroke, 
requiring hospitalizations for valve-related symptoms or 
worsening congestive heart failure (NYHA class III or IV), and 
prosthetic heart valve dysfunction (mean aortic valve gradient 
≥20 mm Hg, effective orifice area ≤0.9-1.1 cm2 and/or Doppler 
velocity index [DVI] <0.35, AND/OR moderate or severe 
prosthetic valve aortic regurgitation [per VARC definition]) 
Note 3: ... bleeding (unless clearly unrelated to valve therapy). 
Note 3:... bleeding (unless clearly unrelated to valve therapy 
based on investigator assessment). 
Note 4: For subjects diagnosed with a neurological event (e.g., 
stroke, transient ischemic attack), a neurological physical exam, 
NIHSS assessment, and mRS must be performed after the event; 
mRS must also be administered at 90 days post-neurological 
event.   
Note 5: The VARC clinical efficacy composite includes the need 
for hospitalization associated with valve-related symptoms or 
worsening congestive heart failure (CHF) as a basis for 
calculation of a “days alive outside the hospital” endpoint. This 
includes 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 

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Table 27.1-1: Table of Changes for REPRISE II Protocol Version AB (Compared to REPRISE II Protocol Version AA) 
Section 
Modified 
Text as Written in  
REPRISE II Protocol Version AA 
Text as Written in  
REPRISE II Protocol Version AB 
Justification for 
Modification 
related to seizure or tachyarrhythmia. 
8.3. Justification 
8.3 Justification for the Study Design 
In order to support the stated objectives of this study (see Section 
4) while also limiting… 
In addition to the risk-benefit analysis noted above (see Section 
4.0), ongoing… 
8.3 Study Design Justification  
In order to support the stated objectives of this study (see 
Section 6) while also limiting… 
In addition to the risk-benefit analysis noted in Section 4.2 (see 
also Section 19), ongoing… 
Updated for clarity 
9.3 Exclusion 
Criteria 
EC 11. Subject … or clopidogrel/ticlopidine (subjects … or 
clopidogrel/ticlopidine). 
EC17. 
Subject has untreated clinically significant coronary 
artery disease 
EC24. Subject has a preexisting conduction system… 
 
EC 11. Subject … or clopidogrel (subjects … or clopidogrel).* 
EC17. 
Subject has untreated coronary artery disease, which in 
the opinion of the treating physician, is clinically significant and 
requires requiring revascularization. 
EC24. Subject has a preexisting untreated conduction system… 
* An alternative P2Y12 inhibitor may be prescribed if subject is 
allergic to or intolerant of clopidogrel. 
Updated for clarity 
and to allow use of 
alternative P2Y12 
inhibitors 
11. Study 
Methods  
Figure 11.1-1 REPRISE Study Design 
Figure 11.1-1 REPRISE Study Design 
Updated figure to add symbols for Gait Speed assessment at 1 
year and post-deployment aortogram 
Updated for clarity 
and/or per VARC 2 
manuscript 
11. Study 
Methods 
Table 11.1-1 
Table 11.1-1 Study Event Schedule 
 
Table 11.1-1 Study Event Schedule 
Added row for post-deployment aortogram and “X” in 
“procedure” column 
Added “X” in 12-Month column for gait speed    
a: No later than 10 days prior to the index procedure(unless 
otherwise specified) 
a: It is recommended that screening occur no later than 10 days 
prior to the index procedure (unless otherwise specified); results 
from these assessments should be submitted to the CRC at least 
10 days prior to the planned procedure to allow for adequate 
scheduling of subject review at a CRC meeting. 
c: … Visits should be an office/clinical visit… 
c: … Visits must be an office/clinical visit… 
e:   Neurological …  For subjects diagnosed with any 
neurological event (stroke, transient ischemic attack, and 
encephalopathy), a neurological physical exam and NIHSS 
should also be performed.  mRS must also be administered at 30 
and 90 days post-neurological event.   
e:   Neurological …  For subjects diagnosed with a neurological 
event (e.g., stroke, transient ischemic attack), a neurological 
physical exam, mRS and NIHSS should also be performed; mRS 
must also be administered at 90 days post-neurological event.   

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Table 27.1-1: Table of Changes for REPRISE II Protocol Version AB (Compared to REPRISE II Protocol Version AA) 
Section 
Modified 
Text as Written in  
REPRISE II Protocol Version AA 
Text as Written in  
REPRISE II Protocol Version AB 
Justification for 
Modification 
f: … Heart rhythm strip should be obtained… 
f: … Heart rhythm strip must be obtained… 
i:   Frailty… and comorbidity (Charlson Index).   
i:   Frailty… and comorbidity (Charlson Index); at 1 year, gait 
speed to walk 5 meters must be assessed again. 
o: Annual imaging… frame integrity. If additional …; data 
should be provided for analysis. 
o: Annual imaging… frame integrity must be performed. If 
additional…; data may be provided for analysis. 
r: Final post-deployment aortogram of the ascending aorta 
should be performed and sent to the CT Core Laboratory. 
r: final post-deployment aortogram of the ascending aorta 
should be performed and sent to the CT Core Laboratory. 
Note that with the addition of this line there is a change in the 
subsequent footnote labeling: “r” becomes “s” and “s” becomes 
“t.” 
Added abbreviation information for AKI, CRC, and mRS  
t:  Device deficiencies, SAEs… 
t:  Device deficiencies (for the Lotus Valve System), SAEs… 
j:  Transthoracic… guidelines (see study Manual of Operations).  
If TTE image quality is suboptimal, transesophageal Doppler 
echocardiography (TEE) may be substituted.  
j:  Transthoracic… guidelines (see study Manual of Operations).   TEE will not provide 
all data needed for 
comparisons with 
TTE data. 
 
g:  Laboratory tests at baseline include CBC, platelet count, 
LDH, haptoglobin, serum creatinine, cardiac enzymes, and 
international normalized ratio if subject is on warfarin. 
g:  Laboratory tests at baseline include CBC, platelet count, 
LDH, haptoglobin, serum creatinine, and cardiac enzymes. 
…. Acute kidney injury (AKI) should be assessed through 
discharge/7 days based on the AKIN system. 
Removed because 
INR assessment is 
standard of care. 
Added reference to 
AKI per VARC 2 
manuscript 
11.4 Screening 
Assessments 
Specific data points will be collected… 
o   A CT angiogram … aortic root dimensions for device sizing.  
It must be performed … measurements and analyses... 
o Either a CT or invasive angiogram ... 
o Figure 11.4 1 shows … valve size (e.g., aortic annulus 
diameter of 23–24mm). 
Sites will be trained on the screening process as detailed in the 
REPRISE II Training Plan (see Section 17.4.1). Specific data 
points will be collected… 
o   A CT angiogram … aortic root dimensions to determine 
eligibility and device sizing. It must be performed … 
measurements and independent analyses... 
o Either a CT or invasive angiogram … for independent 
measurements and review by the CRC to confirm subject’s 
eligibility. 
o Figure 11.4 1 shows … valve size. 
Revised for clarity. 

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Table 27.1-1: Table of Changes for REPRISE II Protocol Version AB (Compared to REPRISE II Protocol Version AA) 
Section 
Modified 
Text as Written in  
REPRISE II Protocol Version AA 
Text as Written in  
REPRISE II Protocol Version AB 
Justification for 
Modification 
Physical examination including weight and height (body mass 
index), and NYHA classification 
o Physical examination including weight and height 
o NYHA classification 
Revised for clarity. 
Sites do not have to 
provide BMI. 
…for independent analyses. If TTE image quality is suboptimal, 
transesophageal Doppler echocardiography (TEE) may be 
substituted. 
…for independent analyses. 
TEE will not provide 
all data needed for 
comparisons with 
TTE data. 
11.5 Baseline 
Assessments 
• Neurological physical examination, which must be performed 
by a neurologist or neurology fellow independent of the study 
• NIH Stroke Scale (NIHSS), which must be performed by 
certified personnel (external certification) independent of the 
study  
•Modified Rankin Score, which must be performed by certified 
personnel (external or internal certification) independent of the 
study 
• Neurological physical examination, which must be performed 
by a neurologist or neurology fellow; assessors should be 
independent of the study 
• NIH Stroke Scale (NIHSS), which must be performed by 
certified personnel (external certification); assessors should be 
independent of the study 
• Modified Rankin Scale score, which must be performed by 
certified personnel (external or internal certification); assessors 
should be independent of the study 
Revised for clarity. 
Note that similar 
changes are made in 
Sections 11.9, 
11.10.1, 11.10.2, 
11.10.3, 11.10.4, and 
11.10.5 
Laboratory Tests 
- International normalized ratio (INR) if subject is on warfarin  
Laboratory Tests 
 
Removed because 
INR assessment is 
standard of care. 
11.6 
Preprocedure 
Medications 
• Antiplatelet therapy …  
Aspirin 
A loading dose … prior to the implant procedure...  
Clopidogrel 
A loading dose … prior to the implant procedure. 
Ticlopidine can be prescribed as an alternative if subject is 
allergic or intolerant to clopidogrel.  
 
• Anticoagulant therapy … care prior to the implant procedure… 
• Antiplatelet therapy …   
Aspirin 
A loading dose… prior to the implant procedure or immediately 
after…  
Clopidogrel 
A loading dose … prior to the implant procedure or immediately 
after. 
Note 1: An alternative P2Y12 inhibitor can be prescribed as an 
alternative if subject is allergic to or intolerant of clopidogrel.  
• Anticoagulant therapy … care during the implant procedure… 
Updated for clarity 
and to allow use of 
alternative P2Y12 
inhibitors. 
11.7.2 
Valvuloplasty 
Information on the balloon valvuloplasty, including number of 
inflations, will be recorded in the eCRFs. 
Information on the balloon valvuloplasty, including number of 
inflations, should be documented in the source data and will be 
captured in the eCRFs. 
Updated for clarity 

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Table 27.1-1: Table of Changes for REPRISE II Protocol Version AB (Compared to REPRISE II Protocol Version AA) 
Section 
Modified 
Text as Written in  
REPRISE II Protocol Version AA 
Text as Written in  
REPRISE II Protocol Version AB 
Justification for 
Modification 
11.7.3 Preparing 
and Using the 
Lotus Valve 
System 
The following summarizes the Lotus Valve System procedure... 
9) A final post-deployment aortogram of the ascending aorta 
should be performed. 
The following information will be collected during the 
procedure. 
• 
Descriptive information on balloon valve annuloplasty … 
• 
Heart rhythm after balloon valvuloplasty… 
• 
Adverse event (AE) assessment (including … 
• 
Device deficiencies assessment  
The following summarizes the Lotus Valve System procedure… 
9) A final post-deployment aortogram of the ascending aorta 
should be performed and forwarded to the Core Laboratory for 
analysis. 
The following information will be collected during the 
procedure. 
• 
Descriptive information on balloon valve annuloplasty … 
• 
Any devices used and adjunctive procedures performed 
during implant procedure  
• 
Heart rhythm after balloon valvuloplasty with rhythm 
strip… 
• 
Adverse event (AE) assessment and associated treatment 
(including … 
• 
Device deficiencies assessment (for the Lotus Valve 
System) 
11.8 Post-
Procedure 
• 
After the Lotus valve implant procedure, aspirin …must be 
given… 
• 
After the Lotus valve implant procedure, clopidogrel is 
required… Ticlopidine can be prescribed as an alternative if 
subject is allergic to or intolerant of clopidogrel. 
 
  
After the Lotus valve implant procedure, aspirin …should be 
given… 
 
After the Lotus valve implant procedure, clopidogrel is 
recommended ... 
Note: An alternative P2Y12 inhibitor (e.g. ticlopidine) can be 
prescribed as an alternative if subject is allergic to or intolerant of 
clopidogrel.  
Updated for clarity 
and to allow use of 
alternative P2Y12 
inhibitors 
11.9 Prior to 
Discharge… 
 
…based on the assessments below.  
 
• 
Complete adverse … device deficiencies assessment  
…based on the assessments below. The REPRISE II eCRFs 
identify the specific data points to be collected. 
• Physical examination including weight and height 
• Complete adverse … device deficiencies assessment (with 
associated treatment) 
Updated for clarity. 
Note that similar 
changes are made in 
Sections 11.10.1, 
11.10.2, 11.10.3, 
11.10.4, 11.10.5  
See also changes 
made in Section 11.5. 

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Table 27.1-1: Table of Changes for REPRISE II Protocol Version AB (Compared to REPRISE II Protocol Version AA) 
Section 
Modified 
Text as Written in  
REPRISE II Protocol Version AA 
Text as Written in  
REPRISE II Protocol Version AB 
Justification for 
Modification 
11.9 and 
11.10 Follow-up 
11.10.1, 11.10.2, 
11.10.3,  
11.10.4, 11.10.5  
TTE… independent analyses. If TTE image quality is 
suboptimal, transesophageal Doppler echocardiography (TEE) 
may be substituted. 
 
TTE… independent analyses. 
 
 
Data are acquired 
using TTE; TEE will 
not provide all data 
needed for 
comparisons 
11.10 Follow-up 
Each follow-up visit … personnel and data … will be recorded in 
the eCRFs. 
Each follow-up visit … personnel; data …will be recorded in 
source documentation and captured in the eCRFs. 
Revised for clarity 
11.10.4 12-
Month  
 
- Gait speed to walk 5 meters  
Added per VARC-2 
manuscript 
11.10.5 Annual 
Follow-up 
- Complete adverse event (AE, SAE, SADE, …deficiencies 
assessment  
- Complete serious adverse event (SAE, SADE, …deficiencies 
assessment (with associated treatment) 
Adverse events are 
not collected beyond 
12 months. 
11.10.7 
Procedure… 
• Documentation of … next of kin, including one that confirms 
the subject is lost to follow-up 
• Documentation of … next of kin 
Revised for clarity. 
11.10.9 Explant 
Procedure 
If a Lotus Valve is explanted during conventional scheduled or 
emergent surgical valve replacement or during an autopsy, please 
refer to the study Manual of Operations for recommendations on 
the explant procedure and shipment of the explanted valve to an 
independent histopathology core laboratory for macroscopic and 
microscopic analyses. 
Information on the explant procedure must be documented in the 
Explant Form of the eCRFs. 
If a Lotus Valve is explanted during conventional scheduled or 
emergent surgical valve replacement or during an autopsy, if 
possible, the explanted valve should be sent to an independent 
histopathology core laboratory for macroscopic and microscopic 
analyses. Please refer to the study Manual of Operations for 
recommendations on the explant procedure and shipment of the 
explanted valve.  
Information on the explant procedure must be documented in 
source notes and captured in the Explant Form of the eCRFs. 
11.12 Source 
Documents 
Where copies… are retained, these shall be signed… 
It is preferable that original source documents (see Table 26.2-
1for definition) are maintained. Where copies… are retained, 
these should be signed… 
12.1.1.2 Sample 
Size 
…and 60 enrolled subjects. Enrollment of the additional 60 
subjects is planned… 
…and 60 enrolled subjects. Enrollment of a total of 120 subjects 
is planned… 
12.2.1 Analysis 
Sets 
…The primary safety endpoint will be evaluated along with 
additional endpoints and measurements on an ITT basis… 
…The primary safety endpoint will be evaluated on an ITT 
basis… 

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Table 27.1-1: Table of Changes for REPRISE II Protocol Version AB (Compared to REPRISE II Protocol Version AA) 
Section 
Modified 
Text as Written in  
REPRISE II Protocol Version AA 
Text as Written in  
REPRISE II Protocol Version AB 
Justification for 
Modification 
13.3.2 CT and 
Rotational… 
An independent Core Laboratory will centrally assess all of the 
CT and rotational X-ray data in this study. These analyses… 
An independent Core Laboratory will centrally assess all of the 
CT and rotational X-ray data in this study to reduce variability. 
These analyses… 
16 Device 
Accountability 
The principal investigator … shall keep records … which shall 
include the following. 
The principal investigator … shall keep records … which shall 
include the following; this will be verified by BSC personnel. 
17.4 Sponsor 
Responsibilities 
All data used in the analysis and reporting of this study will be 
without identifiable reference to specific subject name. 
Data used in the analysis and reporting of this study will not be 
identified by specific subject name. 
17.4.1 Training 
The Sponsor is responsible for providing Investigators with the 
information and training they need to conduct the study properly 
and in accordance with the Clinical Protocol and Training Plan. 
The Sponsor is responsible for providing Investigators with the 
information and training they need to conduct the study properly 
and in accordance with the Training Plan. 
21.1 Definitions 
and 
Classification 
• Mortality: all-cause, cardiovascular, and procedure-related 
• Acute kidney injury (≤72 hours post index procedure): based 
on modified RIFLE… 
• Failure of current therapy for aortic stenosis: requiring 
hospitalization for valve-related symptoms or worsening 
congestive heart failure, NYHA class III or IV 
• New permanent pacemaker implantation resulting from new 
conduction… 
• Mortality: all-cause, cardiovascular, and non-cardiovascular 
• Acute kidney injury (≤72 hours post index procedure): based 
on AKIN System… 
• Hospitalization for valve-related symptoms or worsening 
congestive heart failure, NYHA class III or IV 
• New permanent pacemaker implantation resulting from new or 
worsened conduction… 
Updated per VARC-2 
manuscript 
21.4 Boston 
Scientific 
Device 
Deficiencies 
All Lotus Valve System device deficiencies … should be 
documented on the appropriate eCRF….  
…If an AE results from a device deficiency or other device issue, 
the AE should be reported on the appropriate eCRF. 
Device deficiencies that did not lead to an AE but … fortunate 
should be reported as described in Table 21.3-1. 
All Lotus Valve System device deficiencies … must be 
documented on the appropriate eCRF….  
…If an AE results from a device deficiency or other device issue, 
the AE must be reported on the appropriate eCRF. 
Device deficiencies that did not lead to an AE but … fortunate 
must be reported as described in Table 21.3-1. 
Revised for clarity 
25. Bibliography 
 
Updated to include the additional references added to Table 4.1-1 
Newer references  
26.1 
Abbreviations 
 
Updated to includes additional abbreviations and remove some 
not used 
Revised for clarity 
Table 26.2-1 
Definitions 
ACUTE 
KIDNEY 
INJURY  
(Modified 
RIFLE 
Classificatio
n) 
• Stage 1: … to 150–199% (1.5–2.0 times 
increase compared with baseline) or 
increase of ≥0.3 mg/dl (≥26.4 μmol/L)  
• Stage 2: … to 200–299% (2.0–3.0 times 
increase compared with baseline) 
• Stage 3: … serum creatinine of ≥4.0 mg/dL 
ACUTE 
KIDNEY 
INJURY 
(AKI) 
(AKIN  
System) 
• Stage 1: … to 150–199% (1.5–1.99 × 
increase compared with baseline) OR 
increase of ≥0.3 mg/dl (≥26.4 mmol/L)  
• Stage 2: … to 200–299% (2.0–2.99 × 
increase compared with baseline) 
• Stage 3: … serum creatinine of ≥4.0 mg/dL 
Updated per VARC-2 
manuscript 

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Table 27.1-1: Table of Changes for REPRISE II Protocol Version AB (Compared to REPRISE II Protocol Version AA) 
Section 
Modified 
Text as Written in  
REPRISE II Protocol Version AA 
Text as Written in  
REPRISE II Protocol Version AB 
Justification for 
Modification 
(≥354 μmol/L) with an acute increase of at 
least 0.5 mg/dL (44 μmol/L) 
… urine output (up to 7 days): 
• Stage 1: … more than 6 hours 
• Stage 2: … more than 12 hours 
• Stage 3: Less than 0.5 ml/kg per hour for 
more than 24 hours or anuria 
(≥354 mmol/L) with an acute increase of at 
least 0.5 mg/dL (44 mmol/L) 
… urine output (up to 7 days): 
• Stage 1: …>6 but <12 hours 
• Stage 2: … >12 but <24 hours 
• Stage 3: <0.3 ml/kg per hour for ≥24 hours 
or anuria for ≥12 hours 
ARRHYTH
MIA 
… major arrhythmias. 
… The therapeutic approach to new-onset AF 
should be documented (spontaneous, electrical 
or medical cardioversion, limitation of oral 
anticoagulation and rate or rhythm control). 
 
ARRHYTH
MIA 
… 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]).  
…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. 
BLEEDING  
Life-threatening or Disabling Bleeding 
• Fatal bleeding -OR- 
• … compartment syndrome -OR- 
• … surgery -OR- 
• Overt… units 
Major Bleeding 
• Overt … blood/RBC -AND- 
Minor Bleeding 
 
BLEEDING  Life-threatening or Disabling Bleeding 
• Fatal bleeding (Bleeding Academic 
Research Consortium [BARC] type 5) 
• … compartment syndrome (BARC type 3b 
and 3c)  
• … surgery (BARC type 3b)  
• Overt… units (BARC type 3b) 
Major Bleeding (BARC type 3a) 
• Overt … blood/RBC, or causing 
hospitalization or permanent injury, or 
requiring surgery … 
Minor Bleeding (BARC type 2 or 3a, 
depending on the severity) 

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Table 27.1-1: Table of Changes for REPRISE II Protocol Version AB (Compared to REPRISE II Protocol Version AA) 
Section 
Modified 
Text as Written in  
REPRISE II Protocol Version AA 
Text as Written in  
REPRISE II Protocol Version AB 
Justification for 
Modification 
 
CONDUCT
ION 
DISTURBA
NCES  
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. 
CONVERSI
ON TO 
OPEN 
SURGERY 
Conversion to open sternotomy during the 
TAVR procedure secondary to any procedure-
related complications 
 
DEATH  
Cardiovascular Death 
• … or other vascular disease  
Procedure-Related Death  
Death related to valve implantation that 
occurs within 48 hours of index procedure 
 
DEATH  
Cardiovascular Death 
• … 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) 
 

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Table 27.1-1: Table of Changes for REPRISE II Protocol Version AB (Compared to REPRISE II Protocol Version AA) 
Section 
Modified 
Text as Written in  
REPRISE II Protocol Version AA 
Text as Written in  
REPRISE II Protocol Version AB 
Justification for 
Modification 
DEVICE 
MIGRATIO
N 
…from its original implant location confirmed 
by X-ray, echocardiography, CT scan or MRI 
or valve migration demonstrated by direct 
assessment during open heart surgery or at 
autopsy. 
 
DEVICE 
MIGRATIO
N 
… 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 … 
 
 
FRAILTY 
Slowness, weakness, exhaustion, wasting and 
malnutrition, poor endurance and inactivity, 
loss of independence.  
 
HOSTILE 
CHEST 
Any of the following or other reasons that 
make redo operation through sternotomy or 
right anterior thoracotomy prohibitively 
hazardous: 
• Abnormal chest wall anatomy due to 
severe kyphoscoliosis or other skeletal 
abnormalities (including thoracoplasty, 
Potts’ disease 
• Complications from prior surgery 
• Evidence of severe radiation damage (e.g. 
skin burns, bone destruction, muscle loss, 
lung fibrosis or esophageal stricture) 
• History of multiple recurrent pleural 
effusions causing internal adhesions 
 
INTERNAL 
MAMMAR
Y 
ARTERY… 
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 

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Section 
Modified 
Text as Written in  
REPRISE II Protocol Version AA 
Text as Written in  
REPRISE II Protocol Version AB 
Justification for 
Modification 
posterior table.  
 
LIVER 
DISEASE 
(SEVERE) 
/CIRRHOSI
S 
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 
MYOCARDI
AL 
INFARCTIO
N (MI) 
 
Periprocedural MI (≤72 hours after the 
index procedure) 
• … hemodynamic instability, or imaging…   
 
-AND- 
• Elevated … consisting of 2 or more post-
procedure samples that are >0.6 to 8 h 
apart with a 20% increase in the second 
sample and a peak value exceeding 15× 
the 99th percentile URL (troponin), or a 
peak value exceeding 5× the 99th 
percentile URL (CK-MB) with new 
pathological Q waves in at least 2 
contiguous leads 
Spontaneous MI (>72 hours after the 
index procedure) 
• … cardiac biomarkers with at least … 
following 
o ECG changes … 
 
MYOCAR
DIAL 
INFARCTI
ON (MI) 
 
Periprocedural MI (≤72 hours after the 
index procedure) 
• … hemodynamic instability, new 
pathological Q waves in at least two 
contiguous leads, or imaging … 
 
-AND- 
• Elevated … 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) 
• … cardiac biomarkers (preferably troponin) 
with at least … following 
o Symptoms of ischemia 
o ECG … 
PARAVAL
VULAR 
LEAK  
(as 
measured by 
Leakage due… Diagnosis of paravalvular leak 
may be obtained from TEE, however…  
PARAVAL
VULAR 
REGURGIT
ATION  
 
Leakage due … Diagnosis of paravalvular 
regurgitation may be obtained from 
TEE/TTE; however… 
Revised for clarity 

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Table 27.1-1: Table of Changes for REPRISE II Protocol Version AB (Compared to REPRISE II Protocol Version AA) 
Section 
Modified 
Text as Written in  
REPRISE II Protocol Version AA 
Text as Written in  
REPRISE II Protocol Version AB 
Justification for 
Modification 
TEE) 
 
PERMANE
NT 
PACEMAK
ER (PPM) 
IMPLANTA
TION  
Implantation … new conduction 
disturbances… 
• Procedure-related: … new onset 
conduction disturbances… 
 
PERMANE
NT 
PACEMAK
ER (PPM) 
IMPLANT
ATION  
Implantation … new or worsened conduction 
disturbances … 
• Procedure-related: … new onset or 
worsened conduction disturbances… 
Note: See also definitions for arrhythmia and 
conductance disturbance. 
Updated per VARC-2 
manuscript. 
Added per VARC-2 
manuscript. 
 
PORCELAI
N AORTA 
Heavy circumferential calcification of the 
entire ascending aorta extending to the arch 
such that aortic cross-clamping is not feasible 
RIGHT 
VENTRIC
ULAR 
INSUFFICI
ENCY 
• Defined as … 
o Edema 
 
RIGHT 
VENTRIC
ULAR 
INSUFFICI
ENCY 
• Defined as … 
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.  
STROKE 
 
Stroke is an acute symptomatic episode of 
neurological dysfunction attributed to a 
vascular cause. 
Subclassifications of stroke 
• Ischemic Stroke is defined as an acute 
symptomatic episode ...  
• Hemorrhagic Stroke … acute symptomatic 
episode of focal … caused by a nontraumatic 
intraparenchymal… 
Note 1: The CEC will adjudicate ischemic 
versus hemorrhagic stroke. 
Stroke diagnostic criteria…  
• Duration of a focal or global neurological 
deficit ≥24 h; OR <24 h, if therapeutic 
intervention(s) were performed (e.g. 
thrombolytic therapy or intracranial 
angioplasty); OR available neuroimaging 
STROKE44,4
8   
 
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....  
• Hemorrhagic Stroke … acute episode of 
focal … caused by an intraparenchymal… 
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…  
• Duration of a focal or global neurological 

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Table 27.1-1: Table of Changes for REPRISE II Protocol Version AB (Compared to REPRISE II Protocol Version AA) 
Section 
Modified 
Text as Written in  
REPRISE II Protocol Version AA 
Text as Written in  
REPRISE II Protocol Version AB 
Justification for 
Modification 
documents a new hemorrhage or infarct; OR 
the neurological deficit results in death 
• No other … influences) 
• Confirmation … 
o Neuroimaging procedure (MRI or CT 
scan or cerebral angiography) 
o Lumbar puncture (i.e., spinal fluid 
analysis diagnostic of intracranial 
hemorrhage) 
Note 2: Subjects … neuroimaging studies.  
Stroke definitions  
Diagnosis as above, preferably with positive 
neuroimaging study 
• Non-disabling: Modified Rankin score 
(MRS) <2 at 90 days OR an increase in 
MRS of ≤1.  
• Disabling: Modified Rankin score ≥2 at 90 
days AND an increase in MRS of ≥1.  
Note 3: Modified Rankin score assessments 
should be made by qualified individuals 
according to a certification process. If there is 
discordance between the 30 and 90 day 
Modified Rankin scores, a final determination 
of major versus minor stroke will be 
adjudicated by the CEC. 
 
deficit ≥24 h; OR <24 h, if  available 
neuroimaging documents a new 
hemorrhage or infarct; OR the neurological 
deficit results in death 
• No other … influences), to be determined 
by or in conjunction with designated 
neurologist 
• Confirmation … 
o Neuroimaging procedure (MRI or CT 
scan), but stroke may be diagnosed on 
clinical grounds alone 
Note 3: Subjects … 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. 
STRUCTU
RAL 
VALVE 
DETERIOR
• Valve-related dysfunction: indexed 
effective orifice area <0.85 cm2/m2 [≤0.7 
cm2/m2 for BMI≥30 kg/m2] and mean 
aortic valve gradient ≥20 mmHg or peak 
STRUCTU
RAL 
VALVE 
DETERIOR
Component of time-related valve safety 
defined as follows: 
• Valve-related dysfunction: Mean aortic 
valve gradient ≥20 mmHg, EOA 

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Table 27.1-1: Table of Changes for REPRISE II Protocol Version AB (Compared to REPRISE II Protocol Version AA) 
Section 
Modified 
Text as Written in  
REPRISE II Protocol Version AA 
Text as Written in  
REPRISE II Protocol Version AB 
Justification for 
Modification 
ATION  
velocity ≥3 m/s, or moderate or severe 
prosthetic valve regurgitation) 
 
ATION  
≤0.9-1.1 cm2, and/or DVI <0.35 AND/OR 
moderate or severe prosthetic valve 
regurgitation (per VARC definition) 
TAV-IN-
TAV 
DEPLOYM
ENT 
An additional valve prosthesis is implanted 
within a previously implanted prosthesis 
because of suboptimal device position and 
function during or after the index procedure. 
TAV-IN-
TAV 
DEPLOYM
ENT 
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. 
TRANSIEN
T 
ISCHEMIC 
ATTACK 
(TIA) 
• New focal neurological deficit with rapid 
symptom resolution (usually 1 to 2 h), 
always within 24 hours 
• Neuroimaging without tissue injury (if 
performed) 
 
TRANSIEN
T 
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. 
 
UNPLANN
ED USE OF 
CPB 
Unplanned use of cardiopulmonary bypass 
(CPB) for hemodynamic support at any time 
during the TAVR procedure 
VALVE 
MIGRATIO
N 
After initial correct positioning the valve 
prosthesis moves upward or downward within 
the aortic annulus from its initial position, 
with or without regurgitation. 
 
VALVE 
MIGRATIO
N 
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 
DYSFUNC
TION 
Prosthetic heart valve dysfunction includes 
indexed effective orifice area <0.85 cm2/m2 
[≤0.7 cm2/m2 for BMI≥30 kg/m2] and either a 
mean aortic valve gradient ≥20 mm Hg or a 
peak velocity ≥3m/sec, OR moderate or 
severe prosthetic valve aortic regurgitation. 
VALVE-
RELATED 
DYSFUNC
TION 
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 
The need for hospitalization associated with 
valve-related symptoms or worsening CHF 

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Table 27.1-1: Table of Changes for REPRISE II Protocol Version AB (Compared to REPRISE II Protocol Version AA) 
Section 
Modified 
Text as Written in  
REPRISE II Protocol Version AA 
Text as Written in  
REPRISE II Protocol Version AB 
Justification for 
Modification 
SYMPTOM
S/CHF 
REQUIRIN
G 
HOSPITAL
IZATION 
(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. 
VASCULA
R ACCESS 
SITE AND 
ACCESS 
RELATED 
COMPLIC
ATIONS 
Major Vascular Complications 
• Any thoracic aortic dissection 
• Access site … compartment syndrome) 
leading to either death, need for significant 
blood transfusions (≥4 units), unplanned 
percutaneous or surgical intervention, or 
irreversible end-organ damage (e.g., 
hypogastric artery occlusion causing 
visceral ischemia or spinal artery injury 
causing neurologic impairment) 
• Distal embolization (non-cerebral) from a 
vascular source requiring surgery or 
resulting in amputation or irreversible end-
organ damage 
Minor Vascular Complications 
• Access site or access-related vascular 
injury (dissection, stenosis, perforation, 
VASCULAR 
ACCESS 
SITE AND 
ACCESS 
RELATED 
COMPLICA
TIONS 
Major Vascular Complications 
• Any aortic dissection, aortic rupture, 
annulus rupture, left ventricle perforation, 
or new apical aneurysm/pseudoaneurysm  
• Access site … 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 

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Table 27.1-1: Table of Changes for REPRISE II Protocol Version AB (Compared to REPRISE II Protocol Version AA) 
Section 
Modified 
Text as Written in  
REPRISE II Protocol Version AA 
Text as Written in  
REPRISE II Protocol Version AB 
Justification for 
Modification 
rupture, arterio-venous fistula, or 
pseudoaneurysm requiring compression or 
thrombin injection therapy, or hematoma 
requiring transfusion of ≥2 but <4 units) 
not requiring unplanned percutaneous or 
surgical intervention and not resulting in 
irreversible end-organ damage 
Distal embolization treated with embolectomy 
and/or thrombectomy and not resulting in 
amputation or irreversible end-organ damage 
Closure Device Failure 
Failure of percutaneous access site closure 
resulting in interventional (e.g., stent-graft) or 
surgical correction and not associated with 
death, need for significant blood transfusions 
(≥4 units), or irreversible end-organ damage. 
Pre-planned surgical access or prophylactic 
endovascular approach …  
 
• Any new ipsilateral lower extremity 
ischemia documented by patient 
symptoms, physical exam, and/or 
decreased or absent blood flow on lower 
extremity angiogram 
• Surgery for access site-related nerve 
injury 
• Permanent access site-related nerve injury 
Minor Vascular Complications 
• Access site or access-related vascular 
injury (dissection, stenosis, perforation, 
rupture, arterio-venous fistula, 
pseudoaneurysms , hematomas, 
percutaneous closure device failure*) not 
leading to death, life-threatening or major 
bleeding**, visceral ischaemia or 
neurological impairment 
• Distal embolization treated with 
embolectomy and/or thrombectomy and 
not resulting in amputation or irreversible 
end-organ damage 
• Any unplanned endovascular stenting or 
unplanned surgical intervention not 
meeting the criteria for a major vascular 
complication 
• Vascular repair or the need for vascular 
repair (via surgery, ultrasound-guided 
compression, transcatheter embolization, 
or stent-graft) 
*Percutaneous Closure Device Failure 
Failure of a closure device to achieve 
hemostasis at the arteriotomy site leading to 
alternative treatment (other than manual 
compression or adjunctive endovascular 
ballooning) 
Note 1: Pre-planned surgical access or a 

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Table 27.1-1: Table of Changes for REPRISE II Protocol Version AB (Compared to REPRISE II Protocol Version AA) 
Section 
Modified 
Text as Written in  
REPRISE II Protocol Version AA 
Text as Written in  
REPRISE II Protocol Version AB 
Justification for 
Modification 
planned endovascular approach to vascular 
closure (e.g., “pre-closure”)52,5368,69 should 
be considered as part of the TAVR 
procedure and not as a complication, unless 
untoward clinical consequences are 
documented (e.g., bleeding complications, 
limb ischemia, distal embolization, or 
neurological impairment). 
Note 2: If unplanned percutaneous or 
surgical intervention does not lead to adverse 
outcomes this is not considered a major 
vascular complication.  
** Refers to VARC bleeding definitions 
 
VENTRIC
ULAR 
SEPTAL 
PERFORA
TION 
Angiographic or echocardiographic evidence 
of a new septal perforation during or after the 
TAVR procedure 
27. Appendices 
 
27.1-1 Changes-Protocol Version AA to Version AB 
Table 27.1-1 lists changes between protocol versions AA and AB 
Added Table 27.1-1. 
Added to show 
document version 
changes. 
 
Table 27.1-2: Table of Changes for REPRISE II Protocol Version AC (Compared to REPRISE II Protocol Version AB) 
Section 
Modified 
Text as Written in  
REPRISE II Protocol Version AB 
Text as Written in  
REPRISE II Protocol Version AC 
Justification for 
Modification 
2. Protocol 
Synopsis 
Exclusion… 
EC 17 … treating physician and/or heart team, is clinically... 
EC 17 … treating physician, is clinically... 
 
Updated for clarity  
11. Study 
Methods  
Figure 11.1-1 REPRISE Study Design 
Figure 11.1-1 REPRISE Study Design 
Updated symbol for procedural cine-angiography at index 
procedure. 

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Table 27.1-2: Table of Changes for REPRISE II Protocol Version AC (Compared to REPRISE II Protocol Version AB) 
Section 
Modified 
Text as Written in  
REPRISE II Protocol Version AB 
Text as Written in  
REPRISE II Protocol Version AC 
Justification for 
Modification 
11. Study 
Methods 
Table 11.1-1 
o: Annual imaging… must be performed. If additional...  
 
o: Annual imaging… must be performed. Results must be 
forwarded to the CT/X-Ray Core Laboratory for analysis. If 
additional… 
 
r: Final post-deployment aortogram of the ascending aorta 
should be performed and sent to the CT Core Laboratory. 
r: Procedural cine-angiogram including final post-deployment 
aortogram of the ascending aorta should be sent to the CT/X-
Ray Core Laboratory for analysis. 
11.7.3 Preparing 
and Using … 
9) A final post-deployment aortogram … forwarded to the Core 
Laboratory for analysis. 
9) A final post-deployment aortogram … forwarded with the 
procedural cine-angiogram to the Core Laboratory for analysis. 
27. Appendices 
 
27.1-2 Changes-Protocol Version AB to Version AC 
Table 27.1-2 lists changes between protocol versions AB and AC 
Added Table 27.1-2. 
Added to show 
document version 
changes. 
 
 
Table 27.1-3: Table of Changes for REPRISE II Protocol Version AD (Compared to REPRISE II Protocol Version AC) 
Section 
Modified 
Text as Written in  
REPRISE II Protocol Version AC 
Text as Written in  
REPRISE II Protocol Version AD 
Justification for 
Modification 
2. Protocol 
Synopsis, 
Exclusion 
Criteria and 
Section 9.3 
Exclusion 
Criteria  
EC1. Subject has a unicuspid or bicuspid aortic valve. 
EC1.  Subject has a congenital unicuspid or bicuspid aortic 
valve. 
Updated for clarity. 
2. Protocol 
Synopsis 
Adjunctive 
Pharmacologic 
Therapy 
 
and Section 11.6 
Preprocedure 
Medications 
Note 2: If a subject requires chronic anticoagulation (e.g., 
warfarin, dabigatran, etc.), either clopidogreld or aspirin is 
required in addition to the anticoagulant therapy post-
procedure (but both aspirin and clopidogrel are not 
required). 
 
Note 2: If a subject requires chronic anticoagulation (e.g., 
warfarin, dabigatran, etc.), either clopidogreld or aspirin is 
required prior to and after implant procedure in addition to 
the anticoagulant therapy post-procedure (but both aspirin 
and clopidogrel are not required). 
 
Note 3: If a subject requires chronic anticoagulation (e.g., 
warfarin, dabigatran, etc.), either clopidogrel or aspirin is 
required prior to implant procedure (but both aspirin and 
Updated for clarity 
and to account for 
local practice.  

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Table 27.1-3: Table of Changes for REPRISE II Protocol Version AD (Compared to REPRISE II Protocol Version AC) 
Section 
Modified 
Text as Written in  
REPRISE II Protocol Version AC 
Text as Written in  
REPRISE II Protocol Version AD 
Justification for 
Modification 
clopidogrel are not required). 
11. Study 
Methods 
Table 11.1-1 
 
 
 
and Section 11.4 
Screening 
Assessments 
l: A coronary angiogram must be performed within 180 days 
prior to the index procedure and should be performed 
within 90 days, if possible, to assess extent of aortic 
stenosis and coronary artery status. 
 
 
o A coronary angiogram must be performed within 180 days 
prior to the index procedure and should be performed within 
90 days, if possible; simultaneous aortogram and 
hemodynamics indicating ascending aorta/left ventricle 
(AO/LV) pressure measurements should be performed to 
assess the extent of aortic stenosis and coronary artery status. 
l: A coronary angiogram must be performed within 365 days 
prior to the index procedure. If there is concern regarding 
the current extent of coronary artery disease or aortic 
stenosis, the Case Review Committee may recommend a 
repeat study closer to the time of enrollment.  
 
o  A coronary angiogram must be performed within 365 days 
prior to the index procedure. If there is concern regarding the 
current extent of coronary artery disease or aortic stenosis, 
the Case Review Committee may recommend a repeat 
study closer to the time of enrollment. An aortogram and 
hemodynamics including simultaneous ascending aorta and left 
ventricle pressure measurements should be performed during 
the cardiac catheterization. 
Expanded window 
allowed for coronary 
angiogram so as to 
minimize the need 
for unnecessary 
repetition of invasive 
tests in an elderly 
patient population 
while still ensuring 
that adequate 
assessment of 
coronary artery 
disease and aortic 
stenosis is performed. 
Note that similar 
change is made in 
Section 11.4 
Screening 
Assessments 
(Imaging 
assessments).  
 
 
Table 27.1-4: Table of Changes for REPRISE II Protocol Version AE (Compared to REPRISE II Protocol Version AD) 
Section 
Modified 
Text as Written in  
REPRISE II Protocol Version AD 
Text as Written in  
REPRISE II Protocol Version AE 
Justification for 
Modification 
2. Protocol 
Synopsis, 
Sample Size 
Parameters 
• 
Test significance level () = 0.05 (1-sided) 
• 
Power ≥ 90% 
 
• 
Test significance level () = 0.025 (1-sided) 
• 
Power ≥ 80% 
Updated per 
regulatory agency 
request. 

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Table 27.1-4: Table of Changes for REPRISE II Protocol Version AE (Compared to REPRISE II Protocol Version AD) 
Section 
Modified 
Text as Written in  
REPRISE II Protocol Version AD 
Text as Written in  
REPRISE II Protocol Version AE 
Justification for 
Modification 
2. Protocol 
Synopsis, 
Success Criteria 
The Pocock alpha spending function is used to adjust the alpha-
level for each analysis: 0.02246, 0.01704, and 0.02799, 
respectively. 
The Pocock alpha spending function is used to adjust the alpha-
level for each analysis: 0.01123, 0.00792, and 0.01305, 
respectively. 
12.1.1.1 
Primary Device 
Performance 
Endpoint 
The alpha-level for the interim and final analyses is adjusted 
using the Pocock alpha spending function method for unequal 
information time intervals62; they are 0.02246, 0.01704, and 
0.02799, respectively. 
The alpha-level for the interim and final analyses is adjusted 
using the Pocock alpha spending function method for unequal 
information time intervals62; they are 0.01123, 0.00792, and 
0.01305, respectively. 
12.1.1.2 
Sample Size - 
Primary Device 
Performance 
Endpoint 
• 
Test significance level () = 0.05 (1-sided) 
• 
Power ≥ 90% 
 
• 
Test significance level () = 0.025 (1-sided) 
• 
Power ≥ 80% 
12.3.2 Interim 
Analyses 
… on the full enrolled cohort. The Pocock alpha spending 
function method for unequal information time intervals62 is 
used to adjust the alpha-level for each analysis: 0.02246, 
0.01704, and 0.02799, respectively.    
… on the full enrolled cohort. The Pocock alpha spending 
function method for unequal information time intervals62 is 
used to adjust the alpha-level for each analysis: 0.01123, 
0.00792, and 0.01305, respectively. 
  
Table 27.1-5: Table of Changes for REPRISE II Protocol Version AF (Compared to REPRISE II Protocol Version AE) 
Section 
Modified 
Text as Written in  
REPRISE II Protocol Version AE 
Text as Written in  
REPRISE II Protocol Version AF 
Justification for 
Modification 
Sponsor 
Sadra Medical, Inc., A Subsidiary of Boston Scientific 
Corporation 
Boston Scientific Structural Heart a Division of Boston 
Scientific Corporation 
Sponsor name 
updated 
Clinical 
Contacts 
 
Anne Cornaille 
Senior Clinical Trial Manager– Interventional Cardiology 
Boston Scientific 
Parc Val Saint Quentin  
2 Rue René Caudron, Bâtiment H 
78960 Voisins-le-Bretonneux, France 
Additional clinical 
trial manager  
Footer (all) 
 
Added: S2266/S2290  
Clarification for 
cross referencing 
other study-related 
documents 

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Table 27.1-5: Table of Changes for REPRISE II Protocol Version AF (Compared to REPRISE II Protocol Version AE) 
Section 
Modified 
Text as Written in  
REPRISE II Protocol Version AE 
Text as Written in  
REPRISE II Protocol Version AF 
Justification for 
Modification 
2. Protocol 
Synopsis 
Device Sizes 
…annulus diameter between ≥19 mm and… 
…annulus diameter between ≥20 mm and… 
Change made in 
response to current 
study observations    
2. Protocol 
Synopsis 
Control Device 
 
 Control Device 
For the device performance primary endpoint, a performance 
goal (PG) based on the 30-day mean aortic valve pressure 
gradient derived from published literature will be used as the 
control for analysis.   
 
Comparator 
For the device performance primary endpoint, a performance 
goal (PG) based on the 30-day mean aortic valve pressure 
gradient derived from published literature will be used as the 
comparator for analysis.   
For the primary safety endpoint, a performance goal (PG) 
based on 30 day all-cause mortality data derived from 
published literature will be used as the comparator for 
analysis.  
Clarification that 
there is a 
comparator, not a 
control device. Also, 
a primary safety 
endpoint will be 
assessed on the 
combined main trial 
and extended trial 
cohorts.   
2. Protocol 
Synopsis 
Study Design 
… high risk for surgical aortic valve replacement (SAVR).   
A total of up to 120 subjects will be enrolled in the study at 
up to 15 centers. Two planned interim analyses based on the 
primary endpoint at 30 days post-implant procedure will be 
performed on the first 40 and 60 enrolled subjects.   
 
The REPRISE II study will be conducted in accordance with 
the relevant parts of the International … Helsinki; the 
International Conference on Harmonisation… 
… high risk for surgical aortic valve replacement (SAVR).   
A total of up to 120 subjects will be enrolled in the main 
study at up to 15 centers. Subsequently, up to 130 additional 
subjects will be enrolled at up to 21 centers in the extended 
trial cohort. The statistical hypotheses for the main trial 
cohort and the combined (main + extended) cohorts are 
described below.    
 
The REPRISE II study will be conducted in accordance with 
the International … Helsinki; the relevant parts of the 
International Conference on Harmonisation… 
Clarification  
2. Protocol 
Synopsis 
Planned 
Number of 
Subjects 
A total enrollment of up to 120 subjects is planned. 
A total enrollment of up to 120 subjects is planned for the 
main study. Subsequently, up to 130 additional subjects (250 
subjects in total) will be enrolled in the extended trial cohort. 
2. Protocol 
Synopsis 
Planned 
Number of 
Up to 15 centers in these possible countries: Australia, 
France, Germany and United Kingdom. 
 
The main study will enroll subjects at up to 15 centers in 
these possible countries: Australia, France, Germany and 
United Kingdom. 
The extended trial cohort will enroll subjects at up to 21 

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Table 27.1-5: Table of Changes for REPRISE II Protocol Version AF (Compared to REPRISE II Protocol Version AE) 
Section 
Modified 
Text as Written in  
REPRISE II Protocol Version AE 
Text as Written in  
REPRISE II Protocol Version AF 
Justification for 
Modification 
Centers… 
centers in Australia and European countries.  
2. Protocol 
Synopsis 
Secondary 
Endpoints 
• Device Success based on the Valve Academic Research 
Consortium  (VARC)a  
 
o Absence of procedural mortality 
 
o Correct positioning of a single transcatheter valve into 
the proper anatomical location 
 
oIntended 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) 
Note: At least… 
a: Serruys P, et al. (2012) VARC Clinical Research Updates: 
Important Changes from VARC-2. Transcatheter Valve 
Therapeutics, Seattle, US (manuscript pending publication). 
• Device Success based on the Valve Academic Research 
Consortium definitions  (VARC)a, b  
Note: At least… 
a: Kappetein AP, et al. J Am Coll Cardiol. 2012;60:1438 
b: Leon MB, et al. J Am Coll Cardiol. 2011;57:253 
Indicate both 
VARC 1 and 
VARC 2 
definitions here to 
be able to pool 
REPRISE II 
outcomes with data 
from REPRISE I 
(which used VARC 
1 definitions) and 
to compare with 
published data 
using VARC 1 
definitions. 
2. Protocol 
Synopsis 
Additional 
Measurements 
Note 4: For subjects diagnosed with a neurological event 
(e.g., stroke, transient ischemic attack), a neurological 
physical exam, NIHSS assessment, and mRS must be 
performed after the event; mRS must also be administered at 
90 days post-neurological event.   
Note 4: A total enrollment of up to 120 subjects is planned 
for the main study.  Subsequently, up to 130 additional 
subjects will be enrolled for the extended trial cohort. In the 
main study, for subjects diagnosed with a neurological event 
(e.g., stroke, transient ischemic attack), a neurological 
physical exam, NIHSS assessment, and mRS must be 
performed after the event; mRS must also be administered at 
90 days post-neurological event.  In the extended trial cohort, 
for subjects diagnosed with a neurological event, NIHSS 
assessment and mRS must be performed after the event; mRS 
must also be administered at 90 days post-neurological event; 
the neurological physical exam is not required in the extended 
trial cohort. 
 
2. Protocol 
Synopsis 
Inclusion 
Criteria 
IC3. ..aortic annulus size between ≥19 and… 
IC3. …annulus size between ≥20 mm and… 
Change made in 
response to current 
study observations    

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Table 27.1-5: Table of Changes for REPRISE II Protocol Version AF (Compared to REPRISE II Protocol Version AE) 
Section 
Modified 
Text as Written in  
REPRISE II Protocol Version AE 
Text as Written in  
REPRISE II Protocol Version AF 
Justification for 
Modification 
2. Protocol 
Synopsis 
Exclusion 
Criteria 
EC16.  Subject has any therapeutic invasive cardiac 
procedure within… 
EC24. Subject has preexisting untreated conduction system 
disorder (e.g., Type II second degree atrioventricular block) 
that requires new pacemaker implantation.   
EC16.  Subject has any therapeutic invasive cardiac 
procedure (including balloon aortic valvuloplasty) within… 
EC24. Subject has untreated conduction system disorder (e.g., 
Type II second degree atrioventricular block) that in the 
opinion of the treating physician is clinically significant and 
requires a pacemaker implantation.   
Clarification 
2. Protocol 
Synopsis 
Statistical 
Methods 
Statistical Methods 
Statistical Methods – Main Trial Cohort (N=120) 
Updated statistical 
methods including 
addition of a 
statistically powered 
safety endpoint 
2. Protocol 
Synopsis 
Sample Size 
Parameters 
• 
Two planned … performed on the first … 
• 
A final analysis will be performed on  all subjects (120) 
• 
… 
Note 2: The alpha-level for the interim and final analyses is 
adjusted using the Pocock alpha spending function (see 
Success Criteria below). 
• 
Two planned … performed on the first … 
• 
A final analysis will be performed on  all subjects 
enrolled in the main trial cohort (120 subjects) 
• 
… 
Note 2: The alpha-level for the interim and final analyses of 
the main trial cohort is adjusted using the Pocock alpha 
spending function (see Success Criteria below). 
2. Protocol 
Synopsis 
Success 
Criteria 
Two interim analyses will be conducted on the first 40 and 60 
subjects and a final analysis will be conducted on the fully 
enrolled cohort. The Pocock… 
 
Two interim analyses will be conducted on the first 40 and 60 
subjects and a final analysis will be conducted on the fully 
enrolled main trial cohort (N=120). The Pocock… 
2. Protocol 
Synopsis 
Statistical 
Methods 
 
Statistical Methods – Combined Main and Extended Trial 
Cohort (N=250) 
2. Protocol 
Synopsis 
Primary 
Statistical 
Hypothesis 
 
All-cause mortality at 30 days post implant procedure is less 
than the PG of 16 % (expected rate of 9.8% + testing margin 
of 6.2%) 

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Table 27.1-5: Table of Changes for REPRISE II Protocol Version AF (Compared to REPRISE II Protocol Version AE) 
Section 
Modified 
Text as Written in  
REPRISE II Protocol Version AE 
Text as Written in  
REPRISE II Protocol Version AF 
Justification for 
Modification 
2. Protocol 
Synopsis 
Statistical Test 
Methods 
 
A one-sample z-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 16%.  
2. Protocol 
Synopsis 
Sample Size 
Parameters 
 
 
• 
Expected 30-day all-cause mortality rate = 9.8%  
• 
Performance goal (PG) = 16 % (expected rate of 9.8% + 
testing margin of 6.2%) 
• 
Test significance level () = 0.025 (1-sided) 
• 
Power (1 – ) = 80% 
• 
Expected rate of attrition = 2% 
• 
Planned enrollment of up to 250 subjects (main trial 
cohort enrollment of 120 subjects plus extended trial 
cohort enrollment of 130 subjects) 
Note:  The expected 30-day all-cause mortality rate is 
assumed to be 9.8% based on a literature review of studies 
evaluating the Medtronic CoreValve System and the Edwards 
Lifesciences SAPIEN Transcatheter Heart Valve System. 
2. Protocol 
Synopsis 
Success 
Criteria 
 
If the P value from the one-sample z-test is <0.025, it will be 
concluded that the primary safety endpoint for the Lotus 
Valve is less than the PG. This corresponds to the one-sided 
upper 97.5% confidence bound of the observed 30 day 
mortality rate being <16 %. 
4 Introduction 
This protocol specifies … manufactured by Sadra Medical, a 
Subsidiary… (BSC). The Lotus Valve System… If needed, 
the valve... prior to final release. The valve… 
 
4.1.  Justification for the Use of the Investigational Device 
in Human Subjects 
This protocol specifies… manufactured by Boston 
Scientific Structural Heart a Division of Boston Scientific 
Corporation. The Lotus Valve System... If needed, the 
valve... prior to final release or can be fully retrieved if 
during the procedure the decision is made not to implant. 
The valve… 
Clarification of 
sponsor name and 
valve information. 
Updated 
information on 
TAVR (additional 

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Table 27.1-5: Table of Changes for REPRISE II Protocol Version AF (Compared to REPRISE II Protocol Version AE) 
Section 
Modified 
Text as Written in  
REPRISE II Protocol Version AE 
Text as Written in  
REPRISE II Protocol Version AF 
Justification for 
Modification 
The incidence…, has rapidly accumulated through 
observational studies8,9, 10device-specific registries11-17, 
national registries18-20, and randomized controlled trials21,22. 
An expert consensus document on TAVR was recently 
published23. 
The prospective, single arm,…  through 5 years. To date, the 
study has reached the primary endpoint, which was 
achieved…  and 1 major stroke, which was based on 
preliminary adjudication by the CEC and is pending full 
adjudication based on an assessment to be performed at 90-
day follow-up. Paravalvular regurgitation… acute safety and 
performance of the Lotus Valve System. 
 
4.2 Justification for the Study Design 
As noted above… These include an enhanced… 
 
4.1.  Justification for the Use of the Investigational Device 
in Human Subjects 
4.1.1  Treatment for Aortic Stenosis 
The incidence…, valve has rapidly accumulated through 
observational studies8-15, device-specific registries16-22, 
national registries23-26, and randomized controlled trials21,22. 
Through 2-year follow-up in the PARTNER US IDE trial 
there have been significant reductions in mortality and repeat 
hospitalization rates compared to standard medical therapy in 
subjects unsuitable for SAVR29, and similar mortality rates 
compared to surgical valve replacement in high-surgical-risk 
subjects30. An expert consensus document on TAVR was 
recently published31. 
4.1.2. REPRISE I Study 
The aforementioned results notwithstanding, TAVR with 
early generation devices has been associated with increased 
stroke risk versus surgical valve replacement28,30. 
Cerebrovascular accidents and vascular complications 
associated with TAVR have been significant predictors of 
mortality38,39. The paravalvular regurgitation more commonly 
seen with TAVR compared to surgery has also been 
accompanied by higher early and late mortality21,30,40. While 
careful subject selection may serve to mitigate these risks41-43, 
device design improvements such as seen with the Lotus 
Valve System (Section 5.1) may enable more precise 
placement, minimize or eliminate paravalvular regurgitation, 
and obviate the need for valve-in-valve repeat intervention.  
The prospective, single arm,… through 5 years. 
The primary endpoint was achieved… and 1 major stroke. 
To date, data are available through 3 months47. There were no 
additional MACCE events beyond the primary endpoint. The 
3-month VARC44 combined safety endpoint, including 
published literature) 
and updated 
REPRISE I study 
results to include 3-
month data. 

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Table 27.1-5: Table of Changes for REPRISE II Protocol Version AF (Compared to REPRISE II Protocol Version AE) 
Section 
Modified 
Text as Written in  
REPRISE II Protocol Version AE 
Text as Written in  
REPRISE II Protocol Version AF 
Justification for 
Modification 
MACCE, life threatening/disabling bleeding, major vascular 
complications, and Stage 3 acute kidney injury, was 3/11 (1 
small left femoral dissection treated with balloon inflation 
during the procedure; 2 life-threatening/disabling bleeds 
through 30 days that were unrelated to valve implantation and 
resolved). Conduction disturbances led to implantation of a 
permanent pacemaker before discharge in 4 subjects; 2 of 
these 4 subjects were pacemaker dependent at 3 months. 
While all REPRISE I subjects were NYHA Class II (n=6) or 
III (n=5) at baseline, this distribution was significantly 
improved by 3 months (7 in Class I, 3 in Class II, 1 in Class 
III; P=0.004). The mean aortic valve gradient was 12.0±2.2 
mmHg for the cohort and was below the VARC criterion of 
20 mmHg in all subjects at 3 months, with no moderate or 
severe paravalvular aortic regurgitation. … acute safety and 
performance of the Lotus Valve System. 
Table 4.1-1 has been updated with 7 additional references. 
4.2 Justification for the Study Design 
As noted above... These include a pre-loaded delivery system, 
early leaflet function to maintain hemodynamic stability 
during valve deployment, an enhanced… 
5.3 Device 
Labeling 
• Part/Reference number 
• Lot number 
• Expiration (use by)… 
The following statement appears on the label. 
CAUTION: Exclusively for Clinical Investigations. 
• Part/Reference number 
• Lot number (matches the lot number on the handle) 
• Valve size 
• Expiration (use by)… 
• Temperature storage requirements 
The following statement appears on the label. 
CAUTION: Exclusively for Clinical Investigations. 
Device labeling will be provided in local language(s) as 
per respective national regulations. 
Clarification 
7.1 Primary 
Endpoints 
The primary device… 
 
The primary device…  The primary analysis population will 
be the subject population implanted with the Lotus Valve. 
Outcomes in this as-treated subject population in the main 
Clarification of the 
cohorts assessed for 
each primary 

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Table 27.1-5: Table of Changes for REPRISE II Protocol Version AF (Compared to REPRISE II Protocol Version AE) 
Section 
Modified 
Text as Written in  
REPRISE II Protocol Version AE 
Text as Written in  
REPRISE II Protocol Version AF 
Justification for 
Modification 
The primary safety… 
trial cohort (N=120) will be compared to a performance goal 
(PG; see Section 12.1.1.1). 
The primary safety… The primary safety endpoint will be 
evaluated on an intention-to-treat (ITT) basis (all subjects 
enrolled, whether or not a study device is implanted).  
Outcomes in the combined main and extended trial cohort 
(N=250)  will be compared to a PG (see Section 12.1.1.3). 
endpoint. 
7.2 Secondary 
Endpoints 
Secondary endpoints are listed below. 
 
• Device Success post implant procedure48  
 
o Absence of procedural mortality 
 
o Correct positioning of a single transcatheter valve into 
the proper anatomical location 
 
o 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) 
Note: At least… 
Secondary endpoints are listed below and will be evaluated 
on an ITT basis. Definitions can be found in Table 26.2 1. 
• Device Success based on the Valve Academic Research 
Consortium  (VARC)44, 48  
 
 
Note: At least… 
 
Clarification 
 
To be able to pool 
REPRISE II 
outcomes with data 
from REPRISE I 
(which used VARC 
1 definitions) and 
to compare with 
published data 
using VARC 1 
definitions. 
7.3 Additional 
Measurements 
Note 4: For subjects diagnosed … post-neurological event. 
 
Note 4: In the main trial cohort (N=120), for subjects 
diagnosed … post-neurological event (see Table 11.1-1).  In 
Among the 130 subjects subsequently enrolled (extended trial 
cohort), for subjects diagnosed with a neurological event, 
NIHSS assessment and mRS must be performed after the 
event; mRS must also be administered at 90 days post 
neurological event; the neurological physical exam is not 
required (see Table 11.1-2). 
Clarify that a 
neurological 
physical 
examination is not 
required for the 
extended trial 
cohort. 
8.3 Study 
Design 
Justification 
In order to support … to risk, a total of up to 120 subjects will 
be enrolled in the study at up to 15 centers. Safety and device 
performance results will be reported on all subjects. 
Planned… subjects. 
 
In order to support …to risk, a total of up to 120 subjects will 
be enrolled in the main trial cohort at up to 15 centers in these 
possible countries: Australia, France, Germany and United 
Kingdom. Planned … subjects and a final analysis will be 
conducted on the main trial cohort (N=120). Subsequently, up 
to 130 additional subjects will be enrolled at up to 21 centers 
Explain that the 
main trial cohort 
consists of 120 
subjects and the 
extended trial cohort 
will have 130 

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Table 27.1-5: Table of Changes for REPRISE II Protocol Version AF (Compared to REPRISE II Protocol Version AE) 
Section 
Modified 
Text as Written in  
REPRISE II Protocol Version AE 
Text as Written in  
REPRISE II Protocol Version AF 
Justification for 
Modification 
in Australia and European countries and a statistically 
powered analysis based on the primary safety endpoint will 
be performed on the combined main and extended trial cohort 
(250 subjects). 
additional subjects.  
9.1 Study 
Population and 
Eligibility 
The study… and none of the exclusion criteria (Section 9.3). 
The study… and none of the exclusion criteria (Section 9.3). 
All subjects will then be reviewed by the CRC to confirm 
eligibility and suitability for enrollment in the study. 
Clarification 
9.2 Inclusion 
Criteria 
Table 9.2-1: Inclusion Criteria 
IC3. ..aortic annulus size between ≥19 and… 
Table 9.2-1: Inclusion Criteria 
IC3. ..aortic annulus size between ≥20 and… 
Change made in 
response to current 
study observations    
9.3.1 Exclusion 
Criteria 
EC16. Subject has any therapeutic invasive cardiac procedure 
within… 
EC 24.Subject has preexisting untreated conduction system 
disorder (e.g., Type II second degree atrioventricular block) 
that requires new pacemaker implantation.   
EC16. Subject has any therapeutic invasive cardiac procedure 
(including balloon aortic valvuloplasty) within… 
EC 24. Subject has untreated conduction system disorder 
(e.g., Type II second degree atrioventricular block) that in the 
opinion of the treating physician is clinically significant and 
requires a pacemaker implantation.   
Clarification 
11. Study 
Methods 
11.1 Data Collection 
The study event schedule is shown diagrammatically in 
Figure 11.1 1and discussed in Table 11.1 1 and Sections 11.2 
through 11.11. 
 
Figure 11.1-1 REPRISE Study Design  
Table 11.1-1: Study Event Schedule 
AE assessmentss 
Device deficiencies, SAE, SADE, USADE, ADE and CEC 
event assessment 
e: Neurological…assessors should be independent of the 
study. For subjects…  
h: Consists of STS score, logistic euroSCORE  and… 
s: AEs will be… 
t: Device deficiencies…USADEs, ADEs and CEC…reported 
to Sadra BSC for… 
 
11.1 Data Collection 
The study event schedules are shown diagrammatically and 
discussed in Figure 11.1 1and Table 11.1 1 for the main trial 
cohort (N=120), and in Figure 11.1 2 and Table 11.1 2 for the 
subsequently enrolled 130 additional subjects (extended trial 
cohort).   
 
Figure 11.1-1 REPRISE Study Design – Main Trial Cohort  
Table 11.1-1: Study Event Schedule – Main Trial Cohort 
AE and ADE assessmentss 
Device deficiencies, SAE, SADE, USADE, and CEC event 
assessment 
e: Neurological…assessors should be independent (not 
involved with the care of study subjects). For subjects…  
h: Consists of STS score (2.73), euroSCORE 2011 and… 
s: AEs and ADEs will be… 
t: Device deficiencies…USADEs and CEC…reported to 
Clarify that the main 
trial cohort consists 
of 120 subjects and 
the extended trial 
cohort has 130 
additional subjects; 
the assessments 
removed are not 
required for subjects 
enrolled  in the 
extended trial 
cohort. 
Note that there are 
additional changes 
in Table 111.1-1 and 
Table 11.1-2 for 
clarification on STS 
score, euroSCORE, 

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Table 27.1-5: Table of Changes for REPRISE II Protocol Version AF (Compared to REPRISE II Protocol Version AE) 
Section 
Modified 
Text as Written in  
REPRISE II Protocol Version AE 
Text as Written in  
REPRISE II Protocol Version AF 
Justification for 
Modification 
Boston Scientific for… 
 
Figure 11.1-2 REPRISE Study Design – Extended Trial 
Cohort 
Subject Enrollment Number is 130. 
Removed symbols for “Neurological Physical Exam” and for 
“Annual Imaging (Rotational X-ray)” 
Table 11.1-2: Study Event Schedule – Extended Trial Cohort 
Removed rows for “Neurological Physical Exam” and for 
“Annual Imaging (Rotational X-ray)” and updated the 
footnote numbering accordingly. Added reference to 
rotational angiogram in footnote as shown below: 
Procedural cine-angiogram including the final post-
deployment aortogram of the ascending aorta (including 
recommended rotational angiogram of the valve frame) 
should be sent to the CT/X-Ray Angio Core Laboratory for 
analysis. 
and rotational 
angiogram of the 
valve frame. 
Additional 
clarifications, 
including the 
updating of sponsor 
name. 
11.4 Screening 
Assessments 
Clinical assessments 
o Risk assessments: STS Score (2.73),  euroSCORE 2011, 
heart team assessment including an in-person evaluation by a 
cardiac surgeon 
 
Imaging assessments 
o Within 60 days…volume.  
o A CT angiogram... within 90 days to evaluate… device 
sizing. It must be performed according to the CT Core 
Laboratory procedure guidelines… 
 
Clinical assessments 
o Risk assessments: STS Score (2.73),  euroSCORE 2011, 
heart team assessment including an in-person evaluation by a 
cardiac surgeon, and any frailty assessments 
 
Imaging assessments 
o Within 60 days…volume. Other echocardiographic 
measurements include but are not limited to: aortic valve 
diameter, LVOT, diameter, Sinus of Valsalva diameter, 
annulus to ventricular apex length, mitral hinge point to apex 
length.  
o A CT angiogram... within 90 days, if possible, to evaluate... 
device sizing. It must meet the CT Core Laboratory procedure 
guidelines… 
 
Clarification 

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Section 
Modified 
Text as Written in  
REPRISE II Protocol Version AE 
Text as Written in  
REPRISE II Protocol Version AF 
Justification for 
Modification 
11.4 Screening 
Assessments 
Figure 11.4-1: Assessment… 
19 ---------- 23 ----------27 
Figure 11.4-1: Assessment… 
20 ---------- 23 ----------27 
Change made in 
response to current 
study observations    
11.5 Baseline 
Assessments 
• Neurological physical examination, which must … assessors 
should be independent of the study. 
 
• NIH Stroke Scale (NIHSS), which must …; 
assessors…independent of the study  
• Modified Rankin Scale score, which must …; 
assessors…independent of the study  
• The following frailty… assessments will… 
• 12-lead…must… 
 
• Neurological physical examination required in the main trial 
cohort, which must ...  (see Table 11.1-1); assessors should be 
independent (not involved with the care of study subjects). A 
neurological physical examination is not required in the 
extended trial cohort (see Table 11.1-2). 
 
• NIH Stroke Scale (NIHSS), which must …; 
assessors…independent (not involved with the care of study 
subjects). 
• Modified Rankin Scale score, which must …; 
assessors…independent (not involved with the care of study 
subjects). 
• The following frailty… assessments at screening and/or 
baseline will… 
• 12-lead… at screening and/or baseline must… 
Clarification that a 
neurological 
physical 
examination is not 
required in the 
extended trial 
cohort. 
Clarification 
regarding 
independence of 
assessors and timing 
of some assessments 
11.7.2 
If a significant waist remains after repeated valvuloplasty, it 
is strongly recommended that the Lotus Valve not be 
implanted. 
If the subject is not implanted, then… 
If a significant waist remains after repeated valvuloplasty, it is 
strongly recommended that appropriate valve size be 
reconsidered or, if annulus size is within the lower 
measurement of the annulus size, that the Lotus Valve not be 
implanted. 
If the subject is not implanted with the Lotus Valve, then… 
Clarification 
11.7.3 
Preparing… 
9) A final post-deployment aortogram of the ascending 
aorta should be performed… 
9) A final post-deployment aortogram of the ascending aorta 
(including recommended rotational angiography of the valve 
frame) should be performed… 
11.8 Post- 
Procedure 
• Subject’s heart rhythm should be monitored using telemetry 
for at least 48 hours after the index procedure. 
• It is recommended that the subject’s heart rhythm be 
monitored using telemetry for at least 48 hours after the index 
procedure. 
11.9 Prior to 
Discharge… 
• Neurological physical examination, which must be 
performed by a neurologist or neurology fellow; assessors 
should be independent of the study. 
• Neurological physical examination required in in the 
main trial cohort, which must be performed by a 
neurologist or neurology fellow; assessors should be 
independent (not involved with the care of study subjects; 
Clarification 
regarding 
independence of 
assessors. 

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Table 27.1-5: Table of Changes for REPRISE II Protocol Version AF (Compared to REPRISE II Protocol Version AE) 
Section 
Modified 
Text as Written in  
REPRISE II Protocol Version AE 
Text as Written in  
REPRISE II Protocol Version AF 
Justification for 
Modification 
• NIH Stroke Scale (NIHSS), which must …; 
assessors…independent of the study  
• Modified Rankin Scale score, which must …; 
assessors…independent of the study  
see Table 11.1-1). A neurological physical examination is 
not required in the extended trial cohort (see 11.1-2). 
• NIH Stroke Scale (NIHSS), which must …; 
assessors…independent (not involved with the care of study 
subjects). 
• Modified Rankin Scale score, which must …; 
assessors…independent (not involved with the care of study 
subjects). 
Clarification that a 
neurological 
physical 
examination is not 
required in the 
extended trial 
cohort. 
Clarification that 
rotational X-ray 
angiography is not 
required in the 
extended trial 
cohort. 
Clarification that 
ADE is not reported 
after 12 months. 
11.10.1 
11.10.2 
11.10.3  
• Modified Rankin Scale score, which must …; 
assessors…independent of the study 
• Modified Rankin Scale score, which must …; 
assessors…independent (not involved with the care of study 
subjects). 
11.10.4  
12-Month 
(365±45 Days) 
Follow-up 
• Modified Rankin Scale score, which must …; 
assessors…independent of the study 
• Neurological physical examination, which must …assessors 
should be independent of the study 
• NIH Stroke Scale (NIHSS), which must …; 
assessors…independent of the study  
• Rotational x-ray … Operations).  It must be ... 
 
• Modified Rankin Scale score, which must …; 
assessors…independent (not involved with the care of study 
subjects). 
• Neurological physical examination required in the main trial 
cohort, which must ... fellow (see Table 11.1-1); assessors 
should be independent (not involved with the care of study 
subjects). A neurological physical examination is not required 
in the extended trial cohort (see Table 11.1-2). 
• NIH Stroke Scale (NIHSS), which must …; 
assessors…independent (not involved with the care of study 
subjects). 
• Rotational x-ray angiography … Operations) is required in 
the main trial cohort.  It must be ... Rotational x-ray 
angiography is not required in the extended trial cohort. 
11.10.5 Annual 
Follow-up (±45 
Days) 
• Modified Rankin Scale score, which must …; 
assessors…independent of the study 
• Rotational x-ray … Operations).  It must be …. 
• Complete serious adverse event (SAE, SADE, USADE, 
ADE and CEC events)… 
• Modified Rankin Scale score, which must …; 
assessors…independent (not involved with the care of study 
subjects). 
• Rotational x-ray angiography … Operations) is required in 
the main trial cohort. It must be… Rotational x- ray 
angiography is not required in the extended trial cohort. 
• Complete serious adverse event (SAE, SADE, USADE, and 
CEC events)… 

TP3687 
 
 
 
 
Confidential 
12-Mar-2013 
 
 
Boston Scientific 
FINAL 
 
 
REPRISE II Protocol 
S2266/S2290 
 
 
CDM00051572/Ver AF 
 
 
 
Page 141 of 146 
Table 27.1-5: Table of Changes for REPRISE II Protocol Version AF (Compared to REPRISE II Protocol Version AE) 
Section 
Modified 
Text as Written in  
REPRISE II Protocol Version AE 
Text as Written in  
REPRISE II Protocol Version AF 
Justification for 
Modification 
11.10.6 
Management of 
Missed… 
Missed …as such on a regular basis in accordance with BSC 
standard operating procedures. 
Missed …as such by the sponsor or designee on a regular 
basis in accordance with the applicable standard operating 
procedures. 
Clarification 
12.1.1.1 
Primary Device 
Performance 
Endpoint 
Two interim … . on the full enrolled cohort… This 
corresponds… gradient being <18 mm Hg. 
Two interim … on the main trial cohort (N=120). … This 
corresponds… gradient being <18 mm Hg.  
 
Clarification 
regarding main trial 
cohort analysis. 
12.1.1.2 
Sample Size-
Primary Device 
Performance 
Endpoint 
Two … A final analysis will be carried out on the full 
enrolled cohort.  
Two … A final analysis will be carried out on the fully 
enrolled main trial cohort 
Clarification   that 
the primary device 
performance 
endpoint analysis is 
carried out on the 
main trial cohort. 
12.1.1.3 
Primary Safety 
Endpoint 
Descriptive statistics … post implant procedure). 
Subsequent to the enrollment of the main trial cohort for 
device performance assessment (see Section 12.1.1.2), up to 
130 more subjects will be enrolled in the extended trial cohort 
to perform a statistically powered assessment of the primary 
safety endpoint. The null and alternative hypotheses for the 
primary safety 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 the performance goal. 
Testing will be done for the primary safety endpoint as 
described in the statistical analysis plan. A one-sample z-test 
will be used, the z-test statistic is 
p
D
s
PG
P
z
−
=
30
, 
where  
D
P30
 is the sample 30-day all-cause mortality rate, 
Add statistically 
powered analysis of 
the primary safety 
endpoint. 

TP3687 
 
 
 
 
Confidential 
12-Mar-2013 
 
 
Boston Scientific 
FINAL 
 
 
REPRISE II Protocol 
S2266/S2290 
 
 
CDM00051572/Ver AF 
 
 
 
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Table 27.1-5: Table of Changes for REPRISE II Protocol Version AF (Compared to REPRISE II Protocol Version AE) 
Section 
Modified 
Text as Written in  
REPRISE II Protocol Version AE 
Text as Written in  
REPRISE II Protocol Version AF 
Justification for 
Modification 
PG  is the performance goal,  
N
P
P
s
D
D
p
)
1
(
30
30
−
=
 is the sample standard error, 
N  is the sample size. 
A sensitivity analysis (tipping-point analysis) will be 
performed to assess the impact of subjects with inadequate 
follow-up (i.e., missing data) on the primary safety endpoint 
and to assess the robustness of the conclusion of the primary 
analysis. 
The sample size calculation for the primary safety endpoint is 
based on the following assumptions. 
• 
Expected 30-day all-cause mortality rate = 9.8%  
• 
Performance goal (PG) = 16 % (expected rate of 9.8% + 
testing margin of 6.2%) 
• 
Test significance level () = 0.025 (1-sided) 
• 
Power (1 – ) = 80% 
• 
Expected rate of attrition = 2% 
If the P value from the one-sample z-test is <0.025, it will be 
concluded that the primary safety endpoint for the Lotus 
Valve is less than the PG. This corresponds to the one-sided 
upper 97.5% confidence bound of the observed 30-day 
mortality rate being <16 %. 
The expected rate of 9.8% for 30-day all-cause mortality is 
based on a literature review. 8-13,16-18,20,22,24-28,32-37  Given the 
above assumptions, 233 subjects will be required. In order to 
account for a 5% expected rate of attrition, a total of 250 
subjects is required for the planned hypothesis testing.  

TP3687 
 
 
 
 
Confidential 
12-Mar-2013 
 
 
Boston Scientific 
FINAL 
 
 
REPRISE II Protocol 
S2266/S2290 
 
 
CDM00051572/Ver AF 
 
 
 
Page 143 of 146 
Table 27.1-5: Table of Changes for REPRISE II Protocol Version AF (Compared to REPRISE II Protocol Version AE) 
Section 
Modified 
Text as Written in  
REPRISE II Protocol Version AE 
Text as Written in  
REPRISE II Protocol Version AF 
Justification for 
Modification 
12.2.1 Analysis 
Sets 
 
 
 
12.2.2 Control 
of 
Systematic… 
The primary analysis population for the primary device 
performance endpoint will be the subject population 
implanted with the Lotus Valve. Outcomes will be compared 
to a performance goal (PG). 
 
All subjects who have met the inclusion/exclusion criteria, 
(including a positive recommendation from the CRC) and 
have signed the informed consent form will be eligible for 
enrollment in the study. The investigator’s assessment of TTE 
measurements before device placement will determine subject 
eligibility for the study. 
The primary analysis population for the primary device 
performance endpoint will be the subject population 
implanted with the Lotus Valve (as-treated subject 
population). 
 
All subjects who have met the inclusion/exclusion criteria, 
received a positive recommendation from the CRC, and 
signed the informed consent form will be eligible for 
enrollment in the study. The center’s heart team assessments 
and imaging measurements before device placement will 
contribute to the determination of subject eligibility for the 
study. 
Clarification 
12.3.2 Interim 
Analyses 
… the first 40 and 60 enrolled subjects… carried out on the 
full enrolled cohort. The Pocock alpha…respectively. 
…the first 40 and 60 enrolled subjects… The final analysis of 
the primary device performance endpoint will be conducted 
on the fully enrolled main trial subject cohort (N=120). The 
Pocock alpha … respectively.   
Clarification of 
analyses on the 
main trial cohort 
13.3.2 CT 
and… 
An independent Core Laboratory will centrally assess all of 
the CT and rotational X-ray data… 
An independent Core Laboratory will centrally assess all of 
the CT and rotational X-ray angiography data… 
Clarification 
16. Device 
Accountability 
The principal investigator …verified by BSC personnel. 
• Identification of….Lot numbers) 
The principal investigator …verified by Boston Scientific 
personnel or its designee. 
• Identification of….Lot numbers, valve size) 
17.1 
Statement… 
The REPRISE II study will be conducted in accordance with 
the relevant parts of the International …Helsinki; the 
International Conference on Harmonisation… 
The REPRISE II study will be conducted in accordance with 
the International Helsinki; the relevant parts of the 
International Conference on Harmonisation… 
17.4 Sponsor 
Responsibilities 
All information and data sent to BSC concerning subjects …. 
Only authorized BSC personnel, or a BSC representative will 
have access… 
All information and data sent to Boston Scientific and its 
authorized designee concerning subjects …. Only authorized 
Boston Scientific personnel, representative or designee will 
have access… 
 
Note: Boston Scientific may utilize a contract research 
organization (CRO) or other contractors to act as its 
representative for carrying out designated tasks. 

TP3687 
 
 
 
 
Confidential 
12-Mar-2013 
 
 
Boston Scientific 
FINAL 
 
 
REPRISE II Protocol 
S2266/S2290 
 
 
CDM00051572/Ver AF 
 
 
 
Page 144 of 146 
Table 27.1-5: Table of Changes for REPRISE II Protocol Version AF (Compared to REPRISE II Protocol Version AE) 
Section 
Modified 
Text as Written in  
REPRISE II Protocol Version AE 
Text as Written in  
REPRISE II Protocol Version AF 
Justification for 
Modification 
17.4.1 Training 
In compliance with … includes the following requirements 
for implanting investigators. 
In compliance with … includes the following elements for 
implanting investigators. 
18 Monitoring 
Monitoring will be performed during the study …to assess 
Monitoring will be performed during the study according to 
the monitoring plan to assess… 
19.3.2 Potential 
Benefit… 
Potential benefits… the following. 
• Accurate… 
• Device is minimally obstructive to the blood flow through 
the annulus during delivery because there is no balloon or 
other obstructive device required for deployment  
• Reduced incidence…  
Potential benefits… the following. 
• Pre-loaded delivery system minimizing time required and 
potential issues with preparing the device  
• Accurate…  
• Device is minimally obstructive to the blood flow and 
maintains hemodynamic stability through the annulus during 
delivery because there is no balloon or other obstructive 
device required for deployment and due to early valve leaflet 
function 
• Reduced or obviated need for valve-in-valve repeat 
intervention 
• Reduced incidence…  
21.1 
Definitions and 
Classifications 
…the complications and AEs must be reported as AEs or 
SAEs if they meet the protocol-specified definitions. 
However, the original elective/planned hospitalization(s) itself 
should not be reported as an SAE. 
Any AE experienced by the study subject after enrollment, 
whether… 
 
Based on the VARC… following. 
• Mortality…  
• Vascular complications: major and minor 
•Repeat procedure for valve-related dysfunction (surgical or 
interventional therapy) 
• Hospitalization… 
…the complications and AEs must be reported as AEs or 
SAEs if they meet the protocol-specified definitions. 
Any AE experienced by the study subject beginning from the 
time of Lotus Introducer sheath insertion, whether… 
 
Based on the VARC… following. 
• Mortality…  
• Neurologic event: disabling or non-disabling stroke, and 
TIAs 
• Myocardial infarction…  
• Vascular complications: major and minor 
•Repeat procedure for valve-related dysfunction (surgical or 
interventional therapy) 
• Hospitalization… 
Sentence removed 
to avoid confusion. 
Clarification   
21.3 
Investigator 
Reporting 
Table 21.3-1. Investigator Reporting Requirements 
USADE 
Complete AE electronic case report form (eCRF) page with 
Table 21.3-1. Investigator Reporting Requirements 
USADE 
Complete AE electronic case report form (eCRF) page with 
Simplification and 
clarification of 
requirements 

TP3687 
 
 
 
 
Confidential 
12-Mar-2013 
 
 
Boston Scientific 
FINAL 
 
 
REPRISE II Protocol 
S2266/S2290 
 
 
CDM00051572/Ver AF 
 
 
 
Page 145 of 146 
Table 27.1-5: Table of Changes for REPRISE II Protocol Version AF (Compared to REPRISE II Protocol Version AE) 
Section 
Modified 
Text as Written in  
REPRISE II Protocol Version AE 
Text as Written in  
REPRISE II Protocol Version AF 
Justification for 
Modification 
Requirements 
all available new and updated information 
• Within 1 business day of first becoming aware of the 
event 
• Terminating at the end of the study 
****** 
SAE/SADE 
Complete AE eCRF page with all available new and updated 
information 
• Within 2 business days of first becoming aware of the 
event or as per local/regional regulations 
• Reporting required through the end of the study 
******  
AE 
Complete AE eCRF page, which contains such information as 
date of AE, treatment of AE resolution, assessment of 
seriousness and relationship to the device 
• No later than 10 working days after becoming aware of the 
information 
• Reporting required through 12 months  
 
******  
Device Deficiencies, Failures, Malfunctions, and Product 
Nonconformities 
Complete applicable CRF fields/pages with all available new 
and updated information. 
• Within 1 business day of first becoming aware of the event 
and as per local/regional regulations 
• Reporting required through the end of the study  
 
 
 
all available new and updated information 
• Within 1 business day of first becoming aware of the 
event 
• Beginning from time of Lotus Introducer sheath insertion 
for all subjects 
• Terminating at the end of the study 
Provide copies of all relevant source documents requested by 
Boston Scientific 
• As soon as possible after reporting the event 
******  
SAE/SADE 
Complete AE eCRF page with all available new and updated 
information 
• Within 2 business days of first becoming aware of the 
event or as per local/regional regulations 
• Beginning from time of Lotus Introducer sheath insertion 
for all subjects 
• Reporting required through the end of the study 
******  
AE 
Complete AE eCRF page, which contains such information as 
date of AE, treatment of AE resolution, assessment of 
seriousness and relationship to the device 
• Review with CRA  during next monitoring visit  
• Beginning from time of Lotus Introducer sheath insertion 
for all subjects  
• Reporting required through 12 months   
 
******  
Device Deficiencies, Failures, Malfunctions, and Product 
Nonconformities 
Complete applicable CRF fields/pages with all available new 
and updated information. 

TP3687 
 
 
 
 
Confidential 
12-Mar-2013 
 
 
Boston Scientific 
FINAL 
 
 
REPRISE II Protocol 
S2266/S2290 
 
 
CDM00051572/Ver AF 
 
 
 
Page 146 of 146 
Table 27.1-5: Table of Changes for REPRISE II Protocol Version AF (Compared to REPRISE II Protocol Version AE) 
Section 
Modified 
Text as Written in  
REPRISE II Protocol Version AE 
Text as Written in  
REPRISE II Protocol Version AF 
Justification for 
Modification 
• Within 1 business day of first becoming aware of the event 
and as per local/regional regulations 
• Beginning from time of Lotus Introducer sheath insertion 
for all subjects  
• Reporting required through the end of the study  
26.2 
Definitions 
DEVICE 
SUCCESS 
Device Success as defined by VARC 44 post-implant 
procedure. 
• Absence of procedural mortality… 
Device Success as defined by VARC post-implant procedure. 
VARC 1 44 
• 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 2 48 
• Absence of procedural mortality… 
Indicate both 
VARC 1 and 
VARC 2 
definitions here to 
be able to pool 
REPRISE II 
outcomes with data 
from REPRISE I 
(which used VARC 
1 definitions) and 
to compare with 
published data 
using VARC 1 
definitions.