REPRISE IV: REpositionable Percutaneous Replacement of Stenotic Aortic Valve Through Implantation of LOTUS Edge Valve System in IntermediatE Surgical Risk Subjects
Phase: NA
Conditions: Aortic Valve Stenosis
Sponsor: Boston Scientific Corporation

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Page 1 of 215 
 
 
 
 
REPRISE IV:  REpositionable Percutaneous Replacement of Stenotic 
Aortic Valve through Implantation of LOTUS Edge Valve System in 
IntermediatE Surgical Risk Subjects 
 
REPRISE IV 
S2354 
CLINICAL INVESTIGATION PLAN 
National Clinical Trial Identification Number: NCT03618095 
 
 
Sponsor: 
Boston Scientific Corporation  
300 Boston Scientific Way 
Marlborough, MA 01752 USA 
Australian Representative 
Boston Scientific Pty. Ltd. 
Building 1, Level 6 
191 O’Riordan Street 
Mascot, NSW 2020, Australia 
 
 
 
 
 
 
 
This protocol contains confidential information for use by the Investigators and their 
designated representatives participating in this clinical investigation. The protocol should 
be held confidential and maintained in a secure location. 
Do not copy or distribute without written permission from Boston Scientific Corporation 
 
 
 

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Contact Information 
Role 
Contact  
Clinical Contacts 
Laoti Bussone 
Senior Clinical Trial Manager, Interventional Cardiology 
Boston Scientific Corporation 
100 Boston Scientific Way, Marlborough, MA  01752 USA 
Arjun M. Bhat 
Clinical Trial Manager, Structural Heart – Interventional Cardiology 
Boston Scientific Corporation 
100 Boston Scientific Way, Marlborough, MA  01752 USA 
Blessie Concepcion 
Director, Clinical Trials, Structural Heart – Interventional Cardiology 
Boston Scientific Corporation 
160 Knowles Drive, Los Gatos, CA 95032 USA 
Coordinating Principal 
Investigators 
Interventional Cardiologist Study Co-Principal Investigator 
Christopher U. Meduri, MD, MPH 
Piedmont Heart Institute  
95 Collier Road Northwest, Suite 5015, Atlanta, GA 30309 
Cardiac Surgeon Study Co-Principal Investigator 
Vinod H. Thourani, MD 
MedStar Heart & Vascular Institute 
MedStar Washington Hospital Center  
110 Irving St NW, Washington, DC  20010 USA 
Bicuspid Registry – Coordinating Principal Investigator 
Vivek Rajagopal, MD 
Piedmont Heart Institute  
95 Collier Road Northwest, Suite 5015, Atlanta, GA 30309 USA 
 
Original Release: 16-Nov-2016 
Current Version: 29-Apr-2020 
Revision History 
Revision Number 
Release Date 
Template Version 
Reason for Change 
A 
16-Nov-2016 
90702637 Rev/Ver AG 
Not Applicable 
B 
15-Feb-2017 
90702637 Rev/Ver AG 
See Table 26.1-1 
C 
23-Sep-2018 
90702637 Rev/Ver AG 
D 
21-Nov-2018 
90702637 Rev/Ver AG 
E 
25-Feb-2020 
90702637 Rev/Ver AG 
F 
29-Apr-2020 
90702637 Rev/Ver AL 
 
 
 

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2. Protocol Synopsis 
REPRISE IV:  REpositionable Percutaneous Replacement of Stenotic Aortic Valve 
through Implantation of LOTUS Edge™ Valve System in IntermediatE Surgical Risk 
Subjects 
Study 
Objective(s) 
To evaluate safety and effectiveness of the LOTUS Edge™ Valve System 
when used with the Lotus™ or iSleeve™ Introducer Sets for transcatheter 
aortic valve replacement (TAVR) in symptomatic subjects with severe 
aortic stenosis who are considered at intermediate risk for surgical valve 
replacement including those who have a bicuspid native valve.  
Intended Use 
The LOTUS Edge Valve System is intended to improve aortic valve 
function in symptomatic subjects with severe aortic stenosis who are at 
intermediate risk for standard surgical aortic valve replacement (SAVR), 
including those who have a bicuspid native valve. 
The iSleeve and Lotus Introducer Sets are intended to provide 
percutaneous access to the vascular system. 
Test Device(s) 
and Sizes 
REPRISE IV uses the following investigational device. 
Device 
Name/Size 
Description 
LOTUS 
Edge Valve 
System 
Valve 
diameter: 
- 23mm 
- 25mm 
- 27mm 
Includes 2 main components: 
- a bioprosthetic bovine pericardial aortic valve 
(similar to the Lotus™ Valve System used in the 
REPRISE III IDE study [NCT02202434] and the 
RESPOND post-market surveillance study 
[NCT02031302]) 
- a next generation delivery system designed to 
increase flexibility, trackability, and coaxial 
alignment 
The LOTUS Edge Valve System is introduced 
percutaneously via the femoral artery. 
The iSleeve™ Introducer Set (iSleeve) and the large Lotus Introducer Set 
(LIS-L) can be used as accessories to facilitate vascular introduction and 
deployment of the LOTUS Edge Valve System (23mm, 25mm, and 
27mm valve sizes). The iSleeve has an expandable sheath component and 
a dilator enabling access to transfemoral arteries ≥5.9 mm. The LIS-L is 
intended for use in subjects with femoral vascular access ≥6.5 mm. In 
countries where the introducer sets are approved, the commercial devices 

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REPRISE IV:  REpositionable Percutaneous Replacement of Stenotic Aortic Valve 
through Implantation of LOTUS Edge™ Valve System in IntermediatE Surgical Risk 
Subjects 
will be used. In countries where they are not approved, they will be 
considered investigational devices. 
Comparator 
For the primary endpoint, a performance goal (PG) based on 1-year 
TAVR outcomes derived from published literature will be used as the 
comparator for analysis.   
Study Design 
REPRISE IV is a prospective, multicenter single-arm study designed to 
evaluate the safety and effectiveness of the LOTUS Edge Valve System 
for TAVR in symptomatic subjects who have severe native aortic stenosis 
and are considered at intermediate risk for surgical valve replacement. 
Study cohorts include the following. 
• Main Cohort: A prospective, multicenter, single-arm cohort of 
subjects with severe aortic stenosis who are considered at 
intermediate risk for surgical aortic valve replacement and are 
treated with the LOTUS Edge Valve System. 
o CT Imaging Substudy: Selected centers with the ability to 
perform high quality 4D computed tomography (CT) scans will 
include subjects from the Main Cohort in a CT imaging 
substudy to assess the prevalence of reduced leaflet mobility 
and its relationship, if any, to clinical events. 
• Bicuspid Nested Registry: A prospective, single-arm, nested 
registry cohort of subjects who have a native bicuspid aortic valve, 
are considered at intermediate risk for surgical aortic valve 
replacement and are treated with the LOTUS Edge Valve System.  
• Roll-In Cohort: A roll-in phase with the study device for centers 
that do not have implantation experience with the LOTUS Edge 
Valve System; each of these centers will perform at least 2 roll-in 
cases before commencing enrollment in the evaluable Main 
Cohort and Bicuspid Nested Registry. Data from roll-in subjects 
will be summarized separately from the evaluable Main Cohort 
and Bicuspid Nested Registry. Roll-in subjects will not be 
included in the primary endpoint analysis. 
The REPRISE IV study will be conducted in accordance with 21 CFR 
Parts 11, 50, and 54; the relevant parts of the International Conference on 
Harmonisation (ICH) Guidelines for Good Clinical Practices (GCP); the 
International Standard ISO 14155 Clinical Investigation of Medical 

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REPRISE IV:  REpositionable Percutaneous Replacement of Stenotic Aortic Valve 
through Implantation of LOTUS Edge™ Valve System in IntermediatE Surgical Risk 
Subjects 
Devices for Human Subjects – Good Clinical Practice; ethical principles 
that have their origins in the Declaration of Helsinki; and pertinent 
individual country/state/local laws and regulations. The study shall not 
begin until the required approval/favorable opinion from the Institutional 
Review Board/Human Research Ethics Committee (IRB/HREC) and/or 
regulatory authority has been obtained, if appropriate. 
The study design is summarized in the figure below. 
 
REPRISE IV Study Design Overview 
Planned 
Number of 
Subjects/ 
Investigational 
Centers/ 
Countries 
Subjects will be enrolled at up to 65 centers in the United States and 
Australia. There will be up to 926 subjects enrolled in REPRISE IV as 
shown below. 
Cohort 
Number of Subjects 
Main 
696* 
Bicuspid Nested Registry 
100 
Roll-In  
Up to 130 
* Up to 200 subjects from the main cohort will be enrolled in the CT 
Imaging Substudy. If 200 subjects have not enrolled in the CT 
Imaging Substudy by completion of enrollment in the main cohort, 
additional subjects who meet the REPRISE IV eligibility criteria 
will be enrolled in a separate CT Imaging Cohort to achieve a total 
of 200 subjects in the CT Imaging Substudy. 

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REPRISE IV:  REpositionable Percutaneous Replacement of Stenotic Aortic Valve 
through Implantation of LOTUS Edge™ Valve System in IntermediatE Surgical Risk 
Subjects 
Primary 
Endpoint 
Composite of all-cause mortality and all stroke at 1 year.  
Additional 
Measurements 
Additional measurements based on the VARCa endpoints and definitions 
will be collected peri- and post-procedure, at discharge or 7 days post-
procedure (whichever comes first), 30 days, and annually through 
10 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 Myocardial infarction (MI): periprocedural (≤72 hours post index 
procedure) and spontaneous (>72 hours post index procedure) 
o Bleeding: life-threatening (or disabling) and major (through 
5 years) 
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 (through 5 years) 
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  
o New onset of atrial fibrillation or atrial flutter  
o Coronary obstruction: periprocedural (≤72 hours post index 
procedure) 
o Ventricular septal perforation: periprocedural (≤72 hours post 
index procedure) 
o Mitral apparatus damage: periprocedural (≤72 hours post index 
procedure) 
o Cardiac tamponade: periprocedural (≤72 hours post index 
procedure) 

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REPRISE IV:  REpositionable Percutaneous Replacement of Stenotic Aortic Valve 
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Subjects 
o Prosthetic aortic valve malpositioning, including valve migration, 
valve embolization, or ectopic valve deployment 
o Transcatheter aortic valve (TAV)-in-TAV deployment 
o Prosthetic aortic valve thrombosis 
o Prosthetic aortic valve endocarditis 
• Device Performance endpoints peri- and post-procedure:  
o Successful vascular access, delivery and deployment of the study 
valve, and successful retrieval of the delivery system 
o Successful retrieval of the study valve if retrieval is attempted 
o Successful repositioning of the study valve if repositioning is 
attempted (see Note 1 below) 
o Grade of aortic valve regurgitation: paravalvular, central, and 
combined 
• Device success, defined as absence of procedural mortality, correct 
positioning of a single valve into the proper anatomical location, 
intended performance of the study device (effective orifice area [EOA] 
>0.9 cm2 for BSA <1.6 m2 and EOA >1.1 cm2 for BSA ≥1.6 m2 plus 
either a mean aortic valve gradient <20 mm Hg or a peak velocity 
<3m/sec, and no moderate or severe prosthetic valve aortic 
regurgitation)  
• Additional indications of prosthetic aortic valve performance as 
measured by transthoracic echocardiography (TTE; see Note 2 and 
Note 3 below) 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 (see Note 3 
below) 
• Neurological status as determined by the following: 
o National Institutes of Health Stroke Scale (NIHSS) and modified 
Rankin Scale (mRS) assessments, which must be performed at 
baseline and pre-specified timepoints for all enrolled subjects (see 
Note 4 below). NIHSS and mRS must be performed by a 
neurology professional or certified personnel.  

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through Implantation of LOTUS Edge™ Valve System in IntermediatE Surgical Risk 
Subjects 
o For subjects diagnosed with a stroke, a neurological physical 
exam, mRS, and NIHSS must be performed after the event; mRS 
must also be administered at 90±14 days following a stroke; the 
simplified mRS questionnaire may be used for this follow-up 
assessment. The neurological physical exam must be conducted 
by a neurologist, neurology fellow, neurology physician assistant, 
or neurology nurse practitioner. 
• Health status as evaluated by Kansas City Cardiomyopathy and SF-12 
Quality of Life questionnaires at baseline, 1 month, and 1 and 5 years. 
• For subjects in the Bicuspid Nested Registry, a CT scan at 30 days post 
LOTUS Edge Valve implantation. The data will be evaluated by an 
independent CT core laboratory. 
• For subjects in the CT Imaging Substudy, a 4D CT scan at 30 days and 
at 1 year post LOTUS Edge valve implantation to assess the 
prevalence of reduced leaflet mobility and its relationship, if any, to 
clinical events. The data will be evaluated by an independent CT core 
laboratory. 
Note 1: For the LOTUS Edge valve, repositioning may be achieved with 
partial or full resheathing of the valve. 
Note 2: 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. 
Note 3: Echocardiography and NYHA assessment are not required in 
years 6, 8, and 9 (telephone follow-up only). 
Note 4: NIHSS is required at discharge and 1 year; mRS is required at all 
follow-up visits up to 5 years. 
a:  Leon M, et al. J Am Coll Cardiol. 2011;57:253–69 
Kappetein AP, et al. J Am Coll Cardiol. 2012;60:1438–54 
Method of 
Assigning 
Subjects to 
Treatment 
Main Cohort: Subjects with severe aortic valve stenosis who meet all 
eligibility criteria may be treated with the LOTUS Edge Valve System. 
- 
Up to 200 subjects from the main cohort will be enrolled in the CT 
Imaging Substudy. If 200 subjects have not enrolled in the CT 
Imaging Substudy by completion of enrollment in the main cohort, 
additional subjects who meet the REPRISE IV eligibility criteria 

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Subjects 
will be enrolled in a separate CT Imaging Cohort to achieve a total 
of 200 subjects in the CT Imaging Substudy. 
Bicuspid Nested Registry: Subjects with a native bicuspid aortic valve 
who meet all inclusion criteria and have no other exclusion criterion may 
be treated with the LOTUS Edge Valve System as part of a single-arm, 
nested registry cohort. 
Roll-In Cohort: For centers that do not have implantation experience 
with the LOTUS Edge Valve System 2 to 4 roll-in subjects will be treated 
before commencing enrollment in the Main Cohort and Bicuspid Nested 
Registry. 
Follow-up 
Schedule 
All subjects implanted with a study device will be assessed at baseline, 
peri- and post-procedure, at discharge or 7 days post-procedure 
(whichever comes first), 30 days, 1 year, and then annually for up to 
10 years post-procedure. Subjects who are enrolled but not implanted 
with a study device at the time of the procedure will be followed for 
safety through 1 year. 
The visits at 30 days, 1 ̶ 5 years, 7 years, and 10 years are to be an 
office/clinical or in-person visit but may be done in-hospital should the 
subject be admitted at the time. Telephone follow-up is allowed at 6, 8, 
and 9 years.  Procedures at each scheduled visit are described above under 
“Additional Measurements.” 
Study 
Duration 
Subjects implanted with a study device will be followed for 10 years after 
the index procedure. 
Enrollment is expected to be completed in approximately 24 months; 
therefore, the total study duration is estimated to be approximately 
12 years. 
Participant 
Duration 
The study duration for each subject is expected to be approximately 
10 years. 
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. 

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Subjects 
Anti-Platelet Therapy 
Per society guidelinesb, antiplatelet therapy with aspirin and/or a P2Y12 
inhibitor (clopidogrel recommended) is recommended after TAVR to 
decrease the risk of thrombotic or thromboembolic complications if there 
are no contraindications to these medications. 
Study subjects must receive some antiplatelet therapy (aspirin and/or a 
P2Y12 inhibitor) for at least 1 month following valve implant. A loading 
dose of the same antiplatelet medication (aspirin and/or a P2Y12 inhibitor) 
is required for subjects who have not been on the antiplatelet therapy for 
≥72 hours at the time of the index procedure (see below for recommended 
doses). 
Note 5: It is recommended that subjects be treated with both aspirin and a 
P2Y12 inhibitor for at least 1 month after valve implantation.  
Aspirin Dose 
The recommended loading dose of aspirin is 75–325 mg for subjects who 
have not been on aspirin therapy for ≥72 hours at the time of the index 
procedure. The loading dose must be administered prior to the implant 
procedure. Subjects who have been taking aspirin daily for ≥72 hours at 
the time of the index procedure do not require a loading dose of aspirin. 
After the valve implant procedure, the recommended dose of aspirin is 
≥75 mg daily given for at least 1 month. It is recommended that daily 
aspirin be given indefinitely thereafter as per local standard of care.  
P2Y12 Inhibitor Dose (clopidogrel recommended) 
The recommended loading dose of a P2Y12 inhibitor is ≥300 mg 
clopidogrel, 60 mg prasugrel, or 180 mg ticagrelor for subjects who have 
not been on P2Y12 inhibitor therapy for ≥72 hours at the time of the index 
procedure. The loading dose must be administered prior to the implant 
procedure. Subjects who have been taking a P2Y12 inhibitor daily for 
≥72 hours at the time of the index procedure do not require a loading dose 
of the P2Y12 inhibitor. 
After the valve implant procedure, P2Y12 inhibitor dosing per local 
standard of care is recommended for at least 1 month (clopidogrel is 
recommended with a dose of 75 mg daily). 
Note 6: If a subject requires chronic anticoagulation, either a P2Y12 
inhibitor (clopidogrel recommended) or aspirin is recommended prior to 

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and after the implant procedure in addition to the anticoagulant therapy 
(but both aspirin and a P2Y12 inhibitor are not recommended). After the 
implant procedure, the subject should be treated with an oral 
anticoagulant (warfarin or another vitamin K antagonist recommended) 
and either a P2Y12 inhibitor (clopidogrel recommended) or aspirin for at 
least 1 month.  
b:  Holmes DR, et al. J Am Coll Cardiol. 2012;59:1200–1254 
 
Nishimura R, et al. J Am Coll Cardiol. 2014;63: e57–e185 
 
Nishimura R, et al. Circulation. 2017;135:e1159–e95  
Inclusion 
Criteria 
IC1. 
Subject has documented severe aortic stenosis defined as initial 
AVA ≤1.0 cm2 (or AVA index ≤0.6 cm2/m2) AND a mean 
pressure gradient ≥40 mm Hg OR maximal aortic valve velocity 
≥4.0 m/s OR Doppler velocity index ≤0.25 as measured by 
echocardiography and/or invasive hemodynamicsc,d  
 
Note 7: In cases of low flow, low gradient aortic stenosis with left 
ventricular dysfunction (ejection fraction <50%), dobutamine can 
be used to assess the grade of aortic stenosis (maximum 
dobutamine dose of 20 mcg/kg/min recommended)c; the subject 
may be enrolled if echocardiographic criteria are met with this 
augmentation.  
 
IC2. 
A subject in the Bicuspid Aortic Valve Nested Registry cohort 
must have a documented Sievers Type 0 or Sievers Type 1 
bicuspid aortic valve based on CT assessment and confirmed by 
the CT core lab with hemodynamic parameters that meet the 
criteria in IC1. 
IC3. 
Subject has a documented aortic annulus size of ≥20 mm and 
≤27 mm based on the center’s assessment of pre-procedure 
diagnostic imaging (and confirmed by the Case Review 
Committee [CRC]).  
IC4. 
Subject has symptomatic aortic valve stenosis per IC1 definition 
above with NYHA Functional Class ≥ II.  
IC5. 
Heart team (which must include an experienced cardiac 
interventionalist and an experienced cardiac surgeon) agrees that 
the subject is at intermediate risk of operative mortality (≥3% and 
<8% at 30 days based on the Society of Thoracic Surgeons [STS] 

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Subjects 
risk score and other clinical comorbidities unmeasured by the risk 
calculator) and TAVR is appropriate.  
 
Note 8: Risk of operative mortality must be assessed via an in-
person evaluation by a center cardiac surgeon and must be 
confirmed by the CRC (which must include an experienced 
cardiac surgeon). 
IC6. 
Heart team agrees that the subject is likely to benefit from valve 
replacement.  
IC7. 
Subject (or legal representative) has been informed of 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. 
IC9. 
Subject is expected to be able to take the protocol-required 
adjunctive pharmacologic therapy. 
c: Nishimura RA, et al. J Am Coll Cardiol. 2014;63:e57–e185 
d: Leon M, et al. J Am Coll Cardiol. 2011;57: 253–69 
Exclusion 
Criteria 
EC1. Subject has a unicuspid or bicuspid aortic valve (not applicable to 
subjects in the Bicuspid Nested Registry cohort). 
 
Note 9: Subjects in the Bicuspid Nested Registry cohort will have 
a documented Sievers Type 0 or Sievers Type 1 bicuspid aortic 
valve based on CT assessment and confirmed by the CT core lab. 
Subjects are not eligible for inclusion in the Bicuspid Nested 
Registry cohort if the maximum diameter of the ascending aorta is 
>45 mm or if the subject has another indication for aortic root 
replacement. Subjects with a Sievers Type 2 bicuspid valve are 
not eligible for enrollment in any study cohort. 
EC2. Subject has had an acute myocardial infarction within 30 days 
prior to 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). 

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EC3. Subject has had a cerebrovascular accident or transient ischemic 
attack clinically confirmed by a neurologist or neuroimaging 
within the past 6 months prior to study enrollment. 
EC4. Subject is on renal replacement therapy or has GFR <20 (based on 
hospital preferred method). See AEC1 below if subject is in the 
CT Imaging Substudy. 
EC5. Subject has a pre-existing prosthetic aortic or mitral valve. 
EC6. Subject has severe (4+) aortic, tricuspid, or mitral regurgitation. 
EC7. Subject has moderate to severe mitral stenosis (mitral valve area 
≤1.5 cm2 and diastolic pressure half-time ≥150 ms, Stage C or 
Dc). 
 
EC8. Subject has a need for emergency surgery for any reason. 
EC9. Subject has a history of endocarditis within 6 months of index 
procedure or evidence of an active systemic infection or sepsis. 
EC10. Subject has echocardiographic evidence of new intra-cardiac 
vegetation or intraventricular or paravalvular thrombus requiring 
intervention. 
EC11. Subject has platelet count <50,000 cells/mm3 or 
>700,000 cells/mm3, or white blood cell count <1,000 cells/mm3. 
EC12. Subject will refuse transfusions or has had a gastrointestinal bleed 
requiring hospitalization or transfusion within the past 3 months 
or has other clinically significant bleeding diathesis or 
coagulopathy that would preclude treatment with required 
antiplatelet regimen. 
EC13. Subject has known hypersensitivity to contrast agents that cannot 
be adequately pre-medicated, or has known hypersensitivity to 
aspirin, all P2Y12 inhibitors, heparin, nickel, tantalum, titanium, or 
polyurethanes. 
EC14. Subject has a life expectancy of less than 24 months due to non-
cardiac, comorbid conditions based on the assessment of the 
investigator at the time of enrollment. 
EC15. Subject has hypertrophic cardiomyopathy. 
EC16. Subject has any therapeutic invasive cardiac or vascular procedure 
within 30 days prior to the index procedure (except for balloon 

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aortic valvuloplasty or pacemaker or implantable cardioverter 
defibrillator implantation, which are allowed).  
EC17. Subject has multivessel coronary artery disease with a Syntax 
score >22, and/or an unprotected left main coronary artery. 
EC18.  Subject has severe left ventricular dysfunction with ejection 
fraction <20%. 
EC19. Subject is in cardiogenic shock or has hemodynamic instability 
requiring inotropic support or mechanical support devices. 
EC20. Subject has arterial access that is not acceptable for the study 
device delivery system as defined in the device Instructions For 
Use.  
EC21. Subject has severe vascular disease that would preclude safe 
access (e.g., aneurysm with thrombus that cannot be crossed 
safely; marked tortuosity; significant narrowing of the abdominal 
aorta; severe unfolding of the thoracic aorta; or thick, protruding, 
ulcerated atheroma in the aortic arch). 
EC22. Subject has current problems with substance abuse (e.g., alcohol, 
etc.) that may interfere with the subject’s participation in this 
study. 
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. Enrollment is permissible after 
permanent pacemaker implantation. 
EC25. Subject has severe incapacitating dementia.  
c: Nishimura RA, et al. J Am Coll Cardiol. 2014;63:e57–e185 
Additional 
Exclusion 
Criteria 
Additional exclusion criteria apply to subjects considered for enrollment 
in the CT Imaging Substudy as listed below. 
AEC1.  Subject has eGFR <30 mL/min (chronic kidney disease stage IV 
or stage V). 

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AEC2.  Subject has atrial fibrillation that cannot be rate controlled to 
ventricular response rate < 60 bpm. 
AEC3. Subject is expected to undergo chronic anticoagulation therapy 
after the index procedure. 
 
Note 10: Subjects treated with short-term anticoagulation post 
procedure can be included in the imaging substudy; in these 
subjects the 30-day imaging will be performed 30 days after 
discontinuation of anticoagulation. 
Statistical Methods 
Analysis Sets 
Analysis sets are listed below. 
 - Intention-To-Treat (ITT): This population includes all subjects who 
sign an Informed Consent Form and are enrolled in the study, 
regardless of whether the study device is implanted.  
 - Implanted: This population includes all subjects who sign an 
Informed Consent Form, are enrolled in the study, and are implanted 
with the study device. 
A subject is considered enrolled in the study when an attempt is made to 
insert a LOTUS Edge valve. 
Primary 
Endpoint 
Statistical 
Hypothesis 
In the Main Cohort, the rate of the primary endpoint (composite of all-
cause mortality and all stroke at 1 year) is less than the performance goal 
(PG) of 15.2% (expected rate of 11.1% plus testing margin of 4.1%). 
Statistical Test 
Method for the 
Primary 
Endpoint  
A one-sample z-test will be used to test the one-sided hypothesis that the 
1-year primary endpoint rate for LOTUS Edge in the Main Cohort is less 
than the PG: 
 
H0: PLOTUS Edge  ≥ PG 
 
H1: PLOTUS Edge  < PG 
where PLOTUS Edge is the primary endpoint rate for the LOTUS Edge group 
and PG is the performance goal. 
The primary analysis set for the primary endpoint is the ITT analysis set. 
This endpoint will also be analyzed for the implanted analysis set. 

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REPRISE IV:  REpositionable Percutaneous Replacement of Stenotic Aortic Valve 
through Implantation of LOTUS Edge™ Valve System in IntermediatE Surgical Risk 
Subjects 
Sample Size 
Parameters for 
the Primary 
Endpoint  
The sample size calculation for the primary endpoint (composite of all-
cause mortality and all stroke at 1 year) is based on the following 
assumptions. 
• Expected rate for LOTUS Edge = 11.1%† 
• Testing margin = 4.1% (37% relative to the expected rate) 
• Performance goal (PG) = 15.2% (expected rate of 11.1% plus testing 
margin of 4.1%) 
• Test significance level (α) = 0.025 (1-sided) 
• Power = 87.5%  
• Number of evaluable subjects = 675 
• Expected rate of attrition = 3% 
• Total enrolment (evaluable Main Cohort) = 696 subjects  
† Estimated pooled rate from the fixed effect model based on the TAVR 
arm data from PARTNER II S3ie and SURTAVIf 
e: Thourani VH, et al. Lancet 2016;387:2218-25 
f: Reardon MJ, et al. N Engl J Med 2017:376:1321-31 
Success 
Criteria for 
the Primary 
Endpoint  
If the P value from the one-sample z-test is <0.025, it will be concluded 
that the primary endpoint with the LOTUS Edge Valve System is less 
than the PG. This corresponds to the one-sided upper 97.5% confidence 
bound of the observed composite rate of all-cause mortality and all stroke 
in the Main Cohort at 1 year being < 15.2%. 
Bicuspid 
Nested 
Registry 
The planned enrollment for the Bicuspid Nested Registry cohort is up to 
100 subjects. Descriptive statistics for all endpoints will be summarized 
using both the ITT and implanted analysis sets. 
 
 
 
 

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3. Table of Contents 
1. 
TITLE PAGE  .......................................................................................................................1 
2. 
PROTOCOL SYNOPSIS .........................................................................................................3 
3. 
TABLE OF CONTENTS .......................................................................................................17 
3.1. Table of Figures .....................................................................................................21 
3.2. Table of Tables ......................................................................................................22 
4. 
INTRODUCTION ................................................................................................................24 
4.1. Background ............................................................................................................24 
4.1.1. 
Aortic Stenosis ..........................................................................................24 
4.1.2. 
REPRISE Clinical Program ......................................................................28 
4.1.2.1. 
REPRISE I Study .....................................................................28 
4.1.2.2. 
REPRISE II Study....................................................................30 
4.1.2.3. 
RESPOND Post-Market Surveillance Study ...........................35 
4.1.2.4. 
REPRISE III Randomized Controlled Trial ............................40 
4.1.2.5. 
REPRISE Japan .......................................................................46 
4.1.2.6. 
REPRISE NG DS Study ..........................................................47 
4.1.2.7. 
REPRISE EDGE ......................................................................51 
4.2. Study Rationale .....................................................................................................52 
5. 
DEVICE DESCRIPTION ......................................................................................................53 
5.1. LOTUS Edge Valve System .................................................................................53 
5.1.1. 
LOTUS Edge Valve ..................................................................................54 
5.1.2. 
LOTUS Edge Delivery System ................................................................55 
5.1.3. 
Lotus and iSleeve Introducer Sets ............................................................56 
5.2. Device Labeling .....................................................................................................56 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................................57 
6.1. Study Objectives ....................................................................................................57 
6.2. Study Endpoints ....................................................................................................57 
6.2.1. 
Primary Endpoint ......................................................................................57 
6.2.2. 
Additional Measurements .........................................................................57 
6.3. Overview of Objectives and Endpoints ...............................................................60 
7. 
STUDY DESIGN .................................................................................................................60 
7.1. Scale and Duration ................................................................................................60 

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7.2. Treatment Assignment .........................................................................................62 
7.2.1. 
Treatment ..................................................................................................62 
7.3. Justification for the Study Design ........................................................................62 
8. 
SUBJECT SELECTION ........................................................................................................63 
8.1. Study Population and Eligibility ..........................................................................63 
8.2. Inclusion Criteria ..................................................................................................63 
8.3. Exclusion Criteria .................................................................................................64 
9. 
SUBJECT ACCOUNTABILITY .............................................................................................66 
9.1. Point of Enrollment ...............................................................................................66 
9.2. Discontinuation of Study Intervention ................................................................66 
9.3. Withdrawal ............................................................................................................66 
9.4. Lost to Follow-Up ..................................................................................................67 
9.5. End-of-Study Definition .......................................................................................67 
10. STUDY METHODS .............................................................................................................67 
10.1. Data Collection ......................................................................................................67 
10.2. Study Candidate Screening ..................................................................................74 
10.2.1. Strategies for Recruitment and Retention .................................................74 
10.3. Subject Informed Consent ....................................................................................75 
10.4. Screening Assessments ..........................................................................................75 
10.5. Baseline Assessments ............................................................................................77 
10.6. Pre-procedure Medications ..................................................................................78 
10.7. Index Procedure ....................................................................................................79 
10.8. Post Index Procedure ............................................................................................81 
10.9. Prior to Discharge or 7 Days Post-Procedure (Whichever Comes First) ........82 
10.10. 
Follow-up .................................................................................................83 
10.10.1. 30-Day Follow-up (30±7 Days) ................................................................84 
10.10.2. 12-Month Follow-up (365±30 Days) ........................................................85 
10.10.3. Annual Follow-up (±45 Days) to 5 Years ................................................86 
10.10.4. Follow-up (±60 Days) at 7 and 10 Years ..................................................87 
10.10.5. Follow-up (±60 Days) at 6, 8 and 9 Years ................................................87 
10.11. 
Study Completion ...................................................................................88 

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10.12. 
Source Documents ..................................................................................88 
10.13. 
Local Laboratory/Vendor Documentation ...........................................88 
11. STATISTICAL CONSIDERATIONS ......................................................................................89 
11.1. Endpoints ...............................................................................................................89 
11.1.1. Primary Endpoint ......................................................................................89 
11.1.1.1. Statistical Hypothesis for the Primary Endpoint ......................89 
11.1.1.2. Sample Size Parameters for the Primary Endpoint ..................89 
11.1.1.3. Success Criteria – Primary Endpoint .......................................89 
11.1.1.4. Statistical Methods – Primary Endpoint ..................................90 
11.1.2. Baseline Comparability ............................................................................90 
11.1.3. Post-procedure Measurements ..................................................................90 
11.1.4. Subgroup Analyses ...................................................................................90 
11.2. General Statistical Methods .................................................................................91 
11.2.1. Analysis Sets .............................................................................................91 
11.2.2. Control of Systematic Error/Bias ..............................................................91 
11.2.3. Reporting Events ......................................................................................91 
11.3. Data Analyses ........................................................................................................91 
11.3.1. Other Measurements .................................................................................92 
11.3.2. Interim Analyses .......................................................................................92 
11.3.3. Justification of Pooling .............................................................................92 
11.3.4. Multivariable Analyses .............................................................................92 
11.3.5. Changes to Planned Analyses ...................................................................92 
12. HEALTH ECONOMICS OUTCOMES ...................................................................................92 
13. DATA MANAGEMENT .......................................................................................................93 
13.1. Data Collection, Processing, and Review ............................................................93 
13.2. Data Retention .......................................................................................................93 
13.3. Core Laboratories .................................................................................................94 
13.3.1. Echocardiography Core Laboratory .........................................................94 
13.3.2. CT and Angiography Core Laboratory .....................................................94 
13.3.3. Electrocardiography (ECG) Core Laboratory ..........................................94 
13.3.4. Histopathology Core Laboratory ..............................................................94 
14. DEVIATIONS .....................................................................................................................94 
15. DEVICE ACCOUNTABILITY ..............................................................................................95 

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15.1. Device Accountability for Products Labelled Investigational ...........................95 
15.2. Commercial Device ...............................................................................................96 
16. COMPLIANCE ....................................................................................................................96 
16.1. Statement of Compliance ......................................................................................96 
16.2. Investigator Responsibilities ................................................................................96 
16.2.1. Delegation of Responsibility ....................................................................98 
16.3. Institutional Review Board/Human Research Ethics Committee ....................98 
16.4. Sponsor Responsibilities .......................................................................................99 
16.4.1. Role of Boston Scientific Corporation Representatives ...........................99 
16.4.2. Training with the Investigational Device ...............................................100 
16.5. Insurance ..............................................................................................................101 
17. MONITORING ..................................................................................................................101 
18. POTENTIAL RISKS AND BENEFITS .................................................................................101 
18.1. Anticipated Adverse Events and Risks Associated with Transcatheter Aortic 
Valve Replacement ..............................................................................................102 
18.1.1. Hypoattenuated Leaflet Thickening/Reduced Leaflet Motion/Leaflet 
Thrombosis .............................................................................................103 
18.2. Risks Associated with the Study Device(s) ........................................................104 
18.3. Risks Associated with Participation in the Clinical Study ..............................104 
18.4. Possible Interactions with Concomitant Medical Treatments ........................104 
18.5. Risk Minimization Actions .................................................................................104 
18.6. Anticipated Benefits ............................................................................................105 
18.6.1. Potential Benefits to the TAVR Procedure .............................................105 
18.6.2. Potential Benefit Using the LOTUS Edge Valve System ......................106 
18.7. Risk to Benefit Rationale ....................................................................................106 
19. SAFETY REPORTING .......................................................................................................107 
19.1. Reportable Events by Investigational Center to Boston Scientific .................107 
19.2. Definitions and Classification ............................................................................108 
19.3. Relationship to Study Device(s) .........................................................................110 
19.4. Investigator Reporting Requirements ...............................................................111 
19.5. Device Deficiencies ..............................................................................................113 

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19.5.1. Boston Scientific Device Deficiencies ...................................................113 
19.6. Reporting to Regulatory Authorities / IRBs / HRECs / Investigators ...........114 
20. INFORMED CONSENT ......................................................................................................114 
21. COMMITTEES .................................................................................................................116 
21.1. Safety Monitoring Process ..................................................................................116 
21.1.1. Clinical Events Committee .....................................................................116 
21.1.2. Data Monitoring Committee ...................................................................116 
21.2. Case Review Committee .....................................................................................116 
21.3. Steering Committee .............................................................................................117 
22. SUSPENSION OR TERMINATION ......................................................................................117 
22.1. Premature Termination of the Study ................................................................117 
22.1.1. Criteria for Premature Termination of the Study ....................................117 
22.2. Termination of Study Participation by the Investigator or Withdrawal of 
IRB/HREC Approval ..........................................................................................117 
22.3. Requirements for Documentation and Subject Follow-up ..............................118 
22.4. Criteria for Suspending/Terminating a Study Center .....................................118 
23. PUBLICATION POLICY ....................................................................................................118 
24. BIBLIOGRAPHY ...............................................................................................................119 
25. ABBREVIATIONS AND DEFINITIONS ...............................................................................130 
25.1. Abbreviations ......................................................................................................130 
25.2. Definitions ............................................................................................................131 
26. REVISION HISTORY ........................................................................................................147 
26.1. Summary of Protocol Revision History .............................................................147 
 
3.1. 
Table of Figures 
Figure 4.1-1: REPRISE III Randomized Subject Analysis Groups ........................................ 41 
Figure 5.1-1: Overview of Principal Components of the LOTUS Edge Valve System .......... 54 
Figure 5.1-2: LOTUS Edge Valve Implant ............................................................................. 55 
Figure 5.1-3: LOTUS Edge Controller ................................................................................... 55 

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Figure 5.1-4:  Lotus Introducer Set (Top) and iSleeve Introducer Set (Bottom) .................... 56 
Figure 7.1-1: REPRISE IV Study Design ............................................................................... 61 
Figure 10.1-1: REPRISE IV Data Collection Scheme............................................................ 68 
 
3.2. 
Table of Tables 
Table 4.1-1: TAVR Outcomes at 30 Days and 1 Year – Transfemoral Access ..................... 25 
Table 4.1-2: Outcomes to 5 Years in REPRISE I ................................................................... 29 
Table 4.1-3: Device Performance Endpoints – REPRISE II Main Cohort ............................. 31 
Table 4.1-4: Clinical and Echocardiographic Outcomes to 5 Years ‒ REPRISE II Main 
Cohort (N=120) ................................................................................................... 31 
Table 4.1-5: Clinical and Echocardiographic Outcomes to 4 Years ‒ REPRISE II Full Cohort 
(N=250)................................................................................................................ 33 
Table 4.1-6: Procedural Device Success, RESPOND As-Treated Analysis Set .................... 35 
Table 4.1-7: RESPOND Secondary Endpoints – VARC Safety Assessments at 30 Days and 
1 Year Post-Procedure; As-Treated Analysis Set ................................................ 36 
Table 4.1-8: Core Laboratory Echocardiographic Assessments at Pre-Discharge and 1 Year, 
RESPOND As-Treated Analysis Set ................................................................... 37 
Table 4.1-9: Bicuspid and Non-Bicuspid Groups in RESPOND – As-Treated Analysis Set 
(N=996)................................................................................................................ 38 
Table 4.1-10: RESPOND Extension – VARC Safety Assessments (30 Days) and Core Lab 
Echocardiographic Assessments (Pre-Discharge); As-Treated Analysis Set ...... 39 
Table 4.1-11: Clinical and Echocardiographic Outcomes at 30 Days and 1 Year in REPRISE 
III RCT ................................................................................................................. 43 
Table 4.1-12: 30-Day, 6-Month, and 1-Year Outcomes – REPRISE Japan Evaluable 
Transfemoral Cohort (N=40) ............................................................................... 46 
Table 4.1-13: Valve Performance by TTE, Core Lab Analysis – REPRISE NG DS Cohorts 
A, B and C ........................................................................................................... 49 
Table 4.1-14: Discharge, 30-Day, 6-Month, and 1-Year Clinical Outcomes in REPRISE NG 
DS Cohorts A, B and C ........................................................................................ 49 
Table 4.1-15: 30-Day and 1-Year Outcomes – REPRISE EDGE (N=15) ............................. 51 
Table 6.3-1: Overview of Objectives and Endpoints .............................................................. 60 
Table 8.2-1: REPRISE IV Inclusion Criteria .......................................................................... 63 
Table 8.3-1: REPRISE IV Exclusion Criteria ......................................................................... 64 

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Table 10.1-1: Study Event Schedule ....................................................................................... 69 
Table 10.12-1: Source Documentation Requirements ............................................................ 88 
Table 18.1-1: Risks Associated with Transcatheter Aortic Valve Replacement .................. 102 
Table 19.2-1: Safety Definitions ........................................................................................... 108 
Table 19.3-1: Criteria for Assessing Relationship of Study Device and Procedure to Adverse 
Event .................................................................................................................. 110 
Table 19.4-1: Investigator Reporting Requirements ............................................................. 112 
Table 25.1-1: Abbreviations and Acronyms ......................................................................... 130 
Table 25.2-1: Definitions ...................................................................................................... 132 
Table 26.1-1: Protocol Revision History .............................................................................. 148 
 
 

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4. Introduction 
This protocol specifies procedures and contains information relevant to the clinical 
evaluation of the LOTUS Edge™ Valve System, a transcatheter aortic valve replacement 
(TAVR) device designed and manufactured by Boston Scientific Structural Heart a Division 
of Boston Scientific Corporation (BSC). The LOTUS Edge 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 TAVR. Early leaflet function during 
valve deployment and the presence of a radiopaque tantalum marker on the braided frame 
facilitate optimal initial positioning of the valve. If needed, the valve may be 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 polycarbonate-based 
urethane outer seal (Adaptive Seal™) designed to minimize paravalvular regurgitation 
(PVR).  
The LOTUS Edge Valve System is introduced into the body using either the iSleeve™ 
Introducer Set or the large Lotus Introducer Set. Both sets are designed to facilitate vascular 
introduction and deployment of the system. Both devices have a dilator and sheath 
component, but the iSleeve sheath can expand temporarily as LOTUS Edge is inserted 
through the femoral artery. This allows for an extended range of vascular access. 
Additional device information can be found in Section 5.  
Study subjects will be entered into the Roll-In Cohort, single-arm Main Cohort, or a single-
arm, nested registry cohort of subjects with a native bicuspid aortic valve (Bicuspid Nested 
Registry). Additional information on study design can be found in Section 7. 
4.1. 
Background 
4.1.1. 
Aortic Stenosis 
The incidence of aortic stenosis (AS), which most commonly occurs in the very elderly, 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 process1-3. It is estimated that nearly 5% of 
elderly ≥75 years of age have AS and its prevalence is expected to increase due to an aging 
population2,3. Aortic stenosis is associated with high rates of death and complications after 
the appearance of symptoms2,3.    
Many patients with severe and symptomatic aortic stenosis are successfully treated with 
surgical aortic valve replacement (SAVR), which can reduce symptoms and improve 
survival2-5. However, up to one-third of patients with severe AS are not treated with SAVR 
because of their comorbidities and consequent perioperative risk6-8. With standard medical 
therapy, mortality after 1 year among these patients may be as high as 50%2,3,8. Percutaneous 
transluminal aortic valvuloplasty, which was introduced as an alternative to SAVR in elderly 
and/or high-risk surgical patients, can provide symptomatic relief and/or temporary 
improvement but does not provide definitive treatment in patients with severe calcific AS. It 
is also associated with relatively high mortality and complication rates3,9. 

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Transcatheter aortic valve replacement provides an alternative to the surgical approach in the 
treatment of severe AS. An antegrade (transapical) or retrograde (e.g., transfemoral, 
transaortic through the ascending aorta, trans-subclavian) approach can be used10. Patients 
generally undergo a joint interdisciplinary screening process, including comprehensive 
multimodality imaging11-14, prior to procedure recommendation. Because of the limitations of 
existing surgical risk scores15-18, center heart teams also consider other co-morbidities and 
patient frailty to fully characterize risk19. The use of TAVR has produced significant 
reductions in mortality and repeat hospitalization compared to medical therapy8,20,21. In 
selected high-risk surgical patients, TAVR has also resulted in similar22-24 or lower25-27  
mortality when compared to SAVR. Continuous procedural refinements and device 
improvements have aimed to widen application to lower risk patients28,29. Propensity score 
analyses have suggested comparable mortality after TAVR or SAVR in some intermediate-
risk patients30-32, and 2 recent randomized, controlled trials (RCT) showed similar outcomes 
between the two treatment groups33,34. Meta-analyses have also shown similar long-term 
survival after TAVR compared to SAVR35,36. Currently, TAVR is approved for use in AS 
patients considered inoperable or at intermediate to high surgical risk and expert consensus 
documents have outlined TAVR patient selection criteria4,5,37,38.   
Recently, reduced aortic valve leaflet motion, mainly asymptomatic, has been identified with 
follow-up CT among some TAVR subjects39,40. Therapeutic anticoagulation with warfarin 
was associated with a decreased incidence and leaflet motion could be restored with 
anticoagulation. This phenomenon has not been definitively linked with abnormal clinical 
symptoms. Studies to assess its prevalence and determine any relationship to patient, 
procedural, or pharmacologic factors or clinical events are ongoing.  
Table 4.1-1 summarizes outcomes at 30 days and 1 year from TAVR studies that enrolled 
subjects similar to those planned for this study (intermediate surgical risk, transfemoral 
access), as well as results from studies with inoperable and high-risk surgical patients. 
Table 4.1-1: TAVR Outcomes at 30 Days and 1 Year – Transfemoral Access 
Study  
Device/N 
All-cause 
Death  
Disabling/ 
Major 
Stroke 
Major 
VC 
LT 
Bleeding  
AKI 
30-Day Outcomes – Randomized Studies 
PARTNER 1Aa 
(2011)22 
SAPIEN / 244† 
3.3 
2.9 
14.0 
9.5b 
2.5c 
PARTNER 2Ad 
(2016)33 
SAPIEN XT / 775* 
3.0 
2.3 
8.5 
6.7 
0.5e 
PARTNER 2Bf 
(2015)41 
SAPIEN XT / 284† 
SAPIEN / 276† 
3.5 
5.1 
3.2 
3.0 
9.5 
15.2 
7.8 
12.4 
15.4g 
16.8g 
CoreValve High 
Riskh (2014)25 
CoreValve / 390† 
3.3 
3.9 
5.9 
13.6 
6.0g 
NOTIONi (2015)42 
CoreValve / 142‡ 
2.1 
1.4j 
5.6 
11.3k 
0.7l 
SURTAVIm 
(2017)34 
CoreValve / 864* 
2.2 
1.2 
6.0 
12.2 
1.7l 
CHOICEf (2014)43 
SAPIEN XT / 121† 
CoreValve / 117† 
4.1 
5.1 
2.5 
2.6 
9.9 
11.1 
8.3b 
12.0b 
4.1e 
9.4e 

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Table 4.1-1: TAVR Outcomes at 30 Days and 1 Year – Transfemoral Access 
Study  
Device/N 
All-cause 
Death  
Disabling/ 
Major 
Stroke 
Major 
VC 
LT 
Bleeding  
AKI 
REPRISE IIIf 
(2018)44 
Lotus Valven / 607† 
CoreValven / 305† 
2.5 
2.3 
2.0 
3.3 
7.0 
5.3 
8.0 
5.0 
2.5l 
3.6l 
30-Day Outcomes – Single-Arm Studies 
PARTNER 
NRCAf (2014)45 
SAPIEN / 1023† 
4.3 
2.4 
8.0 
6.8b 
1.6e 
SAPIEN 3o 
(2016)46 
SAPIEN 3 / 953* 
SAPIEN 3 / 491† 
1.1 
1.6 
0.7 
0.8 
6.3 
5.5 
3.6 
5.5 
0.8l 
1.2l 
CoreValve 
Extreme Riskp 
(2014)47 
CoreValve / 489† 
8.4 
2.3 
8.2 
12.7 
11.8 
Evolut R First in 
Manq (2015)48 
Evolut R / 60† 
0.0 
0.0j 
8.3 
5.0 
1.7l 
EVOLUT R US 
Studyr (2017)49 
Evolut R / 241† 
2.5 
3.3 
7.5 
7.1 
1.2l 
PORTICO Pre-CE 
Mark Studyf 
(2018)50 
Portico / 222† 
3.6 
3.2 
7.3 
3.6 
1.4e 
1-Year Outcomes – Randomized Studies 
PARTNER 1Aa 
(2011)22 
SAPIEN / 244† 
22.2 
3.8 
14.4 
16.2b 
5.1c 
PARTNER 2Ad 
(2016)33 
SAPIEN XT / 775* 
10.0 
4.3 
8.8 
11.1 
2.2e 
PARTNER 2Bf 
(2015)41 
SAPIEN XT / 284† 
SAPIEN / 276† 
22.3 
23.3 
4.8 
5.5 
10.3 
16.1 
14.1 
19.9 
31.0e 
31.3e 
CoreValve High 
Riskh (2014)25 
CoreValve / 390† 
14.2 
5.8 
6.2 
16.6 
6.0g 
NOTIONi (2015)42 
CoreValve / 142‡ 
4.9 
2.9j 
– 
– 
– 
SURTAVIm 
(2017)34 
CoreValve / 864* 
6.7 
2.2 
– 
– 
– 
CHOICEf (2015)51 
SAPIEN XT / 121† 
CoreValve / 117† 
17.4 
12.8 
5.8 
3.4 
11.6 
12.0 
14.0b 
12.8b 
– 
– 
REPRISE IIIf 
(2018)44 
Lotus Valves / 607† 
CoreValves / 305† 
11.9 
13.5 
3.6 
7.1 
7.7 
6.1 
9.9 
9.8 
2.6l 
3.7l 
1-Year Outcomes – Single-Arm Studies 
PARTNER 
NRCAf (2014)45 
SAPIEN / 1023† 
19.0 
3.6 
8.4 
12.9b 
3.6e 
CoreValve 
Extreme Risk 
Pivotalp (2014)47 
CoreValve / 489† 
24.3 
4.3 
8.4 
17.6 
11.8 
SAPIEN 3t 
(2016)32 
SAPIEN 3 / 925* 
6.5 
1.7 
– 
– 
– 
PORTICO Pre-CE 
Mark Studyf 
(2018)50 
Portico / 222† 
13.8 
5.8 
8.8 
5.2 
3.0 

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Table 4.1-1: TAVR Outcomes at 30 Days and 1 Year – Transfemoral Access 
Study  
Device/N 
All-cause 
Death  
Disabling/ 
Major 
Stroke 
Major 
VC 
LT 
Bleeding  
AKI 
Data are presented as %; N is the number of subjects with transfemoral/iliofemoral access unless indicated 
otherwise; † = high/extreme surgical risk; * = intermediate surgical risk; ‡ = all comers study. 
The SAPIEN™, SAPIEN XT™, and SAPIEN 3™ Transcatheter Heart Valve Systems are manufactured by 
Edwards Lifesciences, Irvine, CA, USA. The CoreValve® and CoreValve Evolut™ R Transcatheter Aortic Valve 
Systems are manufactured by Medtronic Corp, Dublin, Ireland. The Lotus™ Valve System is manufactured by 
Boston Scientific Corporation, Marlborough, MA, USA. 
a: 70% TF and 30% TA  
b: Major bleeding 
c: Renal replacement therapy 
d: 76% TF and 24% TA  
e: AKIN Stage 3 (including renal replacement therapy) 
f: 100% TF 
g: Modified RIFLE classification per VARC 1 
h: 83% TF and 17% TAo/SC  
i: 97% TF and 3% SC 
j: All stroke  
k: Life-threatening and major 
l: AKIN Stage 2 or 3 
m: 94% TF, 4% TAo, and 2% SC 
n: Outcomes are for the implanted analysis sets: N=601 Lotus; N=303 CoreValve (153 CoreValve and 144 
Evolut R) 
o: 87% TF and 13% TA/TAo (intermediate and high risk) 
p: 99% TF (1% not implanted)  
q:  98% TF and 2% TAo 
r: 90% TF and 10% other 
s: Outcomes are shown for the Implanted analysis sets: N=587 Lotus; N=297 CoreValve 
t: 88% TF and 12% TA/TAo 
Abbreviations: AKI=acute kidney injury; LT=life threatening; PVR=paravalvular regurgitation; SC=subclavian; 
TA=transapical; TAo=trans-aortic; TAVR=transcatheter aortic valve replacement; TF=transfemoral/iliofemoral; 
VARC=Valve Academic Research Consortium; VC=vascular complications 
 
Though infrequent, significant complications can occur with TAVR and subsequently impact 
long-term outcomes and possibly limit use in lower risk patients52. Precise valve positioning 
can be challenging, particularly in the context of markedly altered or unfolded aortic anatomy 
or large and eccentric calcified plaques at the aorto-ventricular interface. Under such 
conditions, TAVR can result in valve misplacement, embolization, the need for a second 
device, or coronary occlusion53. Placement in a heavily calcified native valve can produce an 
incomplete seal between the bioprosthetic valve and aortic annulus, resulting in PVR, which 
in turn has been associated with increased mortality in some studies54-56. The impact of mild 
PVR is less clear57,58 although a recent meta-analysis suggested that mild PVR may also be 
associated with increased all-cause and cardiovascular mortality59. 
The Lotus™ Valve System was designed to address issues with earlier TAVR devices60. 
Controlled mechanical expansion and early leaflet functioning allow for precise positioning. 
If needed, minor repositioning is accomplished through partial valve recapture; full recapture 

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facilitates removal of the valve if a different valve is required. The outer seal is designed to 
minimize PVR. Additional device information can be found in Section 5.1. 
The safety and performance of the Lotus Valve System and the follow-on LOTUS Edge 
Valve System for TAVR in symptomatic high-risk surgical patients with severe AS are under 
evaluation in the REPRISE clinical program as described in Section 4.1.2. REPRISE IV will 
evaluate safety and effectiveness of the LOTUS Edge Valve System for TAVR in 
intermediate-risk surgical patients, including those who have a native bicuspid aortic valve. 
4.1.2. 
REPRISE Clinical Program 
The REPRISE clinical program includes an evolving set of clinical studies intended to 
demonstrate the safety and performance of the Lotus Valve System. To ensure proper use 
and mitigate any procedural complication that could be secondary to misuse or 
misinterpretation of the Instructions for Use (IFU), a comprehensive training and proctorship 
program was implemented by BSC. Given the importance of selecting appropriate subjects, a 
Case Review Committee (CRC) comprised of the Principal Investigators (PI), other 
investigators experienced with TAVR, and the Sponsor was established to confirm subject 
eligibility across study centers during the trial screening process. Safety endpoints for the 
REPRISE studies are adjudicated independently (Clinical Events Committee [CEC] for the 
RCT and single-arm trials; Independent Medical Reviewer [IMR] for the postmarket study). 
Prosthetic valve function and cardiac function endpoints are assessed by independent 
echocardiography and electrocardiography core labs. Clinical endpoint definitions and pre-
specified follow-up measurements are based on Valve Academic Research Consortium 
(VARC) metrics61,62. The Lotus Valve System is evaluated in the single-arm REPRISE I 
(ClinicalTrials.gov Identifier NCT01383720), REPRISE II (NCT01627691), and REPRISE 
Japan (NCT02491255) trials; the REPRISE III (NCT02202434) RCT; and the RESPOND 
(NCT02031302) postmarket safety surveillance study. The LOTUS Edge Valve System and 
the iSleeve Introducer Set are evaluated in the single-arm REPRISE NG DS (NCT02329496) 
and REPRISE EDGE (NCT02854319) studies.  
Described below are results from studies that have reached their primary endpoints.   
4.1.2.1. REPRISE I Study 
The prospective, single arm, multicenter REPRISE I (REpositionable Percutaneous 
Replacement of Stenotic Aortic Valve through Implantation of Lotus™ Valve SystEm; 
NCT01383720) feasibility study (N=11) assessed the acute safety and performance of the 
Lotus Valve System in symptomatic subjects with calcific aortic stenosis who were 
considered high risk for surgical valve replacement63. The primary endpoint was clinical 
procedural success, defined as successful implantation of a Lotus Valve (per the VARC-1 
definitions61) 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.   

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The primary endpoint was achieved in 9/11 subjects63. The device was successfully 
implanted in all 11 subjects but there was a device failure in 1 subject based on a mean 
gradient of 22 mmHg. Ten (10) of 11 subjects had no in-hospital MACCE; there were no 
deaths and 1 major stroke. At discharge TTE, PVR was mild in 2 subjects, trivial in 1 
subject, and absent in the other 8 subjects. Table 4.1-2 shows clinical and echocardiographic 
outcomes to the end of the study (5 years). Valve function was excellent with minimal PVR 
and low clinical event rates. The results of the REPRISE I feasibility study support the safety 
and performance of the Lotus Valve System. 
Table 4.1-2: Outcomes to 5 Years in REPRISE I 
Outcomes  
30 Days 
1 Year 
2 Years 
3 Years 
4 Years 
5 Years 
Clinical Outcomes (CEC Adjudicated, VARC Definitions) 
All-cause mortality 
0.0 (0/11) 
0.0 (0/11) 
0.0 (0/11) 
9.1 (1/11) 
27.3 (3/11) 
36.4 (4/11) 
 
Cardiovascular 
0.0 (0/11) 
0.0 (0/11) 
0.0 (0/11) 
0.0 (0/11) 
9.1 (1/11) 
9.1 (1/11) 
All stroke 
9.1 (1/11) 
9.1 (1/11) 
9.1 (1/11) 
18.2 (2/11) 
18.2 (2/11) 
18. (2/11) 
 
Major stroke 
9.1 (1/11) 
9.1 (1/11) 
9.1 (1/11) 
9.1 (1/11) 
9.1 (1/11) 
9.1 (1/11) 
Major vascular complications 
9.1 (1/11) 
9.1 (1/11) 
9.1 (1/11) 
9.1 (1/11) 
9.1 (1/11) 
9.1 (1/11) 
Life-threatening/disabling 
bleeding 
18.2 (2/11) 
18.2 (2/11) 
18.2 (2/11) 
18.2 (2/11) 
18.2 (2/11) 
18.2 (2/11) 
Major bleeding 
18.2 (2/11) 
18.2 (2/11) 
27.3 (3/11) 
27.3 (3/11) 
27.3 (3/11) 
27.3 (3/11) 
AKI – Stage 2/3 
0.0 (0/11) 
0.0 (0/11) 
0.0 (0/11) 
0.0 (0/11) 
0.0 (0/11) 
0.0 (0/11) 
New PPMa  
36.4 (4/11) 
36.4 (4/11) 
36.4 (4/11) 
36.4 (4/11) 
36.4 (4/11) 
36.4 (4/11) 
Myocardial infarction 
0.0 (0/11) 
0.0 (0/11) 
0.0 (0/11) 
0.0 (0/11) 
0.0 (0/11) 
9.1 (1/11) 
Valve-related dysfunctionc  
0.0 (0/11) 
0.0 (0/11) 
0.0 (0/11) 
0.0 (0/11) 
0.0 (0/11) 
0.0 (0/11) 
Hospitalizationd  
0.0 (0/11) 
0.0 (0/11) 
0.0 (0/11) 
0.0 (0/11) 
0.0 (0/11) 
0.0 (0/11) 
TAV-in-TAV 
0.0 (0/11) 
0.0 (0/11) 
0.0 (0/11) 
0.0 (0/11) 
0.0 (0/11) 
0.0 (0/11) 
Valve thrombosis 
0.0 (0/11) 
0.0 (0/11) 
0.0 (0/11) 
0.0 (0/11) 
0.0 (0/11) 
0.0 (0/11) 
Endocarditis 
0.0 (0/11) 
0.0 (0/11) 
0.0 (0/11) 
0.0 (0/11) 
0.0 (0/11) 
0.0 (0/11) 
Aortic Valve Performance by Transthoracic Echocardiography (Core Lab Assessment) 
EOA (cm2)e 
1.59±0.14 
(11) 
1.51±0.22 
(11) 
1.51±0.19 
(11) 
1.56±0.23 
(8) 
1.55±0.21 
(7) 
1.55±0.37 
(5) 
Mean gradient (mmHg)f 
11.7±3.0 
(11) 
15.4±4.6 
(11) 
15.5±4.4 
(11) 
15.6±4.4 
(8) 
15.6±4.6 
(7) 
14.1±4.1 
(6) 
Paravalvular Aortic Regurgitation 
 
None 
9.1 (1/11) 
9.1 (1/11) 
81.8 (9/11) 
87.5 (7/8) 
100 (7/7) 
80.0 (4/5) 
 
Trace/trivial 
0.0 (0/11) 
9.1 (1/11) 
9.1 (1/11) 
0.0 (0/8) 
0.0 (0/7) 
20.0 (1/5) 
 
Mild  
18.2 (2/11) 
9.1 (1/11) 
9.1 (1/11) 
12.5 (1/8) 
0.0 (0/7) 
0.0 (0/5) 
 
Moderate or Severe 
0.0 (0/11) 
0.0 (0/8) 
0.0 (0/11) 
0.0 (0/8) 
0.0 (0/7) 
0.0 (0/5) 
New York Heart Association Classg 
Class I 
27.3 (3/11) 
45.5 (5/11) 
54.5 (6/11) 
62.5 (5/8) 
57.1 (4/7) 
66.7 (4/6) 
Class II 
63.6 (7/11) 
54.5 (6/11) 
45.5 (5/11) 
12.5 (1/8) 
14.3 (1/7) 
16.6 (1/6) 
Class III 
9.1 (1/11) 
0.0 (0/11) 
0.0 (0/11) 
25.0 (2/8) 
28.6 (2/7) 
16.6 (1/6) 
Class IV 
0.0 (0/11) 
0.0 (0/11) 
0.0 (0/11) 
0.0 (0/8) 
0.0 (0/7) 
0.0 (0/6) 
Numbers are presented as % (count/sample size) or mean±SD (n) 
a: Resulting from new or worsened conduction disturbances 
b: Periprocedural 
c: Requiring repeat procedure (surgical/interventional) 
d: For valve-related symptoms or worsening congestive heart failure  

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Table 4.1-2: Outcomes to 5 Years in REPRISE I 
Outcomes  
30 Days 
1 Year 
2 Years 
3 Years 
4 Years 
5 Years 
e: Baseline effective orifice area (cm2): 0.68 ± 0.19 (11); change from baseline is significant at all time points 
f: Baseline mean aortic gradient (mmHg): 53.9±20.9 (11); change from baseline is significant at all time points 
g: At baseline, 6 subjects were considered Class II and 5 subjects were considered Class III. 
Abbreviations: AKI=acute kidney injury; CEC=clinical events committee; EOA=effective orifice area; 
TAV=transcatheter aortic valve; VARC=Valve Academic Research Consortium 
References: Meredith 201463; Gooley 201864 
 
4.1.2.2. REPRISE II Study 
The REpositionable Percutaneous Replacement of Stenotic Aortic Valve through 
Implantation of Lotus™ Valve System – Evaluation of Safety and Performance 
(REPRISE II; NCT01627691) clinical trial was designed to evaluate the safety and 
performance of the Lotus Valve System for TAVR in symptomatic subjects with calcific 
stenotic aortic valves who were considered high risk for SAVR. This prospective, single-arm, 
multicenter, CE-Mark study enrolled 120 subjects in the main cohort at 14 investigative 
centers in Australia, France, Germany and the United Kingdom. Clinical follow-up will 
extend through 5 years. 
The primary device performance endpoint was the mean aortic valve pressure gradient at 
30 days post implant as measured by echocardiography. This endpoint was analyzed on an 
as-treated (subjects who received the Lotus Valve) basis. A one-sample t-test was used to test 
the one-sided hypothesis that the primary device performance endpoint is less than the 
prespecified performance goal (PG) of 18 mmHg. Two interim analyses were conducted on 
the first 40 and 60 subjects; the alpha-adjustment for multiple comparisons65 was 0.01123 
and 0.00792, respectively. The alpha level adjustment for the final analysis conducted on the 
fully enrolled cohort of 120 subjects was 0.01305. The primary safety endpoint was all-cause 
mortality at 30 days after the implant procedure and was evaluated on an intention-to-treat 
(ITT; all subjects enrolled, whether or not a study device is implanted) basis. 
The 30-day mean aortic valve pressure gradient was 11.45±5.20 mmHg with a one-sided 
98.695% upper confidence bound of 12.64. The P value from the one-sample t-test was 
<0.0001 and so the Lotus Valve was concluded to have a 30-day mean aortic pressure 
gradient <18 mmHg and the primary device performance endpoint was met. Table 4.1-3 
shows device performance endpoints66. Successful vascular access, delivery and deployment 
of the Lotus Valve along with successful retrieval of the delivery system was achieved in all 
120 subjects. Repositioning and/or retrieval was successful in all patients in whom it was 
attempted. Table 4.1-4 shows 30-day, 1-year, 2-year, 3-year, 4-year, and 5-year clinical and 
echocardiographic outcomes. Mortality at 30 days, 1 year, and 5 years was 4.2%, 11.0%, and 
42.6%, respectively; the disabling stroke rate was 1.7%, 3.5%, and 7.0%. Mean aortic valve 
pressure gradient remained low at 12.58±5.66 mmHg (1 year) and 14.43±6.44 mmHg 
(5 years). There were no repeat procedures for valve-related dysfunction through 5 years. 
Core lab assessment of PVR at 30 days indicated no severe regurgitation and 1 case of 
moderate regurgitation; in 83.3% (80/96) of subjects there was trace/trivial or no PVR. The 
low PVR rate observed at 30 days was maintained at 1 year (89% with none/trivial PVR) and 

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out to 5 years (80%with none/trivial PVR). The observed clinical results are consistent with 
other TAVR studies (see Table 4.1-1) and the rates of PVR are lower8,22,25,32,41,43,46-48,51. The 
results of the REPRISE II study support the safety and performance of the Lotus Valve 
System. 
Table 4.1-3: Device Performance Endpoints – REPRISE II Main Cohort  
Outcomes  
REPRISE II 
Successful vascular access, delivery, and deployment of the Lotus Valve System, 
and successful retrieval of the delivery system 
100.0% (120/120) 
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 for the last 
valve attempted 
100.0% (32/32) 
Successful retrieval (complete resheathing of the Lotus Valve in the catheter and 
removal from the body) of the Lotus Valve System if retrieval is attempted 
100.0% (6/6) 
Values are % (count/sample size)  
Reference: Meredith 201466 
 
Table 4.1-4: Clinical and Echocardiographic Outcomes to 5 Years ‒ REPRISE II 
Main Cohort (N=120) 
Outcomes 
30 Days 
1 Year 
2 Years 
3 Years 
4 Years 
5 Years 
Clinical Outcomes (CEC Adjudicated, VARC Definitions) 
All-cause mortality 
4.2 (5/119) 
11.0 (13) 
16.9 (20) 
23.1 (27) 
30.8 (36) 
42.6 (50) 
 Cardiovascular 
4.2 (5/119) 
6.7 (8) 
10.4 (12) 
12.3 (14) 
16.3 (18) 
24.0 (25) 
Stroke 
6.1 (7/115) 
9.5 (11) 
9.5 (11) 
10.5 (12) 
10.5 (12) 
13.0 (14) 
 Disabling stroke 
1.7 (2/115) 
3.5 (4) 
3.5 (4) 
4.5 (5) 
4.5 (5) 
7.0 (7) 
Major vascular 
complications 
2.6 (3/116) 
2.5 (3) 
2.5 (3) 
2.5 (3) 
2.5 (3) 
2.5 (3) 
New PPMa 
29.1(34/117) 
32.2 (38) 
34.2 (40) 
35.4 (41) 
35.3 (41) 
36.4 (42) 
Life-threatening/disabling 
bleeding 
5.1 (6/117) 
5.9 (7) 
7.8 (9) 
7.8 (9) 
11.3 (12) 
15.0 (15) 
Major bleeding 
17.9(21/117) 
21.4 (25) 
23.3 (27) 
23.3 (27) 
23.3 (27) 
23.3 (27) 
MI – Peri-procedural 
(≤72 h) 
3.4 (4/117) 
3.3 (4) 
3.3 (4) 
3.3 (4) 
3.3 (4) 
3.3 (4) 
MI – Spontaneous (>72 h) 
0.0 (0/117) 
0.0 (0) 
0.0 (0) 
1.1 (1) 
1.1 (1) 
2.4 (2) 
AKI Stage 2 
1.7 (2/115) 
1.7 (2) 
1.7 (2) 
3.4 (4) 
1.7 (2) 
1.7 (2) 
AKI Stage 3 
1.7 (2/115) 
1.7 (2) 
1.7 (2) 
1.7 (2) 
1.7 (2) 
1.7 (2) 
Repeat procedureb  
0.0 (0/115) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
Hospitalizationc  
4.3 (5/115) 
5.2 (6) 
8.0 (9) 
12.2 (13) 
17.5 (18) 
19.8 (20) 
Atrial fibrillation – New 
onset 
5.2 (6/115) 
6.0 (7) 
6.0 (7) 
6.0 (7) 
6.0 (7) 
6.0 (7) 
Atrial flutter – New onset 
0.0 (0/115) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
Coronary obstructiond  
0.9 (1/115) 
0.8 (1) 
0.8 (1) 
0.8 (1) 
0.8 (1) 
0.8 (1) 
Ventricular septal 
perforationd 
0.0 (0/115) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
Mitral apparatus damaged 
2.6 (3/115) 
2.6 (3) 
2.6 (3) 
2.6 (3) 
2.6 (3) 
2.6 (3) 
Cardiac tamponaded 
4.3 (5/117) 
4.2 (5) 
4.2 (5) 
4.2 (5) 
4.2 (5) 
4.2 (5) 

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Table 4.1-4: Clinical and Echocardiographic Outcomes to 5 Years ‒ REPRISE II 
Main Cohort (N=120) 
Outcomes 
30 Days 
1 Year 
2 Years 
3 Years 
4 Years 
5 Years 
Prosthetic valve 
malappositione 
0.0 (0/115) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
Prosthetic valve 
thrombosis 
0.0 (0/115) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
Prosthetic valve 
endocarditis 
0.0 (0/115) 
0.9 (1) 
2.8 (3) 
2.8 (3) 
2.8 (3) 
2.8 (3) 
Aortic Valve Performance by Transthoracic Echocardiography (Core Lab Assessment) 
EOA (cm2)f 
1.67±0.43 
(78) 
1.65±0.51 
(79) 
1.66±0.45 
(69) 
1.62±0.48 
(57) 
1.55±0.43 
(55) 
1.60±0.48 
(40) 
Mean gradient (mmHg)g 
11.45±5.20 
(97) 
12.58±5.66 
(92) 
12.30±6.18 
(75) 
11.26±5.23 
(61) 
12.41±6.88 
(55) 
14.43±6.44 
(43) 
Peak aortic gradient 
(mmHg)h 
21.30±9.26 
(97) 
23.09±10.14 
(92) 
21.25±11.03 
(75) 
21.27±9.65 
(61) 
22.20±11.03 
(55) 
26.55±11.34 
(43) 
Peak aortic velocity (m/s)i 
2.25±0.48 
(97) 
2.35±0.50 
(92) 
2.23±0.56 
(75) 
2.25±0.51 
(61) 
2.29±0.54 
(55) 
2.52±.53 
(43) 
Paravalvular Aortic Regurgitation 
 
None 
78.1 (75/96) 
86.4 (76/88) 
87.8 (65/74) 
87.5 (49/56) 
74.1 (43/58) 
59.1 (26/44) 
 
Trace/trivial 
5.2 (5/96) 
2.3 (2/88) 
2.7 (2/74) 
0.0 (0/56) 
10.3 (6/58) 
20.5 (9/44) 
 
Mild  
15.6 (15/96) 
11.4 (10/88) 
9.5 (7/74) 
12.5 (7/56) 
13.8 (8/58) 
15.9 (7/44) 
 
Moderate 
1.0 (1/96) 
0.0 (0/88) 
0.0 (0/74) 
0.0 (0/56) 
1.7 (1/58) 
4.5 (2/44) 
 
Severe  
0.0 (0/96) 
0.0 (0/88) 
0.0 (0/74) 
0.0 (0/56) 
0.0 (0/58) 
0.0 (0/44) 
Values are presented as % (count/sample size), % (n), or mean±SD (n); for clinical events, binary rates are presented 
through 30 days, time-to-event (Kaplan-Meier) data are presented at 1 year and beyond. 
a: Due to new conduction disturbances or arrhythmias 
b: For valve-related dysfunction (surgical or interventional) 
c: For valve-related symptoms or worsening congestive heart failure (NYHA class III or IV) 
d: Peri-procedural 
e: Including valve migration, valve embolization, ectopic valve deployment, or TAV-in-TAV 
f: Baseline effective orifice area (cm2): 0.68 ± 0.19 (11); change from baseline is significant at all time points 
g: Baseline mean aortic gradient (mmHg): 53.9±20.9 (11); change from baseline is significant at all time points 
h: Baseline peak aortic gradient (mmHg): 76.54±23.56 (104); change from baseline is significant at all time points 
i: Baseline peak aortic velocity (m/s): 4.30±0.67 (105); change from baseline is significant at all time points 
Abbreviation: AKI=acute kidney injury; EOA=effective orifice area; MI=myocardial infarction; PPM=permanent 
pacemaker; TAV=transcatheter aortic valve; VARC=Valve Academic Research Consortium 
References: Meredith 201466, 201567, 201668,69; Hildick-Smith 201770; Dumonteil 201871 
 
The REPRISE II study was subsequently expanded to enroll 130 additional subjects in the 
REPRISE II extended trial cohort at centers in Australia and Europe. The main trial cohort 
and the extended trial cohort had the same overall study design. The main trial cohort 
received additional neurologic evaluation and annual imaging assessments to determine valve 
frame integrity. Per the protocol, a statistically powered analysis based on the combined main 
and extended trial cohorts (full cohort, N=250) was performed for the primary safety 
endpoint (mortality at 30 days). The primary safety endpoint was analyzed on an ITT basis. 
A one-sample z test was used to test the one-sided hypothesis that 30-day all-cause mortality 
is less than the prespecified PG of 16% (based on an expected rate of 9.8% plus a testing 

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margin of 6.2%). All-cause mortality at 30 days was 4.4% with an upper confidence bound of 
6.97% and the primary safety endpoint was met72. 
Table 4.1-5 shows device performance endpoints, clinical outcomes, and echocardiographic 
outcomes through 4 years for the full cohort. Outcomes were similar to that reported for the 
main cohort (see Table 4.1-3). At 30 days, the mean aortic valve gradient was 
11.70±6.77 mmHg, mortality was 4.4%, and the disabling stroke rate was 3.3%. Through 
1 year, mortality was 12% and the disabling stroke rate was 3.6%; valve endocarditis (N=2) 
and thrombosis (N=3) were successfully resolved with antibiotics and anticoagulant therapy, 
respectively, without sequelae. The new PPM implant rate was 29.6% at 30 days. Reported 
rates for early conduction abnormalities and the need for PPM implantation after TAVR have 
ranged from 3% to 8% with SAPIEN and 14% to 40% with CoreValve73. Mechanical 
pressure from the valve frame may cause conduction tissue injury or inflammation during 
TAVR, especially with longer stent frames, self-expanding valves, pre- or post-dilatation and 
deep implant depth74. With an expanded length compared to previous generation balloon-
expandable valves, the SAPIEN 3 valve has also been associated with somewhat higher rates 
of PPM75,76. While undesirable, PPM early after TAVR has generally not been associated 
with an increase in mortality77-79, although recent reports from the PARTNER trial and 
registries did find patients with prior pacemaker, new PPM, or chronic left bundle branch 
block had attenuated improvement in left ventricular ejection fraction (LVEF), more repeat 
hospitalization, and higher rates of all-cause death at 1 year compared to patients who had 
none of these conditions80,81. However, PPM was associated with significantly less 
unexpected death in another study82. 
There was no severe PVR and none/trace/trivial PVR in 85% of REPRISE II full-cohort 
subjects at 30 days. A number of independent studies55,56,83-90 and large meta-analyses57,91 
have found an association between PVR post TAVR and early or late mortality; 
moderate/severe PVR, often more common with CoreValve than SAPIEN55,87,88, has been an 
independent predictor of both. A recent meta-analysis suggested that mild PVR may also be 
associated with increased all-cause and cardiovascular mortality59. The low PVR rate 
observed at 30 days with Lotus was maintained at 1 year and 4 years as most subjects (91% 
and 88%, respectively) had none/trace/trivial PVR, 2 subjects had moderate PVR at 4 years, 
and there was no severe PVR. 
In summary, the observed clinical results in the full cohort are consistent with other TAVR 
studies and the PVR rates are lower. The results of the REPRISE II study support the safety 
and performance of the Lotus Valve System. 
Table 4.1-5: Clinical and Echocardiographic Outcomes to 4 Years ‒ REPRISE II Full 
Cohort (N=250) 
Outcomes 
30 Days 
1 Year 
2 Years 
3 Years 
4 Years 
Clinical Outcomes (CEC Adjudicated, VARC Definitions) 
All-cause mortality 
4.4 (11/249) 
11.8 (29) 
19.1 (47) 
28.3 (69) 
38.7 (94) 
 Cardiovascular 
4.0 (10/249) 
7.8 (19) 
9.5 (23) 
14.3 (33) 
19.0 (42) 
Stroke 
7.1 (17/241) 
8.6 (21) 
9.6 (23) 
10.6 (25) 
10.6 (25) 
 Disabling stroke 
3.3 (8/241) 
3.7 (9) 
4.7 (11) 
6.2 (14) 
6.2 (14) 

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Table 4.1-5: Clinical and Echocardiographic Outcomes to 4 Years ‒ REPRISE II Full 
Cohort (N=250) 
Outcomes 
30 Days 
1 Year 
2 Years 
3 Years 
4 Years 
Major vascular complications 
5.4 (13/241) 
5.2 (13) 
5.2 (13) 
5.2 (13) 
5.2 (13) 
New PPMa 
29.6 (72/243) 
33.1 (81) 
35.1 (85) 
35.7 (86) 
36.3 (87) 
Life-threatening/disabling 
bleeding 
7.3 (18/247) 
9.4 (23) 
10.7 (26) 
10.7 (26) 
14.4 (32) 
Major bleeding 
21.5 (53/247) 
23.7 (58) 
25.1 (61) 
25.7 (62) 
25.7 (62) 
MI – Peri-procedural (≤72 h) 
2.9 (7/243) 
2.8 (7) 
2.8 (7) 
2.8 (7) 
2.8 (7) 
MI – Spontaneous (>72 h) 
0.0 (0/243) 
0.0 (0) 
0.0 (0) 
1.6 (3) 
2.2 (4) 
AKI Stage 2 
1.3 (3/240) 
1.2 (3) 
1.2 (3) 
1.2 (3) 
1.2 (3) 
AKI Stage 3 
1.7 (4/240) 
1.6 (4) 
1.6 (4) 
1.6 (4) 
1.6 (4) 
Repeat procedureb  
0.0 (0/240) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
Hospitalizationc  
2.9 (7/240) 
7.1 (17) 
9.9 (23) 
14.1 (31) 
19.7 (41) 
Atrial fibrillation – New onset 
5.8 (14/241) 
6.6 (16) 
6.6 (16) 
6.6 (16) 
6.6 (16) 
Atrial flutter – New onset 
0.8 (2/241) 
0.4 (1) 
0.4 (1) 
0.4 (1) 
0.4 (1) 
Coronary obstructiond  
0.8 (2/241) 
0.8 (2) 
0.8 (2) 
0.8 (2) 
0.8 (2) 
Ventricular septal perforationd 
0.0 (0/240) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
Mitral apparatus damaged 
1.7 (4/240) 
1.6 (4) 
1.6 (4) 
1.6 (4) 
1.6 (4) 
Cardiac tamponaded 
3.7 (9/246) 
3.2 (8) 
3.2 (8) 
3.2 (8) 
3.2 (8) 
Prosthetic valve 
malappositione 
0.0 (0/240) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
Prosthetic valve thrombosis 
0.0 (0/240) 
1.3 (3) 
1.3 (3) 
1.8 (4) 
2.4 (5) 
Prosthetic valve endocarditis 
0.0 (0/240) 
0.9 (2) 
1.8 (4) 
1.8 (4) 
1.8 (4) 
Aortic Valve Performance by Transthoracic Echocardiography (Core Lab Assessment) 
EOA (cm2)f 
1.74±0.45 
(149) 
1.68±0.49 
(157) 
1.64±0.47 
(123) 
1.55±0.47 
(119) 
1.50±0.43  
(95) 
Mean gradient (mmHg)g 
11.70±6.77 
(183) 
12.49±5.35 
(176) 
12.18±5.99 
(135) 
12.19±6.02 
(125) 
12.69±7.13 
(97) 
Peak aortic gradient (mmHg)h 
20.75 ± 9.05 
(183) 
21.90±9.40 
(176) 
21.25±10.15 
(135) 
22.32±10.38 
(125) 
23.11±12.14 
(97) 
Peak aortic velocity (m/s)i 
2.23 ± 0.47 
(183) 
2.29 ± 0.47 
(176) 
2.24±0.53 
(135) 
2.30±0.53 
(125) 
2.33±0.56  
(97) 
Paravalvular Aortic Regurgitation 
 
None 
80.2 (142/177) 
82.2 (134/163) 
87.1 (115/132) 
77.5 (100/129) 
73.7 (73/99) 
 
Trace/trivial 
5.6 (10/177) 
3.1 (5/163) 
3.0 (4/132) 
10.1 (13/129) 
14.1 (14/99) 
 
Mild  
13.6 (24/177) 
14.7 (24/163) 
9.8 (13/132) 
10.9 (14/129) 
10.1 (10/99) 
 
Moderate 
0.6 (1/177) 
0.0 (0/163) 
0.0 (0/132) 
1.6 (2/129) 
2.0 (2/99) 
 
Severe  
0.0 (0/177) 
0.0 (0/163) 
0.0 (0/132) 
0.0 (0/129) 
0.0 (0/99) 
Values are presented as % (count/sample size), % (n), or mean±SD (n); for clinical events, binary rates are presented 
through 30 days, time-to-event (Kaplan-Meier) data are presented at 1 year and beyond. 
a: Due to new conduction disturbances or arrhythmias 
b: For valve-related dysfunction (surgical or interventional) 
c: For valve-related symptoms or worsening congestive heart failure (NYHA class III or IV) 
d: Peri-procedural 
e: Including valve migration, valve embolization, ectopic valve deployment, or TAV-in-TAV 
f: Baseline effective orifice area (cm2): 0.68 ± 0.19 (201); change from baseline is significant at all time points 
g: Baseline mean aortic gradient (mmHg): 45.36±13.75 (216); change from baseline is significant at all time points 
h: Baseline peak aortic gradient (mmHg): 78.41±21.21 (216); change from baseline is significant at all time points 

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Table 4.1-5: Clinical and Echocardiographic Outcomes to 4 Years ‒ REPRISE II Full 
Cohort (N=250) 
Outcomes 
30 Days 
1 Year 
2 Years 
3 Years 
4 Years 
i: Baseline peak aortic velocity (m/s): 4.270±0.60 (217); change from baseline is significant at all time points 
Abbreviation: AKI=acute kidney injury; EOA=effective orifice area; MI=myocardial infarction; PPM=permanent 
pacemaker; TAV=transcatheter aortic valve; VARC=Valve Academic Research Consortium 
References: Meredith 201692, 201793; Tchétché 201794; Blackman 201895 
 
4.1.2.3. RESPOND Post-Market Surveillance Study 
The Repositionable Lotus Valve System – Post-market Evaluation of Real World Clinical 
Outcomes (RESPOND; NCT02031302) study is a prospective, open label, single-arm, 
multicenter, observational post-market surveillance study designed to collect real-world 
clinical and device performance outcomes data with the Lotus Valve System as used in 
routine clinical practice to treat subjects with severe calcific aortic stenosis. There were 1014 
consecutive (defined as a commitment by the participating investigators at each study center 
to enroll all consented subjects admitted for TAVR who are selected to receive a Lotus 
Valve) subjects enrolled at 41 study centers in Europe, New Zealand, Israel, and Colombia. 
Independent data assessments include core laboratory review of baseline, pre-discharge, and 
1-year echocardiography data and adjudication of center-reported mortality and stroke events 
by an independent medical reviewer (IMR). The statistically powered primary endpoint of 
30-day mortality was compared to a predefined performance goal. Clinical follow-up will 
extend through 5 years. Data through 30-day and 1-year follow-up are provided below. 
Procedural device success among the as-treated analysis set is shown in Table 4.1-6. Correct 
positioning of one transcatheter valve in the proper location was achieved in 99.7% of 
subjects. There was no moderate or severe prosthetic valve regurgitation (central or 
paravalvular) in 99.6% of subjects.  
Table 4.1-6: Procedural Device Success, RESPOND As-Treated Analysis Set 
Variable 
N=996 
Procedural mortality 
0.2% (2/996) 
Correct positioning of a single transcatheter valve into the proper anatomical location 
99.7% (993/996) 
Mean aortic valve gradient <20 mmHg 
96.4% (894/927) 
Peak velocity <3m/sec 
96.1% (891/927) 
No moderate or severe prosthetic valve regurgitationa 
99.6% (931/935) 
Numbers are % (count/sample size). 
a: Total prosthetic aortic valve regurgitation (includes central and paravalvular) per VARC 262 definition; 
core-lab adjudicated 
Abbreviation: VARC=Valve Academic Research Consortium 
Reference: Falk 201796 
 
The 30-day primary endpoint, all-cause mortality in the ITT population, was 2.6% (26/1005) 
with a one-sided upper confidence bound of 4.1%96. This was significantly below (P<0.0001) 
the performance goal of 14.0% and the 30-day primary endpoint was met. The statistically 

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powered secondary effectiveness endpoint, rate of moderate or severe PVR pre-discharge (as 
measured by TTE and assessed by an independent core laboratory) in the as-treated analysis 
set was 0.3% (3/934) with a one-sided upper bound of 1.1%. This was significantly below 
(P<0.0001) the performance goal of 16.5% and the powered secondary effectiveness 
endpoint was met. 
Table 4.1-7 shows secondary safety endpoint outcomes assessed at 30 days and 1 year in the 
RESPOND as-treated analysis set. At 30 days, all-cause mortality was 2.2%, in-hospital 
mortality was 1.8%, and disabling stroke was 2.3%. Mortality was 11.7% and disabling 
stroke was 4.0% at 1 year. Table 4.1-8 shows core laboratory TTE assessments pre-discharge 
and at 1 year in the as-treated analysis set. Mean aortic gradient improved significantly 
(P<0.0001) from 38.0±15.5 mmHg at baseline to 10.8±4.6 mmHg at discharge and remained 
low at 1 year (10.8±5.1 mmHg, P<0.0001). There was also a significant (P<0.0001) 
improvement in mean effective orifice area (EOA) from 0.7±0.2 cm2 at baseline to 
1.8±0.5 cm2 at discharge, which was sustained at 1 year (1.8±0.4 cm2, P<0.0001). There 
were no cases of severe PVR at discharge or 1 year. There were 3 cases of moderate PVR at 
discharge and 2 cases (0.4%) at 1 year; in >90% of evaluable subjects PVR was trivial or 
absent. 
Table 4.1-7: RESPOND Secondary Endpoints – VARC Safety Assessments at 30 Days 
and 1 Year Post-Procedure; As-Treated Analysis Set 
Outcome 
30 Days 
1 Year 
IMR-Adjudicated Events 
All-cause mortality and disabling stroke 
4.1% (41/996) 
13.7% (135/988) 
 
All-cause mortality 
2.2% (22/996) 
11.7%(116/988) 
 
 
In-hospital mortality 
1.8% (18/996) 
1.8% (18/996) 
 
 
Cardiovascular 
2.0% (20/996) 
7.5% (74/988) 
 
 
Non-cardiovascular 
0.2% (2/996) 
4.3% (42/988) 
 
Disabling stroke 
2.3% (23/996) 
4.0% (4/998) 
Center-Reported Events 
Major vascular complications  
3.0% (30/996) 
3.3% (33/988) 
Life-threatening or disabling bleeding 
2.2% (22/996) 
3.5% (35/988) 
Acute kidney injury (Stage 2 or 3, including renal replacement 
therapy) 
1.6% (16/996) 
1.7% (17/988) 
New conduction disturbances and need for permanent 
pacemaker implantation 
30.0% (299/996) 
32.0% (316/988) 
Peri-procedural MI (≤72 hours) 
0.4% (4/996) 
0.4% (4/988) 
Spontaneous MI (>72 hours after index procedure) 
0.3% (3/996) 
1.3% (13/988) 
Valve-related dysfunction requiring repeat procedure 
(surgical/interventional) 
0.1% (1/996) 
0.2% (2/988) 
Hospitalization for valve-related symptoms or worsening 
congestive heart failure 
1.4% (14/996) 
7.5% (74/988) 
Prosthetic aortic valve thrombosis 
0.4% (4/996) 
0.8% (8/988) 
Prosthetic aortic valve endocarditis 
0.2% (2/996) 
1.3% (13/988) 

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Table 4.1-7: RESPOND Secondary Endpoints – VARC Safety Assessments at 30 Days 
and 1 Year Post-Procedure; As-Treated Analysis Set 
Outcome 
30 Days 
1 Year 
Numbers are % (count/sample size). 
Abbreviations: IMR=Independent Medical Reviewer; MI=myocardial infarction; VARC=Valve Academic 
Research Consortium 
References: Falk 201796; Van Mieghem 201797 
 
Table 4.1-8: Core Laboratory Echocardiographic Assessments at Pre-Discharge and 
1 Year, RESPOND As-Treated Analysis Set 
Parameter 
Pre-Discharge 
1 Year 
Aortic valve area (effective orifice area) (cm2)a 
1.8±0.5 (854) 
1.8±0.4 (516) 
Mean aortic valve gradient (mmHg)b 
10.8±4.6 (927) 
10.8±5.1 (542) 
Peak aortic gradient (mmHg) 
19.3±8.0 (927) 
19.1±8.8 (542) 
Peak aortic velocity (m/s) 
2.2±0.4 (927) 
2.1±0.5 (542) 
Paravalvular Aortic Regurgitation 
 
None 
80.8% (755/934) 
83.9% (457/545) 
 
Trace/trivial 
11.1% (104/934) 
10.6% (58/545) 
 
Mild  
7.7% (72/934) 
5.1% (28/545) 
 
Moderate 
0.3% (3/934) 
0.4% (2/545) 
 
Severe  
0.0% (0/934) 
0.0% (0/545) 
Numbers are mean±SD or % (count/sample size). 
a: Baseline effective orifice area (cm2): 0.7 ± 0.2 (877) 
b: Baseline mean aortic gradient (mmHg): 38.0 ± 15.5 (923) 
References: Falk 201796; Van Mieghem 201797 
 
Compared to tricuspid aortic valves, bicuspid aortic valves have a larger annulus perimeter, 
asymmetrical valve orifice, and heavily calcified leaflets/raphe98,99. Thus, TAVR in bicuspid 
aortic valves may be subject to an increased risk of complications related to irregular and 
incomplete expansion of the prosthetic valve100. Existing data with first generation TAVR 
valves indicate a higher post-TAVR rate of moderate/severe PVR among patients with 
bicuspid aortic valves (25%) compared with tricuspid aortic valves (15%; P=0.05)101. In 
RESPOND, 31 patients (3.1%) were identified as having a bicuspid aortic valve102; 81.5% 
were classified as Sievers Type 1103, 14.8% as Sievers Type 0, and 3.7% as Sievers Type 2. 
Subjects with bicuspid valves were older and at baseline had a lower mean effective orifice 
area (0.6 cm2 vs. 0.7 cm2, P=0.0043) and a higher mean aortic valve gradient (51.6 mmHg 
vs. 43.6 mmHg, P=0.0132). Table 4.1-9 compares echocardiographic outcomes at pre-
discharge and clinical outcomes at 30 days in the 2 groups. Mean effective orifice area 
increased and mean aortic valve gradient decreased from baseline to discharge in both 
groups. Notably, there were no significant differences between groups in echocardiographic 
or clinical outcome measures after TAVR. Although this substudy is limited by the small 

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number of RESPOND patients with bicuspid anatomy, the observed results support the safety 
and effectiveness of TAVR with the Lotus Valve in bicuspid aortic valve stenosis. 
Table 4.1-9: Bicuspid and Non-Bicuspid Groups in RESPOND – As-Treated Analysis 
Set (N=996) 
Outcome 
Bicuspid (N=31) 
Non-Bicuspid (N=965) 
P value 
30-Day Principal Safety Results (VARC Definitions) 
All-cause mortality 
3.2% (1/31) 
2.2% (21/955) 
0.51 
 
Cardiovascular 
3.2% (1/31) 
2.0% (19/955) 
0.48 
Disabling stroke 
3.2% (1/31) 
2.2% (21/955) 
0.51 
Non-disabling stroke 
0.0% (0/31) 
0.8% (8/955) 
1.00 
Major vascular complications 
6.5% (2/31) 
2.8% (27/955) 
0.23 
New conduction disturbances and need 
for permanent pacemaker implantation 
19.4% (6/31) 
30.4% (290/955) 
0.19 
Life-threatening or disabling bleeding 
6.5% (2/31) 
2.1% (20/955) 
0.15 
Acute kidney injury 
3.2% (1/31) 
2.5% (24/955) 
0.56 
Myocardial infarction 
0.0% (0/31) 
0.6% (6/955) 
1.00 
Valve Performance by TTE (Pre-Discharge – Core Lab Assessment) 
Mean effective orifice area (cm2)a 
1.7±0.43 (28)  
1.8±0.45 (826)  
0.20 
Mean aortic valve gradient (mmHg)b 
11.8±5.06 (29)  
10.8±4.53 (898) 
0.21 
Paravalvular Aortic Regurgitation 
 
None 
69.0% (20/29) 
81.2% (735/905) 
0.10 
 
Trace/Trivial 
17.2% (5/29) 
10.9% ( 99/905) 
0.36 
 
Mild 
13.8% (4/29) 
7.5% ( 68/905) 
0.27 
 
Moderate 
0.0% (0/29) 
0.3% (3/905) 
1.00 
 
Severe 
0.0% (0/29) 
0.0% (0/905) 
– 
Numbers are % (count/sample size) or mean±SD (n). 
a: Baseline effective orifice area (cm2) was significantly different between the 2 groups: 0.6±0.2 
(28) vs. 0.7±0.2 (847), P=0.004 
b: Baseline mean aortic gradient (mmHg) was significantly different between the 2 groups: 
51.6±16.97 (30) vs. 43.6±17.44 (876), P=0.013 
Abbreviations: TTE=transthoracic echocardiography; VARC=Valve Academic Research Consortium 
Reference: Blackman 2016102 
 
After enrollment of the main RESPOND cohort was completed the study was extended to 
enroll an additional cohort (RESPOND Extension) to assess center-driven implantation 
technique with the commercially available Lotus Valve System with Depthguard™ 
technology. Depthguard results in a slightly decreased rate of retraction of the outer sheath 
during valve deployment. This minimizes interaction between the frame and the LVOT 
during deployment and could limit the need for PPM implantation. 
Table 4.1-10 shows clinical outcomes at 30 days and echocardiographic outcomes at pre-
discharge. Mortality and disabling stroke were 0.0% and 2.0%, respectively, and new PPM 
implantation was 18.0%. There were no cases of moderate or severe PVR; in 86% of cases 
PVR was trivial or absent.  

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Table 4.1-10: RESPOND Extension – VARC Safety Assessments (30 Days) and Core 
Lab Echocardiographic Assessments (Pre-Discharge); As-Treated Analysis Set 
Outcome 
N=50 
IMR-Adjudicated Events (30 Days) 
All-cause mortality and disabling stroke 
2.0% (1/50) 
 
All-cause mortality 
0.0% (0/50) 
 
Disabling stroke 
2.0% (1/50) 
Center-Reported Events (30 Days) 
Major vascular complications  
2.0% (1/50) 
Life-threatening or disabling bleeding 
0.0% (0/50) 
Acute kidney injury (Stage 2 or 3, including renal replacement therapy) 
2.0% (1/50) 
New conduction disturbances and need for permanent pacemaker implantation 
18.0% (9/50) 
Peri-procedural MI (≤72 hours) 
0.0% (0/50) 
Spontaneous MI (>72 hours after index procedure) 
0.0% (0/50) 
Valve-related dysfunction requiring repeat procedure (surgical/interventional) 
0.0% (0/50) 
Hospitalization for valve-related symptoms or worsening congestive heart failure 
0.0% (0/50) 
Prosthetic aortic valve thrombosis 
0.0% (0/50) 
Prosthetic aortic valve endocarditis 
0.0% (0/50) 
Echocardiography (Pre-Discharge) 
Aortic valve area (effective orifice area) (cm2)a 
1.7±0.3 (35) 
Mean aortic valve gradient (mmHg)b 
11.8±4.4 (37) 
Peak aortic gradient (mmHg) 
21.1±8.5 (37) 
Peak aortic velocity (m/s) 
2.3±0.4 (37) 
Paravalvular Aortic Regurgitation 
 
None 
64.9% (24/37) 
 
Trace/trivial 
21.6% (8/37) 
 
Mild  
13.5% (5/37) 
 
Moderate 
0.0% (0/37) 
 
Severe  
0.0% (0/37) 
Numbers are mean±SD or % (count/sample size). 
a: Baseline effective orifice area (cm2): 0.7 ± 0.2 (44) 
b: Baseline mean aortic gradient (mmHg): 39.8 ± 13.7 (45) 
Abbreviations: IMR=Independent Medical Reviewer; MI=myocardial infarction; VARC=Valve Academic 
Research Consortium 
Reference: Van Mieghem 2017104 
 
In summary, the observed 30-day and 1-year outcomes among RESPOND subjects and 
30-day outcomes in RESPOND Extension show good hemodynamic results, a very low PVR 
rate, low mortality, and overall favorable event rates. There also were no significant 
differences in pre-discharge echocardiographic or 30-day clinical outcome measures between 
subjects with and without a native bicuspid valve. The results from this study have 
demonstrated that the commercially available Lotus Valve System is a safe and effective 
treatment for subjects with severe calcific aortic stenosis in routine clinical practice. 

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4.1.2.4. REPRISE III Randomized Controlled Trial 
The REPRISE III pivotal study (REpositionable Percutaneous Replacement of Stenotic 
Aortic Valve through Implantation of Lotus™ Valve System – Randomized Clinical 
Evaluation; NCT02202434) includes a prospective, multicenter, randomized, controlled trial 
(RCT) designed to evaluate the safety and effectiveness of the Lotus™ Valve System 
(23mm, 25mm, or 27mm valve; test device) compared to a commercially available self-
expanding transcatheter heart valve (CoreValve® device, Medtronic Corp, Dublin, Ireland; 
26mm, 29mm, and 31mm valve; control device) in symptomatic subjects with severe calcific 
aortic stenosis who are considered extreme or high risk for surgical valve replacement. There 
were 912 subjects randomized at 55 centers in the United States, Germany, France, Australia, 
The Netherlands, and Canada. Subjects were considered enrolled in the study upon 
randomization. Clinical follow-up will extend through 5 years. The trial included 
independent core laboratory analysis and independent event adjudication with data validated 
by independent statisticians. 
The 30-day primary safety composite endpoint for REPRISE III includes all-cause mortality, 
stroke, life-threatening and major bleeding events, stage 2 or 3 acute kidney injury, and 
major vascular complications. The primary effectiveness endpoint for noninferiority includes 
the combined rate of mortality, disabling stroke, and moderate/severe PVR at 1 year post 
implant procedure. Other measurements incorporated the minimum data collection and 
endpoints recommended and defined by the VARC guidelines. Subject screening, data 
collection, and event assessments were as described for REPRISE II (Section 4.1.2.2) Data 
for the primary endpoint in the RCT have been published44. 
A total of 607 subjects were randomized to the Lotus group and 305 were randomized to the 
CoreValve group (ITT analysis set). Subject analysis groups are shown in Figure 4.1-1. The 
first-generation Lotus Valve System was used throughout the study while the second-
generation CoreValve Evolut R device was introduced mid-way in the study. Thus, in the 
implanted analysis set of the CoreValve treatment group 51.5% of subjects received 
CoreValve and 48.5% received CoreValve Evolut R (153/297 and 144/297, respectively). 

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Figure 4.1-1: REPRISE III Randomized Subject Analysis Groups 
The ITT population includes all randomized subjects, whether or not an assigned study device was implanted. 
The implanted population includes ITT subjects who received the assigned, randomized study device. The as-
treated population includes ITT subjects who received a study device, based on treatment actually received. 
The REPRISE III primary safety endpoint was met because in the implanted analysis set the 
rate for the Lotus group (20.3%) was non-inferior to the rate for the CoreValve group 
(17.2%). Non-inferiority was concluded because the one-sided upper 97.5% confidence 
bound on the difference between treatment groups (Lotus minus CoreValve; 3.1%) was less 
than the non-inferiority margin of 10.5% with a P value <0.025 (P=0.0027). Non-inferiority 
was also shown for the ITT and as-treated analysis sets. 
The primary effectiveness endpoint was met because in the implanted analysis set the rate for 
Lotus group (15.4%) was non-inferior to the rate for CoreValve (25.5%). Non-inferiority was 
concluded because the one-sided upper 97.5% confidence bound on the difference between 
treatment groups (Lotus minus CoreValve; -4.41%) was less than the non-inferiority margin 
of 9.5% with a P value <0.025 (P<0.0001). Non-inferiority was also shown for the ITT and 
as-treated analysis sets. The rate of the primary effectiveness endpoint for Lotus was shown 
to be superior to that for CoreValve in the ITT analysis set (P=0.0006) and also in the 
implanted and as-treated analysis sets. 
Table 4.1-11 shows clinical and echocardiographic outcomes at 30 days and 1 year. The 
following were similar between the 2 cohorts:  
• All-cause mortality in the CoreValve arm and Lotus arm was 2.3% and 2.5%, 
respectively (P=0.86), at 30 days and 13.5% and 11.9%, respectively (P=0.51), at 
1 year.  
• Cardiovascular mortality was 2.3% (CoreValve) and 2.3% (Lotus, P=0.99) at 30 days 
and 9.8% (CoreValve) and 7.7% (Lotus, P=0.29) at 1 year. 
• The overall stroke rate in the CoreValve and Lotus cohorts was 4.3% and 4.8%, 
respectively (P=0.72), at 30 days and 9.4% and 7.0%, respectively (P=0.20), at 
1 year. 
Lotus
(N=607)
Implanted 
Analysis Set 
(N=577)
ITT
Analysis Set
(N=912)
As-Treated 
Analysis Set
(N=577)
Crossover (N=10)
CoreValve
(N=305)
As-Treated 
Analysis 
Set (N=307)
Crossover (N=0)
Implanted 
Analysis Set 
(N=297)
No Study Valve Implanted 
(N=20)
No Study Valve Implanted 
(N=8)

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• The rate of major vascular complications was 5.3% (CoreValve) and 7.0% (Lotus, 
P=0.32) at 30 days and 6.1% (CoreValve) and 7.7% (Lotus, P=0.38) at 1 year. 
• Life-threatening/disabling bleeding was 5.0% (CoreValve) and 8.0% (Lotus, P=0.09) 
at 30 days and 9.8% (CoreValve) and 9.9% (Lotus, P=0.96) at 1 year. 
The following were statistically significantly different between the 2 cohorts: 
• The disabling stroke rate in the CoreValve and Lotus cohorts was 3.3% and 2.0%, 
respectively (P=0.23), at 30 days and 7.1% and 3.6%, respectively (P=0.02), at 
1 year. 
• The rate of permanent pacemaker implantation among subjects without a prior 
pacemaker was 19.6% (CoreValve) and 35.5% (Lotus, P <0.001) at 30 days and 
23.0% (CoreValve) and 41.4% (Lotus, P <0.001) at 1 year. 
• The valve thrombosis rate was 0.0% for both cohorts at 30 days; it was 0.0% 
(CoreValve) and 1.5% (Lotus, P=0.03) at 1 year.  
• Repeat procedures for prosthetic valve-related dysfunction occurred in 1.0% of 
CoreValve subjects and 0.0% of Lotus subjects at 30 days (P=0.04) and 2.0% 
(CoreValve) and 0.2% (Lotus) by1 year (P=0.007). 
• Prosthetic valve malpositioning (including valve migration, valve embolization, and 
ectopic valve deployment to discharge/7 days) occurred in 2.6% of subjects in the 
CoreValve group and 0.0% of subjects in the Lotus group (P<0.001). 
• TAV-in-TAV deployment occurred in 3.0% of subjects in the CoreValve group and 
in no subjects in the Lotus group (P <0.001). 
• Mean gradient was significantly lower and EOA was significantly higher in the 
CoreValve group at discharge and beyond (both P <0.001). 
There was significantly less PVR with Lotus compared to CoreValve at all time points 
(P<0.001).

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Table 4.1-11: Clinical and Echocardiographic Outcomes at 30 Days and 1 Year in REPRISE III RCT 
Measure 
30 Daysa 
1-Yeara 
CoreValve (N=305) 
Lotus (N=607) 
P Value 
CoreValve (N=305) 
Lotus (N=607) 
P Value 
Clinical Outcomes (CEC Adjudicated, VARC Definitions) 
All-cause mortality 
2.3% (7/303) 
2.5% (15/601) 
0.86 
13.5% (40/297) 
11.9% (70/587) 
0.51 
 Cardiovascular 
2.3% (7/303) 
2.3% (14/601) 
0.99 
9.8% (29/297) 
7.7% (45/587) 
0.29 
Stroke 
4.3% (13/303) 
4.8% (29/601) 
0.72 
9.4% (28/297) 
7.0% (41/587) 
0.20 
 Disabling stroke 
3.3% (10/303) 
2.0% (12/601) 
0.23 
7.1% (21/297) 
3.6% (21/587) 
0.02 
All-cause mortality or 
disabling stroke 
5.3% (16/303) 
4.0% (24/601) 
0.37 
17.8% (53/297) 
13.3% (78/587) 
0.07 
Major vascular complications 
5.3% (16/303) 
7.0% (42/601) 
0.32 
6.1% (18/297) 
7.7% (45/587) 
0.38 
 
Access site related 
3.3% (10/303) 
4.7% (28/601) 
0.34 
3.7% (11/297) 
5.1% (30/587) 
0.35 
New PPMb 
15.8% (48/303) 
29.1% (175/601) 
<0.001 
18.5% (55/297) 
34.2% (201/587) 
<0.001 
 
No prior PPMb 
19.6% (48/245) 
35.5% (175/493) 
<0.001 
23.0% (55/239) 
41.4% (201/485) 
<0.001 
Life-threatening/disabling 
bleeding 
5.0% (15/303) 
8.0% (48/601) 
0.09 
9.8% (29/297) 
9.9% (58/587) 
0.96 
MI ≤ 72 hours 
1.0% (3/303) 
0.5% (3/601) 
0.41 
1.3% (4/297) 
0.5% (3/587) 
0.23 
MI > 72 hours 
0.3% (1/303) 
0.2% (1/601) 
1.00 
3.4% (10/297) 
2.7% (16/587) 
0.59 
AKI – Stage 2/3  
3.6% (11/303) 
2.5% (15/601) 
0.34 
3.7% (11/297) 
2.6% (15/587) 
0.34 
Repeat procedurec  
1.0% (3/303) 
0.0% (0/601) 
0.04 
2.0% (6/297) 
0.2% (1/587) 
0.007 
Hospitalizationd 
3.0% (9/303) 
1.7% (10/601) 
0.20 
13.8% (41/297) 
11.2% (66/587) 
0.27 
New onset atrial 
fibrillation/flutter  
4.3% (13/303) 
5.8% (35/601) 
0.33 
4.7% (14/297) 
6.6% (39/587) 
0.25 
Coronary obstructione  
0.7% (2/303) 
0.2% (1/601) 
0.26 
0.7% (2/297) 
0.2% (1/587) 
0.26 
Ventricular septal perforatione 
0.0% (0/303) 
0.2% (1/601) 
1.00 
0.0% (0/297) 
0.2% (1/587) 
1.00 
Mitral apparatus damagee 
0.3% (1/303) 
0.0% (0/601) 
0.34 
0.3% (1/297) 
0.0% (0/587) 
0.34 
Cardiac tamponadee 
1.0% (3/303) 
2.5% (15/601) 
0.13 
1.3% (4/297) 
2.6% (15/587) 
0.24 
Prosthetic aortic valve 
malappositionf  
2.6% (8/303) 
0.0% (0/601) 
<0.001 
2.7% (8/297) 
0.0% (0/587) 
<0.001 
TAV-in-TAV deployment 
3.0% (9/303) 
0.0% (0/601) 
<0.001 
3.7% (11/297) 
0.0% (0/587) 
<0.001 
Prosthetic aortic valve 
thrombosis 
0.0% (0/303) 
0.0% (0/601) 
Undefined 
0.0% (0/297) 
1.5% (9/587) 
0.03 

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Table 4.1-11: Clinical and Echocardiographic Outcomes at 30 Days and 1 Year in REPRISE III RCT 
Measure 
30 Daysa 
1-Yeara 
CoreValve (N=305) 
Lotus (N=607) 
P Value 
CoreValve (N=305) 
Lotus (N=607) 
P Value 
Prosthetic aortic valve 
endocarditis 
0.0% (0/303) 
0.2% (1/601) 
1.00 
0.0% (0/297) 
0.7% (4/587) 
0.31 
Valve Performance by TTE (Core Lab Assessment) 
EOA (cm2)g 
1.98±0.51 (238) 
1.59±0.45 (506) 
<0.001 
1.69±0.52 (199) 
1.49±0.45 (420) 
<0.001 
Mean aortic valve gradient 
(mmHg)h 
7.25±3.44 (261) 
12.00±6.08 (544) 
<0.001 
7.89±3.48 (219) 
12.29±5.83 (462) 
<0.001 
Peak aortic gradient (mmHg) 
13.59±6.21 (261) 
21.46±10.27 (545) 
<0.001 
15.22±6.44 (219) 
22.74±10.53 (462) 
<0.001 
Peak aortic velocity (m/s) 
1.80±0.40 (261) 
2.26±0.46 (545) 
<0.001 
1.91±0.41 (219) 
2.33±0.51 (462) 
<0.001 
Paravalvular Aortic Regurgitation 
 None 
24.5% (65/265) 
72.5% (392/541) 
<0.001 
37.0% (81/219) 
79.9% (362/453) 
<0.001 
 Trace/trivial 
14.7% (39/265) 
10.7% (58/541) 
0.10 
10.5% (23/219) 
5.7% (26/453) 
0.03 
 Mild  
48.7% (129/265) 
10.7% (58/541) 
<0.001 
38.8% (85/219) 
11.3% (51/453) 
<0.001 
 Mild-moderate 
0.0% (0/265) 
0.0% (0/541) 
Undefined 
0.0% (0/219) 
0.0% (0/453) 
Undefined 
 Moderate 
7.2% (19/265) 
0.4% (2/541) 
<0.001 
5.9% (13/219) 
0.9% (4/453) 
<0.001 
 Moderate-severe 
0.0% (0/265) 
0.2% (1/541) 
1.00 
0.9% (2/219) 
0.0% (0/453) 
0.11 
 Severe  
0.0% (0/265) 
0.0% (0/541) 
Undefined 
0.0% (0/219) 
0.0% (0/453) 
Undefined 
 AR (severity not evaluable) 
4.9% (13/265) 
5.5% (30/541) 
0.70 
6.8% (15/219) 
2.2% (10/453) 
0.003 
Numbers are presented as % (n); outcomes were adjudicated by the CEC; aortic regurgitation grading is based on Pibarot, et al. (2015)105 
a: From randomization to time point 
b:  Due to new conduction disturbances or arrhythmias; “no prior PPM” indicates subjects without a PPM before the index procedure 
c:  For valve-related dysfunction; surgical or interventional 
d:  For valve-related symptoms or worsening congestive heart failure (NYHA Class III or IV) 
e:  Periprocedural (≤72 hours post index procedure) 
f:  Includes valve migration, valve embolization, or ectopic valve deployment 
g:  Baseline: 0.70±0.19 cm2 (280) for CoreValve and 0.69±0.19 cm2 (541) for Lotus (P=0.33) 
h: Baseline: 43.85±12.31 mmHg (294) for CoreValve and 44.64±13.35 mmHg (575) for Lotus (P=0.40) 
Note: “Discharge” represents discharge from hospitalization or 7 days post-procedure, whichever came first. 
Abbreviations: AR=aortic regurgitation; AKI=acute kidney injury; CEC=Clinical Events Committee; EOA= effective orifice area; MI=myocardial infarction; 
PPM=permanent pacemaker; TAV=transcatheter aortic valve; TTE=transthoracic echocardiography; VARC=Valve Academic Research Consortium 
Reference: Feldman 201844 

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In conclusion, in this large (N=912) randomized comparison of two different types of TAVR 
platforms, the Lotus Valve System was non-inferior to the commercially available CoreValve 
for the composite primary safety endpoint at 30 days. Lotus showed superiority for the 
composite primary effectiveness endpoint at 1 year, driven by significantly fewer disabling 
strokes (3.6% vs 7.1%, P=0.02) and significantly less moderate or severe PVR (0.9% vs 
6.9%, P<0.0001; core lab determination). The frequency of overall stroke at 1 year was 7.0% 
with Lotus and 9.4% with CoreValve; the repositionability of Lotus did not lead to a higher 
stroke rate compared to CoreValve. Recently reported 1-year stroke rates include 5.6% 
among high-risk subjects in the adjudicated SAPIEN 3 registry106 and 8.8% and 12.6% 
among TAVR and SAVR subjects, respectively, in the U.S. CoreValve High Risk Study25. 
Lower stroke rates have been reported in lower-risk subject groups34,49. Moderate or greater 
PVR has been associated with an increased risk of mortality55,56. The impact of mild PVR is 
less clear57,58 although a recent meta-analysis suggested that mild PVR may also be 
associated with increased all-cause and cardiovascular mortality59. Reported rates for 
moderate or greater PVR with newer generation devices have ranged from 1.5% with the 
balloon-expandable SAPIEN 3 valve32 to 5.3% with Evolut R49 with lower rates in 
intermediate compared to high risk subjects. 
There were more new pacemaker implantations (41.4% vs 23.0%, P<0.0001 among subjects 
without a prior pacemaker) at 1 year with Lotus. Pacemaker implantation is associated with 
subject morbidity and increased cost (including repeat hospitalization)81 but has not been 
associated with decreased survival in other studies of high risk subjects77,78,82,107. A recently 
published meta-analysis found that subjects with and without PPM post TAVR had similar 
rates for all-cause mortality, cardiovascular mortality, MI, and stroke at 30 days and 
1 year108. This analysis did show that improvement in LVEF was significantly greater in 
subjects without PPM. Valve thrombosis was uncommon but there were significantly more 
cases, as defined by VARC criteria, with Lotus (1.5% vs. 0%, P=0.03). Most were identified 
based on increased mean aortic gradient at protocol-directed follow-up echocardiography and 
all showed a decrease in mean gradient after anticoagulation therapy. These results are 
consistent with a recent registry report based on CT showing subclinical leaflet thrombosis 
rates of 4% with surgical valves and 12% with TAVR valves and suggesting that the supra-
annular CoreValve may have a lower rate compared to TAVR valves with an annular 
location (CoreValve/Evolut R: 6%; Lotus: 14%; Edwards [Sapien, SAPIEN XT, and 
SAPIEN 3]: 14%; Portico: 30%)109. A recent single-center retrospective analysis (281 
balloon-expandable, 305 self-expanding, 56 Lotus) found an overall incidence of 2.8% for 
clinical valve thrombosis110. Reported rates were 4.6% for SAPIEN valves, 1.0% for 
CoreValve/Evolut R, and 3.6% for Lotus. At 1 year, valve malpositioning, repeat procedures, 
and TAV-in-TAV deployment were all less common with Lotus. The observed rate of TAV-
in-TAV with CoreValve was 2.3%; rates of TAV-in-TAV with CoreValve in prior US 
pivotal CoreValve trials have ranged from 1.3% to 6.7%25,34,47,49. 
Overall, outcomes in the REPRISE III RCT support the safety and efficacy of the Lotus 
Valve System in symptomatic subjects with severe calcific aortic stenosis who are considered 
extreme or high risk for surgical valve replacement. 

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4.1.2.5. REPRISE Japan 
The objective of the REPRISE Japan clinical trial (REpositionable Percutaneous 
Replacement of Stenotic Aortic Valve through Implantation of Lotus™ Valve System – 
Clinical Evaluation in Japan; NCT02491255) was to confirm the safety and effectiveness of 
the Lotus™ Valve System in the Japanese medical environment for TAVR in symptomatic 
subjects with calcific, severe native aortic stenosis considered at high or extreme risk for 
SAVR. The 30-day primary safety composite endpoint includes all-cause mortality, stroke, 
life-threatening and major bleeding events, stage 2 or 3 acute kidney injury, and major 
vascular complications. The primary effectiveness endpoint is a composite at 6 months of all-
cause mortality and disabling stroke and moderate or greater PVR based on core lab 
assessment. Other measurements incorporated the minimum data collection and endpoints 
recommended and defined by the VARC guidelines. Subject screening, data collection, and 
event assessments were as described for REPRISE II (Section 4.1.2.2). 
There were 40 evaluable subjects enrolled at 5 centers in the transfemoral arm of REPRISE 
Japan. The primary safety composite endpoint rate was 15.0% (6/40) at 30 days and the 
primary effectiveness composite endpoint was 5.3% (2/38) at 6 months. Table 4.1-12 shows 
clinical and echocardiographic outcomes at 30 days, 6 months, and 1 year. Mortality through 
1 year was low (7.5%) as was disabling stroke (2.5%). There was no moderate or severe 
PVR. Overall, outcomes were similar to that seen with Lotus in REPRISE II (Section 4.1.2.2) 
and REPRISE III (Section 4.1.2.4) and demonstrated consistent safety and effectiveness 
results with the Lotus Valve System in Japanese subjects.   
Table 4.1-12: 30-Day, 6-Month, and 1-Year Outcomes – REPRISE Japan Evaluable 
Transfemoral Cohort (N=40)  
Outcomes  
30 Days 
6 Months 
1 Year 
Clinical Outcomes (CEC Adjudicated, VARC Definitions) 
All-cause mortality 
0.0% (0/40) 
2.5% (1/40) 
7.5% (3/40) 
 
Cardiovascular 
0.0% (0/40) 
2.5% (1/40) 
5.0% (2/40) 
All stroke 
7.5% (3/40) 
7.5% (3/40) 
7.5% (3/40) 
 
Disabling stroke 
2.5% (1/40) 
2.5% (1/40) 
2.5% (1/40) 
Major vascular complications 
2.5% (1/40) 
2.5% (1/40) 
2.5% (1/40) 
Life-threatening or disabling bleeding 
5.0% (2/40) 
5.0% (2/40) 
5.0% (2/40) 
Major bleeding 
0.0% (0/40) 
0.0% (0/40) 
0.0% (0/40) 
Myocardial infarction 
0.0% (0/40) 
0.0% (0/40) 
0.0% (0/40) 
Acute kidney injury – Stage 2 or 3a 
0.0% (0/40) 
0.0% (0/40) 
0.0% (0/40) 
New PPM implantationb  
22.5% (9/40) 
22.5% (9/40) 
25.0% (10/40) 
 
New PPM in subjects without prior PPM 
23.7% (9/38) 
23.7% (9/38) 
26.3% (10/38) 
Coronary obstruction (periprocedural) 
0.0% (0/40) 
0.0% (0/40) 
0.0% (0/40) 
Ventricular septal perforation (periprocedural) 
0.0% (0/40) 
0.0% (0/40) 
0.0% (0/40) 
Mitral apparatus damage (periprocedural) 
0.0% (0/40) 
0.0% (0/40) 
0.0% (0/40) 
Cardiac tamponade (periprocedural) 
0.0% (0/40) 
0.0% (0/40) 
0.0% (0/40) 
Valve-related dysfunctionc 
0.0% (0/40) 
0.0% (0/40) 
0.0% (0/40) 
Hospitalizationd  
0.0% (0/40) 
0.0% (0/40) 
0.0% (0/40) 

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Table 4.1-12: 30-Day, 6-Month, and 1-Year Outcomes – REPRISE Japan Evaluable 
Transfemoral Cohort (N=40)  
Outcomes  
30 Days 
6 Months 
1 Year 
Atrial fibrillation – new onset 
5.0% (2/40) 
5.0% (2/40) 
5.0% (2/40) 
Atrial flutter – new onset 
0.0% (0/40) 
0.0% (0/40) 
0.0% (0/40) 
Prosthetic aortic valve malpositioninge 
0.0% (0/40) 
0.0% (0/40) 
0.0% (0/40) 
TAV-in-TAV deployment 
0.0% (0/40) 
0.0% (0/40) 
0.0% (0/40) 
Prosthetic aortic valve thrombosis 
0.0% (0/40) 
0.0% (0/40) 
0.0% (0/40) 
Prosthetic aortic valve endocarditis 
0.0% (0/40) 
0.0% (0/40) 
0.0% (0/40) 
Valve Performance by TTE (Core Lab Assessment) 
Aortic valve area (effective orifice area) (cm2)f 
1.54±0.37 (40) 
1.49±0.38 (35) 
1.38±0.31 (35) 
Mean aortic valve gradient (mmHg)g 
13.04±4.87 (40) 
13.40±5.65 (37) 
14.22±6.09 (35) 
Peak aortic gradient (mmHg) 
21.81±8.39 (40) 
22.69±9.26 (37) 
24.44±10.61 (35) 
Peak aortic velocity (cm/s) 
2.30±0.43 (40) 
2.34±0.45 (37) 
2.42±0.51 (36) 
Paravalvular Aortic Regurgitation 
 
None 
60.0% (24/40) 
75.7% (28/37) 
75.0% (27/36) 
 
Trace/trivial 
10.0% (4/40) 
10.8% (4/37) 
8.3% (3/36) 
 
Mild  
27.5% (11/40) 
13.5% (5/37) 
16.7% (6/36) 
 
Mild-moderate 
0.0% (0/40) 
0.0% (0/37) 
0.0% (0/36) 
 
Moderate 
0.0% (0/40) 
0.0% (0/37) 
0.0% (0/36) 
 
Moderate-severe 
0.0% (0/40) 
0.0% (0/37) 
0.0% (0/36) 
 
Severe  
0.0% (0/40) 
0.0% (0/37) 
0.0% (0/36) 
Numbers are presented as % (count/sample size) or mean±SD (n). Data are from the intent-to-treat analysis 
set; aortic regurgitation grading is based on Pibarot, et al. (2015)105.  
a: AKIN Stage 2 or Stage 3 (including renal replacement therapy)111,112; ≤ 7 days post index procedure 
b: Resulting from new or worsened conduction disturbances 
c: Requiring repeat procedure (surgical or interventional) 
d: For valve-related symptoms or worsening congestive heart failure 
e: Including valve migration, valve embolization, ectopic valve deployment (procedural) 
f: Baseline effective orifice area (cm2): 0.58 ± 0.20 (39) 
g: Baseline mean aortic gradient (mmHg): 57.31 ± 20.16 (40) 
Abbreviations: CEC=clinical events committee; PPM=permanent pacemaker; TAV=transcatheter aortic 
valve; TTE=transthoracic echocardiography; VARC=Valve Academic Research Consortium 
Reference: Saito 2017113, 2018114 
 
4.1.2.6. REPRISE NG DS Study 
The REpositionable Percutaneous Replacement of Stenotic Aortic Valve through 
Implantation of LotuS ValvE with the Next Generation Delivery System (REPRISE NG DS) 
study (NCT02329496) is a first-human-use trial evaluating a modified version of the delivery 
system that was studied in REPRISE I, REPRISE II, REPRISE III, and RESPOND. In 
Cohort A of this prospective single-arm study, 10 subjects were enrolled at 2 investigative 
centers in Australia; the device was introduced into the body using the Lotus Introducer Set. 
In Cohort B, an additional 7 subjects were enrolled at the same centers to evaluate acute 
performance and safety of a further optimized version of the LOTUS Edge device (including 

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radiopaque markers on the valve locking assembly). Cohort B also assessed the acute 
performance and safety of an early iteration of the iSleeve™ Introducer Set and its 
compatibility with the LOTUS Edge device. A third cohort (Cohort C) subsequently enrolled 
21 subjects who were treated with a further refined version of the LOTUS Edge delivery 
system. In some Cohort C subjects a further refined version of the iSleeve Introducer was 
used. The primary endpoint in REPRISE NG DS is technical success, defined as follows: 
successful vascular access, delivery and deployment of the Lotus valve and successful 
retrieval with the Lotus NG delivery system; correct positioning of the Lotus valve in the 
proper anatomical location; and a single Lotus valve implanted in the proper anatomical 
location. Clinical follow-up will extend through 1 year. 
The primary endpoint was achieved in 10/10 subjects in Cohort A115, 5/7 in Cohort B (in 
1 subject a valve was not implanted and in 1 subject a valve was implanted using the current 
Lotus Valve System), and 21/21 in Cohort C116. Table 4.1-13 shows core lab analyses of 
prosthetic valve performance as assessed by TTE at discharge/7 days post procedure 
(secondary endpoint) and valve function at 30 days and 1 year for the 3 cohorts. In all 
cohorts, mean aortic valve area and mean gradient improved at discharge and remained 
improved at 30 days and 1 year. There were no cases of moderate or severe PVR at 
discharge, 30 days, or 1 year in any cohort; the majority of patients had no PVR or trace PVR 
at all time points. Table 4.1-14 shows rates of CEC-adjudicated VARC-defined events 
through discharge/7 days, 30 days, 6 months, and 1 year. In Cohort A, one subject 
experienced the majority of events and subsequently died on day 13 post implant. In 
Cohort B, events were minimal. In Cohort C, new permanent pacemakers were placed in 2 
subjects by 1 year for a rate of 9.5% (2/21) among all subjects and 11.1% (2/18) among 
subjects without a prior pacemaker. In summary, outcomes to 1 year in the REPRISE NG DS 
study demonstrate acceptable performance and safety of the Lotus valve with the next 
generation delivery system.

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Table 4.1-13: Valve Performance by TTE, Core Lab Analysis – REPRISE NG DS Cohorts A, B and C 
Measure 
Cohort A (N=10) 
Cohort B (N=6) 
Cohort C (N=21) 
Baseline 
Discharge 
30 Days  
1 Year 
Baseline 
Discharge 
30 Days 
1 Year 
Baseline 
Discharge 
30 Days 
1 Year 
EOA (cm2) 
0.69±0.21 
(10) 
1.55±0.43 
(10) 
1.44±0.45 
(9) 
1.38±0.49 
(6) 
0.54±0.14 
(6) 
1.72±0.39  
(4) 
1.30±0.42 
(5) 
1.40±0.32 
(5) 
0.63±0.19 
(21) 
1.50±0.37 
(21) 
1.28±0.36 
(21) 
1.47±0.43 
(20) 
Mean 
gradient 
(mmHg) 
48.5±13.3 
(10) 
13.4±4.3 
(10) 
15.7±8.0 
(9) 
15.8±9.2 
(6) 
51.3±14.5 
(6) 
10.1±3.9  
(6) 
10.5±0.9 
(5) 
12.9±2.0 
(5) 
51.3±9.5 
(21) 
14.0±4.4 
(21) 
14.7±5.6 
(21) 
14.1±5.1 
(20) 
Paravalvular Aortic Regurgitation 
 None 
N/A 
80.0 (8) 
66.7 (6) 
66.7 (4) 
N/A 
83.3 (5) 
60.0 (3) 
100.0 (5) 
N/A 
95.2 (20) 
85.7 (18) 
75.0 (15) 
 Trace 
N/A 
10.0 (1) 
11.1 (1) 
33.3 (2) 
N/A 
20.0 (1) 
40.0 (2) 
0.0 (0) 
N/A 
4.8 (1) 
9.5 (2) 
20.0 (4) 
 Mild 
N/A 
10.0 (1) 
11.1 (1) 
0.0 (0) 
N/A 
0.0 (0) 
0.0 (0) 
0.0 (0) 
N/A 
0.0 (0) 
4.8 (1) 
5.0 (1) 
 Moderate 
N/A 
0.0 (0) 
0.0 (0) 
0.0 (0) 
N/A 
0.0 (0) 
0.0 (0) 
0.0 (0) 
N/A 
0.0 (0) 
0.0 (0) 
0.0 (0) 
 Severe 
N/A 
0.0 (0) 
0.0 (0) 
0.0 (0) 
N/A 
0.0 (0) 
0.0 (0) 
0.0 (0) 
N/A 
0.0 (0) 
0.0 (0) 
0.0 (0) 
Numbers are presented as mean±standard deviation (n) or % (n); only subjects who received a study valve are included in the core lab analyses. 
Note: “Discharge” represents discharge from hospitalization or 7 days post-procedure, whichever came first. 
Abbreviations: EOA=effective orifice area; N/A=not applicable; NGDS=Next Generation Delivery System; TTE=transthoracic echocardiography 
 
Table 4.1-14: Discharge, 30-Day, 6-Month, and 1-Year Clinical Outcomes in REPRISE NG DS Cohorts A, B and C 
VARC Event 
Cohort A (N=10) 
Cohort B (N=6) 
Cohort C (N=21) 
Discharge  
30-Day  
6-Month 
1-Year 
Discharge 
30-Day 
6-Month 
1-Year 
Discharge 
30-Day 
6-Month 
1-Year 
All-cause mortality 
0.0 (0) 
10.0 (1) 
20.0 (2) 
20.0 (2) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
 Cardiovascular 
0.0 (0) 
10.0 (1) 
10.0 (1) 
10.0 (1) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
Stroke 
10.0 (1) 
10.0 (1) 
10.0 (1) 
10.0 (1) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
4.8 (1) 
4.8 (1) 
4.8 (1) 
4.8 (1) 
 Disabling stroke 
10.0 (1) 
10.0 (1) 
10.0 (1) 
10.0 (1) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
4.8 (1) 
4.8 (1) 
4.8 (1) 
4.8 (1) 
Major vascular 
complications 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
9.5 (2) 
9.5 (2) 
9.5 (2) 
9.5 (2) 
New PPMa 
30.0 (3) 
40.0 (4) 
30.0 (3) 
40.0 (4) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
9.5 (2)b 
9.5 (2)b 
9.5 (2)b 
9.5 (2)b 
Life-threatening/ 
disabling bleeding 
20.0 (2) 
20.0 (2) 
20.0 (2) 
20.0 (2) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
MI 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
9.5 (2) 
AKI – Stage 2/3  
10.0 (1) 
10.0 (1) 
10.0 (1) 
10.0 (1) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
Repeat procedurec  
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 

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Table 4.1-14: Discharge, 30-Day, 6-Month, and 1-Year Clinical Outcomes in REPRISE NG DS Cohorts A, B and C 
VARC Event 
Cohort A (N=10) 
Cohort B (N=6) 
Cohort C (N=21) 
Discharge  
30-Day  
6-Month 
1-Year 
Discharge 
30-Day 
6-Month 
1-Year 
Discharge 
30-Day 
6-Month 
1-Year 
Hospitalizationd 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
16.7 (1) 
16.7 (1) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
9.5 (2) 
New onset atrial 
fibrillation/flutter  
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
9.5 (2) 
9.5 (2) 
9.5 (2) 
9.5 (2) 
Coronary 
obstructione  
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
Ventricular septal 
perforatione 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
Mitral apparatus 
damagee 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
Cardiac 
tamponadee 
10.0 (1) 
10.0 (1) 
10.0 (1) 
10.0 (1) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
Prosthetic aortic 
valve 
malappositionf  
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
Prosthetic aortic 
valve thrombosis 
0.0 (0) 
0.0 (0) 
0.0 (0) 
10.0 (1) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
4.8 (1) 
4.8 (1) 
4.8 (1) 
Prosthetic aortic 
valve endocarditis 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
16.7 (1) 
16.7 (1) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
0.0 (0) 
Numbers are presented as % (n); outcomes were adjudicated by the CEC; ITT analysis set for Cohorts A and C; as-treated analysis set for Cohort B 
a: Due to new conduction disturbances or arrhythmias 
b: In Cohort C, the rate of new PPM implantation among subjects without a prior pacemaker was 11.1%. 
c: For valve-related dysfunction (surgical/interventional) 
d: For valve-related symptoms or worsening congestive heart failure 
e: Periprocedural (≤72 hours post index procedure) 
f: Includes valve migration, valve embolization, ectopic valve deployment, or TAV-in-TAV 
Note: “Discharge” represents discharge from hospitalization or 7 days post-procedure, whichever came first. 
Note: In Cohort A, one subject experienced the majority of events and died on day 13. In Cohort B, there were 2 procedural minor access site related vascular complications and 
1 procedural major bleeding event. In Cohort C, there were 2 minor access site related vascular complications and 2 major bleeding events. 
Abbreviations: AKI=acute kidney injury; CEC=Clinical Events Committee; ITT=intention-to-treat; MI=myocardial infarction; NGDS=Next Generation Delivery System; 
PPM=permanent pacemaker; TAV=transcatheter aortic valve; VARC=Valve Academic Research Consortium 

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4.1.2.7. REPRISE EDGE 
The prospective, single-arm REpositionable Percutaneous Replacement of NatIve StEnotic 
Aortic Valve through Implantation of LOTUS EDGE Valve System – Evaluation of 
Performance and Safety study (REPRISE EDGE; NCT02854319; N=15) has the same 
overall study design as REPRISE NG DS (Section 4.1.2.6) and assessed acute performance 
and safety of the same LOTUS Edge design that was used in Cohort C. The primary endpoint 
was the mean aortic valve pressure gradient at discharge as measured by echocardiography 
and assessed by an independent core laboratory. Secondary endpoints included technical 
success and device performance peri- and post-procedure based in part on VARC criteria. 
At discharge, the mean aortic gradient was 14.4±4.1 mmHg (N=15). Technical success was 
100% and all attempts at repositioning or retrieving the valve were successful, and there was 
no moderate or severe PVR at discharge. Table 4.1-15 shows clinical and echocardiographic 
outcomes at 30 days and 1 year. There was no mortality and 1 disabling stroke through 
1 year; PPM were placed in 2 subjects by 30 days for a rate of 13.3% among subjects without 
a prior PPM. Mean aortic valve area and mean gradient were improved at 30 days and 1 year 
with no moderate or severe PVR. Overall, outcomes with LOTUS Edge are consistent with 
outcomes observed in REPRISE II/II Extension and REPRISE III and with other TAVR 
studies using the VARC metrics. 
Table 4.1-15: 30-Day and 1-Year Outcomes – REPRISE EDGE (N=15)  
Outcomes  
30 Days 
1 Year 
Clinical Outcomes (CEC Adjudicated, VARC Definitions) 
All-cause mortality 
0.0% (0/15) 
0.0% (0/15) 
All stroke 
6.7% (1/15) 
6.7% (1/15) 
 
Disabling stroke 
6.7% (1/15) 
6.7% (1/15) 
Major vascular complications 
20.0% (3/15) 
20.0% (3/15) 
Life-threatening or disabling bleeding 
13.3% (2/15) 
13.3% (2/15) 
Major bleeding 
20.0% (3/15) 
20.0% (3/15) 
Acute kidney injury – Stage 2 or 3a 
0.0% (0/15) 
0.0% (0/15) 
New PPM implantationb  
13.3% (2/15) 
20.0% (3/15) 
 
New PPM in subjects without prior pacemaker 
13.3% (2/15) 
20.0% (3/15) 
Coronary obstruction (periprocedural) 
0.0% (0/15) 
0.0% (0/15) 
Ventricular septal perforation (periprocedural) 
0.0% (0/15) 
0.0% (0/15) 
Mitral apparatus damage (periprocedural) 
0.0% (0/15) 
0.0% (0/15) 
Cardiac tamponade (periprocedural) 
0.0% (0/15) 
0.0% (0/15) 
Myocardial infarction 
0.0% (0/15) 
0.0% (0/15) 
Valve-related dysfunction requiring repeat procedurec 
0.0% (0/15) 
0.0% (0/15) 
Hospitalization for valve-related symptoms or worsening CHF 
0.0% (0/15) 
0.0% (0/15) 
Atrial fibrillation or atrial flutter (new onset) 
0.0% (0/15) 
0.0% (0/15) 
Prosthetic aortic valve malpositioningd 
0.0% (0/15) 
0.0% (0/15) 
TAV-in-TAV deployment 
0.0% (0/15) 
0.0% (0/15) 
Prosthetic aortic valve thrombosis 
0.0% (0/15) 
6.7% (1/15) 
Prosthetic aortic valve endocarditis 
0.0% (0/15) 
6.7% (1/15) 

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Table 4.1-15: 30-Day and 1-Year Outcomes – REPRISE EDGE (N=15)  
Outcomes  
30 Days 
1 Year 
Valve Performance by Transthoracic Echocardiography (Core Lab Assessment) 
Aortic valve area (effective orifice area) (cm2)e 
1.24±0.29 (13) 
1.38±0.34 (11) 
Mean aortic valve gradient (mmHg)f 
14.95±8.40 (15) 
12.98±4.52 (14) 
Peak aortic gradient (mmHg) 
25.65±12.50 (15) 
23.64±8.55 (14) 
Peak aortic velocity (cm/s) 
2.47±0.57 (15) 
2.39±0.42 (14) 
Paravalvular Aortic Regurgitation 
 
None 
66.7% (10/15) 
71.4% (10/14) 
 
Trace/trivial 
13.3% (2/15) 
28.6% (4/14) 
 
Mild  
13.3% (2/15) 
0.0% (0/14) 
 
Mild-moderate 
0.0% (0/15) 
0.0% (0/14) 
 
Moderate 
0.0% (0/15) 
0.0% (0/14) 
 
Moderate-severe 
0.0% (0/15) 
0.0% (0/14) 
 
Severe  
0.0% (0/15) 
0.0% (0/14) 
Values are % (count/sample size) or mean±SD (n). Data are from the per-protocol analysis set (enrolled 
subjects implanted with a LOTUS Edge valve); aortic regurgitation grading is based on Pibarot, et al. 
(2015)105.  
a: AKIN Stage 2 or Stage 3 (including renal replacement therapy); ≤ 7 days post index procedure 
b: Resulting from new or worsened conduction disturbances 
c: Surgical or interventional 
d: Including valve migration, valve embolization, ectopic valve deployment (procedural) 
e: Baseline effective orifice area (cm2): 0.64 ± 0.19 (10) 
f: Baseline mean aortic gradient (mmHg): 49.46 ± 16.01 (13) 
Abbreviations: CEC=clinical events committee; CHF=congestive heart failure; PPM=permanent pacemaker; 
TAV=transcatheter aortic valve; VARC=Valve Academic Research Consortium 
 
4.2. 
Study Rationale 
As noted above, the Lotus Valve System potentially provides a number of performance and 
safety features beyond that of earlier TAVR devices. These include an enhanced ability to 
place the valve correctly at the first attempt, 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 a decision is made to replace it with another valve to optimize implant or not to 
implant, and the aforementioned outer seal designed to minimize PVR. Because the 
investigational device, the LOTUS Edge Valve System, consists of essentially the same pre-
loaded, stent-mounted tissue valve prosthesis as the Lotus Valve System evaluated in the 
REPRISE I, REPRISE II, REPRISE III, REPRISE Japan, and RESPOND studies but with a 
catheter delivery system designed for improved deliverability (evaluated in the REPRISE 
NG DS and REPRISE EDGE studies) the anticipated benefits and risks are very similar. The 
valve component with the addition of tantalum (radiopaque) markers is also intended to 
enhance locking visualization. Like the Lotus Introducer, the iSleeve Introducer Set has a 
dilator and sheath component, but the iSleeve sheath is expandable. This allows for transient 
sheath expansion during delivery system introduction, enabling expanded vascular access 

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and reducing the duration of time the access vessel is expanded and therefore minimizing 
potential for vessel trauma. Both sheaths have a hydrophilic coating that when activated 
increases the lubricity of the surface to aid in delivery. 
The anticipated risks and benefits associated with use of the LOTUS Edge Valve System, 
with either the Lotus or iSleeve Introducer Sets, by trained physicians with extensive TAVR 
experience, and with participation in this clinical investigation are summarized in the 
Investigator Brochure and in Section 18 of this document. The conclusion of this risk-benefit 
analysis demonstrates that the known risks associated with the procedure, and specifically the 
use of the LOTUS Edge Valve System, have been mitigated to acceptable limits, which are 
comparable to that for existing transcatheter aortic valves. It was also concluded that the 
aforementioned design features may improve procedural safety and longer term clinical 
outcomes. No new hazards/harms are introduced by the LOTUS Edge Valve System 
compared to the Lotus Valve System when used with either the Lotus or iSleeve Introducer 
Sets and the overall risk profile of the device has not changed. The available Sponsor-
provided training program and proctorship for physicians further mitigates any residual risk. 
The result is a procedure with residual subject risk comparable to that of currently available 
transcatheter aortic valves and 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 
The investigational LOTUS Edge™ Valve System is intended to improve aortic valve 
function for symptomatic subjects with severe aortic stenosis who are at intermediate risk for 
standard surgical aortic valve replacement (SAVR), including those who have a bicuspid 
native valve. 
5.1. 
LOTUS Edge Valve System 
The Lotus™ Valve System and LOTUS Edge Valve System are both made up of two 
principal elements: a bioprosthetic aortic valve implant and a catheter-based delivery system 
for introduction and delivery of the valve implant (Figure 5.1-1). The device is introduced 
percutaneously using conventional catheterization techniques. Access using a surgical cut-
down approach can also be performed to gain arterial access. Valve sizes include 23mm, 
25mm, and 27mm diameter. The Lotus family of devices provides a number of important 
performance and safety features beyond what is currently offered with first generation TAVR 
systems. Some of these improvements include the ability to reposition the device if the initial 
deployment is considered to be suboptimal and the ability to retrieve the device during the 
procedure if necessary. The LOTUS Edge Valve System is a design iteration of the Lotus 
Valve System, which was assessed in the REPRISE I, REPRISE II, REPRISE Japan, 

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REPRISE III, and RESPOND studies (Section 4.1.2). The LOTUS Edge Valve System has a 
catheter delivery system with enhanced deliverability and tantalum (radiopaque) markers 
have been added to the valve locking assembly (i.e., buckle and post-top components) to aid 
visualization of locking during the procedure. The LOTUS Edge Valve System also 
incorporates a modified leadscrew component, referred to as the Depthguard™ technology, 
which results in a slightly decreased rate of retraction of the outer sheath, during valve 
deployment compared to the Lotus Valve System. Detailed product information can be found 
in the IFU and in the Investigator’s Brochure. 
 
Figure 5.1-1: Overview of Principal Components of the LOTUS Edge Valve System 
 
5.1.1. 
LOTUS Edge Valve 
The LOTUS Edge valve is shown in Figure 5.1-2. It 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 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. Radiopaque markers on the post-top 
and buckle components aid visualization during the locking procedure. 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 existing 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. The valve is available in three sizes: 23mm, 25mm, 
and 27mm. The frame height of all three valve sizes in the deployed state is approximately 
19 mm. 

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Figure 5.1-2: LOTUS Edge Valve Implant 
5.1.2. 
LOTUS Edge Delivery System 
The LOTUS Edge Delivery System is composed of 3 main assemblies: (1) an inner catheter 
assembly (referred to as the multi-lumen catheter), which is attached to the valve implant; 
(2) an outer catheter assembly (referred to as the outer sheath); and (3) a controller assembly, 
which is used to control placement and release of the valve. Changes between the Lotus 
Valve System and the LOTUS Edge Valve System are described in the Investigator 
Brochure. 
The controller assembly is shown in Figure 5.1-3 (locked configuration in the top image). 
The principal control used to deploy the valve is the control knob at the proximal end of the 
controller. This control knob is used to first unsheathe the device and deploy the implant into 
the intermediate functioning, but non-locked, configuration and subsequently to shorten the 
implant and lock it in the final, anchored configuration. The process can be reversed to 
unlock the device or recapture the implant inside the outer sheath. When the valve implant is 
successfully positioned and locked in the desired location the delivery system is permanently 
detached. Additional information on valve implantation and release is found in the IFU. 
 
Figure 5.1-3: LOTUS Edge Controller  
Top: Locked configuration. Bottom: Door pulled forward allowing the valve to be released 
Locking Mechanism
Nitinol Frame
Bovine Pericardium
Adaptive Seal
Flush Ports
Control Knob
Guidewire Port
Release Ring
Release Door

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5.1.3. 
Lotus and iSleeve Introducer Sets 
The large Lotus Introducer Set or, when available, the iSleeve Introducer Set (Figure 5.1-4) 
will be used as an accessory to the LOTUS Edge Valve System during the procedure. In 
countries where the introducer sets are approved, the commercial devices will be used. In 
countries where they are not approved, they will be considered investigational devices. They 
both include a dilator and an introducer sheath with a hydrophilic coating that, when 
activated, increases the lubricity of the surface to aid in delivery. The large Lotus Introducer 
is intended for use with the 23mm, 25mm, or 27mm LOTUS Edge valve in subjects with 
femoral vascular access ≥6.5 mm. The sheath component of the iSleeve is expandable, which 
allows for transient sheath expansion during delivery system introduction. Temporary 
expansion of the access vessel reduces the time the access vessel is expanded during device 
introduction and therefore potentially reduces vessel trauma. The 15F iSleeve is capable of 
introducing the 23mm, 25mm and 27mm LOTUS Edge valve sizes into subjects with femoral 
vascular access ≥5.9 mm. 
 
Figure 5.1-4:  Lotus Introducer Set (Top) and iSleeve Introducer Set (Bottom) 
Detailed information can be found in the respective Instructions For Use. 
5.2. 
Device Labeling 
The study Manual of Operations includes the IFUs for the LOTUS Edge Valve System and, 
when available, the iSleeve Introducer Set. 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 
• Unique identifier 
• Lot number/Serial number 
• Expiration (use by) date (labeled as month/year, device not to be used after the last day 
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The following statement appears on the label.  
Caution: Investigational Device. Limited by Federal Law (USA) to Investigational Use. 
In addition, the following statements appear on the product labeling. 
CAUTION:  Exclusively for Clinical Investigations. 
The IFU for the large Lotus Introducer Set will also be provided in the study Manual of 
Operations. The label will also include the above, with the exception of the investigational 
device statement for countries where the device is commercially available. 
6. Study Objectives and Endpoints 
6.1. 
Study Objectives 
The objective of the REPRISE IV trial is to evaluate the safety and effectiveness of the 
LOTUS Edge Valve System when used with the Lotus or iSleeve Introducer Set for 
transcatheter aortic valve replacement (TAVR) in symptomatic subjects with severe aortic 
stenosis who are considered at intermediate risk for surgical valve replacement, including 
those who have a bicuspid native valve.  
6.2. 
Study Endpoints 
Outcomes will be assessed on an intention-to-treat (ITT) basis and an implanted basis. The 
ITT analysis population includes all subjects who sign the Informed Consent Form (ICF; see 
Section 20) and are enrolled in the trial (see Section 9.1 for point of enrollment), regardless 
of whether a study valve is implanted. The implanted analysis population includes ITT 
subjects who are implanted with the study valve.  Endpoint definitions can be found in Table 
25.2-1. 
6.2.1. 
Primary Endpoint 
The primary endpoint is a composite of all-cause mortality and all stroke at 1 year. The 
primary analysis set for the primary endpoint is the ITT analysis set.  
6.2.2. 
Additional Measurements 
Additional measurements based on the VARC endpoints and definitions61,62 (see Note 1 
below) will be collected peri- and post-procedure, at discharge or 7 days post-procedure 
(whichever comes first), 30 days, and annually up to 10 years post index procedure, unless 
otherwise specified below.  
• Safety endpoints adjudicated by an independent Clinical Events Committee (CEC; 
Section 21.1.1): 
o Mortality: all-cause, cardiovascular, and non-cardiovascular 
o Stroke: disabling and non-disabling 

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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 (through 5 years) 
o Acute kidney injury (AKI; ≤7 days post index procedure): based on the AKIN 
System111,112 Stage 3 (including renal replacement therapy) or Stage 2 
o Major vascular complication (including annular rupture; through 5 years) 
o Repeat procedure for valve-related dysfunction (surgical or interventional therapy) 
o Hospitalization for valve-related symptoms or worsening CHF (NYHA class III or IV) 
o New permanent pacemaker implantation resulting from new or worsened conduction 
disturbances (definitions in Table 25.2-1; see Note 2 below)  
o New onset of atrial fibrillation or atrial flutter 
o Coronary obstruction: periprocedural (≤72 hours post index procedure) 
o Ventricular septal perforation: periprocedural (≤72 hours post index procedure) 
o Mitral apparatus damage: periprocedural (≤72 hours post index procedure) 
o Cardiac tamponade: periprocedural (≤72 hours post index procedure) 
o Prosthetic aortic valve malpositioning, including valve migration, valve embolization, 
or ectopic valve deployment 
o Transcatheter aortic valve (TAV)-in-TAV deployment  
o Prosthetic aortic valve thrombosis 
o Prosthetic aortic valve endocarditis 
• Device performance endpoints peri- and post-procedure:  
o Successful vascular access, delivery and deployment of the study valve and successful 
retrieval of the delivery system 
o Successful retrieval of the study valve if retrieval is attempted 
o Successful repositioning of the study valve if repositioning is attempted (see Note 3 
below)  
o Grade of aortic valve regurgitation: paravalvular, central and combined; the overall 
distribution of paravalvular aortic regurgitation (none, trace/trivial, mild, moderate, 
severe) will be determined as well as the percentage of subjects who have moderate or 
severe paravalvular regurgitation and the percentage of subjects who have mild, 
moderate or severe paravalvular regurgitation  
• Device success, defined as absence of procedural mortality, correct positioning of a 
single transcatheter valve into the proper anatomical location , intended performance of 
the study device (effective orifice area [EOA] >0.9 cm2 for BSA <1.6 m2 and EOA 
>1.1 cm2 for BSA ≥1.6 m2 plus either a mean aortic valve gradient <20 mm Hg or a peak 
velocity <3m/sec, and no moderate or severe prosthetic valve aortic regurgitation) 
• Additional indications of prosthetic aortic valve performance as measured by 
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independent core laboratory, including EOA, 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 test117 (at 1 year compared to baseline)  
o New York Heart Association (NYHA) classification (see Note 5 below) 
• Neurological status (see Note 6 below) as determined by the following: 
o National Institutes of Health Stroke Scale (NIHSS; performed by a neurology 
professional or certified personnel) at discharge and 1 year  
o Modified Rankin Scale (mRS; performed by a neurology professional or certified 
personnel) at all follow-up visits up to 5 years 
• Health status as evaluated by Kansas City Cardiomyopathy118 and SF-12119 Quality of 
Life (QOL) questionnaires at baseline, 1 month, and 1 and 5 years. 
• For subjects in the Bicuspid Nested Registry, a computed tomography scan at 30 days post 
LOTUS Edge Valve implantation. The data will be evaluated by an independent CT core 
laboratory. 
• For subjects in the CT Imaging Substudy, a 4D CT scan at 30 days and at 1 year post 
LOTUS Edge valve implantation to assess the prevalence of reduced leaflet mobility and 
its relationship, if any, to clinical events. The data will be evaluated by an independent CT 
core laboratory. 
Note 1: The most current VARC definitions and endpoints available at the beginning of the 
trial were used. 
Note 2: Clinical indications for permanent pacemaker implantation are outlined in the 
ACCF/AHA/HRS Guidelines for Device-Based Therapy of Cardiac Rhythm 
Abnormalities120. Permanent pacemaker implantation should generally be performed only for 
accepted Class I indications.  
Note 3: For the LOTUS Edge Valve System, repositioning (see definition in Table 25.2-1) 
may be achieved with partial or full resheathing (see definitions in Table 25.2-1) of the 
valve; the proportion of subjects with partial valve resheathing and full valve resheathing 
will be determined. 
Note 4: 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. 
Note 5: Echocardiography and NYHA assessment are not required in years 6, 8, and 9 
(telephone follow-up only). 
Note 6: For subjects diagnosed with a stroke, a neurological physical exam (conducted by a 
neurologist, neurology fellow, neurology physician assistant, or neurology nurse 
practitioner), NIHSS assessment, and mRS must be performed after the event. Additionally, 
mRS must be administered at 90±14 days after a stroke (see Table 10.1-1). If a subject who 

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has not received a study device experiences a stroke within the first 1 year after the index 
procedure, mRS must be performed on that subject after the event; mRS must also be 
administered at 90±14 days after a stroke and the results must be reported to the Sponsor. 
The simplified mRS questionnaire may be used for this follow-up assessment. 
6.3. 
Overview of Objectives and Endpoints 
Table 6.3-1 provides an overview of the aforementioned study objectives and endpoints and 
a justification for the specific endpoints. 
Table 6.3-1: Overview of Objectives and Endpoints 
Objective 
Endpoint 
Rationale for Endpoint 
Primary Endpoint 
 
Evaluate safety 
and effectiveness 
of the valve 
implant  
1-Year Composite: all-cause 
mortality and all stroke 
Critical safety events that are observed in the 
elderly population undergoing TAVR; 
assessments recommended by VARC61,62; assess 
the long-term benefit (1 year) in a large elderly 
population. Events are adjudicated by an 
independent CEC. 
Additional Measurements of Safety and Effectiveness 
 
Evaluate safety 
of the valve 
implant and the 
procedure 
Safety measures at discharge, 
30 days, and annually up to 10 
years post index procedure 
Safety assessments recommended by VARC61,62 
for this elderly population. 
Events are adjudicated by an independent CEC. 
 
Evaluate 
effectiveness of 
the valve implant  
Effectiveness measures at 
discharge, 30 days, and annually 
up to 10 years post index 
procedure 
Effectiveness assessments recommended by 
VARC61,62 for this elderly population. 
Events are adjudicated by an independent CEC. 
Abbreviations: CEC=Clinical Events Committee; VARC=Valve Academic Research Consortium 
 
7. Study Design 
7.1. 
Scale and Duration 
The REPRISE IV clinical study includes a prospective, multicenter, single-arm trial (Main 
Cohort; N=696) designed to evaluate the safety and effectiveness of the LOTUS Edge Valve 
System when used with the Lotus™ Introducer Set or, when available, the iSleeve™ 
Introducer Set for TAVR in symptomatic subjects who have severe aortic stenosis and who 
are at intermediate risk for SAVR. There will be a roll-in phase (up to 130 subjects) for 
centers that do not have previous experience implanting the LOTUS Edge Valve. There will 
also be a single-arm nested registry cohort of subjects who have a bicuspid native valve to 
assess safety and effectiveness (Bicuspid Nested Registry; N=100). Selected centers with the 
ability to perform high quality 4D computed tomography (CT) scans will include up to 
200 subjects from the Main Cohort in a CT Imaging Substudy to assess the prevalence of 
reduced leaflet mobility and its relationship, if any, to clinical events. All subjects in these 

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centers will be approached for consent to participate in the CT study. If 200 subjects have not 
enrolled in the CT Imaging Substudy by completion of enrollment in the main cohort, 
additional subjects who meet the REPRISE IV eligibility criteria will be enrolled in a 
separate CT Imaging Cohort to achieve a total of 200 subjects in the CT Imaging Substudy. 
Figure 7.1-1 shows the study design. 
 
Figure 7.1-1: REPRISE IV Study Design 
All subjects implanted will be followed at baseline, peri- and post-procedure, at discharge or 
7 days post-procedure (whichever comes first), 30 days, and then annually for up to 10 years 
post-procedure. Enrolled subjects who do not have a study device implanted will be assessed 
through 1 year post procedure for safety/adverse events.   
The REPRISE IV study will be conducted in accordance with 21 CFR Parts 11, 50, and 54; 
the relevant parts of the International Conference on Harmonisation (ICH) Guidelines for 
Good Clinical Practices (GCP); the International Standard ISO 14155 Clinical Investigation 
of Medical Devices for Human Subjects – Good Clinical Practice; ethical principles that have 
their origins in the Declaration of Helsinki; and pertinent individual country/state/local laws 
and regulations. The study shall not begin until the required approval/favorable opinion from 
the Institutional Review Board/Human Research Ethics Committee (IRB/HREC) and/or 
regulatory authority has been obtained, if appropriate. See Section 10 below for additional 
information on study design and data collection.  
The REPRISE IV study is registered at ClinicalTrials.gov (identifier NCT03618095). 

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7.2. 
Treatment Assignment 
Screening materials from eligible subjects who are identified by the investigators as having 
met all the inclusion and none of the exclusion criteria (see below Table 8.2-1 and Table 
8.3-1, respectively) and who provide written informed consent will be reviewed by a Case 
Review Committee (CRC; see Section 21.2) to assess and confirm suitability of subjects for 
enrollment. All subjects will have unique identification numbers. 
Note 1: Subjects who have a bicuspid native valve will be enrolled in a separate nested 
registry cohort to assess safety and effectiveness. There will be a roll-in phase for centers that 
do not have previous experience implanting the LOTUS Edge Valve; each of these centers 
will perform at least 2 roll-in cases before commencing enrollment in the Main Cohort and 
Bicuspid Nested Registry cohort.  
Note 2: A roll-in subject cannot have a bicuspid aortic valve.  
7.2.1. 
Treatment  
See Section 5 for a detailed description of the test device and information on device sizes. 
The test device is the LOTUS Edge Valve System, which consists of a bioprosthetic bovine 
pericardial aortic valve and a delivery system. The large Lotus Introducer Set or, when 
available, the iSleeve Introducer Set (see Section 5.1.3) is used as an accessory in the 
procedure. In countries where the introducer sets are approved, the commercial devices will 
be used. In countries where they are not approved, they will be considered investigational 
devices. 
7.3. 
Justification for the Study Design 
There will be up to 926 subjects in REPRISE IV. In order to support the stated objectives of 
this study (see Section 6.1) while also limiting the potential exposure of study subjects to 
risk, up to 130 subjects will be enrolled in the roll-in phase of this study (at centers without 
previous LOTUS Edge valve experience), 696 subjects will be enrolled in the Main Cohort, 
and 100 subjects will be enrolled in the Bicuspid Nested Registry cohort. Up to 65 centers in 
the United States and Australia will participate in the study. Safety and effectiveness results 
will be reported on all enrolled subjects (see Section 19 for information on safety reporting). 
In addition to the risk-benefit analysis noted in Section 4.2 (see also Section 18), ongoing 
dynamic data safety monitoring will be performed throughout the trial to minimize risk to 
subjects (see Section 21.1). All implanted subjects will be followed for up to 10 years post 
index procedure. Per society guidelines10,121 antiplatelet therapy with aspirin and/or a P2Y12 
inhibitor is recommended after TAVR to decrease the risk of thrombotic or thromboembolic 
complications if there are no contraindications to these medications. 

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8. Subject Selection  
8.1. 
Study Population and Eligibility  
The study will include subjects presenting with symptomatic severe aortic stenosis who are 
considered at intermediate risk for surgical valve replacement, including those who have a 
bicuspid native valve. Prior to being eligible for the REPRISE IV study, a subject must meet 
all of the inclusion criteria (Section 8.2) and none of the exclusion criteria (Section 8.3). 
8.2. 
Inclusion Criteria 
Subjects who meet all criteria in Table 8.2-1 may be given consideration for inclusion in this 
clinical investigation, provided no exclusion criterion (see Table 8.3-1) is met.  
Table 8.2-1: REPRISE IV Inclusion Criteria 
IC1.   Subject has documented severe aortic stenosis defined as initial AVA ≤1.0 cm2 (or AVA index of 
≤0.6 cm2/m2) AND a mean pressure gradient ≥40 mm Hg OR maximal aortic valve velocity ≥4.0 m/s 
OR Doppler velocity index ≤0.25, as measured by echocardiography and/or invasive 
hemodynamicsa,b. 
 
 Note: In cases of low flow, low gradient aortic stenosis with left ventricular dysfunction (ejection 
fraction <50%), dobutamine can be used to assess the grade of aortic stenosis (maximum dobutamine 
dose of 20 mcg/kg/min recommended)a; the subject may be enrolled if echocardiographic criteria are 
met with this augmentation. 
 
 a: Nishimura RA, et al. J Am Coll Cardiol. 2014;63:e57–185 
b: Leon M, et al. J Am Coll Cardiol. 2011;57: 253–69 
IC2. 
A subject in the Bicuspid Aortic Valve Nested Registry cohort must have a documented Sievers 
Type 0 or Sievers Type 1 bicuspid aortic valve based on CT assessment and confirmed by the CT 
core lab with hemodynamic parameters that meet the criteria in IC1. 
IC3. 
Subject has a documented aortic annulus size of ≥20 mm and ≤27 mm based on the center’s 
assessment of pre-procedure diagnostic imaging (and confirmed by the CRC). 
IC4. 
Subject has symptomatic aortic valve stenosis per IC1definition above with NYHA Functional Class 
≥ II. 
 
IC5. 
Heart team (which must include an experienced cardiac interventionalist and an experienced cardiac 
surgeon) agrees that the subject is at intermediate risk of operative mortality (≥3% and <8% at 
30 days based on the Society of Thoracic Surgeons [STS] risk score and other clinical comorbidities 
unmeasured by the risk calculator) and TAVR is appropriate.  
 
Note: Risk of operative mortality must be assessed via an in-person evaluation by a center cardiac 
surgeon and must be confirmed by the CRC (which must include an experienced cardiac surgeon). 
IC6. 
Heart team agrees that the subject is likely to benefit from valve replacement. 
IC7. 
Subject (or legal representative) has been informed of 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. 
IC9. 
Subject is expected to be able to take the protocol-required adjunctive pharmacologic therapy. 

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Table 8.2-1: REPRISE IV Inclusion Criteria 
Abbreviations: AVA=aortic valve area; CRC=Case Review Committee; CT=computed tomography; 
NYHA=New York Heart Association; TAVR=transcatheter aortic valve replacement 
 
8.3. 
Exclusion Criteria 
Subjects who meet any one of the following criteria (Table 8.3-1) will be excluded from this 
clinical study. 
Table 8.3-1: REPRISE IV Exclusion Criteria 
EC1. 
Subject has a unicuspid or bicuspid aortic valve (not applicable to subjects in the Bicuspid Nested 
Registry cohort). 
 
Note: Subjects in the Bicuspid Nested Registry cohort will have a documented Sievers Type 0 or 
Sievers Type 1 bicuspid aortic valve based on CT assessment and confirmed by the CT core lab. 
Subjects are not eligible for inclusion in the Bicuspid Nested Registry cohort if the maximum 
diameter of the ascending aorta is >45 mm or if the subject has another indication for aortic root 
replacement. Subjects with a Sievers Type 2 bicuspid valve are not eligible for enrollment in any 
study cohort. 
EC2. 
Subject has had an acute myocardial infarction within 30 days prior to 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 clinically confirmed by a 
neurologist or neuroimaging within the past 6 months prior to study enrollment. 
EC4. 
Subject is on renal replacement therapy or has eGFR <20 (based on hospital preferred method). See 
AEC1 below if subject is in the CT Imaging Substudy. 
EC5. 
Subject has a pre-existing prosthetic aortic or mitral valve. 
EC6. 
Subject has severe (4+) aortic, tricuspid, or mitral regurgitation. 
EC7. 
Subject has moderate or severe mitral stenosis (mitral valve area ≤1.5 cm2 and diastolic pressure 
half-time ≥150 ms, Stage C or D121). 
EC8. 
Subject has a need for emergency surgery for any reason. 
EC9. 
Subject has a history of endocarditis within 6 months of index procedure or evidence of an active 
systemic infection or sepsis. 
EC10. Subject has echocardiographic evidence of new intra-cardiac vegetation or intraventricular or 
paravalvular thrombus requiring intervention. 
EC11. Subject has platelet count <50,000 cells/mm3 or >700,000 cells/mm3, or white blood cell count 
<1,000 cells/mm3. 
EC12. Subject will refuse transfusions or has had a gastrointestinal bleed requiring hospitalization or 
transfusion within the past 3 months or has other clinically significant bleeding diathesis or 
coagulopathy that would preclude treatment with required antiplatelet regimen. 
EC13. Subject has known hypersensitivity to contrast agents that cannot be adequately pre-medicated or 
has known hypersensitivity to aspirin, all P2Y12 inhibitors, heparin, nickel, tantalum, titanium, or 
polyurethanes. 

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Table 8.3-1: REPRISE IV Exclusion Criteria 
EC14. Subject has a life expectancy of less than 24 months due to non-cardiac, comorbid 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 or vascular procedure within 30 days prior to the index 
procedure (except for balloon aortic valvuloplasty or pacemaker or implantable cardioverter 
defibrillator implantation, which are allowed). 
EC17. Subject has multivessel coronary artery disease with a Syntax score >22, and/or unprotected left 
main coronary artery. 
EC18. Subject has severe left ventricular dysfunction with ejection fraction <20%. 
EC19. Subject is in cardiogenic shock or has hemodynamic instability requiring inotropic support or 
mechanical support devices. 
EC20. Subject has arterial access that is not acceptable for the study device delivery systems as defined in 
the device Instructions For Use. 
EC21. Subject has severe vascular disease that would preclude safe access (e.g., aneurysm with thrombus 
that cannot be crossed safely; marked tortuosity; significant narrowing of the abdominal aorta; 
severe unfolding of the thoracic aorta; or thick, protruding, and/or ulcerated atheroma in the aortic 
arch). 
EC22.  Subject has current problems with substance abuse (e.g., alcohol, etc.) that may interfere with the 
subject’s participation in this study. 
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. Enrollment is permissible after permanent pacemaker implantation. 
EC25. Subject has severe incapacitating dementia. 
Additional exclusion criteria apply to subjects considered for enrollment in the CT Imaging Substudy as 
listed below: 
AEC1. Subject has eGFR <30 mL/min (chronic kidney disease stage IV or stage V). 
AEC2. Subject has atrial fibrillation that cannot be rate controlled to ventricular response rate < 60 bpm. 
AEC3. Subject is expected to undergo chronic anticoagulation therapy after the index procedure. 
 
 Note: Subjects treated with short-term anticoagulation post procedure can be included in the imaging 
substudy; in these subjects the 30-day imaging will be performed 30 days after discontinuation of 
anticoagulation. 
Abbreviations: CK=creatine kinase; CT=computed tomography; MI=myocardial infarction 
 

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9. Subject Accountability 
9.1. 
Point of Enrollment 
Subjects who are confirmed eligible for the study by the CRC (see Section 21.2) and who 
provided written informed consent are considered enrolled in the study as soon as an attempt 
is made to insert the LOTUS Edge Valve System into the subject’s femoral artery.  
9.2. 
Discontinuation of Study Intervention 
If a LOTUS Edge valve test device is explanted during conventional scheduled or emergent 
surgical valve replacement or during an autopsy, if possible, the explanted valve should be 
assessed by the independent Histopathology Core Laboratory (Section 13.3.4) 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.  
9.3. 
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. Reasons for withdrawal include but are 
not limited to physician discretion, subject choice to withdraw consent, or death. If such 
withdrawal is due to problems related to 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.   
While all efforts will be made to minimize attrition, subjects may withdraw from the study at 
any time, with or without reason, and without prejudice to further treatment. Withdrawn 
subjects will not undergo any additional study follow-up, nor will they be replaced. The 
reason for withdrawal will be recorded (if given) in all cases of withdrawal. The investigator 
may discontinue a subject from participation in the study if the investigator feels that the 
subject can no longer fully comply with the requirements of the study or if any of the study 
procedures are deemed potentially harmful to the subject. Data that have already been 
collected on withdrawn subjects will be retained and used for analysis, unless local 
regulations apply. No new data will be collected after withdrawal.   
All applicable case report forms up to the point of subject withdrawal and an “End of Study” 
form for the subject must be completed. If the withdrawal is due to investigator discretion, 
the investigator should follow-up with the subject per standard of care. Information on 
determining if a subject is lost to follow-up can be found in Section 9.4. 

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9.4. 
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 (or telephone follow-up as indicated in Table 
10.1-1) without due cause (beginning with the 6-month and 1-year visits; i.e., subjects 
should not be considered lost to follow-up prior to the 1-year follow-up visit) 
• 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 
• Notification from the Investigator to Sponsor reporting subject as lost to follow-up. 
9.5. 
End-of-Study Definition  
This clinical trial will be considered completed when subjects are no longer being examined 
or the last subject’s last study visit as outlined in the data collection schedule (Table 10.1-1) 
has occurred. All subjects who receive a study device will be evaluated at discharge or 7 days 
(whichever comes first), 30 days, and annually up to 10 years post index procedure. Visits at 
30 days, 1–5 years, 7 years and 10 years are office/in-person visits. Telephone follow-up is 
allowed at 6, 8, and 9 years. A subject’s participation in the study will be considered 
complete after the 10-year visit. For subjects who do not receive a study device, participation 
in the study will be considered complete after the 1-year visit. 
10. Study Methods 
10.1. Data Collection 
This section indicates the data needed to fulfill the objectives of this clinical study. Boston 
Scientific Corporation considers data collected from clinical trial subjects to be personal data 
(see definitions of different data categories in Table 25.2-1) and compliance with privacy 
and data protection laws and regulations (for example, the General Data Protection 
Regulation [GDPR]) to be critically important. Data collection for this clinical study has been 
carefully considered to comply with data privacy laws. 
The study event schedule is shown diagrammatically in Figure 10.1-1 and discussed in 
Table 10.1-1 and Section 10.2 through Section 10.11. The methods are based on VARC 
metrics61,62, recommendations in the 2012 ACCF/AATS/SCAI/STS Expert Consensus 
Document on Transcatheter Aortic Valve Replacement10 and the 2014 AHA/ACC Guideline 
for the Management of Patients With Valvular Heart Disease121. 

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Figure 10.1-1: REPRISE IV Data Collection Scheme 
 

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Table 10.1-1: Study Event Schedule  
Assessment 
Screeninga 
Baseline 
Procedure 
Within 
1 Day 
Post-
procedure 
Prior to 
Discharge 
or 7 Days 
Post-
Procedure 
30 Daysb 
(±7 Days) 
Office 
Visit 
12  
Monthsb 
(±30 Days) 
Office 
Visit 
24–60  
Monthsb 
[Annual] 
(±45 Days) 
Office 
Visit 
84 and 
120 
Monthsb 
(±60 Days) 
Office/In 
person 
Visit 
72, 96, and 
108 
Monthsb 
(±60 Days) 
Telephone 
Signed Informed Consent Formc 
X 
– 
– 
– 
– 
– 
– 
– 
– 
– 
Demographics and medical 
history, including cardiac, 
neurological, renal (e.g., 
creatinine) and peripheral 
disease  
X 
– 
– 
– 
– 
– 
– 
– 
– 
– 
NYHA Classification 
X 
– 
– 
– 
X 
X 
X 
X 
X 
– 
NIHSSd 
– 
X 
– 
– 
X 
– 
X 
– 
– 
– 
Modified Rankin Scaled  
– 
X 
– 
– 
X 
X 
X 
X 
– 
– 
12-lead ECGe 
X 
– 
– 
X 
X 
X 
X 
– 
– 
– 
Laboratory testsf 
– 
X 
– 
X 
– 
– 
– 
– 
– 
– 
Risk assessmentsg  
X 
– 
– 
– 
– 
– 
– 
– 
– 
– 
Frailty, disability and 
comorbidityh 
X 
– 
– 
– 
– 
– 
Xh 
– 
– 
– 
Antiplatelet and anticoagulant 
(if applicable) medications 
X 
– 
X 
– 
X 
X 
X 
X 
X 
X 
Other CV medications 
X 
– 
– 
– 
– 
– 
– 
– 
– 
– 
TTEi 
X 
– 
– 
– 
X 
X 
X 
X 
X 
– 
TEEj 
– 
– 
O 
– 
– 
– 
– 
– 
– 
– 
Coronary angiogram/CT 
coronary angiogramk 
X 
– 
– 
– 
– 
– 
– 
– 
– 
– 
CT angiogram of aortic 
structurel 
X 
– 
– 
– 
– 
Xm 
– 
– 
– 
– 
CT angiogram of iliofemoral 
systemn 
X 
– 
– 
– 
– 
– 
– 
– 
– 
– 
QOL surveyso 
– 
X 
– 
– 
– 
X 
X 
Xp 
– 
– 

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Table 10.1-1: Study Event Schedule  
Assessment 
Screeninga 
Baseline 
Procedure 
Within 
1 Day 
Post-
procedure 
Prior to 
Discharge 
or 7 Days 
Post-
Procedure 
30 Daysb 
(±7 Days) 
Office 
Visit 
12  
Monthsb 
(±30 Days) 
Office 
Visit 
24–60  
Monthsb 
[Annual] 
(±45 Days) 
Office 
Visit 
84 and 
120 
Monthsb 
(±60 Days) 
Office/In 
person 
Visit 
72, 96, and 
108 
Monthsb 
(±60 Days) 
Telephone 
Procedural cine-angiography 
(including post-deployment 
aortogram)q 
– 
– 
X 
– 
– 
– 
– 
– 
– 
– 
AE and ADE assessmentsr 
– 
– 
X 
X 
X 
X 
X 
– 
– 
– 
Device deficiencies, SAE, 
SADE, UADE and CEC event 
assessmentss 
– 
– 
X 
X 
X 
X 
X 
X 
X 
X 
4D CT (Imaging Substudy only)t 
– 
– 
– 
– 
– 
X 
X 
– 
– 
– 
Note 1: X = required; O = optional; – = not required; follow-up should be done by study personnel or as noted below. 
a:  Screening materials for CRC review should be submitted electronically at least 5 days in advance of CRC review. 
b: All follow-up dates will be calculated from the date of the (attempted) index procedure. Where indicated, visits must be an office/clinical/in person visit 
but may be done in-hospital should the subject be admitted at the time. Subjects who are enrolled but do not receive a study device will be followed for 1 
year to assess for safety but do not need to have protocol required TTE or ECG. 
c:  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. 
 
Note 2:  The subject should undergo the index procedure within 30 days after signing the study Informed Consent Form. 
d:  NIHSS and mRS must be performed by a neurology professional or certified personnel (external certification for NIHSS; internal or external certification 
for mRS). The NIHSS and mRS assessors should be independent (not involved with the care of study subjects). For subjects diagnosed with a stroke, a 
neurological physical exam, mRS, and NIHSS must be performed after the event; mRS must also be administered at 90±14 days after a stroke; the 
simplified mRS questionnaire may be used for this follow-up assessment. The neurological physical examination must be performed by a neurologist, 
neurology fellow, neurology physician assistant, or neurology nurse practitioner who is independent of the study. If a subject who has not received a study 
device experiences a stroke within the first 1 year after the index procedure, mRS must be performed on that subject after the event; mRS must also be 
administered at 90±14 days after a stroke and the results must be reported to the Sponsor.  
e:  All screening and post-procedure 12-lead ECGs must be performed according to the ECG Core Laboratory guidelines (see study Manual of Operations). If 
the subject is enrolled, the ECG must be provided to the Core Laboratory.   
f:   Laboratory tests at baseline include CBC with platelets, albumin, 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. 

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Table 10.1-1: Study Event Schedule  
Assessment 
Screeninga 
Baseline 
Procedure 
Within 
1 Day 
Post-
procedure 
Prior to 
Discharge 
or 7 Days 
Post-
Procedure 
30 Daysb 
(±7 Days) 
Office 
Visit 
12  
Monthsb 
(±30 Days) 
Office 
Visit 
24–60  
Monthsb 
[Annual] 
(±45 Days) 
Office 
Visit 
84 and 
120 
Monthsb 
(±60 Days) 
Office/In 
person 
Visit 
72, 96, and 
108 
Monthsb 
(±60 Days) 
Telephone 
g:  Consists of STS score, euroSCORE II, and heart team assessment including an in-person evaluation by a center cardiac surgeon that must be confirmed by 
the CRC (which must include an experienced cardiac surgeon).  
h:   Frailty, disability, and comorbidity risk assessments must be captured at screening: height, weight, strength and balance (use of wheelchair, gait speed to 
walk 5 meters, number of falls in the past 6 months, maximal grip strength), and activities of daily living (Katz Index); at 1 year, gait speed to walk 5 
meters must be assessed again.   
i:  Transthoracic echocardiogram (TTE) is required for all subjects who have a study valve implanted in the aortic position. This includes assessment of EOA, 
peak and mean aortic valve pressure gradients, peak aortic velocity, aortic regurgitation assessment, and LVEF. Screening TTE must be performed within 
60 days prior to CRC approval. 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). If a subject does not 
receive an implanted study valve, then no follow-up TTE is required.  
Note 3: In cases of low flow low gradient aortic stenosis with left ventricular dysfunction (ejection fraction <50%), dobutamine can be used to assess the 
grade of aortic stenosis; the subject may be enrolled if echocardiographic criteria are met with this augmentation. In cases where a subject who has met the 
echocardiographic criteria for enrollment receives BAV prior to the index procedure and subsequently no longer meets the REPRISE IV aortic valve 
pressure gradient or EOA criteria, the subject may still be enrolled based on the pre-BAV echocardiographic data. In such cases, the most recent 
echocardiogram done prior to the index procedure (even if after BAV) must be submitted to the Echocardiography Core Laboratory to be included in the 
baseline data.  
j: TEE can be performed at the discretion of the operator. 
k:  A coronary angiogram/CT coronary angiogram must be performed within 365 days prior to CRC approval. 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.     
l:  A CT angiogram of the aortic complex must be performed within 180 days prior to CRC approval (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/X-ray 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 review where results will be assessed to confirm subject’s eligibility. 
m: For subjects in the Bicuspid Nested Registry Cohort, a computed tomography scan at 30 days post LOTUS Edge valve implantation. Please refer to the CT 
Core Laboratory procedure guidelines (see study Manual of Operations). Results must be sent to the CT Core Laboratory. 
n: An assessment of the iliofemoral system must be performed within 180 days prior to CRC approval (and should be performed within 90 days if possible).  
A CT angiogram of the iliofemoral system should be performed for complete visualization of the iliac and femoral arteries to assess for dimensions, 
tortuosity, and calcification. The CT angiogram should be performed per the procedure guidelines (see study Manual of Operations) and sent to the CT 

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Table 10.1-1: Study Event Schedule  
Assessment 
Screeninga 
Baseline 
Procedure 
Within 
1 Day 
Post-
procedure 
Prior to 
Discharge 
or 7 Days 
Post-
Procedure 
30 Daysb 
(±7 Days) 
Office 
Visit 
12  
Monthsb 
(±30 Days) 
Office 
Visit 
24–60  
Monthsb 
[Annual] 
(±45 Days) 
Office 
Visit 
84 and 
120 
Monthsb 
(±60 Days) 
Office/In 
person 
Visit 
72, 96, and 
108 
Monthsb 
(±60 Days) 
Telephone 
Core Laboratory with the screening CT angiogram of the aortic structure. An iliofemoral invasive angiogram may be substituted for the iliofemoral CT 
angiogram. 
o: Includes the Kansas City Cardiomyopathy and SF-12 QOL questionnaires. Baseline QOLs should be performed within 30 days prior to the index 
procedure. 
p:  QOL survey at 60 months. 
q: Procedural cine-angiogram including the baseline images of the aortic complex and the final post-deployment aortogram of the ascending aorta must be 
performed and sent to the CT/X-Ray 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 12-month follow-up.  
s:  Information on device deficiencies for the test device(s) will be monitored and reported to Boston Scientific. Information on all SAEs, SADEs, UADEs, 
and CEC events will be monitored and reported to Boston Scientific for enrolled subjects from the time of enrollment through 5 years. After 5 years, 
serious adverse event assessment (includes SAE, SADE, UADE, and relevant VARC events to be adjudicated by the CEC [see Note 4 below]) for test 
device(s) and device deficiencies assessment for test device(s) with associated treatment will be monitored and reported to Boston Scientific for enrolled 
subjects through termination of the study. For subjects who do not receive a study device, the aforementioned events will be monitored through 1-year 
post-index procedure. Please refer to Section 6.2.2 for a list of CEC events and Table 25.2-1 for definitions of these events, which specify data required for 
CEC adjudication. Complaint reporting of any device deficiencies for any commercially available products used should be carried out using the 
manufacturer’s processes. 
Note 4: Relevant VARC events after 5 years to be adjudicated by the CEC include the following: mortality, stroke, spontaneous myocardial infarction, 
acute kidney injury, repeat procedure for valve-related dysfunction, hospitalization for valve-related symptoms or worsening congestive heart failure 
(NYHA III or IV), new pacemaker, new onset atrial fibrillation or atrial flutter, prosthetic aortic valve malpositioning (valve migration, valve 
embolization, or ectopic valve deployment), TAV-in-TAV, prosthetic aortic valve thrombosis and endocarditis. 
t: For subjects in the CT Imaging Substudy, a 4D CT scan at 30 days and at 1-year post LOTUS Edge valve implantation must be done. Please refer to the 
CT Core Laboratory procedure guidelines (see study Manual of Operations). The data must be sent to the independent CT core laboratory.   

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Table 10.1-1: Study Event Schedule  
Assessment 
Screeninga 
Baseline 
Procedure 
Within 
1 Day 
Post-
procedure 
Prior to 
Discharge 
or 7 Days 
Post-
Procedure 
30 Daysb 
(±7 Days) 
Office 
Visit 
12  
Monthsb 
(±30 Days) 
Office 
Visit 
24–60  
Monthsb 
[Annual] 
(±45 Days) 
Office 
Visit 
84 and 
120 
Monthsb 
(±60 Days) 
Office/In 
person 
Visit 
72, 96, and 
108 
Monthsb 
(±60 Days) 
Telephone 
Abbreviations: AE=adverse event; ADE=adverse device effect; AKI=acute kidney injury; BAV=balloon aortic valvuloplasty; CBC=complete blood count; 
CEC=Clinical Events Committee; CK-MB=creatine kinase-myoglobin band; CRC=Case Review Committee; CT=computed tomography; CV=cardiovascular; 
ECG=electrocardiogram; EOA= effective orifice area; 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; UADE=unanticipated adverse device effect; VARC=Valve Academic Research Consortium 
 
 

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10.2. Study Candidate Screening 
Subjects will be evaluated for eligibility by the center heart team (which must include an 
experienced cardiac interventionalist and an experienced cardiac surgeon). The heart team 
should take into account the Society of Thoracic Surgeons (STS) score as well as other 
clinical comorbidities (including frailty) not accounted for in the risk calculation. Eligible 
subjects will have agreement from the heart team that the subject is at intermediate operative 
risk of mortality with SAVR (see Table 8.2-1 for inclusion criteria). Risk of operative 
mortality and morbidity is to be assessed via an in-person evaluation by a center cardiac 
surgeon and must be confirmed by the CRC (which must include an experienced cardiac 
surgeon). The heart team must also agree that the subject is likely to benefit from valve 
replacement.   
Clinical assessment and evaluation, collected tests and images (e.g., echocardiography, 
computerized tomography [CT], angiography) performed in preparation for TAVR, and any 
planned use of balloon aortic valvuloplasty (BAV) will be reviewed by the CRC (see 
Section 7.2 and Section 21.2). The CRC will be comprised of experienced cardiac surgeons, 
interventional cardiologists, and Sponsor staff proficient with the LOTUS Edge Valve 
System and will confirm subject eligibility for enrollment. 
10.2.1. Strategies for Recruitment and Retention 
The REPRISE IV study will include subjects presenting with documented severe native 
aortic valve stenosis who are indicated for TAVR (see Section 8). It is estimated that nearly 
5% of elderly ≥75 years of age have aortic stenosis and its prevalence is expected to increase 
due to an aging population2,3. Because aortic stenosis most commonly occurs in the very 
elderly, women are well represented in TAVR trials. Traditionally underrepresented 
populations (elderly and women) are expected to be included in the subject population as 
allowed by governing law/national regulation; as the very elderly will represent the majority 
of subjects enrolled in the trial, efforts to maximize retention are by definition targeted to 
traditionally under-represented groups. The inclusion and exclusion criteria are not expected 
to have a negative effect on recruitment or retention of said populations. In the United States, 
the subjects eligible for inclusion in this study are likely to be Medicare patients due to their 
expected age and the results of this study are likely to be highly generalizable to a Medicare 
population.  
All efforts will be made to minimize attrition in REPRISE IV (see Section 9.4). Investigators 
are encouraged to enroll subjects who are willing to comply with the follow-up requirements 
of the study. If a visit is missed, the center should attempt to contact the subject to reschedule 
the missed visit and counsel the subject on the importance of maintaining the assigned visit 
schedule.  

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10.3. Subject 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 IRB/HREC-approved ICF must be signed and 
personally dated by the subject or his/her legally authorized representative. The 
Investigator/designee must also sign the ICF prior to subject enrollment. Any additional 
persons required by the center’s IRB/HREC 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 eCRF 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.  
10.4. Screening Assessments 
Results from the screening tests and procedures listed below must be submitted to the CRC 
(see Section 21.2) for evaluation to confirm a subject’s eligibility for the study. Screening 
assessment documentation should be provided via electronic upload at least 5 days in 
advance of a scheduled CRC review or at least 5 days in advance of the planned procedure 
date. It is planned that CRC reviews will take place at least weekly or as needed to ensure 
timely review and confirmation of subject eligibility. 
Note 1: It is recommended that predilatation be performed unless there is minimal 
calcification of the annulus and leaflets. Subjects in the bicuspid registry must have 
predilatation performed. 
Note 2: Additional concomitant procedures, including percutaneous coronary intervention, 
are not allowed during the index procedure. 
Centers will be trained on the screening process (see Section 16.4.2). Specific data points 
will be collected in the REPRISE IV electronic case report forms (eCRFs) as shown below.  
• Clinical assessments  
o Demographics including age and gender 

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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 Current antiplatelet and other cardiovascular medications 
o 12-lead electrocardiogram (ECG) at screening must be performed according to the 
ECG Core Laboratory guidelines (see study Manual of Operations) and, if subject is 
enrolled, forwarded to the core laboratory for analysis 
o Risk assessments: Society of Thoracic Surgeons (STS) score, euroSCORE II, heart 
team assessment including an in-person evaluation by a center cardiac surgeon and 
any frailty assessments (detailed in next bullet). 
• Frailty, disability, and comorbidity assessments (collected prospectively)122,123  
o Body Mass Index from the physical exam 
o Strength and balance  
- Use of wheelchair 
- Gait speed as measured by a stopwatch for a subject to walk 5 meters 
(3 measures averaged)123-125  
- Number of falls in the past 6 months 
- Maximal grip strength (kg) in the dominant hand (3 measures averaged), using a 
hand-held dynamometer126  
o Activities of daily living: Katz Index122,127 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. 
• Imaging assessments  
o Within 60 days prior to CRC approval, TTE (2-D, M-Mode, and color) must be 
carried out. The evaluation should include assessment of effective orifice area 
(EOA), peak 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. The TTE must be performed according to the Echocardiography Core 
Laboratory procedure guidelines (see study Manual of Operations). For enrolled 
subjects, the TTE must be provided to the echocardiography core laboratory for 
independent analyses. In cases of low flow/low gradient aortic stenosis with left 
ventricular dysfunction (ejection fraction <50%), dobutamine can be used to assess 
the grade of aortic stenosis (maximum dobutamine dose of 20 mcg/kg/min 
recommended)121; the subject may be enrolled if echocardiographic criteria are met 
with this augmentation. In cases where a subject who has met the echocardiographic 

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criteria for enrollment receives BAV prior to the index procedure and subsequently 
no longer meets the REPRISE IV aortic valve pressure gradient or EOA criteria, the 
subject may still be enrolled based on the pre-BAV echocardiographic data. In such 
cases, the most recent echocardiogram done prior to the index procedure (even if 
after BAV) must be submitted to the Echocardiography Core Laboratory to be 
included in the baseline data.     
o A coronary angiogram/CT coronary angiogram must be performed within 365 days 
prior to CRC approval. 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. An aortogram and hemodynamics including simultaneous 
ascending aorta and left ventricle pressure measurements should be performed.  
o A CT angiogram of the aortic complex must be performed 180 days prior to CRC 
approval (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 be provided in advance to the core laboratory for detailed 
measurements and independent analyses, which will be reviewed by the CRC to 
confirm a subject’s eligibility. 
o An assessment of the iliofemoral system must be performed within 180 days prior 
to CRC approval (and should be performed within 90 days if possible). A CT 
angiogram of the iliofemoral system should be performed 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 provided to the 
CT Core Laboratory with the screening CT angiogram of the aortic structure for 
independent measurements and review by the CRC to confirm a subject’s 
eligibility. An iliofemoral invasive angiogram may be substituted for the iliofemoral 
CT angiogram. 
10.5. Baseline Assessments 
The following assessments must be completed within 30 days prior to the index procedure, 
unless otherwise specified below. The REPRISE IV eCRFs identify the specific data points 
to be collected. 
• Confirmation of CRC approval date 
• NIH Stroke Scale (NIHSS), which must be performed by a neurology professional or 
certified personnel (external certification); NIHSS assessors should be independent (not 
involved with the care of study subjects) 
• Modified Rankin Scale (mRS) score, which must be performed by a neurology 
professional or certified personnel (external or internal certification); mRS assessors 
should be independent (not involved with the care of study subjects) 

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• Laboratory tests 
o Complete blood count (CBC) with platelets 
o Albumin 
o Serum creatinine 
o Cardiac enzymes (creatine kinase [CK] is required, CKMB or troponin if CK is 
elevated) 
• Quality Of Life (QOL) Surveys: Kansas City Cardiomyopathy118 and SF-12119 QOL 
Questionnaires  
Note: In cases where a subject who has met the echocardiographic criteria for enrollment 
receives BAV prior to the index procedure and subsequently no longer meets the 
REPRISE IV aortic valve pressure gradient or EOA criteria, the subject may still be enrolled 
based on the pre-BAV echocardiographic data. In such cases, the most recent 
echocardiogram done prior to the index procedure (even if after BAV) must be submitted to 
the Echocardiography Core Laboratory to be included in the baseline data. 
10.6. Pre-procedure Medications 
• Antiplatelet Therapy: 
Per society guidelines10,121 antiplatelet therapy is recommended to reduce the risk of 
thrombotic or thromboembolic complications if there are no contraindications to these 
medications. Study subjects must receive some antiplatelet therapy (aspirin and/or a 
P2Y12 inhibitor) for at least 1 month following valve implant. A loading dose of the 
same antiplatelet medication (aspirin and/or a P2Y12 inhibitor) is required for subjects 
who have not been on the antiplatelet therapy for ≥72 hours at the time of the index 
procedure (see below for recommended doses).  
Aspirin Dose 
The recommended loading dose of aspirin is 75–325 mg for subjects who have not been 
on aspirin therapy for ≥72 hours at the time of the index procedure. The loading dose 
must be administered prior to the implant procedure. Subjects who have been taking 
aspirin daily for ≥72 hours at the time of the index procedure do not require a loading 
dose of aspirin. 
P2Y12 Inhibitor Dose (Clopidogrel Recommended) 
The recommended loading dose of a P2Y12 inhibitor is ≥300 mg clopidogrel, 60 mg 
prasugrel, or 180 mg ticagrelor for subjects who have not been on P2Y12 inhibitor 
therapy for ≥72 hours at the time of the index procedure. The loading dose must be 
administered prior to the implant procedure. Subjects who have been taking a P2Y12 

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inhibitor daily for ≥72 hours at the time of the index procedure do not require a loading 
dose of the P2Y12 inhibitor. 
Note: If a subject is treated with anticoagulation, either a P2Y12 inhibitor or aspirin is 
recommended prior to the implant procedure (but both aspirin and a P2Y12 inhibitor are 
not recommended). 
• 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 
local practice. The choice of antibiotic drug is left to the investigator’s discretion. 
10.7. Index Procedure 
The preparation of the subject for the percutaneous procedure will be performed following 
standard techniques. Transfemoral access must be attempted for all subjects (assessment of 
the iliofemoral system prior to subject enrollment must indicate that transfemoral access is 
considered appropriate). If the transfemoral approach is unsuccessful, the operator will 
decide the best alternative approach to treat the subject.   
Note 1: Additional concomitant procedures, including percutaneous coronary intervention, 
are not allowed during the index procedure. 
Note 2: The subject should undergo the index procedure within 30 days after signing the 
study Informed Consent Form. 
The large Lotus Introducer Set (Section 5.1.3) or, when available, the iSleeve Introducer Set 
(Section 5.1.3) is prepared and introduced in the patient’s femoral artery, as described in the 
iSleeve/Lotus Introducer IFUs. A balloon valvuloplasty on the existing valve following 
standard techniques may be performed with an appropriately sized valvuloplasty balloon 
(avoid oversizing) before implantation of the LOTUS Edge valve. Careful attention should 
be paid to the position of the guidewire throughout the BAV procedure. Prior to introduction 
of the LOTUS Edge Valve System, the subject’s hemodynamic status and heart rhythm must 
be assessed and documented (12-lead ECG is not required). Information on the BAV, 
including number of inflations, should be documented in the source data and will be captured 
in the eCRFs. 
Note 3: It is recommended that predilatation be performed unless there is minimal 
calcification of the annulus and leaflets; BAV must be performed in subjects in the Bicuspid 
Nested Registry cohort. 
Note 4: If the subject becomes hemodynamically unstable after the valvuloplasty for reasons 
unrelated to the aortic valve annulus and/or leaflets, the LOTUS Edge valve implantation 
should be interrupted until the subject is stable.  
The LOTUS Edge valve implantation procedure requires two operators: First and Second 
Operators. Both operators must comply with the IFU and must be adequately trained and 

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certified by BSC personnel before performing the procedure (see Section 16.4.216.4.2 for 
additional information on training). Guidelines provided by the Sponsor for valve size 
selection should be followed.  
The LOTUS Edge Valve System must be prepared in accordance with the IFU. Device 
preparation should only be performed by persons who have completed appropriate training 
with the LOTUS Edge Valve System.   
Prior to insertion of the LOTUS Edge Valve System catheter into the iSleeve/Lotus 
Introducer, the recommended target ACT of ≥250 seconds should be confirmed, with 
additional boluses of heparin administered if needed.  
The LOTUS Edge Valve System IFU should be followed. The following summarizes the 
LOTUS Edge Valve System procedure. 
1) 
The LOTUS Edge delivery catheter is back-loaded onto a 0.035 in (0.89 mm) 
Super/Extra Stiff guidewire, maintaining proper guidewire positioning across the 
existing valve and into the ventricle. 
2) 
The LOTUS Edge catheter is inserted in the iSleeve/Lotus Introducer and carefully 
advanced through the aorta and the aortic arch under fluoroscopy. 
3) 
The catheter is then advanced slowly through the aortic annulus. The valve is then 
mechanically expanded and locked into the desired position.  
4) 
Prior to the release of the LOTUS Edge valve, assessment of its position and function 
is performed using contrast injection 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 frame as a guide.  The valve 
can then be re-expanded. 
6) 
Once the LOTUS Edge valve position is deemed satisfactory and the valve is fully 
locked, the release process is then initiated, and the LOTUS Edge valve is detached 
from the catheter.  
7) 
The nosecone is recaptured, and the system pulled out of the body. 
8) 
A final post-deployment aortogram of the ascending aorta  must be performed and 
forwarded to the core laboratory with the procedural cine-angiogram for analysis. 
9) 
The iSleeve/Lotus Introducer is then removed.  
10) The femoral access is then closed according to standard practice. 
Labels from the devices used during the procedure (e.g., the LOTUS Edge Valve System, 
iSleeve, Lotus Introducer) should be retained so that they can be included in the appropriate 
source documents and reported in the eCRFs.   
During the procedure, designated center study personnel must capture necessary information 
on acute device/delivery system performance and procedure. The following information will 
be collected during the procedure. 

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• Date of procedure 
• Device size (23mm, 25mm, or 27mm) and model  
• Time of puncture (at site of TAVR sheath) and time of vascular closure for TAVR 
sheath (iSleeve/Lotus Introducer insertion and removal time) 
• Descriptive information on balloon valvuloplasty, if performed (e.g., size of balloon, 
number of balloon inflations) 
• Adjunctive procedures performed during implant procedure  
• LOTUS Edge Valve System catheter insertion and removal time 
• Descriptive information on LOTUS Edge valve implantation procedure and information 
on valve repositioning or retrieval (if performed) 
• Adverse event (AE) assessment and associated treatment (including AE, serious 
adverse event [SAE], serious adverse device effect [SADE], unanticipated adverse 
device effect [UADE], adverse device effect [ADE] and Clinical Events Committee 
[CEC] events; see Section 19). 
• Device deficiencies assessment for the LOTUS Edge Valve System  
Note 5: All LOTUS Edge valve implantation procedures will be performed with the 
support/presence of trained BSC personnel (see Section 16.4.1). 
Note 6: In countries where the introducer sets are approved, a device deficiency should be 
reported as a complaint.    
10.8. Post Index Procedure 
The following are to be performed post-procedure. 
• Per society guidelines10,121 antiplatelet therapy with aspirin and/or a P2Y12 inhibitor 
(clopidogrel recommended)  is recommended to reduce the risk of thrombotic or 
thromboembolic complications if there are no contraindications to these medications. 
Study subjects must receive some antiplatelet therapy (aspirin and/or a P2Y12 inhibitor) 
for at least 1 month following valve implantation. It is recommended that subjects be 
treated with both aspirin and a P2Y12 inhibitor for at least 1 month. Extended dual 
antiplatelet therapy may be administered per physician choice. 
 
o After the valve implant procedure, aspirin (recommended dose of ≥75 mg daily) 
should be given for at least 1 month. It is recommended that daily aspirin be given 
indefinitely thereafter as per local standard of care. Aspirin dose may be adjusted to 
the closest approximation based on local tablet formulation availability. 
o After the valve implant procedure, a P2Y12 inhibitor is recommended for at least 1 
month. Dosing should follow local standard of care.  
o If a subject is treated with chronic anticoagulation, either a P2Y12 inhibitor or 
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therapy (but both aspirin and a P2Y12 inhibitor are not recommended). The subject 
should be treated with an oral anticoagulant (OAC) and either a P2Y12 inhibitor 
(clopidogrel recommended) or aspirin for at least 1 month. 
• 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 within 6 to 24 hours post-procedure at intervals per local standard of 
care. 
10.9. 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 IV eCRFs identify the specific data 
points to be collected. 
• NYHA classification 
• NIHSS, which must be performed by a neurology professional or certified personnel 
(external certification); NIHSS assessors should be independent (not involved with the 
care of study subjects).  
• Modified Rankin Scale score, which must be performed by a neurology professional or 
certified personnel (external or internal certification); mRS assessors should be 
independent (not involved with the care of study subjects). 
• 12-lead ECG per the ECG Core Laboratory guidelines (see study Manual of 
Operations) and must be forwarded to the core laboratory for analysis.     
• TTE, including assessment of EOA, peak 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 provided to the Echocardiography 
Core Laboratory for independent analyses.  
 
Note: For all subjects who have a transcatheter valve implanted in the aortic position 
during 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 

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performed will be used for analysis. Subjects who do not receive a transcatheter valve 
during the index procedure are not required to have follow-up TTE.   
• Current antiplatelet and anticoagulant (if applicable) medications 
• Complete adverse event (AE, SAE, SADE, UADE, ADE, and CEC events) assessment 
for test device(s) and device deficiencies assessment for test device(s), with associated 
treatment. 
10.10. Follow-up 
All implanted subjects will be evaluated at 30 days and then annually up to 10 years post 
index procedure. Subjects who do not have a study device implanted will be assessed through 
1 year post index procedure for safety/adverse events. Physical clinic visits or in-person 
follow-up visits are scheduled for appointed times after the date of the procedure through 
5 years and at 7 and 10 years. Telephone follow-up is allowed at 6, 8, and 9 years. It is 
important that this schedule be maintained as closely as possible for all subjects. Boston 
Scientific Corporation 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 10.1-1. Visits/telephone follow-up not completed will be 
considered missed and recorded as protocol deviations. Visits/telephone follow-up completed 
outside these windows will be recorded as protocol deviations. Boston Scientific or its 
designee will review protocol deviations on a regular basis in accordance with applicable 
standard operating procedures. 
Each follow-up must be performed as noted in Table 10.1-1. 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 in Table 25.2-1.    
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.  
Note 1: The follow-up visits at 30 days, 1–5 years, 7 years, and 10 years must be conducted 
in-person. If an in-person assessment cannot be performed, follow-up by telephone should be 
attempted. Subject or subject’s physician should provide rationale for why the in-person 
assessment cannot be performed.  
Note 2: A subject who has received a study valve should not be enrolled in a clinical trial of 
an investigational drug/device/treatment until the subject has reached the REPRISE IV 
primary endpoint (1 year). 

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10.10.1. 30-Day Follow-up (30±7 Days)  
All enrolled subjects must be evaluated in person 30 (±7) days after the index procedure. 
During the 30-day follow-up visit, the following assessments must be completed. The 
REPRISE IV eCRFs identify the specific data points to be collected. 
• NYHA classification  
• Modified Rankin Scale score, which must be performed by a neurology professional or 
certified personnel (external or internal certification); mRS assessors should be 
independent (not involved with the care of study subjects). 
• 12-lead ECG per the ECG Core Laboratory guidelines (see study Manual of 
Operations), which must be forwarded to the core laboratory for analysis.     
• Current antiplatelet, anticoagulant (if applicable) medications 
• TTE including assessment of EOA, peak 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 provided to the 
Echocardiography Core Laboratory for independent analyses. 
 
Note: TTE must be done for all subjects who have a transcatheter valve implanted in 
the aortic position during the index procedure. Subjects who do not receive a 
transcatheter valve during the index procedure are not required to have follow-up TTE.  
• Quality of Life Surveys: Kansas City Cardiomyopathy and SF-12 Quality of Life 
Questionnaires 
Note: Quality of life will be evaluated by the Kansas City Cardiomyopathy118 and SF-
12119 questionnaires at baseline, 1 month, 1 year, and 5 years. A formal health 
economics analysis may be completed if meaningful clinical results are obtained. 
• Complete adverse event (AE, SAE, SADE, UADE, ADE and CEC events) assessment 
for test device(s) and device deficiencies assessment for test device(s), with associated 
treatment 
• For subjects in the Bicuspid Nested Registry cohort, a computed tomography scan at 
30 days post LOTUS Edge valve implantation. The CT scan must be performed per the 
CT Core Laboratory procedure guidelines (see study Manual of Operations) and sent to 
the CT Core Laboratory for independent analyses. 
• For subjects in the CT Imaging Substudy, assessment of prosthetic valve leaflet 
mobility using 4D CT must be performed per the CT Core Laboratory procedure 
guidelines (see study Manual of Operations). All 4D CT scans for subjects enrolled in 
the CT Imaging Substudy must be sent to the CT Core Laboratory for independent 
analyses. 

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Note: The CT scans will be read by the CT Core Laboratory and will not be provided to 
local investigators except as per below. Local reading should be done only for non-
cardiac valve findings such as unexpected lung pathology. A study CT scan can be 
unblinded upon investigator request based on any of the following if the event occurs 
within 2 weeks of the study CT scan.  
o Any neurological event 
o Any potential embolic event 
o Any MI (ST segment elevation MI or non-ST segment elevation MI) 
o Increase in aortic regurgitation to moderate or severe 
o A change in echocardiographic parameters including an increase in mean gradient 
of >10 mmHg or a change in Doppler velocity index (DVI) of >0.05. 
If any of the above events occurs outside of the 2-week window around the study CT 
scan, the investigator must not be unblinded to the core laboratory assessment of the 
study CT scan and instead should perform a separate CT scan if clinically indicated. If 
an additional CT scan is performed for clinical indications, it should be sent to the CT 
Core Laboratory for analysis. 
10.10.2. 12-Month Follow-up (365±30 Days)  
All implanted subjects must be evaluated in person 365 (±30) days after the index procedure. 
During the 12-month follow-up, the following assessments must be completed. The 
REPRISE IV eCRFs identify the specific data points to be collected. 
• Weight and height 
• NYHA classification  
• Modified Rankin Scale score, which must be performed by a neurology professional or 
certified personnel (external or internal certification); mRS assessors should be 
independent (not involved with the care of study subjects).  
• NIHSS, which must be performed by a neurology professional or certified personnel 
(external certification); NIHSS assessors should be independent (not involved with the 
care of study subjects). 
• Gait speed to walk 5 meters 
• 12-lead ECG per the ECG Core Laboratory guidelines (see study Manual of 
Operations) and must be forwarded for analysis     
• Current antiplatelet and anticoagulant (if applicable) medications 
• TTE including assessment of EOA, peak 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 provided to the core laboratory for independent analyses. 

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Note: TTE must be done for all subjects who have a transcatheter valve implanted in 
the aortic position during the index procedure. Subjects who do not receive a 
transcatheter valve during the index procedure are not required to have follow-up TTE.  
• Complete adverse event (AE, SAE, SADE, UADE, ADE and CEC events) assessment 
for test device(s) and device deficiencies assessment for test device(s), with associated 
treatment 
• Quality of Life Surveys: Kansas City Cardiomyopathy and SF-12 Quality of Life 
Questionnaires 
Note: Quality of life will be evaluated by the Kansas City Cardiomyopathy and SF-12 
questionnaires at baseline, 1 month, 1 year, and 5 years. A formal health economics 
analysis may be completed if meaningful clinical results are obtained. 
• For subjects enrolled in the CT Imaging Substudy, assessment of prosthetic valve 
leaflet mobility using 4D CT must be performed per the CT Core Laboratory procedure 
guidelines (see study Manual of Operations). The 4D CT scans done for the CT 
Imaging Substudy must be sent to the CT Core Laboratory for independent analyses. 
 
Note: The CT scans will be read by the CT Core Laboratory and findings will not be 
provided to local investigators except as noted above. Local reading should be done 
only for non-cardiac valve findings such as unexpected lung pathology. A study CT 
scan can be unblinded upon investigator request based on the conditions described in 
Section 10.10.1 if the event occurs within 2 weeks of the study CT scan. 
10.10.3. Annual Follow-up (±45 Days) to 5 Years 
All implanted subjects must be evaluated in person at 24, 36, 48, and 60 months (2, 3, 4, and 
5 years) after the index procedure, with a window of ±45 days. During the annual follow-up, 
the following assessments must be completed. The REPRISE IV eCRFs identify the specific 
data points to be collected. 
• NYHA classification  
• Modified Rankin Scale score, which must be performed by a neurology professional or 
certified personnel (external or internal certification); mRS assessors should be 
independent (not involved with the care of study subjects). 
• Current antiplatelet, anticoagulant (if applicable) 
• TTE, including assessment of EOA, peak 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. 
Note: TTE must be done for all subjects who have a transcatheter valve implanted in 
the aortic position during the index procedure. 

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• Complete serious adverse event (SAE, SADE, UADE, and CEC events) assessment for 
test device(s) and device deficiencies assessment for test device(s) with associated 
treatment. 
• Quality of Life Surveys: Kansas City Cardiomyopathy and SF-12 Quality of Life 
Questionnaires at 5 years 
Note: Quality of life will be evaluated by the Kansas City Cardiomyopathy and SF-12 
questionnaires at baseline, 1 month, 1 year, and 5 years. A formal health economics 
analysis may be completed if meaningful clinical results are obtained. 
10.10.4. Follow-up (±60 Days) at 7 and 10 Years 
All implanted subjects must be evaluated in person at 84 and 120 months (7 and 10 years) 
after the index procedure, with a window of ±60 days. The following assessments must be 
completed. The REPRISE IV eCRFs identify the specific data points to be collected. 
• NYHA classification 
• Current antiplatelet, anticoagulant (if applicable)   
• TTE, including assessment of effective orifice area, peak and mean aortic valve 
gradient pressure, aortic regurgitation assessment, peak aortic velocity, and LVEF per 
the Echocardiography Core Laboratory procedure guidelines. All TTEs must be 
forwarded to the core laboratory for independent analyses. 
Note: TTE must be done for all subjects who have a transcatheter valve implanted in 
the aortic position during the index procedure.   
• Serious adverse event (SAE, SADE, UADE, and relevant VARC events to be 
adjudicated by the CEC) assessment for test device(s) and device deficiencies 
assessment for test device(s) with associated treatment. 
Note: Relevant VARC events to be adjudicated by the CEC include the following: 
mortality, stroke, spontaneous myocardial infarction, acute kidney injury, repeat 
procedure for valve-related dysfunction, hospitalization for valve-related symptoms or 
worsening congestive heart failure (NYHA III or IV), new pacemaker, new onset atrial 
fibrillation or atrial flutter, prosthetic aortic valve malpositioning (valve migration, 
valve embolization, or ectopic valve deployment), TAV-in-TAV, prosthetic aortic 
valve thrombosis and endocarditis. 
10.10.5. Follow-up (±60 Days) at 6, 8 and 9 Years 
All implanted subjects must be evaluated at 72, 96, and 108 months (6, 8 and 9 years) after 
the index procedure, with a window of ±60 days. This evaluation may be conducted by 
telephone. The following assessments must be completed. The REPRISE IV eCRFs identify 
the specific data points to be collected. 
• Current antiplatelet, anticoagulant (if applicable)  

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• Serious adverse event (SAE, SADE, UADE, and relevant VARC events to be 
adjudicated by the CEC) assessment for test device(s) and device deficiencies 
assessment for test device(s) with associated treatment. Please see Section 10.10.4  for 
a list of relevant VARC events. 
10.11. Study Completion 
All subjects who receive a test device will be evaluated at discharge or 7 days (whichever 
comes first), 30 days, and then annually up to 10 years post index procedure. Visits in the 
first 5 years and at 7 and 10 years are office or in-person visits. Evaluations may be 
conducted by telephone at 6, 8 and 9 years. A subject’s participation in the study will be 
considered complete after the 10-year visit. For subjects who do not receive a test device, 
participation in the study will be considered complete after the 1-year visit. Any ongoing 
adverse events after study completion should be managed per standard of care. 
10.12. Source Documents 
When available, original source documents (see Table 25.2-1 for definition) should be 
maintained at the investigative center. In lieu of original source documents, certified copies 
are required to be maintained. A certified copy is a copy (irrespective of the type of media 
used) of the original record that has been verified (i.e., by a dated signature [PI or as 
delegated by the PI] or by generation through a validated process) to have the same 
information, including data that describe the context, content, and structure, as the original. 
Source documentation includes but is not limited to those items noted in Table 10.12-1. 
Table 10.12-1: Source Documentation Requirements 
Requirement 
Disposition 
Printed, optical, or electronic document containing source data. Examples may include but 
are not limited to hospital records, laboratory notes, device accountability records, 
photographic negatives, radiographs, records kept at the investigation center, at the 
laboratories and at the medico-technical departments involved in the clinical investigation. 
Retain at center. 
Note: Please see Table 25.2-1 for definitions of “source data” and “source document.” 
 
10.13. Local Laboratory/Vendor Documentation 
Appropriate certifications and documentation records are required to be maintained at the 
investigative center for local laboratory/vendor work.   

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11. Statistical Considerations 
11.1. Endpoints 
11.1.1. Primary Endpoint 
The primary endpoint is the composite of all-cause mortality and all stroke at 1 year. 
11.1.1.1. Statistical Hypothesis for the Primary Endpoint 
The statistical hypothesis is that the rate of the primary endpoint (composite of all-cause 
mortality and all stroke at 1 year) in the Main Cohort is less than the performance goal (PG) 
of 15.2% (expected rate of 11.1% plus testing margin of 4.1%). 
A one-sample z-test will be used to test the one-sided hypothesis that the 1-year primary 
endpoint rate for LOTUS Edge in the Main Cohort is less than the PG: 
 
H0: PLOTUS Edge  ≥ PG 
 
H1: PLOTUS Edge  < PG 
where PLOTUS Edge is the primary endpoint rate for the LOTUS Edge group and PG is the 
performance goal. 
The primary analysis set for the primary endpoint is the intention-to-treat (ITT) analysis set 
(see Section 11.2.1). This endpoint will also be analyzed for the implanted analysis set. 
11.1.1.2. Sample Size Parameters for the Primary Endpoint  
The sample size calculation for the primary endpoint is based on the following assumptions. 
• Expected rate for LOTUS Edge = 11.1%* 
• Testing margin = 4.1% (37% relative to the expected rate) 
• Performance goal (PG) = 15.2% (expected rate of 11.1% plus testing margin of 4.1%) 
• Test significance level (α) = 0.025 (1-sided) 
• Power = 87.5% 
• Number of evaluable subjects = 675 
• Expected rate of attrition = 3% 
• Total enrollment (evaluable Main Cohort) = 696 subjects  
* Estimated pooled rate from the fixed effect model based on the TAVR arm data from 
PARTNER II S3i32 and SURTAVI34 
11.1.1.3. Success Criteria – Primary Endpoint  
If the P value from the one-sample z-test is <0.025, it will be concluded that the primary 
endpoint with the LOTUS Edge Valve System is less than the PG. This corresponds to the 

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one-sided upper 97.5% confidence bound of the observed composite rate of all-cause 
mortality and all stroke in the Main Cohort at 1 year being < 15.2%. 
11.1.1.4. Statistical Methods – Primary Endpoint 
All subjects who are enrolled will be eligible for evaluation. Handling of dropouts and 
missing data will depend on their frequency and the nature of the outcome measure. 
Sensitivity analyses (e.g., tipping-point analysis) will be performed to assess the impact of 
subjects with inadequate follow-up (i.e., missing data) on the primary endpoint and to assess 
the robustness of the conclusion of the primary analysis. Statistical models that account for 
censored data will be employed in appropriate circumstances (e.g., for time-to-event 
outcomes). Suspected invalid data will be queried and corrected in the database prior to 
statistical analysis. Additional information may be found in the statistical analysis plan 
(SAP).  
11.1.2. Baseline Comparability 
Baseline data will be summarized separately for subjects in the Main Cohort, Roll-In Cohort, 
and Bicuspid Nested Registry Cohort. Subject demographics, clinical and neurological 
history, risk factors, and pre-procedure characteristics will be summarized using descriptive 
statistics (e.g., mean, standard deviation, n, minimum, maximum) for continuous variables 
and frequency tables or proportions for discrete variables. Procedural characteristics will be 
summarized similarly. 
11.1.3. Post-procedure Measurements 
Post-procedure information will be collected at regularly scheduled follow-up examinations 
as detailed in the clinical study schedule (see Table 10.1-1) and will be summarized using 
descriptive statistics for continuous variables (e.g., mean, standard deviation, n, minimum, 
maximum) and frequency tables or proportions for discrete variables. The Kaplan-Meier 
product-limit method will be used to estimate rates for time-to-event endpoints. Adverse 
event and SAE rates will be reported. No formal statistical testing will be done for the Roll-
In Cohort or Bicuspid Nested Registry Cohort.  
11.1.4. Subgroup Analyses 
Primary and pre-specified additional endpoints will be summarized and compared for the 
following subgroups. 
• Gender (male and female) 
No adjustments for multiple comparisons will be made.  Additional analyses may be 
performed as appropriate. 
For the CT Imaging Substudy, data from the 4D CT scan at 30 days and at 1 year post 
LOTUS Edge valve implantation to assess the prevalence of reduced leaflet mobility will be 
summarized and the relationship, if any, to clinical events will be explored.  

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11.2. General Statistical Methods 
All statistical analyses will be performed using the SAS System software, version 9.2 or later 
(Copyright© 2000 SAS Institute Inc., SAS Campus Drive, Cary, North Carolina 27513, USA. 
All rights reserved).  
All statistical analyses will be conducted according to applicable Standard Operating 
Procedures, Work Instructions, and the study-specific SAP. 
11.2.1. Analysis Sets 
The primary endpoint and additional measurements will be analyzed on an ITT and an 
implanted basis. For ITT analyses, all subjects who sign the IRB/HREC-approved study ICF 
(see Section 10.3) and are enrolled in the trial will be included in the analysis, whether or not 
a study valve was implanted. For implanted analyses, ITT subjects who had the study valve 
implanted will be included in the analysis.   
For the Main Cohort, the primary endpoint will be analyzed for the ITT and implanted 
analysis sets. The primary analysis for the primary endpoints will be based on the ITT 
analysis set.  
11.2.2. Control of Systematic Error/Bias 
All subjects who have met the inclusion/exclusion criteria, received a positive 
recommendation from the CRC, and signed the ICF will be eligible for enrollment in the 
study. The center heart team’s assessment of TTE measurements before device placement 
will contribute to the determination of subject eligibility for the study.  
To control for inter-observer variability, data from independent core laboratories (see 
Section 13.3) will be used for analysis. These include an echocardiography core laboratory, a 
CT and procedural angiography core laboratory to assess all CT and procedural angiography 
data using standard techniques, and an electrocardiography core laboratory to independently 
analyze protocol-required 12-lead ECGs performed for each subject. Clinical endpoints will 
also be adjudicated by an independent CEC (Section 21.1.1). 
11.2.3. Reporting Events 
For all subjects, all events that occur from the time of enrollment will be reported. For time 
based clinical events, the cut-off for events for 30-day endpoints will be 30 days, for 1-year 
endpoints it will be 365 days, and for 2–10-year endpoints it will be 365 days times the 
number of years. For events at discharge or 7 days post-procedure, the cut-off for events will 
be the earlier of the date of discharge or 7 days post-procedure for each subject. 
11.3. Data Analyses 
Baseline and outcome variables will be summarized using descriptive statistics for 
continuous variables (mean, standard deviation, number of observations, minimum and 

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maximum) and discrete variables (percentage and count/sample). See Section 11.1 for a 
discussion on analysis of the primary endpoint and additional measurements. 
11.3.1. Other Measurements  
Other measurements not driven by statistical hypotheses are listed in Section 6.2.2. 
11.3.2. Interim Analyses  
No formal interim analyses are planned for the purpose of stopping this trial early for 
effectiveness or futility. Administrative analyses for regulatory agency review may be 
performed. 
11.3.3. Justification of Pooling 
All analyses will be performed using data pooled across clinical centers. An assessment of 
the poolability of subjects across centers will be made by fitting a logistic regression model 
with the primary composite endpoint of all death and all stroke and with the center as the 
main effect. If the P value for the coefficient for the center is ≥0.1, the data can be pooled 
across centers. In the analysis to justify pooling across centers, the centers with fewer than 
10 subjects enrolled will be combined into “virtual centers” based on geographic region so 
that “virtual centers” have ≥10 subjects, but no more than the largest enrolling center. 
11.3.4. Multivariable Analyses 
Univariate and multivariate analyses will be performed to assess the effect of potential 
predictors on the primary endpoint as described in the SAP. 
11.3.5. Changes to Planned Analyses 
Any changes to the planned statistical analyses made prior to performing the analyses will be 
documented in an amended SAP 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. 
12. Health Economics Outcomes 
A formal health economics analysis may be completed as part of this trial, provided 
meaningful clinical results are obtained. Quality of life will be evaluated by the Kansas City 
Cardiomyopathy118 and SF-12119 questionnaires at baseline, 1 month, 1 year, and 5 years. 
These inputs may be used in any health economics analysis performed. 

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13. Data Management 
13.1. Data Collection, Processing, and Review 
Subject data will be recorded in a limited access secure electronic data capture (EDC) 
system. Only personnel trained and authorized will have access to the system. 
The clinical database will reside on a production server hosted by Medidata EDC System 
(New York, NY, USA). All changes made to the clinical data will be captured in an 
electronic audit trail and made available for review by BSC or its representative. The 
associated RAVE software and database have been designed to meet regulatory compliance 
for deployment as part of a validated system compliant with laws and regulations applicable 
to the conduct of clinical studies pertaining to the use of electronic records and signatures. 
Database backups are performed regularly. 
The Investigator provides his/her electronic signature on the appropriate eCRFs in 
compliance with local regulations. A written signature on printouts of the eCRFs must also 
be provided if required by local regulation. Changes to data previously submitted to the 
Sponsor require a new electronic signature by the Investigator acknowledging and approving 
the changes. 
Visual and/or electronic data review will be performed to identify possible data 
discrepancies. Manual and/or automatic queries will be created in the EDC system and will 
be issued to the center for appropriate response. Center staff will be responsible for resolving 
all queries in the database.  
13.2. Data Retention 
The Principal Investigator or his/her designee or investigational center will maintain all 
essential study documents and source documentation that support the data collected on the 
study subjects in compliance with applicable regulatory requirements. Documents must be 
retained for at least 2 years after the last approval of a marketing application or until at least 
2 years have elapsed since the formal discontinuation of the clinical investigation of the 
product. These documents will be retained for a longer period of time by agreement with 
BSC or in compliance with other local regulations. It is BSC’s responsibility to inform the 
Investigator when these documents no longer need to be maintained.  
The Principal Investigator or his/her designee will take measures to ensure that these 
essential documents are not accidentally damaged or destroyed. If for any reason the 
Principal Investigator or his/her designee withdraws responsibility for maintaining these 
essential documents, custody must be transferred to an individual who will assume 
responsibility and BSC must receive written notification of this custodial change. Centers are 
required to inform BSC in writing where paper or electronic files are maintained in case files 
are stored off site and are not readily available. 

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13.3. Core Laboratories 
13.3.1. Echocardiography 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 Angiography Core Laboratory 
An independent core laboratory will centrally assess all of the CT and 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.  
Procedure guidelines 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. 
13.3.4. Histopathology Core Laboratory 
If a LOTUS Edge 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 for 
assessment by an independent histopathology laboratory. 
14. Deviations 
An Investigator must not make any changes or deviate from this protocol, except to protect 
the life and physical well-being of a subject in an emergency. An investigator shall notify the 
Sponsor and the reviewing IRB/HREC of any deviation from the investigational plan to 
protect the life or physical well-being of a subject in an emergency, and those deviations 
which affect the scientific integrity of the clinical investigation. Such notice shall be given as 
soon as possible, but no later than 5 working days after the emergency occurred, or per 
prevailing local requirements, if sooner than 5 working days.  
All deviations from the investigational plan, with the reason for the deviation and the date of 
occurrence, must be documented and reported to the sponsor using the EDC CRF. Centers 
may also be required to report deviations to the IRB/HREC, per local guidelines and 
government regulations.  

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Deviations will be reviewed and evaluated on an ongoing basis and, as necessary, appropriate 
corrective and preventive actions (including IRB/HREC notification, center re-training, or 
center discontinuation/termination) will be put into place by the Sponsor. 
15. Device Accountability  
15.1. Device Accountability for Products Labelled Investigational 
The investigational devices will be released by the Sponsor or designee to the clinical center 
only after the center has been initiated and all regulatory approvals as well as required 
documentation have been collected from the center.  
The investigational devices shall be securely maintained and controlled and used only in this 
clinical study. Additionally, study personnel must follow the instructions related to the 
storage of the investigational devices as noted in the corresponding IFUs. An electronic 
interactive response technology (IRT) will be used for investigational device management 
and accountability during the study.  
The Sponsor or designee shall keep records to document the physical location of all 
investigational devices from shipment of the investigational devices to the investigation 
centers until return or disposal. The IRT will be used to document reception of the 
investigational device at a center. Records shall be kept by authorized center study personnel 
to document the physical location and conditions of storage of all investigational devices. 
Centers must not dispose of any investigational devices for any reason at the center unless 
instructed to do so by BSC. Any investigational device that is disposed of at the center must 
be documented appropriately. Centers 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, transfer, and disposal of the investigational devices, which shall include 
the following; this will be verified by personnel from BSC or its designee. 
• Date of receipt at the center 
• Identification of each investigational device (unique identifier or lot number/batch 
number/serial number, 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 and quantity of unused, expired, or malfunctioning investigational 
devices, if applicable. 
Written procedures may be required by national regulations.  

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Once the Investigator and center are notified in writing by BSC that subject enrollment is 
complete, all unused investigational devices must be returned to BSC or its designee. 
15.2. Commercial Device 
For countries where the introducer sets are commercially available, appropriate information 
on the size and model will be collected.  
16. Compliance 
16.1. Statement of Compliance 
The REPRISE IV study will be conducted in accordance with 21 CFR 814.20 Parts 11, 50, 
54 56, and part 812 or 813; the relevant parts of the International Conference on 
Harmonisation (ICH) Guidelines for Good Clinical Practices (GCP) or the International 
Standard ISO 14155: Clinical Investigation of Medical Devices for Human Subjects – Good 
Clinical Practice; ethical principles that have their origins in the Declaration of Helsinki; and 
applicable individual country/state/local laws and regulations.  
The study shall not begin until the required approval/favorable opinion from the IRB/HREC 
and/or regulatory authority has been obtained, if appropriate. Also, the study shall not begin 
prior to issuance of the center Authorization to Screen, as provided by the Sponsor. Any 
additional requirements imposed by the IRB/HREC or regulatory authority shall be followed, 
if appropriate.   
16.2. Investigator Responsibilities 
The Principal Investigator of an investigational center is responsible for ensuring that the 
study is conducted in accordance with the Clinical Study Agreement, the clinical 
investigation plan/protocol, ISO 14155 or ICH/GCP, ethical principles that have their origins 
in the Declaration of Helsinki, any conditions of approval imposed by the reviewing 
IRB/HREC, and prevailing local and/or country laws and/or regulations, whichever affords 
the greater protection to the subject. 
The Principal Investigator’s responsibilities include, but are not limited to, the following.  
• Prior to beginning the study, sign the Clinical Study Agreement and comply with the 
Investigator responsibilities as described in such Agreement. 
• Prior to beginning the study, sign the Investigator Brochure Signature Page, 
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 

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interest, including financial, that may interfere with the conduct of the clinical study or 
interpretation of results. 
• Complete all LOTUS Edge Valve System (investigational device) training requirements 
as detailed in the REPRISE IV Training Plan (Section 16.4.2). 
• 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 as applicable per the protocol and observed device deficiency. 
• Report to BSC, per the protocol requirements, all SAEs and device deficiencies that 
could have led to a SADE and potential/USADE or UADE. 
• Report to the IRB/HREC and regulatory authorities any SAEs and device deficiencies 
that could have led to a SADE and potential/USADE or UADE, if required by 
applicable laws or regulations or this protocol or by the IRB/HREC, and supply BSC 
with any additional requested information related to the safety reporting of a particular 
event. 
• Maintain the device accountability records and control of the investigational device, 
ensuring that the investigational device is used only by authorized/designated users and 
in accordance with this protocol and instructions/directions for use. 
• Allow the Sponsor and Sponsor representatives to perform monitoring and auditing 
activities and be accessible to the clinical research monitor or auditor and respond to 
questions during monitoring visits or audits. 
• Allow and support regulatory authorities and the IRB/HREC when performing auditing 
activities. 
• Ensure that informed consent is obtained in accordance with applicable laws, this 
protocol and local IRB/HREC requirements. 
• Provide adequate medical care to a subject during and after a subject’s participation in a 
clinical study in the case of adverse events, as described in the ICF. 
• Inform the subject of the nature and possible cause of any adverse events experienced. 
• Inform the subject of any new significant findings occurring during the clinical 
investigation, including the need for additional medical care that may be required. 

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• Provide the subject with well-defined procedures for possible emergency situations 
related to the clinical study, and make the necessary arrangements for emergency 
treatment, including decoding procedures for blinded/masked clinical investigations, as 
needed. 
• Ensure that clinical medical records are clearly marked to indicate that the subject is 
enrolled in this clinical study. 
• Ensure that, if appropriate, subjects enrolled in the clinical investigation are provided 
with some means of showing their participation in the clinical investigation, together 
with identification and compliance information for concomitant treatment measures 
(contact address and telephone numbers shall be provided). 
• Inform, with the subject’s approval or when required by national regulations, the 
subject’s personal physician about the subject’s participation in the clinical 
investigation. 
• Make all reasonable efforts to ascertain the reason(s) for a subject’s premature 
withdrawal from clinical investigation while fully respecting the subject’s rights. 
• Ensure that an adequate investigation 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. 
16.2.1. Delegation of Responsibility 
When specific tasks are delegated by an investigator, including but not limited to conducting 
the informed consent process, the Principal Investigator is responsible for providing 
appropriate training, so the delegate is competent to perform the tasks they have been 
delegated, and adequate supervision of those to whom tasks are delegated. Where there is a 
sub-investigator at a center, the sub-investigator should not be delegated the primary 
supervisory responsibility for the center. The investigator is accountable for regulatory 
violations resulting from failure to adequately supervise the conduct of the clinical study.  
16.3. Institutional Review Board/Human Research Ethics Committee 
The investigational center will obtain the written and dated approval/favorable opinion of 
their IRB/HREC for the clinical investigation before recruiting subjects and implementing all 
subsequent amendments, if required. 
A copy of the written IRB/HREC approval of the protocol (or permission to conduct the 
study) and ICF, must be received by the Sponsor before recruitment of subjects into the study 
and shipment of investigational product. Prior approval must also be obtained for other 
materials related to subject recruitment or which will be provided to the subject. 
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. Any amendment to the protocol 

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will require review and approval by the IRB/HREC before the changes are implemented in 
the study. All changes to the ICF will be IRB/HREC approved; a determination will be made 
regarding whether a new ICF needs to be obtained from subjects who provided consent using 
a previously approved ICF. Annual IRB/HREC approval and renewals will be obtained 
throughout the duration of the study as required by applicable local/country laws or 
regulations or IRB/HREC requirements. Copies of the Investigator’s reports and the 
IRB/HREC continuance of approval must be provided to the Sponsor.  
16.4. Sponsor Responsibilities 
All information and data sent to BSC and its authorized designee concerning subjects or their 
participation in this study will be considered confidential by BSC and will be kept 
confidential in accordance with all applicable laws and regulations. Only authorized BSC 
personnel, representatives, or designees will have access to these confidential records. 
Authorized regulatory personnel have the right to inspect and copy all records pertinent to 
this study. Study data collected during this study may be used by BSC for the purposes of 
this study, publication, and to support future research and/or other business purposes such as 
overseeing and improving the performance of its device, new medical research and proposals 
for developing new medical products or procedures. All data used in the analysis and 
reporting of this study or shared with a third-party researcher will be without identifiable 
reference to specific subjects. 
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.  Information received during the study 
will not be used to market to subjects; subject names will not be placed on any mailing lists 
or sold to anyone for marketing purposes.  
16.4.1. Role of Boston Scientific Corporation Representatives 
Boston Scientific Corporation personnel (including field clinical engineers and specialists) 
who are trained in the use of the investigational device will provide technical support to the 
investigator and other health care personnel (collectively HCP) as needed during LOTUS 
Edge valve implant and testing required by the protocol. Boston Scientific Corporation is 
also responsible for ensuring investigators are trained on the investigational device(s). 
Support may include HCP training (see Section 16.4.2 below), addressing HCP questions, or 
providing clarifications to HCPs concerning the operation of BSC equipment/devices.  
In addition, BSC 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 

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Boston Scientific personnel will not do the following.  
• Practice medicine 
• Provide medical diagnosis or treatment to subjects 
• Discuss a subject’s condition or treatment with a subject without the approval and 
presence of the investigator  
• Independently collect critical study data (defined as primary or secondary endpoint 
data) 
• Enter data in electronic data capture systems or on paper case report forms 
16.4.2. Training with the Investigational Device 
The Sponsor is responsible for providing investigators with the information and training on 
the LOTUS Edge Valve System and iSleeve and Lotus Introducer Sets they need to conduct 
the study properly. The Sponsor is responsible for maintaining documentation of attendance 
at each of the training sessions provided.  
Training on the LOTUS Edge Valve System has been developed that meets the requirements 
of ISO 5840-3 and includes the following elements.  
• Device training to include a detailed description of all device components including a 
summary of the basic principle of operation and hands-on bench top demonstration 
using valve and delivery system components in a simulated implantation model. 
• Patient selection and device sizing to include a review of the Instructions for Use (IFU) 
and pre-procedural and procedural imaging techniques to aid in sizing decisions and 
implantation of the valve. 
• Implantation techniques to include a step-by-step review of the procedure (including 
alternative access, where applicable) while highlighting associated cautions and 
warnings from the IFU. Training should include video representation of implantation 
procedural steps and associated fluoroscopic images of each step. Clinical case reviews 
should be presented to demonstrate intended procedural steps as well as appropriate 
troubleshooting. 
• Proctoring: The investigator and co-investigators as well as the scrub team will be 
proctored by an individual experienced with the LOTUS Edge valve and TAVR on a 
minimum of 5 implantation procedures. 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.  
Note 1: If a physician has prior experience implanting the Lotus valve, he/she will be trained 
per above to the LOTUS Edge Valve System prior to re-starting first implants. Further, if the 
physician was considered proctor-free under the previous Lotus program, a proctor will not 
be required.  

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Note 2: For centers that do not have implantation experience with the LOTUS Edge Valve 
System, at least 2 roll-in cases will be performed before enrollment can commence in the 
Main Cohort or in the Bicuspid Nested Registry. For centers that do not have any previous 
experience implanting the Lotus valve, the roll-in subjects will be treated under the 
supervision of a proctor and will count towards the 5 required proctored cases. For centers 
with prior experience with the Lotus valve who are proctor-free, the roll-in subjects will not 
require the presence of a proctor. 
16.5. Insurance  
Where required by local/country regulation, proof and type of insurance coverage by BSC for 
subjects in the study will be obtained. 
17. Monitoring 
Monitoring will be performed during the study according to the monitoring plan to assess 
continued compliance with the protocol and applicable regulations. In addition, the clinical 
research monitor verifies that study records are adequately maintained, that data are reported 
in a satisfactory manner with respect to timeliness, adequacy, and accuracy, and that the 
Principal Investigator continues to have sufficient staff and facilities to conduct the study 
safely and effectively. The Principal Investigator/institution guarantees direct access to 
original source documents and/or certified copies (please see Section 10.12) by BSC 
personnel, their designees, and appropriate regulatory authorities. 
The study may also be subject to a quality assurance audit by BSC or its designees, as well as 
inspection by appropriate regulatory authorities. It is important that the Principal Investigator 
and relevant study personnel are available during on-site monitoring visits or audits and that 
sufficient time is devoted to the process. 
18. Potential Risks and Benefits 
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 Corporation and review of relevant literature, 
most recently from the Edwards Lifesciences’ Placement of Aortic Transcatheter Valves 
(PARTNER) trial8,20,22,23, the PARTNER II trial (RCT and SAPIEN 3 intermediate risk 
arm)33,41,46, the SAPIEN 3 CE Mark study75, the CoreValve Extreme Risk study47, the 
CoreValve High Risk Study25, the Evolut R CE Mark study48, the Surgical Replacement and 
Transcatheter Aortic Valve Implantation (SURTAVI) trial34, the EVOLUT R US study49, the 
PORTICO Pre-CE Mark study50, and the PORTICO IDE randomized trial/RESOLVE 
registry/SAVORY registry40.   
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. Potential risks and benefits have been 

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included in the study-specific template of the ICF provided to the study centers (see 
Section 20).  
18.1. Anticipated Adverse Events and Risks Associated with Transcatheter Aortic Valve 
Replacement  
Adverse events (in alphabetical order) potentially associated with TAVR (including, but not 
limited to, standard cardiac catheterization, BAV, and the use of anesthesia) as well as 
additional risks related to the use of the LOTUS Edge Valve System and the Lotus and 
iSleeve Introducer Sets include but may not be limited to the risks listed in Table 18.1-1 
below.  
Table 18.1-1: Risks Associated with Transcatheter Aortic Valve Replacement 
Abnormal lab values (including anemia and electrolytes) 
Abnormal pressure gradient 
Allergic reaction (including to medications, anesthesia, contrast, or device materials, including nickel, 
titanium, tantalum, bovine-derived materials or polyurethanes) 
Aneurysm (cardiovascular) 
Angina 
Arrhythmia or new conduction system injury (including need for pacemaker insertion) 
Bleeding or hemorrhage (possibly requiring transfusion or intervention) 
Cardiac arrest 
Cardiac failure/low cardiac output 
Cerebrovascular accident, stroke, transient ischemic attack, or cerebral infarction including asymptomatic 
neuroimaging findings  
Coronary obstruction 
Death  
Device embolization, misplacement or migration 
Emboli (including air, tissue, thrombus or device materials)  
Emergency cardiac surgery 
Endocarditis 
Fever 
Heart failure 
Hematoma or lymphatic problems or other complications at the access sites 
Hemodynamic instability or shock 
Hemolysis and/or hemolytic anemia 
Hypertension/hypotension  
Infection (local and/or systemic, including septicemia) 
Inflammation 
Mitral valve insufficiency or injury 
Myocardial infarction or ischemia  
Myocardial or valvular injury (including perforation or rupture) 
Nerve injury or neurologic deficits (including encephalopathy) 
Non-structural valve dysfunction including implant distortion, improper deployment or sizing 

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Table 18.1-1: Risks Associated with Transcatheter Aortic Valve Replacement 
Pain 
Pericardial effusion or cardiac tamponade 
Peripheral ischemia or infarction 
Permanent disability 
Pleural effusion 
Pulmonary edema 
Renal insufficiency or failure 
Respiratory insufficiency or failure 
Restenosis (including pannus formation) 
Thrombosis/thromboembolism 
Valve dysfunction, deterioration or failure 
Valve-in-valve (need for additional valve within a valve) 
Valve or device thrombosis 
Valvular stenosis or regurgitation (central or paravalvular) 
Vessel injury (including spasm, trauma, dissection, perforation, rupture, arteriovenous fistula, acute coronary 
occlusion, or pseudoaneurysm)  
Wound healing disorders 
Note: Risks are listed in alphabetical order. 
 
As a result of these adverse events, the subject may require medical, percutaneous, or 
surgical intervention, including re-operation and replacement of the valve. These events may 
lead to fatal outcomes.   
As the LOTUS Edge Valve System 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. 
18.1.1. Hypoattenuated Leaflet Thickening/Reduced Leaflet Motion/Leaflet 
Thrombosis 
Hypoattenuated leaflet thickening (HALT128) and reduced leaflet motion (RLM129) 
suggestive of subclinical leaflet thrombosis, as detected by high-resolution CT, has been 
reported with bioprosthetic TAVR and SAVR valves40,109,130,131. It is less common among 
subjects receiving anticoagulant therapy and, in some cases, has been shown to resolve with 
such treatment40,109,110,130-133.   
Clinical signs of HALT and RLM include elevation of transvalvular gradients (as determined 
by echocardiography), central or peripheral thromboembolic events, and unexpected 
recurrence of heart failure. Computed tomography imaging is recommended to appropriately 
assess subjects with echocardiographic and/or clinical suspicion of leaflet thrombosis. 
Additional anticoagulant therapy may be indicated based on symptoms or signs and subject 
bleeding risk40,109,110,130-133.    

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The subset of subjects undergoing 4D CT scans at 30 days and 1 year will be exposed to an 
additional radiation dose of about 20 millisieverts (mSv), which is equivalent to about 10 
years’ worth of natural background radiation. The contrast dye used during the image 
acquisition can cause medical problems such as allergic reactions and increase the risk of 
worsening kidney function or failure.  
18.2. Risks Associated with the Study Device(s)  
Overall, there are no incremental risks expected with the investigational device(s) compared 
to similar devices on the market. 
18.3. Risks Associated with Participation in the Clinical Study 
Risks associated with TAVR and participation in this clinical study are listed above in Table 
18.1-1. 
18.4. Possible Interactions with Concomitant Medical Treatments 
Medications to be used in REPRISE IV constitute standard of care for TAVR as described in 
society guidelines10,121. Please also see Section 10 for medications to be used in this study. 
18.5. Risk Minimization Actions 
Additional risks may exist. Risks can be minimized through compliance with this protocol, 
performing procedures in the appropriate hospital environment, adherence to subject 
selection criteria, close monitoring of the subject's physiologic status during research 
procedures and/or follow-ups and by promptly supplying BSC with all pertinent information 
required by this protocol. 
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 centers that are experienced and skilled in 
TAVR procedures.  
Risk mitigation will be accomplished through the following actions. 
• Clearly defining the inclusion/exclusion criteria to ensure only appropriate subjects are 
enrolled  
• Confirmation of eligible subjects by a Case Review Committee, including experienced 
investigators in TAVR 
• Ensuring that treatment and follow-up of the subject are consistent with current medical 
practices 
• Selection of investigators who are experienced and skilled in TAVR procedures 
• Completion of training and proctorship provided by the Sponsor  

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• Performing all procedures in accordance with the IFU, including the preparation of the 
valve and delivery system 
• Dynamic safety review processes, including assessment by the Data Monitoring 
Committee (DMC, Section 21.1.2) and CEC (Section 21.1.1) adjudication of specified 
events as recommended by VARC61,62. 
In addition to its repositioning and self-centering features designed to facilitate optimal 
positioning, the LOTUS Edge Valve System provides physicians with control throughout the 
procedure by allowing them to pause, assess, lock, un-lock, incrementally reverse, resheathe 
and, if needed, retrieve the valve prior to final release. These features help the physician to do 
the following: place the valve correctly with the first attempt, reposition the device if the 
initial deployment is considered to be suboptimal, and retrieve 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 antiplatelet therapy is 
recommended to minimize any risk of thrombus formation, stroke, or transient ischemic 
attack. Neurological assessments (NIHSS and mRS) will be performed at each required 
follow-up visit to identify any change in the neurological status of the subjects as 
recommended by VARC61,62. 
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 BSC. Qualified employees of BSC, or a 
designee under contract, will conduct monitoring visits at the initiation of the study and at 
interim intervals described in the monitoring plan throughout the course of the study to 
evaluate protocol compliance and determine if there are any issues that could affect the safety 
or welfare of any subject in the study. 
18.6. Anticipated Benefits 
18.6.1. Potential Benefits to the TAVR Procedure 
Transcatheter aortic valve replacement (TAVR) may offer certain advantages when 
compared to surgical replacement of the stenotic aortic valve. Known benefits associated 

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with TAVR, as described in the scientific literature (see summary in Section 4.1.1 of this 
document and details in the Investigator’s 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 
18.6.2. Potential Benefit Using the LOTUS Edge Valve System 
Potential benefits that may be associated specifically with use of the LOTUS Edge 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 need for post-dilation 
• Reduced or obviated need for valve-in-valve repeat intervention 
• Lower risk of ectopic valve placement and valve migration   
• Reduced incidence of paravalvular aortic regurgitation due to the Adaptive Seal 
18.7. 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 Lotus Valve 
System including earlier generations of the device design. When used according to the IFU, 
all known risks associated with the TAVR procedure and the specific use of the LOTUS 
Edge 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. The Adaptive Seal may provide long term benefit as it is designed to minimize 
paravalvular regurgitation, which has been associated with long term mortality in TAVR. 

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19. Safety Reporting 
19.1. Reportable Events by Investigational Center to Boston Scientific 
It is the responsibility of the investigator to assess and report to BSC any event that occurs in 
any of the following categories; reporting requirements are described below in Table 19.4-1. 
• All serious adverse events 
• All device-related adverse events 
• All study procedure-related adverse events 
• All investigational device deficiencies  
• Unanticipated adverse device effects/unanticipated serious adverse device effects  
• New findings/updates in relation to already reported events 
When possible, the medical diagnosis should be reported as the Event Term instead of 
individual symptoms. 
If it is unclear whether or not an event fits one of the above categories, or if the event cannot 
be isolated from the device or procedure, it should be submitted as an adverse event and/or 
device deficiency. 
Any adverse event required by the protocol, experienced by the study subject after informed 
consent and once considered enrolled in the study (as defined in Section 9.1), whether during 
or subsequent to the procedure, must be recorded in the eCRF. 
Underlying diseases are not reported as AEs unless there is an increase in severity or 
frequency during the course of the investigation. Death should not be recorded as an AE but 
should only be reflected as an outcome of ONE (1) specific SAE (see Table 19.2-1 for AE 
definitions). 
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. 
Event reporting (eCRF data entry) is required beginning from the time an attempt is made to 
insert the LOTUS Edge Valve System into the subject’s femoral artery. 
Refer to Section 18 for the known risks associated with the study devices. 
Based on the VARC61,62 recommendations and definitions, the adverse events and/or safety 
endpoints requiring adjudication by the CEC include the following. 

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• Mortality: all-cause, cardiovascular, and non-cardiovascular  
• Stroke: disabling and non-disabling  
• Myocardial infarction (MI): periprocedural (≤72 hours post index procedure) and 
spontaneous (>72 hours post index procedure) 
• Bleeding events: life-threatening (or disabling) and major (through 5 years)  
• Acute kidney injury (≤7 days post index procedure): based on the AKIN System 111,112 
Stage 3 (including renal replacement therapy) or Stage 2  
• Vascular complications: major (including annular rupture; through 5 years) 
• 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 
• New onset of atrial fibrillation or atrial flutter  
• Coronary obstruction: periprocedural (≤72 hours post index procedure) 
• Ventricular septal perforation: periprocedural (≤72 hours post index procedure) 
• Mitral apparatus damage: periprocedural (≤72 hours post index procedure) 
• Cardiac tamponade: periprocedural (≤72 hours post index procedure) 
• Prosthetic aortic valve malpositioning, including valve migration, valve embolization, 
or ectopic valve deployment 
• 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 25.2-1). 
19.2. Definitions and Classification 
Adverse event definitions are provided in Table 19.2-1. Administrative edits were made on 
the safety definitions from ISO 14155 and MEDDEV 2.7/3 for clarification purposes. 
Table 19.2-1: Safety Definitions 
Term 
Definition 
Adverse Event (AE) 
Ref: ISO 14155 
Any untoward medical occurrence, unintended disease or injury, or any untoward 
clinical signs (including an abnormal laboratory finding) in subjects, users or 
other persons, whether or not related to the investigational medical device.  

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Table 19.2-1: Safety Definitions 
Term 
Definition 
Ref: MEDDEV 2.7/3  
 
 
 
 
Note 1: This includes events related to the investigational medical device. 
Note 2: This definition includes events related to the procedures involved. 
Note 3: For users or other persons, this definition is restricted to events related to 
the investigational medical device.  
Adverse Device Effect 
(ADE) 
Ref: ISO 14155 
Ref: MEDDEV 2.7/3  
Adverse event related to the use of an investigational medical device 
Note 1: This includes any adverse event resulting from insufficiencies or 
inadequacies in the instructions for use, the deployment, the implantation, the 
installation, the operation, or any malfunction of the investigational medical 
device. 
Note 2: This definition includes any event resulting from use error or intentional 
abnormal use of the investigational medical device. 
Serious Adverse Event 
(SAE) 
Ref: ISO 14155 
Ref: MEDDEV 2.7/3  
Note 1: This definition meets the reporting objectives and requirements of ISO 
14155 and MEDDEV 2.7/3. 
Adverse event that: 
a) Led to death, 
b) Led to serious deterioration in the health of the subject as defined by either: 
1) a life-threatening illness or injury, or 
2) a permanent impairment of a body structure or a body function, or 
3) in-patient hospitalization or prolongation of existing hospitalization, or 
4) medical or surgical intervention to prevent life-threatening illness or 
injury or permanent impairment to a body structure or a body function 
c) Led to fetal distress, fetal death, or a congenital abnormality or birth defect. 
Note 2: Planned hospitalization for a pre-existing condition, or a procedure 
required by the clinical investigational plan, without a serious deterioration in 
health, is not considered a serious adverse event.  
Serious Adverse 
Device Effect (SADE) 
Ref: ISO 14155 
Ref: MEDDEV 2.7/3  
Adverse device effect that has resulted in any of the consequences characteristic 
of a serious adverse event. 
 
Unanticipated Adverse 
Device Effect (UADE) 
Ref: 21 CFR Part 812 
 
 
Any serious adverse effect on health or safety or any life-threatening problem or 
death caused by, or associated with, a device, if that effect, problem, or death was 
not previously identified in nature, severity, or degree of incidence in the 
investigational plan or application (including a supplementary plan or 
application), or any other unanticipated serious problem associated with a device 
that relates to the rights, safety, or welfare of subjects.   
Unanticipated Serious 
Adverse Device Effect 
(USADE) 
Ref: ISO 14155 
Ref: MEDDEV 2.7/3 
Serious adverse device effect which by its nature, incidence, severity, or outcome 
has not been identified in the current version of the risk analysis report. 
Note: Anticipated serious adverse device effect (ASADE) is an effect which by its 
nature, incidence, severity or outcome has been identified in the risk analysis 
report. 

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Table 19.2-1: Safety Definitions 
Term 
Definition 
Device Deficiency 
Ref: ISO 14155 
Ref: MEDDEV 2.7/3  
An inadequacy of an investigational medical device related to its identity, quality, 
durability, reliability, safety or performance. This may include malfunctions, use 
error, or inadequacy in the information supplied by the manufacturer. 
 
19.3. Relationship to Study Device(s) 
The Investigator must assess the relationship of the reportable AE/SAE to the study device 
and procedure. See criteria in Table 19.3-1:  
Table 19.3-1: Criteria for Assessing Relationship of Study Device and Procedure to 
Adverse Event 
Classification 
Description 
Not Related 
Ref: MEDDEV 2.7/3 
Relationship to the device or procedures can be excluded when: 
• the event is not a known side effect of the product category the device belongs 
to or of similar devices and procedures; 
• the event has no temporal relationship with the use of the investigational 
device or the procedures; 
• the serious event does not follow a known response pattern to the medical 
device (if the response pattern is previously known) and is biologically 
implausible; 
• the discontinuation of medical device application or the reduction of the level 
of activation/exposure - when clinically feasible – and reintroduction of its use 
(or increase of the level of activation/exposure), do not impact on the serious 
event; 
• the event involves a body-site or an organ not expected to be affected by the 
device or procedure; 
• the serious event can be attributed to another cause (e.g. an underlying or 
concurrent illness clinical condition, an effect of another device, drug, 
treatment or other risk factors); 
• the event does not depend on a false result given by the investigational device 
used for diagnosis, when applicable; harms to the subject are not clearly due to 
use error; 
• In order to establish the non-relatedness, not all the criteria listed above might 
be met at the same time, depending on the type of device/procedures and the 
serious event. 
Possibly Related 
Ref: MEDDEV 2.7/3 
The relationship with the use of the investigational device is weak but cannot be 
ruled out completely. Alternative causes are also possible (e.g. an underlying or 
concurrent illness/ clinical condition or/and an effect of another device, drug or 
treatment). Cases where relatedness cannot be assessed or no information has been 
obtained should also be classified as possible. 

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Table 19.3-1: Criteria for Assessing Relationship of Study Device and Procedure to 
Adverse Event 
Classification 
Description 
Probably Related 
Ref: MEDDEV 2.7/3 
The relationship with the use of the investigational device seems relevant and/or 
the event cannot be reasonably explained by another cause, but additional 
information may be obtained. 
Causal Relationship 
Ref: MEDDEV 2.7/3 
The serious event is associated with the investigational device or with procedures 
beyond reasonable doubt when: 
• the event is a known side effect of the product category the device belongs to 
or of similar devices and procedures; 
• the event has a temporal relationship with investigational device 
use/application or procedures; 
• the event involves a body-site or organ that: 
- the investigational device or procedures are applied to; 
- the investigational device or procedures have an effect on; 
• the serious event follows a known response pattern to the medical device (if 
the response pattern is previously known); 
• the discontinuation of medical device application (or reduction of the level of 
activation/exposure) and reintroduction of its use (or increase of the level of 
activation/exposure), impact on the serious event (when clinically feasible); 
• other possible causes (e.g. an underlying or concurrent illness/clinical 
condition or/and an effect of another device, drug or treatment) have been 
adequately ruled out; 
• harm to the subject is due to error in use; 
• the event depends on a false result given by the investigational device used for 
diagnosis, when applicable; 
• In order to establish the relatedness, not all the criteria listed above might be 
met at the same time, depending on the type of device/procedures and the 
serious event. 
 
19.4. Investigator Reporting Requirements 
The communication requirements for reporting to BSC are as shown in Table 19.4-1. 
Note: The “become aware date” for an event that requires reporting per the protocol is the 
date that study personnel listed on the Delegation of Authority Log identify or are notified of 
the event.  

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Table 19.4-1: Investigator Reporting Requirements 
Event Classification 
Communication Method 
Communication Timeline (premarket studies) 
(MEDDEV 2.7/3: CLINICAL 
INVESTIGATIONS: SERIOUS ADVERSE 
EVENT REPORTING UNDER DIRECTIVES 
90/385/EEC AND 93/42/EEC) 
Unanticipated Adverse 
Device Effect / 
Unanticipated Serious 
Adverse Device Effect  
(UADE/USADE) 
Complete AE eCRF page 
with all available new and 
updated information.  
 
• Within 1 business day of first becoming 
aware of the event. 
• Terminating at the end of the study 
Provide all relevant source 
documentation (de-identified/ 
pseudonymized) for reported 
event.  
• At request of Sponsor.  
Serious Adverse Event  
(SAE) 
Complete AE eCRF page 
with all available new and 
updated information.  
• Within 3 calendar days of first becoming 
aware of the event or as per local/regional 
regulations.  
• Reporting required through the end of the 
study 
Provide all relevant source 
documentation (de-identified/ 
pseudonymized) for reported 
event. 
• At request of Sponsor 
Serious Adverse Device 
Effects 
(SADE) 
 
Complete AE eCRF page 
with all available new and 
updated information. 
• Within 3 calendar days of first becoming 
aware of the event or as per local/regional 
regulations.  
• Reporting required through the end of the 
study 
Provide all relevant source 
documentation (de-identified/ 
pseudonymized) for reported 
event.  
• When documentation is available 
• At Sponsor request.  
Device Deficiencies 
(including but not 
limited to failures, 
malfunctions, and 
product 
nonconformities) 
Note:  Any 
Investigational Device 
Deficiency that might 
Complete eCRF page with all 
available new and updated 
information.  
• Within 3 calendar days of first becoming 
aware of the event.  
• Reporting required through 12 months 
 

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Table 19.4-1: Investigator Reporting Requirements 
Event Classification 
Communication Method 
Communication Timeline (premarket studies) 
(MEDDEV 2.7/3: CLINICAL 
INVESTIGATIONS: SERIOUS ADVERSE 
EVENT REPORTING UNDER DIRECTIVES 
90/385/EEC AND 93/42/EEC) 
have led to a serious 
adverse event if a) 
suitable action had not 
been taken or b) 
intervention had not 
been made or c) if 
circumstances had been 
less fortunate is 
considered a reportable 
event. 
Provide all relevant source 
documentation (de-identified/ 
pseudonymized) for reported 
event. 
• At request of Sponsor  
Adverse Event including 
Adverse Device Effects 
(AE/ADE) 
Complete AE eCRF page, 
which contains such 
information as date of AE, 
treatment of AE resolution, 
assessment of seriousness 
and relationship to the 
device.  
• In a timely manner (e.g., recommend within 
10 business days) after becoming aware of 
the information 
• Reporting required through 12 months 
Provide all relevant source 
documentation (de-
identified/pseudonymized) 
for reported event.  
• At request of Sponsor 
Note: The AE eCRF page contains information such as date of AE, treatment of AE resolution, assessment of 
seriousness, and relationship to the device. 
Please note that pre-market studies are clinical studies with investigational devices or with medical devices 
that bear the regulatory approval and are not being used for the same approved indications. 
Abbreviations: AE=adverse event; eCRF=electronic case report form 
 
19.5. Device Deficiencies 
Complaint reporting of any device deficiencies for any commercially available products used 
should be carried out using the manufacturer’s processes.    
19.5.1. Boston Scientific Device Deficiencies 
All device deficiencies (including but not limited to failures, malfunctions, use errors, 
product nonconformities, and inadequacy in the information supplied by the manufacturer) 
related to the investigational device or future iterations must be documented on the 
appropriate eCRF and reported to BSC. If possible, the device should be returned to BSC 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 

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deficiencies, failures, and malfunctions 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 19.4-1. 
19.6. Reporting to Regulatory Authorities / IRBs / HRECs / Investigators 
Boston Scientific Corporation will notify all participating study centers if UADEs, SAEs, 
SADEs, or investigational 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 adverse event information to all 
participating Principal Investigators, IRBs/HRECs, and regulatory authorities, as applicable 
according to local reporting requirements.  
The Principal Investigator is responsible for informing the IRB/HREC and regulatory 
authorities of UADEs, SADEs, SAEs, Device Deficiencies and/or other CEC events as 
applicable according to local reporting requirements. 
20. Informed Consent 
Subject participation in this clinical study is voluntary. Informed Consent is required from 
each subject or his/her legally authorized representative. The Investigator is responsible for 
ensuring that Informed Consent is obtained prior to the use of any 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 and the ICH 
guidelines for GCP, any applicable national regulations, and local Ethics Committee and/or 
Regulatory authority body, as applicable. The ICF must be accepted by BSC or its delegate 
(e.g. CRO), and approved by the center’s IRB/HREC, or central IRB/HREC, if applicable. 
Boston Scientific Corporation will provide a study-specific template of the ICF to 
investigators participating in this study. The ICF template may be modified to meet the 
requirements of the investigative center’s IRB/HREC. Any modification requires acceptance 
from BSC or authorized representative prior to use of the form. The ICF must be in a 
language understandable to the subject and if needed, BSC will assist the center in obtaining 
a written consent translation. Translated consent forms must also have IRB/HREC approval 
prior to their use. Privacy language shall be included in the body of the form or as a separate 
form as applicable.   

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The process of obtaining Informed Consent shall at a minimum include the following steps, 
as well as any other steps required by applicable laws, rules, regulations and guidelines: 
• be conducted by the Principal Investigator or designee authorized to conduct the 
process,  
• include a description of all aspects of the clinical study that are relevant to the subject’s 
decision to participate throughout the clinical study, 
• avoid any coercion of or undue influence of subjects to participate, 
• not waive or appear to waive subject’s legal rights, 
• use native language that is non-technical and understandable to the subject or his/her 
legal representative, 
• provide ample time for the subject to consider participation and ask questions if 
necessary, 
• ensure important new information is provided to new and existing subjects throughout 
the clinical study.  
The ICF shall always be signed and personally dated by the subject or legal representative 
competent to sign the ICF under the applicable laws, rules, regulations and guidelines and by 
the investigator or an authorized designee responsible for conducting the informed consent 
process. If a legal representative signs the ICF, the subject shall be asked to provide informed 
consent for continued participation as soon as his/her medical condition allows. The original 
signed ICF will be retained by the center and a copy of the signed and dated document and 
any other written information must be given to the person signing the form.  
Failure to obtain subject consent will be reported by BSC to the applicable regulatory body 
according to their requirements (e.g., the United States Food and Drug Administration [FDA] 
requirement is within 5 working days of learning of such an event). Any violations of the 
informed consent process must be reported as deviations to the Sponsor and local regulatory 
authorities (e.g. IRB/HREC), 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 applicable laws, protocol, a change in Principal Investigator, administrative changes, or 
following annual review by the IRB/HREC. The new version of the ICF must be approved by 
the IRB/HREC. Boston Scientific Corporation approval is required if changes to the revised 
ICF are requested by the center’s IRB/HREC. The IRB/HREC will determine the subject 
population to be re-consented. 
Study personnel should explain that even if a subject agrees to participate in the study and 
signs an 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. A confidential Screening/Enrollment Log 

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will be maintained by the center to document select information about candidates who fail to 
meet the general or "other specific" entry criteria. 
21. Committees 
21.1. Safety Monitoring Process 
To promote early detection of safety issues, the Clinical Events Committee (CEC) and Data 
Monitoring Committee (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 the Sponsor or designee, which is responsible for 
coordinating the collection of information for the subject dossier from the centers and core 
laboratories. During regularly scheduled monitoring activities, clinical research monitors will 
support the dynamic reporting process through their review of source document and other 
data information. The BSC Medical Safety group includes physicians with expertise in 
cardiology and with the necessary therapeutic and subject matter expertise to evaluate and 
classify the events into the categories outlined above (Section 19). 
21.1.1. Clinical Events Committee 
A Clinical Events Committee (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 
centers and adjudicate study endpoint related clinical events. The responsibilities, 
qualifications, membership, and committee procedures of the CEC are outlined in the CEC 
Charter.  
21.1.2. Data Monitoring Committee 
The Data Monitoring Committee (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 BSC. 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. 
21.2. Case Review Committee 
A Case Review Committee (CRC) will be comprised of experienced cardiac surgeons and 
interventional cardiologists, including the Study Coordinating PIs, Center PIs, other 
Investigators, Proctors and Medical Consultants experienced in TAVR for their 
clinical/medical expertise, and the Sponsor for technical expertise on the LOTUS Edge Valve 

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System requirements. This committee will be responsible for the review of subject screening 
data to confirm eligibility given the increased surgical risk of the subject population being 
studied and to ensure consistency of subjects enrolled across study centers. Responsibilities, 
qualifications, membership, and committee procedures are outlined in the CRC Charter. 
Minutes are written for each CRC review session and the decisions are documented in these 
minutes and provided to the centers as appropriate. 
21.3. Steering Committee 
A Steering Committee consisting of Sponsor Clinical Management, the Study Coordinating 
PIs, cardiac surgeons, and other investigators experienced in TAVR will be convened. 
Responsibilities may include oversight of the overall conduct of the study with regard to 
protocol development, study progress, subject safety, overall data quality and integrity, as 
well as disseminating any study results through appropriate scientific sessions and 
publications. Steering Committee members may participate in the review and approval of all 
requests for data analysis, abstract and manuscript preparation and submission.  
22. Suspension or Termination 
22.1. Premature Termination of the Study 
Boston Scientific Corporation reserves the right to terminate the study at any stage but 
intends to exercise this right only for valid scientific or administrative reasons and reasons 
related to protection of subjects. Investigators, associated IRBs/HRECs, and regulatory 
authorities, as applicable, will be notified in writing in the event of study termination. 
22.1.1. Criteria for Premature Termination of the Study 
Possible reasons for premature study termination include, but are not limited to, the 
following. 
• The occurrence of unanticipated adverse device effects that present a significant or 
unreasonable risk to subjects enrolled in the study. 
• An enrollment rate far below expectation that prejudices the conclusion of the study.  
• A decision on the part of BSC to suspend or discontinue development of the device. 
22.2. Termination of Study Participation by the Investigator or Withdrawal of 
IRB/HREC Approval 
Any investigator or associated IRB/HREC in the REPRISE IV study or regulatory authority 
may discontinue participation in the study or withdraw approval of the study, respectively, 
with suitable written notice to BSC. Investigators, associated IRBs/HRECs, and regulatory 
authorities, as applicable, will be notified in writing in the event of these occurrences. 

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22.3. Requirements for Documentation and Subject Follow-up 
In the event of premature study termination, a written statement as to why the premature 
termination has occurred will be provided to all participating centers by BSC. The 
IRB/HREC and regulatory authorities, as applicable, will be notified. Detailed information 
on how enrolled subjects will be managed thereafter will be provided.  
In the event an IRB/HREC terminates participation in the study, participating investigators, 
associated IRBs/HRECs, and regulatory authorities, as applicable, will be notified in writing. 
Detailed information on how enrolled subjects will be managed thereafter will be provided 
by BSC. 
In the event a Principal Investigator terminates participation in the study, study responsibility 
will be transferred to another investigator, if possible. In the event there are no opportunities 
to transfer Principal Investigator responsibility, detailed information on how enrolled 
subjects will be managed thereafter will be provided by BSC. 
The Principal Investigator or his/her designee must return all study-related documents and 
investigational product to BSC, unless this action would jeopardize the rights, safety, or 
welfare of the subjects. 
22.4. Criteria for Suspending/Terminating a Study Center 
Boston Scientific Corporation reserves the right to stop the inclusion of subjects at a study 
center at any time after the study initiation visit if no subjects have been enrolled for a period 
beyond 4 months after center initiation, or if the center has multiple or severe protocol 
violations/noncompliance without justification and/or fails to follow remedial actions. 
In the event of termination of center participation, all study devices and testing equipment, as 
applicable, will be returned to BSC unless this action would jeopardize the rights, safety or 
well-being of the subjects. The IRB/HREC and regulatory authorities, as applicable, will be 
notified. Study subjects will be contacted, as applicable, and be informed of changes to study 
visit schedule. 
23. Publication Policy 
Boston Scientific Corporation requires disclosure of its involvement as a sponsor or financial 
supporter in any publication or presentation relating to a BSC study or its results. Boston 
Scientific Corporation will submit study results for publication (regardless of study outcome) 
following the conclusion or termination of the study. Boston Scientific Corporation adheres 
to the Contributorship Criteria set forth in the Uniform Requirements of the International 
Committee of Medical Journal Editors (ICMJE; http://www.icmje.org). In order to ensure the 
public disclosure of study results in a timely manner, while maintaining an unbiased 
presentation of study outcomes, BSC personnel may assist authors and investigators in 
publication preparation provided the following guidelines are followed. 
• All authorship and contributorship requirements as described above must be followed. 

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• BSC involvement in the publication preparation and the BSC Publication Policy should 
be discussed with the Coordinating Principal Investigator(s) and/or Steering Committee 
at the onset of the project. 
• The First and Senior authors are the primary drivers of decisions regarding publication 
content, review, approval, and submission.  
The data, analytic methods, and study materials for this clinical trial may be made available 
to other researchers in accordance with the Boston Scientific Data Sharing Policy 
(http://www.bostonscientific.com/en-US/data-sharing-requests.html).  
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surgical and transcatheter bioprosthetic aortic valves: an observational study. Lancet 
2017;389:2383-92. 
110. Jose J, Sulimov DS, El-Mawardy M, et al. Clinical bioprosthetic heart valve thrombosis 
after transcatheter aortic valve replacement: incidence, characteristics, and treatment 
outcomes. J Am Coll Cardiol Intv 2017;10:686-97. 
111. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P. Acute renal failure - 
definition, outcome measures, animal models, fluid therapy and information technology 

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needs: the Second International Consensus Conference of the Acute Dialysis Quality 
Initiative (ADQI) Group. Crit Care 2004;8:R204-12. 
112. Mehta RL, Kellum JA, Shah SV, et al. Acute Kidney Injury Network: report of an 
initiative to improve outcomes in acute kidney injury. Crit Care 2007;11:R31. 
113. Saito S. REPRISE Japan: A prospective clinical investigation of a novel transcatheter 
aortic valve implantation system in Japan.  Cardiovascular Intervention and 
Therapeutics. Kyoto, Japan 2017. 
114. Saito S. One-year results from REPRISE Japan: A prospective clinical investigation of 
a novel transcatheter aortic valve implantation system in Japan.  PCR Tokyo Valves, 
Tokyo 2018. 
115. Meredith I, Walters D, Gooley R, et al. Primary endpoint results of the REPRISE NG 
Delivery System (DS) First Human Use study: Percutaneous aortic valve implantation 
with the next generation of fully repositionable and retrievable aortic valve.  EuroPCR. 
Paris 2015. 
116. Walters DL, Gooley R, Raffel C, et al. First report of clinical outcomes with the next-
generation LOTUS Edge Valve System: Results from the LOTUS Edge Feasibility 
Trial.  ACC. Washington, D.C. 2017. 
117. Cesari M, Kritchevsky SB, Penninx BW, et al. Prognostic value of usual gait speed in 
well-functioning older people--results from the Health, Aging and Body Composition 
Study. J Am Geriatr Soc 2005;53:1675-80. 
118. Green CP, Porter CB, Bresnahan DR, Spertus JA. Development and evaluation of the 
Kansas City Cardiomyopathy Questionnaire: a new health status measure for heart 
failure. J Am Coll Cardiol 2000;35:1245-55. 
119. Ware JE, Kosinski M, Keller SD. A 12-item Short-Form Health Survey: Construction 
of scales and preliminary test of reliability and validity. Medical Care 1996;34:220-6. 
120. Epstein AE, DiMarco JP, Ellenbogen KA, et al. 2012 ACCF/AHA/HRS focused update 
incorporated into the ACCF/AHA/HRS 2008 guidelines for device-based therapy of 
cardiac rhythm abnormalities: a report of the American College of Cardiology 
Foundation/American Heart Association Task Force on Practice Guidelines and the 
Heart Rhythm Society. J Am Coll Cardiol 2013;61:e6-75. 
121. Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC Guideline for the 
management of patients with valvular heart disease: a report of the American College 
of Cardiology/American Heart Association task force on practice guidelines. J Am Coll 
Cardiol 2014;63:e57-185. 
122. Robinson TN, Eiseman B, Wallace JI, et al. Redefining geriatric preoperative 
assessment using frailty, disability and co-morbidity. Ann Surg 2009;250:449-55. 
123. Afilalo J, Mottillo S, Eisenberg MJ, et al. Addition of frailty and disability to cardiac 
surgery risk scores identifies elderly patients at high risk of mortality or major 
morbidity. Circ Cardiovasc Qual Outcomes 2012;5:222-8. 

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124. Afilalo J, Eisenberg MJ, Morin JF, et al. Gait speed as an incremental predictor of 
mortality and major morbidity in elderly patients undergoing cardiac surgery. J Am 
Coll Cardiol 2010;56:1668-76. 
125. Studenski S, Perera S, Patel K, et al. Gait speed and survival in older adults. JAMA 
2011;305:50-8. 
126. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a 
phenotype. J Gerontol Med Sci 2001;56A:M146-56. 
127. Katz S, Downs TD, Cash HR, Grotz RC. Progress in development of the index of ADL. 
Gerontologist 1970;10:20-30. 
128. Blanke P, Weir-McCall JR, Achenbach S, et al. Computed tomography imaging in the 
context of transcatheter aortic valve implantation (TAVI)/transcatheter aortic valve 
replacement (TAVR): an expert consensus document of the Society of Cardiovascular 
Computed Tomography. J Am Coll Cardiol Img 2019;12:1-24. 
129. De Backer O, Dangas GD, Jilaihawi H, et al. Reduced leaflet motion after transcatheter 
aortic-valve replacement. N Engl J Med 2020;382:130-9. 
130. Pache G, Schoechlin S, Blanke P, et al. Early hypo-attenuated leaflet thickening in 
balloon-expandable transcatheter aortic heart valves. Eur Heart J 2016;37:2263-71. 
131. Søndergaard L, De Backer O, Kofoed KF, et al. Natural history of subclinical leaflet 
thrombosis affecting motion in bioprosthetic aortic valves. Eur Heart J 2017;38:2201-7. 
132. Hansson NC, Grove EL, Andersen HR, et al. Transcatheter aortic valve thrombosis: 
incidence, predisposing factors, and clinical implications. J Am Coll Cardiol 
2016;68:2059-69. 
133. Ruile P, Jander N, Blanke P, et al. Course of early subclinical leaflet thrombosis after 
transcatheter aortic valve implantation with or without oral anticoagulation. Clin Res 
Cardiol 2017;106:85-95. 
134. Mehran R, Rao SV, Bhatt DL, et al. Standardized bleeding definitions for 
cardiovascular clinical trials: a consensus report from the Bleeding Academic Research 
Consortium. Circulation 2011;123:2736-47. 
135. Ndrepepa G, Schuster T, Hadamitzky M, et al. Validation of the Bleeding Academic 
Research Consortium definition of bleeding in patients with coronary artery disease 
undergoing percutaneous coronary intervention. Circulation 2012;125:1424-31. 
136. Durack DT, Lukes AS, Bright DK. New criteria for diagnosis of infective endocarditis: 
utilization of specific echocardiographic findings. Duke Endocarditis Service. Am J 
Med 1994;96:200-9. 
137. Thygesen K, Alpert JS, White HD. Universal definition of myocardial infarction. Eur 
Heart J 2007;28:2525-38. 

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138. 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. 
139. Généreux P, Kodali S, Leon MB, et al. Clinical outcomes using a new crossover 
balloon occlusion technique for percutaneous closure after transfemoral aortic valve 
implantation. J Am Coll Cardiol Intv 2011;4:861-7. 
25. Abbreviations and Definitions  
25.1. Abbreviations 
Abbreviations are shown in Table 25.1-1.   
 
 
Table 25.1-1: Abbreviations and Acronyms 
Abbreviation/Acronym 
Definition 
ADE 
adverse device effect 
AE 
adverse event 
AKIN 
Acute Kidney Injury Network 
AR 
aortic regurgitation 
AS 
aortic stenosis 
AV 
atrioventricular 
AVA 
aortic valve area 
AVR 
aortic valve replacement 
BARC 
Bleeding Academic Research Consortium 
BAV 
balloon aortic valvuloplasty 
BMI 
body mass index 
BSA 
body surface area 
BSC 
Boston Scientific Corporation 
CAD 
coronary artery disease 
CBC 
complete blood count 
CEC 
Clinical Events Committee 
CK 
creatine kinase 
CK-MB 
creatine kinase-myoglobin band, a fraction of creatine kinase 
CRC 
Case Review Committee 
CT 
computed tomography 
CVA 
cerebrovascular accident 
DVI 
Doppler velocity index 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOA 
effective orifice area 
GCP 
Good Clinical Practices 
GDPR 
General Data Protection Regulation 
HALT 
hypoattenuated leaflet thickening 

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Table 25.1-1: Abbreviations and Acronyms 
Abbreviation/Acronym 
Definition 
HCP 
Health care personnel 
HREC 
Human Research Ethics Committee 
IB 
Investigator Brochure  
ICF 
Informed Consent form 
ICH 
International Conference on Harmonisation 
iEOA 
indexed effective orifice area 
IFU 
Instructions for Use 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ISO 
International Organization for Standardization 
ITT 
intention-to-treat 
LBBB 
left bundle branch block 
LV 
left ventricle 
LVEF 
left ventricular ejection fraction 
MACCE 
major adverse cardiovascular and cerebrovascular events 
MI 
myocardial infarction 
MRI 
magnetic resonance imaging 
mRS 
Modified Rankin Scale 
NIHSS 
National Institutes of Health Stroke Scale 
NYHA 
New York Heart Association  
OAC 
oral anticoagulant 
PPM 
permanent pacemaker 
QOL 
quality of life 
RLM 
reduced leaflet motion 
SADE 
serious adverse device effect 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAVR 
surgical aortic valve replacement 
TAVI/TAVR 
transcatheter aortic valve implantation/replacement 
TEE 
transesophageal Doppler echocardiography 
TIA 
transient ischemic attack 
TTE 
transthoracic Doppler echocardiography 
UADE 
unanticipated adverse device effect 
URL 
upper reference limit (defined as 99th percentile of normal reference range) 
VARC 
Valve Academic Research Consortium 
 
25.2. Definitions 
Terms are defined in Table 25.2-1. See Table 25.1-1 for abbreviations. 

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Table 25.2-1: Definitions 
Term 
Definition 
ACUTE KIDNEY 
INJURY (AKI) 
(AKIN System111,112) 
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: Subjects receiving renal replacement therapy are considered to meet Stage 
3 criteria irrespective of other criteria. 
ACUTE VESSEL 
OCCLUSION 
The state of complete luminal obstruction with no antegrade blood flow 
ADVERSE EVENT 
(AE)  
Ref: ISO 14155 
Ref: MEDDEV 2.7/3  
 
Any untoward medical occurrence, unintended disease or injury or untoward 
clinical signs (including abnormal laboratory findings) in subjects, users or other 
persons, whether or not related to the investigational medical device. 
Note: This definition includes events related to the investigational medical device 
or the comparator. 
Note: This definition includes events related to the procedures involved. 
Note: For users or other persons, this definition is restricted to events related to 
investigational medical devices. 
ADVERSE EVENT 
BECOME AWARE 
DATE 
The become aware date for an adverse event that requires reporting per the 
protocol is the date that study personnel listed on the Delegation of Authority Log 
identify or are notified of the event. 
ADVERSE DEVICE 
EFFECT (ADE) 
Ref: ISO 14155 
Ref: MEDDEV 2.7/3  
 
Adverse event related to the use of an investigational medical device 
Note: 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: This definition includes any event resulting from use error or from 
intentional misuse of the investigational medical device. 
AORTIC DISSECTION 
Intimal tear resulting in blood splitting the aortic media and producing a false 
lumen that can progress in an antegrade or retrograde direction Aortic dissection 
is further classified using Stanford classification (Types A and B depending on 
whether ascending or descending aorta involved) or DeBakey classification 
(Types I, II and III) [see Figure below]. 

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Table 25.2-1: Definitions 
Term 
Definition 
 
AORTIC 
REGURGITATION 
(AR) 
The leaking of the aortic valve that causes blood to flow in the reverse direction 
during ventricular diastole, from the aorta into the left ventricle. 
The echocardiographic findings in severe aortic regurgitation include the 
following. 
• An AR color jet dimension >60% of the left ventricular outflow tract diameter 
(may not be true if the jet is eccentric)  
• The pressure half-time of the regurgitant jet is <250 msec  
• Early termination of the mitral inflow (due to increase in LV pressure due to 
the AR)  
• Early diastolic flow reversal in the descending aorta.  
 
• Regurgitant volume >60 mL  
• Regurgitant fraction >55% 
ARRHYTHMIA 
Any variation from the normal rhythm of the heartbeat, including sinus 
arrhythmia, premature beat, heart block, atrial fibrillation, atrial flutter and 
tachycardia. Complete heart block, ventricular tachycardia and ventricular 
fibrillation are considered major arrhythmias. Data should be collected on any 
new arrhythmia resulting in hemodynamic instability or requiring therapy 
(therapy includes electrical/medical cardioversion or initiation of a new 
medication [oral anticoagulation, rhythm or rate controlling therapy]).  
New onset atrial fibrillation or atrial flutter (AF) is diagnosed as any arrhythmia 
within hospitalization that has the ECG characteristics of AF and lasts 
sufficiently long to be recorded on a 12-lead ECG, or at least 30 seconds on a 
rhythm strip.  
The therapeutic approach to new-onset AF (spontaneous conversion, electrical or 
medical cardioversion, initiation of oral anticoagulation, and rate or rhythm 
control medications) and any clinical consequences should be documented.   
Note: See also definitions for conductance disturbance and permanent 
pacemaker. 
BLEEDING61,62   
Life-threatening or Disabling Bleeding 
• Fatal bleeding (Bleeding Academic Research Consortium [BARC] type 
5134,135) 
• Bleeding in a critical organ, such as intracranial, intraspinal, intraocular, or 
pericardial necessitating pericardiocentesis, or intramuscular with 
compartment syndrome (BARC type 3b and 3c)  

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Table 25.2-1: Definitions 
Term 
Definition 
• 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. 
CLINICAL 
PROCEDURAL 
SUCCESS  
(IN-HOSPITAL) 
Implantation of the device in the absence of death, disabling stroke, major 
vascular complications, and life-threatening or major bleeding 
CONDUCTION 
DISTURBANCES61,62  
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: High grade AV block is considered persistent if it is present every time the 
underlying rhythm is checked. 
Note: 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 25.2-1: 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. 
DATA CATEGORIES 
Data categories as defined by GDPR are listed below. 
Personal Data: 
GDPR defines “Personal Data” to be any information relating to an identified or 
identifiable natural person (‘data subject’); an identifiable natural person is one 
who can be identified, directly or indirectly, in particular by reference to an 
identifier such as a name, an identification number, location data, an online 
identifier or to one or more factors specific to the physical, physiological, genetic, 
mental, economic, cultural or social identity of that natural person. 
Sensitive Personal Data: 
GDPR defines “Sensitive Personal Data” as a subset of Personal Data, which, due 
to their nature have been classified as deserving additional privacy and security 
protections because their processing may create a risk for an individual’s 
fundamental right and freedom. This subset includes but is not limited to the 
following: racial, ethnic origin or ethnicity; political opinions; religious or 
philosophical beliefs; trade union membership; genetic data; biometric data for 
the purpose of uniquely identifying a natural person; health data (including 
gender, family medical history, etc.); sex life or sexual orientation; criminal 
records or allegations of crimes (requires an even higher standard of protection). 
Identifiers: 
“Identifiers” are Personal Data that can be used alone or in combination with 
other identifiers to identify an individual. Identifiers include but are not limited to 
the following:  
• All government-issued identification numbers (including but not limited to 
names, social security number, certificate/license numbers, passport, national 
ID) 
• All financial account numbers (including but not limited to bank account 
numbers, payment numbers, bank or credit card numbers)  
• All geographic subdivisions smaller than a state, including street address, 
city, county, precinct, ZIP code, and their equivalent geocodes, except for the 
initial three digits of the ZIP code if, according to the current publicly 

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Term 
Definition 
available data from the Bureau of the Census, the geographic unit formed by 
combining all ZIP codes with the same three initial digits contains more than 
20,000 people and/or the initial three digits of a ZIP code for all such 
geographic units containing 20,000 or fewer people is changed to 000 
• All elements of dates (except year) for dates that are directly related to an 
individual, including birth date, admission date, discharge date, death date, 
and all ages over 89 and all elements of dates (including year) indicative of 
such age, except that such ages and elements may be aggregated into a single 
category of age 90 or older 
• Telephone numbers 
• Fax numbers 
• Device identifiers and serial numbers 
• E-mail addresses 
• Web Universal Resource Locators (URLs) 
• Internet Protocol (IP) addresses 
• Medical record numbers 
• Biometric identifiers, including finger and voice prints 
• Health plan beneficiary numbers 
• Full-face photographs and any comparable images 
Any other unique identifying number, characteristic, or code (including subject 
ID number) 
DEATH  
 
All-cause Death 
Death from any cause after a valve intervention. 
Cardiovascular Death 
Any one of the following criteria is met. 
• Any death due to proximate cardiac cause (e.g., myocardial infarction, cardiac 
tamponade, worsening heart failure) 
• Sudden or unwitnessed death  
• Death of unknown cause 
• Death caused by noncoronary vascular conditions such as neurological events, 
pulmonary embolism, ruptured aortic aneurysm, dissecting aneurysm, or other 
vascular disease  
• All procedure-related deaths, including those related to a complication of the 
procedure or treatment for a complication of the procedure  
• All valve-related deaths including structural or nonstructural valve dysfunction 
or other valve-related adverse events  
Non-cardiovascular Death 
• Any death in which the primary cause of death is clearly related to another 
condition (e.g. trauma, cancer, suicide) 
DEVICE DEFICIENCY 
Ref: ISO 14155 
Ref: MEDDEV 2.7/3 
Any inadequacy of an investigational medical device related to its identity, 
quality, durability, reliability, safety or performance.  
Note: Device deficiencies may include malfunctions, use errors, or inadequacy in 
the information supplied by the manufacturer. 
DEVICE FAILURE 
A device failure is identified whenever the criteria for device success are not met.  

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Table 25.2-1: 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 
(VARC 270 definition) 
Absence of procedural mortality, correct positioning of a single valve into the 
proper anatomical location, and intended performance of the study device 
(indexed effective orifice area [iEOA] >0.85 cm2/m2 for BMI <30 kg/cm2 and 
iEOA >0.70 cm2/m2 for BMI ≥30 kg/cm2 plus either a mean aortic valve gradient 
<20 mmHg or a peak velocity <3m/sec, and no 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 criteria136 and necessitates 
the following.  
• Two major criteria -OR- 
• One major and three minor criteria -OR- 
• Five minor criteria 
Major Criteria 
• Positive blood culture for infective endocarditis  
o Typical microorganism consistent with infective endocarditis from 2 
separate blood cultures, as noted below. 
 Viridans streptococci, Streptococcus bovis, or HACEK group 
(Haemophilus [Haemophilus parainfluenzae, Haemophilus aphrophilus, 
and Haemophilus paraphrophilus], Actinobacillus 
actinomycetemcomitans [Aggregatibacter actinomycetemcomitans], 
Cardiobacterium hominis, Eikenella corrodens, Kingella kingae -OR-  
 Community-acquired Staphylococcus aureus or enterococci, in the 
absence of a primary focus  
 
-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. 

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Definition 
 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.  
GENERAL DATA 
PROTECTION 
REGULATION 
The General Data Protection Regulation (GDPR) is a legal framework that sets 
guidelines for the collection and processing of personal information of 
individuals within the European Union. 
HEMOLYSIS 
 
Two plasma free hemoglobin values >40 mg/dL with the two readings taken 
within a single 48-hour period. If the second plasma free hemoglobin assessment 
is not performed within 48 hours following an initial determination of >40 
mg/dL, this would qualify as an AE. 
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) 

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Table 25.2-1: Definitions 
Term 
Definition 
• History of multiple recurrent pleural effusions causing internal adhesions 
HYPO-ATTENUATED 
LEAFLET 
THICKENING 
(HALT)128 
Hypo-attenuated leaflet thickening (HALT) is defined as visually identifiable 
increased leaflet thickness on contrast-enhanced multi-planar reformats, carefully 
aligned with the long and short axis of the valve prosthesis. The extent of HALT 
is classified as follows: 
 
The dashed yellow line indicates the orientation of the long axis views in the 
lower row, aligned with the center of the cusps. The extent of leaflet thickening 
can be graded on a subjective 4-tier grading scale along the curvilinear 
orientation of the leaflet. Typically, hypo-attenuated leaflet thickening appears 
meniscal-shaped on long axis reformats, with greater thickness at the base than 
towards the center of the leaflet. 
IMPLANTED 
ANALYSIS SET 
This population includes all subjects who sign an Informed Consent Form, are 
enrolled in the trial, and are implanted with the assigned, randomized study 
device. 
Note: If a subject receives 2 valves, the subject is assigned to the group 
corresponding to the first valve received.    
INTENT TO TREAT 
(ITT) ANALYSIS SET 
This population includes all subjects who sign an Informed Consent Form, are 
enrolled in the trial, and are randomized, whether or not an assigned study device 
is implanted. Subjects in the ITT population will be followed with their ITT 
cohort.  
Note: If a subject receives 2 valves, the subject is assigned to the group 
corresponding to the first valve received.    
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. 

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

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Table 25.2-1: Definitions 
Term 
Definition 
o ECG changes indicative of new ischemia [new ST-T changes or new 
LBBB] 
o New pathological Q waves in at least two contiguous leads 
o Imaging evidence of new loss of viable myocardium or new wall motion 
abnormality 
• Sudden, unexpected cardiac death, involving cardiac arrest, often with 
symptoms suggestive of myocardial ischemia, and accompanied by 
presumably new ST-segment elevation, or new LBBB, and/or evidence of 
fresh thrombus by coronary angiography and/ or at autopsy, but death 
occurring before blood samples could be obtained, or at a time before the 
appearance of cardiac biomarkers in the blood. 
• Pathological findings of an acute myocardial infarction137. 
NEUROLOGICAL 
EVENT  
Any central, new neurological deficit, whether temporary or permanent and 
whether focal or global, that occurs after the subject emerges from anesthesia 
NEW YORK HEART 
ASSOCIATION 
CLASSIFICATION 
(NYHA) 
Classification system for defining cardiac disease and related functional 
limitations into four broad categorizations: 
Class I 
Subject with cardiac disease but without resulting limitations of 
physical activity. Ordinary physical activity does not cause 
undue fatigue, palpitation, dyspnea, or anginal pain. 
Class II 
Subjects with cardiac disease resulting in slight limitation of 
physical activity. They are comfortable at rest. Ordinary physical 
activity results in fatigue, palpitation, dyspnea, or anginal pain. 
Class III 
Subjects with cardiac disease resulting in marked limitation of 
physical activity. They are comfortable at rest. Less than 
ordinary physical activity causes fatigue, palpitation, dyspnea, or 
anginal pain. 
Class IV 
Subjects with cardiac disease resulting in inability to carry on 
any physical activity without discomfort. Symptoms of cardiac 
insufficiency or of the anginal syndrome may be present even at 
rest. If any physical activity is undertaken, discomfort is 
increased. 
 
NONSTRUCTURAL 
DYSFUNCTION 
 
Any abnormality not intrinsic to the valve itself that results in stenosis or 
regurgitation of the operated valve or hemolysis. The term nonstructural 
dysfunction refers to problems (exclusive of thrombosis and infection) that do not 
directly involve valve components yet result in dysfunction of an operated valve, 
as diagnosed by re-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  

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Table 25.2-1: Definitions 
Term 
Definition 
OPERATIVE RISK 
Operative risk is determined by a center cardiac surgeon and must be confirmed 
by the Case Review Committee (including a cardiac surgeon).  
Intermediate: Estimated 30-day risk of mortality is 3–10% 
High: Estimated 30-day risk of mortality is >10–15%% 
Very High: Estimated 30-day risk of mortality is >15% 
Extreme: Estimated 30-day risk of irreversible morbidity or mortality is ≥50%   
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) 
IMPLANTATION120  
Implantation of new PPM after the index procedure resulting from new or 
worsened conduction disturbances  
• 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.  
REDUCED LEAFLET 
MOBILITY/MOTION 
(RLM)129 
Systolic leaflet excursion/motion is classified as: 
• Grade 0: normal/unrestricted;  
• Grade 1: partially restricted – limited to base;  
• Grade 2: mildly restricted – involving more than the base, but less than 50% 
of the leaflet along curvilinear dimensions;  
• Grade 3: moderately restricted – involving more than 50% but less than 
75% of the leaflet along curvilinear dimensions;  
Grade 4: largely immobile. Quantitative assessment of leaflet motion is 
performed with a blood pool inversion volume rendered cine reconstruction 
throughout the cardiac cycle evaluating the bioprosthetic leaflets. 
REPEAT PROCEDURE 
FOR VALVE-
RELATED 
DYSFUNCTION 
Any surgical or percutaneous interventional catheter procedure that repairs, 
otherwise alters or adjusts, or replaces a previously implanted valve. In addition 
to surgical re-operations, balloon dilatation, interventional manipulation, 
repositioning, or retrieval, and other catheter-based interventions for valve-related 
complications are also considered re-interventions. Cardiac re-interventions will 
be categorized as repeat TAVR, valvuloplasty, or surgical AVR. 
REPOSITIONING OF 
A VALVE 
Any movement of the valve after the lead in phase (after the posts have entered 
the buckles) 

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Table 25.2-1: Definitions 
Term 
Definition 
RESHEATHING OF A 
VALVE 
Full resheathing occurs when the tops of the posts re-enter the Lotus catheter 
during repositioning. 
Partial resheathing occurs when the posts do not re-enter the Lotus catheter 
during repositioning. 
RESPIRATORY 
INSUFFICIENCY 
Inadequate ventilation or oxygenation 
RESPIRATORY 
FAILURE 
The need for ventilatory support for >72 hours associated with an inability to 
wean from the respirator for any reason. 
RIGHT 
VENTRICULAR 
INSUFFICIENCY 
• Defined as sequelae of right ventricular failure including the following. 
o Significantly decreased right ventricular systolic and/or diastolic function 
o Tricuspid valvular regurgitation secondary to elevated pressure 
• Clinical symptoms to include the following. 
o Hepatic congestion 
o Ascites 
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.  
SAFETY ANALYSIS 
SET 
This population includes all subjects in the ITT analysis set who have a study 
device implanted, regardless of the assigned treatment group. 
SERIOUS ADVERSE 
EVENT (SAE) 
Ref: ISO 14155 
Ref: MEDDEV 2.7/3 
 
Adverse event that:  
• Led to a death 
• Led to serious deterioration in the health of the subject, that either resulted in: 
o a life-threatening illness or injury, or 
o a permanent impairment of a body structure or a body function, or 
o in-patient hospitalization or prolongation of existing hospitalization, or 
o medical or surgical intervention to prevent life- threatening illness  
• Led to fetal distress, fetal 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 
Ref: MEDDEV 2.7/3  
Adverse device effect that has resulted in any of the consequences characteristic 
of a serious adverse event 
SOURCE DATA 
(per ISO 14155) 
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) 
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.  

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Table 25.2-1: Definitions 
Term 
Definition 
Note: If thermal paper from a device programmer is to be used for source 
documentation, signed and dated photocopies or printed portable document 
format files should be used instead or the strips should be electronically saved. 
STROKE61,62  
 
Stroke is defined as an acute episode of focal or global neurological dysfunction 
caused by brain, spinal cord, or retinal vascular injury as a result of hemorrhage 
or infarction.  
Stroke Classification 
• Ischemic Stroke is defined as an acute episode of focal cerebral, spinal, or 
retinal dysfunction caused by an infarction of central nervous system tissue.  
• Hemorrhagic Stroke is defined as an acute episode of focal or global cerebral 
or spinal dysfunction caused by an intraparenchymal, intraventricular, or 
subarachnoid hemorrhage 
Note: The CEC will adjudicate ischemic versus hemorrhagic stroke. 
Note: 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: 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: Modified Rankin Scale assessments should be made by a neurology 
professional or by qualified individuals according to a certification process.  
Note: 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. 

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Table 25.2-1: Definitions 
Term 
Definition 
TAV-IN-TAV 
DEPLOYMENT 
An additional valve prosthesis is implanted within a previously implanted 
prosthesis because of suboptimal device position and/or function during or after 
the index procedure. 
TRANSIENT 
ISCHEMIC ATTACK 
(TIA) 
• Transient episode of focal neurological dysfunction caused by brain, spinal 
cord, or retinal ischemia, without acute infarction  
• Duration of a focal or global neurological deficit is <24 h  
• Neuroimaging does not demonstrate a new hemorrhage or infarct (if 
performed) 
Note: The difference between TIA and ischemic stroke is the presence of tissue 
damage or new sensory-motor deficit persisting >24 hours. By definition, TIA 
does not produce lasting disability. 
UNANTICIPATED 
ADVERSE DEVICE 
EFFECT  
Ref: 21CFR Part 812 
(UADE) 
 
Any serious adverse effect on health or safety or any life-threatening problem or 
death caused by, or associated with a device, if that effect, problem, or death was 
not previously identified in nature, severity, or degree of incidence in the protocol 
or application (including a supplementary plan or application), or any other 
unanticipated serious problem associated with a device that relates to the rights, 
safety, or welfare of subjects. 
UNPLANNED USE OF 
CARDIOPUL-
MONARY BYPASS 
Unplanned use of cardiopulmonary bypass 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 
MALPOSITIONING 
Includes valve migration, valve embolization, or ectopic valve 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. 

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Table 25.2-1: Definitions 
Term 
Definition 
VASCULAR ACCESS 
SITE AND ACCESS 
RELATED 
COMPLICATIONS 
Major Vascular Complications 
• Any aortic dissection, aortic rupture, annulus rupture, left ventricle perforation, 
or new apical aneurysm/pseudoaneurysm  
• Access site or access-related vascular injury (dissection, stenosis, perforation, 
rupture, arterio-venous fistula, pseudoaneurysm, hematoma, irreversible nerve 
injury, compartment syndrome, percutaneous closure device failure*) leading 
to death, life-threatening or major bleeding**, visceral ischaemia, or 
neurological impairment 
• Distal embolization (non-cerebral) from a vascular source requiring surgery or 
resulting in amputation or irreversible end-organ damage 
• The use of unplanned endovascular or surgical intervention associated with 
death, major bleeding, visceral ischaemia or neurological impairment 
• Any new ipsilateral lower extremity ischemia documented by patient 
symptoms, physical exam, and/or decreased or absent blood flow on lower 
extremity angiogram 
• Surgery for access site-related nerve injury 
• Permanent access site-related nerve injury 
Minor Vascular Complications 
• Access site or access-related vascular injury (dissection, stenosis, perforation, 
rupture, arterio-venous fistula, pseudoaneurysms, hematomas, percutaneous 
closure device failure*) not leading to death, life-threatening or major 
bleeding**, visceral ischaemia or neurological impairment 
• Distal embolization treated with embolectomy and/or thrombectomy and not 
resulting in amputation or irreversible end-organ damage 
• Any unplanned endovascular stenting or unplanned surgical intervention not 
meeting the criteria for a major vascular complication 
• Vascular repair or the need for vascular repair (via surgery, ultrasound-guided 
compression, transcatheter embolization, or stent-graft) 
*Percutaneous Closure Device Failure 
Failure of a closure device to achieve hemostasis at the arteriotomy site leading to 
alternative treatment (other than manual compression or adjunctive endovascular 
ballooning) 
Note: Pre-planned surgical access or a planned endovascular approach to vascular 
closure (e.g., “pre-closure”)138,139 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: If unplanned percutaneous or surgical intervention does not lead to adverse 
outcomes this is not considered a major vascular complication.  
** Refers to VARC bleeding definitions61,62 
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 

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Table 25.2-1: Definitions 
Term 
Definition 
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; GDPR= General Data Protection Regulation; 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; TAV=transcatheter aortic valve; TAVR=transcatheter 
aortic valve replacement; TEE=transesophageal Doppler echocardiography; TIA=transient ischemic attack; 
URL=upper reference limit (defined as 99th percentile of normal reference range); VARC=Valve Academic 
Research Consortium 
 
26. Revision History 
26.1. Summary of Protocol Revision History 
Protocol revision history is provided in Table 26.1-1.

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Table 26.1-1: Protocol Revision History 
Revision 
Version 
Protocol 
Date 
Template 
Number and 
Version 
Protocol Sections 
Modified 
Summary of Changes 
Justification for 
Changes 
A 
16-Nov-2016 
90702637 
Rev/Ver AG 
– 
Not applicable. 
– 
B 
15-Feb-2017 
90702637 
Rev/Ver AG 
Page 2 
Current Version: 15-Feb-2017 
Updated Table of Revision History 
Updated for clarity 
2, Protocol Synopsis 
- Planned Number of 
Subjects/ 
Investigational 
Centers/ Countries 
Subjects will be enrolled at up to 45 centers in the United States. There 
will be up to 840 subjects in REPRISE IV as shown below. 
Cohort 
Number of Subjects 
Randomized 
620 
Roll-In  
Up to 120 
Bicuspid Nested Registry 
100 
 
Increase of number of 
subjects in the Bicuspid 
Nested Registry 
2, Protocol Synopsis 
– Exclusion Criteria 
EC16.  Subject has any therapeutic invasive cardiac procedure resulting in 
a permanent implant that is performed within 30 days prior to the index 
procedure (unless part of planned strategy for treatment of concomitant 
coronary artery disease and except for pacemaker or implantable 
cardioverter defibrillator implantation which are allowed).  
Updated for clarity 
8.1 Scale and 
Duration 
Updated Figure 8.1-1: REPRISE IV Study Design 
 
Increase of number of 
subjects in the Bicuspid 
Nested Registry 
8.3 Study Design 
Justification 
There will be up to 840 subjects in REPRISE IV. In order to support the 
stated objectives of this study (see Section 6) while also limiting the 
potential exposure of study subjects to risk, up to 120 subjects will be 
enrolled in the roll-in phase of this study (at centers without previous 
LOTUS Edge Valve experience), 620 subjects will be randomized and 
enrolled, and 100 subjects will be enrolled in the Bicuspid Nested 
Registry. 
Increase of number of 
subjects in the Bicuspid 
Nested Registry 
9.3 Exclusion 
Criteria 
EC16.  Subject has any therapeutic invasive cardiac procedure resulting in 
a permanent implant that is performed within 30 days prior to the index 
procedure (unless part of planned strategy for treatment of concomitant 
coronary artery disease and except for pacemaker or implantable 
cardioverter defibrillator implantation which are allowed).  
Updated for clarity 

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Table 26.1-1: Protocol Revision History 
Revision 
Version 
Protocol 
Date 
Template 
Number and 
Version 
Protocol Sections 
Modified 
Summary of Changes 
Justification for 
Changes 
11.1 Data Collection 
Updated Figure 11.1-1: REPRISE IV Data Collection Scheme 
 
 
Updated Table 11.1-1: Study Event Schedule 
Updated for clarity and 
to include CT 
assessment at 30 days 
for subjects enrolled in 
the Bicuspid Nested 
Registry. 
Increase of number of 
subjects in the Bicuspid 
Nested Registry 
11.10.1 30-Day 
Follow-up (30±7 
Days) 
All enrolled subjects… 
• 
Complete adverse event (AE, SAE, SADE, UADE, ADE and CEC 
events) … with associated treatment 
• 
For subjects in the Bicuspid Nested Registry, a computed 
tomography scan at 30 days post LOTUS Edge Valve implantation. 
Updated for clarity and 
to include CT 
assessment at 30 days 
for subjects enrolled in 
the Bicuspid Nested 
Registry. 
27 Appendices 
Added Section 27.1-1 and Table 27.1-1 
Updated for clarity 
C 
23-Sep-2018 
90702637 
Rev/Ver AG 
Page 1 
Sponsor: 
Boston Scientific… USA 
 Australian Representative 
Boston Scientific Pty. Ltd. 
Building 1, Level 6 
191 O’Riordan Street 
 Mascot, NSW 2020, Australia 
Added for Australian 
study centers in 
REPRISE IV 
Page 2 
Clinical Contacts 
Laoti Bussone 
Senior Clinical Trial Manager, Interventional Cardiology 
Boston Scientific Corporation 
100 Boston Scientific Way, Marlborough, MA  01752 USA 
Arjun M. Bhat  
Clinical Trial Manager, Structural Heart – Interventional Cardiology 
Boston Scientific Corporation 
100 Boston Scientific Way, Marlborough, MA  01752 USA 
New project managers  
Study Coordinating Principal Investigators 
New study coordinating 
principal investigators 

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Table 26.1-1: Protocol Revision History 
Revision 
Version 
Protocol 
Date 
Template 
Number and 
Version 
Protocol Sections 
Modified 
Summary of Changes 
Justification for 
Changes 
Interventional Cardiologist Study Co-Principal Investigator 
Ted Feldman, MD 
Evanston Hospital, North Shore University Health System 
Cardiology Division - Walgreen Building 3rd Floor 
2650 Ridge Avenue 
Evanston, IL 60201 USA 
Cardiac Surgeon Study Co-Principal Investigator 
Vinod H. Thourani, MD 
MedStar Heart & Vascular Institute 
MedStar Washington Hospital Center  
110 Irving St NW  
Washington, DC  20010 USA 
Current Version: 23-Sep-2018 
Updated revision history table 
Protocol revision 
Section 2 
Device Name/Size 
Description 
Updated for clarity to 
reflect use of 
commercial introducer 
sets. 
LOTUS Edge… 
Includes 2 main… 
- a bioprosthetic…(similar to the Lotus…) 
- a next… 
…introduced percutaneously via the femoral 
artery. 
iSleeve™ Introducer 
Set 
14 and 15 French (F) 
- a dilator... arteries ≥5.5 mm with the 14F 
sheath (to deliver the 23mm LOTUS 
Edge valve) and ≥5.9 mm with the 15F 
sheath… 
The iSleeve™ Introducer Set (iSleeve) and the large Lotus Introducer Set 
(LIS-L) can be used as accessories to facilitate vascular introduction and 
deployment of the LOTUS Edge Valve System (23mm, 25mm, or 27mm 
valve sizes). The iSleeve has an expandable sheath component and a 
dilator enabling access to transfemoral arteries ≥5.9 mm. The LIS-L is 
intended for use in subjects with femoral vascular access ≥6.5 mm. In 
countries where the introducer sets are approved, the commercial devices 

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will be used. In countries where they are not approved, they will be 
considered investigational devices. 
Comparator 
For the primary endpoint, a performance goal (PG) based on 1-year 
TAVR outcomes derived from published literature will be used as the 
comparator for analysis. 
Updated study design to 
single arm 
Section 2 
Study Design 
REPRISE IV is a prospective, multicenter single-arm study designed… 
subjects who have severe native aortic stenosis… Study cohorts include 
the following. 
- Main Cohort: A prospective, multicenter, single-arm cohort of 
subjects with severe aortic stenosis who are considered at intermediate 
risk for surgical aortic valve replacement and are treated with the 
LOTUS Edge Valve System. 
o CT Imaging Substudy: Selected centers with the ability to perform 
high quality 4D computed tomography (CT) scans will include 
subjects from the Main Cohort in a CT imaging substudy to assess 
the prevalence of reduced leaflet mobility and its relationship, if any, 
to clinical events. 
- Bicuspid Nested Registry: A prospective, single-arm, nested registry 
cohort of subjects who have a native bicuspid aortic valve and are 
considered at intermediate risk for surgical aortic valve replacement and 
are treated with the LOTUS Edge Valve System. 
- Roll-In Cohort: A roll-in phase with the study device for centers that do 
not have implantation…evaluable Main Cohort and Bicuspid Nested 
Registry. Data from roll-in subjects will be summarized separately from 
the evaluable Main Cohort … 
The REPRISE IV study will be conducted in accordance with 21 CFR 
Parts 11, 50, and 54; the relevant parts of the International Conference on 
Harmonisation (ICH) Guidelines for Good Clinical Practices (GCP); or 
the International Standard ISO 14155 Clinical Investigation of Medical 
Devices for Human Subjects – Good Clinical Practice; ethical principles 
that have their origins in the Declaration of Helsinki; and pertinent 
individual country/state/local laws and regulations. The study shall not 
begin until the required approval/favorable opinion from the Institutional 
Addition of a CT 
Imaging Substudy. 
 
Text updated for clarity 
(including addition of a 
new study design 
overview figure) 

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Review Board/Human Research Ethics Committee (IRB/HREC) and/or 
regulatory authority has been obtained, if appropriate. 
The study design is summarized in the figure below. 
 
 
REPRISE IV Study Design Overview 
Section 2 
Planned Number of 
Subjects/ 
Investigational 
Centers/ Countries 
Subjects will be enrolled at up to 50 centers in the United States and 
Australia. There will be up to 896 subjects enrolled in REPRISE IV as 
shown below. 
Updated study design 
(including addition of a 
CT Imaging Substudy) 
and addition of 
Australian investigative 
centers. 
Cohort 
Number of Subjects 
Randomized 
696* 
Bicuspid Nested 
Registry 
100 
Roll-In  
Up to 100 
* Up to 200 subjects from the main cohort will be enrolled in the CT 
Imaging Substudy. If 200 subjects have not enrolled in the CT Imaging 
Substudy by completion of enrollment in the main cohort, additional 
subjects who meet the REPRISE IV eligibility criteria will be enrolled in 
a separate CT Imaging Cohort to achieve a total of 200 subjects in the CT 
Imaging Substudy. 
Section 2 Primary 
Endpoint 
Composite of all-cause mortality and all stroke at 1 year 
Updated study design 
Roll-In
Subject
Enrollment*
Eligibility
Assessment
Index 
Procedure 
Case 
Review 
Committee
* Subjects are considered enrolled when an attempt is made to insert the LOTUS Edge Transfemoral Aortic Valve System into 
the femoral artery.
† Discharge or 7 days, whichever comes first
‡ Enrolled subjects who do not have a study device implanted will be assessed through 1 year post procedure for safety.
Clinical 
Assessment
Baseline
Clinical Follow-up‡
Main Cohort
(with CT Imaging 
Substudy)
1d 7d† 30d 1-5y
Subject 
meets
criteria
Subject 
eligibility
confirmed
Bicuspid 
Registry

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Section 2 
Secondary Endpoint  
No powered secondary endpoint 
Updated study design 
Section 2 
Additional 
Measurements 
Additional measurements… will be collected peri- and post-procedure, 
at discharge or 7 days post-procedure (whichever comes first), 30 days, 
6 months, and 1, 2, 3, 4, and 5 years post index procedure… 
-Neurological status as determined by the following: 
o Neurological physical exam at discharge… 
o National Institutes of Health Stroke Scale (NIHSS) and modified 
Rankin Scale (mRS) assessments, which must be performed at 
baseline and pre-specified timepoints for all enrolled subjects. NIHSS 
and mRS must be performed by a neurology professional or certified 
personnel.  
o For subjects diagnosed with a stroke, a neurological physical exam, 
mRS, and NIHSS must be performed after the event; mRS must also 
be administered at 90±14 days following a stroke; the simplified 
mRS questionnaire may be used for this follow-up assessment. The 
neurological physical exam must be conducted by a neurologist, 
neurology fellow, neurology physician assistant, or neurology nurse 
practitioner… 
- For subjects in the Bicuspid Nested Registry, a CT scan at 30 days post 
LOTUS Edge Valve implantation; the data will be evaluated by an 
independent CT core laboratory. 
- For subjects in the CT Imaging Substudy, a 4D CT scan at 30 days and 
at 1 year post LOTUS Edge valve implantation to assess the prevalence 
of reduced leaflet mobility and its relationship, if any, to clinical events. 
The data will be evaluated by an independent CT core laboratory. 
Note 1: For the LOTUS Edge valve, repositioning may be achieved with 
partial or full resheathing of the valve. 
Note 2: 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. 
Updated time points 
and measurements 
Section 2 
Main Cohort: Subjects with severe aortic valve stenosis who meet all 
eligibility criteria may be treated with the LOTUS Edge Valve System. 
Updated study design 

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Method of Assigning 
Subjects to Treatment 
-Up to 200 subjects from the main cohort will be enrolled in the CT 
Imaging Substudy. If 200 subjects have not enrolled in the CT 
Imaging Substudy by completion of enrollment in the main cohort, 
additional subjects who meet the REPRISE IV eligibility criteria will 
be enrolled in a separate CT Imaging Cohort to achieve a total of 200 
subjects in the CT Imaging Substudy 
Bicuspid Nested Registry: Subjects with a native bicuspid aortic valve 
who meet all inclusion criteria and have no other exclusion criterion 
may be treated with the LOTUS Edge Valve System as part of a single-
arm, nested registry cohort. 
Roll-In Cohort: For centers that do not have implantation experience 
with the LOTUS Edge Valve System at least 2 roll-in subjects will be 
treated before commencing enrollment in the Main Cohort and Bicuspid 
Nested Registry. 
Section 2 
Follow-up Schedule 
All subjects implanted with a study device will be assessed at baseline, 
peri- and post-procedure, at discharge or 7 days post-procedure 
(whichever comes first), 30 days, 6 months, 1 year, and then annually 
for up to 5 years post-procedure. Subjects who are enrolled but not 
implanted with a study device at the time of the procedure will be 
followed for safety through 1 year. 
Visits are to be an office/clinical visit but may be done in-hospital should 
the subject be admitted at the time. Procedures at each scheduled visit are 
described above under “Additional Measurements.” 
Text updated for clarity 
Section 2 
Study Duration 
Subjects implanted with a study device will be followed for 5 years after 
the index procedure. 
Enrollment is expected to be completed in approximately 12 months; 
therefore, the total study duration is estimated to be approximately 6 
years. 
Section 2 
Participant Duration 
The study duration for each subject is expected to be approximately 5 
years. 
Section 2 
Adjunctive 
Pharmacologic 
Therapy 
Anti-Platelet Therapy 
Per society guidelinesb, antiplatelet therapy with aspirin and a P2Y12 
inhibitor (clopidogrel recommended) is recommended after TAVR to 
decrease the risk of thrombotic or thromboembolic complications if 
there are no contraindications to these medications. 
Updated to reflect 
current therapy 
recommendations 

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P2Y12 Inhibitor (clopidogrel recommended) 
A loading dose of a P2Y12 inhibitor (recommended dose of ≥300 mg for 
clopidogrel, 60 mg for prasugrel, 180 mg for ticagrelor) is required for 
subjects who have not been on P2Y12 inhibitor therapy for ≥72 hours at 
the time of the index procedure. The loading dose must be administered 
prior to the implant procedure. 
After the valve implant procedure, a P2Y12 inhibitor is required for at 
least 1 month (clopidogrel is recommended with a dose of 75 mg daily). 
Note 3: If a subject requires chronic anticoagulation, either a P2Y12 
inhibitor (clopidogrel recommended) or aspirin is required prior to and 
after the implant procedure in addition to the anticoagulant therapy (but 
both aspirin and a P2Y12 inhibitor are not required). After the implant 
procedure, the subject must be treated with an oral anticoagulant 
(warfarin or another vitamin K antagonist recommended) and either a 
P2Y12 inhibitor (clopidogrel recommended) or aspirin for at least 1 
month.   
b: Holmes DR, et al. J Am Coll Cardiol. 2012;59:1200–1254 
Nishimura R, et al. J Am Coll Cardiol. 2014;63: e57–e185 
Nishimura R, et al. Circulation. 2017;135:e1159–e95 
Section 2 
Inclusion Criteria 
IC2. A subject in the Bicuspid Aortic Valve Nested Registry cohort 
must have a documented Sievers Type 02 or Sievers Type 1 bicuspid 
valve based on… 
IC3.Subject … Committee [CRC]) and, for the randomized cohort, is 
deemed treatable with an available size of both test and control device. 
IC5. Heart team (which must include an experienced cardiac 
interventionalist and an experienced cardiac surgeon) agrees that the 
subject is at intermediate risk of operative mortality (≥3% and <8% at 
30 days based on the Society of Thoracic Surgeons risk score and other 
clinical comorbidities unmeasured by the risk calculator) and TAVR is 
appropriate. 
IC6.   Heart team (which must include a cardiac interventionalist and an 
experienced cardiac surgeon) agrees that the subject is likely to benefit 
from valve replacement.  
Updated for clarity 

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IC7.  Subject (or legal representative) has been informed of 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. 
IC9. Subject is expected to be able to take the protocol-required 
adjunctive pharmacologic therapy. 
Section 2 
Exclusion Criteria 
EC1. Subject has a unicuspid or bicuspid aortic valve (not applicable to 
subjects in the Bicuspid Nested Registry cohort). 
Note 6: Subjects in the Bicuspid Nested Registry cohort will have a 
documented Sievers Type 02 or Sievers Type 1 bicuspid valve based on 
CT assessment and confirmed by the CT core lab. Subjects are not 
eligible for inclusion in the Bicuspid Nested Registry cohort if the 
maximum diameter of the ascending aorta is >45 mm or if the subject 
has another indication for aortic root replacement. Subjects with a 
Sievers Type 2 bicuspid valve are not eligible for enrollment in any 
study cohort. 
EC4. Subject is on renal replacement therapy or has GFR <20 (based on 
Cockcroft-Gault formula). 
EC7. Subject has moderate to severe mitral stenosis (mitral valve area 
≤1.5 cm2 and diastolic pressure half-time ≥150 ms, Stage C or Dc). 
EC8. Subject has a need for emergency surgery for any reason. 
EC9. Subject has a history of endocarditis within 6 months of index 
procedure or evidence of an active systemic infection or sepsis. 
EC10. Subject has echocardiographic evidence of new intra-cardiac 
vegetation or intraventricular or paravalvular thrombus requiring 
intervention. 
EC11. Subject has platelet count <50,000 cells/mm3 or >700,000 
cells/mm3, or white blood cell count <1,000 cells/mm3. 
EC12. Subject has had a gastrointestinal bleed… 
EC16. Subject has any therapeutic invasive cardiac or vascular 
procedure within 30 days prior to the index procedure (except for 

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balloon aortic valvuloplasty or pacemaker or implantable cardioverter 
defibrillator implantation, which are allowed). 
EC20. Subject has arterial access that is not acceptable for the study 
device (test or control) delivery systems as defined in the device (test or 
control) Instructions For Use. 
EC22.Subject has current problems with substance abuse (e.g., alcohol, 
etc.) that may interfere with the subject’s participation in this study. 
c: Nishimura RA, et al. J Am Coll Cardiol. 2014;63:e57–e185 
Section 2 
Additional Exclusion 
Criteria 
Additional exclusion criteria apply to subjects considered for enrollment 
in the CT Imaging Substudy as listed below. 
AEC1.  Subject has eGFR <30 mL/min (chronic kidney disease stage IV 
or stage V). 
AEC2.  Subject has atrial fibrillation that cannot be rate controlled to 
ventricular response rate < 60 bpm. 
AEC3. Subject is expected to undergo chronic anticoagulation therapy 
after the index procedure. 
Note 7: Subjects treated with short-term anticoagulation post procedure 
can be included in the imaging substudy; in these subjects the 30-day 
imaging will be performed 30 days after discontinuation of 
anticoagulation. 
Added for the CT 
Imaging Substudy 
Section 2  
Analysis Sets 
Analysis sets are listed below. 
- Intention-To-Treat (ITT): This population includes all subjects who 
sign an Informed Consent Form and are enrolled in the study and are 
randomized, regardless of whether the study device is implanted. 
 
- Implanted: This population includes all subjects who sign an Informed 
Consent Form, are enrolled in the study, and are implanted with the 
assigned, randomized study device. 
A subject is considered enrolled in the study when an attempt is made to 
insert a LOTUS Edge Valve. 
Updated study design 
Section 2 
Primary Endpoint 
Statistical Hypothesis 
In the Main Cohort, the rate of the primary endpoint (composite of all-
cause mortality and all stroke at 1 year) is less than the performance goal 
(PG) of 15.2% (expected rate of 11.1% plus testing margin of 4.1%). 
 

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Section 2 
Statistical Test 
Method for the 
Primary Endpoint  
A one-sample z test will be used to test the one-sided hypothesis that the 
1-year composite primary endpoint rate for LOTUS Edge in the Main 
Cohort is less than the PG: 
H0: PLOTUS Edge ≥ PG 
H1: PLOTUS Edge < PG 
where PLOTUS Edge is the primary endpoint rate for the LOTUS Edge 
group and PG is the performance goal. 
The primary analysis set for the primary endpoint is the ITT analysis set. 
This endpoint will also be analyzed for the implanted analysis set. 
 
Section 2 
Sample Size 
Parameters for the 
Primary Endpoint 
The sample size calculation for the primary endpoint (composite of all-
cause mortality and all stroke at 1 year) is based on the following 
assumptions. 
• Expected rate for LOTUS Edge = 11.1%† 
• Testing margin = 4.1% (37% relative to the expected rate) 
• Performance goal (PG) = 15.2% (expected rate of 11.1% plus testing 
margin of 4.1%) 
• Test significance level (α) = 0.025 (1-sided) 
• Power  = 87.5%  
• Number of evaluable subjects = 675 
• Expected rate of attrition = 3% 
• Total enrolment (evaluable Main Cohort) = 696 subjects  
† Estimated pooled rate from the fixed/random effects model based on the 
ITT TAVR arm data from PARTNER II S3ie and SURTAVIf 
e: Thourani VH, et al. Lancet 2016;387:2218-25 
f: Reardon MJ, et al. N Engl J Med 2017:376:1321-31 
 
Section 2 
Success Criteria for 
the Primary Endpoint 
If the P value from the one-sample z-test is <0.025, it will be concluded 
that the primary endpoint with the LOTUS Edge Valve System is less 
than the PG. This corresponds to the one-sided upper 97.5% confidence 
bound of the observed composite rate of all-cause mortality and all stroke 
in the Main Cohort at 1 year being < 15.2%. 
 
Section 2, Statistical 
Test Method Primary 
Endpoint–Superiority 
— 
Updated study design; 
there is no statistical 
test for superiority for 

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Section 2, Sample 
Size Parameters 
Primary Endpoint ‒ 
Superiority 
— 
the primary endpoint 
and there is no 
secondary endpoint 
Section 2, Success 
Criteria Primary 
Endpoint–Superiority 
— 
Section 2, Secondary 
Endpoint Statistical 
Hypothesis 
— 
Section 2, Statistical 
Test Method 
Secondary Endpoint 
— 
Section 2, Sample 
Size Parameters 
Secondary Endpoint 
— 
Section 2, Success 
Criteria Secondary 
Endpoint 
— 
Section 2 
Bicuspid Nested 
Registry 
The planned enrollment for the Bicuspid Nested Registry cohort is up to 
100 subjects. Descriptive statistics for all endpoints will be summarized 
using both the ITT and implanted analysis sets. 
Updated study design 
and for clarity 
Section 4 
Introduction 
The LOTUS Edge Valve System is introduced into the body using either 
the investigational iSleeve™ Introducer Set or the large Lotus 
Introducer Set. Both sets … 
Study subjects will be entered into the Roll-In Cohort, single-arm Main 
Cohort, or… 
Section 4.1.1 
Treatments… 
The incidence of aortic stenosis… 
Many patients with severe and symptomatic aortic stenosis are 
successfully treated with surgical aortic valve replacement (SAVR), 
which can reduce symptoms… 
Propensity score analyses have suggested comparable mortality after 
TAVR or SAVR in some intermediate-risk patients… and 2 recent 
randomized, controlled trials (RCT) showed similar outcomes between 
Additional literature 
references 

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the two treatment groups… Meta-analyses have also shown similar 
long-term survival after TAVR compared to SAVR… Currently, TAVR 
is approved for use in AS patients considered inoperable or at 
intermediate to high surgical risk and expert consensus documents have 
outlined TAVR patient selection criteria...   
 
Added data from the following studies to Table 4.1-1: 
SURTAVI, REPRISE III, CoreValve Extreme Risk Study, EVOLUT R 
US Study, PORTICO Pre-CE Mark Study 
 
…Placement in a heavily calcified native valve can produce an 
incomplete seal between the bioprosthetic valve and aortic annulus, 
resulting in PVR, which in turn has been associated with increased 
mortality in some studies... The impact of mild PVR is less clear… recent 
meta-analysis suggested that mild PVR may also be associated with 
increased all-cause and cardiovascular mortality... 
The Lotus™ Valve System was… 
REPRISE IV will evaluate safety… 
Section 4.1.2 
REPRISE Clinical 
Program 
Described below are results from studies that have reached their primary 
endpoints…   
Added REPRISE III results to Table 4.1-1 
Added REPRISE III 
results to Table 4.1-1 
Section 4.1.2.1 
REPRISE I Study 
… The device was successfully implanted in all 11 subjects but there was 
a device failure in 1 subject based on not meeting one of four VARC-1 
criteria for device success a mean gradient of 22 mmHg. Ten (10)… 
Table 4.1-2 shows clinical and echocardiographic outcomes to the end of 
the study (5 years). Valve function was excellent with minimal PVR and 
low clinical event rates. The results of the REPRISE I feasibility study 
support the safety and performance of the Lotus Valve System. 
Added new Table 4.1-2: Outcomes to 5 Years in REPRISE I 
Data updated from 3 
years to 5 years 
Section 4.1.2.2  
REPRISE II Study 
… Table 4.1-4 shows 30-day, 1-year, 2-year, 3-year, 4-year, and 5-year 
clinical and echocardiographic outcomes. Mortality at 30 days, 1 year, 
and 5 years was 4.2%, 11.0%, and 42.6%, respectively; the disabling 
stroke rate was 1.7%, 3.5%, and 7.0%. Mean aortic valve pressure 
gradient remained low at 12.58±5.66 mmHg (1 year) and 
Data updated to 5 years 
in the Main Cohort and 
4 years in the Full 
Cohort 

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14.43±6.44 mmHg (5 years). There were no repeat procedures for valve-
related dysfunction through 5 years. Core lab assessment of PVR at 
30 days indicated no severe regurgitation and 1 case of moderate 
regurgitation; in 83.3% (80/96) of subjects there was trace/trivial or no 
PVR. The low PVR rate observed at 30 days was maintained at 1 year 
(89% with none/trivial PVR) and out to 5 years (80% with none/trivial 
PVR). The observed… 
Table 4.1-4: Clinical and Echocardiographic Outcomes to 5 Years – 
REPRISE II Main Cohort (N=120) updated with data at 3 years, 4 
years and 5 years 
Table 4.1-5 shows device performance endpoints, clinical outcomes, and 
echocardiographic outcomes through 4 years for the full…  
…independent predictor of both. A recent meta-analysis suggested that 
mild PVR may also be associated with increased all-cause and 
cardiovascular mortality. The low PVR rate observed at 30 days with 
Lotus was maintained at 1 year and 4 years as most subjects (91% and 
88%, respectively) had none/trace/trivial PVR, 2 subjects had moderate 
PVR at 4 years, and there was no severe PVR. 
Table 4.1-5: Clinical and Echocardiographic Outcomes to 4 Years ‒ 
REPRISE II Full Cohort (N=250) updated with data at 2 years, 3 years, 
and 4 years. 
Section 4.1.2.3 
RESPOND Post-
Market Surveillance 
Study 
… Data through 30-day and 1-year follow-up are provided below… 
Table 4.1-7 shows secondary safety endpoint outcomes assessed at 30 
days and 1 year in the RESPOND as-treated analysis set. At 30 days, 
all-cause mortality was 2.2%, in-hospital mortality was 1.8%, and 
disabling stroke was 2.3%. Mortality was 11.7% and disabling stroke 
was 4.0% at 1 year. Table 4.1-8 shows core laboratory TTE assessments 
pre-discharge and at 1 year in the as-treated analysis set. Mean aortic 
gradient improved significantly (P<0.0001) from 38.0±15.5 mmHg at 
baseline to 10.8±4.6 mmHg at discharge and remained low at 1 year 
(10.8±5.1 mmHg, P<0.0001). There was also a significant (P<0.0001) 
improvement in mean effective orifice area (EOA) from 0.7±0.2 cm2 at 
baseline to 1.8±0.5 cm2 at discharge, which was sustained at 1 year 
(1.8±0.4 cm2, P<0.0001). There were no cases of severe PVR at 
discharge or 1 year. There were 3 cases of moderate PVR at discharge 
Data updated from 30 
days to 1 year, add 
RESPOND Extension 

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and 2 cases (0.4%) at 1 year; in >90% of evaluable subjects PVR was 
trivial or absent. 
Table 4.1-7: RESPOND Secondary Endpoints – VARC Safety 
Assessments at 30 Days and 1 Year Post-Procedure; As-Treated 
Analysis Set updated with data at 1 year 
Table 4.1-8: Core Laboratory Echocardiographic Assessments at 
Pre-Discharge and 1 Year, RESPOND As Treated Analysis Set 
updated with data at 1 year 
After enrollment of the main RESPOND cohort was completed the 
study was extended to enroll an additional cohort (RESPOND 
Extension) to assess center-driven implantation technique with the 
commercially available Lotus Valve System with Depthguard™ 
technology. Depthguard results in a slightly decreased rate of retraction 
of the outer sheath during valve deployment. This minimizes interaction 
between the frame and the LVOT during deployment and could limit the 
need for PPM implantation. 
Table 4.1-10 shows clinical outcomes at 30 days and echocardiographic 
outcomes at pre-discharge. Mortality and disabling stroke were 0.0% 
and 2.0%, respectively, and new PPM implantation was 18.0%. There 
were no cases of moderate or severe PVR; in 86% of cases PVR was 
trivial or absent. 
Added Table 4.1-10: RESPOND Extension – VARC Safety 
Assessments (30 Days) and Core Lab Echocardiographic 
Assessments (Pre-Discharge); As-Treated Analysis Set 
In summary, the observed 30-day and 1-year outcomes among 
RESPOND subjects and 30-day outcomes in RESPOND Extension 
show good hemodynamic results, a very low PVR rate, low mortality, 
and overall favorable event rates. There also were no significant 
differences in pre-discharge echocardiographic or 30-day clinical 
outcome measures between subjects with and without a native bicuspid 
valve. The results from this study have demonstrated that the 
commercially available Lotus Valve System is a safe and effective 

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treatment for subjects with severe calcific aortic stenosis in routine 
clinical practice. 
4.1.2.4 REPRISE III 
Randomized 
Controlled Trial 
The REPRISE III pivotal study (REpositionable Percutaneous 
Replacement of Stenotic Aortic Valve through Implantation of Lotus™ 
Valve System – Randomized Clinical Evaluation; NCT02202434) 
includes a prospective, multicenter, randomized, controlled trial (RCT) 
designed to evaluate the safety and effectiveness of the Lotus™ Valve 
System (23mm, 25mm, or 27mm valve; test device) compared to a 
commercially available self-expanding transcatheter heart valve 
(CoreValve® device, Medtronic Corp, Dublin, Ireland; 26mm, 29mm, 
and 31mm valve; control device) in symptomatic subjects with severe 
calcific aortic stenosis who are considered extreme or high risk for 
surgical valve replacement. There were 912 subjects randomized at 55 
centers in the United States, Germany, France, Australia, The 
Netherlands, and Canada. Subjects were considered enrolled in the study 
upon randomization. Clinical follow-up will extend through 5 years. The 
trial included independent core laboratory analysis and independent 
event adjudication with data validated by independent statisticians. 
The 30-day primary safety composite endpoint for REPRISE III 
includes all-cause mortality, stroke, life-threatening and major bleeding 
events, stage 2 or 3 acute kidney injury, and major vascular 
complications. The primary effectiveness endpoint for noninferiority 
includes the combined rate of mortality, disabling stroke, and 
moderate/severe PVR at 1 year post implant procedure. Other 
measurements incorporated the minimum data collection and endpoints 
recommended and defined by the VARC guidelines. Subject screening, 
data collection, and event assessments were as described for REPRISE 
II (Section 4.1.2.2). Data for the primary endpoint in the RCT have been 
published44. 
A total of 607 subjects were randomized to the Lotus group and 305 
were randomized to the CoreValve group (ITT analysis set). Subject 
analysis groups are shown in Figure 4.1 1. The first-generation Lotus 
Valve System was used throughout the study while the second-
generation CoreValve Evolut R device was introduced mid-way in the 
study. Thus, in the implanted analysis set of the CoreValve treatment 
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group 51.5% of subjects received CoreValve and 48.5% received 
CoreValve Evolut R (153/297 and 144/297, respectively). 
Added new Figure 4.1-1: REPRISE III Randomized Subject 
Analysis Groups 
The REPRISE III primary safety endpoint was met because in the 
implanted analysis set the rate for the Lotus group (20.3%) was non-
inferior to the rate for the CoreValve group (17.2%). Non-inferiority 
was concluded because the one-sided upper 97.5% confidence bound on 
the difference between treatment groups (Lotus minus CoreValve; 
3.1%) was less than the non-inferiority margin of 10.5% with a P value 
<0.025 (P=0.0027). Non-inferiority was also shown for the ITT and as-
treated analysis sets. 
The primary effectiveness endpoint was met because in the implanted 
analysis set the rate for Lotus group (15.4%) was non-inferior to the rate 
for CoreValve (25.5%). Non-inferiority was concluded because the one-
sided upper 97.5% confidence bound on the difference between 
treatment groups (Lotus minus CoreValve; -4.41%) was less than the 
non-inferiority margin of 9.5% with a P value <0.025 (P <0.0001). Non-
inferiority was also shown for the ITT and as-treated analysis sets. The 
rate of the primary effectiveness endpoint for Lotus was shown to be 
superior to that for CoreValve in the ITT analysis set (P=0.0006) and 
also in the implanted and as-treated analysis sets. 
Table 4.1 11 shows clinical and echocardiographic outcomes at 30 days 
and 1 year. The following were similar between the 2 cohorts:  
• All-cause mortality in the CoreValve arm and Lotus arm was 2.3% and 
2.5%, respectively (P =0.86), at 30 days and 13.5% and 11.9%, 
respectively (P=0.51), at 1 year.  
• Cardiovascular mortality was 2.3% (CoreValve) and 2.3% (Lotus, 
P=0.99) at 30 days and 9.8% (CoreValve) and 7.7% (Lotus, P=0.29) at 
1 year. 
• The overall stroke rate in the CoreValve and Lotus cohorts was 4.3% 
and 4.8%, respectively (P=0.72), at 30 days and 9.4% and 7.0%, 
respectively (P=0.20), at 1 year. 

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• The rate of major vascular complications was 5.3% (CoreValve) and 
7.0% (Lotus, P=0.32) at 30 days and 6.1% (CoreValve) and 7.7% 
(Lotus, P=0.38) at 1 year. 
• Life-threatening/disabling bleeding was 5.0% (CoreValve) and 8.0% 
(Lotus, P=0.09) at 30 days and 9.8% (CoreValve) and 9.9% (Lotus, 
P=0.96) at 1 year. 
The following were statistically significantly different between the 2 
cohorts: 
• The disabling stroke rate in the CoreValve and Lotus cohorts was 
3.3% and 2.0%, respectively (P=0.23), at 30 days and 7.1% and 3.6%, 
respectively (P=0.02), at 1 year. 
• The rate of permanent pacemaker implantation among subjects without 
a prior pacemaker was 19.6% (CoreValve) and 35.5% (Lotus, P <0.001) 
at 30 days and 23.0% (CoreValve) and 41.4% (Lotus, P <0.001) at 1 
year. 
• The valve thrombosis rate was 0.0% for both cohorts at 30 days; it was 
0.0% (CoreValve) and 1.5% (Lotus, P=0.03) at 1 year.  
• Repeat procedures for prosthetic valve-related dysfunction occurred in 
1.0% of CoreValve subjects and 0.0% of Lotus subjects at 30 days 
(P=0.04) and 2.0% (CoreValve) and 0.2% (Lotus) by1 year (P=0.007). 
• Prosthetic valve malpositioning (including valve migration, valve 
embolization, and ectopic valve deployment to discharge/7 days) 
occurred in 2.6% of subjects in the CoreValve group and 0.0% of 
subjects in the Lotus group (P<0.001). 
• TAV-in-TAV deployment occurred in 3.0% of subjects in the 
CoreValve group and in no subjects in the Lotus group (P<0.001). 
• Mean gradient was significantly lower and EOA was significantly 
higher in the CoreValve group at discharge and beyond (both P <0.001). 
• There was significantly less PVR with Lotus compared to CoreValve 
at all time points (P<0.001). 
Added new Table 4.1-11: Clinical and Echocardiographic Outcomes 
at 30 Days and 1 Year in REPRISE III RCT 
In conclusion, in this large (N=912) randomized comparison of two 
different types of TAVR platforms, the Lotus Valve System was non-

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inferior to the commercially available CoreValve for the composite 
primary safety endpoint at 30 days. Lotus showed superiority for the 
composite primary effectiveness endpoint at 1 year, driven by 
significantly fewer disabling strokes (3.6% vs 7.1%, P=0.02) and 
significantly less moderate or severe PVR (0.9% vs 6.9%, P<0.0001; 
core lab determination). The frequency of overall stroke at 1 year was 
7.0% with Lotus and 9.4% with CoreValve; the repositionability of 
Lotus did not lead to a higher stroke rate compared to CoreValve. 
Recently reported 1-year stroke rates include 5.6% among high-risk 
subjects in the adjudicated SAPIEN 3 registry and 8.8% and 12.6% 
among TAVR and SAVR subjects, respectively, in the U.S. CoreValve 
High Risk Study. Lower stroke rates have been reported in lower-risk 
subject groups. Moderate or greater PVR has been associated with an 
increased risk of mortality. The impact of mild PVR is less clear 
although a recent meta-analysis suggested that mild PVR may also be 
associated with increased all-cause and cardiovascular mortality. 
Reported rates for moderate or greater PVR with newer generation 
devices have ranged from 1.5% with the balloon-expandable SAPIEN 3 
valve to 5.3% with Evolut R with lower rates in intermediate compared 
to high risk subjects. 
There were more new pacemaker implantations (41.4% vs 23.0%, 
P<0.0001 among subjects without a prior pacemaker) at 1 year with 
Lotus. Pacemaker implantation is associated with subject morbidity and 
increased cost (including repeat hospitalization) but has not been 
associated with decreased survival in other studies of high risk subjects. 
A recently published meta-analysis found that subjects with and without 
PPM post TAVR had similar rates for all-cause mortality, 
cardiovascular mortality, MI, and stroke at 30 days and 1 year. This 
analysis did show that improvement in LVEF was significantly greater 
in subjects without PPM. Valve thrombosis was uncommon but there 
were significantly more cases, as defined by VARC criteria, with Lotus 
(1.5% vs. 0%, P=0.03). Most were identified based on increased mean 
aortic gradient at protocol-directed follow-up echocardiography and all 
showed a decrease in mean gradient after anticoagulation therapy. These 
results are consistent with a recent registry report based on CT showing 
subclinical leaflet thrombosis rates of 4% with surgical valves and 12% 

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with TAVR valves and suggesting that the supra-annular CoreValve 
may have a lower rate compared to TAVR valves with an annular 
location (CoreValve/Evolut R: 6%; Lotus: 14%; Edwards [Sapien, 
SAPIEN XT, and SAPIEN 3]: 14%; Portico: 30%). A recent single-
center retrospective analysis (281 balloon-expandable, 305 self-
expanding, 56 Lotus) found an overall incidence of 2.8% for clinical 
valve thrombosis. Reported rates were 4.6% for SAPIEN valves, 1.0% 
for CoreValve/Evolut R, and 3.6% for Lotus. At 1 year, valve 
malpositioning, repeat procedures, and TAV-in-TAV deployment were 
all less common with Lotus. The observed rate of TAV-in-TAV with 
CoreValve was 2.3%; rates of TAV-in-TAV with CoreValve in prior US 
pivotal CoreValve trials have ranged from 1.3% to 6.7%. 
Overall, outcomes in the REPRISE III RCT support the safety and 
efficacy of the Lotus Valve System. 
4.1.2.5 REPRISE 
Japan 
The objective of the REPRISE Japan clinical trial (REpositionable 
Percutaneous Replacement of Stenotic Aortic Valve through 
Implantation of Lotus™ Valve System – Clinical Evaluation in Japan; 
NCT02491255) was to confirm the safety and effectiveness of the 
Lotus™ Valve System in the Japanese medical environment for TAVR 
in symptomatic subjects with calcific, severe native aortic stenosis 
considered at high or extreme risk for SAVR. The 30-day primary safety 
composite endpoint includes all-cause mortality, stroke, life-threatening 
and major bleeding events, stage 2 or 3 acute kidney injury, and major 
vascular complications. The primary effectiveness endpoint is a 
composite at 6 months of all-cause mortality and disabling stroke and 
moderate or greater PVR based on core lab assessment. Other 
measurements incorporated the minimum data collection and endpoints 
recommended and defined by the VARC guidelines. Subject screening, 
data collection, and event assessments were as described for REPRISE 
II (Section 4.1.2.2). 
There were 40 evaluable subjects enrolled at 5 centers in the 
transfemoral arm of REPRISE Japan. The primary safety composite 
endpoint rate was 15.0% (6/40) at 30 days and the primary effectiveness 
composite endpoint was 5.3% (2/38) at 6 months. Table 4.1-12 shows 
clinical and echocardiographic outcomes at 30 days, 6 months, and 1 
year. Mortality through 1 year was low (7.5%) as was disabling stroke 
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(2.5%). There was no moderate or severe PVR. Overall, outcomes were 
similar to that seen with Lotus in REPRISE II (Section 4.1.2.2) and 
REPRISE III (Section 4.1.2.4) and demonstrated consistent safety and 
effectiveness results with the Lotus Valve System in Japanese subjects. 
Added new Table 4.1-12: 30-Day, 6-Month, and 1-Year Outcomes – 
REPRISE Japan  Evaluable Transfemoral Cohort (N=40) 
Section 4.1.2.6 
REPRISE NGDS 
Study 
… evaluating a modified version of the delivery system that was studied 
in REPRISE I, REPRISE II, REPRISE III, and RESPOND. 
…compatibility with the LOTUS Edge device. A third cohort (Cohort 
C) subsequently enrolled 21 subjects who were treated with a further 
refined version of the LOTUS Edge delivery system. In some Cohort C 
subjects a further refined version of the iSleeve Introducer was used. 
The primary endpoint in REPRISE NG DS… 
The primary endpoint was achieved in 10/10 subjects in Cohort A, 5/7 
in Cohort B (in 1 subject a valve was not implanted and in 1 subject a 
valve was implanted using the current Lotus Valve System), and 21/21 
in Cohort C. Table 4.1-13 shows core lab analyses of prosthetic valve 
performance as assessed by TTE at discharge/7 days post procedure 
(secondary endpoint) and valve function at 30 days and 1 year for the 3 
cohorts. In all cohorts, mean aortic valve area and mean gradient 
improved at discharge and remained improved at 30 days and 1 year. 
There were no cases of moderate or severe PVR at discharge, 30 days, 
or 1 year in any cohort; the majority of patients had no PVR or trace 
PVR at all time points. Table 4.1-14 shows rates of CEC-adjudicated 
VARC-defined events through discharge/7 days, 30 days, 6 months, and 
1 year. In Cohort A, one subject experienced the majority of events and 
subsequently died on day 13 post implant. In Cohort B, events were 
minimal. In Cohort C, new permanent pacemakers were placed in 2 
subjects by 1 year for a rate of 9.5% (2/21) among all subjects and 
11.1% (2/18) among subjects without a prior pacemaker. In summary, 
outcomes to 1 year in the REPRISE NG DS study demonstrate 
acceptable performance and safety of the Lotus Valve with the next 
generation delivery system. 
Update previous data 
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Updated Table 4.1-13: Valve Performance by TTE, Core Lab 
Analysis – REPRISE NG DS Cohorts A, B and C with data at 1 year 
and Cohort C data 
Updated Table-4.1-14: Discharge, 30-Day, 6-Month, and 1-Year 
Clinical Outcomes in REPRISE NG DS Cohorts A, B and C with data 
at 6 months and 1 year and Cohort C data 
4. 1.2.7 REPRISE 
EDGE 
The prospective, single-arm REpositionable Percutaneous Replacement 
of NatIve StEnotic Aortic Valve through Implantation of LOTUS EDGE 
Valve System – Evaluation of Performance and Safety study (REPRISE 
EDGE; NCT02854319; N=15) has the same overall study design as 
REPRISE NG DS (Section 4.1.2.5) and assessed acute performance and 
safety of the same LOTUS Edge design that was used in Cohort C. The 
primary endpoint was the mean aortic valve pressure gradient at 
discharge as measured by echocardiography and assessed by an 
independent core laboratory. Secondary endpoints included technical 
success and device performance peri- and post-procedure based in part 
on VARC criteria. 
At discharge, the mean aortic gradient was 14.4±4.1 mmHg (N=15). 
Technical success was 100% and all attempts at repositioning or 
retrieving the valve were successful, and there was no moderate or 
severe PVR at discharge. Table 4.1 15 shows clinical and 
echocardiographic outcomes at 30 days and 1 year. There was no 
mortality and 1 disabling stroke through 1 year; PPM were placed in 2 
subjects by 30 days for a rate of 13.3% among subjects without a prior 
PPM. Mean aortic valve area and mean gradient were improved at 30 
days and 1 year with no moderate or severe PVR. Overall, outcomes 
with LOTUS Edge are consistent with outcomes observed in REPRISE 
II/II Extension and REPRISE III and with other TAVR studies using the 
VARC metrics. 
Added Table 4.1-15: 30-Day, and 1-Year Outcomes – REPRISE 
EDGE (N=15) 
Addition of new study 
data 
Section 4.2 
Justification for the 
Study 
Because the investigational device, the LOTUS Edge Valve System, 
consists of essentially the same pre-loaded, stent-mounted tissue valve 
prosthesis as the Lotus Valve System evaluated in the REPRISE I, 
REPRISE II, REPRISE III, REPRISE Japan, and RESPOND studies but 
Updated to mention 
additional REPRISE 
studies and for clarity 

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with a catheter delivery system designed for improved deliverability 
(evaluated in the REPRISE NG DS and REPRISE EDGE studies) the 
anticipated benefits and risks are very similar. 
… Like the Lotus Introducer, the investigational iSleeve Introducer 
Set…   
Section 5 
Investigational Device Description 
The investigational LOTUS Edge™ Valve System is intended to 
improve aortic valve function for symptomatic subjects with severe 
aortic stenosis who are at intermediate risk for standard surgical aortic 
valve replacement (SAVR), including those who have a bicuspid native 
valve.  
Change in study design 
to a single-arm study 
(no control device) 
Section 5.1 
LOTUS Edge Valve System 
Figure 5.1-1: Overview of Principal Components of the LOTUS 
Edge Valve System – updated with a newer picture 
Figure 5.1-2: LOTUS Edge Valve Implant – updated with a newer 
picture 
The controller assembly is shown in Figure 5.1-3 (locked configuration 
in the top image) and Figure 5.1-4 (controller door pulled forward). 
Figure 5.1 3: LOTUS Edge Controller  
Top: Locked configuration. Bottom: Door pulled forward allowing the 
valve to be released 
The large Lotus Introducer Set or, when available, the iSleeve Introducer 
Set (Figure 5.1-4) will be used as an accessory to the LOTUS Edge 
Valve System during the procedure. In countries where the introducer 
sets are approved, the commercial devices will be used. In countries 
where they are not approved, they will be considered investigational 
devices. They both include a dilator and an introducer sheath with a 
hydrophilic coating that, when activated, increases the lubricity of the 
surface to aid in delivery. The small Lotus Introducer… The large Lotus 
Introducer is intended for use with the 23mm, 25mm, or 27mm LOTUS 
Edge valve in subjects with femoral vascular access ≥6.5 mm. The sheath 
component of the iSleeve is expandable, which allows for transient 
sheath expansion during delivery system introduction. Temporary 
Updated device 
pictures; slight change 
in description of 
iSleeve; removal of the 
small Lotus Introducer 
set 

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expansion of the access vessel reduces the time the access vessel is 
expanded during device introduction and therefore potentially reduces 
vessel trauma. The 14F iSleeve Introducer Set… The 15F iSleeve is 
capable of introducing the 23mm, 25mm and 27mm LOTUS Edge valve 
sizes into subjects with femoral vascular access ≥5.9 mm. 
5.2 Edwards SAPIEN 
3… (Control) 
The control device is… 
(section removed) 
Study design change to 
single-arm version 
5.3 Device Labeling 
5.2 Device Labeling 
The study Manual of Operations includes the IFUs for the LOTUS Edge 
Valve System and, when available, the iSleeve… 
The IFU for the large Lotus Introducer Set will also be provided in the 
study Manual of Operations. The label will also include the above, with 
the exception of the investigational device statement for countries where 
the device is commercially available…   
5.3.2 Control Device 
Information… 
Updated for clarity; 
removed reference to 
control device because 
this is now a single-arm 
study 
7. Study Endpoints 
Outcomes will be assessed on an intention-to-treat (ITT) basis and an 
implanted basis and an as-treated basis. The ITT analysis population 
includes all subjects who sign the Informed Consent Form (ICF; see 
Section 21) and are enrolled in the trial (see Section 10.1 for point of 
enrollment) and are randomized regardless of whether a study device 
valve is implanted. The implanted analysis population includes ITT 
subjects who are implanted with the study valve. The as-treated 
population… Endpoint definitions can be found in Table 26.2-1. 
Text updated for clarity 
with updated study 
design 
Section 7.1 Primary 
Endpoint 
The primary endpoint is a composite of all-cause mortality and all stroke 
and mild or greater paravalvular aortic regurgitation (PVR; based on core 
lab assessment) at 1 year… 
Updated for the single 
arm design 
Section 7.2 
Secondary Endpoint 
— 
(section removed) 
Section 7.3 
Additional 
Measurements 
7.2 Additional Measurements 
Additional measurements… will be collected peri- and post-procedure, 
at discharge or 7 days post-procedure (whichever comes first), 30 days, 
6 months, and 1, 2, 3, 4, and 5 years post index procedure… 
-Neurological status (see Note 5 below) as determined by the following: 
Text updated for clarity 
and addition of CT 
Imaging Substudy 

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o Neurological physical exam…  
o National Institutes of Health Stroke Scale (NIHSS; performed by a 
neurology professional or certified personnel) at discharge and 1 year 
o and modified Rankin Scale (mRS) assessments, which must be 
performed at baseline and pre-specified timepoints for all enrolled 
subjects. NIHSS and mRS must be performed by a neurology 
professional or certified personnel.  
o For subjects diagnosed with a stroke, a neurological physical exam, 
mRS, and NIHSS must be performed after the event; mRS must also 
be administered at 90±14 days following a stroke; the simplified 
mRS questionnaire may be used for this follow-up assessment. The 
neurological physical exam must be conducted by a neurologist, 
neurology fellow, neurology physician assistant, or neurology nurse 
practitioner… 
- For subjects in the Bicuspid Nested Registry, a CT scan at 30 days post 
LOTUS Edge Valve implantation. The data will be evaluated by an 
independent CT core laboratory 
- For subjects in the CT Imaging Substudy, a 4D CT scan at 30 days and 
at 1 year post LOTUS Edge valve implantation to assess the prevalence 
of reduced leaflet mobility and its relationship, if any, to clinical events. 
The data will be evaluated by an independent CT core laboratory. 
 
Note 5: For subjects diagnosed with a stroke, a neurological physical 
exam, mRS, and NIHSS must be performed after the event; mRS must 
also be administered at 90±14 days following a stroke; the simplified 
mRS questionnaire may be used for this follow-up assessment. 
7.3 Overview of Objectives and Endpoints 
Table 7.3-1 provides an overview of the aforementioned study 
objectives and endpoints and a justification for the specific endpoints. 
Table 7.3-1: Overview of Objectives and Endpoints – added table 
Section 8.1 Scale and 
Duration 
The REPRISE IV clinical study includes a prospective, multicenter, 
single-arm trial (Main Cohort; N=696) designed to evaluate the safety 
and effectiveness of the LOTUS Edge Valve System when used with the 
Updated for clarity, 
including the single arm 
design and for addition 

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Lotus™ Introducer Set or, when available, the iSleeve™ Introducer Set 
for TAVR in symptomatic subjects who have severe aortic stenosis and 
who are at intermediate risk for SAVR. There will be a roll-in phase (up 
to 100 subjects) for centers that do not have previous experience 
implanting the LOTUS Edge Valve. There will also be a single-arm 
nested registry cohort of subjects who have a bicuspid native valve to 
assess safety and effectiveness (Bicuspid Nested Registry; N=100). 
Selected centers with the ability to perform high quality 4D computed 
tomography (CT) scans will include up to 200 subjects from the Main 
Cohort in a CT Imaging Substudy to assess the prevalence of reduced 
leaflet mobility and its relationship, if any, to clinical events. All 
subjects in these centers will be approached for consent to participate in 
the CT study. If 200 subjects have not enrolled in the CT Imaging 
Substudy by completion of enrollment in the main cohort, additional 
subjects who meet the REPRISE IV eligibility criteria will be enrolled 
in a separate CT Imaging Cohort to achieve a total of 200 subjects in the 
CT Imaging Substudy Figure 8.1 1 shows the study design. 
Inserted new Figure 8.1-1: REPRISE IV Study Design 
All subjects implanted will be followed at baseline, peri- and post-
procedure, at discharge or 7 days post-procedure (whichever comes 
first), 30 days, 6 months, and then annually for up to 5 years post-
procedure. Enrolled subjects who do not have a study device implanted 
will be assessed through 1 year post procedure for safety/adverse events.   
The REPRISE IV study will be conducted in accordance with 21 CFR 
Parts 11, 50, and 54; the relevant parts of the International Conference 
on Harmonisation (ICH) Guidelines for Good Clinical Practices (GCP); 
the International Standard ISO 14155 Clinical Investigation of Medical 
Devices for Human Subjects – Good Clinical Practice; ethical principles 
that have their origins in the Declaration of Helsinki; and pertinent 
individual country/state/local laws and regulations. The study shall not 
begin until the required approval/favorable opinion from the 
Institutional Review Board/Human Research Ethics Committee 
(IRB/HREC) and/or regulatory authority has been obtained, if 
appropriate. See Section 11 below for additional information on study 
design and data collection.  
of the CT Imaging 
Substudy 

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The REPRISE IV study is registered at ClinicalTrials.gov (identifier 
NCT03618095). 
Section 8.2 
Treatment 
Assignment 
Screening materials…enrollment. All subjects will have unique 
identification numbers. 
Note 1: Subjects who have a bicuspid native valve will be enrolled in a 
separate nested registry cohort to assess safety and effectiveness. There 
will be a roll-in phase for centers that do not have previous experience 
implanting the LOTUS Edge Valve; each of these centers will perform at 
least 2 roll-in cases before commencing enrollment in the Main Cohort 
and Bicuspid Nested Registry cohort. 
Section 8.2.1 
Treatment 
See Section 5 for a detailed description of the test device and 
information on device sizes. 
… The large Lotus Introducer Set or, when available, the iSleeve 
Introducer Set is used as an accessory in the procedure. In countries 
where the introducer sets are approved, the commercial devices will be 
used. In countries where they are not approved, they will be considered 
investigational devices.  
Updated for clarity 
regarding the test valve 
and introducer. 
Section 8.3 Study 
Design Justification 
There will be up to 895 subjects in REPRISE IV. In…, up to 100 subjects 
will be enrolled in the roll-in…, 695 subjects will be enrolled in the Main 
Cohort, and 100 subjects will be enrolled in the Bicuspid Nested Registry 
cohort. Up to 50 centers in the United States and Australia will 
participate... Per… antiplatelet therapy with aspirin and a P2Y12 
inhibitor is recommended after TAVR… 
Updated for the study 
design and for clarity  
Section 9.1 
Study Population and 
Eligibility 
The study will include subjects presenting with symptomatic severe 
aortic stenosis who are considered at intermediate risk for surgical valve 
replacement. Because aortic stenosis most commonly occurs in the very 
elderly, women are well represented in TAVR trials. Traditionally 
underrepresented populations (elderly and women) are expected to be 
included in the subject population as allowed by governing law/national 
regulation; as the very elderly will represent the majority of subjects 
enrolled in the trial, efforts to maximize retention are by definition 
targeted to traditionally under-represented groups. The inclusion and 
exclusion criteria are not expected to have a negative effect on 
recruitment or retention of said populations. In the United States, the 
subjects eligible for inclusion in this study are likely to be Medicare 
Updated for clarity 
 

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patients due to their expected age and the results of this study are likely 
to be highly generalizable to a Medicare population. All efforts will be 
made to minimize attrition in REPRISE IV. 
Prior… 
Section 9.2 Inclusion 
Criteria 
Table 9.2-1: REPRISE IV Inclusion Criteria 
IC2. A subject in the Bicuspid Aortic Valve Nested Registry cohort 
must have documented bicuspid aortic valve morphology based on CT 
assessment and confirmed by the CT core lab with hemodynamic 
parameters that meet the criteria in IC1. 
IC3.  Subject has a documented aortic annulus size of ≥20 mm and ≤27 
mm based on the center’s assessment of pre-procedure diagnostic 
imaging (and confirmed by the CRC) and, for the randomized cohort, is 
deemed treatable with an available size of both test and control device. 
IC5. Heart team (which must include an experienced cardiac 
interventionalist and an experienced cardiac surgeon) agrees that the 
subject is at intermediate risk of operative mortality (≥3% and <8% at 
30 days) and TAVR is appropriate… 
IC6.  Heart team (which must include a cardiac interventionalist and an 
experienced cardiac surgeon) agrees that the subject is likely to benefit 
from valve replacement. 
IC7.  Heart team agrees (a priori) on treatment strategy for concomitant 
coronary artery disease (if present). The strategy must be the same 
regardless of whether the patient is to be treated with a test or control 
device. 
IC7.  Subject (or legal representative) has been informed of 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. 
IC9. Subject is expected to be able to take the protocol-required 
adjunctive pharmacologic therapy. 
Section 9.3 Exclusion 
Criteria 
EC1. Subject has a unicuspid or bicuspid aortic valve (not applicable to 
subjects in the Bicuspid Nested Registry cohort). 

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Note: Subjects in the Bicuspid Nested Registry cohort will have a 
documented Sievers Type 02 or Sievers Type 1 bicuspid valve based on 
CT assessment and confirmed by the CT core lab. Subjects are not 
eligible for inclusion in the Bicuspid Nested Registry cohort if the 
maximum diameter of the ascending aorta is >45 mm or if the subject 
has another indication for aortic root replacement. Subjects with a 
Sievers Type 2 bicuspid valve are not eligible for enrollment in any 
study cohort. 
EC4. Subject is on renal replacement therapy or has or has GFR <20 
(based on Cockcroft-Gault formula). 
EC5. Subject has a pre-existing prosthetic aortic or mitral valve. 
EC6. Subject has severe (4+) aortic, tricuspid, or mitral regurgitation. 
EC7.Subject has moderate to severe mitral stenosis (mitral valve area 
≤1.5 cm2 and diastolic pressure half-time ≥150 ms, Stage C or D). 
EC8. Subject has a need for emergency surgery for any reason. 
EC9. Subject has a history of endocarditis within 6 months of index 
procedure or evidence of an active systemic infection or sepsis. 
EC10. Subject has echocardiographic evidence of new intra-cardiac 
vegetation or intraventricular or paravalvular thrombus requiring 
intervention. 
EC11. Subject requires chronic anticoagulation therapy after the implant 
procedure and cannot be treated with warfarin or other vitamin K 
antagonist (other anticoagulants are not permitted in the first month) for 
at least 1 month concomitant with either aspirin or clopidogrel*. 
EC11.Subject has platelet count <50,000 cells/mm3 or >700,000 
cells/mm3, or white blood cell count <1,000 cells/mm3. 
EC12. Subject has had a gastrointestinal bleed… 
EC16. Subject has any therapeutic invasive cardiac or vascular 
procedure resulting in a permanent implant that is performed within 30 
days prior to the index procedure (unless part of planned strategy for 
treatment of concomitant coronary artery disease except for balloon 
aortic valvuloplasty or pacemaker or implantable cardioverter 
defibrillator implantation, which are allowed). 
EC20. Subject has arterial access that is not acceptable for the study 
device delivery system as defined in the device Instructions For Use. 

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EC22. Subject has current problems with substance abuse (e.g., alcohol, 
etc.) that may interfere with the subject’s participation in this study. 
 
Additional exclusion criteria apply to subjects considered for enrollment 
in the CT Imaging Substudy as listed below: 
AEC1. Subject has eGFR <30 mL/min (chronic kidney disease stage IV 
or stage V). 
AEC2. Subject has atrial fibrillation that cannot be rate controlled to 
ventricular response rate < 60 bpm. 
AEC3. Subject is expected to undergo chronic anticoagulation therapy 
after the index procedure. 
Note: Subjects treated with short-term anticoagulation post procedure 
can be included in the imaging substudy; in these subjects the 30-day 
imaging will be performed 30 days after discontinuation of 
anticoagulation. 
10.1 Point of 
Enrollment 
Subjects who are 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 
Edge Valve System into the subject’s femoral artery. 
Updated per the new 
study design 
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. Reasons for withdrawal include but are not 
limited to physician discretion, subject choice to withdraw consent, or 
death. If such withdrawal is due to problems related to 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.  
While all efforts will be made to minimize attrition, subjects may 
withdraw from the study at any time, with or without reason and without 
prejudice to further treatment. Withdrawn subjects will not undergo any 
additional study follow-up, nor will they be replaced. The 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 
Updated for clarity 

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the requirements of the study or if any of the study procedures are 
deemed potentially harmful to the subject. Data that have already been 
collected on withdrawn subjects will be retained and used for analysis, 
unless local regulations apply. No new data will be collected after 
withdrawal.   
All applicable case report forms up to the point of subject withdrawal and 
an “End of Study” form for the subject must be completed. If the 
withdrawal is due to investigator discretion, the investigator should 
follow-up with the subject per standard of care. Information on 
determining if a subject is lost to follow-up can be found in Section 
11.10.6. 
10.3. End of Study 
Definition 
This clinical trial will be considered completed when subjects are no 
longer being examined or the last subject’s last study visit as outlined in 
the data collection schedule (Table 11.1 1) has occurred. All subjects 
who receive a test device will be evaluated at discharge or 7 days 
(whichever comes first), 30 days, 1 year, 2 years, 3 years, 4 years, and 5 
years post index procedure. All visits are office visits. A subject’s 
participation in the study will be considered complete after the 5-year 
visit. For subjects who do not receive a test device, participation in the 
study will be considered complete after the 1-year visit. 
11.1 Data Collection 
Updated figure and table: 
Figure 11.1-1: REPRISE IV Data Collection Scheme 
Table 11.1-1: Study Event Schedule 
c: Study-specific consent… as necessary. 
Note 2:  The subject should undergo the index procedure within 30 days 
after signing the study Informed Consent Form. 
d: Neurological physical examination must be performed by a 
neurologist, neurology fellow, neurology physician assistant, or 
neurology nurse practitioner who is independent of the study. NIHSS 
and mRS must be performed by a neurology professional or certified 
personnel (external certification for NIHSS; internal or external 
certification for mRS). The NIHSS and mRS assessors should be 
independent (not involved with the care of study subjects). For subjects 
diagnosed with a stroke, a neurological physical exam, mRS, and 

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NIHSS must be performed after the event; mRS must also be 
administered at 90±14 days after a stroke; the simplified mRS 
questionnaire may be used for this follow-up assessment. The 
neurological physical examination must be performed by a neurologist, 
neurology fellow, neurology physician assistant, or neurology nurse 
practitioner who is independent of the study. If a subject who has not 
received a study device (investigational or control) experiences a stroke 
within the first 1 year after the index procedure, mRS must be 
performed on that subject after the event; mRS must also be 
administered at 90±14 days after a stroke and the results must be 
reported to the Sponsor 
h: Frailty, disability, and comorbidity risk assessments must be captured 
at screening: height, weight, cognitive function (Mini-Cognitive 
Assessment for Dementia), strength… 
m: For subjects in the Bicuspid Nested Registry cohort, a computed 
tomography scan at 30 days post LOTUS Edge Valve implantation. 
Please refer to the CT Core Laboratory procedure guidelines (see study 
Manual of Operations). Results must be sent to the CT Core Laboratory. 
q: Procedural cine-angiogram including the baseline images of the aortic 
complex and the final post-deployment aortogram of the ascending aorta 
must be performed and sent to the CT/X-Ray Core Laboratory for 
analysis. Rotational angiography of the valve frame is required with 
results sent to the Core Laboratory. 
t: For subjects in the CT Imaging Substudy, a 4D CT scan at 30 days and 
at 1 year post LOTUS Edge valve implantation must be done. Please 
refer to the CT Core Laboratory procedure guidelines (see study Manual 
of Operations). The data must be sent to the independent CT core 
laboratory.   
Section 11.2 Study 
Candidate Screening 
Subjects will be evaluated for eligibility by the center heart team (which 
must include an experienced cardiac interventionalist and an experienced 
cardiac surgeon). The heart team should take into account the Society of 
Thoracic Surgeons (STS) score as well as other clinical comorbidities not 
accounted for in the risk calculation. Eligible subjects will have 
agreement from the heart team that the subject is at intermediate 

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operative risk of mortality with SAVR (see Table 9.2 1 for inclusion 
criteria; see definition of operative risk in Table 26.2 1). Risk… 
Section 11.4 
Screening 
Assessments 
Results from the screening tests and procedures listed below (including 
any planned concomitant treatment of CAD and any planned use of 
BAV during the index procedure) must be submitted to the CRC …of 
subject eligibility. For the randomized cohort, a subject should be 
randomized after CRC approval and within 7 calendar days of CRC 
approval. 
Note 1: It is recommended that predilatation be performed unless there 
is minimal calcification of the annulus and leaflets. To minimize bias, 
planned use of BAV during the index procedure should not be 
influenced by type of study valve and therefore should be determined 
and reviewed and approved by the CRC prior to subject randomization. 
Subjects… 
Note 2: Additional concomitant procedures, including percutaneous 
coronary intervention, are not allowed during the index procedure. 
Centers will… 
• Clinical assessments… 
o Risk… reimbursement 
o Planned treatment of CAD and lanned use of BAV (i.e., 
predilatation) 
• Frailty… 
o Body Mass… 
o Cognitive Function: Mini-Cognitive Assessment for 
Dementia126,127 (see study Manual of Operations) 
o Strength… 
11.5 Baseline 
Assessments 
The following assessments must be completed within 30 days… 
• Confirmation of CRC approval date 
• Neurological physical examination, which must be performed by a 
neurologist, neurology fellow, neurology physician assistant, or 
neurology nurse practitioner (see Table 11.1 1). 
• NIH Stroke Scale… 
11.6 Pre-procedure 
Medications 
…loading dose. 
P2Y12 Inhibitor 

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A loading dose of a P2Y12 inhibitor (clopidogrel at a dose of ≥300 mg is 
recommended; for other P2Y12 inhibitors recommended doses are 60 mg 
for prasugrel and 180 mg for ticagrelor) is required for subjects who 
have not been on P2Y12 inhibitor therapy for ≥72 hours at the time of 
the index procedure. The loading dose must be administered prior to the 
implant procedure. 
Note: If a subject is treated with anticoagulation, either a P2Y12 inhibitor 
or aspirin is required prior to the implant procedure (but both aspirin and 
a P2Y12 inhibitor are not required). 
Note 1: An alternative P2Y12 inhibitor (e.g., ticlopidine) may be 
prescribed if subject is allergic to or intolerant of clopidogrel.  
Note 2: If a subject requires chronic anticoagulation, either clopidogrel 
or aspirin is required prior to the implant procedure (but both aspirin and 
clopidogrel are not required). The subject should not receive a P2Y12 
inhibitor aside from clopidogrel. 
11.7 Index Procedure 
…technical aspects of the index procedure. 
Note 1: Additional concomitant procedures, including percutaneous 
coronary intervention, are not allowed during the index procedure. 
Note 2: The subject should undergo the index procedure within 30 days 
after signing the study Informed Consent Form. 
 The preparation of the subject for the percutaneous procedure will be 
performed following standard techniques. It is recommended that 
predilatation be performed unless there is minimal calcification of the 
annulus and leaflets. To minimize bias, planned use of BAV during the 
index procedure should not be influenced by type of study valve and 
therefore should be determined before subject randomization. BAV 
must be performed in patients in the bicuspid registry. 
Transfemoral access… The large Lotus Introducer Set or, when 
available, the iSleeve Introducer Set iSleeve/Lotus Introducer is 
prepared and introduced in the patient’s femoral artery, as described in 
the iSleeve/Lotus Introducer IFU. A balloon valvuloplasty… heart 
rhythm must be assessed and documented (12-lead ECG is not 
required)… 
Updated for the new 
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clarity 

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Note 3: It is recommended that predilatation be performed unless there 
is minimal calcification of the annulus and leaflets; BAV must be 
performed in subjects in the Bicuspid Nested Registry cohort. 
Note 4: If the subject becomes… 
 (11.7.1 Edwards SAPIEN 3 removed) 
The LOTUS Edge Valve implantation procedure requires two operators: 
First and Second Operators. Both… 
3) The catheter is… mechanically expanded and locked into the desired 
position… 
5) If the position…using the radiopaque marker frame as a guide. The 
valve… 
• Device deficiencies assessment for the LOTUS Edge Valve System 
and the iSleeve Introducer Set (if used) 
Note 5: All LOTUS Edge Valve implantation procedures will be 
performed with the support/presence of trained BSC personnel (see 
Section 17.4.2). 
Note 6: In countries where the introducer sets are approved, a device 
deficiency should be reported as a complaint. 
11.8 Post-Procedure 
• Per society… Subjects must be treated with aspirin and a P2Y12 
inhibitor for at least 1 month… 
º After the valve implant procedure, treatment with a P2Y12 inhibitor 
is required for at least 1 month. Dosing should follow local standard 
of care.  
º If a subject is treated with chronic anticoagulation, either a P2Y12 
inhibitor or aspirin is required after the implant procedure in addition 
to the anticoagulant therapy (but both aspirin and a P2Y12 inhibitor 
are not required). The subject must be treated with an oral 
anticoagulant (OAC) and either a P2Y12 inhibitor (clopidogrel 
recommended) or aspirin for at least 1 month. After 1 month, subjects 
requiring chronic anticoagulation may be switched from warfarin or 
other vitamin K antagonist to a new oral anticoagulant (NOAC) at the 
discretion of the treating physician. The subject should not receive a 
P2Y12 inhibitor in combination with a NOAC but may be treated with 
a NOAC plus aspirin… 
Updated to reflect 
current therapy 
recommendations 

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• Cardiac enzymes… twice within 6 to 24 hours post-procedure at 
intervals per standard of care. 
11.9 Prior to 
Discharge… 
…collected. 
• NYHA classification 
• Neurological physical examination, which must be performed by a 
neurologist, neurology fellow, neurology physician assistant, or 
neurology nurse practitioner who is independent of the study. 
• NIHSS,… 
Updated for clarity 
11.10 Follow-up 
All implanted subjects will be evaluated at 30 days, 6 months, 12 
months… 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… 
11.10.1 30-Day 
Follow-up… 
• Quality of Life…  
Note: Quality of life will be evaluated by the Kansas City 
Cardiomyopathy and SF-12 questionnaires at baseline, 1 month, 1 year, 
and 5 years. A formal health economics analysis may be completed if 
meaningful clinical results are obtained. 
• Complete adverse event (AE, SAE, SADE, UADE, ADE and CEC 
events) assessment for test and control device(s) and device deficiencies 
assessment for test device(s), with associated treatment 
• For subjects in the Bicuspid Nested Registry cohort, a computed 
tomography scan at 30 days post LOTUS Edge Valve implantation. The 
CT scan must be performed per the CT Core Laboratory procedure 
guidelines (see study Manual of Operations) and sent to the CT Core 
Laboratory for independent analyses. 
• For subjects in the CT Imaging Substudy assessment of prosthetic 
valve leaflet mobility using 4D CT must be performed per the CT Core 
Laboratory procedure guidelines (see study Manual of Operations). All 
4D CT scans for subjects enrolled in the CT Imaging Substudy must be 
sent to the CT Core Laboratory for independent analyses. 
Note: The CT scans will be read by the CT Core Laboratory and will 
not be provided to local investigators except as per below. Local reading 
should be done only for non-cardiac valve findings such as unexpected 
lung pathology. A study CT scan can be unblinded upon investigator 

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request based on any of the following if the event occurs within 2 weeks 
of the study CT scan. 
o Any neurological event 
o Any potential embolic event 
o Any MI (ST segment elevation MI or non-ST segment elevation 
MI) 
o Increase in aortic regurgitation to moderate or severe 
o A change in echocardiographic parameters including an increase in 
mean gradient of >10 mmHg or a change in Doppler velocity index 
(DVI) of >0.05. 
If any of the above events occurs outside of the 2 week window around 
the study CT scan, the investigator must not be unblinded to the core 
laboratory assessment of the study CT scan and instead should perform a 
separate CT scan if clinically indicated. If an additional CT scan is 
performed for clinical indications, it should be sent to the CT Core 
Laboratory for analysis 
11.10.2  
6-Month Follow-
up… 
— 
(section removed) 
11.10.3.  
12-Month Follow-
up… 
• Complete adverse event (AE, SAE, SADE, UADE, ADE and CEC 
events) assessment for test and control device(s) and device deficiencies 
assessment for test device(s), with associated treatment 
• Quality of Life Surveys: Kansas City Cardiomyopathy and SF-12 
Quality of Life Questionnaires 
Note: Health utilities will be evaluated by the Kansas City 
Cardiomyopathy and SF 12 Quality of Life questionnaires at baseline, 1 
month, 1 year, and 5 years. A formal health economics analysis may be 
completed if meaningful clinical results are obtained. 
11.10.4 Annual 
Follow-up… 
All implanted subjects must be evaluated… 
• Complete adverse event (AE, SAE, SADE, UADE, ADE and CEC 
events) assessment for test and control device(s) and device deficiencies 
assessment for test device(s), with associated treatment 
• Quality of Life Surveys: Kansas City Cardiomyopathy and SF-12 
Quality of Life Questionnaires 

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Note: Quality of life will be evaluated by the Kansas City 
Cardiomyopathy and SF 12 questionnaires at baseline, 1 month, 1 year, 
and 5 years. A formal health economics analysis may be completed if 
meaningful clinical results are obtained. 
• For subjects enrolled in the CT Imaging Substudy, assessment of 
prosthetic valve leaflet mobility using 4D CT must be performed per 
the CT Core Laboratory procedure guidelines (see study Manual of 
Operations). The 4D CT scans done for the CT Imaging Substudy must 
be sent to the CT Core Laboratory for independent analyses. 
Note: The CT scans will be read by the CT Core Laboratory and findings 
will not be provided to local investigators except as noted above. Local 
reading should be done only for non-cardiac valve findings such as 
unexpected lung pathology. A study CT scan can be unblinded upon 
investigator request based on the conditions described in Section 11.10.1 
if the event occurs within 2 weeks of the study CT scan. 
11.10.7 Withdrawal 
and Replacement… 
— 
(separate section removed) 
11.10.8 Explant 
Procedure 
11.10.6 Explant Procedure 
If a… valve 
If a SAPIEN 3 control… Information… 
Updated to reflect 
single-arm design 
11.11 Study 
Completion 
All subjects who receive a test or control device will be evaluated at 30 
days, 6 months, 12 months... For subjects who do not receive a test or 
control device, participation in the study will be considered complete after 
the 1-year visit. Any ongoing adverse events after study completion 
should be managed per standard of care. 
Updated for clarity 
11.12 Source 
Documents 
When available, original source documents (see Table 26.2 1 for 
definition) should be maintained at the investigational center. In lieu of 
original source documents, certified copies are required to be 
maintained. A certified copy is a copy (irrespective of the type of media 
used) of the original record that has been verified (i.e., by a dated 
signature [PI or as delegated by PI] or by generation through a validated 
process) to have the same information, including data that describe the 
context, content, and structure, as the original. Source documentation 
includes but is not limited to those items noted in Table 11.12 1. 
New Table 11.12-1 Source Documentation Requirements 

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11.13 Local 
Laboratory/… 
Appropriate certifications and documentation records are required to be 
maintained at the investigative center for local laboratory/vendor work. 
12.1 Endpoints 
— 
(section removed) 
Updated for single-arm 
design 
12.1.1 Primary 
Endpoint 
The primary endpoint is the composite of all-cause mortality, and all 
stroke and mild or greater paravalvular aortic regurgitation (PVR; based 
on core lab assessment) at 1 year. 
12.1.1.1 Statistical 
Hypothesis for the 
Primary Endpoint 
12.1.1.1.1 Primary Hypothesis for the Primary Endpoint 
The statistical hypothesis is that the rate of the primary endpoint 
(composite of all-cause mortality and all stroke at 1 year) in the Main 
Cohort is less than the performance goal (PG) of 15.2% (expected rate 
of 11.1% plus testing margin of 4.1%). 
A one-sample z-test will be used to test the one-sided hypothesis that the 
1-year primary endpoint rate for LOTUS Edge in the Main Cohort is 
less than the PG: 
H0: PLOTUS Edge ≥ PG 
H1: PLOTUS Edge < PG 
where PLOTUS Edge is the primary endpoint rate for the LOTUS Edge 
group and PG is the performance goal. 
The primary analysis set for the primary endpoint is the intention-to-treat 
(ITT) analysis set (see Section 12.2.1). This endpoint will also be 
analyzed for the implanted analysis set. 
12.1.1.1.2 Secondary 
Hypothesis… 
— 
(section removed) 
12.1.1.2 Sample Size 
Parameters for the 
Primary Endpoint 
The sample size calculation for the primary endpoint is based on the 
following assumptions. 
• Expected rate for LOTUS Edge = 11.1%* 
• Testing margin = 4.1% (37% relative to the expected rate) 
• Performance goal (PG) = 15.2% (expected rate of 11.1% plus testing 
margin of 4.1%) 
• Test significance level (α) = 0.025 (1-sided) 
• Power (1 minus ß) = 87.5% 
• Number of evaluable subjects = 675 
• Expected rate of attrition = 3% 

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• Total enrollment (evaluable Main Cohort) = 696  
* Estimated pooled rate from the fixed/random effects model based on the 
ITT TAVR arm data from PARTNER II S3i and SURTAVI 
12.1.1.2.2 Secondary 
Hypothesis… 
— 
(section removed) 
12.1.1.3 Success 
Criteria-Primary 
Endpoint 
If the P value from the one-sample z-test is <0.025, it will be concluded 
that the primary endpoint with the LOTUS Edge Valve System is less 
than the PG. This corresponds to the one-sided upper 97.5% confidence 
bound of the observed composite rate of all-cause mortality and all stroke 
in the Main Cohort at 1 year being < 15.2%. 
12.1.1.4 Statistical 
Methods-Primary 
Endpoint 
All subjects who are enrolled and randomized will be eligible for 
evaluation. Any events or hospitalizations occurring after enrollment but 
prior to the index procedure should be entered in the electronic data 
capture system. Handling of dropouts and missing data will depend on 
their frequency and the nature of the outcome measure. Sensitivity 
analyses (e.g., tipping-point analysis) will be performed to assess the 
impact of subjects with inadequate follow-up (i.e., missing data) on the 
primary endpoint and to assess the robustness of the conclusion of the 
primary analysis. A sensitivity analysis of the primary endpoint, 
including events occurring after enrollment but prior to the index 
procedure, will be performed. This sensitivity analysis of the primary 
endpoint will include the last available post-procedure core lab 
assessment of PVR data for subjects who survive with no stroke through 
1 year but have missing or unanalyzable data for PVR at 1 year. 
Statistical models… 
Updated for clarity 
12.1.2 Secondary 
Endpoint 
— 
(section removed) 
Updated to reflect 
single-arm design and 
for clarity 
12.1.3 Baseline 
Comparability 
Baseline data will be summarized by treatment group for the randomized 
subjects and separately for subjects in the Main Cohort, Roll-In Cohort, 
and Bicuspid Nested Registry cohort. Subject demographics… variables. 
Treatments for the randomized subjects will be compared with a chi-
square or Fisher exact test for discrete variables and a Student t test for 
continuous variables. Procedural characteristics will be summarized 
similarly. 

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12.1.4 Post-
procedure 
Measurements 
12.1.3 Post-procedure Measurements 
Post-procedure information… will be presented. Treatments for the 
randomized subjects will be compared with the chi-square or Fisher exact 
test for discrete variables and the Student t-test for continuous variables. 
No inferences are planned on the additional measurements and, therefore, 
alpha-adjustments for multiple comparisons will not be used. The Kaplan-
Meier… estimate rates for time-to-event endpoints and treatment groups 
will be compared using the Log-rank and Wilcoxon tests. Adverse… 
 
12.1.5 Subgroup 
Analyses for 
Randomized Subjects 
12.1.4 Subgroup Analyses 
Primary and pre-specified additional endpoints… as appropriate. 
For the CT Imaging Substudy, data from the 4D CT scan at 30 days and at 
1 year post LOTUS Edge valve implantation to assess the prevalence of 
reduced leaflet mobility will be summarized and the relationship, if any, 
to clinical events will be explored. 
Updated for clarity and 
for the CT Imaging 
Substudy 
12.2.1 Analysis Sets 
The primary endpoints and additional measurements will be analyzed on 
an intention-to-treat (ITT), an as-treated and an implanted basis.  
Among the randomized cohort, For ITT analyses, all subjects who sign 
the IRB/HREC-approved study ICF (see Section 11.3) and are enrolled 
in the trial and are randomized will be included in the analysis, whether 
or not an assigned study valve (LOTUS Edge Valve or SAPIEN 3 
Valve) was implanted. The as-treated … control subject for the as-
treated analyses).  For implanted analyses, ITT subjects who had the 
assigned, randomized study valve (LOTUS Edge Valve or SAPIEN 3 
Valve) implanted will be included in the analysis. For all analysis sets, if 
a subject… For the Main Cohort, the primary endpoint (both 
hypotheses) and the secondary endpoint will be analyzed for the ITT, 
as-treated, and implanted analysis sets. The primary analysis for the 
primary endpoint (both hypotheses) and the secondary endpoint will be 
based on the ITT analysis set. 
Updated to reflect 
single-arm design 
12.2.3 
Randomization… 
— 
(section removed) 
12.2.4 Reporting 
Events 
12.2.3 Reporting Events 
For all randomized subjects, events from the time of randomization 
onward all events that occur from the time of enrollment will be reported. 
For randomized subjects… For time based clinical events, the cut-off for 

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events for 30-day endpoints will be 30 days, for 6-month endpoints will 
be 180 days, for 1-year endpoints… 
12.3 Data Analyses 
Baseline and… analysis of the primary safety endpoint, primary 
effectiveness endpoint, secondary endpoint, and additional measurements. 
12.3.2 Interim 
Analyses 
…or futility. Administrative analyses for regulatory agency review may 
be performed. 
Updated for clarity 
12.3.3 Justification of 
Pooling 
All analyses for the primary endpoint will be presented performed using 
data pooled across clinical centers. An assessment… made by fitting a 
logistic regression model with the primary composite endpoint of all 
death and all stroke and with the center as the main effect. If the P value 
for the coefficient for the center is ≥0.1, the data can be pooled across 
centers. In the analysis… centers with fewer than 106 subjects enrolled… 
have ≥106 subjects, but… 
12.3.4 
Multivariable… 
Univariate and multivariate analyses will be performed to assess the effect 
of potential predictors on the primary endpoint and the secondary 
endpoint as described… 
13.1 Data 
Collection… 
The clinical database will reside on a production server hosted by 
Medidata EDC System (New York, New York, USA). All,,, 
13.2 Data Retention 
The Principal Investigator or his/her designee or Investigational center 
will maintain all essential study documents and source documentation 
that support the data collected on the study subjects in compliance with 
applicable regulatory requirements. Documents...  
The Principal Investigator or his/her designee will take measures to 
ensure that these essential documents are not accidentally damaged or 
destroyed. If for any reason the Principal Investigator or his/her designee 
withdraws responsibility for maintaining these essential documents, 
custody must be transferred to an individual who will assume 
responsibility and BSC must receive written notification of this custodial 
change. Centers are required to inform BSC in writing where paper or 
electronic files are maintained in case files are stored off site and are not 
readily available. 
13.3.4 
Histopathology… 
If a LOTUS Edge valve (test device) is explanted… 
15. Deviations 
An Investigator… 

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Deviations will be reviewed and evaluated on an ongoing basis and, as 
necessary, appropriate corrective and preventive actions (including 
IRB/HREC notification, center re-training, or center 
discontinuation/termination) will be put into place by the Sponsor. 
16 Device 
Accountability 
16.1 Device Accountability for Products Labelled Investigational  
The LOTUS Edge™ Valve System and iSleeve™ Introducer Set 
investigational devices will be released by the Sponsor or designee to 
the clinical center only after the center has been initiated and all 
regulatory approvals as well as required documentation have been 
collected from the center. The LOTUS Edge™ Valve System and 
iSleeve™ Introducer Set investigational devices shall be securely 
maintained and controlled and used only in this clinical study. 
Additionally, the study personnel must follow the instructions related to 
the storage of the test and control investigational devices as noted in the 
corresponding IFUs. Device Accountability Logs for the LOTUS Edge 
Valve System and iSleeve Introducer will be provided to the centers and 
will be used to track subjects and device allocations during the study. 
An electronic interactive response technology (IRT) will be used for 
investigational device management and accountability during the study.  
The Sponsor or designee shall keep records to document the physical 
location of all investigational devices from shipment of the 
investigational devices to the investigation centers until return or 
disposal. The IRT will be used to document reception of the 
investigational device at a center. Records shall be kept by authorized 
center study personnel to document the physical location and conditions 
of storage of all investigational devices. Centers must not dispose of any 
investigational devices for any reason at the center unless instructed to 
do so by BSC. Any investigational device that is disposed of at the 
center must be documented appropriately. recorded in the Device 
Accountability Log. The PI Centers 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, transfer, and disposal of the 
investigational devices, which shall include the following; this will be 
verified by personnel from BSC or its designee. 
• Date of receipt at the center 

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• Identification… 
• Date of return and quantity of unused… 
16.2 Control Device 
16.2 Commercial Device 
For countries where the introducer sets are commercially available, 
appropriate information on the SAPIEN 3 control device size and 
model… 
17.1 Statement of 
Compliance 
The REPRISE IV study will be conducted in accordance with 21 CFR 
814.20 parts 11, 50, 54, 56, and part 812… 
The study… appropriate. Also, the study shall not begin prior to issuance 
of the center Authorization to Screen, as provided by the Sponsor. Any… 
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 clinical investigation plan/protocol… 
• Provide… results… 
• Complete training requirements associated with the SAPIEN 3 
device… 
• Record, report… adverse event as applicable per the protocol and 
observed device deficiency. 
• Report to BSC, per the protocol requirements, all SAEs and device 
deficiencies that could have led to a SADE and potential/USADE or 
UADE. 
• Report to the IRB/HREC and regulatory authorities any SAEs and 
device deficiencies that could have led to a SADE and potential/USADE 
or UADE, if required by applicable laws the national or regulations or 
this protocol... 
• Allow… be accessible to the clinical research monitor or auditor and 
respond to questions during monitoring visits or audits... 
• Ensure that informed consent is obtained in accordance with applicable 
laws, this protocol and local IRB/HREC requirements... 
• Provide the subject with well-defined procedures for possible 
emergency situations related to the clinical study, and make the necessary 
arrangements for emergency treatment, including decoding procedures for 
blinded/masked clinical investigations, as needed. 

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17.2.1 Delegation of 
Responsibility 
…providing appropriate training so the delegate is competent to perform 
the tasks they have been delegated, and adequate supervision of those to 
whom tasks are delegated. Where there is a sub-investigator at a center, 
the sub-investigator should not be delegated the primary supervisory 
responsibility for the center. The investigator… 
17.3 Institutional 
Review Board 
17.3 Institutional Review Board/Human Research Ethics Committee 
Prior to gaining Approval-to-Enroll status the investigational center will 
provide to the Sponsor documentation verifying that their IRB is 
registered or that registration has been submitted to the appropriate 
agency, as applicable according to national/regulatory requirements.   
The investigational center will obtain the written and dated 
approval/favorable opinion of their IRB/HREC for the clinical 
investigation before recruiting subjects and implementing all subsequent 
amendments, if required.   
A copy… investigational product/equipment... 
Any amendment to the protocol will require review and approval by the 
IRB/HREC before the changes are implemented in the study. All changes 
to the ICF will be IRB/HREC approved; a determination will be made 
regarding whether a new ICF needs to be obtained from subjects who 
provided consent using a previously approved ICF. Annual IRB/HREC 
approval and renewals will be obtained throughout the duration of the 
study as required by applicable local/country laws or regulations or 
IRB/HREC requirements. Copies of the Investigator’s reports and the 
IRB/HREC continuance of approval must be provided to the Sponsor. 
17.4 Sponsor 
Responsibilities 
All information… considered confidential by BSC and will be kept 
confidential in accordance with all applicable laws and regulations. 
Only… research and/or other business purposes such as overseeing and 
improving the performance of its device, new medical research and 
proposals for developing new medical products or procedures. All data 
used in the analysis and reporting of this study or shared with a third-
party researcher will be without identifiable reference to specific 
subjects… 
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 

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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… 
17.4.1 Training with 
the Investigational… 
Training on the LOTUS Edge Valve System has been developed that 
meets the requirements of ISO 5840-3 and includes the following 
elements.  
• Device Description: A detailed description of all components of the 
device including a summary of the basic principles of operation. 
• Patient selection and sizing: A detailed review of pre-procedural 
imaging techniques to aid in patient selection and sizing decisions for 
valve implantation.  
• Step by Step Procedure:  A detailed description of each step of the 
procedure. The training describes any warnings associated with any 
steps, and tips and tricks for valve implantation. 
• Implantation techniques: A detailed review of specific implantation 
techniques based on clinical cases. 
• Device Demonstration: A hands on training to practice the 
implantation procedure in a bench model or a robotic simulation 
system. 
• Device training to include a detailed description of all device 
components including a summary of the basic principle of operation 
and hands-on bench top demonstration using valve and delivery 
system components in a simulated implantation model. 
• Patient selection and device sizing to include a review of the 
Directions for Use (IFU) and pre-procedural and procedural 
imaging techniques to aid in sizing decisions and implantation of 
the valve 
• Implantation techniques to include a step-by-step review of the 
procedure (including alternative access, where applicable) while 
highlighting associated cautions and warnings from the IFU. 
Training should include video representation of implantation 

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procedural steps and associated fluoroscopic images of each step. 
Clinical case reviews should be presented to demonstrate intended 
procedural steps as well as appropriate troubleshooting. 
• Proctoring: The investigator and co-investigators as well as the scrub 
team will be proctored by an experienced TAVR physician on a 
minimum of 5 6 implantation procedures. These are to be performed 
in the investigator’s institution with his/her 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.  
Note 1: The training requirements listed above apply to centers that do 
not have any previous If a physician has prior experience implanting the 
Lotus Valve, he/she will be trained per above to the LOTUS Edge Valve 
System prior to re-starting first implants. If the center has prior 
experience implanting the Lotus Valve but not the LOTUS Edge Valve 
System, the training will be modified to focus on the changes between 
Lotus and LOTUS Edge. These Lotus-experienced physicians will not be 
certified to the LOTUS Edge Valve System until these training 
requirements have been met and three implants with the LOTUS Edge 
Valve System have been completed. Further, if the physician was 
considered proctor-free under the previous Lotus program, a proctor will 
not be required 
Note 2: For centers that do not have implantation experience with the 
LOTUS Edge Valve System, at least 2 roll-in cases will be performed 
before enrollment can commence in the Randomized Main Cohort …  
will count towards the 5 6 required proctored… 
17.4.2 Role of 
Boston Scientific… 
Boston Scientific Corporation personnel (including field clinical 
engineers) who are trained in the use of the investigational device will... 
trained on the investigational device(s) IFU(s). Support may include HCP 
training (see Section 17.4.1), addressing HCP questions, or… 
18 Monitoring 
… In addition, the clinical research monitor verifies… and that the 
Principal Investigator continues to have sufficient staff and facilities to 
conduct the study safely and effectively. The Principal 

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Investigator/institution guarantees direct access to original source 
documents and/or certified copies (please see Section 11.12) by BSC … 
It is important that the Principal Investigator and relevant… 
19 Potential Risks 
and Benefits 
Risks to clinical subjects… the Evolut R CE Mark Study, the Surgical 
Replacement and Transcatheter Aortic Valve Implantation (SURTAVI) 
trial, the EVOLUT R US study, the PORTICO Pre-CE Mark study, and 
the… 
Potential risks and benefits have been included in the study-specific 
template of the ICF provided to the study centers (see Section 21). While 
some risks may be lower with SAPIEN 3 compared to LOTUS Edge (e.g., 
new conduction disturbance that may result in the need for a permanent 
pacemaker), there may also be potential benefits of the LOTUS Edge 
Valve over SAPIEN 3 (e.g., a lower likelihood of PVR and a lower 
likelihood of annular rupture or valve malpositioning). 
Updated to reflect 
single-arm design and 
to include additional 
references 
19.1 Risks 
Associated with… 
19.1 Anticipated Adverse Events and Risks Associated with… 
Adverse events… use of the LOTUS Edge Valve System, and the Lotus 
and iSleeve Introducer Sets and/or SAPIEN 3 include but may not be 
limited to the following. 
• Abnormal lab values (including anemia, electrolytes, hemolysis and/or 
hemolytic anemia) 
• Access site complications (including arteriovenous [AV] fistula, 
hematoma or lymphatic problems) 
•Allergic reaction (including to medications, anesthesia, contrast, or 
device materials, including nickel, titanium, tantalum, bovine-derived 
materials or polyurethanes) 
•Bleeding or hemorrhage (possibly requiring transfusion or intervention 
additional procedure) 
•Cerebrovascular accident, stroke, transient ischemic attack or cerebral 
infarction including asymptomatic neuroimaging findings 
• Device misplacement, migration, or embolization 
• Emboli (including air, calcium, tissue, thrombus or device materials)  
• Endocarditis… 
• Fever or inflammation… 
• Hemolysis and/or hemolytic anemia… 
• Infection (local and/or systemic, including septicemia) 
Updated for clarity 

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• Inflammation 
• Mitral valve insufficiency  
• Myocardial ischemia or infarction 
• Nerve injury or neurologic deficits (including encephalopathy) 
• Pericardial effusion or cardiac tamponade… 
• Restenosis (including pannus formation) 
• Valve dysfunction… 
As a result of these complications adverse events, the subject may 
require medical, percutaneous or surgical intervention, including re-
operation and replacement of the valve. Such complications may be 
These events may lead to fatal outcomes.  
As the LOTUS Edge Valve System and the iSleeve Introducer Set are is 
an investigational device, uncertainty… 
19.2 Risks Associated with the Study Device(s) 
Overall, there are no incremental risks expected with the investigational 
device(s) compared to similar devices on the market. 
19.4 Risk 
Minimization 
Actions 
19.5 Risk Minimization Actions 
Additional risks… Neurological assessments (NIHSS and mRS) will be 
performed… 
19.6.1 Potential 
Benefits… 
…as described in the scientific literature (see summary in Section 4.1 of 
this document and details in Sections 2 and 3 of the Investigator 
Brochure), potentially… 
Updated for clarity 
20.1 Reportable 
Events… 
It is the responsibility… 
• Unanticipated adverse device effects/unanticipated serious adverse 
device effects… 
• If complications or… 
For the randomized cohort event reporting (eCRF data entry) is required 
beginning from the time of randomization.  
For the roll-in cohort and the Bicuspid Nested Registry cohort, event 
reporting… 
Event reporting… 
Refer to Section 19 for the known risks associated with the study devices 
(test and control)… 
Updated for clarity to 
reflect the single-arm 
design 

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20.2 Definitions and 
Classification 
Adverse event definitions are provided in Table 20.2 1. Administrative 
edits were made on the safety definitions from ISO 14155 and 
MEDDEV 2.7/3 for clarification purposes. 
Table 20.2-1: Adverse Event Definitions 
Any untoward medical occurrence… 
Note 1: This definition includes events related to the investigational 
medical device or the comparator. 
Table 20.2… Serious 
Adverse Event 
Definition 
Note 1: This definition meets the reporting objectives and requirements 
of ISO 14155 and MEDDEV 2.7/3. 
Adverse event that:  
…or 
3) in-patient hospitalization or prolongation of existing hospitalization, 
or… 
Note 2: Planned hospitalization for a pre-existing condition, or a 
procedure required by the protocol clinical investigational plan, without a 
serious deterioration in health, is not considered a serious adverse event. 
Changed to address 
updated regulatory 
requirements 
Table 20.2… 
Unanticipated 
Serious Adverse 
Device Effect 
(USADE) Definition 
Added text: 
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. 
Updated for clarity 
20.3 Relationship to 
Study Device(s) 
The Investigator must assess the relationship of the AE/SAE to the study 
device and procedure… 
Table 20.3-1: Criteria for Assessing Relationship of Study Device and 
Procedure to Adverse Event 
20.4 Investigator 
Reporting 
Requirements 
The communication requirements…  event. Centers should report control 
device related deficiencies as per requirements in the control-device IFU. 
Updated requirements 
Table 20.4 1: Investigator Reporting Requirements 

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Unanticipated 
Adverse Device 
Effect/Unanticipated 
Serious Adverse 
Device Effect 
(UADE/USADE) 
Complete adverse 
event (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 enrollment 
for all subjects 
• Terminating at the 
end of the study  
Provide copies of all 
relevant source 
documentation (de-
identified/ 
pseudonymized) for 
reported event 
requested by BSC 
• At request of 
Sponsor 
Serious Adverse 
Event (SAE) 
including Serious 
Adverse Device 
Effects (SADE) 
Complete AE eCRF 
page with all available 
new and updated 
information 
• Within 3 calendar 
days of first 
becoming aware of 
the event or as per 
local/regional 
regulations. 
• Beginning from 
time of enrollment 
for all subjects 
• Reporting required 
through the end of 
the study 
Provide all relevant 
source documentation 
(de-identified/ 
pseudonymized) for 
reported event 
• When 
documentation is 
available At 
request of Sponsor 

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Serious Adverse 
Device Effects 
(SADE) 
Complete AE eCRF 
page with all available 
new and updated 
information. 
• Within 3 calendar 
days of first 
becoming aware of 
the event or as per 
local/regional 
regulations. 
• Reporting required 
through the end of 
the study 
Provide all relevant 
source documentation 
(de-identified/ 
pseudonymized) for 
reported event.  
• When 
documentation is 
available 
• At Sponsor 
request.  
Adverse Event 
including Adverse 
Device Effects 
(AE/ADE) 
Complete AE eCRF 
page, which contains 
such information as 
date of AE, treatment 
of AE resolution, 
assessment of 
seriousness and 
relationship to the 
device. 
• As soon as 
possible before the 
next planned 
monitoring visit  
In a timely manner 
(e.g., recommend 
within 10 business 
days) after 
becoming aware of 
the information 
• Beginning from 
time of enrollment 
for all subjects 
• Reporting required 
through 12 months  
Provide all relevant 
source documentation 
(de-identified/ 
• At request of 
Sponsor 

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pseudonymized) for 
reported event.  
Device Deficiencies 
(including but not 
limited to failures, 
malfunctions, and 
product 
nonconformities) 
Note: … 
Complete applicable 
eCRF fields/page with 
all available new and 
updated information. 
Investigational Device 
• Within 3 calendar 
days of first 
becoming aware of 
the event 
• Reporting required 
through 12 months 
Control Device 
As required per IFU 
and as per 
local/regional 
regulations 
Provide all relevant 
source documentation 
(de-identified/ 
pseudonymized) for 
reported event 
• At request of 
Sponsor 
Note: The… device. 
Please note that pre-market studies are clinical studies with investigational 
devices or with medical devices that bear the regulatory approval and are 
not being used for the same approved indications. 
20.5.1 Boston 
Scientific Device 
Deficiencies 
All LOTUS Edge Valve System and iSleeve Introducer Set device 
deficiencies (including but not limited to failures, malfunctions, use 
errors, product nonconformities, and inadequacy in the information 
supplied by the manufacturer) related to the investigational device or 
future iterations must be documented… 
Updated for clarity 
20.5.2 Control 
Device Deficiencies 
— 
Section removed 
Updated single-arm trial 
design 
20.6. Reporting to 
Regulatory 
20.6. Reporting to Regulatory Authorities / IRBs/ HRECs / 
Investigators 
Updated for clarity 

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Authorities / IRBs/ 
Investigators 
… Boston Scientific Corporation is responsible for reporting AE 
information to all participating Principal Investigators, IRBs/HRECs, 
and regulatory authorities as applicable according to local reporting 
requirements.  
The Principal Investigator is responsible for informing the IRB/HREC 
and regulatory authorities of UADEs, 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/HREC must be provided to BSC in 
accordance with local requirements. 
21 Informed Consent 
Subject participation in this clinical study is voluntary.  Informed 
Consent is required from each subject or his/her legally authorized… 
… and the local Ethics Committee and/or Regulatory authority body, as 
applicable… 
The ICF shall always be signed and personally dated by the subject or 
legal representative competent to sign the ICF under the applicable laws, 
rules, regulations and guidelines and by the investigator or... 
Failure to obtain subject consent will be reported by BSC to the 
applicable regulatory body according to their requirements (e.g., the 
United States Food and Drug Administration [FDA] requirement is 
within 5 working days of learning of such an event). Any violations of 
the informed consent process must be reported as deviations to the 
Sponsor and local regulatory authorities (e.g., IRB/HREC), as 
appropriate… 
… such as if there are amendments to the applicable laws, protocol, a 
change in Principal Investigator, administrative changes, or following 
annual review by the IRB/HREC. The new version of the ICF must be 
approved by the IRB/HREC. Boston Scientific Corporation approval is 
required if changes to the revised ICF are requested by the center’s 
IRB/HREC. The IRB/HREC will determine the subject population to be 
re-consented. 
Study personnel should explain that even if a subject agrees to participate 
in the study and signs an 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. A confidential Screening/Enrollment Log will be 

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Changes 
maintained by the center to document select information about candidates 
who fail to meet the general or "other specific" entry criteria. 
22.1 Safety 
Monitoring Process 
…During regularly scheduled monitoring visits, clinical research 
monitors will support the dynamic reporting process through their review 
of source document and other data information…. 
23.2 Termination 
of… 
Any investigator or associated IRB/HREC in the REPRISE IV study or 
regulatory authority may discontinue participation… 
23.4 Criteria for 
Suspending/… 
… In the event of termination of investigator center participation, all 
study devices and testing equipment, as applicable, will be returned to 
BSC unless this action would jeopardize the rights, safety or well-being of 
the subjects. The IRB/HREC and regulatory authorities, as applicable, 
should will 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 BSC notifies 
the investigational center otherwise. Study subjects will be contacted, as 
applicable, and be informed of changes to study visit schedule. 
24 Publication Policy 
In accordance with the Global SOP – Human Subject Data and Research 
Controls, Boston Scientific Corporation requires disclosure of its 
involvement as a sponsor or financial supporter in any publication or 
presentation relating to a BSC study or its results. In accordance with 
the Global SOP – Human Subject Data and Research Controls, Boston 
Scientific Corporation will submit study results for publication 
(regardless of study outcome) in a timely manner following the 
conclusion or termination of the study. Boston Scientific Corporation 
follows authorship principals as adheres to the Contributorship Criteria 
set forth in the Uniform Requirements… 
…The data, analytic methods, and study materials for this clinical trial 
may be made available to other researchers in accordance with the Boston 
Scientific Data Sharing Policy (http://www.bostonscientific.com/en-
US/data-sharing-requests.html). 
25 Bibliography 
Bibliography updated to accommodate new references in the Introduction, 
etc. 
26.2 Definitions 
Table 26.2-1 Definitions 
Removed “AS-TREATED ANALYSIS SET” 

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IMPLANTED 
ANALYSIS SET 
This population includes all subjects who sign 
the IRB/HREC-approved study Informed 
Consent Form, are enrolled in the trial, and are 
implanted with the assigned, randomized study 
device valve. 
Note 1: If a subject receives 2 valves, the 
subject is assigned to the group corresponding 
to the first valve received. 
INTENT TO TREAT 
(ITT) ANALYSIS 
SET 
This population includes all subjects who sign 
the IRB/HREC-approved study Informed 
Consent Form and are enrolled in the trial and 
are randomized whether or not a assigned study 
device is implanted. Subjects in the ITT 
population will be followed with their ITT 
cohort.  
Note 1: If a subject receives 2 valves, the 
subject is assigned to the group corresponding 
to the first valve received.    
OPERATIVE RISK 
Operative risk is determined by a center cardiac 
surgeon and must be confirmed by the Case 
Review Committee (including a cardiac 
surgeon).  
Intermediate: Estimated 30-day risk of 
mortality is 3–10% 
High: Estimated 30-day risk of mortality is 
>10–15%% 
Very High: Estimated 30-day risk of mortality 
is >15% 
Extreme: Estimated 30-day risk of irreversible 
morbidity or mortality is ≥50%   
27.1.2 Protocol 
Version B to Version 
C 
Table 27.1-2 lists changes between protocol versions B and C. 
Table 27.1-2: Table of Changes for REPRISE IV Protocol Version C 
(Compared to REPRISE IV Protocol Version B) 

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D 
21-Nov-2018 
90702637 
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Page 2 
Study 
Coordinating 
Principal 
Investigators 
Interventional Cardiologist Study Co-Principal 
Investigator 
Christopher U. Meduri, MD, MPH 
Piedmont Heart Institute  
95 Collier Road Northwest, Suite 5015 
Atlanta, GA 30309 
 
Ted Feldman, MD 
Evanston Hospital, North Shore University Health 
System 
Cardiology Division - Walgreen Building 3rd Floor 
2650 Ridge Avenue 
Evanston, IL 60201 USA 
New Study 
Coordinating Principal 
Investigator 
Bicuspid Registry – Coordinating Principal Investigator 
Vivek Rajagopal, MD 
Piedmont Heart Institute  
95 Collier Road Northwest, Suite 5015 
1968 Peachtree Road, NW, Building 95, Suite 5015 
Atlanta, GA 30309 USA 
Updated address 
Current Version: 21-Nov-2018 
Updated Table of Revision History 
Updated for clarity 
11.2 Study Candidate 
Screening 
… Clinical assessment and evaluation, collected tests and images (e.g., 
echocardiography, computerized tomography [CT], angiography) 
performed in preparation for TAVR, any planned concomitant treatment 
of coronary artery disease (CAD), and any planned… 
Concomitant treatment 
of coronary artery 
disease is not allowed 
16.1 Device 
Accountability for 
Products Labeled 
Investigational 
…all unused investigational devices must be returned to BSC or its 
designee. A copy of the Device Accountability Logs must also be 
provided to BSC. 
All Device 
Accountability records 
to be logged 
electronically with no 
separate Device 
Accountability Logs 

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27.1.3 Protocol 
Version C to Version 
D 
Table 27.1-3 lists changes between protocol versions C and D. 
Table 27.1-3: Table of Changes for REPRISE IV Protocol Version D 
(Compared to REPRISE IV Protocol Version C) 
Updated for clarity 
E 
25-Feb-2020 
90702637 
Rev/Ver AG 
Page 2 
Current Version: 25-Feb-2020 
Updated Table of Revision History 
Updated for clarity 
2. Synopsis, Study 
Design 
Updated REPRISE IV Study Design Overview figure to show follow-up 
to 10 years post index procedure. 
FDA request to extend 
study to 10 years 
2. Synopsis, 
Additional 
Measurements 
Additional measurements… will be collected… and annually through 
10 years post index procedure… 
• Safety endpoints… 
o 
Bleeding: Life-threatening… (through 5 years) 
o 
Major vascular complication (through 5 years) 
• Additional indications of prosthetic aortic valve performance as 
measured by transthoracic echocardiography (TTE; see Note 2 and 
Note 3 below) 
• Functional… (see Note 3 below) 
• Neurological… (see Note 4 below) 
Note 3: Echocardiography and NYHA assessment are not required in 
years 6, 8, and 9 (telephone follow-up only). 
Note 4: NIHSS is required at discharge and 1 year; mRS is required at all 
follow-up visits up to 5 years. 
2. Synopsis, Follow-
up Schedule 
All subjects implanted… and then annually for up to 10 years post-
procedure… The visits at 30 days, 1 ̶ 5 years, 7 years, and 10 years are to 
be an office/clinical or in-person visit but may be done in-hospital should 
the subject be admitted at the time. Telephone follow-up is allowed at 6, 
8, and 9 years.  
2. Synopsis, Study 
Duration 
Enrollment…approximately 24 months…the total study duration is 
estimated to be approximately 12 years. 
2. Synopsis, 
Participant Duration 
… study duration for each subject is estimated to be approximately 10 
years. 
7.2 Additional 
Measurements 
Additional measurements… collected… annually up to 10 years post 
index procedure… 
• Safety endpoints… 
Updated for clarity 

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o 
Bleeding: Life-threatening… (through 5 years) 
o 
Major vascular complication (including annular rupture; 
through 5 years) 
• Neurological status… modified Rankin Scale… visits up to 5 years 
Note 5: Echocardiography and NYHA assessment are not required in 
years 6, 8, and 9 (telephone follow-up only). 
7.3 Overview of 
Objectives… 
Table 7.3-1 
Safety measures at discharge, 30 days, and annually up to 10 years post 
index procedure 
FDA request to extend 
study to 10 years 
8.1 Scale… 
All subjects implanted will be followed… annually for up to 10 years 
post-procedure. 
8.3 Study Design… 
All implanted subjects will be followed for up to 10 years post index 
procedure. 
10.3 End of Study 
Definition 
… All subjects who receive a study device will be evaluated at discharge 
or 7 days (whichever comes first), 30 days, and annually up to 10 years 
post index procedure. Visits at 30 days, 1–5 years, 7 years and 10 years 
are office/in-person visits. Telephone follow-up is allowed at 6, 8, and 9 
years. A subject’s participation in the study will be considered complete 
after the 10-year visit. 
11.1 Data Collection 
Figure 11.1-1 REPRISE IV Data Collection Scheme updated to show 
extension of study to 10 years post index procedure 
Table 11.1-1 Study Event Schedule updated to show extension of study to 
10 years post index procedure 
11.1 Data Collection 
Figure 11.1-1 REPRISE IV Data Collection Scheme : In the “Clinical & 
Anatomic Eligibility Criteria Assessment” column added “/CT Coronary 
Angiogram” to the “Coronary Angiogram” box  
Table 11.1-1 Study Event Schedule :  
Assessment: Coronary angiogram/CT coronary angiogram 
Footnote k: A coronary angiogram/CT coronary angiogram must be 
performed… 
Clarify that CT 
angiogram can be used 
for coronary 
assessment, which 
reflects current standard 
of care 

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11.2 Study Candidate 
Screening 
Subjects will be… In the United States, the Centers for Medicare and 
Medicaid Services (CMS) require independent evaluations by 2 cardiac 
surgeons for reimbursement. The heart team… 
Change to CMS 
requirements 
11.4 Screening 
Assessments 
Risk assessments: Society of Thoracic Surgeons (STS) score.... In the 
United States, CMS requires independent evaluations by 2 cardiac 
surgeons for reimbursement. 
11.4 Screening 
Assessments 
• Imaging Assessments 
A coronary angiogram/CT coronary angiogram must.. 
Reflects current 
standard of care 
11.10 Follow-up 
All implanted subjects will be evaluated at 30 days and then annually up 
to 10 years post index procedure... Physical clinic visits or in-person 
follow-up visits are scheduled for appointed times after the date of the 
procedure through 5 years and at 7 and 10 years. Telephone follow-up is 
allowed at 6, 8, and 9 years.  
Visits/telephone follow-up not completed will be considered missed and 
recorded as protocol deviations. Visits/telephone follow-up completed 
outside these windows will be recorded as protocol deviations. Each 
follow-up visit must be performed… 
FDA request to extend 
study to 10 years 
11.10.3 Annual 
Follow-up (±45 
Days) 
Added “to 5 Years” to the section title 
All implanted subjects must be evaluated in person at 24, 36, 48, and 60 
months… 
Updated for clarity 
11.10.4 Follow-up 
(±60 Days) at 7 and 
10 Years 
Added new section 11.10.4 
All implanted subjects must be evaluated in person at 84 and 120 months 
after the index procedure, with a window of ±60 days. The following 
assessments must be completed. The REPRISE IV eCRFs identify the 
specific data points to be collected. 
• NYHA classification  
• Current antiplatelet, anticoagulant (if applicable)  
• TTE, including assessment of effective orifice area, peak and mean 
aortic valve gradient pressure, aortic regurgitation assessment, peak aortic 
velocity, and LVEF per the Echocardiography Core Laboratory procedure 
guidelines. All TTEs must be forwarded to the Core Laboratory for 
FDA request to extend 
study to 10 years 

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independent analyses. 
Note: TTE must be done for all subjects who have a transcatheter valve 
implanted in the aortic position during the index procedure.   
• Serious adverse event (SAE, SADE, UADE, and relevant VARC events 
to be adjudicated by the CEC) assessment for test device(s) and device 
deficiencies assessment for test device(s) with associated treatment. 
Note: Relevant VARC events to be adjudicated by the CEC include the 
following: mortality, stroke, spontaneous myocardial infarction, acute 
kidney injury, repeat procedure for valve-related dysfunction, 
hospitalization for valve-related symptoms or worsening congestive heart 
failure (NYHA III or IV), new pacemaker, new onset atrial fibrillation or 
atrial flutter, prosthetic aortic valve malpositioning (valve migration, 
valve embolization, or ectopic valve deployment), TAV-in-TAV, 
prosthetic aortic valve thrombosis and endocarditis… 
11.10.5 Follow-up 
(±60 Days) at 6, 8 
and 9 Years 
Added new section 11.10.5 
All implanted subjects must be evaluated at 72, 96, and 108 months after 
the index procedure, with a window of ±60 days. This evaluation may be 
conducted by telephone. The following assessments must be completed. 
The REPRISE IV eCRFs identify the specific data points to be collected. 
• Current antiplatelet, anticoagulant (if applicable)  
• Serious adverse event (SAE, SADE, UADE, and relevant VARC events 
to be adjudicated by the CEC) assessment for test device(s) and device 
deficiencies assessment for test device(s) with associated treatment. 
Please see Section 11.10.4 for a list of relevant VARC events. 
11.10.6 Management 
of Missed… 
NOTE: Updated section number from 11.10.4 to 11.10.8 
Missed or late visits (or telephone follow-up as indicated in Table 11.1 
1) will be recorded as protocol deviations and will be reviewed as such 
by the Sponsor or designee on a regular basis in accordance with 
applicable standard operating procedures.  
Note: The follow-up visits at 30 days, 1–5 years, 7 years, and 10 years 
must be conducted in-person. 
11.10.7 Procedure for 
Determining… 
• Failure to complete 2 consecutive visits (or telephone follow-up as 
indicated in Table 11.1 1) without due cause… 

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11.11 Study 
Completion 
All subjects who receive a test device will be evaluated at 30 days and 
then annually up to 10 years post index procedure. Visits in the first 5 
years and at 7 and 10 years are office or in-person visits. Evaluations may 
be conducted by telephone at 6, 8 and 9 years. A subject’s participation in 
the study will be considered complete after the 10-year visit. 
12.2.3 Reporting 
Events 
For time based clinical events, the cut-off for events for 30-day endpoints 
will be 30 days, for 1-year endpoints it will be 365 days, and for 2-10 year 
endpoints it will be 365 days times the number of years. 
20.1 Reportable 
Events… 
Based on the VARC… 
• Bleeding events: Life-threatening… (through 5 years)  
• Vascular complications: major (including annular rupture; through 5 
years) 
Updated for clarity 
27.1.4 Protocol 
Version D to Version 
E 
Table 27.1-4 lists changes between protocol versions D and E. 
Table 27.1-4: Table of Changes for REPRISE IV Protocol Version E 
(Compared to REPRISE IV Protocol Version D) 
F 
29-Apr-2020 
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Rev/Ver AL 
Entire Document 
Document transferred from template version AG to template version AL. 
Updated protocol 
template 
Page 1 
Added National Clinical Trial Identification Number: NCT03618095 
Page 2 
Current Version: 29-Apr-2020 
Updated Table of Revision History 
Synopsis, Planned 
Number of 
Subjects… 
Subjects will be enrolled at up to 5065 centers… There will be up to 
896926 subjects… 
Roll-In: Up to 100130 
Addition of up to 15 
centers 
Synopsis, Adjunctive 
Pharmacologic 
Therapy 
Anti-Platelet Therapy 
Per society guidelinesb, antiplatelet therapy with aspirin and/or a P2Y12 
inhibitor… medications.  
Study subjects must receive some antiplatelet therapy (aspirin and/or a 
P2Y12 inhibitor) for at least 1 month following valve implant. A loading 
dose of the same antiplatelet medication (aspirin and/or a P2Y12 inhibitor) 
is required for subjects who have not been on the antiplatelet therapy for 
≥72 hours at the time of the index procedure (see below for recommended 
doses). 
Reflects current 
standard of care 

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Note 5: It is recommended that subjects be treated with both aspirin and a 
P2Y12 inhibitor for at least 1 month after valve implantation.  
 
Aspirin Dose 
A The recommended loading dose of aspirin (recommended dose of is 
75–325 mg) is required for subjects who… Subjects…loading dose of 
aspirin. 
After the valve implant procedure, aspirin (the recommended dose of 
aspirin is ≥75 mg daily) must be given for at least 1 month… 
 
P2Y12 Inhibitor Dose (clopidogrel recommended) 
A The recommended loading dose of a P2Y12 inhibitor is (recommended 
dose of ≥300 mg for clopidogrel, 60 mg for prasugrel, or 180 mg for 
ticagrelor) is required for subjects who have not... Subjects who have 
been taking a P2Y12 inhibitor daily for ≥72 hours at the time of the index 
procedure do not require a loading dose of the P2Y12 inhibitor. 
After the valve implant procedure, the recommended a P2Y12 inhibitor 
dosing is per local standard of care is required for at least 1 month… 
Note 56: If a subject… or aspirin is required recommended prior to… 
(but both aspirin and a P2Y12 inhibitor are not required recommended). 
After the implant procedure, the subject must should be treated... 
Synopsis, Sample 
Size Parameters 
† Estimated pooled rate from the fixed/random effects model based on the 
ITT TAVR arm data… 
Updated for clarity 
Section 6/Section 7 
Sections 6 and 7 merged into Section 6 Study Objectives and Endpoints 
addition of Sections 6.1 and 6.2 
Updated protocol 
template 
Section 7.1 Scale and 
Duration 
…There will be a roll-in phase (up to 100130 subjects) for… 
Updated Figure 7.1-1 REPRISE IV Study Design 
Addition of up to 15 
centers (additional 30 
Roll-In subjects) 
Section 7.3 
Justification of the… 
There will be up to 896926 subjects… In order to … study subjects to 
risk, up to 100130 subjects… Up to 5065 centers… 
…antiplatelet therapy with aspirin and/or a P2Y12 inhibitor is 
recommended after TAVR… 
Addition of up to 15 
centers 
Reflect current standard 
of care 

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Sections 7 through 11 
Sections 8 through 12 updated to Sections 7 through 11; some subsections 
moved to accommodate new protocol template; for example: 11.10.7 
moved to 9.4; 11.10.8 moved to 9.2 
Updated protocol 
template 
Section 9.2 
Discontinuation of 
Study Intervention 
Section 11.10.8 Explant Procedure moved to Section 9.2.  
Section 9.4 Lost to 
Follow-Up 
Section 11.10.7 Procedure for Determining when a subject is Lost to 
Follow-up moved to Section 9.4. 
Section 10.1 Data 
Collection 
Added paragraph: 
This section indicates the data needed to fulfill the objectives of this 
clinical study. Boston Scientific Corporation considers data collected 
from clinical trial subjects to be personal data (see definitions of different 
data categories in Table 25.2 1) and compliance with privacy and data 
protection laws and regulations (for example, the General Data Protection 
Regulation [GDPR]) to be critically important. Data collection for this 
clinical study has been carefully considered to comply with data privacy 
laws. 
New Section 10.2.1 
Strategies for 
Recruitment and 
Retention 
New section; select information moved from Section 9.1 Study 
Population and Eligibility to new Section 10.2.1  
The REPRISE IV study will include subjects presenting with documented 
severe native aortic valve stenosis who are indicated for TAVR (see 
Section 8). It is estimated that nearly 5% of elderly ≥75 years of age have 
aortic stenosis and its prevalence is expected to increase due to an aging 
population2,3. Because aortic stenosis most commonly occurs in the very 
elderly, women are well represented in TAVR trials. Traditionally 
underrepresented populations (elderly and women) are expected to be 
included in the subject population as allowed by governing law/national 
regulation; as the very elderly will represent the majority of subjects 
enrolled in the trial, efforts to maximize retention are by definition 
targeted to traditionally under-represented groups. The inclusion and 
exclusion criteria are not expected to have a negative effect on 
recruitment or retention of said populations. In the United States, the 
subjects eligible for inclusion in this study are likely to be Medicare 

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patients due to their expected age and the results of this study are likely to 
be highly generalizable to a Medicare population.  
All efforts will be made to minimize attrition in REPRISE IV (see Section 
9.4). Investigators are encouraged to enroll subjects who are willing to 
comply with the follow-up requirements of the study. If a visit is missed, 
the center should attempt to contact the subject to reschedule the missed 
visit and counsel the subject on the importance of maintaining the 
assigned visit schedule. 
Section 10.4 
Screening… 
 Maximum grip… using a Jamar hand-held… 
Updated for clarity 
Section 10.6 Pre-
procedure 
Medications 
 Antiplatelet Therapy: 
Per society guidelines10,121 antiplatelet therapy is recommended to 
reduce the risk of thrombotic or thromboembolic complications if there 
are no contraindications to these medications. Study subjects must 
receive some antiplatelet therapy (aspirin and/or a P2Y12 inhibitor) for 
at least 1 month following valve implant. A loading dose of the same 
antiplatelet medication (aspirin and/or a P2Y12 inhibitor) is required 
for subjects who have not been on the antiplatelet therapy for ≥72 hours 
at the time of the index procedure (see below for recommended doses). 
Aspirin Dose 
A The recommended loading dose of aspirin is (recommended dose of 
75-325 mg) is required for subjects… dose of aspirin. 
P2Y12 Inhibitor Dose (Clopidogrel Recommended) 
A The recommended loading dose of a P2Y12 inhibitor is ≥300 mg 
clopidogrel, at a dose of ≥300 mg is recommended; for other P2Y12 
inhibitors recommended doses are 60 mg for prasugrel, and or 180 mg 
ticagrelor) is required for… Subjects who have been taking a P2Y12 
inhibitor daily for ≥72 hours at the time of the index procedure do not 
require a loading dose of the P2Y12 inhibitor. 
Note: If a subject is treated with anticoagulation, either a P2Y12 
inhibitor or aspirin is required recommended prior to the implant 
Reflect current standard 
of care 

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procedure (but both aspirin and a P2Y12 inhibitor are not required 
recommended). 
Section 10.7 Index 
Procedure 
In the United States, CMS coverage… index procedure. 
Moved Note 1 and Note 2 as shown below. 
The preparation of the subject… approach to treat the subject. 
Note 1: Additional… procedure. 
Note 2: The subject… Form. 
The large Lotus Introducer… 
 
8) A final post-deployment… (including rotational angiography of the 
valve frame) must… 
Change to CMS 
requirements 
 
 
 
 
Updated for clarity 
Section 10.8 Post 
Index Procedure 
• Per society guidelines… Study subjects must receive some antiplatelet 
therapy (aspirin and/or a P2Y12 inhibitor) for at least 1 month following 
valve implant. It is recommended that subjects must be treated with 
aspirin and a P2Y12 inhibitor for at least 1 month following valve 
implantation. Extended… 
o After the valve implant procedure, aspirin (recommended dose of 
≥75 mg daily) must should be given… 
o After the valve implant procedure, a P2Y12 inhibitor is recommended 
required for at least 1 month… 
o If a subject is treated with chronic anticoagulation, either a P2Y12 
inhibitor or aspirin is required recommended after the implant 
procedure in addition to the anticoagulant therapy (but both aspirin 
and a P2Y12 inhibitor are not required recommended). The subject 
must should be treated… 
Reflect current standard 
of care 
Section 10.10 
Follow-up 
Note 1: The follow-up visits at 30 days, 1–5 years, 7 years, and 10 years 
must be conducted in-person. If an in-person assessment cannot be 
performed, follow-up by telephone should be attempted. Subject or 
subject’s physician should provide rationale for why the in-person 
assessment cannot be performed. 
FDA request to extend 
trial to 10 years. 
Section 11.1.1.2 
Sample Size 
Parameters… 
* Estimated pooled rate from the fixed/random effects model based on the 
ITT TAVR arm data from… 
Updated for clarity 

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Section 11.2.2 
Control of 
Systematic… 
…These include an echocardiography core laboratory, a CT and 
procedural rotational X-ray angiography core laboratory to assess all CT 
and procedural angiography rotational X-ray data using… 
New Section 12 
Health Economics… 
New section; select information moved from Sections 11.10.1, 11.10.2, 
and 11.10.3 moved to new Section 12 
Updated protocol 
template 
Sections 14 through 
25 
Section numbers 15 through 26 updated to Sections 14 through 25; 
Section 27 (Appendices) removed as all protocol changes are captured in 
the Revision History Table  
Updated protocol 
template  
New information in the 
literature 
Section 16.3 
Institutional Review 
Board/Human 
Research Ethics 
Committee 
Section 14 Amendments removed; information on amendments found in 
Section 16.3 
…provided to the subject. 
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. Any amendment… 
Updated protocol 
template 
Section 16.4.1 Role 
of Boston 
Scientific… 
Section 17 renumbered to Section 16 per updated protocol template. 
Boston Scientific… engineers and specialists) who… 
Boston Scientific personnel will not do the following. 
• Enter… systems or on paper case report forms. 
Updated for clarity 
Section 16.4.2 
Training with the 
Investigational 
Device 
• Patient… the Directions Instructions for Use (DFUIFU) and… 
• Implantation… from the DFUIFU. Training… 
• Proctoring: The investigator… proctored by an individual experienced 
with the LOTUS Edge valve and TAVR physician on a minimum… 
Updated for clarity 
Updated to allow non-
physician proctors 
Section 18.1 
Anticipated… 
Moved text about risks into new Table 18.1-1 Risks Associated with 
Transcatheter Aortic Valve Replacement 
Updated protocol 
template 
Section 18.1.1 
Hypoattenuated 
Leaflet 
Thickening/Reduced 
Add new section 18.1.1 
Hypoattenuated leaflet thickening (HALT) and reduced leaflet motion 
(RLM) suggestive of subclinical leaflet thrombosis, as detected by high-
Updated for clarity 
 

Confidential  
Form/Template 90702637_Rev/Ver AL 
 
REPRISE IV Study-Specific Protocol 
 
92044854 Rev/Ver F 
 
Page 215 of 215 
  
Table 26.1-1: Protocol Revision History 
Revision 
Version 
Protocol 
Date 
Template 
Number and 
Version 
Protocol Sections 
Modified 
Summary of Changes 
Justification for 
Changes 
Leaflet 
Motion/Leaflet 
Thrombosis 
resolution CT, has been reported with bioprosthetic TAVR and SAVR 
valves40,109,128,129. It is less common among subjects receiving 
anticoagulant therapy and, in some cases, has been shown to resolve with 
such treatment40,109,110,128-131.   
Clinical signs of HALT and RLM include elevation of transvalvular 
gradients (as determined by echocardiography), central or peripheral 
thromboembolic events, and unexpected recurrence of heart failure. 
Computed tomography imaging is recommended to appropriately assess 
subjects with echocardiographic and/or clinical suspicion of leaflet 
thrombosis. Additional anticoagulant therapy may be indicated based on 
symptoms or signs and subject bleeding risk40,109,110,128-131.  
The subset of subjects undergoing 4D CT scans at 30 days and 1 year will 
be exposed to an additional radiation dose of about 20 milliSieverts 
(mSv), which is equivalent to about 10 years’ worth of natural 
background radiation. The contrast dye used during the image acquisition 
can cause medical problems such as allergic reactions and increase the 
risk of worsening kidney function or failure.    
Section 18.3 Risks… 
Risks… listed above in Table 18.1-1. 
New Table 18.1-1 
Section 19.3 
Relationship to… 
In Table 19.3-1 removed the row for “Unlikely Related.” 
Updated regulations 
and definitions 
Section 25.2 
New definitions for Data Categories and General Data Protection 
Regulation; remove definition for Structural Valve Deterioration; added 
definitions for Hypoattenuated Leaflet Thickening and Reduced Leaflet 
Motion 
New Section 26 
Revision History 
Added new Section 26 Revision History; merged the revision history 
tables into 1 table (called Table 26.1-1) per the new protocol template. 
New updates in the table show changes from Protocol Version D to 
Version E to Version F   
Updated for clarity and 
per the new protocol 
template