REPRISE III: Repositionable Percutaneous Replacement of Stenotic Aortic Valve Through Implantation of Lotus™ Valve System - Randomized Clinical Evaluation
Phase: NA
Conditions: Aortic Stenosis
Sponsor: Boston Scientific Corporation

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 1 of 188 
 
 
REPRISE III:  REpositionable Percutaneous Replacement of Stenotic 
Aortic Valve through Implantation of Lotus™ Valve System – Randomized 
Clinical Evaluation  
 
CLINICAL PROTOCOL 
Protocol Number: S2282  
 
Sponsor: 
Boston Scientific Corporation  
300 Boston Scientific Way 
Marlborough, MA 01752 USA 
International Representative 
Boston Scientific Limited 
Ballybrit Business Park 
Galway, Ireland 
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. It should be held 
confidential and maintained in a secure location. 
Do not copy or distribute without written permission from Boston Scientific Corporation. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 1 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 2 of 188 
 
 
Contact Information 
Role 
Contact  
Clinical 
Contacts 
Amy Maurer 
Senior Clinical Trial Manager, Structural Heart – Interventional Cardiology 
Boston Scientific Corporation 
100 Boston Scientific Way 
Marlborough, MA 01752-1234 USA 
Sarah Zanon 
Senior Clinical Trial Manager, Structural Heart – Interventional Cardiology 
Boston Scientific Corporation 
Dornacherplatz 7 
4500 Solothurn, Switzerland   
Blessie Concepcion 
Director, Clinical Trials, Structural Heart – Interventional Cardiology 
Boston Scientific Corporation 
160 Knowles Drive 
Los Gatos, CA 95032 USA 
Study 
Coordinating 
Principal 
Investigators 
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 
Michael J. Reardon, MD 
Methodist DeBakey Heart & Vascular Center  
6550 Fannin Street, Suite 1401 
Houston, TX 77030 USA 
Original Release: 27-Jun-2014;  
Current Version: 06-Oct-2017 
Revision History 
Revision Number 
Release Date 
Template Version 
Reason for Change 
AB 
25-Jul-2014 
90702637 Rev/Ver AD 
See Table 27.1-1 
AC* 
25-Sep-2014 
90702637 Rev/Ver AD 
See Table 27.1-2 
AD 
23-Apr-2015 
90702637 Rev/Ver AD 
See Table 27.1-3 
AE* 
19-Aug-2015 
90702637 Rev/Ver AE 
See Table 27.1-4 
AF 
07-Dec-2015 
90702637 Rev/Ver AE 
See Table 27.1-5 
AG 
22-Dec-2015 
90702637 Rev/Ver AE 
See Table 27.1-6 
AH 
05-May-2016 
90702637 Rev/Ver AF 
See Table 27.1-7 
AI 
19-Jan-2017 
90702637 Rev/Ver AF 
See Table 27.1-8 
AJ 
06-Jun-2017 
90702637 Rev/Ver AF 
See Table 27.1-9 
AK 
06-Oct-2017 
90702637 Rev/Ver AF 
See Table 27.1-10 
*Versions AA, AC and AE were not implemented. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 2 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 3 of 188 
 
 
2. Protocol Synopsis 
REPRISE III:  REpositionable Percutaneous Replacement of Stenotic Aortic Valve 
through Implantation of Lotus™ Valve System – Randomized Clinical Evaluation 
Objective(s) 
To evaluate the safety and effectiveness of the Lotus™ Valve System and 
LOTUS Edge™ Valve System for transcatheter aortic valve replacement 
(TAVR) in symptomatic subjects with calcific, severe native aortic stenosis 
who are considered at extreme or high risk for surgical valve replacement. 
Intended Use 
The Lotus Valve System and LOTUS Edge Valve System are intended to 
improve aortic valve function for symptomatic subjects with calcific, severe 
native aortic stenosis who are at extreme or high risk for standard surgical 
valve replacement. 
Test Device(s) 
and Sizes 
The Lotus Valve System and LOTUS Edge Valve System consisting of two 
main components: 
 
- a bioprosthetic bovine pericardial aortic valve, and 
 
- a delivery system. 
Devices sizes for the Lotus Valve System include 21 mm, 23 mm, 25 mm, 
and 27 mm diameter. 
Device sizes for the LOTUS Edge Valve System include 23 mm, 25 mm, 
27 mm and 29 mm diameter. 
Note: LOTUS Edge is a design iteration of the Lotus Valve System. In 
addition to the design features of the Lotus Valve System, it has tantalum 
(radiopaque) markers on the valve locking assembly (i.e., buckle and post-
top components) to aid in visualization of locking during the procedure and 
a catheter delivery system designed for improved deliverability. Changes 
between the Lotus Valve System and the LOTUS Edge Valve System 
including the 29 mm valve size are fully described in the Investigator 
Brochure. 
Control Device 
and Sizes 
Commercially available self-expanding CoreValve® Transcatheter Aortic 
Valve Replacement System (CoreValve) that is introduced percutaneously 
via the femoral artery using conventional catheterization techniques 
(Medtronic, Inc., Minneapolis, MN, USA). 
Devices sizes include 26 mm, 29 mm, and 31 mm diameter. 
Note 1: Every subject in the randomized cohort must be deemed treatable 
with an available size of both the test (Lotus) device and the control 
(CoreValve) device. The CoreValve device in the planned size must be 
approved for use and commercially available at the investigational center 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 3 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 4 of 188 
 
 
REPRISE III:  REpositionable Percutaneous Replacement of Stenotic Aortic Valve 
through Implantation of Lotus™ Valve System – Randomized Clinical Evaluation 
where the implant procedure is being performed. 
Note 2: A center may use the CoreValve® Evolut™ R Recapturable TAVR 
System with the aforementioned size matrix if it is approved and 
commercially available, but only if the center no longer has access to 
CoreValve. 
Study Design 
REPRISE III is designed to evaluate the safety and effectiveness of the 
Lotus Valve System and LOTUS Edge Valve System for TAVR in 
symptomatic subjects who have calcific, severe native aortic stenosis and 
who are at high or extreme risk for surgical aortic valve replacement 
(SAVR). Study cohorts include the following. 
 
- A prospective, multicenter, 2:1 randomized (Lotus Valve System 
[23 mm, 25 mm, and 27 mm valve sizes] versus a commercially 
available CoreValve Transcatheter Aortic Valve Replacement 
System [26 mm, 29 mm, and 31 mm valve sizes]), controlled trial 
 
- A non-randomized roll-in phase with only the test device (23 mm, 
25 mm, and 27 mm valve sizes) for centers that do not have previous 
experience implanting the Lotus valve; each of these centers will 
perform at least 2 roll-in cases before commencing randomization. 
Data from roll-in subjects will be summarized separately from the 
randomized population.  
 
- A non-randomized, nested registry cohort of subjects who will 
receive the 21 mm Lotus Valve (Lotus 21 mm Nested Registry). 
Participating centers will be centers that have enrolled subjects in 
REPRISE III. 
 
–  An additional cohort of subjects who will receive the Lotus Valve 
(23 mm, 25 mm, and 27 mm valve sizes) beginning after enrollment 
of the randomized cohort is completed (U.S. Continued Access 
Study cohort). This cohort will be used to further assess performance 
and safety. Participating centers will be United States centers that 
have enrolled subjects in REPRISE III. Selected centers with the 
ability to perform high quality 4D computed tomography (CT) scans 
will include U.S. Continued Access Study subjects in a CT Imaging 
Substudy to assess the prevalence of reduced leaflet mobility and its 
relationship, if any, to clinical events.  
 
- A non-randomized, nested registry cohort of subjects who will 
receive the 23 mm, 25 mm or 27 mm LOTUS Edge Valve (LOTUS 
Edge Nested Registry). Participating centers will be centers that have 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 4 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 5 of 188 
 
 
REPRISE III:  REpositionable Percutaneous Replacement of Stenotic Aortic Valve 
through Implantation of Lotus™ Valve System – Randomized Clinical Evaluation 
enrolled subjects in REPRISE III with the Lotus Valve System. 
- A non-randomized, nested registry cohort of subjects who will 
receive the 29 mm LOTUS Edge Valve (LOTUS Edge 29 mm 
Nested Registry). Participating centers will be centers that have 
enrolled subjects in REPRISE III with the Lotus Valve System. For 
centers that do not have prior experience implanting the LOTUS 
Edge, each will perform at least 2 roll-in cases with the 29 mm 
LOTUS Edge Valve System before commencing enrollment in the 
evaluable registry cohort. Data from the 29 mm roll-in subjects will 
be summarized separately from the evaluable cohort.     
The REPRISE III study will be conducted in accordance with the relevant 
parts of the International Conference on Harmonisation (ICH) Guidelines 
for Good Clinical Practices (GCP) or the International Standard ISO 14155: 
2011; ethical principles that have their origins in the Declaration of 
Helsinki; and pertinent individual country/state/local laws and regulations. 
Planned 
Subjects/ 
Centers/ 
Countries 
Subjects will be enrolled at up to 60 centers in the United States, Canada, 
Western Europe, and Australia. There will be up to 2142 subjects in 
REPRISE III.  
- 
Up to 120 subjects will be enrolled and included in a roll-in phase 
(test device only) among centers that do not have previous experience 
implanting the Lotus Valve (a minimum of 2 roll-in subjects per 
center) before randomization begins.  
- 
There will be 912 subjects enrolled and randomized.  
- 
Up to 20 subjects will be enrolled in the Lotus 21 mm Nested 
Registry.  
- 
After enrollment in the randomized cohort is completed, up to 1000 
subjects will be enrolled in the U.S. Continued Access Study cohort 
to receive the Lotus Valve (23 mm, 25 mm, and 27 mm valve sizes); 
participating centers will be United States centers that have enrolled 
subjects in REPRISE III.  
o Approximately 200 of the 1000 subjects enrolled in the U.S. 
Continued Access Study will be included in a CT Imaging 
Substudy.  
- 
At least 50 subjects will be enrolled in the LOTUS Edge Nested 
Registry (23 mm, 25 mm and 27 mm valve sizes). 
- 
Up to 20 subjects will be enrolled in the LOTUS Edge 29 mm Nested 
Registry. Among centers that do not have prior experience implanting 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 5 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 6 of 188 
 
 
REPRISE III:  REpositionable Percutaneous Replacement of Stenotic Aortic Valve 
through Implantation of Lotus™ Valve System – Randomized Clinical Evaluation 
the LOTUS Edge Valve, up to 20 subjects will be enrolled in the 
LOTUS Edge 29 mm Valve roll-in phase (29 mm valve only; a 
minimum of 2 roll-in subjects per center) before enrolling in the 
LOTUS Edge 29 mm Nested Registry. 
Primary 
Endpoints 
Primary Safety Endpoint: Composite of all-cause mortality, stroke, life-
threatening and major bleeding events, stage 2 or 3 acute kidney injury, or 
major vascular complications at 30 days 
Primary Effectiveness Endpoint: Composite of all-cause mortality, 
disabling stroke, or moderate or greater paravalvular aortic regurgitation 
(based on core lab assessment) at 1 year  
Powered statistical analyses for the primary safety endpoint and the primary 
effectiveness endpoint will be carried out on the randomized cohort. 
Secondary 
Endpoint 
Moderate or greater paravalvular aortic regurgitation (based on core lab 
assessment) at 1 year 
Powered statistical analysis for the secondary endpoint will be carried out 
on the randomized cohort. 
Additional 
Measurements 
Additional measurements based on the VARCa,b endpoints and definitions 
(see Note 1 below) 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, 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 
o Acute kidney injury (≤7 days post index procedure): based on the 
AKIN System Stage 3 (including renal replacement therapy) or 
Stage 2 
o Major vascular complication 
o Repeat procedure for valve-related dysfunction (surgical or 
interventional therapy) 
o Hospitalization for valve-related symptoms or worsening congestive 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 6 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 7 of 188 
 
 
REPRISE III:  REpositionable Percutaneous Replacement of Stenotic Aortic Valve 
through Implantation of Lotus™ Valve System – Randomized Clinical Evaluation 
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) 
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 2 below) 
o Grade of aortic valve regurgitation: paravalvular, central, and 
combined 
 Clinical procedural success (30 days), defined as implantation of the 
study device in the absence of death, disabling stroke, major vascular 
complications, and life-threatening or major bleeding 
 Procedural 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) plus no serious adverse events at 30 days 
 Additional indications of prosthetic aortic valve performance as 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 7 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 8 of 188 
 
 
REPRISE III:  REpositionable Percutaneous Replacement of Stenotic Aortic Valve 
through Implantation of Lotus™ Valve System – Randomized Clinical Evaluation 
measured by transthoracic echocardiography (TTE; see 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 
 Modified device success (30 days), reported for subjects randomized and 
implanted with an assigned study device and defined as follows: absence 
of mortality with the originally implanted transcatheter valve in the 
proper anatomical location, no additional aortic valve procedures, and 
with the intended performance of the prosthetic valve (either a mean 
aortic valve gradient <20 mm Hg or a peak velocity <3m/sec with no 
moderate or severe prosthetic valve aortic regurgitation)   
 For subjects who received a permanent pacemaker related to the index 
procedure, results of pacemaker interrogation at 30 days and 1 year  
 Functional status as evaluated by the following: 
o 5-m gait speed test (at 1 year compared to baseline)  
o New York Heart Association (NYHA) classification 
 Neurological status (see Note 4 below) as determined by the following: 
o Neurological physical exam at discharge and 1 year (conducted by a 
neurologist, neurology fellow, neurology physician assistant, or 
neurology nurse practitioner)  
o National Institutes of Health Stroke Scale (NIHSS) at discharge and 
1 year  
o Modified Rankin Scale (mRS) at all time points 
 Health status as evaluated by Kansas City Cardiomyopathy and SF-12 
Quality of Life questionnaires at baseline; 1 and 6 months; and 1, 3, and 
5 years 
Additionally, assessment of leaflet mobility using 4D CT will be carried out 
at 30 days and 1 year for subjects in the CT Imaging Substudy of the U.S. 
Continued Access Study. The data will be evaluated by an independent CT 
core lab. 
Note 1: The most current VARC definitions and endpoints available at the 
beginning of the trial were used. 
Note 2: For the Lotus Valve (test), repositioning may be achieved with 
partial or full resheathing of the valve. 
Note 3: 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 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 8 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 9 of 188 
 
 
REPRISE III:  REpositionable Percutaneous Replacement of Stenotic Aortic Valve 
through Implantation of Lotus™ Valve System – Randomized Clinical Evaluation 
study performed will be used for analysis. 
Note 4: For subjects diagnosed with a neurological event (e.g., stroke, 
transient ischemic attack), 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; mRS must also be administered 90±14 days post-neurological 
event.   
a:  Kappetein AP, et al. J Am Coll Cardiol. 2012;60:1438 
b:  Leon M, et al. J Am Coll Cardiol. 2011;57:253 
Follow-up 
Schedule 
All subjects implanted with a test or control 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 test or control device at the time of the procedure will be followed 
for safety through 1 year. 
Study 
Duration 
Subjects implanted with a test or control device will be followed for 5 years 
after the procedure. 
Adjunctive 
Pharmacologic 
Therapy 
Anticoagulant Therapy 
Anticoagulant therapy (e.g., unfractionated heparin) per local standard of 
care must be administered during the implant procedure, with a 
recommended target activated clotting time of ≥250 seconds during the 
index procedure. 
Anti-Platelet Therapy 
Per society guidelinesc, antiplatelet therapy with aspirin and clopidogreld is 
recommended after TAVR to decrease the risk of thrombotic or 
thromboembolic complications if there are no contraindications to these 
medications. 
Aspirin 
A loading dose of aspirin (recommended dose of 75–325 mg) is required 
for subjects who have not been taking aspirin for 72 hours at the time of 
the index procedure. The loading dose must be administered prior to the 
implant procedure. Subjects who have been taking aspirin daily for 72 
hours at the time of the index procedure do not require a loading dose. 
After the valve implant procedure, aspirin (recommended dose of ≥75 mg 
daily) must be given for at least 1 month. It is recommended that daily 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 9 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 10 of 188 
 
 
REPRISE III:  REpositionable Percutaneous Replacement of Stenotic Aortic Valve 
through Implantation of Lotus™ Valve System – Randomized Clinical Evaluation 
aspirin be given indefinitely thereafter as per local standard of care.  
Clopidogrel 
A loading dose of clopidogrel (recommended dose of ≥300 mg) is required 
for subjects who have not been taking clopidogrel for 72 hours at the time 
of the index procedure.  The loading dose must be administered prior to the 
implant procedure. 
After the valve implant procedure, clopidogreld (recommended dose of 
75 mg daily) is required for at least 1 month. 
Note: If a subject requires chronic anticoagulation, either clopidogrel or 
aspirin is required prior to and after the implant procedure in addition to the 
anticoagulant therapy (but both aspirin and clopidogrel are not required). 
After the implant procedure, the subject must be treated with warfarin 
(other anticoagulants are not permitted in the first month) and either 
clopidogrel (other P2Y12 inhibitors are not permitted in combination with 
warfarin) or aspirin for at least 1 month. After 1 month, subjects requiring 
chronic anticoagulation may be switched from warfarin 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.  
c:  Holmes, D. R., et al. J Am Coll Cardiol. 2012;59:1200-1254 
 
Nishimura, R., et al. J Am Coll Cardiol. 2014;63:2438-88 
d:  An alternative P2Y12 inhibitor may be prescribed if subject is allergic to 
or intolerant of clopidogrel. 
Inclusion 
Criteria 
IC1.  Subject has documented calcific, severe native aortic stenosis with an 
initial AVA of ≤1.0 cm2 (or AVA index of ≤0.6 cm2/m2) and a mean 
pressure gradient ≥40 mm Hg or jet velocity ≥4.0 m/s, as measured 
by echocardiography and/or invasive hemodynamics. 
IC2.  Subject has a documented aortic annulus size of ≥18 mm and ≤29 mm 
based on the center’s assessment of pre-procedure diagnostic imaging 
(and confirmed by the Case Review Committee [CRC]) and, for the 
randomized cohort, is deemed treatable with an available size of both 
test and control device. For the U.S. Continued Access Study cohort 
the acceptable aortic annulus size is ≥20 mm and ≤27 mm. 
IC3.  Subject has symptomatic aortic valve stenosis with NYHA Functional 
Class ≥ II. 
IC4.   There is agreement by the heart team (which must include a site 
investigator interventionalist and a site investigator cardiac surgeon) 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 10 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 11 of 188 
 
 
REPRISE III:  REpositionable Percutaneous Replacement of Stenotic Aortic Valve 
through Implantation of Lotus™ Valve System – Randomized Clinical Evaluation 
that subject is at high or extreme operative risk for surgical valve 
replacement (see note below for definitions of extreme and high risk, 
the required level of surgical assessment, and CRC confirmation) and 
that TAVR is appropriate. Additionally, subject has at least one of the 
following. 
 Society of Thoracic Surgeons (STS) score ≥8% -OR- 
 If STS <8, subject has at least one of the following conditions:  
o Hostile chest  
o Porcelain aorta  
o Severe pulmonary hypertension (>60 mmHg) 
o Prior chest radiation therapy 
o Coronary artery bypass graft(s) at risk with re-operation 
o Severe lung disease (need for supplemental oxygen, FEV1 
<50% of predicted, DLCO <60%, or other evidence of severe 
pulmonary dysfunction) 
o Neuromuscular disease that creates risk for mechanical 
ventilation or rehabilitation after surgical aortic valve 
replacement 
o Orthopedic disease that creates risk for rehabilitation after 
surgical aortic valve replacement 
o Childs Class A or B liver disease (subjects with Childs Class C 
disease are not eligible for inclusion in this trial) 
o Frailty as indicated by at least one of the following: 5‑meter 
walk >6 seconds, Katz ADL score of 3/6 or less, body mass 
index <21, wheelchair bound, unable to live independently 
o Age ≥90 years 
o Other evidence that subject is at high or extreme risk for 
surgical valve replacement (CRC must confirm agreement with 
site heart team that subject meets high or extreme risk 
definition) 
IC5.  Heart team (which must include a cardiac interventionalist and an 
experienced cardiac surgeon) assessment that the subject is likely to 
benefit from valve replacement.  
IC6.  Subject (or legal representative) understands the study requirements 
and the treatment procedures, and provides written informed consent. 
IC7.  Subject, family member, and/or legal representative agree(s) and 
subject is capable of returning to the study hospital for all required 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 11 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 12 of 188 
 
 
REPRISE III:  REpositionable Percutaneous Replacement of Stenotic Aortic Valve 
through Implantation of Lotus™ Valve System – Randomized Clinical Evaluation 
scheduled follow up visits. 
 
Note: Extreme operative risk and high operative risk are defined as 
follows:  
 
Extreme Operative Risk: Predicted operative mortality or serious, 
irreversible morbidity risk ≥50% at 30 days.  
 
High Operative Risk: Predicted operative mortality or serious, 
irreversible morbidity risk ≥15% at 30 days. 
 
Risk of operative mortality and morbidity 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).  
Exclusion 
Criteria 
EC1.  Subject has a congenital unicuspid or bicuspid aortic valve. 
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 within the past 6 months prior to study enrollment. 
EC4.  Subject has end-stage renal disease 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 a need for emergency surgery for any reason. 
EC8.  Subject has a history of endocarditis within 6 months of index 
procedure or evidence of an active systemic infection or sepsis. 
EC9.  Subject has echocardiographic evidence of new intra-cardiac 
vegetation or intraventricular or paravalvular thrombus requiring 
intervention. 
EC10. Subject has Hgb <9 g/dL, platelet count <50,000 cells/mm3 or 
>700,000 cells/mm3, or white blood cell count <1,000 cells/mm3. 
EC11. Subject requires chronic anticoagulation therapy after the implant 
procedure and cannot be treated with warfarin (other anticoagulants 
are not permitted in the first month) for at least 1 month concomitant 
with either aspirin or clopidogrel. 
 
EC12. Subject 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 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 12 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 13 of 188 
 
 
REPRISE III:  REpositionable Percutaneous Replacement of Stenotic Aortic Valve 
through Implantation of Lotus™ Valve System – Randomized Clinical Evaluation 
treatment with required antiplatelet regimen, or will refuse 
transfusions. 
EC13. Subject has known hypersensitivity to contrast agents that cannot be 
adequately pre-medicated, or has known hypersensitivity to aspirin, 
all P2Y12 inhibitors, heparin, nickel, tantalum, titanium, or 
polyurethanes. 
EC14. Subject has a life expectancy of less than 12 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 implantation, which are allowed).  
EC17. Subject has untreated coronary artery disease, which in the opinion 
of the treating physician is clinically significant and requires 
revascularization. 
EC18. Subject has 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 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 symptomatic carotid or vertebral 
disease).  
EC21. Subject has thick (>5 mm) protruding or ulcerated atheroma in the 
aortic arch  
EC22. Subject has arterial access that is not acceptable for the test and 
control device delivery systems as defined in the device Instructions 
For Use. 
EC23. Subject has current problems with substance abuse (e.g., alcohol, 
etc.). 
EC24. Subject is participating in another investigational drug or device 
study that has not reached its primary endpoint. 
EC25. 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 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 13 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 14 of 188 
 
 
REPRISE III:  REpositionable Percutaneous Replacement of Stenotic Aortic Valve 
through Implantation of Lotus™ Valve System – Randomized Clinical Evaluation 
implantation.   
EC26. Subject has severe incapacitating dementia.  
Additional exclusion criteria apply for subjects considered for enrollment in 
the CT Imaging substudy of the U.S. Continued Access Study 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 TAVR 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. 
Statistical Methods 
Analysis Sets 
Analysis sets for the randomized cohort are listed below. 
As-Treated: This population includes all subjects who sign an Informed 
Consent Form, are enrolled in the trial, are randomized, and received a 
study device, but is based on the treatment actually received. 
Intention-To-Treat (ITT): 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. 
Implanted: 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. 
For all randomized cohort analysis sets, if a subject receives 2 valves, the 
subject is assigned to the group corresponding to the first valve received. 
Among the roll-in (initial cohort with the 23, 25 and 27 mm Lotus), Lotus 
21 mm Nested Registry, LOTUS Edge Nested Registry, roll-in with the 
29 mm LOTUS Edge, LOTUS Edge 29 mm Nested Registry, and U.S. 
Continued Access cohorts, for ITT analyses all subjects who sign an 
Informed Consent Form and are enrolled in the study will be included in 
the analysis sample, regardless of whether the study device was implanted. 
The As-Treated population is the same as the Implanted population for 
these cohorts and includes all subjects who sign an Informed Consent Form 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 14 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 15 of 188 
 
 
REPRISE III:  REpositionable Percutaneous Replacement of Stenotic Aortic Valve 
through Implantation of Lotus™ Valve System – Randomized Clinical Evaluation 
and are implanted with the Lotus Valve. 
Primary 
Safety 
Endpoint 
Statistical 
Hypothesis 
The primary safety endpoint (composite of all-cause mortality, stroke, life-
threatening and major bleeding events, stage 2 or 3 acute kidney injury, or 
major vascular complications at 30 days) rate for the Lotus Valve is non-
inferior to that for CoreValve.  
Statistical Test 
Method for the 
Primary 
Safety 
Endpoint 
A Farrington-Manning standardized test will be used to test the one-sided 
hypothesis of non-inferiority of the Lotus Valve versus CoreValve: 
 
H0: PS_Lotus minus PS_Control ≥ Δ (Inferior) 
 
H1: PS_Lotus minus PS_Control < Δ (Non-inferior) 
where PS_Lotus and PS_Control are the rates of the primary safety endpoint for 
the Lotus Valve group (test) and the CoreValve group (control), 
respectively, and Δ (delta) is the non-inferiority margin. 
The primary analysis set for the primary safety endpoint is the implanted 
analysis set. This endpoint will also be analyzed for the ITT and as-treated 
analysis sets.  
Sample Size 
Parameters 
for the 
Primary 
Safety 
Endpoint 
 Expected Lotus Valve (test) rate = 40% 
 Expected CoreValve (control) rate = 40% 
 Non-inferiority margin (Δ) = 10.5% 
 Test significance level () = 0.025 (1-sided) 
 Test : Control ratio = 2:1 
 Expected rate of attrition = 5% 
 Given enrollment of 912 subjects (608 Lotus Valve, 304 CoreValve) and 
5% attrition, there is approximately 85% power to show non-inferiority 
with the given expected rates 
Success 
Criteria for 
the Primary 
Safety 
Endpoint 
If the P value from the Farrington-Manning standardized test is <0.025, the 
rate of the primary safety endpoint for the Lotus Valve will be concluded to 
be non-inferior to the CoreValve rate. This corresponds to the one-sided 
upper 97.5% confidence bound on the difference between treatment groups 
(Lotus Valve minus CoreValve) for the observed rate of the primary safety 
endpoint being less than delta. 
Primary 
Effectiveness 
The primary effectiveness endpoint (composite of all-cause mortality, 
disabling stroke, or moderate or greater paravalvular aortic regurgitation 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 15 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 16 of 188 
 
 
REPRISE III:  REpositionable Percutaneous Replacement of Stenotic Aortic Valve 
through Implantation of Lotus™ Valve System – Randomized Clinical Evaluation 
Endpoint 
Statistical 
Hypothesis 
[based on core lab assessment] at 1 year) rate for the Lotus Valve group is 
noninferior to that for the CoreValve group. If non-inferiority is shown for 
the Lotus group for the primary safety and primary effectiveness endpoints, 
superiority is shown for the secondary endpoint, and the rate for the Lotus 
group is less than the rate for the CoreValve group for the primary 
effectiveness endpoint, then a test of superiority will be performed for the 
primary effectiveness endpoint. 
Statistical Test 
Method for the 
Primary 
Effectiveness 
Endpoint ‒ 
Non-
Inferiority 
A Farrington-Manning standardized test will be used to test the one-sided 
hypothesis of non-inferiority of the Lotus Valve versus CoreValve: 
 
H0: PE_Lotus minus PE_Control ≥ Δ (Inferior) 
 
H1: PE_Lotus minus PE_Control < Δ (Non-inferior) 
where PE_Lotus and PE_Control correspond to the rates of the primary 
effectiveness endpoint for the Lotus Valve group (test) and the CoreValve 
group (control), respectively. 
The primary analysis set for the primary effectiveness endpoint is the 
implanted analysis set. This endpoint will also be analyzed for the ITT and 
as-treated analysis sets. 
Sample Size 
Parameters 
for the 
Primary 
Effectiveness 
Endpoint ‒ 
Non-
Inferiority 
 Expected Lotus Valve (test) rate PE_Lotus = 32%  
 Expected CoreValve (control) rate PE_Control = 32% 
 Non-inferiority margin (Δ) = 9.5% 
 Test significance level () = 0.025 (1-sided) 
 Test : Control ratio = 2:1 
 Power (1) = 80% 
 Total number of evaluable subjects = 819 
 Expected rate of attrition = 10% 
N = 912 subjects (608 Lotus Valve, 304 CoreValve) 
Success 
Criteria for 
the Primary 
Effectiveness 
Endpoint ‒ 
Non-
Inferiority 
If the P value from the Farrington-Manning standardized test is <0.025, the 
rate of the primary effectiveness endpoint for the Lotus Valve will be 
concluded to be non-inferior to the CoreValve rate. This corresponds to the 
one-sided upper 97.5% confidence bound on the difference between 
treatment groups (Lotus Valve minus CoreValve) for the observed rate of 
the primary effectiveness endpoint being less than delta. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 16 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 17 of 188 
 
 
REPRISE III:  REpositionable Percutaneous Replacement of Stenotic Aortic Valve 
through Implantation of Lotus™ Valve System – Randomized Clinical Evaluation 
Statistical Test 
Method for the 
Primary 
Effectiveness 
Endpoint – 
Superiority 
A chi-square test will be used to test the two-sided hypothesis of superiority 
of the Lotus Valve versus CoreValve: 
 
H0: PE_Lotus = PE_Control 
 
H1: PE_Lotus ≠ PE_Control  
where PE_Lotus and PE_Control correspond to the rates of the primary 
effectiveness endpoint for the Lotus Valve group (test) and the CoreValve 
group (control), respectively. 
The primary analysis set for superiority test of the primary effectiveness 
endpoint is the ITT analysis set. This endpoint will also be analyzed for the 
as-treated and implanted analysis sets. 
Sample Size 
Parameters 
for the 
Primary 
Effectiveness 
Endpoint ‒ 
Superiority 
 Expected Lotus Valve (test) rate PE_Lotus = 22%  
 Expected CoreValve (control) rate PE_Control = 32% 
 Test significance level () = 0.05 (2-sided) 
 Test : Control ratio = 2:1 
 Power (1) = 80% 
 Total number of evaluable subjects = 684 
 Expected rate of attrition = 10% 
 Given enrollment of 912 subjects (608 Lotus Valve, 304 CoreValve) and 
10% attrition, there is approximately 86% power to show superiority 
with the given expected rates 
Success 
Criteria for 
the Primary 
Effectiveness 
Endpoint ‒ 
Superiority 
If the P value from the chi-square test is <0.05 and the rate of the Lotus 
Valve group is less than the rate of the CoreValve group, the rate of the 
primary effectiveness endpoint for the Lotus Valve will be concluded to be 
superior to the CoreValve rate. This corresponds to the two-sided upper 
95% confidence bound on the difference between treatment groups (Lotus 
Valve minus CoreValve) for the observed rate of the primary effectiveness 
endpoint being less than zero. 
Secondary 
Endpoint 
Statistical 
Hypothesis 
The secondary endpoint of moderate or greater paravalvular aortic 
regurgitation rate at 1 year (based on core lab assessment) for the Lotus 
Valve group is superior to that for the CoreValve group. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 17 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 18 of 188 
 
 
REPRISE III:  REpositionable Percutaneous Replacement of Stenotic Aortic Valve 
through Implantation of Lotus™ Valve System – Randomized Clinical Evaluation 
Statistical Test 
Method for the 
Secondary 
Endpoint 
A chi-square test will be used to test the two-sided hypothesis of 
superiority: 
 
H0: PAR_Lotus = PAR_Control  
 
H1: PAR_Lotus ≠ PAR_Control    
where PAR_Lotus and PAR_Control correspond to the moderate or greater 
paravalvular aortic regurgitation rates at 1 year for the Lotus Valve group 
(test) and the CoreValve group (control), respectively. 
The primary analysis set for the secondary endpoint is the ITT analysis set.  
This endpoint will also be analyzed for the as-treated and implanted 
analysis sets. 
Sample Size 
Parameters 
for the 
Secondary 
Endpoint 
 Expected Lotus Valve (test) rate PAR_Lotus  = 1.1% 
 Expected CoreValve (control) rate PAR_Control = 5.3% 
 Test significance level () = 0.05 (2-sided) 
 Test : Control ratio = 2:1 
 Expected rate of attrition = 25% 
 Given enrollment of 912 subjects (608 Lotus Valve, 304 CoreValve) and 
25% attrition, there is approximately 86% power to show superiority 
with the given expected rates 
Success 
Criteria for 
the Secondary 
Endpoint 
If the P value from the chi square test is <0.05, and the rate of moderate or 
greater paravalvular aortic regurgitation at 1 year for the Lotus Valve group 
is less than the rate of the CoreValve group, the moderate or greater 
paravalvular aortic regurgitation rate at 1 year for the Lotus Valve group 
will be concluded to be superior to that of the CoreValve group. This 
corresponds to the two-sided upper 95% confidence bound on the 
difference between treatment groups (Lotus Valve minus CoreValve) for 
the observed rate of the secondary endpoint being less than zero. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 18 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 19 of 188 
 
 
3. Table of Contents 
1. 
TITLE PAGE  ........................................................................................................................ 1 
2. 
PROTOCOL SYNOPSIS .......................................................................................................... 3 
3. 
TABLE OF CONTENTS ........................................................................................................ 19 
3.1. Table of Figures ...................................................................................................... 24 
3.2. Table of Tables ....................................................................................................... 24 
4. 
INTRODUCTION ................................................................................................................. 26 
4.1. Justification for the Use of the Investigational Device in Human Subjects ...... 26 
4.1.1. 
Treatments for Aortic Stenosis .................................................................. 26 
4.1.2. 
REPRISE I Study ....................................................................................... 30 
4.1.3. 
REPRISE II Study ..................................................................................... 32 
4.1.4. 
REPRISE NG DS Study ............................................................................ 37 
4.2. Justification for the Study ..................................................................................... 41 
5. 
DEVICE DESCRIPTION ....................................................................................................... 41 
5.1. Lotus Valve System and LOTUS Edge Valve System Investigational Devices 
(Test) ........................................................................................................................ 42 
5.1.1. 
Lotus Valve and LOTUS Edge Valve ....................................................... 42 
5.1.2. 
Lotus and LOTUS Edge Delivery System ................................................. 43 
5.1.3. 
Lotus Introducer Set .................................................................................. 44 
5.2. CoreValve Transcatheter Aortic Valve Replacement System (Control) .......... 45 
5.3. Device Labeling ...................................................................................................... 45 
5.3.1. 
Test Device ................................................................................................ 45 
5.3.2. 
Control Device ........................................................................................... 46 
6. 
OBJECTIVES ...................................................................................................................... 46 
7. 
ENDPOINTS ........................................................................................................................ 46 
7.1. Primary Endpoints ................................................................................................. 46 
7.1.1. 
Primary Safety Endpoint ............................................................................ 46 
7.1.2. 
Primary Effectiveness Endpoint ................................................................ 47 
7.1.3. 
Secondary Endpoint ................................................................................... 47 
7.2. Additional Measurements ..................................................................................... 47 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 19 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 20 of 188 
 
 
8. 
DESIGN .............................................................................................................................. 50 
8.1. Scale and Duration ................................................................................................. 50 
8.2. Treatment Assignment........................................................................................... 51 
8.2.1. 
Treatment ................................................................................................... 52 
8.3. Study Design Justification ..................................................................................... 52 
9. 
SUBJECT SELECTION ......................................................................................................... 53 
9.1. Study Population and Eligibility ........................................................................... 53 
9.2. Inclusion Criteria ................................................................................................... 53 
9.3. Exclusion Criteria .................................................................................................. 54 
10. SUBJECT ACCOUNTABILITY .............................................................................................. 56 
10.1. Point of Enrollment ................................................................................................ 56 
10.1.1. Roll-in Subjects ......................................................................................... 56 
10.1.2. Randomized Subjects ................................................................................. 56 
10.1.3. Lotus 21 mm Nested Registry Subjects ..................................................... 57 
10.1.4. U.S. Continued Access Study Subjects ..................................................... 57 
10.1.5. LOTUS Edge 23−27 mm Nested Registry Subjects ................................. 57 
10.1.6. LOTUS Edge 29 mm Roll-in and Nested Registry Subjects ..................... 57 
10.2. Withdrawal ............................................................................................................. 57 
11. STUDY METHODS .............................................................................................................. 58 
11.1. Data Collection ....................................................................................................... 58 
11.2. Study Candidate Screening ................................................................................... 64 
11.3. Subject Informed Consent ..................................................................................... 64 
11.4. Screening Assessments ........................................................................................... 65 
11.5. Baseline Assessments ............................................................................................. 67 
11.6. Preprocedure Medications .................................................................................... 67 
11.7. Index Procedure ..................................................................................................... 68 
11.7.1. Medtronic CoreValve (Control) Cohort .................................................... 68 
11.7.2. Lotus Valve (Test) Cohort ......................................................................... 69 
11.7.2.1. Valvuloplasty ............................................................................ 69 
11.7.2.2. Preparing and Using the Lotus Valve System or LOTUS Edge 
Valve System ............................................................................ 69 
11.8. Post-Procedure ....................................................................................................... 71 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 20 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 21 of 188 
 
 
11.9. Prior to Discharge or 7 Days Post-Procedure (Whichever Comes First) ......... 72 
11.10. 
Follow-up .................................................................................................. 73 
11.10.1. 30-Day Follow-up (307 Days) ................................................................. 74 
11.10.2. 6-Month (18030 Days) Follow-up ........................................................... 75 
11.10.3. 12-Month (36530 Days) Follow-up ......................................................... 76 
11.10.4. Annual Follow-up (45 Days) ................................................................... 77 
11.10.5. Management of Missed or Late Visits ....................................................... 78 
11.10.6. Procedure for Determining when a Subject is Lost to Follow-up ............. 78 
11.10.7. Withdrawal and Replacement of Subjects ................................................. 78 
11.10.8. Explant Procedure ...................................................................................... 78 
11.11. 
Study Completion .................................................................................... 79 
11.12. 
Source Documents ................................................................................... 79 
12. STATISTICAL CONSIDERATIONS ....................................................................................... 79 
12.1. Endpoints ................................................................................................................ 79 
12.1.1. Primary Safety Endpoint ............................................................................ 80 
12.1.1.1. Statistical Hypothesis for the Primary Safety Endpoint ........... 80 
12.1.1.2. Sample Size Parameters for the Primary Safety Endpoint........ 80 
12.1.1.3. Statistical Methods – Primary Safety Endpoint ........................ 81 
12.1.2. Primary Effectiveness Endpoint ................................................................ 81 
12.1.2.1. Statistical Hypothesis for the Primary Effectiveness Endpoint 81 
12.1.2.2. Sample Size Parameters for the Primary Effectiveness 
Endpoint .................................................................................... 82 
12.1.2.3. Statistical Methods – Primary Effectiveness Endpoint ............. 83 
12.1.3. Secondary Endpoint ................................................................................... 83 
12.1.3.1. Statistical Hypothesis for the Secondary Endpoint ................... 83 
12.1.3.2. Sample Size Parameters for the Secondary Endpoint ............... 84 
12.1.3.3. Statistical Methods – Secondary Endpoint ............................... 84 
12.1.4. Baseline Comparability ............................................................................. 84 
12.1.5. Post-procedure Measurements ................................................................... 85 
12.1.6. Subgroup Analyses for Randomized Subjects ........................................... 85 
12.1.7. Subgroup Analyses for U.S. Continued Access Study Subjects ............... 85 
12.2. General Statistical Methods .................................................................................. 86 
12.2.1. Analysis Sets .............................................................................................. 86 
12.2.2. Control of Systematic Error/Bias ............................................................... 86 
12.2.3. Randomization Scheme ............................................................................. 87 
12.2.4. Reporting Events ....................................................................................... 87 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 21 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 22 of 188 
 
 
12.3. Data Analyses ......................................................................................................... 87 
12.3.1. Other Measurements .................................................................................. 87 
12.3.2. Interim Analyses ........................................................................................ 88 
12.3.3. Justification of Pooling .............................................................................. 88 
12.3.4. Multivariable Analyses .............................................................................. 88 
12.3.5. Changes to Planned Analyses .................................................................... 88 
13. DATA MANAGEMENT ........................................................................................................ 89 
13.1. Data Collection, Processing, and Review ............................................................. 89 
13.2. Data Retention ........................................................................................................ 89 
13.3. Core Laboratories .................................................................................................. 90 
13.3.1. Transthoracic Echocardiography (TTE) Core Laboratory ........................ 90 
13.3.2. CT and Rotational X-Ray Angiography Core Laboratory ........................ 90 
13.3.3. Electrocardiography (ECG) Core Laboratory ........................................... 90 
13.3.4. Histopathology Core Laboratory ............................................................... 90 
14. AMENDMENTS ................................................................................................................... 90 
15. DEVIATIONS ...................................................................................................................... 90 
16. DEVICE ACCOUNTABILITY ............................................................................................... 91 
16.1. Investigational Device ............................................................................................ 91 
16.2. Control Device ........................................................................................................ 92 
17. COMPLIANCE ..................................................................................................................... 92 
17.1. Statement of Compliance ....................................................................................... 92 
17.2. Investigator Responsibilities ................................................................................. 92 
17.2.1. Delegation of Responsibility ..................................................................... 94 
17.3. Institutional Review Board/ Ethics Committee ................................................... 94 
17.4. Sponsor Responsibilities ........................................................................................ 95 
17.4.1. Training with the Lotus Valve System/LOTUS Edge Valve System ........ 95 
17.4.2. Role of Boston Scientific Corporation Representatives ............................ 96 
17.5. Insurance ................................................................................................................. 96 
18. MONITORING ..................................................................................................................... 96 
19. POTENTIAL RISKS AND BENEFITS .................................................................................... 97 
19.1. Risks Associated with Transcatheter Aortic Valve Implantation Procedure .. 97 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 22 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 23 of 188 
 
 
19.2. Risk Minimization Actions .................................................................................... 99 
19.3. Anticipated Benefits ............................................................................................. 100 
19.3.1. Potential Benefits to the TAVR Procedure .............................................. 100 
19.3.2. Potential Benefit Using the Lotus Valve System/LOTUS Edge Valve 
System...................................................................................................... 101 
19.4. Risk to Benefit Rationale ..................................................................................... 101 
20. INFORMED CONSENT....................................................................................................... 101 
21. SAFETY REPORTING ........................................................................................................ 103 
21.1. Definitions and Classification ............................................................................. 103 
21.2. Relationship to Study Device(s) .......................................................................... 105 
21.3. Investigator Reporting Requirements ................................................................ 106 
21.4. Device Deficiencies ............................................................................................... 107 
21.4.1. Boston Scientific Device Deficiencies .................................................... 107 
21.4.2. Control Device Deficiencies .................................................................... 108 
21.5. Reporting to Regulatory Authorities / IRBs / ECs / Investigators .................. 108 
22. COMMITTEES .................................................................................................................. 108 
22.1. Safety Monitoring Process ................................................................................... 108 
22.1.1. Clinical Events Committee ...................................................................... 108 
22.1.2. Data Monitoring Committee .................................................................... 109 
22.2. Case Review Committee ...................................................................................... 109 
22.3. Steering Committee .............................................................................................. 109 
23. SUSPENSION OR TERMINATION ...................................................................................... 109 
23.1 Premature Termination of the Study ................................................................. 109 
23.1.1 
Criteria for Premature Termination of the Study ..................................... 110 
23.2 Termination of Study Participation by the Investigator or Withdrawal of 
IRB/EC Approval ................................................................................................. 110 
23.3 Requirements for Documentation and Subject Follow-up ............................... 110 
23.4 Criteria for Suspending/Terminating a Study Center ...................................... 110 
24. PUBLICATION POLICY ..................................................................................................... 111 
25. BIBLIOGRAPHY ................................................................................................................ 111 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 23 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 24 of 188 
 
 
26. ABBREVIATIONS AND DEFINITIONS ................................................................................ 121 
26.1. Abbreviations ....................................................................................................... 121 
26.2. Definitions ............................................................................................................. 123 
27. APPENDICES .................................................................................................................... 136 
27.1. Changes in Protocol Versions ............................................................................. 136 
27.1.1. Protocol Version AA to Version AB ....................................................... 136 
27.1.2. Protocol Version AB to Version AC ....................................................... 136 
27.1.3. Protocol Version AC to Version AD ....................................................... 136 
27.1.4. Protocol Version AD to Version AE ....................................................... 136 
27.1.5. Protocol Version AE to Version AF ........................................................ 136 
27.1.6. Protocol Version AF to Version AG ....................................................... 136 
27.1.7. Protocol Version AG to Version AH ....................................................... 137 
27.1.8. Protocol Version AH to Version AI ........................................................ 137 
27.1.9. Protocol Version AI to Version AJ .......................................................... 137 
27.1.10. Protocol Version AJ to Version AK ........................................................ 137 
 
3.1. Table of Figures 
Figure 5.1-1: Lotus™ Valve System and LOTUS Edge™ Valve System ............................. 42 
Figure 5.1-2: Lotus and LOTUS Edge Valve Implant ............................................................ 43 
Figure 5.1-3: Lotus Controller ................................................................................................ 44 
Figure 11.1-1: REPRISE III Study Design ............................................................................. 59 
 
3.2. Table of Tables 
Table 4.1-1: Events from Peri-Operative to 30 Days (Transfemoral Approach) ................... 28 
Table 4.1-2: 30-Day Outcomes in REPRISE II Main Cohort (N=120) .................................. 33 
Table 4.1-3: 1-Year and 2-Year Outcomes in REPRISE II Main Cohort (N=120) ................ 34 
Table 4.1-4: 30-Day and 1-Year Outcomes in the REPRISE II Full Cohort (N=250) ........... 36 
Table 4.1-5: Echocardiographic Outcomes in REPRISE NG DS Cohorts A and B............... 38 
Table 4.1-6: Clinical Outcomes in REPRISE NG DS Cohorts A and B ................................ 38 
Table 4.1-7: Echocardiographic Outcomes in REPRISE NG DS Cohort C ........................... 40 
Table 4.1-8: Clinical Outcomes in REPRISE NG DS Cohort C ............................................ 40 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 24 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 25 of 188 
 
 
Table 9.2-1: REPRISE III Inclusion Criteria .......................................................................... 53 
Table 9.3-1: REPRISE III Exclusion Criteria ......................................................................... 54 
Table 9.3-2: Additional Exclusion Criteria for the 4D CT Imaging Substudy of the U.S. 
Continued Access Study ...................................................................................... 56 
Table 11.1-1: Study Event Schedule ....................................................................................... 60 
Table 21.1-1: Adverse Event Definitions ............................................................................. 103 
Table 21.2-1: Criteria for Assessing Relationship of Study Device to Adverse Event ........ 106 
Table 21.3-1: Investigator Reporting Requirements ............................................................. 106 
Table 26.1-1: Abbreviations and Acronyms ......................................................................... 121 
Table 26.2-1: Definitions ...................................................................................................... 123 
Table 27.1-1: Table of Changes for REPRISE III Protocol Version AB (Compared to 
REPRISE III Protocol Version AA) .................................................................. 138 
Table 27.1-2: Table of Changes for REPRISE III Protocol Version AC (Compared to 
REPRISE III Protocol Version AB) .................................................................. 138 
Table 27.1-3: Table of Changes for REPRISE III Protocol Version AD (Compared to 
REPRISE III Protocol Version AC) .................................................................. 139 
Table 27.1-4: Table of Changes for REPRISE III Protocol Version AE (Compared to 
REPRISE III Protocol Version AD) .................................................................. 152 
Table 27.1-5: Table of Changes for REPRISE III Protocol Version AF (Compared to 
REPRISE III Protocol Version AE) .................................................................. 153 
Table 27.1-6: Table of Changes for REPRISE III Protocol Version AG (Compared to 
REPRISE III Protocol Version AF) ................................................................... 160 
Table 27.1-7: Table of Changes for REPRISE III Protocol Version AH (Compared to 
REPRISE III Protocol Version AG) .................................................................. 163 
Table 27.1-8: Table of Changes for REPRISE III Protocol Version AI  (Compared to 
REPRISE III Protocol Version AH) .................................................................. 168 
Table 27.1-9: Table of Changes for REPRISE III Protocol Version AJ  (Compared to 
REPRISE III Protocol Version AI) .................................................................... 180 
Table 27.1-10: Table of Changes for REPRISE III Protocol Version AK (Compared to 
REPRISE III Protocol Version AJ) ................................................................... 188 
 
 
 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 25 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 26 of 188 
 
 
4. Introduction 
This protocol specifies procedures and contains information relevant to the clinical 
evaluation of the Lotus™ Valve System and LOTUS Edge™ Valve System, transfemoral 
aortic valve replacement devices designed and manufactured by Boston Scientific Structural 
Heart a Division of Boston Scientific Corporation (BSC). The Lotus Valve System and 
LOTUS Edge™ Valve System both consist of a pre-loaded, stent-mounted tissue valve 
prosthesis and catheter delivery system designed to enable predictable and precise placement 
of the valve during transcatheter aortic valve replacement (TAVR). Early leaflet function 
during valve deployment and the presence of a radiopaque tantalum marker on the braided 
frame 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 leakage. 
Additionally, the LOTUS Edge valve has tantalum (radiopaque) markers on the valve 
locking assembly (i.e., buckle and post-top components) to aid in visualization of locking 
during the procedure and a catheter delivery system designed for improved deliverability. 
More detailed description of the devices can be found in Section 5 and in the Investigator 
Brochure. With the Lotus Valve System as the test device, study subjects will be entered into 
the roll-in cohort, randomized (test versus control) cohort, a single-arm, nested registry 
cohort of subjects who receive the 21 mm Lotus Valve (Lotus 21 mm Nested Registry), or 
the U.S. Continued Access Study cohort (which will include a 4D computed tomography 
[CT] substudy cohort). Study subjects will also be enrolled in a single-arm, nested registry 
with the 23 mm, 25 mm, and 27 mm LOTUS Edge Valve System (LOTUS Edge Nested 
Registry). Additionally, study subjects will be entered into a roll-in cohort and a single-arm, 
nested registry cohort of subjects who receive the 29 mm LOTUS Edge Valve System 
(LOTUS Edge 29 mm Nested Registry). Additional information on study design can be 
found in Section 8. 
4.1. 
Justification for the Use of the Investigational Device in Human Subjects 
4.1.1. Treatments for Aortic Stenosis  
The incidence of aortic stenosis (AS), 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 as a result of an 
aging population4-6. Aortic stenosis is associated with high rates of death and complications 
after the appearance of symptoms7,8.  
The standard of care for AS in patients who do not have serious comorbidities is surgical 
aortic valve replacement (SAVR), which has been shown to reduce symptoms and improve 
survival5,7,9-11. Between 1999 and 2011, the rate of surgical AVR for elderly subjects in the 
United States has increased and outcomes have improved11. However, up to one-third of 
patients with severe AS are not treated with SAVR because of their comorbidities and 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 26 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 27 of 188 
 
 
consequent peri-operative risk (e.g., advanced age, left ventricular dysfunction, etc.)5,12-14. 
With standard medical therapy, mortality after 1 year among these patients may be as high as 
50%13-15. Percutaneous transluminal aortic valvuloplasty, which was introduced as an 
alternative to SAVR in elderly and/or high-surgical-risk subjects, can provide symptomatic 
relief and/or temporary improvement but does not provide definitive treatment in subjects 
with severe calcific AS. It is also associated with relatively high mortality and complication 
rates16. 
Transcatheter aortic valve replacement (TAVR) has recently emerged as a less invasive 
treatment strategy in subjects who are not suitable candidates for open-heart surgery17-21 and 
more than 60,000 transcatheter aortic valve prostheses have been implanted worldwide22. 
Patients with severe aortic stenosis undergo a joint interdisciplinary screening process, 
including comprehensive multimodality imaging23-26, prior to procedure recommendation. 
Because existing surgical risk scores imperfectly characterize risk27-30, center Heart Teams 
also consider other co-morbidities and patient frailty. While not captured well by any of the 
standard risk scores, these added measures help to more fully characterize a patient 
population that potentially benefits from TAVR31.  
Transcatheter aortic valve replacement was initially performed through a retrograde 
transfemoral approach and an antegrade transapical approach. Two additional retrograde 
approaches, transaortic through the ascending aorta and trans-subclavian, were subsequently 
described19,32. Evidence of the safety of the procedure using either a balloon expandable or a 
self-expanding bioprosthetic heart valve has rapidly accumulated through observational 
studies33-39, device-specific registries40-54, and national registries55-62. In the randomized 
Placement of Aortic Transcatheter Valves (PARTNER) trial, patients unsuitable for surgical 
valve replacement who underwent TAVR with a balloon-expandable device experienced 
significant reductions in mortality and repeat hospitalization compared to those receiving 
conventional medical therapy at 1 and 2 years14,63 and high-surgical-risk patients receiving 
either TAVR or surgical replacement had a similar mortality risk64,65. In the randomized U.S. 
CoreValve High Risk Study, TAVR with a self-expanding transcatheter aortic-valve 
bioprosthesis was associated with a significantly higher rate of survival at 1 year compared to 
SAVR66. 
Recently, reduced aortic valve leaflet motion, mainly asymptomatic, has been identified with 
follow-up CT among some TAVR subjects67,68. 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.  
A recently published expert consensus document lists TAVR as a reasonable alternative to 
SAVR in AS patients with high surgical risk8 and a subsequent consensus document outlines 
patient selection for TAVR.69  The potential of TAVR to be a treatment option for a 
considerable number of patients with AS has resulted in significant advances in the 
technology aiming to simplify the procedure and minimize adverse events70,71. Standardized 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 27 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 28 of 188 
 
 
endpoint definitions were published by the Valve Academic Research Consortium (VARC) 
in 2011 (VARC-172) and updated in 2012 (VARC-273). 
Table 4.1-1 summarizes the peri-operative event rates through 30 days post-procedure from 
several TAVR studies that enrolled subjects similar to those planned for this study, as well as 
results from inoperable and high risk subjects in PARTNER, the U.S. CoreValve Extreme 
Risk Pivotal Trial, and the U.S. CoreValve High Risk Study. A more detailed summary of 
the available literature is presented in the Investigator Brochure. 
Table 4.1-1: Events from Peri-Operative to 30 Days (Transfemoral Approach) 
Study  
Device/N 
Death  
(%) 
MI  
(%) 
Stroke* 
(%) 
Bleeding  
(%) 
AKI 
 (%) 
VC  
(%) 
Webb, et al. 
200933 
EW/113a 
8 
N/A 
5.3 
11.6 
4.4 
8 
Rodés-Cabau, 
et al. 201041 
EW/168a 
9.5 
0.6 
3.0 
N/A 
N/A 
N/A 
Thomas, et al. 
201042 
EW/463a 
6.3 
N/A 
2.4 
9.9  
1.3  
22.9 
Leon, et al. 
201014 
EW/267b 
5 
0 
5 
16.8 
1.1 
16.2c 
30.7 
Smith, et al. 
201164 
EW/244a,d 
3.4 
0 
3.8 
9.3 
2.9 
14c 
22.7 
Piazza, et al. 
200840 
CV/646 
8 
0.6 
1.9e  
N/A 
N/A 
1.2 
Munoz-Garcia, 
et al. 201274 
CV/133f 
4.5 
0.8 
1.5 
N/A 
N/A 
2.2c 
Buchanan, et 
al. 201135 
CV, EW/305 
4.7 
1.3 
1.0 
33.1 
10.2g 
15.7c 
Moat, et al. 
201157 
CV, EW/599 
5.5 
1.0 
4.0h 
N/A 
N/A 
6.2 
Zahn, et al. 
201156 
CV, EW/697i 
12.4 
0.3 
2.8e  
N/A 
N/A 
17.1j  
Bosmans, et al. 
201158 
CV/133a 
EW/99a 
8 CV; 
6 EW 
N/A 
5e,k 
N/A 
6k,l  
N/A 
Tamburino, et 
al. 201236 
CV, EW/218m 
6.9 
0.0 
2.3 
5.5 
N/A 
N/A 
Gilard, et al. 
201259 
CV, 
EW/2361a 
8.5 
0.8 
2.2 
1.2n 
N/A 
5.5c 
Spargias, et al. 
201360 
CV/67, 
EW/59 
1.0 
N/A 
0.0e 
2.0c 
N/A 
9.0o 
Mack, et al. 
201362 
EW/3833a,d,h 
EW/1139a,b,h 
EW/1687a,d 
EW/489a,b 
3.8a,d,h 
5.4a,b,h 
5.0a,d 
6.7a,b 
0.5a,d,h 
0.8a,b,h 
N/Aa,b,d 
3.8a,d,e,h 
5.4a,b,e,h 
3.2a,d,e 
1.6a,b,e 
3.2a,c,d,h 
3.6a,b,c,h 
N/Aa,b,d 
1.3a,d,h,l 
1.7a,b,h,l 
1.5 a,d,l 
1.6 a,b,l 
6.4c,h,k 
Popma, et al. 
201475 
CV/489b 
8.4 
1.2 
2.3 
12.7n 
24.9c 
11.8 
8.2c 
Adams, et al. 
201466 
CV/390a,d 
3.3 
0.8 
3.9 
13.6n 
28.1c 
6.0 
5.9c 
Van Mieghem, 
EW&XT/281 
6.1 
1.2 
2.2 
13.2n 
7.3p 
11.5c 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 28 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 29 of 188 
 
 
Table 4.1-1: Events from Peri-Operative to 30 Days (Transfemoral Approach) 
Study  
Device/N 
Death  
(%) 
MI  
(%) 
Stroke* 
(%) 
Bleeding  
(%) 
AKI 
 (%) 
VC  
(%) 
et al. 201338 
CV/361 
19.6c 
Testa, et al. 
201476 
CV/1531m 
5.9 
2.0 
2.0 
15.0c 
N/A 
2.7c 
Abdel-Wahab, 
et al. 201477 
CV/117; 
EW/121 
5.1 CV; 
4.1 EW 
0 CV; 0.8 
EW 
2.6e CV; 
5.8e EW 
12.0n CV  
8.3n EW 
14.5c CV 
19.0c EW 
9.4 CV 
4.1 EW 
11.1c CV 
9.9c EW 
Webb, et al. 
201478 
S3/96 
2.1 
2.1 
0.0 
3.1n 
19.8c 
1.0p 
4.2c 
Wenaweser, et 
al. 201479 
CV/336q 
SXT/317q 
4.8 
0.4 
2.5 
6.3n 
8.4c 
2.5g 
6.3c,h 
Tarsia, et al. 
201480 
CV/53 
EW and 
SXT/56 
1.9 CV  
14.3 
EW/SXT 
N/A 
1.9 CV  
0.0 
EW/SXT 
7.5 CV 
8.9 
EW/SXT 
N/A 
1.9 CV 
7.1 
EW/SXT 
De Brito, et al. 
201581 
CV/360f 
SXT/58f 
9.1 
0.7 
2.2 
7.6n 
7.3c 
5.6 g 
8.5c 
* Disabling or major stroke 
a:  Transfemoral approach population only 
b:  Inoperable subjects 
c:  Major 
d:  High risk subjects 
e: All stroke 
f:  Femoral access in >90% of cases 
g:  Stage 3 
h:   In hospital 
i: 92.4% transfemoral and 3.2% subclavian; 84% of all procedures were CV 
j: Groin problem with need of transfusion 
k: All subjects 
l:  Dialysis 
m:  Femoral access in 84% of cases 
n: Life-threatening bleeding 
o: All vascular complications 
p: Stage 2/3 
q: 93% of subjects received either SXT or CV; 79% of subjects had transfemoral access   
Abbreviations: AKI=acute kidney injury; CV=CoreValve; EW=Edwards; MI=myocardial infarction; N/A=not 
available; S3=SAPIEN 3 (Edwards); SXT=SAPIEN XT (Edwards);VC=vascular complications 
 
The Lotus Valve System is designed to address issues with earlier TAVR devices82. 
Controlled mechanical expansion and early leaflet functioning allow for precise positioning. 
If needed, minor repositioning is accomplished through partial valve recapture; full recapture 
facilitates removal of the valve if a different size or valve is required. The valve also has a 
polyurethane outer seal (Adaptive™ Seal) designed to minimize paravalvular regurgitation 
(PVR), which has been associated with mortality in some studies83.  
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 29 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 30 of 188 
 
 
The safety and performance of the Lotus Valve System and LOTUS Edge Valve System for 
TAVR in extreme and high surgical risk symptomatic subjects with calcific, severe native 
aortic stenosis are under evaluation in the REPRISE clinical program (see Section 4.1.2 
through Section 4.1.4). The Lotus Valve System is under study in the ongoing REPRISE I 
(ClinicalTrials.gov Identifier NCT01383720), REPRISE II (NCT01627691), and REPRISE 
Japan (NCT02491255) single-arm trials; the REPRISE III (NCT02202434) randomized 
controlled trial; and the RESPOND (NCT02031302) postmarket safety surveillance study. 
The LOTUS Edge Valve System (23 mm, 25 mm and 27 mm valve sizes) is currently under 
study in the REPRISE NG DS (NCT02329496) and the REPRISE EDGE (NCT02854319) 
single-arm trials. The REPRISE NG DS study recently completed enrollment in Australia, 
while the REPRISE Edge study is currently conducted in Europe. The REPRISE EDGE 
29 mm EU study is intended to evaluate performance and safety of the 29 mm LOTUS Edge 
Valve System among centers in Europe. 
4.1.2. REPRISE I Study 
As discussed above, TAVR in patients unsuitable for SAVR has reduced mortality14,75 and 
treatment of selected patients at high surgical risk has resulted in similar64 or better66 survival 
at 1 year. These results notwithstanding, TAVR with early generation devices has been 
associated with increased stroke risk and vascular complications when compared to surgical 
valve replacement64-66, which have been significant predictors of mortality84,85. There are also 
other infrequent but substantial complications that impact long-term outcomes and may limit 
the use of TAVR in lower risk subjects. Precise valve positioning can be challenging with 
first-generation devices, and valve misplacement can lead to severe problems, including 
coronary occlusion and valve embolization 86. Incomplete apposition of the prosthesis with 
the native valve can occur in the presence of significant amounts of calcium or with 
suboptimal implantation, resulting in paravalvular regurgitation87,88. This has been associated 
with increased mortality in several longitudinal registries45,89,90. While careful patient 
selection may serve to mitigate these risks91-93, device design improvements such as seen 
with the Lotus Valve System (including the ability to fully reposition and retrieve the valve 
and a unique adaptive seal to prevent leakage, see Section 5.1) may enable more precise 
placement and minimize or eliminate paravalvular regurgitation.  
The prospective, single arm, multicenter REPRISE I (REpositionable Percutaneous 
Replacement of Stenotic Aortic Valve through Implantation of Lotus™ Valve SystEm) 
feasibility study (N=11) assessed the acute safety and performance of the Lotus Valve 
System in symptomatic subjects with calcific aortic stenosis who were considered high risk 
for surgical valve replacement94. The primary endpoint was clinical procedural success, 
defined as successful implantation of a Lotus Valve (per the VARC-1 definitions72) without 
in-hospital major adverse cardiovascular and cerebrovascular events (MACCE, defined as 
all-cause mortality, periprocedural myocardial infarction ≤72 hours after the index procedure, 
major stroke, urgent/emergent conversion to surgery or repeat procedure for valve-related 
dysfunction) through discharge or 7 days post-procedure, whichever came first.  Clinical 
follow-up will extend through 5 years. Safety endpoints are adjudicated by an independent 
Clinical Events Committee (CEC); prosthetic valve function and cardiac function endpoints 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 30 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 31 of 188 
 
 
are assessed by independent echocardiography and electrocardiography core labs. The study 
is registered at ClinicalTrials.gov, Identifier NCT01383720. 
To ensure proper use of the Lotus Valve System and mitigate any procedural complication 
that could be secondary to misuse or misinterpretation of the Instructions For Use, a 
comprehensive training and proctorship program was implemented in this study supported by 
an experienced proctoring physician assigned by Boston Scientific. Given the importance of 
selecting appropriate subjects, a Case Review Committee (CRC) comprised of the Principal 
Investigators, other investigators experienced with TAVR, and the Sponsor was established. 
This committee was responsible for reviewing and confirming subject eligibility across study 
sites during the screening process. 
The primary endpoint was achieved in 9/11 subjects94. 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 criteria72 for device success (the mean gradient of 22 mmHg in this 
subject was greater than the VARC-1 cutoff of 20 mmHg). The Echocardiography Core Lab 
concluded that the device failure resulted from a hyperdynamic state in the subject and noted 
that the prosthetic valve appeared to be functioning well. Ten (10) of 11 subjects had no in-
hospital MACCE; there were no deaths and 1 major stroke. Paravalvular regurgitation at 
discharge TTE was mild in 2 subjects, trivial in 1 subject, and absent in the other 8 subjects; 
these outcomes compare favorably with published data14,40,56,64,95.  
To date, data are available through 3 years94,96,97. There were no additional MACCE events 
beyond the primary endpoint through 2 years and 1 noncardiovascular death in the interval 
between 2 and 3 years. The 3-year VARC-172 combined safety endpoint, including MACCE, 
life threatening/disabling bleeding, major vascular complications, and Stage 3 acute kidney 
injury, was 4/11; the aforementioned subject with the major stroke also had a small left 
femoral dissection treated with balloon inflation during the procedure and there were 2 life-
threatening/disabling bleeds through 30 days that were unrelated to valve implantation and 
resolved, and there was 1 noncardiovascular death due to uncontrolled sepsis. Conduction 
disturbances led to implantation of a permanent pacemaker (PPM) before discharge in 4 
subjects; 2 of these 4 subjects had paced rhythms at 1 year. While all REPRISE I subjects 
were NYHA Class II (n=6) or III (n=5) at baseline, this distribution was significantly 
improved between baseline and 30 days (3 in Class I, 7 in Class II, 1 in Class III; P=0.02), 
baseline and 1 year (5 in Class I, 6 in Class II; P=0.004), baseline and 2 years (6 in Class I, 
5 in Class II; P=0.004), and baseline and 3 years (5 in Class I, 1 in Class II, 2 in Class III; 
P=0.004). The mean aortic valve gradient was 11.7±3.0 mmHg for the cohort at 30 days, 
15.4±4.6 mmHg at 1 year, 15.4±4.4 mmHg at 2 years, and 15.6±4.4 mmHg at 3 years. 
Paravalvular aortic regurgitation was mild (2/11) or absent (9/11) at 30 days, mild (1/11) or 
absent/trivial (10/11) at 1 year, absent/trivial (11/11) at 2 years, and absent (7/8) or mild (1/8) 
at 3 years; there was no moderate or severe paravalvular aortic regurgitation at any time post 
implantation of the Lotus Valve. The results of the REPRISE I feasibility study support the 
safety and performance of the Lotus Valve System. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 31 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 32 of 188 
 
 
4.1.3. REPRISE II Study 
The REpositionable Percutaneous Replacement of Stenotic Aortic Valve through 
Implantation of Lotus™ Valve System – Evaluation of Safety and Performance 
(REPRISE  II) 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 surgical valve replacement. 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. As noted above for 
REPRISE I (Section 4.1.2), a comprehensive training and proctorship program was 
implemented and a CRC was responsible for reviewing and confirming subject eligibility 
across study sites during the screening process. The study is registered at ClinicalTrials.gov, 
Identifier NCT01627691. 
Safety endpoints in the ongoing REPRISE II study are adjudicated by an independent CEC; 
prosthetic valve function and cardiac function endpoints are assessed by independent 
echocardiography and electrocardiography core labs. 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 comparisons 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 intent-to-treat 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 4.1-2 
shows device performance endpoints, clinical outcomes, and echocardiographic outcomes 
through 30 days98. 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. 
Mortality was 4.2% and the disabling stroke rate was 1.7%. There were no repeat procedures 
for valve-related dysfunction. Core lab assessment of paravalvular aortic regurgitation 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 paravalvular regurgitation. The observed 
clinical results are consistent with other TAVR studies (see Table 4.1-1) and the rates of 
paravalvular regurgitation are lower14,64,66,75,77. Table 4.1-3 shows 1-year99 and 2-year100 
clinical (time-to-event analysis) and echocardiographic outcomes. At 2 years, mortality was 
17% and the disabling stroke rate was 3.5%. The low paravalvular aortic regurgitation rate 
observed at 30 days was maintained at 2 years as most subjects (91%) had none/trivial 
paravalvular aortic regurgitation and there was no moderate or severe paravalvular 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 32 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 33 of 188 
 
 
regurgitation. The results of the REPRISE II study support the safety and performance of the 
Lotus Valve System. 
Table 4.1-2: 30-Day Outcomes in REPRISE II Main Cohort (N=120)  
Outcomes  
REPRISE II (N=120) 
Clinical Outcomes at 30 Days (CEC Adjudicated) 
All-cause mortality 
4.2% (5/119) 
 
Cardiovascular 
4.2% (5/119) 
All stroke 
6.1% (7/115) 
 
Disabling stroke 
1.7% (2/115) 
Major vascular complications 
2.6% (3/116) 
Life-threatening or disabling bleeding 
5.1% (6/117) 
Major bleeding 
17.9% (21/117) 
Acute kidney injury – Stage 2 or 3 
3.5% (4/115) 
Coronary obstruction (periprocedural) 
0.9% (1/115) 
Valve-related dysfunction requiring repeat procedure (surgical/interventional) 
0.0% (0/115) 
New permanent pacemaker implantation resulting from new or worsened 
conduction disturbances 
 
29.1% (34/117) 
Periprocedural MI (≤72 hours after index procedure) 
3.4% (4/117) 
Hospitalization for valve-related symptoms or worsening congestive heart failure 
4.3% (5/115) 
Atrial fibrillation or atrial flutter (new onset) 
5.2% (6/115) 
Ventricular septal perforation (periprocedural) 
0.0% (0/115) 
Mitral apparatus damage (periprocedural) 
2.6% (3/115) 
Cardiac tamponade (periprocedural) 
4.3% (5/117) 
Prosthetic aortic valve malpositioning 
0.0% (0/115) 
Prosthetic aortic valve thrombosis 
0.0% (0/115) 
Prosthetic aortic valve endocarditis 
0.0% (0/115) 
Device Performance Endpoints  
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) 
Valve Performance by Transthoracic Echocardiography (30 Days-Core Lab Assessment) 
Aortic valve area (effective orifice area) (cm2) 
1.67±0.43 (78) 
Mean aortic valve gradient (mmHg) 
11.45±5.20 (97) 
Peak aortic gradient (mmHg) 
21.30±9.26 (97) 
Peak aortic velocity (cm/s) 
2.25±0.48 (97) 
Paravalvular Aortic Regurgitation 
 
None 
78.1% (75/96) 
 
Trace/trivial 
5.2% (5/96) 
 
Mild  
15.6% (15/96) 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 33 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 34 of 188 
 
 
Table 4.1-2: 30-Day Outcomes in REPRISE II Main Cohort (N=120)  
Outcomes  
REPRISE II (N=120) 
 
Moderate 
1.0% (1/96) 
 
Severe  
0.0% (0/96) 
Values are % (count/sample size) or mean±SD (n) 
Note: Denominators for clinical event rates are based on the number of subjects who have either had an event 
within 30 days post-procedure or who were event-free with last follow-up at least 23 days post-procedure. 
Reference: Meredith, 201498 
 
Table 4.1-3: 1-Year and 2-Year Outcomes in REPRISE II Main Cohort (N=120)  
Outcomes  
REPRISE II 
1 Year 
REPRISE II 
2 Years 
Clinical Outcomes at 1 Year and 2 Years (CEC Adjudicated) 
All-cause mortality 
11.0% (13) 
16.9% (20) 
 
Cardiovascular 
6.7% (8) 
10.4% (12) 
All stroke 
9.5% (11) 
9.5% (11) 
 
Disabling stroke 
3.5% (4) 
3.5% (4) 
Major vascular complications 
2.5% (3) 
2.5% (3) 
Life-threatening or disabling bleeding 
5.9% (7) 
7.8% (9) 
Major bleeding 
21.4% (25) 
23.3% (27) 
Acute kidney injury – Stage 2 or 3 
3.4% (4) 
3.4% (4) 
Valve-related dysfunction requiring repeat procedure 
(surgical/interventional) 
0.0% (0) 
0.0% (0) 
New permanent pacemaker implantation resulting from new or 
worsened conduction disturbances  
32.2% (38) 
34.2% (40) 
Spontaneous MI (> 72 hours after index procedure) 
0.0% (0) 
0.0% (0) 
Hospitalization for valve-related symptoms or worsening 
congestive heart failure 
5.2% (6) 
8.0% (9) 
Atrial fibrillation or atrial flutter (new onset) 
6.0% (7) 
6.0% (7) 
Prosthetic aortic valve malpositioning 
0.0% (0) 
0.0% (0) 
Prosthetic aortic valve thrombosis 
0.0% (0) 
0.0% (0) 
Prosthetic aortic valve endocarditis 
0.9% (1) 
2.8% (3) 
Valve Performance by Transthoracic Echocardiography (1 Year and 2-Years -Core Lab Assessment) 
Aortic valve area (effective orifice area) (cm2) 
1.65±0.51 (79) 
1.66±0.45 (69) 
Mean aortic valve gradient (mmHg) 
12.58±5.66 (92) 
12.30±6.18 (75) 
Peak aortic gradient (mmHg) 
23.09±10.14 (92) 
21.25±11.03 (75) 
Peak aortic velocity (cm/s) 
2.35±0.50 (92) 
2.23±0.56 (75) 
Paravalvular Aortic Regurgitation 
 
None 
86.4% (76/88) 
87.8% (65/74) 
 
Trace/trivial 
2.3% (2/88) 
2.7% (2/74) 
 
Mild  
11.4% (10/88) 
9.5% (7/74) 
 
Moderate 
0.0% (0/88) 
0.0% (0/74) 
 
Severe  
0.0% (0/88) 
0.0% (0/74) 
Values are % (n); % (count/sample size), or mean±SD (n) 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 34 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 35 of 188 
 
 
Table 4.1-3: 1-Year and 2-Year Outcomes in REPRISE II Main Cohort (N=120)  
Outcomes  
REPRISE II 
1 Year 
REPRISE II 
2 Years 
Clinical event rates are presented as Kaplan-Meier estimates. 
References: Meredith, 2015, 201699,100 
 
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; enrollment in this 
extended cohort was completed in April 2014. 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 intent-to-treat basis (all subjects 
enrolled, whether or not a study device is implanted). 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 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 met101. 
Table 4.1-4 shows device performance endpoints, clinical outcomes, and echocardiographic 
outcomes through 30 days and 1 year for the full cohort (N=250)101,102. Outcomes at 30 days 
in the full cohort were similar to that reported for the main cohort (see Table 4.1-2) with a 
mean aortic valve gradient of 11.70±6.77 mmHg. Mortality was 4.4% and the disabling 
stroke rate was 3.3%. The new PPM implant rate was 29.6%. 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 CoreValve103. In a recent report, 12-month 
clinical outcomes were similar among subjects with and without periprocedural PPM104. 
Another study (mean follow-up of 22±17 months) found that PPM implantation post TAVR 
had a negative effect on left ventricular function but was not associated with any increase in 
overall or cardiovascular death or rehospitalization for heart failure and was a protective 
factor for the occurrence of sudden or unknown death (P=0.023)105. Implantation of a new 
PPM following TAVR with SAPIEN (retrospective analysis from the combined PARTNER 
trial and NRCA registry) was associated with a higher rate of repeat hospitalization at 
30 days and 1 year (10.6% vs. 5.9%, P=0.02 at 30 days; 23.9% vs. 18.2%, P=0.05 at 1 year) 
but not mortality (7.5% vs. 5.8%, P=0.40 at 30 days; 26.3% vs. 20.8%, P=0.08 at 1 year)106. 
There was no severe paravalvular regurgitation and trace/trivial or no paravalvular 
regurgitation in 85.8% of REPRISE II subjects. Reported moderate or severe aortic 
regurgitation after TAVR has ranged from 6% to 21%107 and has been associated with 
increased mortality in several longitudinal registries45,59,89,90. 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 low paravalvular aortic regurgitation rate observed at 30 days was maintained 
at 1 year as most subjects (85%) had none/trivial paravalvular aortic regurgitation and there 
was no moderate or severe paravalvular regurgitation. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 35 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 36 of 188 
 
 
In summary, the observed clinical results 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 4.1-4: 30-Day and 1-Year Outcomes in the REPRISE II Full Cohort (N=250) 
Outcomes  
REPRISE II  
(30 Days) 
REPRISE II 
(1 Year) 
Clinical Outcomes at 30 Days and 1 Year (CEC Adjudicated) 
All-cause mortality 
4.4% (11/249) 
11.6% (29/249) 
 
Cardiovascular 
4.0% (10/249) 
7.6% (19/249) 
All stroke 
7.1% (17/241) 
8.4% (21/249) 
 
Disabling stroke 
3.3% (8/241) 
3.6% (9/249) 
Major vascular complications 
5.4% (13/241) 
5.2% (13/249) 
Life-threatening or disabling bleeding 
7.3% (18/247) 
9.2% (23/249) 
Major bleeding 
21.5% (53/247) 
23.3% (58/249) 
Acute kidney injury – Stage 2 or 3 
2.9% (7/240) 
2.9% (7/240) 
Coronary obstruction (periprocedural) 
0.8% (2/241) 
– 
Valve-related dysfunction requiring repeat procedure 
(surgical/interventional) 
0.0% (0/240) 
0.0% (0/249) 
New permanent pacemaker implantation resulting from new or 
worsened conduction disturbances  
29.6% (72/243) 
32.5% (81/249) 
Periprocedural MI (≤72 hours after index procedure) 
2.9% (7/243) 
– 
Spontaneous MI (>72 hours after index procedure) 
– 
0.0% (0/249) 
Hospitalization for valve-related symptoms or worsening 
congestive heart failure 
2.9% (7/240) 
6.8% (17/249) 
Atrial fibrillation or atrial flutter (new onset) 
6.6% (16/241) 
6.8% (17/249) 
Ventricular septal perforation (periprocedural) 
0.0% (0/240) 
– 
Mitral apparatus damage (periprocedural) 
1.7% (4/240) 
– 
Cardiac tamponade (periprocedural) 
3.7% (9/246) 
– 
Prosthetic aortic valve malpositioning 
0.0% (0/240) 
0.0% (0/249) 
Prosthetic aortic valve thrombosis 
0.0% (0/240) 
1.2% (3/249) 
Prosthetic aortic valve endocarditis 
0.0% (0/240) 
0.8% (2/249) 
Device Performance Endpoints  
Successful vascular access, delivery, and deployment of the 
Lotus Valve System, and successful retrieval of the delivery 
system 
98.8% (247/250) 
– 
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% (85/85) 
– 
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 
92.3% (12/13) 
– 
Valve Performance by Transthoracic Echocardiography (30 Days-Core Lab Assessment) 
Aortic valve area (effective orifice area) (cm2) 
1.74±0.45 (149) 
1.68±0.49 (157) 
Mean aortic valve gradient (mmHg) 
11.70±6.77 (183) 
12.49±5.35 (176) 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 36 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 37 of 188 
 
 
Table 4.1-4: 30-Day and 1-Year Outcomes in the REPRISE II Full Cohort (N=250) 
Outcomes  
REPRISE II  
(30 Days) 
REPRISE II 
(1 Year) 
Peak aortic gradient (mmHg) 
20.75±9.05 (183) 
21.90±9.40 (176) 
Peak aortic velocity (cm/s) 
2.23±0.47 (183) 
2.29±0.47 (176) 
Paravalvular Aortic Regurgitation 
 
None 
80.2% (142/177) 
82.2% (134/163) 
 
Trace/trivial 
5.6% (10/177) 
3.1% (5/163) 
 
Mild  
13.6% (24/177) 
14.7% (24/163) 
 
Moderate 
0.6% (1/177) 
0.0% (0/163) 
 
Severe  
0.0% (0/177) 
0.0% (0/163) 
Values are % (count/sample size) or mean±SD (n) 
Note: For 30-day outcomes, denominators for clinical event rates are based on the number of subjects who have 
either had an event within 30 days post-procedure or who were event-free with last follow-up at least 23 days 
post-procedure. Outcomes at 1 year are based on the as-treated group (N=249). 
Reference: Meredith, 2014101; Meredith, 2015102 
4.1.4. REPRISE NG DS Study 
The LOTUS Edge Valve System with a modified iteration of the delivery system studied in 
REPRISE I and REPRISE II was evaluated in the REpositionable Percutaneous Replacement 
of Stenotic Aortic Valve through Implantation of LotuS ValvE with the Next Generation 
Delivery System (REPRISE NG DS) first-human-use trial. Acute performance and safety of 
iterative designs have been evaluated in three cohorts: Cohort A, Cohort B and Cohort C. 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 
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. Cohort C completed enrollment in September 
2016 with 21 subjects treated with the LOTUS Edge Valve System, which features a further 
refined version of the delivery system, implanted with either the Lotus or expandable iSleeve 
Introducer. Device sizes evaluated included the 23 mm, 25 mm and 27 mm. The primary 
endpoint of the study was technical success, defined as follows: successful vascular access, 
delivery and deployment of the Lotus valve and successful retrieval with the LOTUS Edge 
delivery system; correct positioning of the Lotus valve in the proper anatomical location; and 
only one Lotus valve implanted in the proper anatomical location. Other measurements 
incorporated data collection and endpoints recommended and defined by the VARC 172 and 
VARC 273 guidelines. Clinical follow-up will extend through 1 year. 
The primary endpoint was achieved in 10/10 subjects in Cohort A108 and 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). Table 4.1-5 shows core lab analyses of prosthetic valve performance as 
assessed by TTE for the 2 cohorts. In both cohorts, mean aortic valve area and mean gradient 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 37 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 38 of 188 
 
 
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 either cohort. Table 4.1-6 shows 
rates of CEC-adjudicated VARC-defined events during the index procedure, through 
discharge/7 days, 30 days and 1 year. In Cohort A, one subject experienced the majority of 
events and subsequently died on day 13 post implant. Another subject died on day 119; the 
primary cause of death was multiorgan failure, which was not considered related to the index 
procedure. In Cohort B, events were minimal through 1 year post implant. Acute and 30-day 
outcomes were sustained through 1 year in both cohorts. Overall, the results in Cohorts A 
and B of the REPRISE NG DS study demonstrate acceptable performance and safety of the 
LOTUS Edge System.   
Table 4.1-5: Echocardiographic Outcomes in REPRISE NG DS Cohorts A and B 
Measure 
Cohort A 
Cohort B 
Discharge  
30 Days 
1 Year 
Discharge  
30 Days 
1 Year 
Aortic valve area 
(effective orifice 
area) (cm2) 
1.55±0.43 
(10) 
1.44±0.45 
(9) 
1.38±0.49 
(6) 
1.84±0.38 
(3) 
1.32±0.48 
(4) 
1.40±0.32 
(5) 
Mean aortic valve 
gradient (mmHg) 
13.42±4.30 
(10) 
15.72±8.04 
(9) 
15.80±9.20 
(6) 
9.80±4.28 
(5) 
10.28±0.75 
(4) 
12.86±1.98 
(5) 
Paravalvular Aortic Regurgitation 
 
None 
80.0% (8/10) 
66.7% (6/9) 
66.7% (4/6) 
80.0% 
(4/5) 
50.0% (2/4) 
100.0% (5/5) 
 
Trace/Trivial 
10.0% (1/10) 
11.1% (1/9) 
33.3% (2/6) 
20.0% 
(1/5) 
50.0% (2/4) 
0.0% (0/5) 
 
Mild 
10.0% (1/10) 
11.1% (1/9) 
0.0% (0/6) 
0.0% (0/5) 
0.0% (0/4) 
0.0% (0/5) 
 
Moderate 
0.0% (0/10) 
0.0% (0/9) 
0.0% (0/6) 
0.0% (0/5) 
0.0% (0/4) 
0.0% (0/5) 
 
Severe 
0.0% (0/10) 
0.0% (0/9) 
0.0% (0/6) 
0.0% (0/5) 
0.0% (0/4) 
0.0% (0/5) 
 
Regurgitation, 
but severity not 
evaluable 
0.0% (0/10) 
11.1% (1/9) 
0.0% (0/6) 
0.0% (0/5) 
0.0% (0/4) 
0.0% (0/5) 
Numbers are presented as mean±standard deviation (n) or % (count/sample size). 
Note: “Discharge” represents discharge from hospitalization or 7 days post-procedure, whichever came first. 
 
Table 4.1-6: Clinical Outcomes in REPRISE NG DS Cohorts A and B 
VARC Event 
Cohort A (N=10) 
Cohort B (N=7) 
Discharge  
30 Days  
1 Year 
Discharge 
30 Days 
1 Year 
All-cause mortality 
0.0% 
(0/10) 
10.0% 
(1/10) 
20.0% 
(2/10) 
0.0% (0/7) 
0.0% 
(0/5) 
0.0% 
(0/6) 
 Cardiovascular 
0.0% 
(0/10) 
10.0% 
(1/10) 
10.0% 
(1/10) 
0.0% (0/7) 
0.0% 
(0/5) 
0.0% 
(0/6) 
Stroke 
10.0% 
(1/10) 
10.0% 
(1/10) 
10.0% 
(1/10) 
0.0% (0/7) 
0.0% 
(0/5) 
0.0% 
(0/6) 
 Disabling stroke 
10.0% 
(1/10) 
10.0% 
(1/10) 
10.0% 
(1/10) 
0.0% (0/7) 
0.0% 
(0/5) 
0.0% 
(0/6) 
Major vascular complications 
0.0% 
(0/10) 
0.0% 
(0/10) 
0.0% 
(0/10) 
0.0% (0/7) 
0.0% 
(0/5) 
0.0% 
(0/6) 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 38 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 39 of 188 
 
 
Table 4.1-6: Clinical Outcomes in REPRISE NG DS Cohorts A and B 
VARC Event 
Cohort A (N=10) 
Cohort B (N=7) 
Discharge  
30 Days  
1 Year 
Discharge 
30 Days 
1 Year 
New PPM 
0.0% 
(0/10) 
30.0% 
(3/10) 
40.0% 
(4/10) 
0.0% (0/7) 
0.0% 
(0/5) 
0.0% 
(0/6) 
Life-threatening/disabling bleeding 
20.0% 
(2/10) 
20.0% 
(2/10) 
20.0% 
(2/10) 
0.0% (0/7) 
0.0% 
(0/5) 
0.0% 
(0/6) 
Myocardial infarction 
0.0% 
(0/10) 
0.0% 
(0/10) 
0.0% 
(0/10) 
0.0% (0/7) 
0.0% 
(0/5) 
0.0% 
(0/6) 
Acute kidney injury – Stage 2/3  
10.0% 
(1/10) 
10.0% 
(1/10) 
10.0% 
(1/10) 
0.0% (0/7) 
0.0% 
(0/5) 
0.0% 
(0/6) 
Repeat procedure for valve-related 
dysfunction (surgical/interventional) 
0.0% 
(0/10) 
0.0% 
(0/10) 
0.0% 
(0/10) 
0.0% (0/7) 
0.0% 
(0/5) 
0.0% 
(0/6) 
Hospitalization for valve-related 
symptoms or worsening CHF  
0.0% 
(0/10) 
0.0% 
(0/10) 
0.0% 
(0/10) 
0.0% (0/7) 
0.0% 
(0/5) 
16.7% 
(1/6) 
New onset atrial fibrillation/flutter  
0.0% 
(0/10) 
0.0% 
(0/10) 
0.0% 
(0/10) 
0.0% (0/7) 
0.0% 
(0/5) 
0.0% 
(0/6) 
Coronary obstruction 
(periprocedural) 
0.0% 
(0/10) 
N/A 
0.0% 
(0/10) 
0.0% (0/7) 
N/A 
0.0% 
(0/6) 
Ventricular septal perforation 
(periprocedural) 
0.0% 
(0/10) 
N/A 
0.0% 
(0/10) 
0.0% (0/7) 
N/A 
0.0% 
(0/6) 
Mitral apparatus damage 
(periprocedural) 
0.0% 
(0/10) 
N/A 
0.0% 
(0/10) 
0.0% (0/7) 
N/A 
0.0% 
(0/6) 
Cardiac tamponade (periprocedural) 
0.0% 
(0/10) 
N/A 
10.0% 
(1/10) 
0.0% (0/7) 
N/A 
0.0% 
(0/6) 
Prosthetic aortic valve 
malpositioning  
0.0% 
(0/10) 
0.0% 
(0/10) 
0.0% 
(0/10) 
0.0% (0/7) 
0.0% 
(0/5) 
0.0% 
(0/6) 
Prosthetic aortic valve thrombosis 
0.0% 
(0/10) 
0.0% 
(0/10) 
10.0% 
(1/10) 
0.0% (0/7) 
0.0% 
(0/5) 
0.0% 
(0/6) 
Prosthetic aortic valve endocarditis 
0.0% 
(0/10) 
0.0% 
(0/10) 
0.0% 
(0/10) 
0.0% (0/7) 
0.0% 
(0/5) 
16.7% 
(1/6) 
Numbers are presented as % (count/sample size); outcomes were adjudicated by the CEC; ITT analysis set 
Note: “Discharge” represents discharge from hospitalization or 7 days post-procedure, whichever came first; 
“periprocedural” represents ≤72 hours post index procedure. 
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. 
Abbreviations: CEC=Clinical Events Committee; CHF=congestive heart failure; ITT=intention-to-treat; 
N/A=not applicable; NGDS=Next Generation Delivery System; PPM=permanent pacemaker; VARC=Valve 
Academic Research Consortium 
 
Using the latest iteration of the LOTUS Edge Valve System with either the Lotus or 
expandable iSleeve Introducer, the primary endpoint was achieved in 21/21 subjects in 
Cohort C, which resulted in improved valve performance and no moderate or severe PVR at 
discharge/7 days and 30 days post implant (Table 4.1-7) based on echocardiographic core lab 
analysis. A summary of clinical outcomes through discharge/7 days and 30 days is presented 
in Table 4.1-8. There was no mortality. Disabling stroke occurred on day 0 in one subject. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 39 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 40 of 188 
 
 
Only 2/21 subjects (9.5%) were implanted with a new permanent pacemaker (PPM) through 
30 days post implant, which is lower than previously observed in studies with the Lotus 
Valve System. This may be attributed to the design of the LOTUS Edge delivery system with 
its flexibility and ability to minimize the depth of the valve frame during deployment within 
the annulus, thereby reducing the potential for unnecessary interaction with the left 
ventricular outflow tract and the conduction system of the heart. These outcomes in the 
REPRISE NG DS Cohort C subjects demonstrate acceptable performance and safety of the 
LOTUS Edge System through 30 days post implant.  
Table 4.1-7: Echocardiographic Outcomes in REPRISE NG DS Cohort C 
Measure 
Discharge  
30 Days 
Aortic valve area (effective orifice area) (cm2) 
1.50±0.37 (21) 
1.28±0.36 (21) 
Mean aortic valve gradient (mmHg) 
14.04±4.41 (21) 
14.69±5.57 (21) 
Paravalvular Aortic Regurgitation  
 
None 
95.2% (20/21) 
85.7% (18/21) 
 
Trace/Trivial 
4.8% (1/21) 
9.5% (2/21) 
 
Mild 
0.0% (0/21) 
4.8% (1/21) 
 
Moderate 
0.0% (0/21) 
0.0% (0/21) 
 
Severe 
0.0% (0/21) 
0.0% (0/21) 
 
Regurgitation, but severity not evaluable 
0.0% (0/21) 
0.0% (0/21) 
Numbers are presented as mean±standard deviation (n) or % (count/sample size). 
Note: “Discharge” represents discharge from hospitalization or 7 days post-procedure, whichever came first. 
 
Table 4.1-8: Clinical Outcomes in REPRISE NG DS Cohort C 
VARC Event 
Discharge  
30 Days  
All-cause mortality 
0.0% (0/21) 
0.0% (0/21) 
 Cardiovascular 
0.0% (0/21) 
0.0% (0/21) 
Stroke 
4.8% (1/21) 
4.8% (1/21) 
 Disabling stroke 
4.8% (1/21) 
4.8% (1/21) 
Major vascular complications 
9.5% (2/21) 
9.5% (2/21) 
New PPM 
9.5% (2/21) 
9.5% (2/21) 
Life-threatening/disabling bleeding 
0.0% (0/21) 
0.0% (0/21) 
Myocardial infarction 
0.0% (0/21) 
0.0% (0/21) 
Acute kidney injury – Stage 2/3  
0.0% (0/21) 
0.0% (0/21) 
Repeat procedure for valve-related dysfunction (surgical/interventional) 
0.0% (0/21) 
0.0% (0/21) 
Hospitalization for valve-related symptoms or worsening CHF  
0.0% (0/21) 
0.0% (0/21) 
New onset atrial fibrillation/flutter  
9.5% (2/21) 
9.5% (2/21) 
Coronary obstruction (periprocedural) 
0.0% (0/21) 
0.0% (0/21) 
Ventricular septal perforation (periprocedural) 
0.0% (0/21) 
0.0% (0/21) 
Mitral apparatus damage (periprocedural) 
0.0% (0/21) 
0.0% (0/21) 
Cardiac tamponade (periprocedural) 
0.0% (0/21) 
0.0% (0/21) 
Prosthetic aortic valve malpositioning  
0.0% (0/21) 
0.0% (0/21) 
Prosthetic aortic valve thrombosis 
0.0% (0/21) 
0.0% (0/21) 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 40 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 41 of 188 
 
 
Table 4.1-8: Clinical Outcomes in REPRISE NG DS Cohort C 
VARC Event 
Discharge  
30 Days  
Prosthetic aortic valve endocarditis 
0.0% (0/21) 
4.8% (1/21) 
Numbers are presented as % (count/sample size); outcomes were adjudicated by the CEC; ITT analysis set 
Note: “Discharge” represents discharge from hospitalization or 7 days post-procedure, whichever came first; 
“periprocedural” represents ≤72 hours post index procedure. 
Abbreviations: CEC=Clinical Events Committee; CHF=congestive heart failure; ITT=intention-to-treat; 
PPM=permanent pacemaker; VARC=Valve Academic Research Consortium 
 
4.2. 
Justification for the Study  
As noted above, the Lotus Valve System and LOTUS Edge Valve System potentially provide 
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 the decision is made to replace it with another 
valve to optimize implant or not to implant, and the aforementioned outer seal designed to 
minimize paravalvular leakage. The anticipated risks and benefits associated both with the 
Lotus Valve System/LOTUS Edge Valve System and with participation in this clinical 
investigation are summarized in the Investigator Brochure and in Section 19 of this 
document. The conclusion of this risk-benefit analysis demonstrates that the known risks 
associated with the procedure, and specifically the use of the Lotus Valve System/LOTUS 
Edge Valve System, have been mitigated to acceptable limits. It was also concluded that the 
aforementioned design features may improve procedural safety and longer term clinical 
outcomes. The available Sponsor-provided training program and proctorship for physicians 
further mitigates 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. 
No new hazards/harms are introduced by the LOTUS Edge Valve System compared to the 
Lotus Valve System when used with the Lotus Introducer Set. Since the overall risk profile 
of the device has not changed, it can be concluded that the potential benefits of the use of the 
LOTUS Edge Valve System with the Lotus Introducer Set out-weigh the risks. 
 
5. Device Description 
The study devices are intended to improve aortic valve function for symptomatic subjects 
with calcific, severe native aortic stenosis who are at extreme or high risk for standard 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 41 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 42 of 188 
 
 
surgical valve replacement. Test devices include the Lotus™ Valve System available in valve 
sizes of 21 mm, 23 mm, 25 mm, and 27 mm diameter, and the LOTUS Edge™ Valve System 
available in valve sizes of 23 mm, 25 mm, 27 mm, and 29 mm diameter (Section 5.1). Every 
subject in the randomized cohort must be deemed treatable with an available size of both the 
test and the control device. The control device (Section 5.2) in the planned size must be 
approved for use and commercially available at the investigational center where the implant 
procedure is being performed. 
5.1. Lotus Valve System and LOTUS Edge Valve System Investigational Devices (Test) 
The Lotus Valve System and LOTUS Edge Valve System (Figure 5.1-1) have two main 
parts: a bioprosthetic aortic valve implant and a catheter-based delivery system for 
introduction and delivery of the valve implant. The device is introduced percutaneously via 
the femoral artery using conventional catheterization techniques. Femoral access using the 
surgical cut-down approach can also be performed to gain access into the aortic vessel. Lotus 
Valve System device sizes used in the randomized cohort and the U.S. Continued Access 
Study cohort include 23 mm, 25 mm, and 27 mm diameter. Devices in the Lotus 21 mm 
Nested Registry cohort are 21 mm in diameter. The LOTUS Edge Valve System is a design 
iteration of the Lotus Valve System. LOTUS Edge device sizes used in the Nested Registries 
include 23 mm, 25 mm, 27 mm, and 29 mm diameter. More detailed product information is 
contained in the Investigator Brochure and Instructions For Use (IFU) for both devices. 
 
Figure 5.1-1: Lotus™ Valve System and LOTUS Edge™ Valve System 
5.1.1. Lotus Valve and LOTUS Edge Valve 
The Lotus Valve and LOTUS Edge Valve (Figure 5.1-2) consist of 3 bovine pericardial 
leaflets. The commissures of the leaflets are attached to the valve frame through portions of 
the locking components. The valve frame is made of a single nitinol wire strand woven into a 
braid. The wire ends of this frame are encapsulated by a tantalum crimp that is used as a 
radiopaque marker, and which is located in the center of the frame height. The braided 
structure is designed to foreshorten and expand radially when delivered, and is then locked in 
this position using a post and buckle locking mechanism. Additionally, the LOTUS Edge 
Valve has radiopaque tantalum markers on the valve locking assembly (i.e., buckle and post-
top components) to aid in visualization of locking under fluoroscopy during the procedure. 
Door (covering Release Ring)
Control Knob
Valve Implant
Delivery Catheter
Controller
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 42 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 43 of 188 
 
 
The Adaptive Seal™ is made of a polycarbonate-based urethane and is located on the outside 
bottom half of the frame. This seal provides a barrier between the native annulus and the 
frame to help reduce paravalvular leakage. 
The valve is deployed in a beating heart and rapid pacing is not required during valve 
deployment. The valve begins to function early in the deployment process, facilitating 
maintenance of cardiac output and hemodynamic stability during deployment.  
The Lotus Valve device is designed to produce a final diameter of 21 mm, 23 mm, 25 mm, or 
27 mm (depending on valve size) when the valve is locked. In the deployed state, the frame 
height of the 21mm valve is approximately 15 mm; the frame height of the three larger valve 
sizes is approximately 19 mm. Similarly, the LOTUS Edge Valve is designed to produce a 
final diameter of 23 mm, 25 mm, or 27 mm (depending on valve size) when the valve is 
locked, with a frame height of approximately 19 mm for all three sizes. The valve component 
of the 29 mm LOTUS Edge device is scaled from the 21 mm, 23 mm, 25 mm, and 27 mm 
valve sizes. Additionally, the LOTUS Edge 29 mm valve has a pad sewn between the braid 
and buckle to prevent interaction between the two components during sheathing and 
unsheathing of the valve. The frame height of the 29 mm valve in the deployed state is 
21 mm. 
 
Figure 5.1-2: Lotus and LOTUS Edge Valve Implant 
5.1.2. Lotus and LOTUS Edge Delivery System 
The Lotus Valve and LOTUS Edge Valve have a Delivery System comprised of the catheter 
and the Lotus Controller. 
 The catheter is a sheath in which mandrels allowing the shortening, locking, unlocking, 
and elongation of the valve, as well as its releasing, connect from the Lotus Controller to 
the valve.  The catheter has a hydrophilic coating to facilitate the insertion. The tip of the 
catheter seats on the shoulder of a nosecone to provide a smooth transition.  
 The Lotus Controller is shown in Figure 5.1-3.  
o The Lotus Controller has 3 ports; 2 of the ports are for flushing purposes and one is 
the Guidewire Port. 
Nitinol Frame
Bovine Pericardium
Adaptive Seal
Locking Mechanism
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 43 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 44 of 188 
 
 
o The Control Knob at the proximal end of the Lotus Controller is the primary control 
used to deploy the valve. It operates both the sheathing/unsheathing function as well 
as the locking/unlocking function. 
 The sheathing/unsheathing capability allows the implant to be pulled into or 
pushed out of the outer sheath.   
 The locking function shortens the valve implant into the locked configuration; the 
unlocking function elongates the valve. 
o The Release Ring is used when the operator is ready to release the valve. A Safety 
Cover covers the Release Ring to avoid inadvertent premature release.  
Overall, the Delivery System for the LOTUS Edge Valve System is similar to that of the 
Lotus Valve System. Additionally, it has 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. The multi-lumen 
catheter and outer sheath components of LOTUS Edge have been modified to enhance 
deliverability.  
 
Figure 5.1-3: Lotus Controller 
5.1.3. Lotus Introducer Set 
The Lotus Introducer Set will be used as an accessory to the Lotus Valve and LOTUS Edge 
Valve Systems during the procedure. It is composed of a dilator and an introducer sheath 
manufactured with materials commonly used in medical devices having contact with 
circulating blood. The small Lotus Introducer (LIS-S) is suitable for use with the Lotus Valve 
System in subjects requiring the 21 mm or 23 mm valve with femoral artery lumen diameter 
≥6.0 mm. The large Lotus Introducer (LIS-L) is suitable for use with the Lotus Valve System 
Proximal
Control
Lotus Controller
Distal port
Safety 
Cover
Release Ring
Guidewire
port
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 44 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 45 of 188 
 
 
in subjects requiring the 25 mm or 27 mm valve with femoral artery lumen diameter 
≥6.5 mm. The large Lotus Introducer (LIS-L) is also suitable for use with the LOTUS Edge 
Valve System in subjects requiring the 23 mm, 25 mm, 27 mm or 29 mm valve with femoral 
artery lumen diameter ≥6.5 mm. In countries where the Lotus Introducer Set is approved, the 
commercial devices will be used. In countries where it is not approved, it will be considered 
an investigational device. 
5.2. 
CoreValve Transcatheter Aortic Valve Replacement System (Control) 
The control device is the commercially available self-expanding CoreValve® Transcatheter 
Aortic Valve Replacement System (CoreValve) that is introduced percutaneously via the 
femoral artery using conventional catheterization techniques (Medtronic, Inc., Minneapolis, 
MN, USA). 
Devices sizes include the CoreValve 26 mm, 29 mm, and 31 mm diameter.  
Note 1: Every subject in the randomized cohort must be deemed treatable with an available 
size of both the test (Lotus) device and the control (CoreValve) device.  The CoreValve 
device in the planned size must be approved for use and commercially available at the 
investigational center where the implant procedure is being performed. 
Note 2: A center may use the CoreValve® Evolut™ R Recapturable TAVR System with the 
aforementioned size matrix if it is approved and commercially available, but only if the 
center no longer has access to CoreValve. 
5.3. Device Labeling 
5.3.1. Test Device 
The study Manual of Operations includes the IFU for the Lotus Valve System and the IFU 
for the LOTUS Edge Valve System. Study devices are labeled on the top and one side (one 
label wraps around the top and side) of the outer carton and on the sterile pouch. Packaging 
will include peelable, self-adhesive labels for each unit shipped. The labeling will include the 
following information. 
 Product Name 
 Part/Reference number  
 Lot number 
 Expiration (use by) date 
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. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 45 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 46 of 188 
 
 
Device labeling will be provided in local language(s) as per respective national regulations. 
5.3.2. Control Device 
Information is provided in the IFU supplied with the commercially available CoreValve® or 
CoreValve® Evolut™ R System (if used because a center no longer has access to CoreValve). 
 
6. Objectives 
The objective of the REPRISE III trial is to evaluate the safety and effectiveness of the 
Lotus™ Valve System and LOTUS Edge™ Valve System for transcatheter aortic valve 
replacement (TAVR) in symptomatic subjects with calcific, severe native aortic stenosis who 
are considered at extreme or high risk for surgical valve replacement.  
 
7. Endpoints 
Outcomes will be assessed on an intention-to-treat (ITT) basis, an implanted basis, and an as-
treated basis. The ITT analysis population of the randomized cohort includes subjects who 
sign an Informed Consent Form (see Section 0), are enrolled in the trial (see Section 10.1 for 
point of enrollment), and are randomized, whether or not an assigned study device is 
implanted. The implanted analysis population includes ITT subjects who are implanted with 
an assigned, randomized study device. The as-treated population includes subjects who sign 
an Informed Consent Form, are enrolled in the trial, are randomized, and received a study 
device, with the analysis based on the treatment actually received. For all analysis sets, if a 
subject receives 2 valves, the subject is assigned to the group corresponding to the first valve 
received. Among the roll-in (initial cohort with 23 mm, 25 mm, and 27 mm Lotus Valve 
System and subsequent cohort with 29 mm LOTUS Edge Valve System), Lotus 21 mm 
Nested Registry, LOTUS Edge Nested Registry, LOTUS Edge 29 mm Nested Registry, and 
U.S. Continued Access Study cohorts, for ITT analyses, all subjects who sign the IRB/IEC-
approved study ICF and are enrolled in the trial will be included in the analysis sample, 
regardless of whether the study device was implanted. For these cohorts, the as-treated 
population includes all subjects implanted with the Lotus/LOTUS Edge valve. Endpoint 
definitions can be found in Table 26.2-1. 
7.1. Primary Endpoints 
7.1.1. Primary Safety Endpoint 
The primary safety endpoint is a composite of all-cause mortality, stroke, life-threatening and 
major bleeding events, stage 2 or 3 acute kidney injury, or major vascular complications at 
30 days. The primary analysis set for the primary safety endpoint is the implanted analysis 
set.  
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 46 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 47 of 188 
 
 
7.1.2. Primary Effectiveness Endpoint 
The primary effectiveness endpoint is a composite of all-cause mortality, disabling stroke, or 
moderate or greater paravalvular aortic regurgitation (based on core lab assessment) at 
1 year. The primary analysis set for the primary effectiveness endpoint is the implanted 
analysis set. 
7.1.3. Secondary Endpoint 
The secondary endpoint is the rate of moderate or greater paravalvular aortic regurgitation 
based on core lab assessment at 1 year. The primary analysis set for the secondary endpoint 
is the ITT analysis set. 
7.2. Additional Measurements 
Additional measurements based on the VARC endpoints and definitions72,73 (see Note 1 
below) 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, 
unless otherwise specified below.  
 Safety endpoints (see Note 2 below) adjudicated by an independent Clinical Events 
Committee (CEC; Section 22.1.1): 
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 
o Acute kidney injury (≤7 days post index procedure): based on the AKIN System109,110 
Stage 3 (including renal replacement therapy) or Stage 2 
o Major vascular complication 
o Repeat procedure for valve-related dysfunction (surgical or interventional therapy) 
o Hospitalization for valve-related symptoms or worsening CHF (NYHA class III or IV) 
o New permanent pacemaker implantation resulting from new or worsened conduction 
disturbances (definitions in Table 26.2-1; see Note 3 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  
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 47 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 48 of 188 
 
 
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 4 
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  
 Clinical procedural success (30 days), defined as implantation of the study device in the 
absence of death, disabling stroke, major vascular complications, and life-threatening or 
major bleeding  
 Procedural success (30 days), 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) plus no serious adverse events at 30 days 
 Additional indications of prosthetic aortic valve performance as measured by 
transthoracic echocardiography (TTE; see Note 5 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 (see Note 6 below). 
 Modified device success (30 days), reported for subjects randomized and implanted with 
an assigned study device and defined as follows: absence of mortality with the originally 
implanted transcatheter valve in the proper anatomical location, no additional aortic valve 
procedures, and with the intended performance of the prosthetic valve (either a mean 
aortic valve gradient <20 mm Hg or a peak velocity <3m/sec with no moderate or severe 
prosthetic valve aortic regurgitation) 
 Functional status as evaluated by the following: 
o 5-m gait speed test111 (at 1 year compared to baseline)  
o New York Heart Association (NYHA) classification 
 Neurological status (see Note 7 below) as determined by the following: 
o Neurological physical exam by a neurologist, neurology fellow, neurology physician 
assistant, or neurology nurse practitioner at discharge and 1 year 
o National Institutes of Health Stroke Scale (NIHSS) at discharge and 1 year  
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 48 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 49 of 188 
 
 
o Modified Rankin Scale (mRS) at all time points 
 Health status as evaluated by Kansas City Cardiomyopathy112 and SF-12113 Quality of 
Life (QOL) questionnaires at baseline; 1 and 6 months; and 1, 3, and 5 years 
 Resource utilization associated with the procedure and/or follow-up. 
Additionally, assessment of leaflet thickening and mobility using 4D CT will be carried out 
at 30 days and 1 year post index procedure for subjects in the CT Imaging Substudy of the 
U.S. Continued Access Study. The CT scans will be evaluated by an independent CT Core 
Laboratory and should be blinded to local investigators for cardiac valve findings (local 
reading should be only for non-cardiac valve findings such as unexpected lung pathology; 
see Section 11.10.1 for additional information). 
Note 1: The most current VARC definitions and endpoints available at the beginning of the 
trial were used. 
Note 2: The VARC-272,73 safety composite at 30 days includes all-cause mortality, all stroke 
(disabling and non-disabling), life-threatening bleeding, acute kidney injury (Stage 2 or 3), 
coronary artery obstruction requiring intervention, major vascular complication, and repeat 
procedure for valve-related dysfunction. The VARC-2 time-related valve safety composite 
includes structural valve deterioration (valve-related dysfunction requiring repeat procedure 
[TAVR or SAVR]), prosthetic valve endocarditis, prosthetic valve thrombosis, 
thromboembolic events (e.g., stroke), and VARC bleeding (unless clearly unrelated to valve 
therapy based on investigator assessment) 
Note 3:  Clinical indications for permanent pacemaker implantation are outlined in the 
ACCF/AHA/HRS Guidelines for Device-Based Therapy of Cardiac Rhythm 
Abnormalities114. Permanent pacemaker implantation should generally be performed only for 
accepted Class I indications.  
Note 4: For the Lotus Valve System, repositioning may be achieved with partial or full 
resheathing of the valve; the proportion of subjects with partial valve resheathing and full 
valve resheathing will be determined. 
Note 5: 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 6: The VARC-272,73 clinical efficacy composite (after 30 days) includes all-cause 
mortality, all stroke, required hospitalization for valve-related symptoms or worsening CHF 
(NYHA class III or IV), and prosthetic heart valve dysfunction (mean aortic valve gradient 
≥20 mmHg, effective orifice area ≤0.9-1.1 cm2 and/or Doppler velocity index [DVI] <0.35, 
AND/OR moderate or severe prosthetic valve aortic regurgitation [per VARC definition]). 
The need for hospitalization associated with valve-related symptoms or worsening CHF 
serves as a basis for calculation of a “days alive outside the hospital” endpoint. This includes 
heart failure, angina, or syncope due to aortic valve disease requiring intervention or 
intensified medical management; clinical symptoms of CHF with objective signs including 
pulmonary edema, hypoperfusion, or documented volume overload AND administration of 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 49 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 50 of 188 
 
 
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.  
Note 7: For subjects diagnosed with a neurological event (e.g., stroke, transient ischemic 
attack), 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 
post-neurological event (see Table 11.1-1). If a subject who has not received a study device 
(investigational or control) experiences a neurological event within the first 1 year after the 
index procedure, mRS must be performed on that subject after the event and at 90±14 days 
post-neurological event and the results must be reported to the Sponsor.     
 
8. Design 
8.1. 
Scale and Duration 
The REPRISE III clinical study includes a prospective, multicenter, randomized controlled 
trial designed to evaluate the safety and efficacy of the Lotus Valve System for TAVR in 
symptomatic subjects who have calcific, severe native aortic stenosis and who are at extreme 
or high risk for surgical valve replacement. There will be a non-randomized roll-in phase 
with only the test device for centers that do not have previous experience implanting the 
Lotus Valve. There will also be a single-arm, non-randomized, nested registry cohort of 
subjects who receive the 21 mm Lotus Valve to assess safety and effectiveness (Lotus 21 mm 
Nested Registry); participating centers will be centers that have enrolled subjects in 
REPRISE III. After enrollment of the randomized cohort is completed, an additional cohort 
of subjects will be enrolled in a U.S. Continued Access Study cohort with the Lotus Valve 
(23 mm, 25 mm, and 27 mm valve sizes) to further assess performance and safety. Selected 
centers with the ability to perform high quality 4D CT scans will include U.S. Continued 
Access Study subjects in a CT Imaging Substudy to assess the prevalence of reduced leaflet 
mobility and its relationship, if any, to clinical events. Centers participating in the CT 
Imaging Substudy should ask all subjects eligible for enrollment in the U.S. Continued 
Access Study to consider participation in the substudy. Enrollment in the substudy will end 
after approximately 200 consecutive subjects who provide consent for participation are 
enrolled. An additional single-arm, non-randomized, nested registry cohort of subjects who 
will receive the 23 mm, 25 mm, or 27 mm LOTUS Edge Valve System (LOTUS Edge 
Nested Registry) will be conducted to confirm performance of the Lotus Valve implantation 
procedure with the Edge delivery system. There will also be a non-randomized, roll-in phase 
with the 29 mm LOTUS Edge Valve for centers that do not have prior experience implanting 
the LOTUS Edge Valve System, and a nested registry cohort of subjects who will receive the 
29 mm LOTUS Edge Valve System (LOTUS Edge 29 mm Nested Registry). Participating 
centers will be centers that have enrolled subjects in REPRISE III with the Lotus Valve 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 50 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 51 of 188 
 
 
System. 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. Implanted subjects participating in the CT Imaging 
Substudy will undergo additional 4D CT assessment at 30 days and 1 year. Enrolled subjects 
who do not have a study device implanted will be assessed through 1 year post procedure for 
safety/adverse events.   
The REPRISE III study will be conducted in accordance with the relevant parts of the 
International Conference on Harmonisation (ICH) Guidelines for Good Clinical Practices 
(GCP) or the International Standard ISO 14155: 2011; ethical principles that have their 
origins in the Declaration of Helsinki; and pertinent individual country/state/local laws and 
regulations. See Section 11 below for additional information on study design and data 
collection.  
The REPRISE III study will be registered at ClinicalTrials.gov prior to enrollment of the first 
subject. 
8.2. 
Treatment Assignment 
Screening materials from eligible subjects who are identified by the investigators as having 
met the inclusion and exclusion criteria (see below Table 9.2-1 and Table 9.3-1, respectively) 
and who provide written informed consent, will be reviewed by a Case Review Committee 
(CRC; see Section 22.2) to assess and confirm suitability of subjects for enrollment.  
For the randomized cohort, eligible subjects will be randomized in a 2:1 allocation to receive 
either the Lotus Valve System (test) or a commercially available self-expanding CoreValve® 
Transcatheter Aortic Valve Replacement System (control). The randomization schedules will 
be computer-generated, using a pseudo-random number generator. Randomization will be 
stratified by center and by high or extreme risk status (see Section 26.2 for definitions). All 
randomized subjects will have unique identification numbers. Random permuted blocks will 
be employed to ensure approximate balance of treatment allocation within each stratum. 
Instructions on randomization are provided in the Manual of Operations. Subject should be 
randomized within 7 calendar days of CRC approval. Subjects should be treated within 14 
calendar days of randomization and no later than 30 calendar days after randomization. 
Note: There will be a non-randomized roll-in phase with only the test device for centers that 
do not have previous experience implanting the Lotus Valve; each of these centers will 
perform at least 2 roll-in cases before commencing randomization. All roll-in subjects will 
have unique identification numbers. Subjects receiving the 21 mm Lotus Valve will be 
enrolled in a non-randomized, nested registry cohort to assess safety and effectiveness. After 
enrollment of the randomized cohort is completed, subjects will be enrolled in a U.S. 
Continued Access Study cohort with the Lotus Valve (23 mm, 25 mm, and 27 mm valve 
sizes) to further assess performance and safety. Additionally, subjects will be enrolled in a 
non-randomized, nested registry cohort with the 23 mm, 25 mm or 27 mm LOTUS Edge 
Valve (LOTUS Edge Nested Registry) to confirm performance of the Lotus Valve 
implantation procedure with the Edge delivery system. There will also be a non-randomized, 
roll-in phase with the 29 mm LOTUS Edge Valve for centers that do not have previous 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 51 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 52 of 188 
 
 
experience implanting the LOTUS Edge Valve System (at least 2 roll-in cases/center), and a 
nested registry cohort of subjects who will receive the 29 mm LOTUS Edge Valve System 
(LOTUS Edge 29 mm Nested Registry).  
8.2.1. Treatment  
See Section 5 for a detailed description of the devices and information on device sizes. 
The test device is the Lotus Valve System or the LOTUS Edge Valve System, both of which 
consist of a bioprosthetic bovine pericardial aortic valve and a delivery system. The Lotus 
Introducer Set is used as an accessory in the procedure.  
The control device is the commercially available CoreValve Transcatheter Aortic Valve 
Replacement System.  
8.3. 
Study Design Justification  
There will be up to 2142 subjects in REPRISE III. 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 Valve experience), 912 subjects will be randomized and enrolled, up to 
20 subjects will be enrolled in the Lotus 21 mm Nested Registry, up to 1000 subjects will be 
enrolled in the U.S. Continued Access Study cohort, at least 50 subjects will be enrolled in 
the LOTUS Edge Nested Registry, up to 20 subjects will be enrolled in the roll-in cohort 
with the 29 mm LOTUS Edge Valve, and up to 20 subjects will be enrolled in the LOTUS 
Edge 29 mm Nested Registry. Up to 60 centers in the United States, Canada, Western 
Europe, and Australia will participate in the study. Centers in the United States that enrolled 
subjects in the randomized cohort will be eligible to enroll subjects in the U.S. Continued 
Access Study cohort. Safety and effectiveness results will be reported on all enrolled subjects 
(see Section 21 for information on safety reporting).  Selected centers with the ability to 
perform high quality 4D CT scans will include approximately 200 U.S. Continued Access 
Study subjects in a CT Imaging Substudy to assess the prevalence of reduced leaflet mobility 
and its relationship, if any, to clinical events. In addition to the risk-benefit analysis noted in 
Section 4.2 (see also Section 19), ongoing dynamic data safety monitoring will be performed 
throughout the trial to minimize risk to subjects (see Section 22.1). All implanted subjects 
will be followed for up to 5 years post index procedure. Per society guidelines8,115 antiplatelet 
therapy with aspirin and clopidogrel is recommended after TAVR to decrease the risk of 
thrombotic or thromboembolic complications if there are no contraindications to these 
medications.  
 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 52 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 53 of 188 
 
 
9. Subject Selection  
9.1. 
Study Population and Eligibility  
The study will include subjects presenting with symptomatic calcific, severe native aortic 
stenosis who are considered at extreme or high risk for surgical valve replacement (see 
definitions of operative risk in Section 26.2). Traditionally underrepresented populations are 
expected to be included in the subject population. Because aortic stenosis most commonly 
occurs in the very elderly, women represent the majority of subjects enrolled in many TAVR 
trials. All efforts will be made to minimize attrition in REPRISE III. Since the very elderly 
will represent the majority of subjects enrolled in the trial, these efforts are by definition 
targeted to traditionally under-represented groups. 
Prior to being eligible for the REPRISE III study, a subject must meet all of the inclusion 
criteria (Section 9.2) and none of the exclusion criteria (Section 9.3). The inclusion and 
exclusion criteria are not expected to have a negative effect on recruitment or retention of 
traditionally under-represented populations. 
9.2. 
Inclusion Criteria 
Subjects who meet all of the following criteria (Table 9.2-1) may be given consideration for 
inclusion in this clinical investigation, provided no exclusion criterion (Table 9.3-1) is met. 
Centers participating in the 4D CT substudy of the U.S. Continued Access Study must have 
the ability to perform high quality 4D CT scans; subjects in this substudy must meet none of 
the additional exclusion criteria listed in Table 9.3-2.   
Table 9.2-1: REPRISE III Inclusion Criteria 
IC1.   Subject has documented calcific, severe native aortic stenosis with an initial AVA of ≤1.0 cm2 (or AVA 
index of ≤0.6 cm2/m2) and a mean pressure gradient ≥40 mm Hg or jet velocity ≥4.0 m/s, as measured by 
echocardiography and/or invasive hemodynamics. 
IC2.   Subject has a documented aortic annulus size of ≥18 mm and ≤29 mm based on the center’s assessment 
of pre-procedure diagnostic imaging (and confirmed by the Case Review Committee [CRC]) and, for the 
randomized cohort, is deemed treatable with an available size of both test and control device. For the 
U.S. Continued Access Study cohort the acceptable aortic annulus size is ≥20 mm and ≤27 mm. 
IC3.   Subject has symptomatic aortic valve stenosis with NYHA Functional Class ≥ II 
IC4.   There is agreement by the heart team (which must include a site investigator interventionalist and a site 
investigator cardiac surgeon) that subject is at high or extreme operative risk for surgical valve 
replacement (see Note 1 below for definitions of extreme and high risk, the required level of surgical 
assessment, and CRC confirmation) and that TAVR is appropriate. Additionally, subject has at least one 
of the following. 
 Society of Thoracic Surgeons (STS) score ≥8% -OR- 
 If STS <8, subject has at least one of the following conditions:  
o Hostile chest  
o Porcelain aorta  
o Severe pulmonary hypertension (>60 mmHg) 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 53 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 54 of 188 
 
 
Table 9.2-1: REPRISE III Inclusion Criteria 
o Prior chest radiation therapy 
o Coronary artery bypass graft(s) at risk with re-operation 
o Severe lung disease (need for supplemental oxygen, FEV1 <50% of predicted, DLCO <60%, other 
evidence of major pulmonary dysfunction) 
o Neuromuscular disease that creates risk for mechanical ventilation or rehabilitation after surgical 
aortic valve replacement 
o Orthopedic disease that creates risk for rehabilitation after surgical aortic valve replacement 
o Childs Class A or B liver disease (subjects with Childs Class C disease are not eligible for 
inclusion in this trial) 
o Frailty as indicated by at least one of the following: 5‑meter walk >6 seconds, Katz ADL score of 
3/6 or less, body mass index <21, wheelchair bound, unable to live independently 
o Age ≥90 years 
o Other evidence that subject is at high or extreme risk for surgical valve replacement (CRC must 
confirm agreement with site heart team that subject meets high or extreme risk definition) 
IC5.   Heart team (which must include a cardiac interventionalist and an experienced cardiac surgeon) 
assessment that the subject is likely to benefit from valve replacement.  
IC6.   Subject (or legal representative) understands the study requirements and the treatment procedures, and 
provides written informed consent. 
IC7.   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. 
Note:  Extreme operative risk and high operative risk are defined as follows:  
 
Extreme Operative Risk: Predicted operative mortality or serious, irreversible morbidity risk ≥50% at 
30 days.  
 
High Operative Risk: Predicted operative mortality or serious, irreversible morbidity risk ≥15% at 
30 days. 
 
Risk of operative mortality and morbidity 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).  
Abbreviations: AVA=aortic valve area; CRC=Clinical Review Committee; NYHA=New York Heart 
Association; STS=Society of Thoracic Surgeons 
 
9.3. 
Exclusion Criteria 
Subjects who meet any one of the following criteria (Table 9.3-1) will be excluded from this 
clinical study. 
Table 9.3-1: REPRISE III Exclusion Criteria 
EC1.  Subject has a congenital unicuspid or bicuspid aortic valve. 
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 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 54 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 55 of 188 
 
 
Table 9.3-1: REPRISE III Exclusion Criteria 
elevation and/or troponin elevation). 
EC3.  Subject has had a cerebrovascular accident or transient ischemic attack within the past 6 months prior to 
study enrollment. 
EC4.  Subject has end-stage renal disease or has GFR <20 (based on Cockcroft-Gault formula). 
EC5.  Subject has a pre-existing prosthetic heart aortic or mitral valve. 
EC6.  Subject has severe (4+) aortic, tricuspid, or mitral regurgitation. 
EC7.  Subject has a need for emergency surgery for any reason. 
EC8.  Subject has a history of endocarditis within 6 months of index procedure or evidence of an active 
systemic infection or sepsis. 
EC9.  Subject has echocardiographic evidence of new intra-cardiac vegetation or intraventricular or 
paravalvular thrombus requiring intervention. 
EC10. Subject has Hgb <9 g/dL, platelet count <50,000 cells/mm3 or >700,000 cells/mm3, or white blood cell 
count <1,000 cells/mm3. 
EC11. Subject requires chronic anticoagulation therapy after the implant procedure and cannot be treated with 
warfarin (other anticoagulants are not permitted in the first month) for at least 1 month concomitant with 
either aspirin or clopidogrel. 
EC12. Subject 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, or will refuse transfusions. 
EC13. Subject has known hypersensitivity to contrast agents that cannot be adequately pre-medicated, or has 
known hypersensitivity to aspirin, all P2Y12 inhibitors, heparin, nickel, tantalum, titanium, or 
polyurethanes. 
EC14. Subject has a life expectancy of less than 12 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 implantation, which are allowed).  
EC17. Subject has untreated coronary artery disease, which in the opinion of the treating physician is clinically 
significant and requires revascularization. 
EC18. Subject has 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 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 symptomatic carotid or vertebral disease).  
EC21. Subject has thick (>5 mm) protruding or ulcerated atheroma in the aortic arch  
EC22. Subject has arterial access that is not acceptable for the test and control device delivery systems as 
defined in the device Instructions For Use. 
EC23. Subject has current problems with substance abuse (e.g., alcohol, etc.). 
EC24. Subject is participating in another investigational drug or device study that has not reached its primary 
endpoint. 
EC25. 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.     
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 55 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 56 of 188 
 
 
Table 9.3-1: REPRISE III Exclusion Criteria 
EC26. Subject has severe incapacitating dementia. 
* An alternative P2Y12 inhibitor may be prescribed if subject is allergic to or intolerant of clopidogrel. 
Abbreviations: AV= atrioventricular; CK=creatine kinase; MI=myocardial infarction; PCI=percutaneous 
coronary intervention 
 
Additional exclusion criteria apply for subjects considered for enrollment in the CT Imaging 
substudy of the U.S. Continued Access Study as shown in Table 9.3-2. 
Table 9.3-2: Additional Exclusion Criteria for the 4D CT Imaging Substudy of the U.S. 
Continued Access Study 
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 TAVR 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: AEC=additional exclusion criterion; CT=computed tomography; eGFR=estimated glomerular 
filtration rate; TAVR=transcatheter aortic valve replacement 
 
 
10. Subject Accountability 
10.1. Point of Enrollment 
10.1.1. Roll-in Subjects 
There will be a non-randomized roll-in phase with only the test device for centers that do not 
have previous experience implanting the Lotus Valve. For this roll-in phase, subjects 
confirmed eligible for the study by the CRC (see Section 22.2) and who provided written 
informed consent are considered enrolled in the study as soon as an attempt is made to insert 
the Lotus Valve System (initial cohort with the 23 mm, 25 mm, and 27 mm Lotus Valve) into 
the subject’s femoral artery.  
10.1.2. Randomized Subjects 
Subjects confirmed eligible for the study by the CRC (see Section 22.2) and who provided 
written informed consent are considered enrolled in the study upon randomization.    
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 56 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 57 of 188 
 
 
10.1.3. Lotus 21 mm Nested Registry Subjects 
For the Lotus 21 mm Nested Registry, subjects confirmed eligible for the study by the CRC 
(see Section 22.2) and who provided written informed consent are considered enrolled in the 
study as soon as an attempt is made to insert the Lotus Valve System into the subject’s 
femoral artery.  
10.1.4. U.S. Continued Access Study Subjects 
For the U.S. Continued Access Study cohort, subjects confirmed eligible for the study by the 
CRC (see Section 22.2) and who provided written informed consent are considered enrolled 
in the study as soon as an attempt is made to insert the Lotus Valve System into the subject’s 
femoral artery. 
10.1.5. LOTUS Edge 23−27 mm Nested Registry Subjects 
For the LOTUS Edge 23-27 mm Nested Registry, subjects confirmed eligible for the study 
by the CRC (see Section 22.2) and who provided written informed consent are considered 
enrolled in the study as soon as an attempt is made to insert the LOTUS Edge Valve System 
into the subject’s femoral artery. 
10.1.6. LOTUS Edge 29 mm Roll-in and Nested Registry Subjects 
There will also be a non-randomized, roll-in phase with the 29 mm LOTUS Edge Valve for 
centers that do not have prior experience implanting the LOTUS Edge Valve System. 
Participating centers will be centers that have enrolled subjects in REPRISE III with the 
Lotus Valve System. For the LOTUS Edge 29 mm Roll-in cohort and Nested Registry, 
subjects confirmed eligible for the study by the CRC (see Section 22.2) and who provided 
written informed consent are considered enrolled in the study as soon as an attempt is made 
to insert the LOTUS Edge Valve System into the subject’s femoral artery.  
10.2. Withdrawal 
All subjects enrolled in the clinical study (including those withdrawn from the clinical study 
or lost to follow-up) shall be accounted for and documented. If a subject withdraws from the 
clinical investigation, the reason(s) shall be reported. If such withdrawal is due to problems 
related to investigational device safety or performance, the investigator shall ask for the 
subject’s permission to follow his/her status/condition outside of the clinical study.   
 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 57 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 58 of 188 
 
 
11. Study Methods 
11.1. Data Collection 
The study event schedule is shown diagrammatically in Figure 11.1-1 and discussed in Table 
11.1-1 and Sections 11.2 through 11.12. The methods are based on recommendations in the 
2012 ACCF/AATS/SCAI/STS Expert Consensus Document on Transcatheter Aortic Valve 
Replacement8 and the 2014 AHA/ACC Guideline for the Management of Patients With 
Valvular Heart Disease115.
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 58 of 188 

S2282 
Boston Scientific 
Confidential 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
 
Page 59 of 188 
 
 
 
 
 
 
Figure 11.1-1: REPRISE III Study Design 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 59 of 188 

S2282 
Boston Scientific 
Confidential 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
 
Page 60 of 188 
 
 
 
Table 11.1-1: 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 
6 Monthsb 
(±30 Days)  
Office Visit 
12 Monthsb 
(±30 Days)  
Office  
Visit 
24–60  
Monthsb 
[Annual] 
(±45 Days)  
Office Visit 
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 
Neurological physical 
examd 
 
X 
 
 
X 
 
 
X 
 
NIHSSd 
 
X 
 
 
X 
 
 
X 
 
Modified Rankin Scaled  
 
X 
 
 
X 
X 
X 
X 
X 
12-lead ECGe 
X 
 
 
X 
X 
X 
X 
X 
 
Heart rhythm stripe 
 
 
Xe 
 
 
 
 
 
 
Laboratory testsf 
 
X 
 
X 
 
 
 
 
 
Risk assessmentsg  
X 
 
 
 
 
 
 
 
 
Frailty, disability and 
comorbidityh 
X 
 
 
 
 
 
 
X 
 
Antiplatelet and 
anticoagulant (if 
applicable) medications 
X 
 
X 
 
X 
X 
X 
X 
X 
Other CV medications 
X 
 
 
 
 
 
 
 
 
TTEi 
X 
 
 
 
X 
X 
X 
X 
X 
TEEj 
 
 
X 
 
 
 
 
 
 
Coronary angiogramk 
X 
 
 
 
 
 
 
 
 
CT angiogram of aortic 
structurel 
X 
 
 
 
 
 
 
 
 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 60 of 188 

S2282 
Boston Scientific 
Confidential 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
 
Page 61 of 188 
 
 
 
Table 11.1-1: 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 
6 Monthsb 
(±30 Days)  
Office Visit 
12 Monthsb 
(±30 Days)  
Office  
Visit 
24–60  
Monthsb 
[Annual] 
(±45 Days)  
Office Visit 
CT angiogram of 
iliofemoral systemm 
X 
 
 
 
 
 
 
 
 
Annual imaging 
(rotational X-ray)n 
 
 
 
 
 
 
 
X 
X 
QOL surveyso 
 
X 
 
 
 
X 
X 
X 
Xp 
Procedural cine-
angiography (including 
post-deployment 
aortogram)q 
 
 
X 
 
 
 
 
 
 
Pacemaker interrogationr 
 
 
 
 
 
X 
 
X 
 
AE and ADE assessmentss 
 
 
X 
X 
X 
X 
X 
X 
 
Device deficiencies, SAE, 
SADE, USADE, UADE 
and CEC event 
assessmentst 
 
 
X 
X 
X 
X 
X 
X 
X 
4D CT imaging of 
prosthetic valveu 
 
 
 
 
 
X 
 
X 
 
a: It is recommended that screening materials for CRC review be submitted electronically within 5 days of a scheduled CRC call in order to be considered for review 
(unless otherwise specified). 
b: All follow-up dates will be calculated from the date of the (attempted) index procedure (or randomization in randomized subjects where no implant is attempted).  
Visits must be an office/clinical visit, but may be done in-hospital should the subject be admitted at the time. Subjects who are enrolled but do not receive a study 
device (test or control) 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.  
d:   Neurological physical examination must be performed by a neurologist, neurology fellow, neurology physician assistant, or neurology nurse practitioner. NIHSS and 
mRS must be performed by a neurology professional or certified personnel (external certification for NIHSS; internal or external certification for mRS). The assessors 
should be independent (not involved with the care of study subjects). For subjects diagnosed with a neurological event (e.g., stroke, transient ischemic attack), a 
neurological physical exam, mRS, and NIHSS must be performed after the event; mRS must also be administered at 90±14 days post-neurological event. If a subject 
who has not received a study device (investigational or control) experiences a neurological event within the first 1 year after the index procedure, mRS must be 
performed on that subject after the event and at 90±14 days post-neurological event 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).  Heart 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 61 of 188 

S2282 
Boston Scientific 
Confidential 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
 
Page 62 of 188 
 
 
 
Table 11.1-1: 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 
6 Monthsb 
(±30 Days)  
Office Visit 
12 Monthsb 
(±30 Days)  
Office  
Visit 
24–60  
Monthsb 
[Annual] 
(±45 Days)  
Office Visit 
rhythm strip should be obtained after BAV and before study valve insertion (12-lead ECG is not required during the procedure). 
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. 
g:  Consists of STS score, euroSCORE II (2011), 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). In the United States, the Centers for Medicare and Medicaid Services require independent evaluations by 
2 cardiac surgeons for reimbursement.  
h:   Frailty, disability, and comorbidity risk assessments must be captured at screening: height, weight, cognitive function (Mini-Cognitive Assessment for Dementia), 
strength and balance (use of wheelchair, gait speed to walk 5 meters, number of falls in the past 6 months, maximal grip strength), 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 valve implanted in the aortic position. This includes assessment of EOA, peak and mean 
aortic valve pressure gradients, aortic regurgitation assessment, and LVEF. Screening TTE must be performed within 60 days prior to CRC review. 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 valve, then no follow-up TTE is required.  
Note: In cases of low flow low gradient aortic stenosis, 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 III 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 is recommended but not required during the implant procedure. 
k:  A coronary angiogram must be performed within 365 days prior to CRC review. 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 review (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 meeting where results will be 
reviewed to confirm subject’s eligibility. 
m:  An assessment of the iliofemoral system must be performed within 180 days prior to CRC review (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 Core Laboratory with the 
screening CT angiogram of the aortic structure. An iliofemoral invasive angiogram may be substituted for the iliofemoral CT angiogram. 
n: Annual imaging using rotational x-ray to assess for structural valve frame integrity must be performed on subjects who receive the Lotus Valve. Please refer to the 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 62 of 188 

S2282 
Boston Scientific 
Confidential 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
 
Page 63 of 188 
 
 
 
Table 11.1-1: 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 
6 Monthsb 
(±30 Days)  
Office Visit 
12 Monthsb 
(±30 Days)  
Office  
Visit 
24–60  
Monthsb 
[Annual] 
(±45 Days)  
Office Visit 
Imaging Core Laboratory procedure guidelines (see study Manual of Operations). Results must be forwarded to the CT/X-Ray Core Laboratory for analysis. If 
additional imaging is performed (e.g., cardiac CT or MRI scan), data may be provided for analysis.  
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 36 and 60 months. 
q: Procedural cine-angiogram including final post-deployment aortogram of the ascending aorta must be done and sent to the CT/X-Ray Core Laboratory for analysis. 
r: For  subjects who received a permanent pacemaker related to the index procedure, pacemaker dependence must be captured at  the 30-day and 1-year visits via 
pacemaker interrogation. Pacemaker interrogation should also include assessment of the percentage of beats where the ventricles are paced. 
s: AEs and ADEs will be monitored and collected from the time of enrollment through 12-month follow-up. For subjects who do not receive the study device, AEs will 
be monitored through 1-year follow-up.  
t:  Information on device deficiencies for the test and the control devices, as well as all SAEs, SADEs, UADEs, USADEs, and CEC events will be monitored and 
reported to Boston Scientific for all enrolled subjects from the time of enrollment through termination of the study. For subjects who do not receive a study device 
(test or control), the mentioned events will be monitored through 1 year post-index procedure. Please refer to Section 7.2 for a list of CEC events and Table 26.2-1 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 also be carried out using the manufacturer’s processes.   
u: This applies to subjects in the CT Imaging Substudy of the U.S. Continued Access Study. Please refer to the CT Core Laboratory procedure guidelines (see study 
Manual of Operations). Results must be sent to the CT Core Laboratory (Section 13.3.2). 
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; USADE=unanticipated serious adverse device effect 
 
 
 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 63 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 64 of 188 
 
 
11.2. Study Candidate Screening 
Subjects will be evaluated for eligibility by the center heart team (which must include a 
cardiac interventionalist and an experienced cardiac surgeon). Assessment will be based on 
results from the Society of Thoracic Surgeons (STS) score (≥8%) and/or agreement by the 
heart team that the subject is at extreme or high operative risk of serious morbidity or 
mortality with surgical valve replacement (see Table 9.2-1 for inclusion criteria and operative 
risk definitions). 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). In the United States, the Centers for Medicare and 
Medicaid Services (CMS) require independent evaluations by 2 cardiac surgeons for 
reimbursement. The heart team must also agree that the subject is likely to benefit from valve 
replacement.   
Clinical assessment and evaluation as well as all collected tests and images (e.g., 
echocardiography, computerized tomography [CT], angiography) performed in preparation 
for TAVR will be reviewed by the CRC (see Section 8.2 and Section 22.2). The CRC will be 
comprised of experienced cardiac surgeons, interventional cardiologists, and Sponsor staff 
proficient with the Lotus Valve System and will confirm subject eligibility for enrollment. 
11.3. Subject Informed Consent 
Informed consent (see Section 0) must be obtained from a potential subject prior to 
conducting any preoperative assessments that are not part of the local routine preparation and 
evaluation of a subject for TAVR, even if the subject’s eligibility has not yet been completely 
determined.   
The Investigator/designee, who has been trained on the protocol, will explain the nature and 
scope of the study, potential risks and benefits of participation, and answer questions for the 
subject. If the subject agrees to participate, the Informed Consent form (ICF) must be signed 
and personally dated by the subject or his/her legally authorized representative. The 
Investigator/designee must also sign the ICF prior to subject enrollment. Any additional 
persons required by the center’s Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) to sign the ICF must also comply. Study personnel should explain to the 
subject that even if the subject agrees to participate in the study and signs the ICF, the heart 
team and/or the CRC may determine that the subject is not a suitable candidate for the study 
and/or TAVR procedure. 
If during the course of the preoperative evaluations, the subject is found not to be eligible for 
inclusion in the study, the subject should be notified. Reason for ineligibility will be 
accounted for as “screening failure” and will be documented as such in the screening module. 
If the subject has signed the ICF, but is found not eligible for inclusion in the study prior to 
or during the procedure, the subject should receive the appropriate treatment as identified by 
the clinical investigator. Information regarding the screening failure will be captured on the 
screening module and subject will be included in the “screening cohort” accountability. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 64 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 65 of 188 
 
 
11.4. Screening Assessments 
The following screening tests and procedures must be performed and submitted to the CRC 
(Section 22.2) for evaluation to confirm a subject’s eligibility for the study.  Screening 
assessment documentation should be provided at least 5 days in advance of a scheduled CRC 
meeting via electronic upload. It is planned that CRC meetings will take place at least weekly 
or as needed to ensure timely review and confirmation of subject eligibility. For the 
randomized cohort, only after CRC approval of a subject’s suitability for enrollment should 
the subject be randomized (within 7 calendar days).  
Sites will be trained on the screening process as detailed in the REPRISE III Training Plan 
(see Section 17.4.1). Specific data points will be collected in the REPRISE III electronic 
Case Report Forms (eCRFs) as shown below.  
 Clinical assessments  
o Demographics including age and gender 
o Medical history (general medical; cardiac [including previous cardiac surgery]; 
neurological, renal [including creatinine] and peripheral disease; and other medical 
conditions)   
o Physical examination including weight and height 
o NYHA classification 
o 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 forwarded to 
Core Laboratory for analysis  
o Risk assessments: STS Score, euroSCORE II (2011), heart team assessment including 
an in-person evaluation by a center cardiac surgeon and any frailty assessments 
(detailed in next bullet). In the United States, CMS requires independent evaluations 
by 2 cardiac surgeons for reimbursement. 
 Frailty, disability, and comorbidity assessments (collected prospectively)  
o Body Mass Index from the physical exam 
o Cognitive function: Mini-Cognitive Assessment for Dementia116,117 (see study 
Manual of Operations).     
o Strength and balance  
 Use of wheelchair 
 Gait speed as measured by a stopwatch for a subject to walk 5 meters (3 measures 
averaged)118-120  
 Number of falls in the past 6 months 
 Maximal grip strength (kg) in the dominant hand (3 measures averaged), using a 
Jamar hand-held dynamometer121  
o Activities of daily living: Katz Index117,122 is based on an evaluation of the functional 
independence or dependence of a subject in bathing, dressing, going to toilet, 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 65 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 66 of 188 
 
 
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 review, TTE (2-D, M-Mode, and color) must be carried 
out. The evaluation should include assessment of effective orifice area (EOA), peak 
systolic and mean aortic valve gradient pressure, aortic regurgitation assessment, 
mitral regurgitation, LVEF, left ventricular end-diastolic and end-systolic diameter, 
tricuspid regurgitation (TR) jet velocity, and left atrial (LA) volume. The TTEs must 
be performed according to the Echocardiography Core Laboratory procedure 
guidelines (see study Manual of Operations).  All TTEs for enrolled subjects must be 
sent to the Echocardiography Core Laboratory for independent analyses. In cases of 
low flow, low gradient aortic stenosis dobutamine can be used to assess the grade of 
aortic stenosis (maximum dobutamine dose of 20 mcg/kg/min recommended)8; 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 balloon aortic valvuloplasty (BAV) prior to the index procedure and 
subsequently no longer meets the REPRISE III 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 must be performed within 365 days prior to CRC review. 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 the CRC 
review and should be performed within 90 days, if possible, to evaluate the aortic 
valve anatomy and aortic root dimensions to determine eligibility and device sizing. It 
must meet the CT Core Laboratory procedure guidelines (see study Manual of 
Operations) and forwarded in advance to the Core Laboratory for detailed 
measurements and independent analyses, which will be reviewed by the CRC to 
confirm subject’s eligibility. 
o An assessment of the iliofemoral system must be performed within 180 days prior to 
the CRC review (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 sent to the CT Core Laboratory with 
the screening CT angiogram of the aortic structure for independent measurements and 
review by the CRC to confirm subject’s eligibility. An iliofemoral invasive 
angiogram may be substituted for the iliofemoral CT angiogram. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 66 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 67 of 188 
 
 
11.5. Baseline Assessments 
The following assessments must be completed within 30 days prior to the index procedure, 
unless otherwise specified below. The REPRISE III electronic eCRFs identify the specific 
data points to be collected. 
 Confirmation of eligibility criteria 
 Neurological physical examination, which must be performed by a neurologist, 
neurology fellow, neurology physician assistant, or neurology nurse practitioner (see 
Table 11.1-1); assessors should be independent (not involved with the care of study 
subjects).  
 NIH Stroke Scale (NIHSS), which must be performed by a neurology professional or 
certified personnel (external certification); assessors should be independent (not 
involved with the care of study subjects) 
 Modified Rankin Scale score, which must be performed by a neurology professional or 
certified personnel (external or internal certification); assessors should be independent 
(not involved with the care of study subjects) 
 Laboratory tests 
o Complete blood count (CBC) with platelets 
o Albumin 
o Serum creatinine 
o Cardiac enzymes (CK is required, CKMB or troponin if CK is elevated) 
 Quality Of Life (QOL) Surveys: Kansas City Cardiomyopathy112 and SF-12113 QOL 
Questionnaires must be administered to the subject within 30 days prior to the 
procedure. 
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 III 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. 
11.6. Preprocedure Medications 
 Antiplatelet Therapy: 
Subjects must be treated with aspirin and a thienopyridine prior to valve implantation.  
 
Aspirin 
 
A loading dose of aspirin (recommended dose of 75–325 mg) is required for subjects who 
have not been taking aspirin for 72 hours at the time of the index procedure. The 
loading dose must be administered prior to the implant procedure. Subjects who have 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 67 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 68 of 188 
 
 
been taking aspirin daily for 72 hours at the time of the index procedure do not require a 
loading dose. 
 
Clopidogrel 
A loading dose of clopidogrel (recommended dose of ≥300 mg) is required for subjects 
who have not been taking clopidogrel for 72 hours at the time of the index procedure.  
The loading dose must be administered prior to the implant procedure. 
Note 1: An alternative P2Y12 inhibitor (e.g., ticlopidine) may be prescribed if subject is 
allergic to or intolerant of clopidogrel.  
Note 2: If the study-specific dosages and durations for antiplatelet medications conflict 
with country-specific labeling for the medications, the country-specific labeling should 
take precedence. 
Note 3: If a subject requires chronic anticoagulation, 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. 
 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 of ≥250 seconds during the implantation procedure. 
 Additionally, the subject should be given prophylactic antibiotic therapy according to the 
local practice. The choice of antibiotic drug is left to the investigator’s discretion. 
11.7. Index Procedure 
For sites in the US, CMS coverage criteria require that both the cardiac surgeon and 
interventional cardiologist members of the heart team participate in the technical aspects of 
the index procedure. 
The preparation of the subject for the percutaneous procedure will be performed following 
standard techniques. 
11.7.1. Medtronic CoreValve (Control) Cohort 
The IFU associated with the control device (CoreValve) should be followed. 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. 
Labels from devices used during the procedure (e.g., CoreValve, Introducer, etc.) 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. 
 Date of procedure 
 Specifics of device type (such as size and model) 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 68 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 69 of 188 
 
 
 Time of first vascular puncture (femoral) and time of vascular closure (skin-to-skin 
time) 
 Introducer insertion and removal time 
 Descriptive information on balloon valvuloplasty (e.g., size of balloon, number of 
balloon inflations) 
 Any devices used and adjunctive procedures performed during implant procedure  
 Heart rhythm after balloon valvuloplasty with rhythm strip should be recorded (12-lead 
ECG is not required). 
 Valve catheter insertion and removal time 
 Descriptive information on valve implantation procedure  
 Adverse event (AE) assessment and associated treatment (including AE, serious 
adverse event [SAE], serious adverse device effect [SADE], unanticipated adverse 
device effect [UADE]/unanticipated serious adverse device effect [USADE], adverse 
device effect [ADE] and Clinical Events Committee [CEC] events; see Section 21). 
 Device deficiencies assessment 
11.7.2. Lotus Valve (Test) Cohort 
The Lotus Introducer is prepared and introduced in the patient’s femoral artery, as described 
in the Lotus Introducer IFU. 
11.7.2.1. Valvuloplasty 
A balloon valvuloplasty on the native valve following standard techniques must be 
performed with an appropriately sized valvuloplasty balloon (avoid oversizing). Careful 
attention should be paid to the position of the guidewire throughout the procedure. Prior to 
introduction of the Lotus Valve System or LOTUS Edge Valve System, the subject’s 
hemodynamic status and heart rhythm must be assessed, and a heart rhythm strip should be 
obtained (12-lead ECG is not required).  
Information on the balloon valvuloplasty, including number of inflations, should be 
documented in the source data and will be captured in the eCRFs. 
Note: If the subject becomes hemodynamically unstable after the valvuloplasty for reasons 
unrelated to the aortic valve annulus and/or leaflets, the Lotus Valve implantation (using the 
Lotus Valve System or the LOTUS Edge Valve System) should be interrupted until the 
subject is stable.  
11.7.2.2. Preparing and Using the Lotus Valve System or LOTUS Edge Valve System 
The Lotus Valve implantation procedure (using the Lotus Valve System or the LOTUS Edge 
Valve System) requires two operators: First and Second Operators. Both operators must 
comply with the IFU and must be adequately trained and certified by BSC personnel in 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 69 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 70 of 188 
 
 
accordance with the training plan before performing the procedure (see Section 17.4.1 for 
additional information on training). Guidelines provided by the Sponsor for valve size 
selection should be followed.  
The Lotus Valve System/LOTUS Edge Valve System must be prepared in accordance with 
the applicable IFU. Device preparation should only be performed by persons who have 
completed appropriate training with the Lotus Valve System or LOTUS Edge Valve System 
(as applicable).   
Prior to insertion of the Lotus Valve System/LOTUS Edge Valve System catheter into the 
Lotus Introducer, the recommended target ACT of ≥250 seconds should be confirmed, with 
additional boluses of heparin administered if needed.  
The Lotus Valve System or LOTUS Edge Valve System IFU should be followed, as 
applicable. The following summarizes the Lotus Valve System/ LOTUS Edge Valve System 
procedure. 
1) The Lotus/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 native 
valve and into the ventricle. 
2) The Lotus/LOTUS Edge catheter is inserted in the 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 into the desired position.  
4) Prior to the release of the Lotus 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 radiopaque marker as a guide.  
The valve can then be re-expanded. 
6) Once the Lotus Valve position is deemed satisfactory and the valve is fully locked, the 
release process is then initiated and the Lotus 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 (including rotational 
angiography of the valve frame, required only for Lotus) must be performed and 
forwarded to the Core Laboratory with the procedural cine-angiogram for analysis. 
9) The 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 Valve System/LOTUS 
Edge Valve System, Lotus Introducer) should be retained so that they can be included in the 
appropriate source documents and reported in the eCRFs.   
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 70 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 71 of 188 
 
 
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. 
 Date of procedure 
 Device size (21 mm, 23 mm, 25 mm, 27 mm, or 29 mm) and model  
 Time of first vascular puncture (femoral) and time of vascular closure (skin-to-skin 
time) 
 Lotus Introducer insertion and removal time 
 Descriptive information on balloon valvuloplasty (e.g., size of balloon, number of 
balloon inflations) 
 Any devices used and adjunctive procedures performed during implant procedure  
 Heart rhythm after balloon valvuloplasty with rhythm strip should be recorded (12-lead 
ECG is not required). 
 Lotus Valve System or LOTUS Edge Valve System catheter insertion and removal time 
 Descriptive information on Lotus 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]/unanticipated serious adverse device effect [USADE], adverse 
device effect [ADE] and Clinical Events Committee [CEC] events; see Section 21). 
 Device deficiencies assessment (for the Lotus Valve System/LOTUS Edge Valve 
System) 
Note: All Lotus Valve implantation procedures will be performed with the support/presence 
of trained BSC personnel.    
11.8. Post-Procedure 
The following are to be performed post-procedure. 
 Per society guidelines, antiplatelet therapy with aspirin and a thienopyridine is 
recommended to reduce the risk of thrombotic or thromboembolic complications if 
there are no contraindications to these medications8,115. Subjects must be treated with 
aspirin and clopidogrel for at least 1 month following valve implantation. Extended 
dual antiplatelet therapy may be administered per physician choice.  
o After the valve implant procedure, aspirin (recommended dose of ≥75 mg daily) 
must be given for at least 1 month. It is recommended that daily aspirin be given 
indefinitely thereafter as per local standard of care. Aspirin dose may be adjusted to 
the closest approximation based on local tablet formulation availability. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 71 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 72 of 188 
 
 
o After the valve implant procedure, clopidogrel (recommended dose of 75 mg daily) 
is required for at least 1 month. 
 
Note: An alternative P2Y12 inhibitor (e.g., ticlopidine) may be prescribed if subject 
is allergic to or intolerant of clopidogrel.  
o If a subject requires chronic anticoagulation, either clopidogrel or aspirin is required 
after the implant procedure in addition to the anticoagulant therapy (but both aspirin 
and clopidogrel are not required). The subject must be treated with warfarin (other 
anticoagulants are not permitted in the first month) and either clopidogrel (other 
P2Y12 inhibitors are not permitted in combination with warfarin) or aspirin for at 
least 1 month. After 1 month, subjects requiring chronic anticoagulation may be 
switched from warfarin 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. 
 Prophylactic antibiotic regimen should be completed as per local practice. 
 Additional medications may be used at the investigator’s discretion. 
 It is recommended that the subject’s heart rhythm be monitored using telemetry for at 
least 48 hours after the index procedure.       
 12-lead ECG must be completed within 24 hours post-procedure per the ECG Core 
Laboratory guidelines (see study Manual of Operations) and must be forwarded to the 
Core Laboratory for analysis.   
 Cardiac enzymes (CK is required, CK-MB or troponin if CK is elevated) must be 
collected twice at intervals per standard of care within 6-24 hours post-procedure. 
11.9. Prior to Discharge or 7 Days Post-Procedure (Whichever Comes First) 
Subjects must be evaluated prior to discharge or 7 days post-procedure (whichever comes 
first) based on the assessments below. The REPRISE III eCRFs identify the specific data 
points to be collected. 
 Weight and height  
 NYHA classification 
 Neurological physical examination, which must be performed by a neurologist, 
neurology fellow, neurology physician assistant, or neurology nurse practitioner; 
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); 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); assessors should be independent 
(not involved with the care of study subjects). 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 72 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 73 of 188 
 
 
 12-lead ECG per the Core Laboratory guidelines (see study Manual of Operations) and 
must be forwarded for analysis.   
 TTE, including assessment of effective orifice area, peak systolic and mean aortic valve 
gradient pressure, aortic regurgitation assessment, mitral regurgitation, LVEF, left 
ventricular end-diastolic and end-systolic diameter, TR jet velocity and LA volume, per 
the Echocardiography Core Laboratory procedure guidelines (see study Manual of 
Operations).  All TTEs for enrolled subjects must be sent to the Echocardiography Core 
Laboratory for independent analyses.  
 
Note: For all subjects who have a 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 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/USADE, ADE, and CEC events) 
and device deficiencies assessment (with associated treatment) 
11.10. 
Follow-up 
All implanted subjects will be evaluated at 30 days, 6 months, 12 months, 24 months, 
36 months, 48 months, and 60 months post index procedure. Subjects who do not have a 
study device implanted will be assessed through 1 year post procedure for safety/adverse 
events. Physical clinic visits or follow-up visits are scheduled for appointed times after the 
date of the procedure. It is important that this schedule be maintained as closely as possible 
for all subjects. Boston Scientific 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 11.1-1. Visits not completed will be 
considered missed and recorded as protocol deviations. Visits completed outside these 
windows will be recorded as protocol deviations. After 6 months, visits will be scheduled on 
an annual basis from 1 through 5 years. Each follow-up visit must be performed by study 
personnel; data from the required tests and images as well as medical assessments will be 
recorded in source documentation and captured in the eCRFs. The determination of specified 
study endpoints and measurements such as valve function and CEC events will require data 
from images and tests as outlined in the event definitions (Table 26.2-1).    
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: 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 III primary 
effectiveness endpoint (1 year). 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 73 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 74 of 188 
 
 
11.10.1. 30-Day Follow-up (307 Days)  
All enrolled subjects must be evaluated 30 days after the index procedure. During the 30-day 
follow-up, the following assessments must be completed. The REPRISE III 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); assessors should be independent 
(not involved with the care of study subjects). 
 12-lead ECG per the Core Laboratory guidelines (see study Manual of Operations) and 
must be forwarded to the Core Laboratory for analysis. 
 Current antiplatelet, anticoagulant (if applicable) medications 
 TTE including assessment of effective orifice area, peak systolic and mean aortic valve 
gradient pressure, aortic regurgitation assessment, mitral regurgitation, LVEF, left 
ventricular end-diastolic and end-systolic diameter, TR jet velocity and LA volume.  
TTE must be performed per the Echocardiography Core Laboratory procedure 
guidelines (see study Manual of Operations). All TTEs for enrolled subjects must be 
sent to the Echocardiography Core Laboratory for independent analyses.  
Note: TTE must be done for all subjects who have a 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 
 Complete adverse event (AE, SAE, SADE, UADE/USADE, ADE and CEC events) and 
device deficiencies assessment (with associated treatment) 
 For subjects who received a permanent pacemaker related to the index procedure, 
pacemaker dependence and percentage of beats where the ventricles are paced via 
pacemaker interrogation; please see the study Manual of Operations for determining 
pacemaker dependency. 
 For subjects enrolled in the CT Imaging Substudy of the U.S. Continued Access Study, 
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 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 74 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 75 of 188 
 
 
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 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 (18030 Days) Follow-up  
All implanted subjects must be evaluated at 6 months after the index procedure. During the 
6-month follow-up, the following assessments must be completed. The REPRISE III 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); assessors should be independent 
(not involved with the care of study subjects). 
 12-lead ECG per the Core Laboratory guidelines (see study Manual of Operations) and 
must be forwarded for analysis 
 Current antiplatelet, anticoagulant (if applicable) medications 
 TTE, including assessment of effective orifice area, peak systolic and mean aortic valve 
gradient pressure, aortic regurgitation assessment, mitral regurgitation, LVEF, left 
ventricular end-diastolic and end-systolic diameter, TR jet velocity and LA volume, per 
the Echocardiography Core Laboratory procedure guidelines (see study Manual of 
Operations).  It must be sent to the Core Laboratory for independent analysis. 
Note: TTE must be done for all subjects who have a 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/USADE, ADE and CEC events) and 
device deficiencies assessment (with associated treatment) 
 Quality of Life Surveys: Kansas City Cardiomyopathy and SF-12 Quality of Life 
Questionnaires 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 75 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 76 of 188 
 
 
11.10.3. 12-Month (36530 Days) Follow-up 
All implanted subjects must be evaluated at 12 months after the index procedure. During the 
12-month follow-up, the following assessments must be completed. The REPRISE III eCRFs 
identify the specific data points to be collected. 
 Physical examination including weight and height  
 NYHA classification  
 Modified Rankin Scale score, which must be performed by a neurology professional or 
certified personnel (external or internal certification); assessors should be independent 
(not involved with the care of study subjects). 
 Neurological physical examination, which must be performed by a neurologist, 
neurology fellow, neurology physician assistant, or neurology nurse practitioner (see 
Table 11.1-1); 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); assessors should be independent (not involved with the care of 
study subjects). 
 Gait speed to walk 5 meters  
 Rotational x-ray angiography performed on subjects who received the Lotus Valve to 
assess for structural valve frame integrity per the Imaging Core Laboratory procedure 
guidelines (see study Manual of Operations).  It must be forwarded to the Core 
Laboratory for analysis.  
 12-lead ECG per the 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 effective orifice area, peak systolic and mean aortic valve 
gradient pressure, aortic regurgitation assessment, mitral regurgitation, LVEF, left 
ventricular end-diastolic and end-systolic diameter, TR jet velocity and LA volume, per 
the Echocardiography Core Laboratory procedure guidelines (see study Manual of 
Operations).  It must be forwarded to the Core Laboratory for independent analysis. 
Note: TTE must be done for all subjects who have a 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/USADE, ADE and CEC events) and 
device deficiencies assessment (with associated treatment) 
 Quality of Life Surveys: Kansas City Cardiomyopathy and SF-12 Quality of Life 
Questionnaires 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 76 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 77 of 188 
 
 
 For subjects who received a permanent pacemaker related to the index procedure, 
pacemaker dependence and percentage of beats where the ventricles are paced via 
pacemaker interrogation; please see the study Manual of Operations for determining 
pacemaker dependency. 
 For subjects enrolled in the CT Imaging Substudy of the U.S. Continued Access Study, 
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.  
11.10.4. Annual Follow-up (45 Days) 
All enrolled subjects implanted with a Lotus Valve must be evaluated at 24, 36, 48, and 60 
months after the index procedure. During the annual follow-up, the following assessments 
must be completed. The REPRISE III eCRFs identify the specific data points to be collected. 
 Physical examination including weight and height  
 NYHA classification  
 Modified Rankin Scale score, which must be performed by a neurology professional or 
certified personnel (external or internal certification); assessors should be independent 
(not involved with the care of study subjects). 
 Current antiplatelet, anticoagulant (if applicable) 
 TTE, including assessment of effective orifice area, peak systolic and mean aortic valve 
gradient pressure, aortic regurgitation assessment, mitral regurgitation, LVEF, left 
ventricular end-diastolic and end-systolic diameter, TR jet velocity, and LA volume, 
per the Echocardiography Core Laboratory procedure guidelines. All TTEs must be 
forwarded to the Core Laboratory for independent analyses. 
Note: TTE must be done for all subjects who have a valve implanted in the aortic 
position during the index procedure.   
 Rotational x-ray angiography performed on subjects who received the Lotus Valve to 
assess for structural valve frame integrity per the Imaging Core Laboratory procedure 
guidelines (see study Manual of Operations).  It must be forwarded to the Core 
Laboratory for analysis. If additional imaging is performed (e.g., cardiac CT or MRI 
scan), data may also be provided for analysis.  
 
 Complete serious adverse event (SAE, SADE, USADE, and CEC events) and device 
deficiencies assessment (with associated treatment). 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 77 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 78 of 188 
 
 
 Quality of Life Surveys: Kansas City Cardiomyopathy and SF-12 Quality of Life 
Questionnaires at 3 years and 5 years 
11.10.5. Management of Missed or Late Visits 
Missed or late visits will be recorded as protocol deviations and will be reviewed as such by 
the Sponsor or designee on a regular basis in accordance with applicable standard operating 
procedures.  
Note: An in-person visit is required. 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 subject cannot come in for the follow-up visit.   
11.10.6. Procedure for Determining when a Subject is Lost to Follow-up    
A subject will be considered “lost to follow-up” and terminated from the study when all of 
the following criteria have been met. 
 Failure to complete 2 consecutive visits without due cause (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 
11.10.7. Withdrawal and Replacement of Subjects 
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 but no new data will 
be collected after withdrawal.   
11.10.8. Explant Procedure 
If a Lotus Valve test device is explanted during conventional scheduled or emergent surgical 
valve replacement or during an autopsy, if possible, the explanted valve should be sent to an 
independent histopathology core laboratory for macroscopic and microscopic analyses. 
Please refer to the study Manual of Operations for recommendations on the explant 
procedure and shipment of the explanted valve.  
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 78 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 79 of 188 
 
 
If a control device is explanted during conventional scheduled or emergent surgical valve 
replacement or during an autopsy, please follow the directions in the associated IFU. 
Information on the explant procedure must be documented in source notes and captured in 
the Explant Form of the eCRFs. 
11.11. 
Study Completion 
All subjects who receive a test or control device will be evaluated at 30 days, 6 months, 
12 months, 24 months, 36 months, 48 months, and 60 months post index procedure. All visits 
are office visits. A subject’s participation in the study will be considered complete after the 
60-month visit. For subjects who do not receive a test or control device, participation in the 
study will be considered complete after the 1-year visit. 
11.12. 
Source Documents 
It is preferable that original source documents (see Table 26.2-1 for definition) are 
maintained, when available. Where copies of the original source document as well as 
printouts of original electronic source documents are retained, it is recommended that these 
be signed and dated by a member of the investigation center team with a statement that it is a 
true reproduction of the original source document.  
 
12. Statistical Considerations 
12.1. 
Endpoints 
Data will be summarized separately from subjects in the roll-in (up to 120 subjects with the 
23 mm, 25 mm or 27 mm Lotus Valve), randomized, Lotus 21 mm Nested Registry, LOTUS 
Edge Nested Registry, roll-in with the 29 mm LOTUS Edge Valve (up to 20 subjects), 
LOTUS Edge 29 mm Nested Registry, and U.S. Continued Access Study populations. 
Descriptive statistics will be used to summarize the data from subjects in the roll-in, Lotus 
21 mm Nested Registry, LOTUS Edge Nested Registry, roll-in with the 29 mm LOTUS 
Edge, LOTUS Edge 29 mm Nested Registry, and U.S. Continued Access Study cohorts and 
no statistical inference will be made.  
In the randomized cohort, testing of endpoints will be carried out in a hierarchal manner in 
order to ensure the experiment-wise type I error rate is controlled. Testing will be done in 3 
steps with each step needing to reject the null hypothesis in order to proceed to the next step: 
1. Test the primary safety endpoint (Section 12.1.1) and the primary hypothesis of the 
primary effectiveness endpoint (Section 12.1.2.1.1). If the null hypothesis for both 
endpoints is rejected to show non-inferiority of the Lotus group to the CoreValve 
group, then proceed to step 2. 
2. Test the secondary endpoint (Section 12.1.3); if the null hypothesis is rejected to show 
superiority of the Lotus group over the CoreValve group, then proceed to step 3. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 79 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 80 of 188 
 
 
3. Test the secondary hypothesis of the primary effectiveness endpoint 
(Section 12.1.2.1.2). 
12.1.1. Primary Safety Endpoint 
The primary safety endpoint is the composite of all-cause mortality, stroke, life-threatening 
and major bleeding events, stage 2 or 3 acute kidney injury, or major vascular complications 
evaluated at 30 days after the implant procedure. 
12.1.1.1. Statistical Hypothesis for the Primary Safety Endpoint 
The statistical hypothesis is that the rate of the primary safety endpoint (composite of all-
cause mortality, stroke, life-threatening and major bleeding events, stage 2 or 3 acute kidney 
injury, or major vascular complications at 30 days) for the Lotus Valve is non-inferior to that 
for CoreValve. 
The primary safety endpoint is expressed as the proportion of subjects who experience 
mortality, stroke, life-threatening and major bleeding events, stage 2 or 3 acute kidney injury, 
or major vascular complications within 30 days after the index procedure among all subjects 
who either experience mortality/stroke/life-threatening or major bleeding events/stage 2 or 3 
acute kidney injury/major vascular complications within 30 days after the index procedure or 
are followed for at least 23 days after the index procedure. 
The null and alternative hypotheses for the primary safety endpoint are as follows: 
 
H0: PS_Lotus minus PS_Control ≥ Δ (Inferior) 
 
H1: PS_Lotus minus PS_Control < Δ (Non-inferior) 
where PS_Lotus and PS_Control are the rates of the primary safety endpoint at 30 days for the 
Lotus Valve (test) group and the CoreValve group (control), respectively, and Δ (delta) is the 
non-inferiority margin. 
A Farrington-Manning standardized test will be used to test the one-sided hypothesis of 
noninferiority in the difference between the rates of the two treatment groups, as described in 
the Statistical Analysis Plan. If the P value from the Farrington-Manning standardized test is 
<0.025, the rate of the primary safety endpoint for the Lotus Valve will be concluded to be 
non-inferior to the CoreValve rate. This corresponds to the one-sided upper 97.5% 
confidence bound on the difference between treatment groups (Lotus Valve minus 
CoreValve) for the observed rate of the primary safety endpoint at 1 year being less than the 
non-inferiority margin. 
12.1.1.2. Sample Size Parameters for the Primary Safety Endpoint 
The sample size calculation for the primary safety endpoint is based on the following 
assumptions. 
 
Expected Lotus Valve (test) rate = 40% 
 
Expected CoreValve (control) rate = 40% 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 80 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 81 of 188 
 
 
 
Non-inferiority margin (Δ) = 10.5% 
 
Test significance level () = 0.025 (1-sided) 
 
Test : Control ratio = 2:1 
 
Expected rate of attrition = 5% 
Given enrollment of 912 subjects (608 Lotus Valve, 304 CoreValve) and 5% attrition, there 
is approximately 85% power to show non-inferiority with the given expected rates. 
12.1.1.3. Statistical Methods – Primary Safety 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; events with onset date starting from the time of the 
index procedure will be included in the primary endpoint analysis.  
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. The 
sensitivity analysis of the primary endpoint, including events occurring after enrollment but 
prior to the index procedure, will be performed. 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. 
12.1.2. Primary Effectiveness Endpoint 
The primary effectiveness endpoint is the composite of all-cause mortality, disabling stroke, 
or moderate or severe paravalvular aortic regurgitation (based on independent core lab 
assessment) at 1 year. 
12.1.2.1. Statistical Hypothesis for the Primary Effectiveness Endpoint 
12.1.2.1.1 Primary Hypothesis 
The primary statistical hypothesis is that the rate of the primary effectiveness endpoint 
(composite of all-cause mortality, disabling stroke, or moderate or severe paravalvular aortic 
regurgitation [based on independent core lab assessment] at 1 year) for the Lotus Valve 
group is non-inferior to that for the CoreValve group. 
The null and alternative hypotheses for the primary hypothesis of the primary effectiveness 
endpoint are as follows: 
 
H0: PE_Lotus minus PE_Control ≥ Δ (Inferior) 
 
H1: PE_Lotus minus PE_Control < Δ (Non-inferior) 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 81 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 82 of 188 
 
 
where PE_Lotus and PE_Control correspond to the rates of the primary effectiveness endpoint for 
the Lotus Valve group (test) and the CoreValve group (control), respectively, and Δ (delta) is 
the non-inferiority margin. 
A Farrington-Manning test will be used to test the one-sided hypothesis of non-inferiority in 
the difference between the rates of the two treatment groups, as described in the Statistical 
Analysis Plan. If the P value from the Farrington-Manning standardized test is <0.025, the 
rate of the primary effectiveness endpoint for the Lotus Valve will be concluded to be non-
inferior to the CoreValve rate. This corresponds to the one-sided upper 97.5% confidence 
bound on the difference between treatment groups (Lotus Valve minus CoreValve) for the 
observed rate of the primary effectiveness endpoint being less than the noninferiority margin. 
12.1.2.1.2 Secondary Hypothesis 
The secondary statistical hypothesis is that the rate of the primary effectiveness endpoint 
(composite of all-cause mortality, disabling stroke, or moderate or severe paravalvular aortic 
regurgitation [based on independent core lab assessment] at 1 year) for the Lotus Valve 
group is superior to that for the CoreValve group. This test will be carried out only if the null 
hypothesis from the statistical hypothesis is rejected for the primary safety endpoint 
(Section 12.1.1), the primary hypothesis of the primary effectiveness endpoint 
(Section 12.1.2), and the secondary endpoint (Section 12.1.3), and the rate for the primary 
effectiveness endpoint for the Lotus group is less than that of the CoreValve group. 
The null and alternative hypotheses for the secondary hypothesis of the primary effectiveness 
endpoint are as follows: 
 
H0: PE_Lotus = PE_Control 
 
H1: PE_Lotus ≠ PE_Control  
where PE_Lotus and PE_Control correspond to the rates of the primary effectiveness endpoint for 
the Lotus Valve group (test) and the CoreValve group (control), respectively. 
A chi-square test will be used to test the two-sided hypothesis of superiority between the 
rates of the two treatment groups, as described in the Statistical Analysis Plan. If the P value 
from the chi-square test is <0.05 and the rate of the Lotus Valve group is less than the rate of 
the CoreValve group, the rate of the primary effectiveness endpoint for the Lotus Valve will 
be concluded to be superior to the CoreValve rate. This corresponds to the two-sided upper 
95% confidence bound on the difference between treatment groups (Lotus Valve minus 
CoreValve) for the observed rate of the primary effectiveness endpoint being less than zero. 
12.1.2.2. Sample Size Parameters for the Primary Effectiveness Endpoint 
12.1.2.2.1 Primary Hypothesis 
The sample size calculation for the primary hypothesis of the primary effectiveness endpoint 
at 1 year is based on the following assumptions. 
 
Expected Lotus Valve (test) rate = 32% 
 
Expected CoreValve (control) rate = 32% 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 82 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 83 of 188 
 
 
 
Non-inferiority margin (Δ) = 9.5% 
 
Test significance level () = 0.025 (1-sided) 
 
Test : Control ratio = 2:1 
 
Power (1) = 80% 
 
Total number of evaluable subjects = 819  
 
Expected rate of attrition = 10% 
Given the above assumptions, at least 912 randomized subjects (608 Lotus Valve, 304 
CoreValve) are needed to account for attrition. 
12.1.2.2.2 Secondary Hypothesis 
The sample size calculation for the secondary hypothesis of the primary effectiveness 
endpoint at 1 year is based on the following assumptions. 
 
Expected Lotus Valve (test) rate = 22% 
 
Expected CoreValve (control) rate = 32% 
 
Test significance level () = 0.05 (2-sided) 
 
Test : Control ratio = 2:1 
 
Expected rate of attrition = 10% 
Given enrollment of 912 subjects (608 Lotus Valve, 304 CoreValve) and 10% attrition, there 
is approximately 86% power to show superiority with the given expected rates. 
12.1.2.3. Statistical Methods – Primary Effectiveness Endpoint 
Procedures similar to that described in Section 12.1.1.3 and discussed in the Statistical 
Analysis Plan will be applied to analysis of the primary effectiveness endpoint. 
12.1.3. Secondary Endpoint 
The secondary endpoint is the rate of moderate or greater paravalvular aortic regurgitation 
(based on review by an independent core lab) at 1 year. To control for experiment-wise type I 
error, testing for the secondary endpoint will be conducted only if the null hypotheses for the 
primary safety and the primary analysis of the primary effectiveness endpoints are rejected.  
That is, non-inferiority must be shown for the primary safety endpoint and the primary 
effectiveness endpoint for testing to be conducted for the secondary endpoint. 
12.1.3.1. Statistical Hypothesis for the Secondary Endpoint 
The statistical hypothesis is that the secondary endpoint of moderate or greater paravalvular 
aortic regurgitation rate at 1 year (based on review by an independent core lab) for the Lotus 
Valve is superior to that for the CoreValve group. 
The null and alternative hypotheses for the secondary endpoint are as follows: 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 83 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 84 of 188 
 
 
 
H0: PAR_Lotus = PAR_Control  
H1: PAR_Lotus ≠ PAR_Control    
where PAR_Lotus  and PAR_Control correspond to the rates of moderate or greater paravalvular 
aortic regurgitation at 1 year for the Lotus Valve group (test) and the CoreValve group 
(control), respectively. 
A chi-square test will be used to test the two-sided hypothesis of superiority between the 
rates of the two treatment groups, as described in the Statistical Analysis Plan. If the P value 
from the chi-square test is <0.05 and the rate of the Lotus Valve group is less than the rate of 
the CoreValve group, the rate of moderate or greater paravalvular aortic regurgitation for the 
Lotus Valve group will be concluded to be superior to that of the CoreValve group.  
12.1.3.2. Sample Size Parameters for the Secondary Endpoint 
The sample size calculation for the secondary endpoint (moderate/severe paravalvular aortic 
regurgitation rate at 1 year) is based on the following assumptions. 
 
Expected Lotus Valve (test) rate PAR_Lotus  = 1.1% 
 
Expected CoreValve (control) rate PAR_Control  = 5.3% 
 
Test significance level () = 0.05 (2-sided) 
 
Test : Control ratio = 2:1 
 
Expected rate of attrition = 25% 
Given enrollment of 912 subjects (608 Lotus Valve, 304 CoreValve) and 25% attrition, there 
is approximately 86% power to show superiority with the given expected rates. 
12.1.3.3. Statistical Methods – Secondary Endpoint 
Procedures similar to that described in Section 12.1.1.3 and discussed in the Statistical 
Analysis Plan will be applied to analysis of the secondary endpoint. 
12.1.4. Baseline Comparability 
Baseline data will be summarized by treatment group for the randomized subjects and 
separately for subjects in the roll-in (with the 23 mm, 25 mm, or 27 mm Lotus Valve), Lotus 
21 mm Nested Registry, LOTUS Edge Nested Registry, roll-in with the 29 mm LOTUS Edge 
Valve, LOTUS Edge 29 mm Nested Registry, and U.S. Continued Access Study cohorts. 
Subject demographics, clinical and neurological history, risk factors, and preprocedure 
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. 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. 
Treatment differences for the randomized subjects and their 95% confidence intervals will be 
presented. Procedural characteristics will be summarized similarly. No formal statistical 
testing will be done for the roll-in (with the 23 mm, 25 mm, or 27 mm Lotus Valve), Lotus 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 84 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 85 of 188 
 
 
21 mm Nested Registry, LOTUS Edge Nested Registry, roll-in with the 29 mm LOTUS Edge 
Valve, LOTUS Edge 29 mm Nested Registry, or U.S. Continued Access Study subjects. 
12.1.5. Post-procedure Measurements 
Post-procedure information will be collected at regularly scheduled follow-up examinations 
as detailed in the clinical study schedule (Table 11.1-1) and 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. Estimates will be 
reported by treatment group and, for randomized subjects, differences between treatment 
groups and their 95% confidence intervals 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 product-limit method will be used to estimate rates for time-to-event 
endpoints and treatment groups will be compared using the Log-rank and Wilcoxon tests. 
Adverse event and SAE rates will be reported. No formal statistical testing will be done for 
the roll-in (with the 23 mm, 25 mm, or 27 mm Lotus Valve), Lotus 21 mm Nested Registry, 
LOTUS Edge Nested Registry, roll-in with the 29 mm LOTUS Edge Valve, LOTUS Edge 
29 mm Nested Registry, or U.S. Continued Access Study subjects.  
12.1.6. Subgroup Analyses for Randomized Subjects 
Primary and pre-specified additional endpoints will be summarized and treatment groups will 
be compared for the following subgroups of randomized subjects. 
 Gender (male and female) 
 Extreme risk and high risk (see Table 26.2-1 for definitions of extreme and high 
operative risk) 
 Region (North America, outside North America) 
No adjustments for multiple comparisons will be made.  Additional analyses may be 
performed as appropriate. 
12.1.7. Subgroup Analyses for U.S. Continued Access Study Subjects 
Primary and pre-specified additional endpoints will be summarized and treatment groups will 
be compared for the following subgroups of U.S. Continued Access Study subjects.  
 Gender (male and female) 
 Extreme risk and high risk (see Table 26.2-1 for definitions of extreme and high 
operative risk) 
No adjustments for multiple comparisons will be made. Additional analyses may be 
performed as appropriate. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 85 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 86 of 188 
 
 
12.2. General Statistical Methods 
All statistical analyses will be performed using the SAS System software, version 9.2 or later 
(Copyright© 2000 SAS Institute Inc., SAS Campus Drive, Cary, North Carolina 27513, USA. 
All rights reserved).  
All statistical analyses will be conducted according to applicable Standard Operating 
Procedures, Work Instructions, and the study-specific Statistical Analysis Plan.  
12.2.1. Analysis Sets 
The primary endpoints and additional measurements will be analyzed on an ITT, an as-
treated, and an implanted basis. Among the randomized cohort, for ITT analyses, all subjects 
who sign the IRB/IEC-approved study ICF (see Section 11.3), are enrolled in the trial, and 
are randomized will be included in the analysis, whether or not an assigned study valve 
(Lotus Valve or CoreValve) was implanted. The as-treated population includes all subjects 
who sign the IRB/IEC-approved study ICF, are enrolled in the trial, and are randomized, with 
the analysis based on the treatment actually received (for example, if a subject is assigned to 
receive a test device but instead receives a control device, that subject will be considered a 
control subject for the as-treated analyses). For implanted analyses, ITT subjects who had the 
assigned, randomized study valve (Lotus Valve or CoreValve) implanted will be included in 
the analysis. For all analysis sets, if a subject receives 2 valves, the subject is assigned to the 
group corresponding to the first valve received. Among the roll-in (with the 23 mm, 25 mm, 
or 27 mm Lotus Valve), Lotus 21 mm Nested Registry, LOTUS Edge Nested Registry, roll-
in with the 29 mm LOTUS Edge Valve, LOTUS Edge 29 mm Nested Registry, and U.S. 
Continued Access Study cohorts, for ITT analyses, all subjects who sign the IRB/IEC-
approved study ICF and are enrolled in the trial will be included in the analysis sample, 
regardless of whether the study device was implanted. For these cohorts, the as-treated 
population includes all subjects implanted with the Lotus Valve. The as-treated and 
implanted analysis sets are the same for these cohorts. 
For the randomized cohort, the primary safety endpoint, primary effectiveness endpoint (both 
hypotheses), and the secondary endpoint will all be analyzed for the ITT, as-treated, and 
implanted analysis sets. The primary analysis for the primary hypothesis of the primary 
effectiveness endpoint and the primary safety endpoint will be based on the implanted 
analysis set. The primary analysis set for the secondary hypothesis of the primary 
effectiveness endpoint and the secondary endpoint will be based on the ITT analysis set. 
After 1 year, all analyses will be based on the safety analysis set. All subjects who sign the 
written ICF, are enrolled in the study, and have a study device implanted regardless of the 
device and treatment assignment will be included in the safety analysis set. 
12.2.2. Control of Systematic Error/Bias 
All subjects who have met the inclusion/exclusion criteria, received a positive 
recommendation from the CRC, and signed the Informed Consent Form will be eligible for 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 86 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 87 of 188 
 
 
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 lab, a CT 
and rotational X-ray angiography core laboratory to assess all CT and rotational X-ray data 
using standard techniques, and an electrocardiography core laboratory to independently 
analyze protocol-required 12-lead ECGs performed for each subject. 
12.2.3. Randomization Scheme 
A computer generated list of random treatment allocations (i.e., a randomization schedule) 
will be used to assign subjects to treatment in a 2:1 ratio of Lotus Valve to CoreValve. 
Randomization will be stratified by center and risk factor (extreme and high operative risk 
with a targeted enrollment of at least 30% of subjects in each group; see Table 26.2-1 for 
operative risk definitions). Additional information is provided in the study Manual of 
Operations.  
12.2.4. Reporting Events 
For all subjects in the roll-in (with the 23 mm, 25 mm, or 27 mm Lotus Valve), Lotus 21 mm 
Nested Registry, LOTUS Edge Nested Registry, roll-in with the 29 mm LOTUS Edge Valve, 
LOTUS Edge 29 mm Nested Registry, and U.S. Continued Access Study cohorts, all events 
that occur from the start of the index procedure will be reported. For all randomized subjects, 
events from the time of randomization onward will be reported. For randomized subjects who 
do not have an attempted procedure, events from the date of randomization to 1 year post-
randomization will be reported. For time based clinical events, the cut-off for events for 30-
day endpoints will be 30 days, for 6-month endpoints will be 180 days, for 1-year endpoints 
will be 365 days, and for 2-5 year endpoints 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. 
12.3. Data Analyses 
Baseline and outcome variables will be summarized using descriptive statistics for 
continuous variables (mean, standard deviation, number of observations, minimum and 
maximum) and discrete variables (percentage and count/sample). See Section 12.1 for a 
discussion on analysis of the primary safety endpoint, primary effectiveness endpoint, 
secondary endpoint, and additional measurements. 
12.3.1. Other Measurements  
Other measurements not driven by statistical hypotheses are listed in Section 7.2. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 87 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 88 of 188 
 
 
12.3.2. Interim Analyses  
No formal interim analyses are planned for the purpose of stopping this trial early for 
effectiveness or futility.  
An administrative analysis of 30-day data for the first 300 randomized subjects will be 
performed by a statistician independent of BSC for regulatory agency review after these 300 
subjects have completed their 30-day follow-up visits. 
An administrative analysis of 30-day data for subjects in the Lotus 21 mm Nested Registry 
will be performed for regulatory agency review after these subjects have completed their 
30-day follow-up visits. 
Administrative analyses of outcomes from the LOTUS Edge Valve System (LOTUS Edge 
Nested Registry) will be performed for regulatory agency review after subjects have 
completed their implant procedure.  
There will be an administrative analysis of 30-day data from implanted subjects receiving the 
LOTUS Edge 29 mm valve in REPRISE III and the similarly designed REPRISE Edge 29 
mm EU study. This analysis will be performed for regulatory agency review on the first 30 
implanted subjects from the combined cohort and will be carried out after these pooled 
subjects have completed their 30-day follow-up visits. 
12.3.3. Justification of Pooling 
Analyses for the primary safety and effectiveness endpoints and the secondary endpoint will 
be presented using data pooled across institutions and surgical (high or extreme) risk groups. 
An assessment of the poolability of subjects across centers and surgical risk groups will be 
made using logistic regression. Main effects for the center (risk group) and treatment and the 
interaction of the center (risk group) by treatment will be included in separate logistic 
regression models with the primary safety endpoint, the primary effectiveness endpoint, and 
the secondary endpoint as the outcome. If the P value for center (risk group) by treatment 
interaction is ≥0.15, it can be concluded that the treatment effect is not different across the 
centers (risk groups) and the data can be pooled. In the analysis to justify pooling across 
centers, the centers with fewer than 6 subjects enrolled in the study will be combined into 
“virtual centers” based on geographic region so that “virtual centers” have ≥6 subjects but no 
more than the largest enrolling center. 
12.3.4. Multivariable Analyses 
Univariate and multivariate analyses will be performed to assess the effect of potential 
predictors on the primary safety and effectiveness endpoints and the secondary endpoint as 
described in the Statistical Analysis Plan. 
12.3.5. Changes to Planned Analyses 
Any changes to the planned statistical analyses made prior to performing the analyses will be 
documented in an amended Statistical Analysis Plan approved before performing the 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 88 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 89 of 188 
 
 
analyses. Changes from the planned statistical methods after performing the analyses will be 
documented in the clinical study report along with a reason for the deviation. 
 
13. Data Management 
13.1. Data Collection, Processing, and Review 
Subject data will be recorded in a limited access secure electronic data capture (EDC) 
system. Only personnel trained and authorized will have access to the system. 
The clinical database will reside on a production server hosted by Medidata. All changes 
made to the clinical data will be captured in an electronic audit trail and available for review 
by 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 Investigator will maintain at the investigative center all essential study documents and 
source documentation that support the data collected on the study subjects in compliance 
with ICH/GCP guidelines. Documents must be retained for at least 2 years after the last 
approval of a marketing application or until at least 2 years have elapsed since the formal 
discontinuation of the clinical investigation of the product. These documents will be retained 
for a longer period of time by agreement with BSC or in compliance with other local 
regulations. It is BSC’s responsibility to inform the Investigator when these documents no 
longer need to be maintained. The Investigator will take measures to ensure that these 
essential documents are not accidentally damaged or destroyed. If for any reason the 
Investigator withdraws responsibility for maintaining these essential documents, custody 
must be transferred to an individual who will assume responsibility and BSC must receive 
written notification of this custodial change.  
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 89 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 90 of 188 
 
 
13.3. Core Laboratories 
13.3.1. Transthoracic Echocardiography (TTE) Core Laboratory 
An independent Core Laboratory will review echocardiography images from all centers and 
every subject enrolled in this study for qualitative and quantitative analysis. These analyses 
will minimize bias and inconsistencies by providing an independent interpretation of all 
measurements using standard techniques. The TTE procedure guideline is provided by the 
core laboratory in the study Manual of Operations. 
13.3.2. CT and Rotational X-Ray Angiography Core Laboratory 
An independent Core Laboratory will centrally assess all of the CT and rotational X-ray 
angiography data in this study to reduce variability. These analyses will minimize bias and 
inconsistencies by providing an independent interpretation of all measurements using 
standard techniques. The screening CT Angiogram procedure guidelines and annual imaging 
acquisition protocol are provided by the core laboratory in the study Manual of Operations. 
Data from subjects in the 4D CT Imaging Substudy will also be evaluated by the independent 
CT Core Laboratory; procedure guidelines for 4D CT scanning are provided by the core 
laboratory in the 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 Valve (test device) is explanted during conventional scheduled or emergent 
surgical valve replacement or during an autopsy, please refer to the study Manual of 
Operations for recommendations on the explant procedure and shipment of the explanted 
valve to an independent histopathology laboratory for analyses. 
 
14. Amendments  
If a protocol revision is necessary which affects the rights, safety or welfare of the subjects or 
scientific integrity of the data, an amendment is required. Appropriate approvals (e.g., 
IRB/EC/FDA/CA) of the revised protocol must be obtained prior to implementation. 
 
15. Deviations 
An Investigator must not make any changes or deviate from this protocol, except to protect 
the life and physical well-being of a subject in an emergency. An investigator shall notify the 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 90 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 91 of 188 
 
 
Sponsor and the reviewing IRB/EC of any deviation from the investigational plan to protect 
the life or physical well-being of a subject in an emergency, and those deviations which 
affect the scientific integrity of the clinical investigation. Such notice shall be given as soon 
as possible, but no later than 5 working days after the emergency occurred, or per prevailing 
local requirements, if sooner than 5 working days.  
All deviations from the investigational plan, with the reason for the deviation and the date of 
occurrence, must be documented and reported to the Sponsor using the EDC CRF.  Centers 
may also be required to report deviations to the IRB/EC, per local guidelines and government 
regulations.  
Deviations will be reviewed and evaluated on an ongoing basis and, as necessary, appropriate 
corrective and preventive actions (including notification, center re-training, or 
discontinuation) will be put into place by the Sponsor. 
 
16. Device Accountability 
16.1. Investigational Device 
The Lotus Valve System/LOTUS Edge Valve System (investigational device) will be 
released by the Sponsor 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 Valve System/LOTUS Edge Valve System shall be securely maintained, 
controlled, and used only in this clinical study. Additionally, the study personnel must follow 
the instructions related to the storage of the test and control devices as noted in the 
corresponding IFUs. Device Accountability Logs for the Lotus Valve System/LOTUS Edge 
Valve System will be provided to the centers and will be used to track subjects and device 
allocations during the study.  
The Sponsor shall keep records to document the physical location of all investigational 
devices from shipment of investigational devices to the investigation centers until return or 
disposal. 
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 recorded in the Device Accountability Log. The PI must document the reasons for any 
discrepancy noted in device accountability. 
The principal investigator or an authorized designee shall keep records documenting the 
receipt, use, return and disposal of the investigational devices, which shall include the 
following; this will be verified by personnel from BSC or its designee. 
 Date of receipt 
 Identification of each investigational device (Part/Reference, Lot numbers, valve size) 
 Expiry date, as applicable 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 91 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 92 of 188 
 
 
 Date of use 
 Subject identification 
 Date on which the investigational device was returned/explanted from subject, if 
applicable 
 Date of return of unused, expired, or malfunctioning investigational devices, if 
applicable 
Written procedures may be required by national regulations. 
Once the Investigator and Center are notified in writing by BSC that subject enrollment is 
complete, 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. 
16.2. Control Device 
Appropriate information on control device size and model will be collected. 
 
17. Compliance 
17.1. Statement of Compliance 
The REPRISE III study will be conducted in accordance with the relevant parts of the 
International Conference on Harmonisation (ICH) Guidelines for Good Clinical Practices 
(GCP) or the International Standard ISO 14155: 2011; ethical principles that have their 
origins in the Declaration of Helsinki; and pertinent individual country/state/local laws and 
regulations. 
17.2. Investigator Responsibilities 
The Principal Investigator of an investigational center is responsible for ensuring that the 
study is conducted in accordance with the Clinical Study Agreement, the investigational 
plan/protocol, ISO 14155 or ICH/GCP, ethical principles that have their origins in the 
Declaration of Helsinki, any conditions of approval imposed by the reviewing IRB/EC, and 
prevailing local and/or country laws and/or regulations, whichever affords the greater 
protection to the subject. 
The Principal Investigator’s responsibilities include, but are not limited to, the following.  
 Prior to beginning the study, sign the Investigator Agreement and Protocol Signature 
page documenting his/her agreement to conduct the study in accordance with the 
protocol. 
 Provide his/her qualifications and experience to assume responsibility for the proper 
conduct of the study and that of key members of the center team through up-to-date 
curriculum vitae or other relevant documentation and disclose potential conflicts of 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 92 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 93 of 188 
 
 
interest, including financial, that may interfere with the conduct of the clinical study or 
interpretation of results. 
 Complete training requirements associated with the CoreValve device. 
 Complete all Lotus Valve (investigational device) training requirements as detailed in 
the REPRISE III Training Plan (see Section 17.4.1). This includes training on the Lotus 
Valve System/LOTUS Edge Valve System as applicable. 
 Make no changes in or deviate from this protocol, except to protect the life and physical 
well-being of a subject in an emergency; document and explain any deviation from the 
approved protocol that occurred during the course of the clinical investigation. 
 Create and maintain source documents throughout the clinical study and ensure their 
availability with direct access during monitoring visits or audits; ensure that all clinical-
investigation-related records are retained per requirements. 
 Ensure the accuracy, completeness, legibility, and timeliness of the data reported to the 
Sponsor in the CRFs and in all required reports. 
 Record, report, and assess (seriousness and relationship to the device/procedure) every 
adverse event and observed device deficiency. 
 Report to BSC, per the protocol requirements, all SAEs and device deficiencies that 
could have led to a SADE. 
 Report to the IRB/EC and regulatory authorities any SAEs and device deficiencies that 
could have led to a SADE, if required by the national regulations or this protocol or by 
the IRB/EC, and supply 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 monitor and respond to questions during monitoring 
visits. 
 Allow and support regulatory authorities and the IRB/EC when performing auditing 
activities. 
 Ensure that informed consent is obtained in accordance with this protocol and local 
IRB/EC requirements. 
 Provide adequate medical care to a subject during and after a subject’s participation in a 
clinical study in the case of adverse events, as described in the ICF. 
 Inform the subject of the nature and possible cause of any adverse events experienced. 
 Inform the subject of any new significant findings occurring during the clinical 
investigation, including the need for additional medical care that may be required. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 93 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 94 of 188 
 
 
 Provide the subject with well-defined procedures for possible emergency situations 
related to the clinical study, and make the necessary arrangements for emergency 
treatment as needed. 
 Ensure that clinical medical records are clearly marked to indicate that the subject is 
enrolled in this clinical study. 
 Ensure that, if appropriate, subjects enrolled in the clinical investigation are provided 
with some means of showing their participation in the clinical investigation, together 
with identification and compliance information for concomitant treatment measures 
(contact address and telephone numbers shall be provided). 
 Inform, with the subject’s approval or when required by national regulations, the 
subject’s personal physician about the subject’s participation in the clinical 
investigation. 
 Make all reasonable efforts to ascertain the reason(s) for a subject’s premature 
withdrawal from clinical investigation while fully respecting the subject’s rights. 
 Ensure that an adequate investigation center team and facilities exist and are maintained 
and documented during the clinical investigation. 
 Ensure that maintenance and calibration of the equipment relevant for the assessment of 
the clinical investigation is appropriately performed and documented, where applicable. 
17.2.1. Delegation of Responsibility 
When specific tasks are delegated by an investigator, included but not limited to conducting 
the informed consent process, the investigator is responsible for providing appropriate 
training and adequate supervision of those to whom tasks are delegated. The investigator is 
accountable for regulatory violations resulting from failure to adequately supervise the 
conduct of the clinical study.  
17.3. Institutional Review Board/ Ethics Committee 
Prior to gaining Approval-to-Enroll status, the investigational center will provide to the 
Sponsor documentation verifying that their IRB/EC is registered or that registration has been 
submitted to the appropriate agency, as applicable according to national/regulatory 
requirements.   
A copy of the written IRB/EC and/or competent authority approval of the protocol (or 
permission to conduct the study) and Informed Consent Form, must be received by the 
Sponsor before recruitment of subjects into the study and shipment of investigational 
product/equipment. Prior approval must also be obtained for other materials related to subject 
recruitment or which will be provided to the subject. 
Annual IRB/EC approval and renewals will be obtained throughout the duration of the study 
as required by local/country or IRB/EC requirements. Copies of the Investigator’s reports 
and the IRB/EC continuance of approval must be provided to the Sponsor.  
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 94 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 95 of 188 
 
 
17.4. 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. 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. Data 
used in the analysis and reporting of this study will not be identified by specific subject 
name. 
Note: Boston Scientific may utilize a contract research organization (CRO) or other 
contractors to act as its representative for carrying out designated tasks.  
Boston Scientific Corporation will keep subjects’ health information confidential in 
accordance with all applicable laws and regulations.  Boston Scientific Corporation may use 
subjects’ health information to conduct this research, as well as for additional purposes, such 
as overseeing and improving the performance of its device, new medical research and 
proposals for developing new medical products or procedures, and other business purposes. 
Information received during the study will not be used to market to subjects; subject names 
will not be placed on any mailing lists or sold to anyone for marketing purposes.  
17.4.1. Training with the Lotus Valve System/LOTUS Edge Valve System 
The Sponsor is responsible for providing Investigators with the information and training on 
the Lotus Valve System/LOTUS Edge Valve System they need to conduct the study 
properly. The Sponsor is responsible for maintaining documentation of attendance at each of 
the training sessions provided.  
A Lotus Training Plan has been developed for this study that meets the requirements of 
ISO 5840-3:2013 and includes the following elements.  
 Device Description:  A detailed description of all components of the device including a 
summary of the basic principle of operation. 
 CT and Procedural Angiography:  A detailed review of pre-procedural and procedural 
imaging techniques to aid in sizing decisions and implantation of the Lotus Valve. 
 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 a 
Lotus Valve implantation. 
 Implantation Techniques and Sizing:  A detailed review of specific implantation 
techniques and valve sizing based on clinical cases. 
 Device Demonstration:  A hands-on training using standard Lotus Valve components to 
practice the implantation procedure in a bench model or a robotic simulation system. 
 Proctoring: The investigator and co-investigators as well as the scrub team will be 
proctored by an experienced TAVR physician on a minimum of 6 Lotus Valve 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 95 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 96 of 188 
 
 
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 previous 
experience implanting the Lotus Valve. For these centers there will be a roll-in phase (initial 
cohort with the 23 mm, 25 mm, and 27 mm Lotus Valve System) with at least 2 roll-in 
subjects per center treated under the supervision of a proctor. The roll-in subjects will count 
towards the 6 required proctored cases.   
Note 2: Device training specific to the use of the LOTUS Edge Valve System will be 
provided to investigators at participating centers prior to enrollment in the LOTUS Edge 
Nested Registry, 29 mm roll-in cohort and LOTUS Edge 29 mm Nested Registry. For the 
participating investigators who have had sufficient experience implanting the Lotus Valve 
but not with the LOTUS Edge Valve System, additional training will be provided focused on 
the changes between Lotus and LOTUS Edge. For Lotus-experienced investigators, at least 2 
roll-in cases with the 29 mm LOTUS Edge Valve System will be performed before 
enrollment can commence in the LOTUS Edge 29 mm Nested Registry.  
17.4.2. Role of Boston Scientific Corporation Representatives 
Boston Scientific Corporation personnel (including field clinical engineers) will provide 
training and technical support to the investigator and other health care personnel (collectively 
HCP) as needed during Lotus Valve implant and testing required by the protocol. Boston 
Scientific Corporation is also responsible for ensuring investigators are trained on the 
Directions for Use. Support may include 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. 
17.5. Insurance  
Where required by local/country regulation, proof and type of insurance coverage by BSC for 
subjects in the study will be obtained.  
 
18. Monitoring 
Monitoring will be performed during the study according to the monitoring plan to assess 
continued compliance with the protocol and applicable regulations. In addition, the monitor 
verifies that study records are adequately maintained, that data are reported in a satisfactory 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 96 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 97 of 188 
 
 
manner with respect to timeliness, adequacy, and accuracy, and that the Investigator 
continues to have sufficient staff and facilities to conduct the study safely and effectively. 
The Investigator/institution guarantees direct access to original source documents by 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 Investigator and 
relevant study personnel are available during on-site monitoring visits or audits and that 
sufficient time is devoted to the process. 
 
19. Potential Risks and Benefits 
Risks to clinical subjects associated with their participation in this clinical investigation, 
arising from the clinical procedures set out in the study protocol, have been identified from 
prior studies conducted by Boston Scientific Corporation and review of relevant literature, 
most recently from the Edwards Lifesciences’ Placement of Aortic Transcatheter Valves 
(PARTNER) Trial14,63-65, the PARTNER II trial123, the SAPIEN 3 CE Mark study78, the 
CoreValve Extreme Risk Study75, the CoreValve High Risk Study66, and the PORTICO IDE 
randomized trial/RESOLVE registry/SAVORY registry68.   
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 included in the study-specific template of the ICF 
provided to the study centers (see Section 0). 
19.1. Risks Associated with Transcatheter Aortic Valve Implantation Procedure  
Adverse events (in alphabetical order) potentially associated with transcatheter aortic valve 
implantation (including standard cardiac catheterization, BAV, and the use of anesthesia) as 
well as additional risks related to the use of the Lotus Valve System/LOTUS Edge Valve 
System and/or CoreValve include but may not be limited to the following. 
 Abnormal lab values (including anemia and electrolytes) 
 Allergic reaction (including to medications, anesthesia, contrast, or device materials) 
 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 or transient ischemic attack  
 Coronary obstruction 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 97 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 98 of 188 
 
 
 Death  
 Device misplacement or migration 
 Endocarditis  
 Emboli (including air, calcium, tissue, thrombus or device materials)  
 Fever 
 Heart failure 
 Hemolysis and/or hemolytic anemia 
 Hematoma or lymphatic problems at the access sites 
 Hemodynamic instability or shock 
 Hypertension/hypotension  
 Infection (local and/or systemic, including septicemia) 
 Inflammation 
 Mitral valve insufficiency 
 Myocardial infarction 
 Myocardial or valvular injury (including perforation or rupture) 
 Nerve injury 
 Pain 
 Pericardial effusion or cardiac tamponade 
 Peripheral ischemia or infarction 
 Permanent disability 
 Pleural effusion 
 Pulmonary edema 
 Renal insufficiency or failure 
 Respiratory insufficiency or failure 
 Valve dysfunction, deterioration or failure 
 Valvular stenosis or regurgitation (central or paravalvular) 
 Valve or device thrombosis 
 Vessel injury (including spasm, trauma, dissection, perforation, rupture, arteriovenous 
fistula, or pseudoaneurysm)  
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 98 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 99 of 188 
 
 
As a result of these complications, the subject may require medical, percutaneous or surgical 
intervention, including re-operation and replacement of the implanted valve. Such 
complications can be fatal.   
As the Lotus Valve/LOTUS Edge Valve is an investigational device, uncertainty remains 
over risks of experiencing some or all of the complications listed above. There may be risks 
that are unknown at this time. 
19.2. Risk Minimization Actions 
Additional risks may exist. Risks can be minimized through compliance with this protocol, 
performing procedures in the appropriate hospital environment, adherence to subject 
selection criteria, close monitoring of the subject's physiologic status during research 
procedures and/or follow-ups and by promptly supplying 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. 
o Clearly defining the inclusion/exclusion criteria to ensure only appropriate subjects 
are enrolled  
o Confirmation of eligible subjects by a Case Review Committee, including 
experienced investigators in TAVR 
o Ensuring that treatment and follow-up of the subject are consistent with current 
medical practices 
o Selection of investigators who are experienced and skilled in TAVR procedures 
o Completion of training and proctorship provided by the Sponsor  
o Performing all procedures in accordance with the IFU, including the preparation of 
the valve and delivery system 
o Dynamic safety review processes, including assessment by the Data Monitoring 
Committee (DMC, Section 22.1) and CEC (Section 22.1) adjudication of specified 
events as recommended by VARC72,73. 
In addition to its repositioning and self-centering features designed to facilitate optimal 
positioning, the Lotus Valve System/LOTUS Edge Valve System provides physicians with 
control throughout the procedure by allowing them to pause, assess, lock, un-lock, 
incrementally reverse, resheath and, if needed, retrieve the valve prior to final release. 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 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 99 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 100 of 188 
 
 
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 anti-platelet therapy is 
recommended to minimize any risk of thrombus formation, stroke, or transient ischemic 
attack. Neurological assessments will be performed at each required follow-up visit to 
identify any change in the neurological status of the subjects as recommended by VARC72,73. 
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. 
19.3. Anticipated Benefits 
19.3.1. Potential Benefits to the TAVR Procedure 
Transcatheter aortic valve replacement (TAVR) may offer certain advantages when 
compared to surgical replacement of the stenotic native aortic valve, particularly in high risk 
subjects. Known benefits associated with TAVR, as described in the scientific literature (see 
summary in Section 4.1 of this document and details in Sections 2 and 3 of the investigator 
brochure), potentially include the following. 
 Minimally invasive procedure and reduced risks related to open heart surgery 
 Shorter stay in the intensive care unit and overall hospital stay 
 Reduced blood loss 
 More rapid recovery 
 Reduced need for general anesthesia and associated risks 
 Opportunity to receive a new aortic prosthesis in spite of having been refused surgery 
or being of high surgical risk profile 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 100 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 101 of 188 
 
 
19.3.2. Potential Benefit Using the Lotus Valve System/LOTUS Edge Valve System 
Potential benefits that may be associated specifically with use of the Lotus™ Valve 
System/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 
19.4. Risk to Benefit Rationale 
Review of the aforementioned clinical benefits versus risks takes into account the known 
risks/benefits that have been identified in the published literature on other TAVR devices. 
The estimation of risk also includes prior limited clinical experience with the 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 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. No new 
hazards/harms are introduced by the LOTUS Edge Valve System compared to the Lotus 
Valve System when used with the Lotus Introducer Set. Because the overall risk profile of 
the device has not changed, it can be concluded that the potential benefits of the use of the 
LOTUS Edge Valve System with the Lotus Introducer Set out-weigh the risks. 
 
20. Informed Consent 
Subject participation in this clinical study is voluntary.  Informed Consent is required from 
all subjects or their legally authorized representative. The Investigator is responsible for 
ensuring that Informed Consent is obtained prior to the use of any investigational devices, 
study-required procedures and/or testing, or data collection.  
The obtaining and documentation of Informed Consent must be in accordance with the 
principles of the Declaration of Helsinki; the relevant parts of ISO 14155: 2011 and the ICH 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 101 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 102 of 188 
 
 
guidelines for GCP; any applicable national regulations; and local Ethics Committee and/or 
Regulatory authority body, as applicable. The ICF must be approved by the center’s IRB/EC, 
or central IRB, if applicable. 
Boston Scientific 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/EC.  Any modification requires approval 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/EC approval prior to their 
use. Privacy language shall be included in the body of the form or as a separate form as 
applicable.   
The process of obtaining Informed Consent shall: 
 be conducted by the Principal Investigator or designee authorized to conduct the process,  
 include a description of all aspects of the clinical study that are relevant to the subject’s 
decision to participate throughout the clinical study, 
 avoid any coercion of or undue influence of subjects to participate, 
 not waive or appear to waive subject’s legal rights, 
 use native language that is non-technical and understandable to the subject or his/her 
legal representative, 
 provide ample time for the subject to consider participation and ask questions if 
necessary, 
 ensure important new information is provided to new and existing subjects throughout the 
clinical study. 
The ICF shall always be signed and personally dated by the subject or legal representative 
and by the investigator or an authorized designee responsible for conducting the informed 
consent process. If a legal representative signs, the subject shall be asked to provide informed 
consent for continued participation as soon as his/her medical condition allows. The original 
signed ICF will be retained by the center and a copy of the signed and dated document and 
any other written information must be given to the person signing the form.  
Failure to obtain subject consent will be reported by BSC to the applicable regulatory body 
according to their requirements. Any violations of the informed consent process must be 
reported as deviations to the Sponsor and local regulatory authorities (e.g. IRB/EC), as 
appropriate. 
If new information becomes available that can significantly affect a subject's future health 
and medical care, that information shall be provided to the affected subject(s) in written form 
via a revised ICF or, in some situations, enrolled subjects may be requested to sign and date 
an addendum to the ICF. In addition to new significant information during the course of a 
study, other situations may necessitate revision of the ICF, such as if there are amendments 
to the protocol, a change in Principal Investigator, administrative changes, or following 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 102 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 103 of 188 
 
 
annual review by the IRB/EC. The new version of the ICF must be approved by the IRB/EC. 
Boston Scientific Corporation approval is required if changes to the revised ICF are 
requested by the center’s IRB/EC. The IRB/EC will determine the subject population to be 
re-consented. 
 
21. Safety Reporting 
21.1. Definitions and Classification 
Adverse event definitions are provided in Table 21.1-1. 
Table 21.1-1: Adverse Event Definitions 
Term 
Definitiona 
Adverse Event (AE) 
Ref: ISO 14155:2011 
Any untoward medical occurrence, unintended disease or injury or 
untoward clinical signs (including abnormal laboratory findings) in 
subjects, users or other persons, whether or not related to the 
investigational medical device 
Note 1: This definition includes events related to the investigational 
medical device or the comparator. 
Note 2: This definition includes events related to the procedures involved. 
Note 3: For users or other persons, this definition is restricted to events 
related to investigational medical devices. 
Adverse Device Effect (ADE) 
Ref: ISO 14155:2011 
Adverse event related to the use of an investigational medical device 
Note 1: This definition includes adverse events resulting from insufficient 
or inadequate instructions for use, deployment, implantation, installation, 
or operation, or any malfunction of the investigational medical device.  
Note 2: This definition includes any event resulting from use error or from 
intentional misuse of the investigational medical device. 
Serious Adverse Event (SAE) 
Ref: ISO 14155:2011 
Adverse event that: 
 Led to a death  
 Led to serious deterioration in the health of the subject, that either 
resulted in: 
o 
a life-threatening illness or injury, or 
o 
a permanent impairment of a body structure or a body function, or 
o 
in-patient or prolonged hospitalization, or 
o 
medical or surgical intervention to prevent life- threatening illness 
or injury or permanent impairment to a body structure or a body 
function, 
 Led to 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 14155:2011 
Adverse device effect that has resulted in any of the consequences 
characteristic of a serious adverse event. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 103 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 104 of 188 
 
 
Table 21.1-1: Adverse Event Definitions 
Term 
Definitiona 
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 14155:2011 
Serious adverse device effect which by its nature, incidence, severity or 
outcome has not been identified in the current version of the risk analysis 
report  
Note: Anticipated serious adverse device effect (ASADE) is an effect 
which by its nature, incidence, severity or outcome has been identified in 
the risk analysis report. 
Device Deficiency 
Ref: ISO 14155:2011 
Ref: MEDDEV 2.7/3 12/2010 
A device deficiency is Any inadequacy of a medical device with respect to 
its identity, quality, durability, reliability, safety or performance. Note 
1: Device deficiencies include malfunctions, use errors, and inadequate 
labeling. 
Note 2: All device deficiencies that could have led to a SADE if a) suitable 
action had not been taken or b) if intervention had not been made or c) if 
circumstances had been less fortunate shall be reported as required by the 
local IRB/EC, national regulations, or the protocol.  
a: Other definitions may apply per local reporting requirements. 
 
Underlying diseases are not reported as AEs unless there is an increase in severity or 
frequency during the course of the investigation. Death should not be recorded as an AE, but 
should only be reflected as an outcome of a specific SAE (see Table 21.1-1 for AE 
definitions).  
In-patient hospitalization is defined as the subject being admitted to the hospital, with the 
following exceptions. 
 A hospitalization that is uncomplicated and elective/planned (i.e., planned prior to 
enrollment) does not have to be reported as an SAE. 
 If complications or AEs occur during an elective/planned (i.e., planned prior to 
enrollment) hospitalization after enrollment, the complications and AEs must be 
reported as AEs or SAEs if they meet the protocol-specified definitions. 
For the randomized cohort, event reporting (eCRF) is required beginning from the time of 
randomization.  
For the roll-in, Lotus 21 mm Nested Registry, LOTUS Edge Nested Registry, roll-in with the 
29 mm LOTUS Edge, LOTUS Edge 29 mm Nested Registry, and U.S. Continued Access 
Study cohorts, event reporting (eCRF) is required beginning from the time an attempt is 
made to insert the Lotus Valve System/LOTUS Edge Valve System into the subject’s 
femoral artery. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 104 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 105 of 188 
 
 
Refer to Section 19 for the known risks associated with the study devices (test and control). 
Based on the VARC72,73 recommendations and definitions, the adverse events and/or safety 
endpoints requiring adjudication by the CEC include the following. 
 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  
 Acute kidney injury (≤7 days post index procedure): based on the AKIN System109,110 
Stage 3 (including renal replacement therapy) or Stage 2  
 Vascular complications: major  
 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 26.2-1). 
21.2. Relationship to Study Device(s) 
The Investigator must assess the relationship of the AE/SAE to the study device as related or 
unrelated. See criteria in Table 21.2-1. 
 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 105 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 106 of 188 
 
 
Table 21.2-1: Criteria for Assessing Relationship of Study Device to Adverse Event 
Classification 
Description 
Unrelated 
The adverse event is determined to be due to a concurrent illness or effect of another 
device/drug and is not related to the investigational product. 
Related 
 The adverse event is determined to be potentially related to the investigational 
product, and an alternative etiology is equally or less likely compared to the 
potential relationship to investigational product. 
 There is a strong relationship to investigational product, or recurs on re-challenge, 
and another etiology is unlikely. 
 There is no other reasonable medical explanation for the event. 
 
21.3. Investigator Reporting Requirements 
The communication requirements for reporting to BSC are as shown in Table 21.3-1.  
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.  
Centers should report control device-related deficiencies as per requirements in the control-
device Instructions For Use. 
Table 21.3-1: Investigator Reporting Requirements 
Event Classification 
Communication Method  
Communication Timeline  
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 
documents requested by BSC  
 As soon as possible after reporting the 
event 
Serious Adverse Event 
(SAE) including 
Serious Adverse Device 
Effects (SADE) 
  
Complete AE eCRF page with all 
available new and updated information 
 Within 2 business days of first 
becoming aware of the event or as per 
local/regional regulations. 
 Beginning from time of enrollment 
for all subjects 
 Reporting required through the end of 
the study 
Provide all relevant source 
documentation (unidentified) for 
reported event 
 When documentation is available 
Adverse Event (AE)  
Complete AE eCRF page 
 As soon as possible before the next 
planned monitoring visit  
 Beginning from time of enrollment 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 106 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 107 of 188 
 
 
Table 21.3-1: Investigator Reporting Requirements 
Event Classification 
Communication Method  
Communication Timeline  
for all subjects 
 Reporting required through 12 months  
Device Deficiencies, 
Failures, Malfunctions, 
and Product 
Nonconformities 
Complete applicable eCRF fields/pages 
with all available new and updated 
information. 
Investigational Device: 
 Within 1 business day of first 
becoming aware of the event and as 
per local/regional regulations 
 Beginning from time of Lotus 
Introducer sheath insertion for all 
subjects 
 Reporting required through the end of 
the study 
Control Device: 
 As required per IFU and as per 
local/regional regulations 
Note: The AE eCRF page contains information such as date of AE, treatment of AE resolution, assessment of 
seriousness, and relationship to the device. 
Abbreviations: AE=adverse event; BSC=Boston Scientific Corporation; eCRF=electronic case report form; 
IFU=Instructions for Use  
 
21.4. Device Deficiencies 
21.4.1. Boston Scientific Device Deficiencies 
All Lotus Valve System/LOTUS Edge Valve System device deficiencies (including but not 
limited to failures, malfunctions, use errors, product nonconformities, and labeling errors) 
must be documented on the appropriate eCRF and, if possible, the device should be returned 
to 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 deficiencies should also be documented in the subject’s medical record.  
Device deficiencies and other device issues should not be reported as AEs. Instead, they 
should be reported on the appropriate eCRF. If an AE results from a device deficiency or 
other device issue, the AE must be reported on the appropriate eCRF. 
Device deficiencies that did not lead to an AE but could have led to a SAE if a) suitable 
action had not been taken, or b) intervention had not been made, or c) circumstances had 
been less fortunate must be reported as described in Table 21.3-1. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 107 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 108 of 188 
 
 
21.4.2. Control Device Deficiencies 
Device deficiencies related to use of the control device (CoreValve) should be reported per 
the IFU and per applicable local/regional requirements. If an AE results from a device 
deficiency or other device issue, the AE must be reported on the appropriate eCRF. 
21.5. Reporting to Regulatory Authorities / IRBs / ECs / Investigators 
Boston Scientific Corporation will notify all participating study centers if UADEs, USADEs, 
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 AE information to all participating 
investigators and regulatory authorities as applicable according to local reporting 
requirements.  
The PI is responsible for informing the IRB/EC, and regulatory authorities of UADEs, 
USADEs, SADEs, SAEs, Device Deficiencies and/or other CEC events as applicable 
according to local reporting requirements. A copy of the Investigator’s reports and other 
relevant reports (if applicable) to the IRB/IEC must be provided to BSC in accordance with 
local requirements. 
 
22. Committees 
22.1. 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 visits, clinical research monitors will 
support the dynamic reporting process through their review of source document information. 
22.1.1. Clinical Events Committee  
A CEC will be used in this study. A CEC is an independent group of individuals with 
pertinent expertise, including cardiovascular interventional therapy, cardiovascular surgery, 
and neurology, which reviews and adjudicates important endpoints and relevant adverse 
events reported by study investigators. The CEC will review a safety event dossier, which 
may include copies of subject source documents provided by study sites, and adjudicate 
study endpoint related clinical events. The responsibilities, qualifications, membership, and 
committee procedures of the CEC are outlined in the CEC charter. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 108 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 109 of 188 
 
 
22.1.2. Data Monitoring Committee 
The DMC is responsible for the oversight review of all AEs and all SAEs in the roll-in, 
randomized, Lotus 21 mm Nested Registry cohorts, LOTUS Edge Nested Registry, and the 
29 mm LOTUS Edge Valve roll-in and Nested Registry cohorts. 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. 
22.2. 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 Valve 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. 
22.3. 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.  
 
23. Suspension or Termination 
23.1 Premature Termination of the Study 
Boston Scientific Corporation reserves the right to terminate the study at any stage but 
intends to exercise this right only for valid scientific or administrative reasons and reasons 
related to protection of subjects.  Investigators, associated IRBs/ECs, and regulatory 
authorities, as applicable, will be notified in writing in the event of study termination. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 109 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 110 of 188 
 
 
23.1.1 Criteria for Premature Termination of the Study 
Possible reasons for premature study termination include, but are not limited to, the 
following. 
 The occurrence of unanticipated adverse device effects that present a significant or 
unreasonable risk to subjects enrolled in the study. 
 An enrollment rate far below expectation that prejudices the conclusion of the study.  
 A decision on the part of BSC to suspend or discontinue development of the device. 
23.2 Termination of Study Participation by the Investigator or Withdrawal of IRB/EC 
Approval 
Any investigator or IRB/EC in the REPRISE III study may discontinue participation in the 
study or withdrawal approval of the study, respectively, with suitable written notice to BSC. 
Investigators, associated IRBs/ECs, and regulatory authorities, as applicable, will be notified 
in writing in the event of these occurrences. 
23.3 Requirements for Documentation and Subject Follow-up 
In the event of premature study termination a written statement as to why the premature 
termination has occurred will be provided to all participating centers by BSC. The IRB/EC 
and regulatory authorities, as applicable, will be notified. Detailed information on how 
enrolled subjects will be managed thereafter will be provided.  
In the event an IRB/EC terminates participation in the study, participating investigators, 
associated IRBs/ECs, and regulatory authorities, as applicable, will be notified in writing. 
Detailed information on how enrolled subjects will be managed thereafter will be provided 
by BSC. 
In the event an investigator terminates participation in the study, study responsibility will be 
transferred to a co-investigator, if possible. In the event there are no opportunities to transfer 
investigator responsibility; detailed information on how enrolled subjects will be managed 
thereafter will be provided by BSC. The investigator must return all documents and 
investigational product to BSC, unless this action would jeopardize the rights, safety, or 
welfare of the subjects. 
23.4 Criteria for Suspending/Terminating a Study Center 
Boston Scientific Corporation reserves the right to stop the inclusion of subjects at a study 
center at any time after the study initiation visit if no subjects have been enrolled or if the 
center has multiple or severe protocol violations/noncompliance without justification and/or 
fails to follow remedial actions. 
In the event of termination of investigator participation, all study devices and testing 
equipment, as applicable, will be returned to BSC unless this action would jeopardize the 
rights, safety or well-being of the subjects. The IRB/EC and regulatory authorities, as 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 110 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 111 of 188 
 
 
applicable, should be notified. All subjects enrolled in the study at the center will continue to 
be followed per this protocol. The Principal Investigator at the center must make provision 
for these follow-up visits unless BSC notifies the investigational center otherwise. 
 
24. Publication Policy 
In accordance with the Global SOP – Human Subject Data and Research Controls, BSC 
requires disclosure of its involvement as a sponsor or financial supporter in any publication 
or presentation relating to a BSC study or its results. In accordance with the Global SOP – 
Human Subject Data and Research Controls, BSC will submit study results for publication 
(regardless of study outcome) in a timely manner. Boston Scientific Corporation follows 
authorship principals as 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. 
 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.  
 
25. Bibliography 
1. 
Lindroos M, Kupari M, Heikkila J, Tilvis R. Prevalence of aortic valve abnormalities in 
the elderly: an echocardiographic study of a random population sample. J Am Coll 
Cardiol 1993;21:1220-5. 
2. 
Nkomo VT, Gardin JM, Skelton TN, Gottdiener JS, Scott CG, Enriquez-Sarano M. 
Burden of valvular heart diseases: a population-based study. Lancet 2006;368:1005-11. 
3. 
Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics--2011 
update: a report from the American Heart Association. Circulation 2011;123:e18-e209. 
4. 
Iung B, Baron G, Butchart EG, et al. A prospective survey of patients with valvular 
heart disease in Europe: The Euro Heart Survey on Valvular Heart Disease. Eur Heart J 
2003;24:1231-43. 
5. 
Brown JM, O'Brien SM, Wu C, Sikora JA, Griffith BP, Gammie JS. Isolated aortic 
valve replacement in North America comprising 108,687 patients in 10 years: changes 
in risks, valve types, and outcomes in the Society of Thoracic Surgeons National 
Database. J Thorac Cardiovasc Surg 2009;137:82-90. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 111 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 112 of 188 
 
 
6. 
Chiam PT, Ruiz CE. Percutaneous transcatheter aortic valve implantation: Evolution of 
the technology. Am Heart J 2009;157:229-42. 
7. 
Bonow RO, Carabello BA, Kanu C, et al. ACC/AHA 2006 guidelines 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 (writing 
committee to revise the 1998 Guidelines for the Management of Patients With Valvular 
Heart Disease): developed in collaboration with the Society of Cardiovascular 
Anesthesiologists: endorsed by the Society for Cardiovascular Angiography and 
Interventions and the Society of Thoracic Surgeons. Circulation 2006;114:e84-231. 
8. 
Holmes DR, Jr., Mack MJ, Kaul S, et al. 2012 ACCF/AATS/SCAI/STS Expert 
consensus document on transcatheter aortic valve replacement. J Am Coll Cardiol 
2012;59:1200-54. 
9. 
Vahanian A, Baumgartner H, Bax J, et al. Guidelines on the management of valvular 
heart disease: The Task Force on the Management of Valvular Heart Disease of the 
European Society of Cardiology. Eur Heart J 2007;28:230-68. 
10. Thourani VH, Myung R, Kilgo P, et al. Long-term outcomes after isolated aortic valve 
replacement in octogenarians: a modern perspective. Ann Thorac Surg 2008;86:1458-
64. 
11. Barreto-Filho JA, Wang Y, Dodson JA, et al. Trends in aortic valve replacement for 
elderly patients in the United States, 1999-2011 JAMA 2013;310:2078-85. 
12. Iung B, Cachier A, Baron G, et al. Decision-making in elderly patients with severe 
aortic stenosis: why are so many denied surgery? Eur Heart J 2005;26:2714-20. 
13. Varadarajan P, Kapoor N, Bansal RC, Pai RG. Clinical profile and natural history of 
453 nonsurgically managed patients with severe aortic stenosis. Ann Thorac Surg 
2006;82:2111-5. 
14. Leon MB, Smith CR, Mack M, et al. Transcatheter aortic-valve implantation for aortic 
stenosis in patients who cannot undergo surgery. N Engl J Med 2010;363:1597-607. 
15. Ben-Dor I, Pichard AD, Gonzalez MA, et al. Correlates and causes of death in patients 
with severe symptomatic aortic stenosis who are not eligible to participate in a clinical 
trial of transcatheter aortic valve implantation. Circulation 2010;122:S37-42. 
16. Hara H, Pedersen WR, Ladich E, et al. Percutaneous balloon aortic valvuloplasty 
revisited: time for a renaissance? Circulation 2007;115:e334-8. 
17. Saia F, Marrozzini C, Dall'Ara G, et al. How many patients with severe symptomatic 
aortic stenosis excluded for cardiac surgery are eligible for transcatheter heart valve 
implantation? J Cardiovasc Med (Hagerstown) 2010;11:727-32. 
18. Thomas M. The global experience with percutaneous aortic valve replacement. J Am 
Coll Cardiol Intv 2010;3:1103-9. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 112 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 113 of 188 
 
 
19. Bourantas CV, Farooq V, Onuma Y, Piazza N, Van Mieghem NM, Serruys PW. 
Transcatheter aortic valve implantation: New developments and upcoming clinical 
trials. EuroIntervention 2012;8:617-27. 
20. Godino C, Pavon AG, Colombo A. Long-term results after transcatheter aortic valve 
implantation: positive and side effects. Minerva Cardioangiol 2013;61:377-91. 
21. Hamm CW, Arsalan M, Mack MJ. The future of transcatheter aortic valve 
implantation. Eur Heart J 2016;37:803-10. 
22. Lange R, Bleiziffer S, Elhmidi Y, Piazza N. Transcatheter aortic valve implantation: 
The European experience. J Thorac Cardiovasc Surg 2013;145:S17-21. 
23. Delgado V, Ewe SH, Ng AC, et al. Multimodality imaging in transcatheter aortic valve 
implantation: key steps to assess procedural feasibility. EuroIntervention 2010;6:643-
52. 
24. Smith LA, Dworakowski R, Bhan A, et al. Real-time three-dimensional 
transesophageal echocardiography adds value to transcatheter aortic valve implantation. 
J Am Soc Echocardiogr 2013;26:359-69. 
25. Leipsic J, Yang TH, Min JK. Computed tomographic imaging of transcatheter aortic 
valve replacement for prediction and prevention of procedural complications. Circ 
Cardiovasc Imaging 2013;6:597-605. 
26. Kasel AM, Cassese S, Bleiziffer S, et al. Standardized imaging for aortic annular 
sizing: implications for transcatheter valve selection. J Am Coll Cardiol Img 
2013;6:249-62. 
27. Piazza N, Wenaweser P, van Gameren M, et al. Relationship between the logistic 
EuroSCORE and the Society of Thoracic Surgeons Predicted Risk of Mortality score in 
patients implanted with the CoreValve ReValving system--a Bern-Rotterdam Study. 
Am Heart J 2010;159:323-9. 
28. De Feo M, Vicchio M, Della Corte A, et al. Lack of definite indication criteria for 
choosing between transcatheter implantation and surgical replacement of the aortic 
valve. J Cardiovasc Med (Hagerstown) 2013;14:158-63. 
29. D'Ascenzo F, Ballocca F, Moretti C, et al. Inaccuracy of available surgical risk scores 
to predict outcomes after transcatheter aortic valve replacement. J Cardiovasc Med 
(Hagerstown) 2013;14:894-8. 
30. Lichtenstein KM, Kim JM, Gao M, et al. Surgical risk algorithm as a measure of 
successful adoption of transapical transcatheter aortic valve implantation. J Thorac 
Cardiovasc Surg 2014;146:1524-8. 
31. Stortecky S, Schoenenberger AW, Moser A, et al. Evaluation of multidimensional 
geriatric assessment as a predictor of mortality and cardiovascular events after 
transcatheter aortic valve implantation. J Am Coll Cardiol Intv 2012;5:489-96. 
32. Bapat VN, Bruschi G. Transaortic access is the key to success. EuroIntervention 2013;9 
Suppl:S25-32. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 113 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 114 of 188 
 
 
33. Webb JG, Altwegg L, Boone RH, et al. Transcatheter aortic valve implantation: impact 
on clinical and valve-related outcomes. Circulation 2009;119:3009-16. 
34. De Carlo M, Giannini C, Ettori F, et al. Impact of treatment choice on the outcome of 
patients proposed for transcatheter aortic valve implantation. EuroIntervention 
2010;6:568-74. 
35. Buchanan GL, Chieffo A, Montorfano M, et al. The role of sex on VARC outcomes 
following transcatheter aortic valve implantation with both Edwards SAPIEN and 
Medtronic CoreValve ReValving System® devices: the Milan registry. 
EuroIntervention 2011;7:556-63. 
36. Tamburino C, Barbanti M, Capodanno D, et al. Comparison of complications and 
outcomes to one year of transcatheter aortic valve implantation versus surgical aortic 
valve replacement in patients with severe aortic stenosis. Am J Cardiol 2012;109:1487-
93. 
37. Willson AB, Rodés-Cabau J, Wood DA, et al. Transcatheter aortic valve replacement 
with the St. Jude Medical Portico Valve: first-in-human experience. J Am Coll Cardiol 
2012;60:581-6. 
38. Van Mieghem NM, Chieffo A, Dumonteil N, et al. Trends in outcome after 
transfemoral transcatheter aortic valve implantation. Am Heart J 2013;165:183-92. 
39. Wenaweser P, Stortecky S, Schwander S, et al. Clinical outcomes of patients with 
estimated low or intermediate surgical risk undergoing transcatheter aortic valve 
implantation. Eur Heart J 2013;34:1894-905. 
40. Piazza N, Grube E, Gerckens U, et al. Procedural and 30-day outcomes following 
transcatheter aortic valve implantation using the third generation (18 Fr) CoreValve 
ReValving System: results from the multicentre, expanded evaluation registry 1-year 
following CE mark approval. EuroIntervention 2008;4:242-9. 
41. Rodés-Cabau J, Webb JG, Cheung A, et al. Transcatheter aortic valve implantation for 
the treatment of severe symptomatic aortic stenosis in patients at very high or 
prohibitive surgical risk: acute and late outcomes of the multicenter Canadian 
experience. J Am Coll Cardiol 2010;55:1080-90. 
42. Thomas M, Schymik G, Walther T, et al. Thirty-day results of the SAPIEN aortic 
Bioprosthesis European Outcome (SOURCE) Registry: A European registry of 
transcatheter aortic valve implantation using the Edwards SAPIEN valve. Circulation 
2010;122:62-9. 
43. Thomas M, Schymik G, Walther T, et al. One-year outcomes of Cohort 1 in the 
Edwards SAPIEN Aortic Bioprosthesis European Outcome (SOURCE) registry: The 
European registry of transcatheter aortic valve implantation using the Edwards SAPIEN 
valve. Circulation 2011;124:425-33. 
44. Lefèvre T, Kappetein AP, Wolner E, et al. One year follow-up of the multi-centre 
European PARTNER transcatheter heart valve study. Eur Heart J 2011;32:148-57. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 114 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 115 of 188 
 
 
45. Tamburino C, Capodanno D, Ramondo A, et al. Incidence and predictors of early and 
late mortality after transcatheter aortic valve implantation in 663 patients with severe 
aortic stenosis. Circulation 2011;123:299-308. 
46. Ussia GP, Barbanti M, Petronio AS, et al. Transcatheter aortic valve implantation: 3-
year outcomes of self-expanding CoreValve prosthesis. Eur Heart J 2012;33:969-76. 
47. Walther T, Thielmann M, Kempfert J, et al. PREVAIL TRANSAPICAL: multicentre 
trial of transcatheter aortic valve implantation using the newly designed bioprosthesis 
(SAPIEN-XT) and delivery system (ASCENDRA-II). Eur J Cardiothorac Surg 
2012;42:278-83. 
48. Walther T, Thielmann M, Kempfert J, et al. One-year multicentre outcomes of 
transapical aortic valve implantation using the SAPIEN XT valve: the PREVAIL 
transapical study. Eur J Cardiothorac Surg 2013;43:986-92. 
49. Wendler O, Walther T, Schroefel H, et al. Transapical aortic valve implantation: mid-
term outcome from the SOURCE registry. Eur J Cardiothoracic Surg 2013;43:505-11. 
50. Barbanti M, Ussia GP, Cannata S, Giarratana A, Sgroi C, Tamburino C. 3-year 
outcomes of self-expanding CoreValve prosthesis - The Italian Registry. Ann 
Cardiothorac Surg 2012;1:182-4. 
51. Muñoz-Garcia AJ, Del Valle R, Trillo-Nouche R, et al. The Ibero-American 
transcatheter aortic valve implantation registry with the CoreValve prosthesis. Early 
and long-term results. Int J Cardiol 2013;169:359-65. 
52. Nijhoff F, Agostoni P, Amrane H, et al. Transcatheter aortic valve implantation in 
patients with severe aortic valve stenosis and large aortic annulus, using the self-
expanding 31-mm Medtronic CoreValve prosthesis: First clinical experience. J Thorac 
Cardiovasc Surg 2014;148:492-9. 
53. D'Onofrio A, Salizzoni S, Agrifoglio M, et al. Medium term outcomes of transapical 
aortic valve implantation: Results from the Italian registry of trans-apical aortic valve 
implantation. Ann Thorac Surg 2013;96:830-5. 
54. Walters DL, Sinhal A, Baron D, et al. Initial experience with the balloon expandable 
Edwards-SAPIEN Transcatheter Heart Valve in Australia and New Zealand: The 
SOURCE ANZ registry: Outcomes at 30 days and one year. Int J Cardiol 
2014;170:406-12. 
55. Eltchaninoff H, Prat A, Gilard M, et al. Transcatheter aortic valve implantation: early 
results of the FRANCE (FRench Aortic National CoreValve and Edwards) registry. Eur 
Heart J 2011;32:191-7. 
56. Zahn R, Gerckens U, Grube E, et al. Transcatheter aortic valve implantation: first 
results from a multi-centre real-world registry. Eur Heart J 2011;32:198-204. 
57. Moat NE, Ludman P, de Belder MA, et al. Long-term outcomes after transcatheter 
aortic valve implantation in high-risk patients with severe aortic stenosis: the U.K. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 115 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 116 of 188 
 
 
TAVI (United Kingdom Transcatheter Aortic Valve Implantation) Registry. J Am Coll 
Cardiol 2011;58:2130-8. 
58. Bosmans JM, Kefer J, De Bruyne B, et al. Procedural, 30-day and one year outcome 
following CoreValve or Edwards transcatheter aortic valve implantation: results of the 
Belgian national registry. Interact Cardiovasc Thorac Surg 2011;12:762-7. 
59. Gilard M, Eltchaninoff H, Iung B, et al. Registry of transcatheter aortic-valve 
implantation in high-risk patients. N Engl J Med 2012;366:1705-15. 
60. Spargias K, Toutouzas K, Chrissoheris M, et al. The Athens TAVR Registry of newer 
generation transfemoral aortic valves: 30-day outcomes. Hellenic J Cardiol 2013;54:18-
24. 
61. Hamm CW, Mollmann H, Holzhey D, et al. The German Aortic Valve Registry 
(GARY): in-hospital outcome. Eur Heart J 2014;35:1588-98. 
62. Mack MJ, Brennan JM, Brindis R, et al. Outcomes following transcatheter aortic valve 
replacement in the United States. JAMA 2013;310:2069-77. 
63. Makkar RR, Fontana GP, Jilaihawi H, et al. Transcatheter aortic-valve replacement for 
inoperable severe aortic stenosis. N Engl J Med 2012;366:1696-704. 
64. Smith CR, Leon MB, Mack MJ, et al. Transcatheter versus surgical aortic-valve 
replacement in high-risk patients. N Engl J Med 2011;364:2187-98. 
65. Kodali SK, Williams MR, Smith CR, et al. Two-year outcomes after transcatheter or 
surgical aortic-valve replacement. N Engl J Med 2012;366:1686-95. 
66. Adams DH, Popma JJ, Reardon MJ, et al. Transcatheter aortic-valve replacement with 
a self-expanding prosthesis. N Engl J Med 2014;370:1790-8. 
67. Laschinger JC, Wu C, Ibrahim NG, Shuren JE. Reduced leaflet motion in bioprosthetic 
aortic valves — the FDA perspective. N Engl J Med 2015;373:1996-8. 
68. Makkar RR, Fontana G, Jilaihawi H, et al. Possible subclinical leaflet thrombosis in 
bioprosthetic aortic valves. N Engl J Med 2015;373:2015-24. 
69. Mack MJ, Holmes DR, Webb J, et al. Patient selection for transcatheter aortic valve 
replacement. J Am Coll Cardiol 2013;62:S1-S10. 
70. Fanning JP, Platts DG, Walters DL, Fraser JF. Transcatheter aortic valve implantation 
(TAVI): Valve design and evolution. Int J Cardiol 2013;168:1822-31. 
71. Sinning JM, Werner N, Vasa-Nicotera M, et al. Innovations and novel technologies in 
TAVI. Second generation transcatheter heart valves. Minerva Cardioangiol 
2013;61:155-63. 
72. Leon MB, Piazza N, Nikolsky E, et al. Standardized endpoint definitions for 
Transcatheter Aortic Valve Implantation clinical trials: a consensus report from the 
Valve Academic Research Consortium. J Am Coll Cardiol 2011;57:253-69. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 116 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 117 of 188 
 
 
73. Kappetein AP, Head SJ, Genereux P, et al. Updated standardized endpoint definitions 
for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 
consensus document. J Am Coll Cardiol 2012;60:1438-54. 
74. Munoz-Garcia AJ, Hernandez-Garcia JM, Jimenez-Navarro MF, et al. Survival and 
predictive factors of mortality after 30 days in patients treated with percutaneous 
implantation of the CoreValve aortic prosthesis. Am Heart J 2012;163:288-94. 
75. Popma JJ, Adams DH, Reardon MJ, et al. Transcatheter aortic valve replacement using 
a self-expanding bioprosthesis in patients with severe aortic stenosis at extreme risk for 
surgery. J Am Coll Cardiol 2014;63:1972-81. 
76. Testa L, Latib A, Rossi ML, et al. CoreValve implantation for severe aortic 
regurgitation: a multicentre registry. EuroIntervention 2014;10:739-45. 
77. Abdel-Wahab M, Mehilli J, Frerker C, et al. Comparison of balloon-expandable vs self-
expandable valves in patients undergoing transcatheter aortic valve replacement: The 
CHOICE randomized clinical trial. JAMA 2014;311:1503-14. 
78. Webb J, Gerosa G, Lefèvre T, et al. Multicenter evaluation of a next-generation 
balloon-expandable transcatheter aortic valve. J Am Coll Cardiol 2014;64:2235-43. 
79. Wenaweser P, Stortecky S, Heg D, et al. Short-term clinical outcomes among patients 
undergoing transcatheter aortic valve implantation in Switzerland: the Swiss TAVI 
registry. EuroIntervention 2014;10:982-9. 
80. Tarsia G, Smaldone C, Viceconte NG, et al. Lower cardiovascular mortality with 
Medtronic CoreValve versus Edwards SAPIEN in patients with aortic valve stenosis 
undergoing transcatheter aortic valve implantation. Int J Cardiol 2014;177:520-2. 
81. De Brito FS, Jr., Carvalho LA, Sarmento-Leite R, et al. Outcomes and predictors of 
mortality after transcatheter aortic valve implantation: results of the Brazilian Registry. 
Catheter Cardiovasc Interv 2015;85:E153-E62. 
82. Meredith IT, Hood KL, Haratani N, Allocco DJ, Dawkins KD. The Lotus™ Valve: a 
next-generation transcatheter aortic valve replacement system. EuroIntervention 
2012;8:Q70-Q4. 
83. Lerakis S, Hayek SS, Douglas PS. Paravalvular aortic leak after transcatheter aortic 
valve replacement: current knowledge. Circulation 2013;127:397-407. 
84. Stortecky S, Windecker S, Pilgrim T, et al. Cerebrovascular accidents complicating 
transcatheter aortic valve implantation: frequency, timing and impact on outcomes. 
EuroIntervention 2012;8:62-70. 
85. Lange R, Bleiziffer S, Piazza N, et al. Incidence and treatment of procedural 
cardiovascular complications associated with trans-arterial and trans-apical 
interventional aortic valve implantation in 412 consecutive patients. Eur J Cardiothorac 
Surg 2011;40:1105-13. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 117 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 118 of 188 
 
 
86. Geisbüsch S, Bleiziffer S, Mazzitelli D, Ruge H, Bauernschmitt R, Lange R. Incidence 
and management of CoreValve dislocation during transcatheter aortic valve 
implantation. Circ Cardiovasc Interv 2010;3:531-6. 
87. John D, Buellesfeld L, Yuecel S, et al. Correlation of device landing zone calcification 
and acute procedural success in patients undergoing transcatheter aortic valve 
implantations with the self-expanding CoreValve prosthesis. J Am Coll Cardiol Intv 
2010;3:233-43. 
88. Ewe SH, Ng AC, Schuijf JD, et al. Location and severity of aortic valve calcium and 
implications for aortic regurgitation after transcatheter aortic valve implantation. Am J 
Cardiol 2011;108:1470-7. 
89. Abdel-Wahab M, Zahn R, Horack M, et al. Aortic regurgitation after transcatheter 
aortic valve implantation: incidence and early outcome. Results from the German 
Transcatheter Aortic Valve Interventions registry. Heart 2011;97:899-906. 
90. Sinning JM, Vasa-Nicotera M, Chin D, et al. Evaluation and management of 
paravalvular aortic regurgitation after transcatheter aortic valve replacement. J Am Coll 
Cardiol 2013;62:11-20. 
91. Buellesfeld L, Wenaweser P, Gerckens U, et al. Transcatheter aortic valve 
implantation: predictors of procedural success--the Siegburg-Bern experience. Eur 
Heart J 2010;31:984-91. 
92. Piazza N, Lange R, Martucci G, Serruys PW. Patient selection for transcatheter aortic 
valve implantation: Patient risk profile and anatomical selection criteria. Arch 
Cardiovasc Dis 2012;105:165-73. 
93. van Mieghem NM, Head SJ, van der Boon RM, et al. The SURTAVI model: proposal 
for a pragmatic risk stratification for patients with severe aortic stenosis. 
EuroIntervention 2012;8:258-66. 
94. Meredith IT, Worthley SG, Whitbourn RJ, et al. Transfemoral aortic valve replacement 
with the repositionable Lotus Valve System in high surgical risk patients: The 
REPRISE I study. EuroIntervention 2014;9:1264-70. 
95. Chodor P, Wilczek K, Przybylski R, et al. Immediate and 6-month outcomes of 
transapical and transfemoral Edwards-Sapien prosthesis implantation in patients with 
aortic stenosis. Kardiol Pol 2010;68:1124-31. 
96. Meredith IT, Worthley SG, Whitbourn RJ, et al. First report of two-year outcomes with 
the repositionable Lotus Aortic Valve Replacement System: Results from the REPRISE 
I feasibility study. In: TCT. Washington, D.C.; 2014. 
97. Meredith IT, Worthley SG, Whitbourn RJ, et al. First report of three-year outcomes 
with the repositionable and fully retrievable Lotus™ Aortic Valve Replacement 
System: results from the REPRISE I feasibility study. In: TCT. San Francisco; 2015. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 118 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 119 of 188 
 
 
98. Meredith IT, Walters D, Dumonteil N, et al. Transcatheter aortic valve replacement for 
severe symptomatic aortic stenosis using a repositionable valve system: 30-day primary 
endpoint results from the REPRISE II study. J Am Coll Cardiol 2014;64:1339-48. 
99. Meredith IT, Walters D, Dumonteil N, et al. One-year outcomes with the fully 
repositionable and retrievable Lotus™ transcatheter aortic replacement valve in 120 
high-risk surgical patients with severe aortic stenosis: results from the REPRISE II 
study. J Am Coll Cardiol Intv 2016;9:376-84. 
100. Meredith IT. Two-year outcomes with the fully repositionable and retrievable Lotus™ 
transcatheter aortic replacement valve in 120 high-risk surgical patients with severe 
aortic stenosis: results from the REPRISE II CE-Mark study. In: TCT. San Francisco; 
2015. 
101. Meredith IT, Dumonteil N, Blackman DJ, et al. Repositionable percutaneous aortic 
valve replacement: 30-day outcomes in 250 high surgical risk patients in the REPRISE 
II extended trial cohort. In: EuroPCR London Valves. London; 2014. 
102. Meredith IT, Dumonteil N, Blackman DJ, et al. One-year outcomes with a fully 
repositionable and retrievable percutaneous aortic valve in 250 high surgical risk 
patients:  Results from the REPRISE II trial extended cohort. In: Euro PCR London 
Valves. Berlin; 2015. 
103. Webb JG, Wood DA. Current status of transcatheter aortic valve replacement. J Am 
Coll Cardiol 2012;60:483-92. 
104. Buellesfeld L, Stortecky S, Heg D, et al. Impact of permanent pacemaker implantation 
on clinical outcome among patients undergoing transcatheter aortic valve implantation. 
J Am Coll Cardiol 2012;60:493-501. 
105. Urena M, Webb JG, Tamburino C, et al. Permanent pacemaker implantation after 
transcatheter aortic valve implantation: impact on late clinical outcomes and left 
ventricular function. Circulation 2014;129:1233-43. 
106. Nazif TM, Dizon JM, Hahn RT, et al. Predictors and clinical outcomes of permanent 
pacemaker implantation after transcatheter aortic valve replacement: The PARTNER 
(Placement of AoRtic TraNscathetER Valves) Trial and Registry. J Am Coll Cardiol 
Intv 2015;8:60-9. 
107. Gotzmann M, Lindstaedt M, Mugge A. From pressure overload to volume overload: 
Aortic regurgitation after transcatheter aortic valve implantation. Am Heart J 
2012;163:903-11. 
108. 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. In: Euro 
PCR. Paris; 2015. 
109. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P. Acute renal failure - 
definition, outcome measures, animal models, fluid therapy and information technology 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 119 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 120 of 188 
 
 
needs: the Second International Consensus Conference of the Acute Dialysis Quality 
Initiative (ADQI) Group. Crit Care 2004;8:R204-12. 
110. 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. 
111. 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. 
112. 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. 
113. 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. 
114. 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. 
115. 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. 
116. Borson S, Scanlan JM, Chen P, Ganguli M. The Mini-Cog as a screen for dementia: 
validation in a population-based sample. J Am Geriatr Soc 2003;51:1451-4. 
117. Robinson TN, Eiseman B, Wallace JI, et al. Redefining geriatric preoperative 
assessment using frailty, disability and co-morbidity. Ann Surg 2009;250:449-55. 
118. 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. 
119. Studenski S, Perera S, Patel K, et al. Gait speed and survival in older adults. JAMA 
2011;305:50-8. 
120. 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. 
121. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a 
phenotype. J Gerontol A Biol Sci Med Sci 2001;56:M146-56. 
122. Katz S, Downs TD, Cash HR, Grotz RC. Progress in development of the index of ADL. 
Gerontologist 1970;10:20-30. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 120 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 121 of 188 
 
 
123. Leon M. A randomized evaluation of the SAPIEN XT Transcatheter Valve System in 
patients with aortic stenosis who are not candidates for surgery: PARTNER II, 
Inoperable Cohort. In: ACC. San Francisco; 2013. 
124. 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. 
125. 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. 
126. 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. 
127. Thygesen K, Alpert JS, White HD. Universal definition of myocardial infarction. Eur 
Heart J 2007;28:2525-38. 
128. 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. 
129. 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. 
 
26. Abbreviations and Definitions  
26.1. Abbreviations 
Abbreviations are shown in Table 26.1-1.   
 
 
Table 26.1-1: Abbreviations and Acronyms 
Abbreviation/Acronym 
Definition 
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 
BMI 
body mass index 
BSA 
body surface area 
BSC 
Boston Scientific Corporation 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 121 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 122 of 188 
 
 
 
 
Table 26.1-1: Abbreviations and Acronyms 
Abbreviation/Acronym 
Definition 
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 
eGFR 
estimated glomerular filtration rate 
GCP 
Good Clinical Practices 
ICF 
Informed Consent form 
ICH 
International Conference on Harmonisation 
IEC/IRB 
Independent Ethics Committee/Institutional Review Board 
IFU 
Instructions for Use 
ISO 
International Organization For Standardization 
ITT 
intention to treat 
LBBB 
left bundle branch block 
LDH 
lactate dehydrogenase 
LV 
left ventricle 
LVEF 
left ventricular ejection fraction 
MACCE 
major adverse cardiovascular and cerebrovascular events 
MI 
myocardial infarction 
MRI 
magnetic resonance imaging 
mRS 
Modified Rankin Scale 
NIHSS 
National Institutes of Health Stroke Scale 
NOAC 
new oral anticoagulant 
NYHA 
New York Heart Association classification 
PPM 
permanent pacemaker 
QOL 
quality of life 
SADE 
serious adverse device effect 
SAE 
serious adverse event 
SAVR 
surgical aortic valve replacement 
TAVR 
transcatheter aortic valve replacement 
TEE 
transesophageal Doppler echocardiography 
TIA 
transient ischemic attack 
TTE 
transthoracic Doppler echocardiography 
UADE 
unanticipated adverse device effect 
USADE 
unanticipated serious adverse device effect 
URL 
upper reference limit (defined as 99th percentile of normal reference range) 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 122 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 123 of 188 
 
 
 
 
Table 26.1-1: Abbreviations and Acronyms 
Abbreviation/Acronym 
Definition 
VARC 
Valve Academic Research Consortium 
 
26.2. Definitions 
Terms are defined in Table 26.2-1.  See Table 26.1-1 for abbreviations. 
Table 26.2-1: Definitions 
Term 
Definition 
ACUTE KIDNEY 
INJURY (AKI) 
(AKIN  System109,110) 
Change in serum creatinine (up to 7 days) compared to baseline: 
 Stage 1: Increase in serum creatinine to 150–199% (1.5–1.99 × increase 
compared with baseline) OR increase of ≥0.3 mg/dl (≥26.4 mmol/L)  
 Stage 2: Increase in serum creatinine to 200–299% (2.0–2.99 × increase 
compared with baseline) 
 Stage 3: Increase in serum creatinine to ≥300% (>3 × increase compared with 
baseline) OR serum creatinine of ≥4.0 mg/dL (≥354 mmol/L) with an acute 
increase of at least 0.5 mg/dL (44 mmol/L) 
-OR-  
Based on urine output (up to 7 days): 
 Stage 1: <0.5 ml/kg per hour for >6 but <12 hours 
 Stage 2: <0.5 ml/kg per hour for >12 but <24 hours 
 Stage 3: <0.3 ml/kg per hour for ≥24 hours or anuria for ≥12 hours 
Note 1: Subjects receiving renal replacement therapy are considered to meet Stage 
3 criteria irrespective of other criteria. 
ACUTE VESSEL 
OCCLUSION 
The state of complete luminal obstruction with no antegrade blood flow 
ADVERSE EVENT  
Ref: ISO 14155:2011 
(AE) 
Any untoward medical occurrence, unintended disease or injury or untoward 
clinical signs (including abnormal laboratory findings) in subjects, users or other 
persons, whether or not related to the investigational medical device. 
Note 1: This definition includes events related to the investigational medical device 
or the comparator. 
Note 2: This definition includes events related to the procedures involved. 
Note 3: For users or other persons, this definition is restricted to events related to 
investigational medical devices. 
ADVERSE 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  
Ref: ISO 14155:2011 
(ADE) 
Adverse event related to the use of an investigational medical device 
Note 1: This definition includes adverse events resulting from insufficient or 
inadequate instructions for use, deployment, implantation, installation, or operation, 
or any malfunction of the investigational medical device.  
Note 2: This definition includes any event resulting from use error or from 
intentional misuse of the investigational medical device. 
AORTIC 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 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 123 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 124 of 188 
 
 
Table 26.2-1: Definitions 
Term 
Definition 
I, II and III) [see Figure below]. 
 
AORTIC 
REGURGITATION 
(AR) 
The leaking of the aortic valve that causes blood to flow in the reverse direction 
during ventricular diastole, from the aorta into the left ventricle. 
The echocardiographic findings in severe aortic regurgitation include the following. 
 An AR color jet dimension >60% of the left ventricular outflow tract diameter 
(may not be true if the jet is eccentric)  
 The pressure half-time of the regurgitant jet is <250 msec  
 Early termination of the mitral inflow (due to increase in LV pressure due to the 
AR)  
 Early diastolic flow reversal in the descending aorta.  
 
 Regurgitant volume >60 mL  
 Regurgitant fraction >55% 
ARRHYTHMIA 
Any variation from the normal rhythm of the heartbeat, including sinus arrhythmia, 
premature beat, heart block, atrial fibrillation, atrial flutter and tachycardia. 
Complete heart block, ventricular tachycardia and ventricular fibrillation are 
considered major arrhythmias. Data should be collected on any new arrhythmia 
resulting in hemodynamic instability or requiring therapy (therapy includes 
electrical/medical cardioversion or initiation of a new medication [oral 
anticoagulation, rhythm or rate controlling therapy]).  
New onset atrial fibrillation or atrial flutter (AF) is diagnosed as any arrhythmia 
within hospitalization that has the ECG characteristics of AF and lasts sufficiently 
long to be recorded on a 12-lead ECG, or at least 30 seconds on a rhythm strip.  
The therapeutic approach to new-onset AF (spontaneous conversion, electrical or 
medical cardioversion, initiation of oral anticoagulation, and rate or rhythm control 
medications) and any clinical consequences should be documented.   
Note 1: See also definitions for conductance disturbance and permanent pacemaker. 
AS-TREATED 
ANALYSIS SET 
This population includes all subjects who sign an Informed Consent Form, are 
enrolled in the trial, are randomized, and receive a study device, but subjects are 
analyzed based on the treatment actually received. For example, if a subject is 
assigned to receive a test device but instead receives a control device, that subject 
will be considered a control subject for the as-treated analyses of implant 
subgroups. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 124 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 125 of 188 
 
 
Table 26.2-1: Definitions 
Term 
Definition 
Note 1: If a subject receives 2 valves, the subject is assigned to the group 
corresponding to the first valve received.    
BLEEDING72,73   
Life-threatening or Disabling Bleeding 
 Fatal bleeding (Bleeding Academic Research Consortium [BARC] type 5124,125) 
 Bleeding in a critical organ, such as intracranial, intraspinal, intraocular, or 
pericardial necessitating pericardiocentesis, or intramuscular with compartment 
syndrome (BARC type 3b and 3c)  
 Bleeding causing hypovolemic shock or severe hypotension requiring 
vasopressors or surgery (BARC type 3b)  
 Overt source of bleeding with drop in hemoglobin of ≥5 g/dL or whole blood or 
packed red blood cells (RBC) transfusion ≥4 units (BARC type 3b)* 
Major Bleeding (BARC type 3a) 
 Overt bleeding either associated with a drop in the hemoglobin level of at least 
3.0g/dL or requiring transfusion of 2 or 3 units of whole blood/RBC, or causing 
hospitalization or permanent injury, or requiring surgery AND does not meet 
criteria of life-threatening or disabling bleeding  
Minor Bleeding (BARC type 2 or 3a, depending on the severity) 
 Any bleeding worthy of clinical mention (e.g., access site hematoma) that does 
not qualify as life-threatening, disabling, or major 
* Given one unit of packed RBC typically will raise blood hemoglobin 
concentration by 1 g/dL, an estimated decrease in hemoglobin will be calculated. 
CARDIAC 
DECOMPENSATION 
Inability of the heart to maintain adequate circulation 
CARDIAC 
TAMPONADE 
Evidence of a new pericardial effusion associated with hemodynamic instability 
and clearly related to the TAVR procedure. Clinical syndrome caused by the 
accumulation of fluid in the pericardial space, resulting in reduced ventricular 
filling and subsequent hemodynamic compromise. 
CARDIOGENIC 
SHOCK 
An insufficient forward cardiac output to maintain adequate perfusion of vital 
organs to meet ongoing demands for oxygenation and metabolism. Cardiogenic 
shock is due to either inadequate left ventricular pump function (such as in 
congestive heart failure) or inadequate left ventricular filling (such as in cardiac 
tamponade). Cardiogenic shock is defined as sustained hypotension (>30 minutes) 
with evidence of tissue hypoperfusion including oliguria (<30 mL/h), cool 
extremities, cyanosis, and altered mental status. 
CEREBRAL 
INFARCTION 
Evidence of brain cell death from imaging studies or pathological examination. If 
there are clinical symptoms, then it is a stroke; otherwise, it is an asymptomatic 
cerebral infarction.  
CHRONIC RENAL 
INSUFFICIENCY 
Subject has chronic impairment of kidney function. 
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 
DISTURBANCES72,73  
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 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 125 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 126 of 188 
 
 
Table 26.2-1: Definitions 
Term 
Definition 
(LBBB), left anterior fascicular block, or left posterior fascicular block, including 
block requiring permanent pacemaker implant 
Note 1: High grade AV block is considered persistent if it is present every time the 
underlying rhythm is checked. 
Note 2: See also definitions for arrhythmia and permanent pacemaker. 
CONVERSION TO 
OPEN SURGERY 
Conversion to open sternotomy during the TAVR procedure secondary to any 
procedure-related complications 
CORONARY 
OBSTRUCTION 
 
Angiographic or echocardiographic evidence of a new, partial or complete, 
obstruction of a coronary ostium, either by the valve prosthesis itself, the native 
leaflets, calcifications, or dissection, occurring during or after the TAVR procedure. 
 
Mechanical coronary artery obstruction following TAVR or surgical AVR that 
typically occurs during the index procedure. Possible mechanisms for mechanical 
coronary obstruction include the following.  
 Impingement of the coronary ostia by the valve support structure in the setting of 
suboptimal valve positioning and/or ‘small aortic root’ anatomy  
 Embolization from calcium, thrombus, air, or endocarditis displacement of 
native aortic valve leaflets towards the coronary ostia during TAVR  
 Suture-related kinking or obstruction or cannulation related obstruction of the 
coronary ostia associated with surgical AVR 
The diagnosis of TAVR-associated coronary obstruction can be determined by 
imaging studies (coronary angiography, intravascular ultrasound, multi-slice CT 
angiography, or echocardiography), surgical exploration, or autopsy findings. 
Cardiac biomarker elevations and ECG changes indicating new ischemia provide 
corroborative evidence. 
DEATH  
 
All-cause Death 
Death from any cause after a valve intervention. 
Cardiovascular Death 
Any one of the following criteria is met. 
 Any death due to proximate cardiac cause (e.g., myocardial infarction, cardiac 
tamponade, worsening heart failure) 
 Sudden or unwitnessed death  
 Death of unknown cause 
 Death caused by noncoronary vascular conditions such as neurological events, 
pulmonary embolism, ruptured aortic aneurysm, dissecting aneurysm, or other 
vascular disease  
 All procedure-related deaths, including those related to a complication of the 
procedure or treatment for a complication of the procedure  
 All valve-related deaths including structural or nonstructural valve dysfunction 
or other valve-related adverse events  
Non-cardiovascular Death 
 Any death in which the primary cause of death is clearly related to another 
condition (e.g. trauma, cancer, suicide) 
DEVICE DEFICIENCY 
Ref: ISO 14155:2011 
Ref:MEDDEV 2.7/3 
12/2010 
inadequacy of a medical device with respect to its identity, quality, durability, 
reliability, safety or performance.  
Note 1: Device deficiencies include malfunctions, use errors, and inadequate 
labeling. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 126 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 127 of 188 
 
 
Table 26.2-1: Definitions 
Term 
Definition 
DEVICE FAILURE 
A device failure is identified whenever the criteria for device success are not met.  
DEVICE MIGRATION 
Device migration is defined as an upward or downward displacement of the 
implanted valve from its original implant location, after initial correct positioning 
within the aortic annulus from its initial position, with or without consequences. 
This can be confirmed by X-ray, echocardiography, CT scan or MRI or valve 
migration demonstrated by direct assessment during open heart surgery or at 
autopsy. 
DEVICE RELATED 
COMPLICATIONS 
Complications associated with the device as it relates to delivery, placement, 
efficacy or durability; these may involve the implanted device or the delivery 
system.   
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 criteria126 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. 
 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-  
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 127 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 128 of 188 
 
 
Table 26.2-1: Definitions 
Term 
Definition 
o New valvular regurgitation (worsening or changing of preexisting murmur not 
sufficient) 
Minor Criteria 
 Predisposition: predisposing heart condition or intravenous drug use 
 Fever: temperature >38.0° C (100.4° F) 
 Vascular phenomena: major arterial emboli, septic pulmonary infarcts, mycotic 
aneurysm, intracranial hemorrhage, conjunctival hemorrhages, and Janeway 
lesions 
 Immunologic phenomena: glomerulonephritis, Osler's nodes, Roth spots, and 
rheumatoid factor 
 Microbiological evidence: positive blood culture but does not meet a major 
criterion as noted above or serological evidence of active infection with 
organism consistent with infective endocarditis 
 Echocardiographic findings: consistent with infective endocarditis but do not 
meet a major criterion as noted above  
Implanted valve endocarditis includes any infection involving an implanted 
valve. The diagnosis of operated valvular endocarditis is based on one of the 
following criteria.  
 Fulfillment of the Duke endocarditis criteria as defined above 
 Evidence of abscess, paravalvular leak, pus, or vegetation confirmed as 
secondary to infection by histological or bacteriologic studies during a re-
operation 
 Findings of abscess, pus, or vegetation involving a repaired or replaced valve 
during an autopsy. 
EXPLANT 
Removal of the investigational valve implant for any reason. 
FRAILTY 
Slowness, weakness, exhaustion, wasting and malnutrition, poor endurance and 
inactivity, loss of independence.  
HEMOLYSIS 
 
Two plasma free hemoglobin values >40 mg/dL with the two readings taken within 
a single 48-hour period. If the second plasma free hemoglobin assessment is not 
performed within 48 hours following an initial determination of >40 mg/dL, this 
would qualify as an AE. 
HOSTILE CHEST 
Any of the following or other reasons that make redo operation through sternotomy 
or right anterior thoracotomy prohibitively hazardous: 
 Abnormal chest wall anatomy due to severe kyphoscoliosis or other skeletal 
abnormalities (including thoracoplasty, Potts’ disease) 
 Complications from prior surgery 
 Evidence of severe radiation damage (e.g. skin burns, bone destruction, muscle 
loss, lung fibrosis or esophageal stricture) 
 History of multiple recurrent pleural effusions causing internal adhesions 
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 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 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 1: If a subject receives 2 valves, the subject is assigned to the group 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 128 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 129 of 188 
 
 
Table 26.2-1: Definitions 
Term 
Definition 
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. 
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. 
MODIFIED DEVICE 
SUCCESS 
Absence of mortality with the originally implanted transcatheter valve in the proper 
anatomical location, no additional aortic valve procedures, and with the intended 
performance of the prosthetic valve (either a mean aortic valve gradient <20 mm 
Hg or a peak velocity <3m/sec with no moderate or severe prosthetic valve aortic 
regurgitation)   
MYOCARDIAL 
INFARCTION (MI) 
Periprocedural MI (≤72 hours after the index procedure) 
 New ischemic symptoms (e.g., chest pain or shortness of breath) or new 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 129 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 130 of 188 
 
 
Table 26.2-1: Definitions 
Term 
Definition 
 
ischemic signs (e.g., ventricular arrhythmias, new or worsening heart failure, 
new ST-segment changes, hemodynamic instability, new pathological Q waves 
in at least two contiguous leads, or imaging evidence of new loss of viable 
myocardium or new wall motion abnormality)  
 
-AND- 
 Elevated cardiac biomarkers (preferably CK-MB) within 72 h after the index 
procedure, consisting of at least one sample post-procedure with a peak value 
exceeding 15× upper reference limit (troponin) or 5× for CK-MB. If cardiac 
biomarkers are increased at baseline (>99th percentile), a further increase of at 
least 50% post-procedure is required AND the peak value must exceed the 
previously stated limit. 
Spontaneous MI (>72 hours after the index procedure) 
Any one of the following criteria applies. 
 Detection of rise and/or fall of cardiac biomarkers (preferably troponin) with at 
least one value above the 99th percentile URL, together with evidence of 
myocardial ischemia with at least one of the following 
o Symptoms of ischemia 
o ECG changes indicative of new ischemia [new ST-T changes or new LBBB] 
o New pathological Q waves in at least two contiguous leads 
o Imaging evidence of new loss of viable myocardium or new wall motion 
abnormality 
 Sudden, unexpected cardiac death, involving cardiac arrest, often with symptoms 
suggestive of myocardial ischemia, and accompanied by presumably new ST-
segment elevation, or new LBBB, and/or evidence of fresh thrombus by 
coronary angiography and/ or at autopsy, but death occurring before blood 
samples could be obtained, or at a time before the appearance of cardiac 
biomarkers in the blood. 
 Pathological findings of an acute myocardial infarction127. 
NEUROLOGICAL 
EVENT  
Any central, new neurological deficit, whether temporary or permanent and 
whether focal or global, that occurs after the subject emerges from anesthesia 
NEW YORK HEART 
ASSOCIATION 
CLASSIFICATION 
(NYHA) 
Classification system for defining cardiac disease and related functional limitations 
into four broad categorizations: 
 
Class I 
Subject with cardiac disease but without resulting limitations of 
physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain. 
Class II 
Subjects with cardiac disease resulting in slight limitation of 
physical activity. They are comfortable at rest. Ordinary physical 
activity results in fatigue, palpitation, dyspnea, or anginal pain. 
Class III 
Subjects with cardiac disease resulting in marked limitation of 
physical activity. They are comfortable at rest. Less than ordinary 
physical activity causes fatigue, palpitation, dyspnea, or anginal 
pain. 
Class IV 
Subjects with cardiac disease resulting in inability to carry on any 
physical activity without discomfort. Symptoms of cardiac 
insufficiency or of the anginal syndrome may be present even at 
rest. If any physical activity is undertaken, discomfort is increased. 
 
NONSTRUCTURAL 
Any abnormality not intrinsic to the valve itself that results in stenosis or 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 130 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 131 of 188 
 
 
Table 26.2-1: Definitions 
Term 
Definition 
DYSFUNCTION 
 
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  
OPERATIVE RISK 
Operative risk is determined by a center cardiac surgeon and must be confirmed by 
the Case Review Committee (including a cardiac surgeon).  
Extreme Risk: Predicted operative mortality or serious, irreversible morbidity risk 
≥50% at 30 days  
High Risk: Predicted operative mortality or serious, irreversible morbidity risk 
≥15% at 30 days 
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) 
IMPLANTATION114  
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 1: See also definitions for arrhythmia and conductance disturbance. 
PORCELAIN AORTA 
Heavy circumferential calcification of the entire ascending aorta extending to the 
arch such that aortic cross-clamping is not feasible 
PROCEDURE 
RELATED 
COMPLICATIONS 
Complications associated with any part of the vascular access procedure, associated 
treatments or necessary secondary interventions that do not necessarily involve the 
device.  This includes morbidity associated with either pre-medication, or 
anesthesia, or other adjunct to the surgical procedure.  Other technical errors 
including inappropriate subject selection, inappropriate operator techniques, 
measurements, or judgment that do not involve the device itself are also included.   
PROCEDURE-
RELATED EVENTS 
Events occurring during or as a direct result of the index procedure.  
REPEAT PROCEDURE 
FOR VALVE-
RELATED 
DYSFUNCTION 
Any surgical or percutaneous interventional catheter procedure that repairs, 
otherwise alters or adjusts, or replaces a previously implanted valve. In addition to 
surgical re-operations, enzymatic, balloon dilatation, interventional manipulation, 
repositioning, or retrieval, and other catheter-based interventions for valve-related 
complications are also considered re-interventions. Cardiac re-interventions will be 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 131 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 132 of 188 
 
 
Table 26.2-1: Definitions 
Term 
Definition 
categorized as repeat TAVR, valvuloplasty, or surgical AVR. 
 Conversion to open surgery 
 Conversion to open sternotomy during the TAVR procedure secondary to any 
procedure-related complications. 
 Unplanned use of CPB 
 Unplanned use of CPB for hemodynamic support at any time during the TAVR 
procedure. 
RESPIRATORY 
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 
DEVICE EFFECT 
Ref: ISO 14155:2011 
(SADE) 
Adverse device effect that has resulted in any of the consequences characteristic of 
a serious adverse event 
SERIOUS ADVERSE 
EVENT  
Ref: ISO 14155:2011 
(SAE) 
Adverse event that resulted in the following. 
 Led to a death 
 Led to serious deterioration in the health of the subject, that resulted in one or 
more of the following. 
o Life-threatening illness or injury 
o Permanent impairment of a body structure or a body function 
o In-patient or prolonged hospitalization 
o Medical or surgical intervention to prevent life- threatening illness or injury or 
permanent impairment to a body structure or a body function, 
 Led to fetal distress, fetal death or a congenital abnormality or birth defect 
Note 1: Planned hospitalization for a pre-existing condition, or a procedure required 
by the protocol, without serious deterioration in health, is not considered a serious 
adverse event. 
SOURCE DATA 
(per ISO 14155:2011) 
All information in original records of clinical findings, observations, or other 
activities in a clinical investigation, necessary for the reconstruction and evaluation 
of the clinical investigation 
SOURCE DOCUMENT 
Printed, optical or electronic document containing source data. Examples: Hospital 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 132 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 133 of 188 
 
 
Table 26.2-1: Definitions 
Term 
Definition 
(per ISO 14155:2011) 
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.  
STROKE72,73  
 
Stroke is defined as an acute episode of focal or global neurological dysfunction 
caused by brain, spinal cord, or retinal vascular injury as a result of hemorrhage or 
infarction  
Stroke Classification 
 Ischemic Stroke is defined as an acute episode of focal cerebral, spinal, or retinal 
dysfunction caused by an infarction of central nervous system tissue.  
 Hemorrhagic Stroke is defined as an acute episode of focal or global cerebral or 
spinal dysfunction caused by an intraparenchymal, intraventricular, or 
subarachnoid hemorrhage 
Note 1: The CEC will adjudicate ischemic versus hemorrhagic stroke. 
Note 2: A stroke may be classified as undetermined if there is insufficient 
information to allow categorization as ischemic or hemorrhagic 
Stroke Diagnostic Criteria  
 Rapid onset of a focal or global neurological deficit with at least one of the 
following: change in level of consciousness, hemiplegia, hemiparesis, numbness 
or sensory loss affecting one side of the body, dysphasia or aphasia, hemianopia, 
amaurosis fugax, or other neurological signs or symptoms consistent with stroke 
 Duration of a focal or global neurological deficit ≥24 h; OR <24 h, if  available 
neuroimaging documents a new hemorrhage or infarct; OR the neurological 
deficit results in death 
 No other readily identifiable nonstroke cause for the clinical presentation (e.g., 
brain tumor, trauma, infection, hypoglycemia, peripheral lesion, pharmacological 
influences), to be determined by or in conjunction with designated neurologist 
 Confirmation of the diagnosis by at least one of the following.  
o Neurology or neurosurgical specialist  
o Neuroimaging procedure (MRI or CT scan), but stroke may be diagnosed on 
clinical grounds alone 
Note 3: Subjects with non-focal global encephalopathy will not be reported as a 
stroke without unequivocal evidence based upon neuroimaging studies (CT scan or 
brain MRI).  
Stroke Definitions 
Diagnosis as above, preferably with positive neuroimaging study 
 Non-disabling: Modified Rankin Scale (mRS) score <2 at 90 days OR one that 
does not result in an increase of at least one mRS category from an individual’s 
pre-stroke baseline 
 Disabling: Modified Rankin Scale score ≥2 at 90 days AND an increase of at 
least one mRS category from an individual’s pre-stroke baseline  
Note 4: Modified Rankin Scale assessments should be made by a neurology 
professional or by qualified individuals according to a certification process.  
Note 5: Assessment of the mRS score should occur at all scheduled visits in a 
study; mRS also should be performed after a stroke and at 90 days after the onset of 
any stroke. 
STRUCTURAL VALVE 
DETERIORATION  
Component of time-related valve safety defined as follows. 
 Valve-related dysfunction: Mean aortic valve gradient ≥20 mmHg, EOA 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 133 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 134 of 188 
 
 
Table 26.2-1: Definitions 
Term 
Definition 
≤0.9-1.1 cm2, and/or DVI <0.35 AND/OR moderate or severe prosthetic valve 
regurgitation (per VARC definition) 
 Requiring repeat procedure (TAVR or SAVR). 
TAV-IN-TAV 
DEPLOYMENT 
An additional valve prosthesis is implanted within a previously implanted 
prosthesis because of suboptimal device position and/or function during or after the 
index procedure. 
TRANSIENT 
ISCHEMIC ATTACK 
(TIA) 
 Transient episode of focal neurological dysfunction caused by brain, spinal cord, 
or retinal ischemia, without acute infarction  
 Duration of a focal or global neurological deficit is <24 h  
 Neuroimaging does not demonstrate a new hemorrhage or infarct (if performed) 
Note: The difference between TIA and ischemic stroke is the presence of tissue 
damage or new sensory-motor deficit persisting >24 hours. By definition, TIA does 
not produce lasting disability. 
UNANTICIPATED 
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. 
UNANTICIPATED 
SERIOUS ADVERSE 
DEVICE EFFECT  
Ref: ISO 14155:2011 
(USADE) 
Serious adverse device effect which by its nature, incidence, severity, or outcome 
has not been identified in the current version of the risk analysis report  
Note 1: An anticipated serious adverse device effect (ASADE) is an effect which 
by its nature, incidence, severity, or outcome has been identified in the risk analysis 
report. 
UNPLANNED USE OF 
CARDIOPULMONARY 
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 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 134 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 135 of 188 
 
 
Table 26.2-1: Definitions 
Term 
Definition 
artery disease or acute coronary syndrome; documented loss of consciousness not 
related to seizure or tachyarrhythmia. 
VALVE THROMBOSIS 
Any thrombus attached to or near an implanted valve that occludes part of the blood 
flow path, interferes with valve function, or is sufficiently large to warrant 
treatment. Note that valve-associated thrombus identified at autopsy in a patient 
whose cause of death was not valve-related or at operation for an unrelated 
indication should not be reported as valve thrombosis. 
VASCULAR ACCESS 
SITE AND ACCESS 
RELATED 
COMPLICATIONS 
Major Vascular Complications 
 Any aortic dissection, aortic rupture, annulus rupture, left ventricle perforation, 
or new apical aneurysm/pseudoaneurysm  
 Access site or access-related vascular injury (dissection, stenosis, perforation, 
rupture, arterio-venous fistula, pseudoaneurysm, hematoma, irreversible nerve 
injury, compartment syndrome, percutaneous closure device failure*) leading to 
death, life-threatening or major bleeding**, visceral ischaemia, or neurological 
impairment 
 Distal embolization (non-cerebral) from a vascular source requiring surgery or 
resulting in amputation or irreversible end-organ damage 
 The use of unplanned endovascular or surgical intervention associated with 
death, major bleeding, visceral ischaemia or neurological impairment 
 Any new ipsilateral lower extremity ischemia documented by patient symptoms, 
physical exam, and/or decreased or absent blood flow on lower extremity 
angiogram 
 Surgery for access site-related nerve injury 
 Permanent access site-related nerve injury 
Minor Vascular Complications 
 Access site or access-related vascular injury (dissection, stenosis, perforation, 
rupture, arterio-venous fistula, pseudoaneurysms , hematomas, percutaneous 
closure device failure*) not leading to death, life-threatening or major 
bleeding**, visceral ischaemia or neurological impairment 
 Distal embolization treated with embolectomy and/or thrombectomy and not 
resulting in amputation or irreversible end-organ damage 
 Any unplanned endovascular stenting or unplanned surgical intervention not 
meeting the criteria for a major vascular complication 
 Vascular repair or the need for vascular repair (via surgery, ultrasound-guided 
compression, transcatheter embolization, or stent-graft) 
*Percutaneous Closure Device Failure 
Failure of a closure device to achieve hemostasis at the arteriotomy site leading to 
alternative treatment (other than manual compression or adjunctive endovascular 
ballooning) 
Note 1: Pre-planned surgical access or a planned endovascular approach to vascular 
closure (e.g., “pre-closure”)128,129 should be considered as part of the TAVR 
procedure and not as a complication, unless untoward clinical consequences are 
documented (e.g., bleeding complications, limb ischemia, distal embolization, or 
neurological impairment). 
Note 2: If unplanned percutaneous or surgical intervention does not lead to adverse 
outcomes this is not considered a major vascular complication.  
** Refers to VARC bleeding definitions72,73 
VENTRICULAR 
Angiographic or echocardiographic evidence of a new septal perforation during or 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 135 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 136 of 188 
 
 
Table 26.2-1: Definitions 
Term 
Definition 
SEPTAL 
PERFORATION 
after the TAVR procedure 
VESSEL 
PERFORATION 
Unexpected puncture of the vessel with evidence of extravasation into extraluminal 
surrounding tissue or space requiring treatment using interventional or surgical 
techniques 
Abbreviations: ADE=adverse device effect; AE=adverse event; AR=aortic regurgitation; AVA=aortic valve 
area; AVR= aortic valve replacement; CEC= Clinical Events Committee; CK= creatine kinase; CT=computed 
tomography; DVI=Doppler velocity index; ECG=electrocardiogram; EOA=effective orifice area; FEV= forced 
expiratory volume; LBBB=left bundle branch block; LV= left ventricle; MI=myocardial infarction; 
MRI=magnetic resonance imaging; NYHA=New York Heart Association; PPM=permanent pacemaker; 
RBC=red blood cell; SADE=serious adverse device effect; SAE=serious adverse event; TAV=transcatheter 
aortic valve; TAVR=transcatheter aortic valve replacement; TEE=transesophageal Doppler echocardiography; 
TIA=transient ischemic attack; USADE= unanticipated serious adverse device effect; URL=upper reference 
limit (defined as 99th percentile of normal reference range); VARC=Valve Academic Research Consortium 
 
 
27. Appendices 
27.1. Changes in Protocol Versions 
27.1.1. Protocol Version AA to Version AB 
Table 27.1-1 lists changes between protocol versions AA and AB. 
27.1.2. Protocol Version AB to Version AC 
Table 27.1-2 lists changes between protocol versions AB and AC. 
27.1.3. Protocol Version AC to Version AD 
Table 27.1-3 lists changes between protocol versions AC and AD. 
27.1.4. Protocol Version AD to Version AE 
Table 27.1-4 lists changes between protocol versions AD and AE. 
27.1.5. Protocol Version AE to Version AF 
Table 27.1-5 lists changes between protocol versions AE and AF. 
27.1.6. Protocol Version AF to Version AG 
Table 27.1-6 lists changes between protocol versions AF and AG. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 136 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 137 of 188 
 
 
27.1.7. Protocol Version AG to Version AH 
Table 27.1-7 lists changes between protocol versions AG and AH. 
27.1.8. Protocol Version AH to Version AI 
Table 27.1-8 lists changes between protocol versions AH and AI. 
27.1.9. Protocol Version AI to Version AJ 
Table 27.1-9 lists changes between protocol versions AI and AJ. 
27.1.10. Protocol Version AJ to Version AK 
Table 27.1-10 lists changes between protocol versions AJ and AK. 
 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 137 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 138 of 188 
 
 
 
 
Table 27.1-1: Table of Changes for REPRISE III Protocol Version AB (Compared to REPRISE III Protocol Version AA) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AA 
Text as Written in  
REPRISE III Protocol Version AB 
Justification for 
Modification 
Page 1 
Parc d’Affaires, Le Val Saint-Quentin  
2 rue René Caudron, 78960 Voisins le Bretonneux, France 
55 Av. des Champs Pierreux, TSA 51101 
92729 Nanterre Cedex, France 
Corrected Sponsor 
contact address for 
Europe 
 
Table 27.1-2: Table of Changes for REPRISE III Protocol Version AC (Compared to REPRISE III Protocol Version AB) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AB 
Text as Written in  
REPRISE III Protocol Version AC 
Justification for 
Modification 
Page 2 
Current Version: 25-Jul-2014 
Current Version: 25-Sep-2014 
 
Inserted Table of Revision History 
Updated for clarity 
and to account for 
local practice.  
2. Protocol 
Synopsis, Test 
Devices and 
Sizes  
The Lotus Valve System consisting of two… 
The Lotus Valve System is an investigational device consisting 
of two… 
2. Protocol 
Synopsis, 
Control Device 
and Sizes 
 
Commercially available self-expanding CoreValve® 
Transcatheter Aortic Valve Replacement System (CoreValve) 
that is introduced…  
 
Note 1: Every subject... control (CoreValve) valve size approved 
for use and commercially available at the investigational center... 
Note 2: A center…size matrix if it is approved and commercially 
available, but only… 
Although commercially available in other countries, the self-
expanding CoreValve® Transcatheter Aortic Valve Replacement 
System (CoreValve) is an unapproved medical device available 
to Authorized Prescribers in Australia.  It is introduced… 
 
Note 1: Every subject... control (CoreValve) valve size available 
to Authorized Prescribers in Australia at the investigational 
center... 
Note 2: A center…size matrix if it is available, but only… 
2. Protocol 
Synopsis, study 
Design 
 
REPRISE III is a prospective, multicenter, 2:1 randomized 
(Lotus Valve System versus a commercially available 
CoreValve… 
REPRISE III is a prospective, multicenter, 2:1 randomized 
(Lotus Valve System versus CoreValve… 
5.2 
CoreValve… 
System 
The control device is the commercially available self-expanding 
CoreValve® Transcatheter Aortic Valve Replacement System 
(CoreValve) that is introduced… 
The control device is the self-expanding CoreValve® 
Transcatheter Aortic Valve Replacement System (CoreValve), 
which is an unapproved medical device available to Authorized 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 138 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 139 of 188 
 
 
 
Table 27.1-2: Table of Changes for REPRISE III Protocol Version AC (Compared to REPRISE III Protocol Version AB) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AB 
Text as Written in  
REPRISE III Protocol Version AC 
Justification for 
Modification 
(Control) 
 
Note1: Every subject… and the control (CoreValve) valve 
approved for use and commercially available at the 
investigational center where… 
Note 2: A center… size matrix if it is approved and commercially 
available, but… 
Prescribers in Australia. It is introduced… 
 
Note 1: Every subject… and the control (CoreValve) valve 
available to Authorized Prescribers at the investigational center 
where… 
Note 2: A center…size matrix if it is available, but… 
5.3.2 Control 
Device 
Information is provided in the IFU supplied with the 
commercially available CoreValve… 
Information is provided in the IFU supplied with the 
CoreValve… 
8.2 Treatment 
Assignment 
Eligible subjects… or a commercially available self-expanding 
CoreValve® Transcatheter Aortic Valve Replacement System 
(control). 
Eligible subjects… or the self-expanding CoreValve® 
Transcatheter Aortic Valve Replacement System (control). 
8.2.1 Treatment 
The control device is the commercially available CoreValve… 
The control device is the CoreValve…. 
11.7.1 
Medtronic… 
• Descriptive information on balloon valve annuloplasty (e.g., 
size of balloon… 
• Descriptive information on balloon valvuloplasty (e.g., size of 
balloon… 
Updated for clarity 
11.7.2.2 
Preparing… 
• Descriptive information on balloon valve annuloplasty (e.g., 
size of balloon… 
• Descriptive information on balloon valvuloplasty (e.g., size of 
balloon… 
27 Appendices 
― 
Added Section 27.1-2 and Table 27.1-2 
Note: Version AC was a Boston Scientific Corporation (BSC) internal update only; Version AC was not implemented and was not distributed outside of BSC. 
 
Table 27.1-3: Table of Changes for REPRISE III Protocol Version AD (Compared to REPRISE III Protocol Version AC) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AC 
Text as Written in  
REPRISE III Protocol Version AD 
Justification for 
Modification 
Page 2 
Current Version: 25-Sep-2014 
Inserted Table of Revision History 
Added Clinical Contact: Sarah Zanon, Senior Clinical Trial 
Manager, Structural Heart – Interventional Cardiology, Boston 
Scientific Corporation, Dornacherplatz 7, 4500 Solothurn, 
Switzerland   
Current Version: dd-Mar-2015 
Updated Table of Revision History 
Updated for clarity  
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 139 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 140 of 188 
 
 
 
Table 27.1-3: Table of Changes for REPRISE III Protocol Version AD (Compared to REPRISE III Protocol Version AC) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AC 
Text as Written in  
REPRISE III Protocol Version AD 
Justification for 
Modification 
2. Protocol 
Synopsis, Test 
Devices and 
Sizes 
The Lotus Valve System is an investigational device consisting 
of two… 
The Lotus Valve System consists of two… 
2. Protocol 
Synopsis, 
Control Device 
and Sizes 
 
Although commercially available in other countries, the self-
expanding CoreValve® Transcatheter Aortic Valve Replacement 
System (CoreValve) is an unapproved medical device available 
to Authorized Prescribers in Australia.  It is introduced… 
Note 1: Every subject... control (CoreValve) valve size available 
to Authorized Prescribers in Australia at the investigational 
center... 
Note 2: A center…size matrix if it is available, but only… 
Commercially available self-expanding CoreValve® 
Transcatheter Aortic Valve Replacement System (CoreValve) 
that is introduced… 
Note 1: Every subject... test (Lotus) device and the control 
(CoreValve) device. The CoreValve device in the planned size 
must be approved for use and commercially available at the 
investigational center... 
Note 2: A center…size matrix if it is approved and commercially 
available, but only… 
2. Protocol 
Synopsis, Study 
Design 
REPRISE III is a prospective, multicenter, 2:1 randomized 
(Lotus Valve System versus CoreValve… 
REPRISE III is a prospective, multicenter, 2:1 randomized 
(Lotus Valve System versus a commercially available 
CoreValve… 
2. Protocol 
Synopsis, 
Additional 
Measurements 
 Neurological physical exam at discharge and 1 year 
(conducted by a neurologist or neurology fellow) 
Note 4: For subjects diagnosed with a neurological event...  a 
neurological physical exam (conducted by a neurologist or 
neurology fellow), NIHSS assessment… 
 Neurological physical exam at discharge and 1 year 
(conducted by a neurologist, neurology fellow, neurology 
physician assistant, or neurology nurse practitioner) 
Note 4: For subjects diagnosed with a neurological event...  a 
neurological physical exam (conducted by a neurologist, 
neurology fellow, neurology physician assistant, or neurology 
nurse practitioner), NIHSS assessment… 
2. Protocol 
Synopsis, 
Adjunctive 
Pharmacologic 
Therapy 
Note: If a subject requires chronic anticoagulation with warfarin 
(other anticoagulants are not permitted), either clopidogrel or 
aspirin is required prior to and after the implant procedure in 
addition to the anticoagulant therapy (but both aspirin and 
clopidogrel are not required). Subjects treated with warfarin 
should not be treated with a P2Y12 inhibitor other than 
clopidogrel.  
c:  Holmes, D. R., et al. J Am Coll Cardiol. 2012;59:1200-1254 
 
Nishimura, R., et al. J Am Coll Cardiol. 2014;doi: 
Note: If a subject requires chronic anticoagulation, either 
clopidogrel or aspirin is required prior to and after the implant 
procedure in addition to the anticoagulant therapy (but both 
aspirin and clopidogrel are not required). After the implant 
procedure, the subject must be treated with warfarin (other 
anticoagulants are not permitted in the first month) and either 
clopidogrel (other P2Y12 inhibitors are not permitted in 
combination with warfarin) or aspirin for at least 1 month. After 
1 month, subjects requiring chronic anticoagulation may be 
switched from warfarin to a new oral anticoagulant (NOAC) at 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 140 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 141 of 188 
 
 
 
Table 27.1-3: Table of Changes for REPRISE III Protocol Version AD (Compared to REPRISE III Protocol Version AC) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AC 
Text as Written in  
REPRISE III Protocol Version AD 
Justification for 
Modification 
10.1016/j.jacc.2014.02.536 
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. 
c:  Holmes, D. R., et al. J Am Coll Cardiol. 2012;59:1200-1254 
 
Nishimura, R., et al. J Am Coll Cardiol. 2014;63:2438-88 
2. Protocol 
Synopsis, 
Inclusion 
Criteria 
IC1. Subject has… an initial AVA of ≤1.0 cm2 (or AVA index of 
<0.6 cm2/m2) and a mean pressure gradient >40 mmHg or jet 
velocity >4.0 m/s… echocardiography. 
IC1. Subject has… an initial AVA of ≤1.0 cm2 (or AVA index of 
≤0.6 cm2/m2) and a mean pressure gradient ≥40 mmHg or jet 
velocity ≥4.0 m/s… echocardiography and/or invasive 
hemodynamics. 
To be consistent with 
approved control 
(CoreValve) 
Instructions For Use 
IC4. ● If STS <8, subject has… 
IC4. ● If STS <8, subject has… 
 
 
 Age ≥90 years 
(Added text) 
In-hospital mortality 
rate of heart valve 
surgery in patients 
≥90 years is >10%*, 
which is above the 
8% risk set for study 
inclusion.  
*Assmann A. 
Interactive 
CardioVascular Thor 
Surg 2013;17:340 
Speziale G. J Thorac 
Cardiovasc Surg 
2011;141:725 
Bridges C. J Am Coll 
Surg 2003:197:347 
2. Protocol 
Synopsis, 
Exclusion 
Criteria 
EC6. Subject has severe (≥3+) aortic… 
EC11. Subject is being treated with chronic anticoagulation 
therapy other than warfarin. 
Note: Subjects who require chronic anticoagulation with warfarin 
must be able to be treated additionally with either aspirin or 
clopidogrel. 
EC6. Subject has severe (4+) aortic… 
EC11. Subject requires chronic anticoagulation therapy after the 
implant procedure and cannot be treated with warfarin (other 
anticoagulants are not permitted in the first month) for at least 1 
month concomitant with either aspirin or clopidogrel. 
Note: Subjects who require chronic anticoagulation with warfarin 
must be able to be treated additionally with either aspirin or 
Updated for clarity 
 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 141 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 142 of 188 
 
 
 
Table 27.1-3: Table of Changes for REPRISE III Protocol Version AD (Compared to REPRISE III Protocol Version AC) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AC 
Text as Written in  
REPRISE III Protocol Version AD 
Justification for 
Modification 
clopidogrel.  (text removed) 
EC9. Subject has echocardiographic evidence of new intra-
cardiac mass, thrombus or vegetation or one requiring treatment. 
 
EC9. Subject has echocardiographic evidence of new intra-
cardiac vegetation or intraventricular or paravalvular thrombus. 
 
Some intra-cardiac 
masses increase risk 
of TAVR 
complications 
whereas others do 
not; this update 
clarifies which 
should be included as 
exclusion criteria 
EC12. Subject has active peptic ulcer disease or gastrointestinal 
bleed… within the past 3 months, other clinically… 
 
EC12. Subject has had a gastrointestinal bleed… within the past 
3 months, or has other clinically significant bleeding diathesis or 
coagulopathy that would preclude treatment with required 
antiplatelet regimen, or will … 
 
Definition of active 
peptic ulcer disease is 
considered 
ambiguous by some 
centers (i.e., are 
subjects who are well 
controlled on medical 
therapy considered to 
have the active 
disease). This 
modification clarifies 
this and limits the 
exclusion to those 
with increased risk of 
adverse events. 
EC20. Subject has severe peripheral vascular disease including 
aneurysm defined as maximal luminal diameter ≥5 cm or with 
documented presence of thrombus, marked tortuosity, 
narrowing… 
EC20. Subject has severe vascular disease that would preclude 
safe access (e.g., aneurysm with thrombus that cannot be crossed 
safely, marked tortuosity, significant narrowing… or vertebral 
disease). 
Updated text is 
clearer about 
conditions that would 
increase the risk of 
adverse events. 
Table 4.1-1 
- 
The table was updated with 6 new references. 
Provided additional 
current literature 
information. 
4.1.2 
The aforementioned results notwithstanding, TAVR with early 
As discussed above, TAVR in patients unsuitable for SAVR has 
Provided additional 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 142 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 143 of 188 
 
 
 
Table 27.1-3: Table of Changes for REPRISE III Protocol Version AD (Compared to REPRISE III Protocol Version AC) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AC 
Text as Written in  
REPRISE III Protocol Version AD 
Justification for 
Modification 
REPRISE I 
Study 
generation devices has been associated with increased stroke risk 
and vascular complications when compared to surgical valve 
replacement64-66. Cerebrovascular accidents and vascular 
complications associated with TAVR have been significant 
predictors of mortality75,76. The paravalvular regurgitation more 
commonly seen with TAVR compared to surgery has also been 
accompanied by higher early and late mortality45,65,77. While 
careful patient selection may serve to mitigate these risks87-89, 
device design improvements such as seen with the Lotus Valve 
System (Section 5.1) … 
…subjects with calcified stenotic aortic valves who… 
To date, data are available through 1 year81… The 1-year 
VARC-1… 
…and 1 year (5 in Class I, 6 in Class II; P=0.004). The mean… 
and 15.4±4.6 mmHg at 1 year. Paravalvular… or absent/trivial 
(10/11) at 1 year… 
reduced mortality14, 73 and treatment of selected patients at high 
surgical risk has resulted in similar64 or better66 survival at 1 year. 
These results notwithstanding, TAVR with early generation 
devices has been associated with increased stroke risk and 
vascular complications when compared to SAVR64-66, which 
have been significant predictors of mortality80,81. There are also 
other infrequent but substantial complications that impact long-
term outcomes and may limit the use of TAVR in lower risk 
subjects. Precise valve positioning can be challenging with first-
generation devices, and valve misplacement can lead to severe 
problems, including coronary occlusion and valve 
embolization82. Incomplete apposition of the prosthesis with the 
native valve can occur in the presence of significant amounts of 
calcium or with suboptimal implantation, resulting in 
paravalvular regurgitation83,84. This has been associated with 
increased mortality in several longitudinal registries45,85,86. While 
careful patient selection may serve to mitigate these risks87-89, 
device design improvements such as seen with the Lotus Valve 
System (including the ability to fully reposition and retrieve the 
valve and a unique adaptive seal to prevent leakage, see Section 
5.1)… 
… subjects with calcific aortic stenosis who… 
To date, data are available through 2 years90,92… The 2-year 
VARC-1… 
…and baseline and 2 years (6 in Class I, 5 in Class II; P=0.004). 
The mean… and 15.4±4.4 mmHg at 2 years. Paravalvular… and 
absent/trivial (11/11) at 2 years… 
current literature 
information and 
updated REPRISE I 
with data from 2 
years to include the 
most current data. 
4.1.3 
REPRISE II 
Study 
…enrolled 120 subjects at 14 investigative… 
…shows 6 month94 clinical... Mortality was 8.4% and the 
disabling stroke rate was 3.5%. Most subjects (81%) had 
none/trivial paravalvular aortic regurgitation at 6 months… 
…enrolled 120 subjects in the main cohort at 14 investigative… 
…shows 6 month94 and 1 year95 clinical. .. At 1 year, mortality 
was 11.0% and the disabling stroke rate was 3.5%. The low 
paravalvular aortic regurgitation rate observed at 30 days was 
maintained at 1 year as most subjects (86%) had none/trivial 
paravalvular aortic regurgitation… 
Table 4.1-3 updated with 1-year data in addition to 6-month data. 
Updated with data 
from 1 year for the 
main cohort (N=120) 
and with 30-day data 
from the full cohort 
(N=250) to include 
the most current data 
available. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 143 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 144 of 188 
 
 
 
Table 27.1-3: Table of Changes for REPRISE III Protocol Version AD (Compared to REPRISE III Protocol Version AC) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AC 
Text as Written in  
REPRISE III Protocol Version AD 
Justification for 
Modification 
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; enrollment in this extended 
cohort was completed in April 2014. 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 intent-to-
treat basis (all subjects enrolled, whether or not a study device is 
implanted). 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 margin of 6.2%). 
Table 4.1 4 shows device performance endpoints, clinical 
outcomes, and echocardiographic outcomes through 30 days for 
the full cohort (N=250)96. Outcomes in the full cohort were 
similar to that reported for the main cohort (see Table 4.1 2) with 
a mean aortic valve gradient of 11.70±6.77 mmHg. Mortality was 
4.4% and the disabling stroke rate was 3.3%. The new PPM 
implant rate was 29.6%. 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 
CoreValve97. In a recent report, 12-month clinical outcomes were 
similar among subjects with and without periprocedural PPM98. 
Another study (mean follow-up of 22±17 months) found that 
PPM implantation post TAVR had a negative effect on left 
ventricular function but was not associated with any increase in 
overall or cardiovascular death or rehospitalization for heart 
failure and was a protective factor for the occurrence of sudden 
or unknown death (P=0.023)99. Implantation of a new PPM 
following TAVR with SAPIEN (retrospective analysis from the 
combined PARTNER trial and NRCA registry) was associated 
with a higher rate of repeat hospitalization at 30 days and 1 year 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 144 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 145 of 188 
 
 
 
Table 27.1-3: Table of Changes for REPRISE III Protocol Version AD (Compared to REPRISE III Protocol Version AC) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AC 
Text as Written in  
REPRISE III Protocol Version AD 
Justification for 
Modification 
(10.6% vs. 5.9%, P=0.02 at 30 days; 23.9% vs. 18.2%, P=0.05 at 
1 year) but not mortality (7.5% vs. 5.8%, P=0.40 at 30 days; 
26.3% vs. 20.8%, P=0.08 at 1 year)100. There was no severe 
paravalvular regurgitation and trace/trivial or no paravalvular 
regurgitation in 85.8% of REPRISE II subjects. Reported 
moderate or severe aortic regurgitation after TAVR has ranged 
from 6% to 21%101 and has been associated with increased 
mortality in several longitudinal registries45,59,85,86. 
In summary, the observed clinical results are consistent with 
other TAVR studies and the PVR rates are lower… 
Table 4.1 4 was added. 
5. Device 
Description 
…both the test and the control device approved for use and 
commercially available at… 
…both the test and the control device. The control device in the 
planned size must be approved for use and commercially 
available at… 
Updated for clarity 
5.2 
CoreValve… 
System 
(Control) 
The control device is the self-expanding CoreValve® 
Transcatheter Aortic Valve Replacement System (CoreValve), 
which is an unapproved medical device available to Authorized 
Prescribers in Australia. It is introduced… 
Note 1: Every subject… both the test (Lotus) and the control 
(CoreValve) valve available to Authorized Prescribers at the 
investigational center where… 
Note 2: A center…size matrix if it is available, but… 
The control device is the commercially available self-expanding 
CoreValve® Transcatheter Aortic Valve Replacement System 
(CoreValve) that is introduced… 
Note1: Every subject… both the test (Lotus) device and the 
control (CoreValve) device. The CoreValve device in the planned 
size must be approved for use and commercially available at the 
investigational center where… 
Note 2: A center… size matrix if it is approved and commercially 
available, but… 
5.3.2 Control 
Device 
Information is provided in the IFU supplied with the 
CoreValve… 
Information is provided in the IFU supplied with the 
commercially available CoreValve… 
7.2 Additional 
Measurements 
• Neurological status… by the following: 
   Neurological physical exam by a neurologist or neurology 
fellow at discharge and 1 year 
Note 7: For subjects diagnosed with a neurological event … a 
neurological physical exam (conducted by a neurologist or 
neurology fellow), NIHSS assessment… 
…If a subject who has not received a study device… within the 
first 30 days after the index… 
• Neurological status… by the following: 
   Neurological physical exam by a neurologist, neurology 
fellow, neurology physician assistant, or neurology nurse 
practitioner at discharge and 1 year 
Note 7: For subjects diagnosed with a neurological event … a 
neurological physical exam (conducted by a neurologist, 
neurology fellow, neurology physician assistant, or neurology 
nurse practitioner), NIHSS assessment… 
Updated for clarity 
and a correction 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 145 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 146 of 188 
 
 
 
Table 27.1-3: Table of Changes for REPRISE III Protocol Version AD (Compared to REPRISE III Protocol Version AC) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AC 
Text as Written in  
REPRISE III Protocol Version AD 
Justification for 
Modification 
…If a subject who has not received a study device… within the 
first 1 year after the index… 
8.2 Treatment 
Assignment 
Eligible subjects… or the self-expanding CoreValve® 
Transcatheter Aortic Valve Replacement System (control). 
Eligible subjects… or a commercially available self-expanding 
CoreValve® Transcatheter Aortic Valve Replacement System 
(control). 
Updated for clarity 
8.2.1 Treatment 
The control device is the CoreValve…. 
The control device is the commercially available CoreValve… 
Table 9.2-1 
IC1. Subject has… an initial AVA of ≤1.0 cm2 (or AVA index of 
<0.6 cm2/m2) and a mean pressure gradient >40 mmHg or jet 
velocity >4.0 m/s… echocardiography… 
IC1. Subject has… an initial AVA of ≤1.0 cm2 (or AVA index of 
≤0.6 cm2/m2) and a mean pressure gradient ≥40 mmHg or jet 
velocity ≥4.0 m/s… echocardiography and/or invasive 
hemodynamics. 
To be consistent with 
approved control 
(CoreValve) 
Instructions For Use 
IC4. ● If STS <8, subject has… 
 
IC4. ● If STS <8, subject has… 
 
 
 Age ≥90 years 
(Added text) 
In-hospital mortality 
rate of heart valve 
surgery in patients 
≥90 years is >10%*, 
which is above the 
8% risk set for study 
inclusion.  
*Assmann A. 
Interactive 
CardioVascular Thor 
Surg 2013;17:340. 
Speziale G. J Thorac 
Cardiovasc Surg 
2011;141:725. 
Bridges C. J Am Coll 
Surg 2003:197:347. 
Table 9.3-1 
EC6. Subject has severe (≥3+) aortic… 
EC11. Subject is being treated with chronic anticoagulation 
therapy other than warfarin. Subject requires chronic 
anticoagulation therapy (warfarin) and cannot tolerate 
concomitant therapy with either aspirin or clopidogrel. 
  
EC6. Subject has severe (4+) aortic… 
EC11. Subject requires chronic anticoagulation therapy after the 
implant procedure and cannot be treated with warfarin (other 
anticoagulants are not permitted in the first month) for at least 1 
month concomitant with either aspirin or clopidogrel. 
Note: Subjects who require chronic anticoagulation with warfarin 
Updated for clarity 
 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 146 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 147 of 188 
 
 
 
Table 27.1-3: Table of Changes for REPRISE III Protocol Version AD (Compared to REPRISE III Protocol Version AC) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AC 
Text as Written in  
REPRISE III Protocol Version AD 
Justification for 
Modification 
Note: Subjects who require chronic anticoagulation with warfarin 
must be able to be treated additionally with either aspirin or 
clopidogrel. 
 
must be able to be treated additionally with either aspirin or 
clopidogrel.  (text removed) 
EC9. Subject has echocardiographic evidence of new intra-
cardiac mass, thrombus or vegetation or one requiring treatment. 
EC9. Subject has echocardiographic evidence of new intra-
cardiac vegetation or intraventricular or paravalvular thrombus. 
Some intra-cardiac 
masses increase risk 
of TAVR 
complications 
whereas others do 
not; this update 
clarifies which 
should be exclusion 
criteria. 
EC12. Subject has active peptic ulcer disease or gastrointestinal 
bleed… clinically significant bleeding diathesis or 
coagulopathy or will refuse transfusions. 
 
EC12. Subject has gastrointestinal bleed… clinically significant 
bleeding diathesis or coagulopathy that would preclude 
treatment with required antiplatelet regimen, or will 
refuse transfusions. 
 
 
Definition of active 
peptic ulcer disease is 
considered 
ambiguous by some 
centers (i.e., are 
subjects who are well 
controlled on medical 
therapy considered to 
have the active 
disease). This 
modification clarifies 
this and limits the 
exclusion to those 
with increased risk of 
adverse events. 
EC20. Subject has severe peripheral vascular disease including 
aneurysm defined as maximal luminal diameter ≥5 cm or with 
documented presence of thrombus, marked… 
EC20. 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 symptomatic 
carotid or vertebral disease).  
Updated text is 
clearer about 
conditions that would 
increase the risk of 
adverse events. 
Figure 11.1-1 
Figure says “Heart Rhythm.” 
Updated figure to say “Heart Rhythm Strip” 
Updated for clarity 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 147 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 148 of 188 
 
 
 
Table 27.1-3: Table of Changes for REPRISE III Protocol Version AD (Compared to REPRISE III Protocol Version AC) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AC 
Text as Written in  
REPRISE III Protocol Version AD 
Justification for 
Modification 
Table 11.1-1 
 
b: All follow-up dates will be calculated from the date of the 
index procedure. Visits… 
d: Neurological physical exam… neurologist or neurology 
fellow. NIHSS…performed by certified personnel... 
…If a subject who has not received a study device… within the 
first 30 days after the index… 
b: All follow-up dates will be calculated from the date of the 
(attempted) index procedure (or randomization in randomized 
subjects where no implant is attempted).  Visits… 
d: Neurological physical exam… neurologist, neurology fellow, 
neurology physician assistant, or neurology nurse practitioner. 
NIHSS…performed by a neurology professional or certified 
personnel... 
…If a subject who has not received a study device… within the 
first 1 year after the index…  
Updated for clarity 
and a correction  
e: All baseline and post-procedure 12-lead …Lotus Valve 
insertion.  
Baseline column of the 12-lead ECGe row has the following: X 
Procedure column of the 12-lead ECGe row has the following: Xe 
e: All screening and post-procedure 12-lead …study valve 
insertion (12-lead ECG is not required during the procedure). 
Removed from the Baseline column of the 12-lead ECGe row the 
following: X 
Removed from the Procedure column of the 12-lead ECGe row 
the following: Xe 
Added a new row labeled “Heart rhythm stripe” which has the 
following in the Procedure column: Xe 
Updated for clarity 
g: Consists of STS score (v2.73), euroSCORE II… 
i: …on the pre-BAV echocardiographic data. 
g: Consists of STS score (v2.73), euroSCORE II… (removed 
version number) 
i: …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. 
g: To allow for 
updated STS score 
calculator 
i: Updated for clarity 
11.4 Screening 
Assessments 
   12-lead electrocardiogram (ECG) at screening and/or 
baseline must… 
   Risk assessments: STS Score (2.73), euroSCORE II… 
   12-lead electrocardiogram (ECG) at screening must… 
   Risk assessments: STS Score (2.73), euroSCORE II… 
(removed version number) 
Updated for clarity 
• Frailty, disability, and comorbidity assessments (collected 
prospectively)  
   O Nutritional assessment  
        
 
   O Body Mass Index…  
• Frailty, disability, and comorbidity assessments (collected 
prospectively)  
   O Nutritional assessment (removed the 2 bullets) 
        
 
   O Body Mass Index…  
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 148 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 149 of 188 
 
 
 
Table 27.1-3: Table of Changes for REPRISE III Protocol Version AD (Compared to REPRISE III Protocol Version AC) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AC 
Text as Written in  
REPRISE III Protocol Version AD 
Justification for 
Modification 
• Imaging… 
       Within 60 days… pre-BAV echocardiographic data. 
• Imaging… 
       Within 60 days… 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. 
11.5 Baseline 
Assessments 
• Neurological physical… by a neurologist or neurology fellow 
(see Table 11.1-1)… 
• NIH …performed by certified personnel (external… 
• Modified Rankin …performed by certified personnel 
(external… 
• Laboratory tests 
   O Complete blood count (CBC) with platelets  
   O Serum creatinine… 
• 12-lead electrocardiogram (ECG) at screening and/or baseline 
must be performed… 
• Neurological physical… by a neurologist, neurology fellow, 
neurology physician assistant, or neurology nurse practitioner 
(see Table 11.1-1)… 
• NIH …performed by a neurology professional or certified 
personnel (external… 
• Modified Rankin …performed by a neurology professional or 
certified personnel (external… 
• Laboratory tests 
   O Complete blood count (CBC) with platelets  
   O Albumin 
     O Serum creatinine… 
• 12-lead electrocardiogram (ECG) at screening and/or baseline 
must be performed… (removed the bullet) 
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 III 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. 
11.6 
Preprocedure 
Medications 
Note 3: If a subject requires chronic anticoagulation with 
warfarin (other anticoagulants are not permitted), either 
clopidogrel or aspirin is required prior to the implant procedure 
in addition to the anticoagulant therapy (but both aspirin and 
clopidogrel are not required). Subjects treated with warfarin 
Note 3: 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.  
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 149 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 150 of 188 
 
 
 
Table 27.1-3: Table of Changes for REPRISE III Protocol Version AD (Compared to REPRISE III Protocol Version AC) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AC 
Text as Written in  
REPRISE III Protocol Version AD 
Justification for 
Modification 
should not be treated with a P2Y12 inhibitor other than 
clopidogrel. 
11.7.1 
Medtronic… 
A final post-deployment aortogram of the ascending aorta and 
rotational angiography of the valve frame must be performed… 
 
A final post-deployment aortogram of the ascending aorta must 
be performed… 
 
Valve frame 
angiogram is 
unnecessary as do not 
expect fracture at 
procedure. 
11.7.1 
Medtronic… 
• Heart rhythm… recorded 
• Heart rhythm… recorded (12-lead ECG is not required) 
Updated for clarity 
11.7.2.1 
Valvuloplasty 
Prior to…heart rhythm strip should be obtained. 
Prior to…heart rhythm strip should be obtained (12-lead ECG is 
not required). 
11.7.2.2 
Preparing… 
8) A final … (including recommended rotational angiography of 
the valve frame) must be performed… 
• Heart rhythm… recorded 
8) A final … (including recommended rotational angiography of 
the valve frame, required only for Lotus) must be performed…  
• Heart rhythm… recorded (12-lead ECG is not required) 
The rotational 
angiography is 
required for Lotus to 
allow comparison 
with required annual 
assessment; updated 
heart rhythm bullet 
for clarity. 
11.8 Post-
Procedure 
  If a subject requires chronic anticoagulation with warfarin 
(other anticoagulants are not permitted), either clopidogrel or 
aspirin is required after the implant procedure in addition to the 
anticoagulant therapy (but both aspirin and clopidogrel are not 
required). Subjects treated with warfarin should not be treated 
with a P2Y12 inhibitor other than clopidogrel. 
   If a subject requires chronic anticoagulation, either 
clopidogrel or aspirin is required after the implant procedure in 
addition to the anticoagulant therapy (but both aspirin and 
clopidogrel are not required). The subject must be treated with 
warfarin (other anticoagulants are not permitted in the first 
month) and either clopidogrel (other P2Y12 inhibitors are not 
permitted in combination with warfarin) or aspirin for at least 1 
month. After 1 month, subjects requiring chronic anticoagulation 
may be switched from warfarin 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 for clarity 
11.9 Prior to 
Discharge 
• Neurological physical… by a neurologist or neurology fellow… 
• NIH …performed by certified personnel (external... 
• Neurological physical… by a neurologist, neurology fellow, 
neurology physician assistant, or neurology nurse practitioner… 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 150 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 151 of 188 
 
 
 
Table 27.1-3: Table of Changes for REPRISE III Protocol Version AD (Compared to REPRISE III Protocol Version AC) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AC 
Text as Written in  
REPRISE III Protocol Version AD 
Justification for 
Modification 
• Modified Rankin …performed by certified personnel 
(external… 
• NIH …performed by a neurology professional or certified 
personnel (external... 
• Modified Rankin …performed by a neurology professional or 
certified personnel (external… 
11.10.1 30-Day 
• Modified Rankin …performed by certified personnel 
(external… 
• Modified Rankin …performed by a neurology professional or 
certified personnel (external… 
11.10.2  6-
Month 
• Modified Rankin …performed by certified personnel 
(external… 
• Modified Rankin …performed by a neurology professional or 
certified personnel (external… 
11.10.3 12-
Month ... 
• Modified Rankin …performed by certified personnel 
(external...  
• Neurological physical… by a neurologist or neurology fellow 
(see Table 11.1-1)… 
• NIH …performed by certified personnel (external... 
• Modified Rankin …performed by a neurology professional or 
certified personnel (external.. 
• Neurological physical… by a neurologist, neurology fellow, 
neurology physician assistant, or neurology nurse practitioner 
(see Table 11.1-1)... 
• NIH …performed by a neurology professional or certified 
personnel (external… 
11.10.4 
Annual… 
• Modified Rankin …performed by certified personnel 
(external… 
• Modified Rankin …performed by a neurology professional or 
certified personnel (external… 
12.2.1 Analysis 
Sets 
…For ITT analyses…enrolled in the trial, are randomized, and 
received a study device, will be included… 
…For ITT analyses…enrolled in the trial, and are randomized 
will be included… 
Updated for clarity 
and correction 
12.2.4 Reporting 
Events 
For subjects who have a procedure or an attempted procedure, all 
events that occur from the date of the (attempted) procedure 
onward will be reported.  For subjects who do not have a 
(attempted) procedure, events from the date of randomization to 
30 days post-randomization will be reported. 
For all roll-in subjects, all events that occur from the start of the 
index procedure will be reported. For all randomized subjects, 
events from the time of randomization onward will be reported. 
For randomized subjects who do not have an attempted 
procedure, events from the date of randomization to 1 year post-
randomization will be reported. 
12.3.2 Interim 
Analyses 
No formal interim analyses... for European regulatory agency 
review after these 300 patients… 
No formal interim analyses... for regulatory agency review after 
these 300 patients… 
Updated for clarity 
17.4.1 Training 
with the Lotus… 
• Directions for Use:  An overview of the current Instructions for 
Use (IFU) manual. 
• Directions for Use:  An overview of the current Instructions for 
Use (IFU) manual. (text removed) 
Clarification of 
training. 
17.4.2 Role of 
Boston 
…testing required by the protocol. Support may… 
…testing required by the protocol. Boston Scientific Corporation 
is also responsible for ensuring investigators are trained on the 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 151 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 152 of 188 
 
 
 
Table 27.1-3: Table of Changes for REPRISE III Protocol Version AD (Compared to REPRISE III Protocol Version AC) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AC 
Text as Written in  
REPRISE III Protocol Version AD 
Justification for 
Modification 
Scientific… 
Directions for Use. Support may… 
19. Potential 
Risks… 
…the PARTNER II trial123, the CoreValve Extreme Risk Study75 
and… 
…the PARTNER II trial123, the SAPIEN 3 CE Mark study75, the 
CoreValve Extreme Risk Study73 and… 
Including most 
current data. 
Table 26.1-1 
- 
Added the abbreviation “NOAC” – new oral anticoagulant  
Updated for clarity 
Table 26.2-1 
STROKE 
Note 4: Modified Rankin Scale assessments should be made by 
by qualified individuals according to a certification process. 
Note 4: Modified Rankin Scale assessments should be made by a 
neurology professional or by qualified individuals according to a 
certification process. 
27 Appendices 
- 
Added Section 27.1-3 and Table 27.1-3 
List changes made. 
Note: Version AC was a Boston Scientific Corporation (BSC) internal update only; Version AC was not implemented and was not distributed outside of BSC. 
 
Table 27.1-4: Table of Changes for REPRISE III Protocol Version AE (Compared to REPRISE III Protocol Version AD) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AD 
Text as Written in  
REPRISE III Protocol Version AE 
Justification for 
Modification 
Page 2 
Current Version: 23-Apr-2015 
Current Version: 19-Aug-2015 
Updated Table of Revision History 
Updated for clarity  
2. Protocol 
Synopsis, Test 
Devices and 
Sizes  
The Lotus Valve System consisting of two… 
Devices sizes include 23 mm, 25 mm, and 27 mm diameter. 
The Lotus Valve System consisting of two… 
Devices sizes include 21 mm, 23 mm, 25 mm, and 27 mm 
diameter. 
Addition of the 
21 mm Lotus Valve 
to the test matrix and 
the 23 mm 
CoreValve Evolut to 
the control matrix 
2. Protocol 
Synopsis, 
Control Device 
and Sizes 
 
Commercially available self-expanding CoreValve® 
Transcatheter Aortic Valve Replacement System (CoreValve) 
that is introduced…  
 
Devices sizes include 26 mm, 29 mm, and 31 mm diameter. 
Commercially available self-expanding CoreValve® 
Transcatheter Aortic Valve Replacement System (CoreValve) 
that is introduced…  
 
Devices sizes include 23 mm (CoreValve® Evolut™ 23mm), 
26 mm, 29 mm, and 31 mm diameter. 
2. Protocol 
Synopsis, 
Inclusion 
Criteria 
IC2. Subject has a documented aortic annulus size of ≥20 mm 
and ≤27 mm… 
IC2. Subject has a documented aortic annulus size of ≥18 mm 
and ≤27 mm… 
Smaller valve size 
can be used with 
smaller annulus sizes  
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 152 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 153 of 188 
 
 
 
Table 27.1-4: Table of Changes for REPRISE III Protocol Version AE (Compared to REPRISE III Protocol Version AD) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AD 
Text as Written in  
REPRISE III Protocol Version AE 
Justification for 
Modification 
5.1 Lotus Valve 
System… (Test) 
Device sizes include 23 mm, 25 mm, and 27 mm diameter. 
Device sizes include 21 mm, 23 mm, 25 mm, and 27 mm 
diameter. 
Addition of the 
21 mm Lotus Valve 
to the test matrix and 
the 23 mm 
CoreValve Evolut to 
the control matrix 
5.1.1 Lotus 
Valve 
The device is designed to produce a final diameter of 23 mm, 
25 mm, or 27 mm… The frame height of all valve sizes in the 
deployed state is approximately 19 mm. 
The device is designed to produce a final diameter of 21 mm, 
23 mm, 25 mm, or 27 mm… In the deployed state, the frame 
height of the 21mm valve is approximately 15 mm; the frame 
height of the three larger valve sizes is approximately 19 mm. 
5.1.3 Lotus 
Introducer Set 
The Lotus Introducer is suitable for use in subjects requiring the 
23 mm valve with femoral artery lumen diameter ≥6.0 mm or…   
The Lotus Introducer is suitable for use in subjects requiring the 
21 mm or 23 mm valve with femoral artery lumen diameter 
≥6.0 mm or…   
5.2 CoreValve 
…System 
(Control) 
Devices sizes include 26 mm, 29 mm, and 31 mm diameter. 
Devices sizes include the CoreValve® Evolut™ 23 mm diameter 
and the CoreValve 26 mm, 29 mm, and 31 mm diameter. 
5.3.2 Control 
Device 
Information is provided in the IFU supplied with the 
commercially available CoreValve… 
Information is provided in the IFU supplied with the 
commercially available CoreValve and CoreValve® Evolut™ 
23mm … 
Table 9.2-1 
IC2. Subject has a documented aortic annulus size of ≥20 mm 
and ≤27 mm… 
IC2. Subject has a documented aortic annulus size of ≥18 mm 
and ≤27 mm… 
Smaller valve size 
can be used with 
smaller annulus sizes 
11.7.2.2 
Preparing… 
• Device size (23 mm, 25 mm, or 27 mm) and model 
• Device size (21 mm, 23 mm, 25 mm, or 27 mm) and model 
Addition of the 
21 mm Lotus Valve 
to the test matrix 
27 Appendices 
- 
Added Section 27.1-4 and Table 27.1-4 
List changes made. 
 
Table 27.1-5: Table of Changes for REPRISE III Protocol Version AF (Compared to REPRISE III Protocol Version AE) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AE 
Text as Written in  
REPRISE III Protocol Version AF 
Justification for 
Modification 
Page 1 Sponsor: 
Boston Scientific Corporation 
160 Knowles Drive 
Los Gatos, CA 95032 USA 
 
International Representative 
Boston Scientific International SA 
Boston Scientific Corporation 
300 Boston Scientific Way 
Marlborough, MA 01752, USA 
 
International Representative 
Boston Scientific Limited 
Updated addresses 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 153 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 154 of 188 
 
 
 
Table 27.1-5: Table of Changes for REPRISE III Protocol Version AF (Compared to REPRISE III Protocol Version AE) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AE 
Text as Written in  
REPRISE III Protocol Version AF 
Justification for 
Modification 
European Headquarters, Paris 
55 Av. des Champs Pierreux, TSA 51101 
92729 Nanterre Cedex, France 
Ballybrit Business Park 
Galway, Ireland 
Page 2 
Current Version: 19-Aug-2015 
Current Version: 07-Dec-2015 
Updated Table of Revision History 
Updated for clarity  
2. Protocol 
Synopsis – 
Control Device 
and Sizes 
Devices sizes include 23 mm (CoreValve® Evolut™ 23mm), 
26 mm, 29 mm, and 31 mm diameter. 
Note 1: Every subject must be deemed treatable… 
Devices sizes include 26 mm, 29 mm, and 31 mm diameter. 
Note 1: Every subject in the randomized cohort must be deemed 
treatable… 
2. Protocol 
Synopsis – 
Study Design 
REPRISE III is a prospective, multicenter, 2:1 randomized 
(Lotus Valve System versus a commercially available CoreValve 
Transcatheter Aortic Valve Replacement System), controlled trial 
designed to evaluate the safety and effectiveness of the Lotus 
Valve System for TAVR in symptomatic subjects who have 
calcific, severe native aortic stenosis and who are at high or 
extreme risk for surgical aortic valve replacement (SAVR).   
There will be a non-randomized roll-in phase… Roll-in subjects 
will not be included in the endpoint analyses. 
The REPRISE III study will… 
REPRISE III is designed to evaluate the safety and effectiveness 
of the Lotus Valve System for TAVR in symptomatic subjects 
who have calcific, severe native aortic stenosis and who are at 
high or extreme risk for surgical aortic valve replacement 
(SAVR). Study cohorts include the following. 
– A prospective, multicenter, 2:1 randomized (Lotus Valve 
System [23 mm, 25 mm, and 27 mm valve sizes] versus a 
commercially available CoreValve Transcatheter Aortic Valve 
Replacement System [26 mm, 29 mm, and 31 mm valve sizes]), 
controlled trial 
- A non-randomized roll-in phase with only the test device 
(23 mm, 25 mm, and 27 mm valve sizes) for centers… 
randomized population. 
– A non-randomized, nested registry cohort of subjects who will 
receive the 21 mm Lotus Valve (Lotus 21 mm Nested Registry). 
Participating centers will be centers that have enrolled subjects in 
REPRISE III. 
The REPRISE III study will… 
Updated to include 
the 21mm Nested 
Registry 
2. Protocol 
Synopsis – 
Planned 
Subjects/… 
Subjects will be enrolled at up to 60 centers in the United States, 
Canada, Western Europe, and Australia. There will be up to 1032 
subjects in REPRISE III…   and randomized. 
Subjects will be enrolled at up to 60 centers in the United States, 
Canada, Western Europe, and Australia. There will be up to 1052 
subjects in REPRISE III…   and randomized. Up to 20 subjects 
will be enrolled in the Lotus 21 mm Nested Registry.   
2. Protocol 
Synopsis – 
Primary 
Primary Safety Endpoint: … at 30 days. 
Primary Effectiveness Endpoint:… at 1 year 
Primary Safety Endpoint: … at 30 days. 
Primary Effectiveness Endpoint:… at 1 year 
Powered statistical analyses for the primary safety endpoint and 
Updated for clarity 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 154 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 155 of 188 
 
 
 
Table 27.1-5: Table of Changes for REPRISE III Protocol Version AF (Compared to REPRISE III Protocol Version AE) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AE 
Text as Written in  
REPRISE III Protocol Version AF 
Justification for 
Modification 
Endpoints 
the primary effectiveness endpoint will be carried out on the 
randomized cohort. 
2. Protocol 
Synopsis – 
Secondary 
Endpoint 
Moderate or greater paravalvular aortic regurgitation (based on 
core lab assessment) at 1 year 
Moderate or greater paravalvular aortic regurgitation (based on 
core lab assessment) at 1 year 
Powered statistical analysis for the secondary endpoint will be 
carried out on the randomized cohort. 
2. Protocol 
Synopsis – 
Inclusion… 
IC2.  Subject… and is deemed treatable with an available size of 
both test and control device. 
IC2.  Subject… and, for the randomized cohort, is deemed 
treatable with an available size of both test and control device. 
2. Protocol 
Synopsis – 
Analysis Sets 
As-Treated: This population… 
For all analysis sets… first valve received. 
Analysis sets for the randomized cohort are listed below. 
   As-Treated: This population… 
For all randomized cohort analysis sets… first valve received. 
Among the roll-in and the Lotus 21 mm Nested Registry cohorts, 
for ITT analyses all subjects who sign an Informed Consent Form 
and are enrolled in the study will be included in the analysis 
sample, regardless of whether the study device was implanted. 
The As-Treated population is the same as the Implanted 
population for these two cohorts and includes all subjects who 
sign an Informed Consent Form and are implanted with the Lotus 
valve. 
Updated for clarity 
and to include the 
Lotus 21 mm Nested 
Registry cohort. 
4.0 Introduction 
Additional device information can be found in found in Section 
5.  
Additional device information can be found in Section 5. Study 
subjects will be entered into the roll-in cohort, randomized (test 
versus control) cohort, or a single-arm, non-randomized, nested 
registry cohort of subjects who receive the 21 mm Lotus Valve 
(Lotus 21 mm Nested Registry). Additional information on study 
design can be found in Section 8. 
Updated for clarity 
4.1.2 REPRISE 
I Study 
To date, data are available through 2 years… There were no 
additional MACCE events beyond the primary endpoint. The 2-
year… was 3/11… resolved… While… baseline and 2 years… 
The mean… at 2 years. Paravalvular… at 2 years… 
To date, data are available through 3 years… There were no 
additional MACCE events beyond the primary endpoint through 
2 years and 1 noncardiovascular death in the interval between 2 
and 3 years. The 3-year… was 4/11… resolved, and there was 1 
noncardiovascular death due to uncontrolled sepsis. … While… 
baseline and 2 years… and baseline and 3 years (5 in Class I, 1 in 
Class II, 2 in Class III; P=0.004). The mean… at 2 years, and 
15.6±4.4 mmHg at 3 years. Paravalvular… at 2 years and absent 
Updated REPRISE I 
data to 3 years 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 155 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 156 of 188 
 
 
 
Table 27.1-5: Table of Changes for REPRISE III Protocol Version AF (Compared to REPRISE III Protocol Version AE) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AE 
Text as Written in  
REPRISE III Protocol Version AF 
Justification for 
Modification 
(7/8) or mild (1/8) at 3 years… 
4.1.3 REPRISE 
II Study 
The 30 day mean aortic valve pressure gradient was… 
Table 4.1-3 shows 6-month and 1-year clinical… 
At 1 year, mortality was 11.0% and the disabling stroke rate was 
3.5%. The low paravalvular aortic regurgitation rate observed at 
30 days was maintained at 1 year as most subjects (86%) had 
none/trivial paravalvular aortic regurgitation; there was no severe 
paravalvular regurgitation.. 
 
Table 4.1-3 with 6-month and 1-year data for the REPRISE II 
main cohort (N=120). 
 
The REPRISE II study was subsequently expanded… plus a 
testing margin of 6.2%). 
 
Table 4.1 4 shows device performance endpoints, clinical 
outcomes, and echocardiographic outcomes through 30 days for 
the full cohort (N=250). Outcomes in the full cohort …several 
longitudinal registries. 
 
 
Table 4.1-4 with 30-day data for the REPRISE II full cohort 
(N=250). 
The 30 day mean aortic valve pressure gradient was… 
Table 4.1-3 shows 1-year and 2-year clinical… 
At 2 years, mortality was 17% and the disabling stroke rate was 
3.5%. The low paravalvular aortic regurgitation rate observed at 
30 days was maintained at 2 years as most subjects (91%) had 
none/trivial paravalvular aortic regurgitation and there was no 
moderate or severe paravalvular regurgitation… 
 
Table 4.1-3 updated to show 1-year and 2-year data for the 
REPRISE II main cohort (N=120). 
 
The REPRISE II study was subsequently expanded… plus a 
testing 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 met… 
 
Table 4.1 4 shows device performance endpoints, clinical 
outcomes, and echocardiographic outcomes through 30 days and 
1 year for the full cohort (N=250. Outcomes at 30 days in the full 
cohort… several longitudinal registries. 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 low paravalvular aortic regurgitation rate 
observed at 30 days was maintained at 1 year as most subjects 
(91%) had none/trivial paravalvular aortic regurgitation and there 
was no moderate or severe paravalvular regurgitation. 
 
Table 4.1-4 updated to include 1-year data for the REPRISE II 
full cohort (N=250). 
Updated REPRISE II 
main cohort data to 
2 years and REPRISE 
II full cohort data to 
1 year 
5. Device 
Description 
… Every subject must be deemed… 
… Every subject in the randomized cohort must be deemed… 
Updated for clarity 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 156 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 157 of 188 
 
 
 
Table 27.1-5: Table of Changes for REPRISE III Protocol Version AF (Compared to REPRISE III Protocol Version AE) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AE 
Text as Written in  
REPRISE III Protocol Version AF 
Justification for 
Modification 
5.1 Lotus Valve 
System… 
… Device sizes include 21 mm, 23 mm, 25 mm, and 27 mm 
diameter. More detailed… 
… Device sizes used in the randomized cohort include 23 mm, 
25 mm, and 27 mm diameter. Devices in the Lotus 21 mm 
Nested Registry cohort are 21 mm in diameter. More detailed… 
Updated to include 
the Lotus 21 mm 
Nested Registry 
5.2 CoreValve 
Transcatheter… 
Devices sizes include the CoreValve® Evolut™ 23 mm diameter 
and the CoreValve 26 mm… 
Note 1: Every subject must be deemed treatable… 
Devices sizes include the CoreValve 26 mm… 
Note 1: Every subject in the randomized cohort must be deemed 
treatable… 
Updated for clarity; 
no CoreValve 23 mm 
device is used. 
5.3.2 Control 
Device 
Information… available CoreValve® and CoreValve® Evolut™ 
23 mm diameter or… 
Information… available CoreValve® or… 
7. Endpoints 
Outcomes will be assessed…  The ITT analysis population 
includes…first valve received. Endpoint definitions… 
Outcomes will be assessed…  The ITT analysis population of the 
randomized cohort includes …first valve received. Among the 
roll-in and Lotus 21 mm Nested Registry cohorts, for ITT 
analyses, all subjects who sign the IRB/IEC-approved study ICF 
and are enrolled in the trial will be included in the analysis 
sample, regardless of whether the study device was implanted. 
For these two cohorts, the as-treated population includes all 
subjects implanted with the Lotus valve. Endpoint definitions… 
Clarify analysis 
populations for roll-
in, randomized, and 
Lotus 21 mm Nested 
Registry cohorts.  
8.1 Scale and 
Duration 
The REPRISE III clinical study includes a prospective, 
multicenter, randomized controlled trial … previous experience 
implanting the Lotus Valve.   
The REPRISE III clinical study includes a prospective, 
multicenter, randomized controlled trial … previous experience 
implanting the Lotus Valve. There will also be a single-arm, non-
randomized nested registry cohort of subjects who receive the 21 
mm Lotus Valve to assess safety and effectiveness (Lotus 21 mm 
Nested Registry); participating centers will be centers that have 
enrolled subjects in REPRISE III. 
Clarification of 
overall study design. 
8.2 Treatment 
Assignment 
Eligible subjects will be randomized… 
 
Note: There will be… numbers. 
For the randomized cohort, eligible subjects will be 
randomized… 
Note: There will be… numbers. Subjects receiving the 21 mm 
Lotus Valve will be enrolled in a non-randomized, nested registry 
cohort to assess safety and effectiveness. 
8.3 Study 
Design 
Justification 
There will be up to 1032 subjects in REPRISE III. In order to 
support… 912 subjects will be randomized and enrolled. Up to 
60… 
There will be up to 1052 subjects in REPRISE III. In order to 
support… 912 subjects will be randomized and enrolled, and up 
to 20 subjects will be enrolled in the Lotus 21 mm Nested 
Registry. Up to 60… 
9.2 Inclusion 
Criteria 
IC2.  Subject… and is deemed… 
IC2.  Subject … and, for the randomized cohort, is deemed… 
Updated for clarity 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 157 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 158 of 188 
 
 
 
Table 27.1-5: Table of Changes for REPRISE III Protocol Version AF (Compared to REPRISE III Protocol Version AE) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AE 
Text as Written in  
REPRISE III Protocol Version AF 
Justification for 
Modification 
10.1.3 Lotus 
21 mm Nested 
Registry 
Subjects 
— 
For the Lotus 21 mm Nested Registry cohort, subjects confirmed 
eligible for the study by the CRC (see Section 22.2) and who 
provided written informed consent are considered enrolled in the 
study as soon as an attempt is made to insert the Lotus Valve 
System into the subject’s femoral artery. 
New section added to 
clarify point of 
enrollment for the 
Lotus 21 mm Nested 
Registry cohort. 
11.1 Data 
Collection 
Figure 11.1-1 REPRISE III Study Design  
 Updated Figure 11.1-1 REPRISE III Study Design to include the 
21 mm Nested Registry 
 
Clarify that there will 
be up to 20 additional 
subjects enrolled in 
the study.  
11.4 Screening 
Assessments 
The following screening… subject eligibility. Only after CRC 
approval…  
The following screening… subject eligibility. For the 
randomized cohort, only after CRC approval…  
Updated for clarity 
12.1 Endpoints 
Data from roll-in subjects (up to 120 subjects) will be 
summarized separately from the randomized population. Roll-in 
subjects will not be included in the endpoint analyses.  
Testing of endpoints… 
 
12.1.4 Baseline Comparability 
Baseline data will be summarized… and separately for the roll-in 
subjects. … No formal statistical testing will be done for the roll-
in subjects. 
 
12.1.5 Post-procedure Measurements 
… No formal statistical testing will be done for the roll-in 
subjects. 
Data will be summarized separately from subjects in the roll-in 
(up to 120 subjects), randomized, and Lotus 21 mm Nested 
Registry populations. Descriptive statistics will be used to 
summarize the data from subjects in the roll-in and Lotus 21 mm 
Nested Registry and no statistical inference will be made.  
In the randomized cohort, testing of endpoints… 
 
12.1.4 Baseline Comparability 
Baseline data will be summarized… and separately for the roll-in 
subjects and subjects in the Lotus 21 mm Nested Registry. … No 
formal statistical testing will be done for the roll-in or Lotus 
21 mm Nested Registry subjects. 
 
12.1.5 Post-procedure Measurements 
… No formal statistical testing will be done for the roll-in or 
Lotus 21 mm Nested Registry subjects. 
Updated for clarity 
including analyses 
for Lotus 21 mm 
Nested Registry 
cohort. 
 
12.2.1 Analysis 
Sets 
The primary endpoints… and an implanted basis. For ITT 
analyses… first valve received.  
 
The primary safety endpoint… 
The primary endpoints… and an implanted basis. Among the 
randomized cohort, for ITT analyses… first valve received. 
Among the roll-in and Lotus 21 mm Nested Registry cohorts, for 
ITT analyses, all subjects who sign the IRB/IEC-approved study 
ICF and are enrolled in the trial will be included in the analysis 
sample, regardless of whether the study device was implanted. 
For these two cohorts, the As-Treated population includes all 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 158 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 159 of 188 
 
 
 
Table 27.1-5: Table of Changes for REPRISE III Protocol Version AF (Compared to REPRISE III Protocol Version AE) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AE 
Text as Written in  
REPRISE III Protocol Version AF 
Justification for 
Modification 
subjects implanted with the Lotus Valve. The As-Treated and 
Implanted analysis sets are the same for these two cohorts. 
 
For the randomized cohort, the primary safety endpoint… 
12.2.4 Reporting 
Events 
For all roll-in subjects, all events… For all randomized… 
For all subjects in the roll-in and Lotus 21 mm Nested Registry 
cohorts, all events… For all randomized… 
Updated for clarity 
12.3.2 Interim 
Analyses 
… after these 300 patients have completed their 30-day follow-up 
visits. 
… after these 300 subjects have completed their 30-day follow-
up visits. 
An administrative analysis of 30-day data for subjects in the 
Lotus 21 mm Nested Registry will be performed for regulatory 
agency review after these subjects have completed their 30-day 
follow-up visits. 
Clarification of 
interim analyses 
19. Potential 
Risks… 
Risks… review of relevant literature, most recently… and the 
CoreValve High Risk Study. 
Risks… review of relevant literature, most recently… the 
CoreValve High Risk Study66, and the PORTICO IDE 
randomized trial/RESOLVE registry/SAVORY registry. 
Additional literature 
reference 
21.1 Definitions 
and 
Classification 
• If complications… protocol-specified definitions. 
Any AE experienced by the study subject beginning from the 
time of randomization must be recorded in the eCRF. 
• If complications… protocol-specified definitions. 
For the randomized cohort, event reporting (eCRF) is required 
beginning from the time of randomization. 
For the roll-in cohort and the Lotus 21 mm Nested Registry 
cohort, event reporting (eCRF) is required beginning from the 
time an attempt is made to insert the Lotus Valve System into the 
subject’s femoral artery. 
Clarify timing for the 
different cohorts. 
21.2 
Relationship… 
The Investigator must assess the relationship of the AE to the 
study device… 
The Investigator must assess the relationship of the AE/SAE to 
the study device… 
Updated for clarity 
27.1.5 Protocol 
Version AE to 
Version AF 
— 
Table 27.1-5 lists changes between protocol versions AE and AF. 
 
New Table 27.1-5. 
Provide list of 
changes between 
version AE and 
version AF. 
Note: Version AE was a BSC internal update only and was not implemented. 
Abbreviations: BSC=Boston Scientific Corporation; ICF=Informed Consent form; ITT=intent-to-treat; SAE=serious adverse event; TAVR=transcatheter aortic valve replacement 
 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 159 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 160 of 188 
 
 
 
Table 27.1-6: Table of Changes for REPRISE III Protocol Version AG (Compared to REPRISE III Protocol Version AF) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AF 
Text as Written in  
REPRISE III Protocol Version AG 
Justification for 
Modification 
Page 2 
Current Version: 07-Dec-2015 
Current Version: 22-Dec-2015 
Updated Table of Revision History 
Updated for clarity  
2. Protocol 
Synopsis – 
Study Design 
- 
– An additional cohort of subjects who will receive the Lotus 
Valve (23 mm, 25 mm, and 27 mm valve sizes) beginning after 
enrollment of the randomized cohort is completed (U.S. 
Continued Access Study cohort). This cohort will be used to 
further assess performance and safety. Participating centers will 
be United States centers that have enrolled subjects in REPRISE 
III. 
Updated to include 
the U.S. Continued 
Access study 
2. Protocol 
Synopsis – 
Planned 
Subjects/… 
Subjects will be enrolled at up to 60 centers in the United States, 
Canada, Western Europe, and Australia. There will be up to 1032 
subjects in REPRISE III…   Nested Registry. 
Subjects will be enrolled at up to 60 centers in the United States, 
Canada, Western Europe, and Australia. There will be up to 2052 
subjects in REPRISE III…  Nested Registry. After enrollment in 
the randomized cohort is completed, up to 1000 subjects will be 
enrolled in the U.S. Continued Access Study cohort to receive the 
Lotus Valve (23 mm, 25 mm, and 27 mm valve sizes); 
participating centers will be United States centers that have 
enrolled subjects in REPRISE III.    
2. Protocol 
Synopsis – 
Inclusion… 
IC2.  Subject… control device. 
IC2.  Subject… control device. For the U.S. Continued Access 
Study cohort the acceptable aortic annulus size is ≥20 mm and 
≤27 mm. 
Updated for clarity, 
the U.S. Continued 
Access study 
2. Protocol 
Synopsis – 
Analysis Sets 
Among the roll-in and the Lotus 21 mm Nested Registry cohorts, 
for ITT analyses… 
Among the roll-in, Lotus 21 mm Nested Registry, and U.S. 
Continued Access Study cohorts, for ITT analyses… 
Updated to include 
the U.S. Continued 
Access study cohort 
4.0 Introduction 
…Valve (Lotus 21 mm Nested Registry). Additional… 
…Valve (Lotus 21 mm Nested Registry), or the U.S. Continued 
Access Study cohort. Additional… 
5.2 CoreValve 
Transcatheter… 
Devices sizes include the CoreValve® Evolut™ 23 mm diameter 
and the CoreValve 26 mm… 
Note 1: Every subject must be deemed treatable… 
Devices sizes include the CoreValve 26 mm… 
Note 1: Every subject in the randomized cohort must be deemed 
treatable… 
Updated for clarity; 
no CoreValve 23 mm 
device is used. 
5.3.2 Control 
Device 
Information… available CoreValve® and CoreValve® Evolut™ 
23 mm diameter or… 
Information… available CoreValve® or… 
7. Endpoints 
Outcomes will be assessed…  The ITT analysis population 
includes…first valve received. Endpoint definitions… 
Outcomes will be assessed…  The ITT analysis population of the 
randomized cohort includes …first valve received. Among the 
roll-in and Lotus 21 mm Nested Registry cohorts, for ITT 
analyses, all subjects who sign the IRB/IEC-approved study ICF 
Clarify analysis 
populations for roll-
in, randomized, and 
Lotus 21 mm Nested 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 160 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 161 of 188 
 
 
 
Table 27.1-6: Table of Changes for REPRISE III Protocol Version AG (Compared to REPRISE III Protocol Version AF) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AF 
Text as Written in  
REPRISE III Protocol Version AG 
Justification for 
Modification 
and are enrolled in the trial will be included in the analysis 
sample, regardless of whether the study device was implanted. 
For these two cohorts, the as-treated population includes all 
subjects implanted with the Lotus valve. Endpoint definitions… 
Registry cohorts.  
8.1 Scale and 
Duration 
… that have enrolled subjects in REPRISE III.  
… that have enrolled subjects in REPRISE III. After enrollment 
of the randomized cohort is completed, an additional 
cohort of subjects will be enrolled in a U.S. Continued 
Access Study cohort with the Lotus Valve (23 mm, 
25 mm, and 27 mm valve sizes) to further assess 
performance and safety. 
Updated to include 
the U.S. Continued 
Access study cohort 
8.2 Treatment 
Assignment 
Note: There will be… to assess safety and effectiveness. 
Note: There will be… to assess safety and effectiveness. After 
enrollment of the randomized cohort is completed, subjects will 
be enrolled in a U.S. Continued Access Study cohort with the 
Lotus Valve (23 mm, 25 mm, and 27 mm valve sizes) to further 
assess performance and safety. 
8.3 Study 
Design 
Justification 
There will be up to 1052 subjects in REPRISE III… Nested 
Registry. Up to 60… in the study. Safety… 
There will be up to 2052 subjects in REPRISE III… Nested 
Registry, and up to 1000 subjects will be enrolled in the U.S. 
Continued Access Study cohort. Up to 60… in the study. Centers 
in the United States that enrolled subjects in the randomized 
cohort will be eligible to enroll subjects in the U.S. Continued 
Access Study cohort. Safety… 
9.2 Inclusion 
Criteria 
IC2.  Subject… control device. 
IC2.  Subject … control device. For the U.S. Continued 
Access Study cohort the acceptable aortic annulus size is 
≥20 mm and ≤27 mm. 
U.S. Continued 
Access Study 
includes only 23mm, 
25mm, and 27mm 
Lotus Valve sizes. 
10.1.4 U.S. 
Continued 
Access Subjects 
— 
For the U.S. Continued Access Study cohort, subjects confirmed 
eligible for the study by the CRC (see Section 22.2) and who 
provided written informed consent are considered enrolled in the 
study as soon as an attempt is made to insert the Lotus Valve 
System into the subject’s femoral artery. 
New section added to 
clarify point of 
enrollment for the 
U.S. Continued 
Access Study cohort. 
11.1 Data 
Collection 
Figure 11.1-1 REPRISE III Study Design  
Updated Figure 11.1-1 REPRISE III Study Design to include the 
U.S. Continued Access Study. 
 
Clarify that there will 
be up to 1000 
additional subjects 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 161 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 162 of 188 
 
 
 
Table 27.1-6: Table of Changes for REPRISE III Protocol Version AG (Compared to REPRISE III Protocol Version AF) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AF 
Text as Written in  
REPRISE III Protocol Version AG 
Justification for 
Modification 
enrolled in the study.  
12.1 Endpoints 
Data will be summarized separately… Nested Registry 
populations. Descriptive statistics will be used to summarize the 
data from subjects in the roll-in and Lotus 21 mm Nested 
Registry and no statistical inference will be made.  
 
12.1.4 Baseline Comparability 
Baseline data will be summarized… and separately for the roll-in 
subjects and subjects in the Lotus 21 mm Nested Registry. … No 
formal statistical testing will be done for the roll-in or Lotus 
21 mm Nested Registry subjects. 
 
12.1.5 Post-procedure Measurements 
… No formal statistical testing will be done for the roll-in or 
Lotus 21 mm Nested Registry subjects. 
Data will be summarized separately… Nested Registry, and U.S. 
Continued Access Study populations. Descriptive statistics will 
be used to summarize the data from subjects in the roll-in, Lotus 
21 mm Nested Registry, and U.S. Continued Access Study 
cohorts and no statistical inference will be made.  
 
12.1.4 Baseline Comparability 
Baseline data will be summarized… and separately for subjects 
in the roll-in, Lotus 21 mm Nested Registry, and U.S. Continued 
Access Study cohorts. … No formal statistical testing will be 
done for the roll-in, Lotus 21 mm Nested Registry, or U.S. 
Continued Access Study subjects. 
 
12.1.5 Post-procedure Measurements 
… No formal statistical testing will be done for the roll-in, Lotus 
21 mm Nested Registry, or U.S. Continued Access Study 
subjects. 
Updated for clarity 
including analyses 
for U.S. Continued 
Access Study cohort. 
 
12.1.7 Subgroup 
Analyses for 
U.S. Continued 
Access Study 
Subjects 
— 
Primary and pre-specified additional endpoints will be 
summarized and treatment groups will be compared for the 
following subgroups of U.S. Continued Access Study subjects.  
• Gender (male and female) 
• Extreme risk and high risk (see Table 26.2 1 for definitions of 
extreme and high operative risk) 
No adjustments for multiple comparisons will be made. 
Additional analyses may be performed as appropriate. 
12.2.1 Analysis 
Sets 
Among the roll-in and Lotus 21 mm Nested Registry cohorts, for 
ITT analyses… For these two cohorts, the As-Treated… same for 
these two cohorts. 
Among the roll-in, Lotus 21 mm Nested Registry, and U.S. 
Continued Access Study cohorts, for ITT analyses… For these 3 
cohorts, the As-Treated… same for these 3 cohorts. 
12.2.4 Reporting 
Events 
For all subjects in the roll-in and Lotus 21 mm Nested Registry 
cohorts, all events… 
For all subjects in the roll-in, Lotus 21 mm Nested Registry, and 
U.S. Continued Access Study cohorts, all events…  
21.1 Definitions 
and 
For the roll-in cohort and the Lotus 21 mm Nested Registry 
cohort, event reporting… 
For the roll-in, Lotus 21 mm Nested Registry, and U.S. 
Continued Access Study cohorts, event reporting… 
Updated to include 
the U.S. Continued 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 162 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 163 of 188 
 
 
 
Table 27.1-6: Table of Changes for REPRISE III Protocol Version AG (Compared to REPRISE III Protocol Version AF) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AF 
Text as Written in  
REPRISE III Protocol Version AG 
Justification for 
Modification 
Classification 
Access Study 
22.1.2 Data 
Monitoring 
Committee 
The DMC is responsible for the oversight review of all AEs. The 
DMC will… 
The DMC is responsible for the oversight review of all AEs and 
all SAEs in the roll-in, randomized, and Lotus 21 mm Nested 
Registry cohorts. The DMC will… 
Updated for clarity 
24. Publication 
Policy 
In accordance with the Corporate Policy for the Conduct of 
Human Subject Research, BSC requires disclosure of its 
involvement as a sponsor or financial supporter in any 
publication or presentation relating to a BSC study or its results. 
In accordance with the Corporate Policy for the Conduct of 
Human Subject Research, BSC will submit… 
In accordance with the Global SOP – Human Subject Data and 
Research Controls, BSC requires disclosure of its involvement as 
a sponsor or financial supporter in any publication or presentation 
relating to a BSC study or its results. In accordance with the 
Global SOP – Human Subject Data and Research Controls, BSC 
will submit… 
Global SOP replaced 
Corporate Policy  
27.1.6 Protocol 
Version AF to 
Version AG 
— 
Table 27.1-6 lists changes between protocol versions AF and AG. 
 
New Table 27.1-6. 
Provide list of 
changes between 
version AF and 
version AG. 
Abbreviations: BSC=Boston Scientific Corporation; DMC=Data Monitoring Committee; ITT=intent-to-treat; SAE=serious adverse event; SOP=Standard Operating Procedure. 
 
Table 27.1-7: Table of Changes for REPRISE III Protocol Version AH (Compared to REPRISE III Protocol Version AG) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AG 
Text as Written in  
REPRISE III Protocol Version AH 
Justification for 
Modification 
Page 2 
Current Version: 22-Dec-2015 
Current Version: 03-May -2016 
Updated Table of Revision History 
Updated to include 
the CT Imaging 
substudy of the U.S. 
Continued Access 
study 
2. Protocol 
Synopsis – 
Study Design 
-An additional... in REPRISE III. 
-An additional... in REPRISE III. Selected centers with the 
ability to perform high quality 4D computed tomography (CT) 
scans will include U.S. Continued Access Study subjects in a CT 
Imaging Substudy to assess the prevalence of reduced leaflet 
mobility and its relationship, if any, to clinical events.   
2. Protocol 
Synopsis – 
Planned 
Subjects/… 
Subjects… in REPRISE III. 
Subjects… in REPRISE III.  Up to 200 of the 1000 subjects 
enrolled in the U.S. Continued Access Study will be included in a 
CT Imaging Substudy. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 163 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 164 of 188 
 
 
 
Table 27.1-7: Table of Changes for REPRISE III Protocol Version AH (Compared to REPRISE III Protocol Version AG) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AG 
Text as Written in  
REPRISE III Protocol Version AH 
Justification for 
Modification 
2. Protocol 
Synopsis – 
Additional 
Measurements 
… and 5 years. 
… and 5 years. 
Additionally, assessment of leaflet mobility using 4D CT will be 
carried out at 30 days and 1 year for subjects in the CT Imaging 
Substudy of the U.S. Continued Access Study. The data will be 
evaluated by an independent CT core lab. 
2. Protocol 
Synopsis – 
Exclusion 
Criteria 
– 
Additional exclusion criteria apply for subjects considered for 
enrollment in the CT Imaging substudy of the U.S. Continued 
Access Study 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 TAVR 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. 
4. Introduction 
…or the U.S. Continued Access Study cohort. 
…or the U.S. Continued Access Study cohort (which will include 
a 4D computed tomography [CT] substudy cohort). 
4.1.1  
Treatments for 
Aortic Stenosis 
…higher rate of survival at 1 year compared to SAVR. 
 
A recently published expert consensus...    
…higher rate of survival at 1 year compared to SAVR. 
Recently, reduced aortic valve leaflet motion, mainly 
asymptomatic, has been identified with follow-up CT among 
some TAVR subjects. 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. 
 
A recently published expert consensus … 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 164 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 165 of 188 
 
 
 
Table 27.1-7: Table of Changes for REPRISE III Protocol Version AH (Compared to REPRISE III Protocol Version AG) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AG 
Text as Written in  
REPRISE III Protocol Version AH 
Justification for 
Modification 
7.2 Additional 
Measurements 
• Resource utilization associated with the procedure and/or 
follow-up 
 
 
 
• Resource utilization associated with the procedure and/or 
follow-up 
 
Additionally, assessment of leaflet thickening and mobility using 
4D CT will be carried out at 30 days and 1 year post index 
procedure for subjects in the CT Imaging Substudy of the U.S. 
Continued Access Study. The CT scans will be evaluated by an 
independent CT Core Laboratory and should be blinded to local 
investigators for cardiac valve findings (local reading should be 
only for non-cardiac valve findings such as unexpected lung 
pathology; see Section 11.10.1 for additional information). 
8.1 Scale and 
Duration 
… a U.S. Continued Access Study cohort … to further assess 
performance and safety. 
 
All subjects implanted... Enrolled… 
… a U.S. Continued Access Study cohort … to further assess 
performance and safety. Selected centers with the ability to 
perform high quality 4D CT scans will include U.S. Continued 
Access Study subjects in a CT Imaging Substudy to assess the 
prevalence of reduced leaflet mobility and its relationship, if any, 
to clinical events. Centers participating in the CT Imaging 
Substudy should ask all subjects eligible for enrollment in the 
U.S. Continued Access Study to consider participation in the 
substudy. Enrollment in the substudy will end after 
approximately 200 consecutive subjects who provide consent for 
participation are enrolled. 
 
All subjects implanted... Implanted subjects participating in the 
CT Imaging Substudy will undergo additional 4D CT assessment 
at 30 days and 1 year.  Enrolled… 
8.3 Study 
Design 
Justification 
There will be up to 2052 subjects in REPRISE III… Centers in 
the United States that enrolled subjects in the randomized cohort 
will be eligible to enroll subjects in the U.S. Continued Access 
Study cohort… safety reporting). In addition to… medications. 
There will be up to 2052 subjects in REPRISE III… Centers in 
the United States that enrolled subjects in the randomized cohort 
will be eligible to enroll subjects in the U.S. Continued Access 
Study cohort… safety reporting). Selected centers with the ability 
to perform high quality 4D CT scans will include approximately 
200 U.S. Continued Access Study subjects in a CT Imaging 
Substudy to assess the prevalence of reduced leaflet mobility and 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 165 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 166 of 188 
 
 
 
Table 27.1-7: Table of Changes for REPRISE III Protocol Version AH (Compared to REPRISE III Protocol Version AG) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AG 
Text as Written in  
REPRISE III Protocol Version AH 
Justification for 
Modification 
its relationship, if any, to clinical events. In addition 
to…medications. 
9.2 Inclusion 
Criteria 
…provided no exclusion criterion (Table 9.3-1) is met. 
…provided no exclusion criterion (Table 9.3-1) is met. Centers 
participating in the 4D CT substudy of the U.S. Continued 
Access Study must have the ability to perform high quality 4D 
CT scans; subjects in this substudy must meet none of the 
additional exclusion criteria listed in Table 9.3-2. 
9.3 Exclusion 
Criteria 
- 
Additional exclusion criteria apply for subjects considered for 
enrollment in the CT Imaging substudy of the U.S. Continued 
Access Study as shown in Table 9.3 2. 
Added Table 9.3-2 
11.1 Data 
Collection 
Figure 11.1-1 REPRISE III Study Design  
Updated Figure 11.1-1 REPRISE III Study Design to include the 
4D CT assessment at 30 days and 1 year for the CT Imaging 
substudy 
Table 11.1-1 Study Event Schedule 
Updated Table 11.1-1 Study Event Schedule to include a row for 
the 4D CT assessment at 30 days and 1 year for the CT Imaging 
substudy 
Footnote u: This applies to subjects in the CT Imaging Substudy 
of the U.S. Continued Access Study. Please refer to the CT 
Core Laboratory procedure guidelines (see study Manual of 
Operations). Results must be sent to the CT Core Laboratory 
(Section 13.3.2). 
11.10.1 30-Day 
Follow-up 
 
 
• For subjects… pacemaker dependency. 
 
• For subjects… pacemaker dependency. 
• For subjects enrolled in the CT Imaging Substudy of the U.S. 
Continued Access Study, assessment of prosthetic valve leaflet 
mobility using 4D CT must be performed per the 4D 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 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 166 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 167 of 188 
 
 
 
Table 27.1-7: Table of Changes for REPRISE III Protocol Version AH (Compared to REPRISE III Protocol Version AG) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AG 
Text as Written in  
REPRISE III Protocol Version AH 
Justification for 
Modification 
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 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. 
11.10.3 12-
Month Follow-
up 
• For subjects… pacemaker dependency. 
 
• For subjects… pacemaker dependency. 
• For subjects enrolled in the CT Imaging Substudy of the U.S. 
Continued Access Study, assessment of prosthetic valve leaflet 
mobility using 4D CT must be performed per the 4D 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 
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. 
13.3.2 CT and 
Rotational X-
Ray… 
An independent Core Laboratory… of Operations. 
An independent Core Laboratory… of Operations. Data from 
subjects in the 4D CT Imaging Substudy will also be evaluated by 
an independent CT Core Laboratory; procedure guidelines for 4D 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 167 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 168 of 188 
 
 
 
Table 27.1-7: Table of Changes for REPRISE III Protocol Version AH (Compared to REPRISE III Protocol Version AG) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AG 
Text as Written in  
REPRISE III Protocol Version AH 
Justification for 
Modification 
CT scanning are provided by the core laboratory in the Manual of 
Operations 
26.1 
Abbreviations 
Table 26.1-1 
Added abbreviation “eGFR” (estimated glomerular filtration rate) 
27.1.7 Protocol 
Version AG to 
Version AH 
— 
Table 27.1-7 lists changes between protocol versions AG and 
AH. 
 
New Table 27.1-7. 
Abbreviations: BSC=Boston Scientific Corporation; DMC=Data Monitoring Committee; ITT=intent-to-treat; SAE=serious adverse event; SOP=Standard Operating Procedure. 
 
Table 27.1-8: Table of Changes for REPRISE III Protocol Version AI  (Compared to REPRISE III Protocol Version AH) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AH 
Text as Written in  
REPRISE III Protocol Version AI  
Justification for 
Modification 
Page 2 
Current Version: 05-May-2016 
Current Version: 19-Jan-2017 
Updated Table of Revision History 
Updated to include 
the 29 mm LOTUS 
Edge Nested Registry 
2. Protocol 
Synopsis, 
Objective  
To evaluate the safety and effectiveness of the Lotus™ Valve 
System for transcatheter… 
To evaluate the safety and effectiveness of the Lotus™ Valve 
System and LOTUS Edge™ Valve System for transcatheter… 
2. Protocol 
Synopsis, 
Intended Use 
The Lotus Valve System is intended… 
The Lotus Valve System and LOTUS Edge Valve System are 
intended… 
2. Protocol 
Synopsis, Test 
Devices and… 
The Lotus Valve System consisting of two main components: 
 
- a bioprosthetic bovine pericardial aortic valve, and 
 
- a delivery system. 
Devices sizes include 21 mm, 23 mm, 25 mm, and 27 mm 
diameter. 
 
The Lotus Valve System and LOTUS Edge Valve System 
consisting of two main components: 
 
- a bioprosthetic bovine pericardial aortic valve, and 
 
- a delivery system. 
Devices sizes for the Lotus Valve System include 21 mm, 
23 mm, 25 mm, and 27 mm diameter. 
Device size for the LOTUS Edge Valve System is 29 mm 
diameter. 
Note: LOTUS Edge is a design iteration of the Lotus Valve 
System. In addition to the design features of the Lotus Valve 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 168 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 169 of 188 
 
 
 
Table 27.1-8: Table of Changes for REPRISE III Protocol Version AI  (Compared to REPRISE III Protocol Version AH) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AH 
Text as Written in  
REPRISE III Protocol Version AI  
Justification for 
Modification 
System, it has tantalum (radiopaque) markers on the valve 
locking assembly (i.e., buckle and post-top components) to aid in 
visualization of locking during the procedure and a catheter 
delivery system designed for improved deliverability. Changes 
between the Lotus Valve System and the LOTUS Edge Valve 
System including the 29 mm valve size are fully described in the 
Investigator Brochure. 
2. Protocol 
Synopsis, Study 
Design 
REPRISE III is designed to evaluate the safety and effectiveness 
of the Lotus Valve System for TAVR… 
 
…Substudy to assess the prevalence of reduced leaflet mobility 
and its relationship, if any, to clinical events.  
 
REPRISE III is designed to evaluate the safety and effectiveness 
of the Lotus Valve System and LOTUS Edge™ Valve System for 
TAVR… 
 
…Substudy to assess the prevalence of reduced leaflet mobility 
and its relationship, if any, to clinical events.  
-  A non-randomized, nested registry cohort of subjects who will 
receive the 29 mm LOTUS Edge Valve (LOTUS Edge 29 mm 
Nested Registry). Participating centers will be centers that have 
enrolled subjects in REPRISE III with the Lotus Valve System. 
For centers that do not have prior experience implanting the 
LOTUS Edge, each will perform at least 2 roll-in cases with the 
29 mm LOTUS Edge Valve System before commencing 
enrollment in the evaluable registry cohort. Data from the 29 
mm roll-in subjects will be summarized separately from the 
evaluable cohort. 
2. Protocol 
Synopsis, 
Planned 
Subjects… 
There will be up to 2052 subjects in REPRISE III. 
 
…included in a CT Imaging Substudy. 
There will be up to 2092 subjects in REPRISE III. 
 
…included in a CT Imaging Substudy.  
- Up to 20 subjects will be enrolled in the LOTUS Edge 29 mm 
Nested Registry. Among centers that do not have prior 
experience implanting the LOTUS Edge Valve, up to 20 subjects 
will be enrolled in the LOTUS Edge 29 mm Valve roll-in phase 
(29 mm valve only; a minimum of 2 roll-in subjects per center) 
before enrolling in the LOTUS Edge 29 mm Nested Registry. 
2. Protocol 
Synopsis, 
Inclusion… 
IC 2. Subject has a documented aortic annulus size of ≥18 mm 
and ≤27 mm based 
IC 2. Subject has a documented aortic annulus size of ≥18 mm 
and ≤29 mm based 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 169 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 170 of 188 
 
 
 
Table 27.1-8: Table of Changes for REPRISE III Protocol Version AI  (Compared to REPRISE III Protocol Version AH) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AH 
Text as Written in  
REPRISE III Protocol Version AI  
Justification for 
Modification 
2. Protocol 
Synopsis, 
Analysis Sets… 
Among the roll-in, Lotus 21 mm Nested Registry, and… 
Among the roll-in (initial cohort with the 23 mm, 25 mm, and 
27 mm Lotus), Lotus 21 mm Nested Registry, roll-in with the 
29 mm LOTUS Edge, LOTUS Edge 29 mm Nested Registry, 
and… 
4. Introduction 
…evaluation of the Lotus™ Valve System, a transfemoral aortic 
valve replacement device designed and manufactured by Boston 
Scientific Structural Heart a Division of Boston Scientific 
Corporation (BSC). The Lotus Valve System consists of a pre-
loaded… paravalvular leakage. … study subjects… cohort). 
Additional… 
 
…evaluation of the Lotus™ Valve System and LOTUS Edge™ 
Valve System, transfemoral aortic valve replacement devices 
designed and manufactured by Boston Scientific Structural Heart 
a Division of Boston Scientific Corporation (BSC). The Lotus 
Valve System and LOTUS Edge™ Valve System both consist of 
a pre-loaded… paravalvular leakage. Additionally, the LOTUS 
Edge valve has tantalum (radiopaque) markers on the valve 
locking assembly (i.e., buckle and post-top components) to aid in 
visualization of locking during the procedure and a catheter 
delivery system designed for improved deliverability. More 
detailed description of the devices can be found in Section 5 and 
in the Investigator Brochure. With the Lotus Valve System as the 
test device, study subjects… cohort). Additionally, study subjects 
will be entered into a roll-in cohort and a single-arm, nested 
registry cohort of subjects who receive the 29 mm LOTUS Edge 
Valve System (LOTUS Edge 29 mm Nested Registry). 
Additional…  
4.1.1 Treatments 
for Aortic 
Stenosis 
Table 4.1-1 
Table 4.1-1 
The Lotus Valve System is designed to address issues with 
earlier TAVR devices82. Controlled mechanical expansion and 
early leaflet functioning allow for precise positioning. If needed, 
minor repositioning is accomplished through partial valve 
recapture; full recapture facilitates removal of the valve if a 
different size or valve is required. The valve also has a 
polyurethane outer seal (Adaptive™ Seal) designed to minimize 
paravalvular regurgitation (PVR), which has been associated with 
mortality in some studies83.  
The safety and performance of the Lotus Valve System and 
LOTUS Edge Valve System for TAVR in extreme and high 
surgical risk symptomatic subjects with calcific, severe native 
aortic stenosis are under evaluation in the REPRISE clinical 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 170 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 171 of 188 
 
 
 
Table 27.1-8: Table of Changes for REPRISE III Protocol Version AI  (Compared to REPRISE III Protocol Version AH) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AH 
Text as Written in  
REPRISE III Protocol Version AI  
Justification for 
Modification 
program (see Section 4.1.2 through Section 4.1.4). The Lotus 
Valve System is under study in the ongoing REPRISE I 
(ClinicalTrials.gov Identifier NCT01383720), REPRISE II 
(NCT01627691), and REPRISE Japan (NCT02491255) single-
arm trials; the REPRISE III (NCT02202434) randomized 
controlled trial; and the RESPOND (NCT02031302) postmarket 
safety surveillance study. The LOTUS Edge Valve System (23 
mm, 25 mm and 27 mm valve sizes) is currently under study in 
the REPRISE NG DS (NCT02329496) and the REPRISE EDGE 
(NCT02854319) single-arm trials. The REPRISE NG DS study 
recently completed enrollment in Australia, while the REPRISE 
Edge study is currently enrolling in Europe. The REPRISE 
EDGE 29 mm EU study is intended to evaluate performance and 
safety of the 29 mm LOTUS Edge Valve System among centers 
in Europe. 
4.1.3 
REPRISE II 
The low paravalvular aortic regurgitation rate observed at 30 
days was maintained at 1 year as most subjects (91%) had 
none/trivial… 
Table 4.1-4 
Outcomes 
REPRISE II  
(30 Days) 
REPRISE II 
(1 Year) 
   None 
80.2% (142/177) 
83.4% (136/163) 
   Trace/Trivial 
5.6% (10/177) 
8.0% (13/163) 
   Mild 
13.6% (24/177) 
8.6% (14/163) 
The low paravalvular aortic regurgitation rate observed at 30 
days was maintained at 1 year as most subjects (85%) had 
none/trivial… 
Table 4.1-4 
Outcomes 
REPRISE II  
(30 Days) 
REPRISE II 
(1 Year) 
   None 
80.2% (142/177) 
82.2% (134/163) 
   Trace/Trivial 
5.6% (10/177) 
3.1% (5/163) 
   Mild 
13.6% (24/177) 
14.7% (24/163) 
Updated data 
4.1.4  
REPRISE NG  
DS Study 
− 
4.1.4  REPRISE NG DS Study 
The LOTUS Edge Valve System with a modified iteration of the 
delivery system studied in REPRISE I and REPRISE II was 
evaluated in the REpositionable Percutaneous Replacement of 
Stenotic Aortic Valve through Implantation of LotuS ValvE with 
the Next Generation Delivery System (REPRISE NG DS) first-
human-use trial. 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 
New data to support 
inclusion of the 
29 mm LOTUS Edge 
Nested Registry. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 171 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 172 of 188 
 
 
 
Table 27.1-8: Table of Changes for REPRISE III Protocol Version AI  (Compared to REPRISE III Protocol Version AH) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AH 
Text as Written in  
REPRISE III Protocol Version AI  
Justification for 
Modification 
enrolled at the same centers to evaluate acute performance and 
safety of a further optimized version of the LOTUS Edge device 
(including 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. Device sizes evaluated included 
the 23mm, 25mm and 27mm. The primary endpoint of the study 
was technical success, defined as follows: successful vascular 
access, delivery and deployment of the Lotus valve and 
successful retrieval with the LOTUS Edge delivery system; 
correct positioning of the Lotus valve in the proper anatomical 
location; and only one Lotus valve implanted in the proper 
anatomical location. Other measurements incorporated data 
collection and endpoints recommended and defined by the 
VARC 172 and VARC 273 guidelines. Clinical follow-up will 
extend through 1 year. 
The primary endpoint was achieved in 10/10 subjects in Cohort 
A108 and 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). Table 4.1 5 shows core lab analyses of prosthetic 
valve performance as assessed by TTE for the 2 cohorts. In both 
cohorts, mean aortic valve area and mean gradient improved at 
discharge and remained improved at 30 days. There were no 
cases of moderate or severe PVR at discharge or 30 days in either 
cohort. Table 4.1 6 shows rates of CEC-adjudicated VARC-
defined events during the index procedure, through discharge/7 
days, and to 30 days. 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 summary, acute and 30-day 
outcomes in the REPRISE NG DS study demonstrate acceptable 
performance and safety of the LOTUS Edge System.   
Added new Table 4.1-5 and new Table 4.1-6. 
4.2 Justification 
for the Study 
As noted above, the Lotus Valve System potentially provides a 
number… The anticipated risks and benefits associated both with 
the Lotus Valve System and with participation… The conclusion 
of this risk-benefit analysis demonstrates that the known risks 
As noted above, the Lotus Valve System and LOTUS Edge 
Valve System potentially provide a number… The anticipated 
risks and benefits associated both with the Lotus Valve 
System/LOTUS Edge Valve System and with participation… 
Updated to include 
the 29 mm LOTUS 
Edge Nested Registry 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 172 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 173 of 188 
 
 
 
Table 27.1-8: Table of Changes for REPRISE III Protocol Version AI  (Compared to REPRISE III Protocol Version AH) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AH 
Text as Written in  
REPRISE III Protocol Version AI  
Justification for 
Modification 
associated with the procedure, and specifically the use of the 
Lotus Valve System, have been mitigated… out-weigh the risks. 
The conclusion of this risk-benefit analysis demonstrates that the 
known risks associated with the procedure, and specifically the 
use of the Lotus Valve System/LOTUS Edge Valve System, have 
been mitigated… out-weigh the risks. 
No new hazards/harms are introduced by the 29 mm LOTUS 
Edge Valve System compared to the 21 mm, 23 mm, 25 mm and 
27 mm Lotus Valve System when used with the Lotus Introducer 
Set. Since the overall risk profile of the device has not changed, it 
can be concluded that the potential benefits of the use of the 
29 mm LOTUS Edge Valve System with the Lotus Introducer 
Set out-weigh the risks. 
5. Device 
Description 
The study devices… replacement. Every subject… The control 
device in the planned… 
The study devices… replacement. Test devices include the 
Lotus™ Valve System available in valve sizes of 21 mm, 23 mm, 
25 mm, and 27 mm diameter, and the LOTUS Edge™ Valve 
System available in a valve size of 29 mm diameter (Section 5.1). 
Every subject… The control device (Section 5.2) in the 
planned… 
5.1 LOTUS 
Valve System  
Investigational 
Device (Test) 
5.1 LOTUS Valve System  Investigational Device (Test) 
The Lotus Valve System (Figure 5.1-1) has two… 
 
…into the aortic vessel. Device sizes used in the randomized 
cohort include 23 mm, 25 mm, and 27 mm diameter. Devices in 
the Lotus 21 mm Nested Registry cohort are 21 mm in diameter. 
More detailed product information is contained in the 
Investigator Brochure and Instructions For Use (IFU). 
 
 
Figure 5.1 1: Lotus™ Valve System  
5.1.1 Lotus Valve 
The Lotus Valve (Figure 5.1 2) consists of… 
…locking mechanism. 
 
5.1 LOTUS Valve System and LOTUS Edge Valve System 
Investigational Devices (Test) 
The Lotus Valve System and LOTUS Edge Valve System 
(Figure 5.1-1) have two… 
…into the aortic vessel. Lotus Valve System device sizes used in 
the randomized cohort and the U.S. Continued Access Study 
cohort include 23 mm, 25 mm, and 27 mm diameter. Devices in 
the Lotus 21 mm Nested Registry cohort are 21 mm in diameter. 
The LOTUS Edge Valve System is a design iteration of the Lotus 
Valve System. Devices in the LOTUS Edge 29 mm Nested 
Registry cohort are 29 mm in diameter. More detailed product 
information is contained in the Investigator Brochure and 
Instructions For Use (IFU) for both devices. 
Figure 5.1 1: Lotus™ Valve System and LOTUS Edge™ 
Valve System 
5.1.1 Lotus Valve and LOTUS Edge Valve 
The Lotus Valve and LOTUS Edge Valve (Figure 5.1 2) consist 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 173 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 174 of 188 
 
 
 
Table 27.1-8: Table of Changes for REPRISE III Protocol Version AI  (Compared to REPRISE III Protocol Version AH) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AH 
Text as Written in  
REPRISE III Protocol Version AI  
Justification for 
Modification 
 
… The device is designed to produce a final diameter of 21 mm, 
23 mm, 25 mm, or 27 mm (depending on valve size) when the 
valve is locked. In the deployed state, the frame height of the 
21mm valve is approximately 15 mm; the frame height of the 
three larger valve sizes is approximately 19 mm. 
 
 
Figure 5.1 2: Lotus Valve Implant 
 
 
5.1.2 Lotus Delivery System 
The Lotus Delivery System is made of the catheter and the Lotus 
Controller. 
 
 
…inadvertent premature release.  
 
5.1.3 Lotus Introducer Set 
The Lotus Introducer Set will be used as an accessory to the 
Lotus Valve System during the procedure…. for use in subjects 
requiring the 25 mm or 27 mm valve… 
of… 
…locking mechanism. Additionally, the LOTUS Edge Valve has 
radiopaque tantalum markers on the valve locking assembly (i.e., 
buckle and post-top components) to aid in visualization of 
locking under fluoroscopy during the procedure. 
…The Lotus Valve device is designed to produce a final diameter 
of 21 mm, 23 mm, 25 mm, or 27 mm (depending on valve size) 
when the valve is locked. In the deployed state, the frame height 
of the 21mm valve is approximately 15 mm; the frame height of 
the three larger valve sizes is approximately 19 mm. The valve 
component of the 29 mm LOTUS Edge device is scaled from the 
23 mm, 25 mm, and 27 mm valve sizes. Additionally, the 
LOTUS Edge 29 mm valve has a pad sewn between the braid and 
buckle to prevent interaction between the two components during 
sheathing and unsheathing of the valve. The frame height of the 
29 mm valve in the deployed state is 21 mm. 
Figure 5.1 2: Lotus and LOTUS Edge Valve Implant 
5.1.2 Lotus and LOTUS Edge Delivery System 
The Lotus Valve and LOTUS Edge Valve have a Delivery 
System comprised of the catheter and the Lotus Controller. 
…inadvertent premature release.  
Overall, the Delivery System for the LOTUS Edge Valve System 
is similar to that of the Lotus Valve System. Additionally, it has a 
modified leadscrew component, which results in a slightly 
decreased rate of retraction of the outer sheath during valve 
deployment compared to the Lotus Valve System. The multi-
lumen catheter and outer sheath components of LOTUS Edge 
have been modified to enhance deliverability. 
5.1.3 Lotus Introducer Set 
The Lotus Introducer Set will be used as an accessory to the 
Lotus Valve and LOTUS Edge Valve Systems during the 
procedure…. for use in subjects requiring the 25 mm, 27 mm, or 
29 mm valve… 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 174 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 175 of 188 
 
 
 
Table 27.1-8: Table of Changes for REPRISE III Protocol Version AI  (Compared to REPRISE III Protocol Version AH) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AH 
Text as Written in  
REPRISE III Protocol Version AI  
Justification for 
Modification 
5.3.1 Test 
Device 
The study Manual of Operations includes the IFU for the Lotus 
Valve System. Study devices… 
The study Manual of Operations includes the IFU for the Lotus 
Valve System and the IFU for the LOTUS Edge Valve System. 
Study devices… 
6. Objectives 
The objective of the REPRISE III trial is to evaluate the safety 
and effectiveness of the Lotus™ Valve System for 
transcatheter… 
The objective of the REPRISE III trial is to evaluate the safety 
and effectiveness of the Lotus™ Valve System and LOTUS 
Edge™ Valve System (29 mm valve) for transcatheter… 
7. Endpoints 
Among the roll-in, Lotus 21 mm Nested Registry, and U.S. 
Continued Access Study cohorts, for ITT analyses… 
…implanted with the Lotus valve. 
Among the roll-in, (initial cohort with 23 mm, 25 mm, and 27 
mm Lotus Valve System and subsequent cohort with 29 mm 
LOTUS Edge Valve System), Lotus 21 mm Nested Registry, 
LOTUS Edge 29 mm Nested Registry, and U.S. Continued 
Access Study cohorts, for ITT analyses… 
…implanted with the Lotus/LOTUS Edge valve. 
8.1 Scale and 
Duration 
…who provide consent for participation are enrolled.   
…who provide consent for participation are enrolled.  There will 
also be a non-randomized, roll-in phase with the 29 mm LOTUS 
Edge Valve for centers that do not have prior experience 
implanting the LOTUS Edge Valve System, and a nested registry 
cohort of subjects who will receive the 29 mm LOTUS Edge 
Valve System (LOTUS Edge 29 mm Nested Registry). 
Participating centers will be centers that have enrolled subjects in 
REPRISE III with the Lotus Valve System. 
8.2 Treatment 
Assignment 
Note: …to further assess performance and safety.  
Note: …to further assess performance and safety. There will also 
be a non-randomized, roll-in phase with the 29 mm LOTUS Edge 
Valve for centers that do not have previous experience 
implanting the LOTUS Edge Valve System (at least 2 roll-in 
cases/center), and a nested registry cohort of subjects who will 
receive the 29 mm LOTUS Edge Valve System (LOTUS Edge 
29 mm Nested Registry). 
8.2.1 Treatment 
The test device is the Lotus Valve System, which consists of a… 
The test device is the Lotus Valve System or the LOTUS Edge 
Valve System, both of which consist of a… 
8.3 Study 
Design 
Justification 
There will be up to 2052 subjects in REPRISE III. In order... 
Registry, and up to 1000 subjects will be enrolled in the U.S. 
Continued Access Study cohort. Up to… 
There will be up to 2092 subjects in REPRISE III. In order… 
Registry, up to 1000 subjects will be enrolled in the U.S. 
Continued Access Study cohort, up to 20 subjects will be 
enrolled in the roll-in cohort with the 29 mm LOTUS Edge 
Valve, and up to 20 subjects will be enrolled in the LOTUS Edge 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 175 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 176 of 188 
 
 
 
Table 27.1-8: Table of Changes for REPRISE III Protocol Version AI  (Compared to REPRISE III Protocol Version AH) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AH 
Text as Written in  
REPRISE III Protocol Version AI  
Justification for 
Modification 
29 mm Nested Registry. Up to… 
Table 9.2-1 
IC.2 … annulus size of ≥18 mm and ≤27 mm… 
IC.2 … annulus size of ≥18 mm and ≤29 mm… 
10.1.1 Roll-in 
Subjects 
…insert the Lotus Valve System into the subject’s femoral artery. 
…insert the Lotus Valve System (initial cohort with the 23 mm, 
25 mm, and 27 mm Lotus Valve) into the subject’s femoral 
artery. 
10.1.5 LOTUS 
Edge 29 mm 
Roll-in and 
Nested Registry 
Subjects 
- 
There will also be a non-randomized, roll-in phase with the 
29 mm LOTUS Edge Valve for centers that do not have prior 
experience implanting the LOTUS Edge Valve System. 
Participating centers will be centers that have enrolled subjects in 
REPRISE III with the Lotus Valve System. For the LOTUS Edge 
29 mm Roll-in cohort and Nested Registry, subjects confirmed 
eligible for the study by the CRC (see Section 22.2) and who 
provided written informed consent are considered enrolled in the 
study as soon as an attempt is made to insert the LOTUS Edge 
Valve System into the subject’s femoral artery. 
Figure 11.1-1 
- 
Updated figure to include 29mm Nested Registry and 29mm roll-
in subjects. 
11.7.2.1 
Valvuloplasty 
…Prior to introduction of the Lotus Valve System, the 
subject’s… 
Note: If the subject becomes hemodynamically unstable after the 
valvuloplasty for reasons unrelated to the aortic valve annulus 
and/or leaflets, the Lotus Valve implantation should… 
…Prior to introduction of the Lotus Valve System or LOTUS 
Edge Valve System, the subject’s… 
Note: If the subject becomes hemodynamically unstable after the 
valvuloplasty for reasons unrelated to the aortic valve annulus 
and/or leaflets, the Lotus Valve implantation (using the Lotus 
Valve System or the LOTUS Edge Valve System) should… 
11.7.2.2 
Preparing… 
LOTUS… or 
LOTUS Edge 
Valve System 
The Lotus Valve implantation procedure requires… 
The Lotus 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 Valve. 
 
Prior to insertion of the Lotus Valve catheter… 
 
The Lotus Valve System IFU should be followed. The following 
summarizes the Lotus Valve System procedure. 
1) The Lotus delivery catheter is… 
2) The Lotus catheter is… 
The Lotus Valve implantation procedure (using the Lotus Valve 
System or the LOTUS Edge Valve System) requires… 
The Lotus Valve System/LOTUS Edge Valve System must be 
prepared in accordance with the applicable IFU. Device 
preparation should only be performed by persons who have 
completed appropriate training with the Lotus Valve System or 
LOTUS Edge Valve System (as applicable). 
Prior to insertion of the Lotus Valve System/LOTUS Edge Valve 
System catheter… 
The Lotus Valve System or LOTUS Edge Valve System IFU 
should be followed, as applicable. The following summarizes the 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 176 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 177 of 188 
 
 
 
Table 27.1-8: Table of Changes for REPRISE III Protocol Version AI  (Compared to REPRISE III Protocol Version AH) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AH 
Text as Written in  
REPRISE III Protocol Version AI  
Justification for 
Modification 
 
Labels from the devices used during the procedure (e.g., the 
Lotus Valve System, Lotus Introducer)… 
 
 
The following information will be collected during the 
procedure… 
• Device size (21 mm, 23 mm, 25 mm, 27 mm) and model… 
• Lotus Valve catheter insertion and removal time… 
• Device deficiencies assessment (for the Lotus Valve System) 
Lotus Valve System/ LOTUS Edge Valve System procedure. 
1) The Lotus/LOTUS Edge delivery catheter is… 
2) The Lotus/LOTUS Edge catheter is… 
 
Labels from the devices used during the procedure (e.g., the 
Lotus Valve System/LOTUS Edge Valve System, Lotus 
Introducer)… 
 
The following information will be collected during the 
procedure… 
• Device size (21 mm, 23 mm, 25 mm, 27 mm, or 29 mm) and 
model… 
• Lotus Valve System or LOTUS Edge Valve System catheter 
insertion and removal time… 
• Device deficiencies assessment (for the Lotus Valve 
System/LOTUS Edge Valve System) 
12.1 Endpoints 
Data will be summarized separately from subjects in the roll-in 
(up to 120 subjects), randomized, Lotus 21 mm Nested Registry, 
and U.S. Continued Access Study populations. Descriptive 
statistics will be used to summarize the data from subjects in the 
roll-in, Lotus 21 mm Nested Registry, and U.S. Continued… 
Data will be summarized separately from subjects in the roll-in 
(up to 120 subjects with the 23 mm, 25 mm or 27 mm Lotus 
Valve), randomized, Lotus 21 mm Nested Registry, roll-in with 
the 29 mm LOTUS Edge Valve (up to 16 subjects), LOTUS 
Edge 29 mm Nested Registry, and U.S. Continued Access Study 
populations. Descriptive statistics will be used to summarize the 
data from subjects in the roll-in, Lotus 21 mm Nested Registry, 
roll-in with the 29 mm LOTUS Edge, LOTUS Edge 29 mm 
Nested Registry, and U.S. Continued… 
12.1.4 Baseline 
Comparability 
Baseline data will be summarized by treatment group for the 
randomized subjects and separately for subjects in the roll-in, 
Lotus 21 mm Nested Registry, and… 
No formal statistical testing will be done for the roll-in, Lotus 
21 mm Nested Registry, or… 
Baseline data will be summarized by treatment group for the 
randomized subjects and separately for subjects in the roll-in, 
Lotus 21 mm Nested Registry, roll-in with the 29 mm LOTUS 
Edge Valve, LOTUS Edge 29 mm Nested Registry, and… 
No formal statistical testing will be done for the roll-in (with the 
23 mm, 25 mm, or 27 mm Lotus Valve), Lotus 21 mm Nested 
Registry, roll-in with the 29 mm LOTUS Edge Valve, LOTUS 
Edge 29 mm Nested Registry, or… 
12.1.5 Post-
No formal statistical testing will be done for the roll-in, Lotus 
No formal statistical testing will be done for the roll-in (with the 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 177 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 178 of 188 
 
 
 
Table 27.1-8: Table of Changes for REPRISE III Protocol Version AI  (Compared to REPRISE III Protocol Version AH) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AH 
Text as Written in  
REPRISE III Protocol Version AI  
Justification for 
Modification 
procedure 
Measurements 
21 mm Nested Registry, or… 
23 mm, 25 mm, or 27 mm Lotus Valve), Lotus 21 mm Nested 
Registry, roll-in with the 29 mm LOTUS Edge Valve, LOTUS 
Edge 29 mm Nested Registry, or… 
12.2.1 Analysis 
Sets 
… Among the roll-in, Lotus 21 mm Nested Registry, and U.S. 
Continued Access Study cohorts, for ITT analyses... For these 3 
cohorts, the as-treated population includes all subjects implanted 
with the Lotus Valve. The as-treated and implanted analysis sets 
are the same for these 3 cohorts. 
… Among the roll-in (with the 23 mm, 25 mm, or 27 mm Lotus 
Valve), Lotus 21 mm Nested Registry, roll-in with the 29 mm 
LOTUS Edge Valve, LOTUS Edge 29 mm Nested Registry, and 
U.S. Continued Access Study cohorts, for ITT analyses… For 
these cohorts, the as-treated population includes all subjects 
implanted with the Lotus Valve. The as-treated and implanted 
analysis sets are the same for these cohorts. 
12.2.4 Reporting 
Events 
For all subjects in the roll-in, Lotus 21 mm Nested Registry, 
LOTUS Edge 29 mm Nested Registry, and…. 
For all subjects in the roll-in, (with the 23 mm, 25 mm, or 27 mm 
Lotus Valve), Lotus 21 mm Nested Registry, roll-in with the 
29 mm LOTUS Edge Valve, LOTUS Edge 29 mm Nested 
Registry, and…. 
12.3.2 Interim 
Analyses 
…completed their 30-day follow-up visits. 
…completed their 30-day follow-up visits. 
There will be an administrative analysis of 30-day data from  
implanted subjects receiving the LOTUS Edge 29 mm valve in 
the REPRISE III and the similarly designed REPRISE Edge 29 
mm EU study. This analysis will be performed for regulatory 
agency review on the first 30  implanted subjects from the 
combined cohort and will be carried out after these pooled 
subjects have completed their 30 day follow-up visits. 
16.1 
Investigational 
Device 
The Lotus Valve System (investigational device)… 
The Lotus Valve System shall be securely maintained… 
Device Accountability Logs for the Lotus Valve System will 
be… 
The Lotus Valve System/LOTUS Edge Valve System 
(investigational device)… 
The Lotus Valve System/LOTUS Edge Valve System shall be 
securely maintained… 
Device Accountability Logs for the Lotus Valve System/LOTUS 
Edge Valve System will be… 
17.2 Investigator 
Responsibilities 
• Complete all Lotus Valve (investigational device) training 
requirements as detailed in the REPRISE III Training Plan (see 
Section 17.4.1).  
• Complete all Lotus Valve (investigational device) training 
requirements as detailed in the REPRISE III Training Plan (see 
Section 17.4.1). This includes training on the Lotus Valve 
System /LOTUS Edge Valve System as applicable. 
17.4.1 Training 
with the Lotus 
The Sponsor is responsible for providing Investigators with the 
information and training on the Lotus Valve System they need… 
The Sponsor is responsible for providing Investigators with the 
information and training on the Lotus Valve System/LOTUS 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 178 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 179 of 188 
 
 
 
Table 27.1-8: Table of Changes for REPRISE III Protocol Version AI  (Compared to REPRISE III Protocol Version AH) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AH 
Text as Written in  
REPRISE III Protocol Version AI  
Justification for 
Modification 
Valve System/ 
LOTUS Edge 
Valve System 
 
Note: The training requirements listed above apply to centers that 
do not have previous experience implanting the Lotus Valve. For 
these centers there will be a roll-in phase with at least 2 roll-in 
subjects per center treated under the supervision of a proctor. The 
roll-in subjects will count towards the 6 required proctored cases.   
Edge Valve System they need… 
Note 1: The training requirements listed above apply to centers 
that do not have previous experience implanting the Lotus Valve. 
For these centers there will be a roll-in phase (initial cohort with 
the 23 mm, 25 mm, and 27 mm Lotus Valve System) with at least 
2 roll-in subjects per center treated under the supervision of a 
proctor. The roll-in subjects will count towards the 6 required 
proctored cases. 
Note 2: Device training specific to the use of the 29 mm LOTUS 
Edge Valve System will be provided to investigators at 
participating centers prior to enrollment in the 29 mm roll-in 
cohort and LOTUS Edge 29 mm Nested Registry. For the 
participating investigators who have had sufficient experience 
implanting the Lotus Valve but not with the LOTUS Edge Valve 
System, additional training will be provided focused on the 
changes between Lotus and LOTUS Edge. For these Lotus-
experienced investigators, at least 2 roll-in cases with the 29 mm 
LOTUS Edge Valve System will be performed before enrollment 
can commence in the LOTUS Edge 29 mm Nested Registry. 
19.1 Risks… 
…the use of the Lotus Valve System and/or CoreValve… 
 
As the Lotus Valve is an investigational device… 
…the use of the Lotus Valve System/LOTUS Edge Valve System 
and/or CoreValve… 
As the Lotus Valve/LOTUS Edge Valve is an investigational 
device… 
19.2 Risk… 
In addition…, the Lotus Valve System provides… 
In addition…, the Lotus Valve System/LOTUS Edge Valve 
System provides… 
19.3.2 
Potential… 
Potential benefits… use of the Lotus™ Valve System 
compared… 
Potential benefits… use of the Lotus™ Valve System/LOTUS 
Edge™ Valve System compared… 
19.4 Risk to 
Benefit 
Rationale 
…which has been associated with long term mortality in TAVR. 
…which has been associated with long term mortality in TAVR. 
No new hazards/harms are introduced by the 29 mm LOTUS 
Edge Valve System compared to the 21, 23, 25 and 27 mm Lotus 
Valve System when used with the Lotus Introducer Set.  Since 
and the overall risk profile of the device has not changed, it can 
be concluded that the potential benefits of the use of the 29 mm 
LOTUS Edge Valve System with the Lotus Introducer Set out-
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 179 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 180 of 188 
 
 
 
Table 27.1-8: Table of Changes for REPRISE III Protocol Version AI  (Compared to REPRISE III Protocol Version AH) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AH 
Text as Written in  
REPRISE III Protocol Version AI  
Justification for 
Modification 
weigh the risks. 
21.1 Definitions 
and 
Classifications 
For the roll-in, Lotus 21 mm Nested Registry, and… insert the 
Lotus Valve System into the subject’s femoral artery. 
For the roll-in, Lotus 21 mm Nested Registry, roll-in with the 
29 mm LOTUS Edge, LOTUS Edge 29 mm Nested Registry, 
and… insert the Lotus Valve System/LOTUS Edge Valve 
System into the subject’s femoral artery. 
21.4.1 Boston… 
All Lotus Valve System device…. 
All Lotus Valve System/LOTUS Edge Valve System device… 
22.1.2 Data 
Monitoring… 
… Lotus 21 mm Nested Registry cohorts. 
 
…Lotus 21 mm Nested Registry cohorts, and the 29 mm LOTUS 
Edge Valve roll-in and Nested Registry cohorts. 
27.1.8 Protocol 
Version AH to 
Version AI 
- 
Table 27.1-8 lists changes between protocol versions AH and AI. 
 
Added Table 27.1-8. 
Abbreviations: CT=computed tomography; IFU=Instructions for Use;  ITT=intent-to-treat 
 
Table 27.1-9: Table of Changes for REPRISE III Protocol Version AJ  (Compared to REPRISE III Protocol Version AI) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AI 
Text as Written in  
REPRISE III Protocol Version AJ  
Justification for 
Modification 
Page 1 
Suite 5.01, Level 5  
247 Coward Street 
Mascot, NSW 2020, Australia 
Building 1, Level 6 
191 O’Riordan Street  
Mascot NSW 2020 Australia 
Updated new 
Sponsor address in 
Australia 
Page 2 
Current Version: 19-Jan-2017 
Current Version: 06-Jun-2017 
Updated Table of Revision History 
Updated to include a 
non-randomized, 
nested registry cohort 
of at least 50 subjects 
who will receive the 
23 mm, 25 mm or 27 
mm LOTUS Edge 
Valve (LOTUS Edge 
Nested Registry) to 
confirm performance 
of the Lotus Valve 
implantation 
2. Protocol 
Synopsis, Test 
Devices and… 
Device size for the LOTUS Edge Valve System is 29 mm 
diameter. 
Device sizes for the LOTUS Edge Valve System include 23 mm, 
25 mm, 27 mm and 29 mm diameter. 
2. Protocol 
Synopsis, Study 
Design 
REPRISE III is designed to evaluate the safety and effectiveness 
of the Lotus Valve System for TAVR… 
 
REPRISE III is designed to evaluate the safety and effectiveness 
of the Lotus Valve System and LOTUS Edge™ Valve System for 
TAVR… 
- A non-randomized, nested registry cohort of subjects who will 
receive the 23 mm, 25 mm or 27 mm LOTUS Edge Valve 
(LOTUS Edge Nested Registry). Participating centers will be 
centers that have enrolled subjects in REPRISE III with the 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 180 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 181 of 188 
 
 
 
Table 27.1-9: Table of Changes for REPRISE III Protocol Version AJ  (Compared to REPRISE III Protocol Version AI) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AI 
Text as Written in  
REPRISE III Protocol Version AJ  
Justification for 
Modification 
Lotus Valve System. 
procedure with the 
Edge delivery 
system. 
2. Protocol 
Synopsis, 
Planned 
Subjects… 
There will be up to 2092 subjects in REPRISE III. 
 
There will be up to 2142 subjects in REPRISE III. 
- At least 50 subjects will be enrolled in the LOTUS Edge 
Nested Registry (23 mm, 25 mm and 27 mm valve sizes). 
2. Protocol 
Synopsis, 
Analysis Sets… 
Among the roll-in (initial cohort with the 23 mm, 25 mm, and 27 
mm Lotus), Lotus 21 mm Nested Registry, roll-in with the 29 
mm LOTUS Edge, LOTUS Edge 29 mm Nested Registry, and… 
Among the roll-in (initial cohort with the 23 mm, 25 mm, and 
27 mm Lotus), Lotus 21 mm Nested Registry, LOTUS Edge 
Nested Registry, roll-in with the 29 mm LOTUS Edge, LOTUS 
Edge 29 mm Nested Registry, and… 
4. Introduction 
With the Lotus Valve System as the test device, study subjects 
will be entered into the roll-in cohort, randomized (test versus 
control) cohort, a single-arm, nested registry cohort of subjects 
who receive the 21 mm Lotus Valve (Lotus 21 mm Nested 
Registry), or the U.S. Continued Access Study cohort (which will 
include a 4D computed tomography [CT] substudy cohort). 
Additionally, study subjects will be entered into a roll-in cohort 
and a single-arm, nested registry cohort of subjects who receive 
the 29 mm LOTUS Edge Valve System (LOTUS Edge 29 mm 
Nested Registry). Additional…  
With the Lotus Valve System as the test device, study subjects 
will be entered into the roll-in cohort, randomized (test versus 
control) cohort, a single-arm, nested registry cohort of subjects 
who receive the 21 mm Lotus Valve (Lotus 21 mm Nested 
Registry), or the U.S. Continued Access Study cohort (which will 
include a 4D computed tomography [CT] substudy cohort). Study 
subjects will also be enrolled in a single-arm, nested registry with 
the 23, 25 and 27 mm LOTUS Edge Valve System (LOTUS 
Edge Nested Registry). Additionally, study subjects will be 
entered into a roll-in cohort and a single-arm, nested registry 
cohort of subjects who receive the 29 mm LOTUS Edge Valve 
System (LOTUS Edge 29 mm Nested Registry). 
4.1.1 Treatments 
for Aortic 
Stenosis 
The REPRISE NG DS study recently completed enrollment in 
Australia, while the REPRISE Edge study is currently enrolling 
in Europe.  
The REPRISE NG DS study recently completed enrollment in 
Australia, while the REPRISE Edge study is currently conducted 
in Europe.  
Updated status of 
REPRISE Edge 
study. 
4.1.4  
REPRISE NG  
DS Study 
Cohort C completed enrollment in September 2016 with 21 
subjects treated with the LOTUS Edge Valve System, which 
features a further refined version of the delivery system (results 
pending).  
The primary endpoint was achieved in 10/10 subjects in Cohort 
A108 and 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). Table 4.1 5 shows core lab analyses of prosthetic 
valve performance as assessed by TTE for the 2 cohorts. In both 
cohorts, mean aortic valve area and mean gradient improved at 
discharge and remained improved at 30 days. There were no 
Cohort C completed enrollment in September 2016 with 21 
subjects treated with the LOTUS Edge Valve System, which 
features a further refined version of the delivery system, 
implanted with either the Lotus or improved expandable iSleeve 
Introducer.  
…In both 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, or 30 days or 1-year in either cohort. Table 4.1 6 
shows rates of CEC-adjudicated VARC-defined events during the 
index procedure, through discharge/7 days, and to 30 days and 1 
Updated to add 1 
year results from 
REPRISE NG DS 
Cohorts A and B, and 
outcomes from 
Cohort C through 
discharge and 30 
days with the LOTUS 
Edge Valve System 
to support inclusion 
of the LOTUS Edge 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 181 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 182 of 188 
 
 
 
Table 27.1-9: Table of Changes for REPRISE III Protocol Version AJ  (Compared to REPRISE III Protocol Version AI) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AI 
Text as Written in  
REPRISE III Protocol Version AJ  
Justification for 
Modification 
cases of moderate or severe PVR at discharge or 30 days in either 
cohort. Table 4.1 6 shows rates of CEC-adjudicated VARC-
defined events during the index procedure, through discharge/7 
days, and to 30 days. 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 summary, acute and 30-day 
outcomes in the REPRISE NG DS study demonstrate acceptable 
performance and safety of the LOTUS Edge System.   
Table 4.1-5 and Table 4.1-6. 
year. In Cohort A, one subject experienced the majority of events 
and subsequently died on day 13 post implant. Another subject 
died on day 119; the primary cause of death was multiorgan 
failure, which was not considered related to the index procedure. 
In Cohort B, events were minimal through 1 year post implant. 
To date, acute and 30-day outcomes were sustained through 1 
year in both cohorts. Overall, the results in Cohorts A and B of 
the REPRISE NG DS study demonstrate acceptable performance 
and safety of the LOTUS Edge System.  Added 1 year results in 
Table 4.1-5 and Table 4.1-6. 
 
Using the latest iteration of the LOTUS Edge Valve System with 
either the Lotus or expandable iSleeve Introducer, the primary 
endpoint was achieved in 21/21 subjects in Cohort C, which 
resulted in improved valve performance and no moderate or 
severe PVR at discharge/7 days and 30 days post implant (Table 
4.1-7) based on echocardiographic core lab analysis. A summary 
of clinical outcomes through discharge/7 days and 30 days is 
presented in Table 4.1-8. There was no mortality. Disabling 
stroke occurred on day 0 in one subject. Only 2/21 subjects 
(9.5%) were implanted with a new permanent pacemaker (PPM) 
through 30 days post implant, which is lower than previously 
observed in studies with the Lotus Valve System. This may be 
attributed to the design of the LOTUS Edge delivery system with 
its flexibility and ability to minimize the depth of the valve frame 
during deployment within the annulus, thereby reducing the 
potential for unnecessary interaction with the left ventricular 
outflow tract and the conduction system of the heart. These 
outcomes in the REPRISE NG DS Cohort C subjects demonstrate 
acceptable performance and safety of the LOTUS Edge System 
through 30 days post implant. 
Added Table 4.1-7 and Table 4.1-8. 
Nested Registry. 
4.2 Justification 
for the Study 
No new hazards/harms are introduced by the 29 mm LOTUS 
Edge Valve System compared to the 21 mm, 23 mm, 25 mm and 
27 mm Lotus Valve System when used with the Lotus Introducer 
Set. Since the overall risk profile of the device has not changed, it 
No new hazards/harms are introduced by the LOTUS Edge Valve 
System compared to the Lotus Valve System when used with the 
Lotus Introducer Set. Since the overall risk profile of the device 
has not changed, it can be concluded that the potential benefits of 
Removed references 
specific to the 29mm 
LOTUS Edge device 
since the text in these 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 182 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 183 of 188 
 
 
 
Table 27.1-9: Table of Changes for REPRISE III Protocol Version AJ  (Compared to REPRISE III Protocol Version AI) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AI 
Text as Written in  
REPRISE III Protocol Version AJ  
Justification for 
Modification 
can be concluded that the potential benefits of the use of the 29 
mm LOTUS Edge Valve System with the Lotus Introducer Set 
out-weigh the risks. 
the use of the LOTUS Edge Valve System with the Lotus 
Introducer Set out-weigh the risks. 
sections now refers to 
all sizes of LOTUS 
Edge. 
5. Device 
Description 
Test devices include the Lotus™ Valve System available in valve 
sizes of 21 mm, 23 mm, 25 mm, and 27 mm diameter, and the 
LOTUS Edge™ Valve System available in a valve size of 29 mm 
diameter (Section 5.1). 
Test devices include the Lotus™ Valve System available in valve 
sizes of 21 mm, 23 mm, 25 mm, and 27 mm diameter, and the 
LOTUS Edge™ Valve System available in valve sizes of 23 mm, 
25 mm, 27 mm, and of 29 mm diameter (Section 5.1).  
Updated to include 
the LOTUS Edge 
Nested Registry (23 
mm, 25 mm, 27 mm) 
and device 
description 
5.1 LOTUS 
Valve System  
Investigational 
Device (Test) 
5.1 LOTUS Valve System and LOTUS Edge Valve System 
Investigational Devices (Test) 
…into the aortic vessel. Lotus Valve System device sizes used in 
the randomized cohort and the U.S. Continued Access Study 
cohort include 23 mm, 25 mm, and 27 mm diameter. Devices in 
the Lotus 21 mm Nested Registry cohort are 21 mm in diameter. 
The LOTUS Edge Valve System is a design iteration of the Lotus 
Valve System. Devices in the LOTUS Edge 29 mm Nested 
Registry cohort are 29 mm in diameter. More detailed product 
information is contained in the Investigator Brochure and 
Instructions For Use (IFU) for both devices. 
5.1.1 Lotus Valve and LOTUS Edge Valve 
…The Lotus Valve device is designed to produce a final diameter 
of 21 mm, 23 mm, 25 mm, or 27 mm (depending on valve size) 
when the valve is locked. In the deployed state, the frame height 
of the 21mm valve is approximately 15 mm; the frame height of 
the three larger valve sizes is approximately 19 mm. The valve 
component of the 29 mm LOTUS Edge device is scaled from the 
23 mm, 25 mm, and 27 mm valve sizes. Additionally, the 
LOTUS Edge 29 mm valve has a pad sewn between the braid and 
buckle to prevent interaction between the two components during 
sheathing and unsheathing of the valve. The frame height of the 
29 mm valve in the deployed state is 21 mm… 
5.1.2 Lotus and LOTUS Edge Delivery System 
…Overall, the Delivery System for the LOTUS Edge Valve 
System is similar to that of the Lotus Valve System. 
Additionally, it has a modified leadscrew component, which 
5.1 LOTUS Valve System and LOTUS Edge Valve System 
Investigational Devices (Test) 
…into the aortic vessel. Lotus Valve System device sizes used in 
the randomized cohort and the U.S. Continued Access Study 
cohort include 23 mm, 25 mm, and 27 mm diameter. Devices in 
the Lotus 21 mm Nested Registry cohort are 21 mm in diameter. 
The LOTUS Edge Valve System is a design iteration of the Lotus 
Valve System. LOTUS Edge device sizes used in the Nested 
Registries include 23 mm, 25 mm, 27 mm, and 29 mm roll-in and 
Nested Registry cohorts are 29 mm in diameter. More detailed 
product information is contained in the Investigator Brochure and 
Instructions For Use (IFU) for both devices. 
5.1.1 Lotus Valve and LOTUS Edge Valve 
…The Lotus Valve device is designed to produce a final diameter 
of 21 mm, 23 mm, 25 mm, or 27 mm (depending on valve size) 
when the valve is locked. In the deployed state, the frame height 
of the 21mm valve is approximately 15 mm; the frame height of 
the three larger valve sizes is approximately 19 mm. Similarly, 
the LOTUS Edge Valve is designed to produce a final diameter 
of 23 mm, 25 mm, or 27 mm (depending on valve size) when the 
valve is locked, with a frame height of approximately 19 mm for 
all three sizes. The valve component of the 29 mm LOTUS Edge 
device is scaled from the 23 mm, 25 mm, and 27 mm valve sizes. 
Additionally, the LOTUS Edge 29 mm valve has a pad sewn 
between the braid and buckle to prevent interaction between the 
two components during sheathing and unsheathing of the valve. 
The frame height of the 29 mm valve in the deployed state is 21 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 183 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 184 of 188 
 
 
 
Table 27.1-9: Table of Changes for REPRISE III Protocol Version AJ  (Compared to REPRISE III Protocol Version AI) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AI 
Text as Written in  
REPRISE III Protocol Version AJ  
Justification for 
Modification 
results in a slightly decreased rate of retraction of the outer sheath 
during valve deployment compared to the Lotus Valve System. 
The multi-lumen catheter and outer sheath components of 
LOTUS Edge have been modified to enhance deliverability. 
mm… 
5.1.2 Lotus and LOTUS Edge Delivery System 
…Overall, the Delivery System for the LOTUS Edge Valve 
System is similar to that of the Lotus Valve System. 
Additionally, it has 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. The multi-
lumen catheter and outer sheath components of LOTUS Edge 
have been modified to enhance deliverability. 
5.3 Device 
Labeling  
5.3.1 Test Device 
… 
• Expiration (use by) date (labeled as month/year, device not to 
be used after the last day of the indicated month) 
5.3.1 Test Device 
… 
• Expiration (use by) date  
Updated to clarify 
6. Objectives 
The objective of the REPRISE III trial is to evaluate the safety 
and effectiveness of the Lotus™ Valve System and LOTUS 
Edge™ Valve System (29 mm valve) for transcatheter… 
The objective of the REPRISE III trial is to evaluate the safety 
and effectiveness of the Lotus™ Valve System and LOTUS 
Edge™ Valve System for transcatheter… 
Updated to include 
the LOTUS Edge 
Nested Registry (23 
mm, 25 mm, 27 mm) 
7. Endpoints 
Among the roll-in, (initial cohort with 23 mm, 25 mm, and 27 
mm Lotus Valve System and subsequent cohort with 29 mm 
LOTUS Edge Valve System), Lotus 21 mm Nested Registry, 
LOTUS Edge 29 mm Nested Registry, and U.S. Continued 
Access Study cohorts, for ITT analyses… 
Among the roll-in, (initial cohort with 23 mm, 25 mm, and 27 
mm Lotus Valve System and subsequent cohort with 29 mm 
LOTUS Edge Valve System), Lotus 21 mm Nested Registry, 
LOTUS Edge Nested Registry, LOTUS Edge 29 mm Nested 
Registry, and U.S. Continued Access Study cohorts, for ITT 
analyses… 
8.1 Scale and 
Duration 
 …There will also be a non-randomized, roll-in phase with the 29 
mm LOTUS Edge Valve for centers that do not have prior 
experience implanting the LOTUS Edge Valve System, and a 
nested registry cohort of subjects who will receive the 29 mm 
LOTUS Edge Valve System (LOTUS Edge 29 mm Nested 
Registry). Participating centers will be centers that have enrolled 
subjects in REPRISE III with the Lotus Valve System. 
 
An additional single-arm, non-randomized, nested registry cohort 
of subjects who will receive the 23 mm, 25 mm, or 27 mm 
LOTUS Edge Valve System (LOTUS Edge Nested Registry) will 
be conducted to confirm performance  of the Lotus Valve 
implantation procedure with the Edge delivery system. There will 
also be a non-randomized, roll-in phase with the 29 mm LOTUS 
Edge Valve for centers that do not have prior experience 
implanting the LOTUS Edge Valve System, and a nested registry 
cohort of subjects who will receive the 29 mm LOTUS Edge 
Valve System (LOTUS Edge 29 mm Nested Registry). 
8.2 Treatment 
Note: …to further assess performance and safety. There will also 
Note: …to further assess performance and safety. Additionally, 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 184 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 185 of 188 
 
 
 
Table 27.1-9: Table of Changes for REPRISE III Protocol Version AJ  (Compared to REPRISE III Protocol Version AI) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AI 
Text as Written in  
REPRISE III Protocol Version AJ  
Justification for 
Modification 
Assignment 
be a non-randomized, roll-in phase with the 29 mm LOTUS Edge 
Valve for centers that do not have previous experience 
implanting the LOTUS Edge Valve System (at least 2 roll-in 
cases/center), and a nested registry cohort of subjects who will 
receive the 29 mm LOTUS Edge Valve System (LOTUS Edge 
29 mm Nested Registry). 
subjects will be enrolled in a non-randomized, nested registry 
cohort with the 23 mm, 25 mm or 27 mm LOTUS Edge Valve 
(LOTUS Edge Nested Registry) to confirm performance of the 
Lotus Valve implantation procedure with the Edge delivery 
system. There will also be a non-randomized, roll-in phase with 
the 29 mm LOTUS Edge Valve for centers that do not have 
previous experience implanting the LOTUS Edge Valve System 
(at least 2 roll-in cases/center), and a nested registry cohort of 
subjects who will receive the 29 mm LOTUS Edge Valve System 
(LOTUS Edge 29 mm Nested Registry). 
8.3 Study 
Design 
Justification 
There will be up to 2092 subjects in REPRISE III. In order… 
Registry, up to 1000 subjects will be enrolled in the U.S. 
Continued Access Study cohort, up to 20 subjects will be 
enrolled in the roll-in cohort with the 29 mm LOTUS Edge 
Valve, and up to 20 subjects will be enrolled in the LOTUS Edge 
29 mm Nested Registry… 
There will be up to 2142 subjects in REPRISE III. 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 Valve experience), 912 
subjects will be randomized and enrolled, up to 20 subjects will 
be enrolled in the Lotus 21 mm Nested Registry, up to 1000 
subjects will be enrolled in the U.S. Continued Access Study 
cohort, at least 50 subjects  will be enrolled in the LOTUS Edge 
Nested Registry, up to 20 subjects will be enrolled in the roll-in 
cohort with the 29 mm LOTUS Edge Valve, and up to 20 
subjects will be enrolled in the LOTUS Edge 29 mm Nested 
Registry…  
10.1.5 LOTUS 
Edge 23-27 mm 
Nested Registry 
Subjects 
 
For the LOTUS Edge 23-27 mm Nested Registry, subjects 
confirmed eligible for the study by the CRC (see Section 22.2) 
and who provided written informed consent are considered 
enrolled in the study as soon as an attempt is made to insert the 
LOTUS Edge Valve System into the subject’s femoral artery. 
Figure 11.1-1 
 
Updated figure to include LOTUS Edge Nested Registry  
12.1 Endpoints 
Data will be summarized separately from subjects in the roll-in 
(up to 120 subjects with the 23 mm, 25 mm or 27 mm Lotus 
Valve), randomized, Lotus 21 mm Nested Registry, roll-in with 
the 29 mm LOTUS Edge Valve (up to 16 subjects), LOTUS 
Edge 29 mm Nested Registry, and U.S. Continued Access Study 
populations. Descriptive statistics will be used to summarize the 
Data will be summarized separately from subjects in the roll-in 
(up to 120 subjects with the 23 mm, 25 mm or 27 mm Lotus 
Valve), randomized, Lotus 21 mm Nested Registry, LOTUS 
Edge Nested Registry, roll-in with the 29 mm LOTUS Edge 
Valve (up to 20 subjects), LOTUS Edge 29 mm Nested Registry, 
and U.S. Continued Access Study populations. Descriptive 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 185 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 186 of 188 
 
 
 
Table 27.1-9: Table of Changes for REPRISE III Protocol Version AJ  (Compared to REPRISE III Protocol Version AI) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AI 
Text as Written in  
REPRISE III Protocol Version AJ  
Justification for 
Modification 
data from subjects in the roll-in, Lotus 21 mm Nested Registry, 
roll-in with the 29 mm LOTUS Edge, LOTUS Edge 29 mm 
Nested Registry, and U.S. Continued Study cohorts and no 
statistical inference will be made. 
statistics will be used to summarize the data from subjects in the 
roll-in, Lotus 21 mm Nested Registry, LOTUS Edge Nested 
Registry, roll-in with the 29 mm LOTUS Edge, LOTUS Edge 29 
mm Nested Registry, and U.S. Continued Access Study cohorts 
and no statistical inference will be made. 
12.1.4 Baseline 
Comparability 
Baseline data will be summarized by treatment group for the 
randomized subjects and separately for subjects in the roll-in, 
Lotus 21 mm Nested Registry, roll-in with the 29 mm LOTUS 
Edge Valve, LOTUS Edge 29 mm Nested Registry, and… 
 
No formal statistical testing will be done for the roll-in (with the 
23 mm, 25 mm, or 27 mm Lotus Valve), Lotus 21 mm Nested 
Registry, roll-in with the 29 mm LOTUS Edge Valve, LOTUS 
Edge 29 mm Nested Registry, or U.S. Continued Access Study 
subjects. 
Baseline data will be summarized by treatment group for the 
randomized subjects and separately for subjects in the roll-in 
(with the 23 mm, 25 mm, or 27 mm Lotus Valve), Lotus 21 mm 
Nested Registry, LOTUS Edge Nested Registry, roll-in with the 
29 mm LOTUS Edge Valve, LOTUS Edge 29 mm Nested 
Registry, and … 
No formal statistical testing will be done for the roll-in (with the 
23 mm, 25 mm, or 27 mm Lotus Valve), Lotus 21 mm Nested 
Registry, LOTUS Edge Nested Registry, roll-in with the 29 mm 
LOTUS Edge Valve, LOTUS Edge 29 mm Nested Registry, or 
U.S. Continued Access Study subjects. 
12.1.5 Post-
procedure 
Measurements 
No formal statistical testing will be done for the roll-in (with the 
23 mm, 25 mm, or 27 mm Lotus Valve), Lotus 21 mm Nested 
Registry, roll-in with the 29 mm LOTUS Edge Valve, LOTUS 
Edge 29 mm Nested Registry, or… 
No formal statistical testing will be done for the roll-in (with the 
23 mm, 25 mm, or 27 mm Lotus Valve), Lotus 21 mm Nested 
Registry, LOTUS Edge Nested Registry, roll-in with the 29 mm 
LOTUS Edge Valve, LOTUS Edge 29 mm Nested Registry, or… 
 
12.2.1 Analysis 
Sets 
… Among the roll-in (with the 23 mm, 25 mm, or 27 mm Lotus 
Valve), Lotus 21 mm Nested Registry, roll-in with the 29 mm 
LOTUS Edge Valve, LOTUS Edge 29 mm Nested Registry, and 
U.S. Continued Access Study cohorts, for ITT analyses… For 
these cohorts, the as-treated population includes all subjects 
implanted with the Lotus Valve. The as-treated and implanted 
analysis sets are the same for these cohorts. 
… Among the roll-in (with the 23 mm, 25 mm, or 27 mm Lotus 
Valve), Lotus 21 mm Nested Registry, LOTUS Edge Nested 
Registry, roll-in with the 29 mm LOTUS Edge Valve, LOTUS 
Edge 29 mm Nested Registry, and U.S. Continued Access Study 
cohorts, for ITT analyses… For these cohorts, the as-treated 
population includes all subjects implanted with the Lotus Valve. 
The as-treated and implanted analysis sets are the same for these 
cohorts. 
12.2.4 Reporting 
Events 
For all subjects in the roll-in, (with the 23 mm, 25 mm, or 27 mm 
Lotus Valve), Lotus 21 mm Nested Registry, roll-in with the 29 
mm LOTUS Edge Valve, LOTUS Edge 29 mm Nested Registry, 
and… 
For all subjects in the roll-in, (with the 23 mm, 25 mm, or 27 mm 
Lotus Valve), Lotus 21 mm Nested Registry, LOTUS Edge 
Nested Registry, roll-in with the 29 mm LOTUS Edge Valve, 
LOTUS Edge 29 mm Nested Registry, and…. 
12.3.2 Interim 
There will be an administrative analysis of 30-day data from 
Administrative analyses of outcomes from the LOTUS Edge 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 186 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 187 of 188 
 
 
 
Table 27.1-9: Table of Changes for REPRISE III Protocol Version AJ  (Compared to REPRISE III Protocol Version AI) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AI 
Text as Written in  
REPRISE III Protocol Version AJ  
Justification for 
Modification 
Analyses 
implanted subjects receiving the LOTUS Edge 29 mm valve in 
the REPRISE III and the similarly designed REPRISE Edge 29 
mm EU study. This analysis will be performed for regulatory 
agency review on the first 30 implanted subjects from the 
combined cohort and will be carried out after these pooled 
subjects have completed their 30 day follow-up visits. 
Valve System (LOTUS Edge Nested Registry) will be performed 
for regulatory agency review after subjects have completed their 
implant procedure.   
 
There will be an administrative analysis of 30-day data from  
implanted subjects receiving the LOTUS Edge 29 mm valve in 
the REPRISE III and the similarly designed REPRISE Edge 29 
mm EU study. This analysis will be performed for regulatory 
agency review on the first 30  implanted subjects from the 
combined cohort and will be carried out after these pooled 
subjects have completed their 30 day follow-up visits. 
17.4.1 Training 
with the Lotus 
Valve System/ 
LOTUS Edge 
Valve System 
The Sponsor is responsible for providing Investigators with the 
information and training on the Lotus Valve System they need… 
 
Note 2: Device training specific to the use of the 29 mm LOTUS 
Edge Valve System will be provided to investigators at 
participating centers prior to enrollment in the 29 mm roll-in 
cohort and LOTUS Edge 29 mm Nested Registry. For the 
participating investigators who have had sufficient experience 
implanting the Lotus Valve but not with the LOTUS Edge Valve 
System, additional training will be provided focused on the 
changes between Lotus and LOTUS Edge. For these Lotus-
experienced investigators, at least 2 roll-in cases with the 29 mm 
LOTUS Edge Valve System will be performed before enrollment 
can commence in the LOTUS Edge 29 mm Nested Registry. 
The Sponsor is responsible for providing Investigators with the 
information and training on the Lotus Valve System/LOTUS 
Edge Valve System they need… 
Note 2: Device training specific to the use of the LOTUS Edge 
Valve System will be provided to investigators at participating 
centers prior to enrollment in the LOTUS Edge Nested Registry, 
29 mm roll-in cohort and LOTUS Edge 29 mm Nested Registry. 
For the participating investigators who have had sufficient 
experience implanting the Lotus Valve but not with the LOTUS 
Edge Valve System, additional training will be provided focused 
on the changes between Lotus and LOTUS Edge. For Lotus-
experienced investigators, at least 2 roll-in cases with the 29 mm 
LOTUS Edge Valve System will be performed before enrollment 
can commence in the LOTUS Edge 29 mm Nested Registry. 
 
19.4 Risk to 
Benefit 
Rationale 
…which has been associated with long term mortality in TAVR. 
No new hazards/harms are introduced by the 29 mm LOTUS 
Edge Valve System compared to the 21, 23, 25 and 27 mm Lotus 
Valve System when used with the Lotus Introducer Set.  Since 
and the overall risk profile of the device has not changed, it can 
be concluded that the potential benefits of the use of the 29 mm 
LOTUS Edge Valve System with the Lotus Introducer Set out-
weigh the risks. 
…which has been associated with long term mortality in TAVR. 
No new hazards/harms are introduced by the LOTUS Edge Valve 
System compared to the Lotus Valve System when used with the 
Lotus Introducer Set.  Since and the overall risk profile of the 
device has not changed, it can be concluded that the potential 
benefits of the use of the LOTUS Edge Valve System with the 
Lotus Introducer Set out-weigh the risks. 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 187 of 188 

S2282 
 
Boston Scientific  
Confidential 
 
REPRISE III Study-Specific Protocol 
 
 
90899936 Rev/Ver AK 
 
Page 188 of 188 
 
 
 
Table 27.1-9: Table of Changes for REPRISE III Protocol Version AJ  (Compared to REPRISE III Protocol Version AI) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AI 
Text as Written in  
REPRISE III Protocol Version AJ  
Justification for 
Modification 
21.1 Definitions 
and 
Classifications 
For the roll-in, Lotus 21 mm Nested Registry, roll-in with the 29 
mm LOTUS Edge, LOTUS Edge 29 mm Nested Registry, and… 
insert the Lotus Valve System/LOTUS Edge Valve System into 
the subject’s femoral artery. 
For the roll-in, Lotus 21 mm Nested Registry, LOTUS Edge 
Nested Registry, roll-in with the 29 mm LOTUS Edge, LOTUS 
Edge 29 mm Nested Registry, and… insert the Lotus Valve 
System/LOTUS Edge Valve System into the subject’s femoral 
artery. 
22.1.2 Data 
Monitoring… 
…Lotus 21 mm Nested Registry cohorts, and the 29 mm LOTUS 
Edge Valve roll-in and Nested Registry cohorts. 
 
…Lotus 21 mm Nested Registry cohorts, LOTUS Edge Nested 
Registry, and the 29 mm LOTUS Edge Valve roll-in and Nested 
Registry cohorts. 
27.1.8 Protocol 
Version AH to 
Version AI 
- 
Table 27.1-9 lists changes between protocol versions AI and AJ. 
 
Added Table 27.1-9. 
Added table to lists 
changes between 
protocol versions. 
Abbreviations: CT=computed tomography; IFU=Instructions for Use;  ITT=intent-to-treat 
 
Table 27.1-10: Table of Changes for REPRISE III Protocol Version AK (Compared to REPRISE III Protocol Version AJ) 
Section 
Modified 
Text as Written in  
REPRISE III Protocol Version AJ 
Text as Written in  
REPRISE III Protocol Version AK  
Justification for 
Modification 
Page 44 
The Lotus Introducer is suitable for use in subjects requiring the 
21 mm or 23 mm valve with femoral artery lumen diameter ≥6.0 
mm or for use in subjects requiring the 25 mm, 27 mm, or 29 mm 
valve with femoral artery lumen diameter ≥6.5 mm 
The small Lotus Introducer (LIS-S) is suitable for use with the 
Lotus Valve System in subjects requiring the 21 mm or 23 mm 
valve with femoral artery lumen diameter ≥6.0 mm. The large 
Lotus Introducer (LIS-L) is suitable for use with the Lotus Valve 
System in subjects requiring the 25 mm or 27 mm valve with 
femoral artery lumen diameter ≥6.5 mm. The large Lotus 
Introducer (LIS-L) is also suitable for use with the LOTUS Edge 
Valve System in subjects requiring the 23 mm, 25 mm, 27 mm or 
29 mm valve with femoral artery lumen diameter ≥6.5 mm. 
The Lotus Introducer 
suitable for use in 
subjects requiring 
any size LOTUS 
Edge Valve System 
(23, 25, 27, 29 mm) 
requires femoral 
artery lumen 
diameter size 
≥6.5 mm. 
 
 
Boston Scientific Confidential. Unauthorized use is prohibited.
Released
90899936 AK.4
REPRISE III Protocol
Page 188 of 188