Early Feasibility Study of the Neovasc Tiara™ Mitral Transcatheter Heart Valve With the Tiara™ Transapical Delivery System
Phase: NA
Conditions: Mitral Valve Regurgitation
Sponsor: Shockwave Medical, Inc.

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 1 of 83 
 
 
Early Feasibility Study of the Neovasc Tiara™ Mitral Transcatheter Heart Valve 
with the Tiara™ Transapical Delivery System (TIARA-I) 
 
 
CLINICAL PROTOCOL 
(Clinical Investigation Plan) 
 
 
Clinical Study Number: 047-CPT-001 
Version E 
Effective Date: 17 November 2015 
 
 
Study Sponsor: 
Neovasc Medical Inc.  
13700 Mayfield Place, Unit 2135 
Richmond, BC  
Canada, V6V 2E4 
Phone: (604) 270-4344 
Fax: (604) 270-4384 
 
 
 
 
 
 
PROPRIETARY DATA: This document and the information contained herein may not be 
reproduced, used or disclosed without written permission from Neovasc Medical Inc. 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 3 of 83 
 
 
Sponsor: 
 
 
 
 
Neovasc Medical Inc. 
 
13700 Mayfield Place, Unit 2135 
 
Richmond, BC Canada V6V 2E4 
 
Phone: (604) 270-4344 
 
Fax: (604) 270-4384 
 
 
 
 
Sponsor Representative: 
Vicki Bebeau 
Vice President, Clinical and Regulatory 
Affairs 
 
900 Long Lake Road 
 
Suite #300 
 
New Brighton, MN 55112 
 
Phone: (855) 802-5180 Ext. 300 
Fax: (651) 219-5465 
 
 
 
Reportable Events: 
Phone: (855) 802-5180 Ext. 885 
 
Email: tiara@neovasc.com 
 
Fax: 651-219-5465 
 
 
 
 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 4 of 83 
 
TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................. 4 
1 
SYNOPSIS ................................................................................................................................ 7 
2 
INTRODUCTION ..................................................................................................................... 14 
2.1 
BACKGROUND ................................................................................................................ 14 
2.1.1 
Disease Process ............................................................................................. 14 
2.1.2 
Alternative Therapies/Techniques .................................................................. 15 
2.1.3 
Study Purpose ................................................................................................ 15 
2.2 
STUDY DEVICE ............................................................................................................... 15 
2.2.1 
Device Description – Tiara Valve ................................................................... 16 
2.2.2 
Delivery System Description – Tiara Delivery System ................................... 17 
2.2.3 
Tiara Implant Procedure ................................................................................. 18 
2.2.4 
Prior Testing ................................................................................................... 19 
2.2.5 
Prior Clinical Studies ...................................................................................... 19 
3 
RISK ANALYSIS .................................................................................................................... 20 
3.1 
RISKS ............................................................................................................................ 20 
3.1.1 
Risks Associated with Investigational Products ............................................. 20 
3.1.2 
Risks Associated with Study Procedure ......................................................... 22 
3.1.3 
Risk Management ........................................................................................... 23 
3.2 
BENEFITS ...................................................................................................................... 24 
3.3 
STUDY JUSTIFICATION .................................................................................................... 25 
4 
STUDY OBJECTIVES ............................................................................................................ 25 
4.1 
PRIMARY OBJECTIVE ...................................................................................................... 25 
4.1.1 
Primary Endpoint ............................................................................................ 25 
4.1.2 
Secondary Endpoints ..................................................................................... 25 
5 
STUDY DESIGN ..................................................................................................................... 28 
6 
STUDY POPULATION ........................................................................................................... 28 
6.1 
DEMOGRAPHIC AND CLINICAL CHARACTERISTICS ............................................................. 28 
6.2 
INCLUSION CRITERIA ...................................................................................................... 28 
6.3 
EXCLUSION CRITERIA ..................................................................................................... 30 
6.4 
EARLY WITHDRAWAL CRITERIA AND PROCEDURES .......................................................... 32 
7 
INVESTIGATIONAL DEVICE MANAGEMENT ..................................................................... 33 
7.1 
DEVICE ACCOUNTABILITY AND RECORDS ........................................................................ 33 
7.2 
STUDY DEVICE RETURN ................................................................................................. 34 
8 
PROCEDURES AND METHODS ........................................................................................... 34 
8.1 
TRAINING OF INVESTIGATIONAL CENTER PERSONNEL ...................................................... 34 
8.2 
INFORMED CONSENT ...................................................................................................... 34 
8.3 
SUBJECT ENROLLMENT .................................................................................................. 35 
8.4 
SUBJECT SCREENING (UP TO 3 MONTHS PRIOR TO PROCEDURE) ...................................... 35 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 5 of 83 
 
8.5 
STUDY VISITS AND PROCEDURES .................................................................................... 36 
8.5.1 
Baseline Visit (up to 7 days prior to the procedure) ....................................... 36 
8.5.2 
Procedure Visit ............................................................................................... 37 
8.5.3 
Day 1 Post-Procedure .................................................................................... 38 
8.5.4 
Discharge or at Day 10 (whichever is earlier) ................................................ 38 
8.5.5 
30 Day Visit (+ 7 days) ................................................................................... 39 
8.5.6 
90 Day Visit (± 14 days) ................................................................................. 40 
8.5.7 
180 Day Visit (± 21 days) ............................................................................... 40 
8.5.8 
Annual (Years 1–5) (± 30 days) ...................................................................... 41 
8.5.9 
Unscheduled Visits ......................................................................................... 42 
9 
HEALTH CARE RESOURCE UTILIZATION ......................................................................... 42 
10  MEDICATIONS AND FOLLOW-UP VISITS ........................................................................... 42 
10.1 
ANTICOAGULATION/ANTIPLATELET THERAPY ................................................................... 42 
10.2 
GUIDELINE DIRECTED MEDICAL THERAPY ....................................................................... 44 
10.3 
SCHEDULING FOLLOW-UP VISITS/MISSED SUBJECT VISITS .............................................. 44 
10.4 
CLINICAL STUDY TERMINATION ....................................................................................... 45 
10.5 
DATA COLLECTION METHODS ......................................................................................... 45 
10.6 
SOURCE DOCUMENTATION REQUIREMENTS .................................................................... 46 
10.7 
QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES ........................................... 46 
11  DATA MANAGEMENT ........................................................................................................... 46 
12  REPORTABLE EVENTS/EFFECTS ...................................................................................... 47 
12.1 
REPORTING EXPECTATIONS ............................................................................................. 47 
12.2 
ADVERSE EVENT ............................................................................................................ 47 
12.3 
ADVERSE DEVICE EFFECT .............................................................................................. 47 
12.4 
SERIOUS ADVERSE EVENT ............................................................................................. 47 
12.5 
SERIOUS ADVERSE DEVICE EFFECT ................................................................................ 48 
12.6 
UNANTICIPATED ADVERSE DEVICE EFFECT ..................................................................... 48 
12.7 
DEATHS AND EXPLANTS ................................................................................................. 48 
12.7.1  Subject Deaths ............................................................................................... 48 
12.7.2  Device Explants .............................................................................................. 49 
12.8 
DEVICE DEFICIENCY, FAILURE, MALFUNCTION, AND MISUSE ............................................. 49 
13  STATISTICAL ANALYSIS...................................................................................................... 49 
13.1 
ANALYSIS POPULATIONS ................................................................................................ 49 
13.1.1  Primary Endpoint ............................................................................................ 50 
13.1.2  Secondary Endpoints ..................................................................................... 50 
13.1.3  Analysis of Baseline Characteristics ............................................................... 52 
13.1.4  Analysis of Endpoints ..................................................................................... 52 
14  MONITORING ......................................................................................................................... 53 
14.1 
MONITORING METHODS .................................................................................................. 53 
14.2 
MONITORING PLAN ......................................................................................................... 53 
14.3 
PROTOCOL DEVIATION(S) .............................................................................................. 54 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 6 of 83 
 
14.4 
COMMUNICATION PROCEDURES ...................................................................................... 55 
15  STUDY COMMITTEES ........................................................................................................... 55 
15.1 
EXECUTIVE STEERING COMMITTEE ................................................................................. 55 
15.2 
CLINICAL EVENT COMMITTEE/DATA AND SAFETY MONITORING BOARD ............................. 55 
15.3 
CORE LABORATORIES ..................................................................................................... 56 
15.4 
CENTRAL SCREENING COMMITTEE .................................................................................. 56 
16  ETHICAL AND REGULATORY CONSIDERATIONS ............................................................ 56 
16.1 
APPLICABLE REGULATIONS AND GUIDELINES ................................................................... 56 
16.2 
DATA PROTECTION AND SUBJECT CONFIDENTIALITY ........................................................ 57 
16.3 
INFORMED CONSENT AND REVIEW COMMITTEES ............................................................. 57 
16.4 
INVESTIGATOR RESPONSIBILITIES ................................................................................... 57 
16.4.1  General Duties ................................................................................................ 57 
16.4.2  Investigator Records ....................................................................................... 58 
16.4.3  Investigator Reports ....................................................................................... 58 
16.5 
SPONSOR RESPONSIBILITIES .......................................................................................... 59 
16.5.1  General Duties ................................................................................................ 59 
16.5.2  Selection of Investigators ............................................................................... 59 
16.5.3  Monitoring the Study ....................................................................................... 59 
16.5.4  Sponsor Records ............................................................................................ 59 
16.5.5  Sponsor Reports ............................................................................................. 59 
16.6 
STUDY CHANGES ........................................................................................................... 60 
16.7 
STUDY SUSPENSION OR PREMATURE TERMINATION ......................................... 60 
16.7.1  Study ............................................................................................................... 60 
16.7.2  Single Site ....................................................................................................... 61 
16.7.3  Subject Follow-up ........................................................................................... 61 
16.8 
STUDY COMPLETION OR TERMINATION AND CLOSE-OUT .................................................. 61 
16.9 
AUDITS AND INSPECTIONS .............................................................................................. 61 
16.10  PUBLICATION POLICY ..................................................................................................... 61 
17  REFERENCES ........................................................................................................................ 62 
18  SCHEDULE OF STUDY ACTIVITIES AND TESTS ............................................................... 63 
19  ABBREVIATIONS AND DEFINITIONS .................................................................................. 65 
20  STUDY ENDPOINT DEFINITIONS ........................................................................................ 68 
21  STUDY-REQUIRED TEST AND EXAMINATION DEFINITIONS .......................................... 78 
21.1 
DEFINITION OF GRADE D SYMPTOMATIC SEVERE MITRAL REGURGITATION ....................... 78 
21.2 
STS SCORE CALCULATION/DEFINITIONS ......................................................................... 80 
21.1 
CSHA CLINICAL FRAILTY ............................................................................................... 81 
21.1 
NYHA, MRS, NIHSS, 6MWT, AND KCCQ ..................................................................... 82 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 7 of 83 
 
1 
SYNOPSIS  
Title: 
Neovasc Tiara™ Mitral Valve Early Feasibility Study 
Early Feasibility Study of the Neovasc Tiara™ Mitral Transcatheter 
Heart Valve with the Tiara™ Transapical Delivery System 
Study 
Objective: 
To evaluate the safety and initial performance of the Neovasc Tiara 
Mitral Transcatheter Heart Valve with the Tiara Transapical Delivery 
System. 
Data collected in this clinical study will include 6-month safety and 
performance of the device and delivery system as well as up to 5-
year clinical outcomes. 
Intended 
Use: 
The Neovasc Tiara Mitral Heart Valve, a self-expanding transcatheter 
mitral valve, and the transapical Tiara Delivery System are intended 
for use in symptomatic subjects with severe mitral regurgitation (MR) 
who are at high risk (as defined in the protocol) for open mitral valve 
surgery and who are deemed anatomically eligible for Transcatheter  
Mitral Valve Replacement (TMVR). 
Study 
Design: 
This Early Feasibility study is an international, multicenter, single-
arm, prospective, safety and performance clinical study. 
Number of 
Subjects and 
Follow-up: 
A maximum of 30 subjects will be implanted in the study at a 
maximum of 10 sites. A  maximum of 15 subjects will be implanted in 
the United States.  It is estimated that 100 subjects will be screened.  
All implanted study subjects will be assessed at the following 
intervals: Screening, Baseline, Procedure, Day 1, hospital discharge 
(or 10 days, whichever is earlier), 30 days, 90 days, 180 days, 1 year, 
and once annually thereafter for 5 years. 
Estimated 
Timeline: 
First subject in: November 2014 
Last subject in:  March 2016 
Last subject out: March 2021 
Population: 
Subjects, 18 years of age or older, with severe symptomatic mitral 
regurgitation who are at high risk for open mitral valve surgery and 
who are deemed anatomically eligible for TMVR. 
Selected 
Eligibility 
Criteria: 
Inclusion Criteria: 
1. Age 18 years or older. 
2. NYHA Class III or IV heart failure. 
3. Severe symptomatic mitral regurgitation (Stage D) by 2014 
AHA/ACC Valvular Heart Disease Guidelines [4] classification 
(several valve hemodynamic criteria are required for 
assessment of MR severity, but not all criteria for each 
category will be present in each subject):  

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 8 of 83 
 
Note: Subjects may have either primary (Degenerative) or 
secondary (Functional) MR. As per the guidelines, definition of 
Stage D varies by primary or secondary etiology. 
 
Primary (Degenerative) 
Secondary (Functional) 
Valve Anatomy 
1. Severe mitral valve 
prolapse with loss of 
coaptation or flail 
leaflet 
2. Rheumatic valve 
changes with leaflet 
restriction and loss of 
central coaptation 
3. Prior Infective 
Endocarditis 
4. Thickening of leaflets 
with radiation heart 
disease 
1. Regional wall motion 
abnormalities and/or 
LV dilation with 
severe tethering of 
mitral leaflet 
2. Annular dilation with 
severe loss of central 
coaptation of the 
mitral leaflets 
Valve 
Hemodynamics 
1. Central jet MR >40% 
LA or holosystolic 
eccentric jet MR 
2. Vena contracta ≥0.7 
cm 
3. Regurgitant volume 
≥60 mL 
4. Regurgitant fraction 
≥50% 
5. ERO ≥0.40 cm2 
6. Angiographic grade 
3–4+ 
1. ERO ≥0.20 cm2 
2. Regurgitant volume 
≥30 mL 
3. Regurgitant fraction 
≥50% 
 
 
 
 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 9 of 83 
 
 
Primary (Degenerative) 
Secondary (Functional) 
Hemodynamic 
Consequences/
Associated 
Cardiac Findings 
1. Moderate or severe 
LA enlargement 
2. LV enlargement 
3. Pulmonary 
hypertension present 
1. Regional wall motion 
abnormalities with 
reduced LV systolic 
function 
2. LV dilation and 
systolic dysfunction 
due to primary 
myocardial disease 
Symptoms 
1. Decreased exercise 
tolerance 
2. Exertional dyspnea 
1. HF symptoms due to 
MR persist even after 
revascularization and 
optimization of 
medical therapy 
2. Decreased exercise 
tolerance 
3. Exertional dyspnea 
4. High surgical risk for open mitral valve surgery as determined by 
the examining cardiac surgeon and the local institutional Heart 
Valve Team based on a Society of Thoracic Surgeons (STS) 
mitral valve replacement Predicted Risk of Mortality (PROM) 
≥ 8% and/or the Heart Valve Team assessing the risk of operative 
mortality ≥ 8% (modified from 2014 AHA/ACC Valvular Heart 
Disease Guidelines definition of High Risk). 
5. Subject meets the anatomical eligibility criteria for available 
size(s) of the Tiara Mitral Valve.  Anatomical eligibility (beyond 
annulus size) will be determined by the Central Screening 
Committee (CSC).  
6. The subject has been informed of the nature of the investigational 
device, required study follow-up procedures and visits and agrees 
to participate, and has provided written informed consent. 
Exclusion Criteria: 
1. Deemed too frail by objective frailty assessments or with severe 
comorbidities such that the subject is unlikely to benefit from the 
procedure as determined by the CSC. 
2. Subject is listed for cardiac transplantation. 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 10 of 83 
 
3. Previous cardiac procedures: 
 
PCI within 30 days of enrollment  
 
Drug Eluting Stent implantation within 3 months of enrollment  
 
Bare Metal Stent implantation within 30 days of enrollment  
 
Coronary artery bypass graft (CABG) within 30 days of 
enrollment 
 
Any previous mitral valve replacement surgery 
 
Previous TAVR within 30 days of enrollment 
 
Previous mitral valve repair surgery within 30 days of 
enrollment 
4. Evidence of any myocardial infarction (MI) within 30 days of 
enrollment. 
5. All cardiac structures will be reviewed and eligibility determined 
by the CSC: 
 
Degree of mitral stenosis, mitral annular calcification, and 
other valve anatomic pathology 
 
Previously implanted medical devices that may interfere with 
the procedure 
 
Ventricular dysfunction with ejection fraction ≤ 25% within 30 
days of enrollment 
 
Left ventricular outflow tract (LVOT) obstruction 
 
Evidence of left atrial and/or left ventricular thrombus (within 
3 months of  enrollment), vegetation or cardiac mass 
 
Apex not amenable to transapical access as deemed by the 
examining cardiac surgeon(s) 
 
Right ventricular (RV) dilatation or degree of right-sided failure 
 
Severe tricuspid regurgitation (TR) 
 
Presence of an intracardiac shunt 
 
Clinically significant untreated Coronary Artery Disease (CAD) 
6. Cerebrovascular accident and/or TIA within 30 days of 
enrollment. 
7. Subjects who are on chronic hemodialysis or who have a 
creatinine value > 3.0 mg/dL. 
8. Pregnant or planning pregnancy within next 12 months. 
9. Documented bleeding or coagulation disorders which limit 
anticoagulant therapy. 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 11 of 83 
 
10. Documented recent (within 3 months of enrollment) GI bleeding. 
11. Active infections requiring antibiotic therapy. 
12. Known hypersensitivity or contraindication to: 
 
Aspirin, or heparin, or clopidogrel (Plavix)  
 
Allergy to contrast media which cannot be managed medically 
 
Nitinol or its components (e.g., nickel or titanium) 
13. Subject is unable to undergo transesophageal echocardiography 
(TEE) during the implantation procedure. 
14. Subject is currently participating in another investigational drug or 
device clinical trial that may interfere with the results of either trial. 
(Note: Patients enrolled in a clinical trial involving products that 
are now commercially available are eligible). 
15. Subjects with a life expectancy of less than 12 months outside of 
mitral valve-related disease. 
Data 
Collection 
Time Points: 
 
Screening 
 
Baseline 
 
Procedure 
 
Day 1/Post-procedure 
 
Day 10/Discharge 
 
30 days 
 
90 days 
 
180 days 
 
Annually to 5 years 
Primary 
Safety and 
Effectiveness 
Endpoint: 
 
Freedom from all-cause mortality and major adverse events 
defined as disabling stroke, myocardial infarction (peri-procedural 
or spontaneous), renal failure requiring dialysis, life-threatening 
bleeding, and cardiac surgical or transcatheter reintervention at 
30 days from the implant procedure or hospital discharge, 
whichever is later. 
Secondary 
Endpoints: 
 
Freedom from all-cause mortality and major adverse events 
defined as disabling stroke, myocardial infarction (peri-procedural 
or spontaneous), renal failure requiring dialysis, life-threatening  
bleeding, and cardiac surgical or transcatheter reintervention at 
90 days, 180 days, one (1) year and annually to five (5) years 
from the implant procedure. 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 12 of 83 
 
 
Individual components of the primary endpoint (major adverse 
events of all-cause mortality, disabling stroke, myocardial 
infarction [peri-procedural or spontaneous], renal failure requiring 
dialysis, life-threatening bleeding, and cardiac surgical or 
transcatheter reintervention) at 30 days from the implant 
procedure or hospital discharge (whichever is later), 90 days, 180 
days, 1 year, and annually to 5 years from the implant procedure. 
 
Individual 30 day rates of the following device/procedure-related 
major adverse events (MAEs): 
 
All mortality 
 
All stroke 
 
Residual MR > mild (1+) 
 
Life threatening bleeding 
 
Acute Kidney Injury Grade 3 
 
New pacemaker/Left Bundle Branch Block (LBBB) 
 
Coronary occlusion/myocardial infarction 
 
Urgent/emergent surgery or reintervention 
 
Composite safety endpoint of the following at 30 days or hospital 
discharge, whichever is later: 
 
Freedom from all cause mortality and 
 
Freedom from major adverse events defined as 
disabling stroke, myocardial infarction, renal failure 
requiring dialysis, life threatening bleeding, and 
cardiac surgical or transcatheter reintervention. 
 
Progression of heart failure (HF) (readmission for HF, need for HF 
device implantation, cardiac transplantation or listing for 
transplantation) at 1 year from the implant procedure. 
 
Incidence of mitral valvular insufficiency of ≥ moderate at post-
procedure, discharge, 30 days, 90 days, 180 days, 1 year, and 
annually to 5 years as compared to baseline. 
 
Incidence of the composite and of individual components of major 
adverse events (all-cause mortality, disabling stroke, myocardial 
infarction [peri-procedural or spontaneous], renal failure requiring 
dialysis, life-threatening bleeding, and cardiac surgical or 
transcatheter reintervention) at 90 days, 180 days, 1 year, and 
annually to year 5 from the implant procedure. 
 
Device migration defined as any movement of any valve 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 13 of 83 
 
structure(s) compared with the final implant location, resulting in 
hemodynamic or patho-anatomic consequences (e.g., mitral 
paravalvular leak or left ventricular outflow tract obstruction). 
 
Device fracture (adjudicated as affecting valve performance or not 
affecting valve performance). 
 
Device success defined as (measured at each assessment 
interval): 
 
Successful delivery and deployment of the device in 
the correct position and retrieval of the delivery 
catheter resulting in: 
 
Mitral regurgitation < moderate (2+),  
 
Effective valve orifice area ≥ 1.5 cm2 as 
assessed by post-procedural echocardiogram,  
 
MV gradient <5 mmHg,  
 
no migration, fracture, or endocarditis,  
 
stroke free,  
 
no additional valve/access related 
interventional or surgical procedures. 
 
Procedure success defined as device success without the 
occurrence of procedure/device related major adverse events 
(defined above) in-hospital or at 30 days, whichever is later.  
 
Performance (as assessed at 30 days, 90 days, 180 days, and 
once annually for 5 years as compared to baseline): 
 
Clinical performance as measured by NYHA 
Functional Class, 6 Minute Walk Test (6MWT), and the 
Kansas City Cardiomyopathy Questionnaire (KCCQ). 
 
Hemodynamic performance as assessed by 
echocardiography: mean MV gradient, mitral 
regurgitation, effective orifice area of the MV, LV 
systolic and diastolic dimensions as well as volume. 
 
Stroke free survival. 
 
Original intended device in place. 
 
No additional valve/access-related interventional or 
surgical procedures. 
 
One (1) year non-hierarchical composite of device success and 
no need for HF hospitalization or HF hospitalization equivalent. 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 14 of 83 
 
 
Individual patient success (6 months and 1 year) defined as 
device success and all of the following: 
 
No rehospitalizations or reinterventions for HF 
(includes HF hospitalization equivalents, new listing for 
heart transplant, need for VAD or CRT) 
 
NYHA class improvement by at least 1 level from 
baseline 
 
KCCQ improvement >10 vs. baseline  
 
6MWT improvement >50 meters vs. baseline 
 
Days alive and out of hospital at one (1) year. 
Health Care 
Resource 
Utilization: 
For subjects enrolled in the US, inpatient health care resource 
utilization will be assessed by collection of all hospital bills, charges 
submitted by hospitals to third party payers, and reimbursement to 
the hospitals. 
2 
INTRODUCTION 
2.1 
BACKGROUND 
2.1.1 DISEASE PROCESS 
Mitral regurgitation (MR) is the most prevalent significant valvular disease and affects up 
to 2% of the population, with an increasing incidence with age [1]. The prevalence of 
significant MR is 0.2% between the ages of 18–44 but rises to 10% in those ≥ 70 years 
old. With the aging of the population valvular heart disease and particularly MR is 
expected to rise even further. Indeed MR is > 2x more prevalent in the elderly than aortic 
valve disease, including aortic stenosis [2, 3]. 
MR may be either primary (also termed degenerative) or secondary (also termed 
functional) [4]. Primary mitral regurgitation in the developed world is most often due to 
mitral valve prolapse, which in the younger population presents with myxomatous 
degeneration of the valve while in older patients fibroelastic deficiency disease leads to 
chordal rupture. Secondary or functional MR may be caused by ischemic heart disease 
(usually with a previous myocardial infarction) or a cardiomyopathy. There are estimated 
to be between 1.6 and 2.8 million patients with secondary MR in the United States. 
The presence of even moderate MR after a myocardial infarction is associated with a 
doubling of mortality [5]. As MR progresses patients develop worsening heart failure with 
LV dilatation, which further worsens the MR. Once significant LV dilatation and impaired 
LV function have occurred the prognosis following surgery is markedly worse. The 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 15 of 83 
 
outcome in octagenerians is also poor. More than 50% of patients with severe MR who 
are potential candidates for surgery are denied this opportunity, most often due to 
comorbid conditions, advanced age, or impaired LV function [6]. 
2.1.2 ALTERNATIVE THERAPIES/TECHNIQUES 
Surgical treatment, whether by mitral valve replacement (with either a mechanical valve 
or a bioprosthetic valve) or mitral valve repair, has been the standard therapeutic 
approach for severe mitral regurgitation. Additional surgical therapies include mitral 
annuloplasty and implantation of a Carpentier ring. 
While surgical technique has improved many patients remain at high risk for surgery, 
defined by the AHA/ACC Guidelines as having an STS score of 8% or higher, or having 
significant frailty, two comorbid organ system compromises, or specific procedure-
related impediments [4]. Recently various percutaneous techniques have been 
developed [7]. Technical innovations to reduce MR include percutaneous edge-to-edge 
leaflet plication, leaflet coaptation, leaflet ablation, direct or indirect annuloplasty, 
percutaneous chordal remodeling, and LV remodeling. While most of these 
percutaneous developments are either still in animal testing or in feasibility tests, the 
MitraClip (Abbott Cardiovascular System) was approved by the FDA in the United States 
for the treatment of degenerative severe symptomatic mitral regurgitation in patients who 
have too high a risk for surgery [8]. 
Medical therapy for severe mitral regurgitation includes use of diuretics, angiotensin 
converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARB), and beta 
blockers. Medical therapy, while of benefit in reducing congestive symptoms, is still 
associated with high morbidity and mortality in severe mitral regurgitation. 
2.1.3 STUDY PURPOSE 
The objective of this early feasibility study is to evaluate the safety and initial 
performance of the Neovasc Tiara Mitral Transcatheter Heart Valve with the Tiara 
Transapical Delivery System. 
Data collected in this clinical study will include 6 month safety and performance of the 
device and delivery system as well as up to five-year clinical outcomes.  
2.2 
STUDY DEVICE 
The Tiara Mitral Transcatheter Heart Valve is designed to be used in combination with 
the Tiara Delivery System for transapical mitral valve implantation in patients with severe 
symptomatic mitral regurgitation (Stage D by the 2014 AHA/ACC Valvular Heart Disease 
Guidelines classification) who are deemed to be at high risk for conventional mitral valve 
replacement. 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 16 of 83 
 
The following devices will be available for clinical investigational use under this study: 
Product Name 
Valve Size 
Model No. 
Neovasc Tiara™ Mitral Transcatheter 
Heart Valve  
35mm 
TAMV001 
Neovasc Tiara™ Delivery System (32Fr) 
35mm 
TADSTA001 
Neovasc Tiara™ Mitral Transcatheter 
Heart Valve  
40mm 
40TAMV01 
Neovasc Tiara™ Delivery System (36Fr) 
40mm 
36TAMDS01 
2.2.1 DEVICE DESCRIPTION – TIARA VALVE 
The Tiara Mitral Valve System (TMVS) (Figures 1 and 2) is a catheter-based self-
expanding mitral bioprosthesis that is implanted using a transapical approach.  
The Tiara valve is comprised of a medical-grade Nitinol stent with an electropolished 
finish and gold markers. The valve’s three leaflets are made of glutaraldehyde-treated 
bovine pericardial tissue; Neovasc maintains an EDQM TSE certificate for bovine 
pericardium (R1-CEP 2008-116) and the company’s quality system is certified to 
ISO 13485 for the design, development, manufacture, and distribution of bioprosthetic 
heart valves and components derived from bovine pericardial tissue. The atrial and 
ventricular “skirts” are made of medical-grade polyester fabrics. Each valve is packaged 
with an embossed polytetrafluoroethylene serial tag for identification.  
It is specifically designed to fit the complex anatomical structure of the mitral apparatus. 
The valve assembly is D-shaped to match the natural orifice of the mitral valve and to 
prevent impingement of the aorta or obstruction of the left ventricular outflow tract. The 
Tiara valve does not rely solely on radial force for securement. The atrial (inflow) portion 
engages the area of the left atrium surrounding the mitral annulus. It has a full atrial skirt 
to reduce paravalvular leakage (PVL). The ventricular side is seated securely on the 
fibrous trigones and the posterior shelf (an area situated on the roof of the left ventricle 
behind the posterior mitral leaflet due to left ventricular dilation in MR patients). Anterior 
and posterior tabs engage the mitral leaflets and chordae within the left ventricle 
(outflow) to draw the native anatomy against the body of the valve to prevent PVL. 
 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 17 of 83 
 
 
Figure 1: Tiara Valve in the Mitral Apparatus 
 
Figure 2: Tiara Valve 
2.2.2 DELIVERY SYSTEM DESCRIPTION – TIARA DELIVERY SYSTEM 
The 35mm Tiara valve is loaded onto a short 32Fr delivery catheter. The 32Fr Tiara 
delivery system (Figure 3) is utilized for loading of the 35mm valve and is compatible 
with a 0.035” guidewire.  
The 40mm Tiara valve is loaded onto a short 36Fr delivery catheter. The 36Fr Tiara 
delivery system (Figure 4) is utilized for loading of the 40mm valve and is compatible 
with a 0.035” guidewire. 
The distal (deployment) end of both the 32Fr and 36Fr systems feature an atraumatic, 
self-dilating tip. In addition, there is a radiopaque marker band embedded in the tip of the 
catheter, as well as a marker band embedded in the dilator tip. A protective sheath 
Full atrial skirt 
Left ventricular 
outflow tract 
Anterior and posterior 
anchoring tabs  

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 18 of 83 
 
covers and maintains the valve in the loaded configuration during placement. A central 
knob in the handle is used to advance and deploy the valve. 
 
 
Figure 3: Tiara Delivery System – 32Fr 
 
Figure 4: Tiara Delivery System – 36Fr 
2.2.3 TIARA IMPLANT PROCEDURE 
Tiara valve implantation is achieved transapically using a delivery system inserted 
through the apex of the heart. Deployment of the device is controlled by a single 
thumbwheel on the handle of the Tiara Delivery System and is guided by a combination 
of fluoroscopic and echocardiographic imaging (TEE). The patient is expected to remain 
hemodynamically stable throughout the procedure. Rapid pacing may be used for a 
short period (~10 seconds) during the final stage of the implant procedure to facilitate 
optimal placement of the prosthetic valve. 
In all stages of valve deployment until the final step of deploying the ventricular tabs, it is 
possible to recapture the partially deployed valve into the delivery catheter, reposition 
and complete the implant procedure, or alternatively, at the discretion of the operator, 
withdraw the catheter and unimplanted valve from the patient. 
Characteristics unique to the Tiara implant procedure (TMVR) vs. traditional mitral valve 
replacement (MVR) include: 
 
A mini-thoracotomy is utilized for transapical heart access with the Tiara implant 
vs. a full sternotomy with MVR 
 
There is no need for cardiopulmonary bypass with the Tiara implant 
 
Less anesthesia time is anticipated with the Tiara implant 
31 cm 
26.2 cm 
32Fr 
Thumbwheel 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 19 of 83 
 
 
Quicker recovery time is anticipated with the Tiara implant  
 
Ability to treat subjects with the Tiara implant who are high risk for open heart 
surgery 
2.2.4 PRIOR TESTING 
The Tiara Mitral Valve System has been in development since 2009. Extensive 
preclinical testing has been conducted, as summarized below. 
Nonclinical in vitro testing has been conducted in accordance with ISO 5840-3, 
Cardiovascular implants – Cardiac valve prostheses – Part 3: Heart valve substitutes 
implanted by transcatheter techniques and FDA’s Draft Guidance for Industry and FDA 
Staff – Heart Valves – Investigational Device Exemption (IDE) and Premarket Approval 
(PMA) Applications. Tests include tensile strength, resheathing force, function testing, 
hydrodynamic performance, accelerated wear, corrosion resistance, magnetic 
resonance imaging (MRI) compatibility, radiopacity, and finite element analysis. 
All biocompatibility testing was performed in accordance with Good Laboratory Practices 
(GLP) at an ISO 17025:2005 certified facility (NAMSA, Northwood OH). The valve and 
delivery system have met the requirements for cytotoxicity, sensitization, irritation, and 
hemocompatibility. 
The magnetic resonance (MR) compatibility of the Nitinol (NiTi) stent of the Tiara Mitral 
Transcatheter Heart Valve was determined to be MRI conditional. 
Animal studies were conducted to demonstrate the feasibility of various device design 
and procedure iterations. 
Long-term testing in sheep has demonstrated that the device is well tolerated. Histology 
data showed an appropriate healing response to the implant, with mature collagenized 
fibrous tissue growth covering the stent frame. The myocardium adjacent to and beneath 
the anchoring structures showed scarring around the device without necrosis or 
significant inflammation. 
2.2.5 PRIOR CLINICAL STUDIES 
As of October 2015, Tiara valves have been implanted in nine (9) patients in Canada 
(St. Paul’s Hospital, Vancouver, BC) through Health Canada’s Special Access 
Programme. 
This recent clinical experience demonstrates the importance of patient selection with the 
use of any transcatheter valve, which includes critical assessment of patient anatomy 
utilizing CT scan, TEE, and transthoracic echocardiography (TTE) prior to implantation 
to ensure appropriate sizing and positioning for device deployment.  

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 20 of 83 
 
The current protocol is calibrated to enroll such patients and in addition has a screening 
committee to ensure appropriate patient selection (Section 15.4). 
3 
RISK ANALYSIS 
3.1 
RISKS 
3.1.1 RISKS ASSOCIATED WITH INVESTIGATIONAL PRODUCTS 
There may be possible risks associated with the use of the TMVS including the Tiara 
Mitral Valve and the Tiara Delivery System; these risks include, but are not limited to: 
 
Access site complications (pain, bleeding, hematoma, pseudoaneurysm, 
infection) 
 
Accessory device failure 
 
Acute kidney injury (AKI) 
 
All-cause mortality 
 
Allergic reaction (e.g., to medications, contrast media, Nitinol) 
 
Anaphylactic shock/toxic reaction 
 
Aneurysm or pseudoaneurysm 
 
Angina 
 
Aortic valve damage or dysfunction 
 
Atrial perforation 
 
Bleeding, including anticoagulant/antiplatelet-related 
 
Cardiac arrhythmias/conduction disturbances 
 
Cardiac arrest 
 
Cardiac perforation 
 
Cardiogenic shock 
 
Cardiac failure/low cardiac output/decompensation/hemodynamic compromise 
 
Coronary flow obstruction due to compression of a coronary artery by the 
implanted Tiara valve 
 
Damage to the prosthetic valve 
 
Device embolization 
 
Device migration or malposition (requiring intervention) 
 
Device fracture 
 
Dyspnea 
 
Edema 
 
Embolization of debris – device- or procedure-related 
 
Endocarditis 
 
Esophageal irritation or perforation 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 21 of 83 
 
 
Failure to retrieve system components 
 
Hemolysis 
 
Hemolytic anemia 
 
Inability to complete implant procedure 
 
Increased procedure time 
 
Leak, transvalvular and/or paravalvular 
 
LVOT obstruction 
 
Mitral valve apparatus damage or dysfunction 
 
MRI incompatibility 
 
Myocardial infarction 
 
Myocardial perforation/rupture 
 
Neurological dysfunction (e. g., stroke, TIA, neurological changes/deficits) 
 
Nonstructural dysfunction (entrapment by pannus overgrowth/endothelialization) 
 
Structural deterioration, including but not limited to: calcification, leaflet tears, 
and/or chordal rupture(s)  
 
Systemic embolization 
 
Thrombosis, thromboembolism 
 
Transvalvular flow disturbances 
 
Valve deployment in unintended location 
 
Valve regurgitation 
 
Valve stenosis 
 
Valve thrombosis 
 
Virus or other transmissible agent 
These adverse events/complications could lead to: 
 
Reoperation (non-emergent or emergent coronary bypass, heart valve 
replacement) 
 
Attempted recovery/explant 
 
Permanent disability 
 
Death 
 
Conversion to open surgery 
 
Transfusion 
 
Explantation 
 
Extended hospitalization 
 
Permanent pacemaker 
 
Multi-system organ failure 
There are no known interactions of the study device(s) with concomitant medication. 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 22 of 83 
 
3.1.2 RISKS ASSOCIATED WITH STUDY PROCEDURE 
Complications associated with standard cardiac catheterization, the use of anesthesia, 
and the use of transcatheter heart valves via a transapical approach may include but are 
not limited to the following: 
 
Acute ventricular failure/rupture 
 
Abnormal lab values  
 
Allergic reaction to anesthesia or to contrast media 
 
Allergic reaction to antiplatelet agents and/or warfarin 
 
Anaphylactic shock/toxic reaction 
 
Anemia 
 
Angina 
 
Annulus rupture 
 
Arrhythmia 
 
Bleeding, procedure related; may require transfusion, medical, or surgical 
intervention 
 
Cardiovascular injury including perforation or dissection of vessels, atrium, 
ventricle, myocardium or valvular structures that may require intervention 
 
Conduction disturbances/system injury which may require a permanent 
pacemaker 
 
Coronary sinus perforation 
 
Dyspnea  
 
Embolization including air, thrombus, device particulates, calcific, external 
particulates 
 
Apical AV fistula or pseudoaneurysm 
 
Fever 
 
Heart failure 
 
Heart murmur 
 
Hematoma 
 
Hepatic dysfunction 
 
Hypertension/hypotension 
 
Infection including septicemia and endocarditis 
 
Inflammation/immunological reaction 
 
Myocardial infarction 
 
Neurological dysfunction (e.g., stroke, TIA, neurological changes/deficits) 
 
Pain or bruising at the access site 
 
Pericardial effusion/cardiac tamponade  
 
Pleural effusion 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 23 of 83 
 
 
Pulmonary edema 
 
Radiation injury 
 
Renal failure/insufficiency or acute kidney injury 
 
Respiratory insufficiency or respiratory failure 
 
Right heart failure 
 
Syncope 
 
Valve thrombosis  
 
Valve calcification 
These adverse events/complications could lead to: 
 
Death 
 
Reoperation (non-emergent or emergent coronary bypass, heart valve 
replacement) 
 
Attempted recovery/explant 
 
Permanent disability 
 
Conversion to open surgery 
 
Transfusion 
 
Explantation 
 
Extended hospitalization 
 
Permanent pacemaker 
3.1.3 RISK MANAGEMENT 
Additional warnings and actions to minimize risks to the patient include (but are not 
limited to) the following: 
 
The devices are designed, intended, and distributed for single use only. Do not 
resterilize or reuse the devices. There is no data to support the sterility, 
nonpyrogenicity, and functionality of the devices after reprocessing. 
 
Correct sizing of the Tiara Mitral Transcatheter Heart Valve and native mitral 
annulus structure is essential to help prevent paravalvular leak, migration, and/or 
annular injury. 
 
Accelerated deterioration of the Tiara Mitral Transcatheter Heart Valve may 
occur in patients with an altered calcium metabolism. 
 
If pacing is used:  Observation of the pacing lead throughout the procedure is 
essential to avoid the potential risk of pacing lead perforation. 
 
In the event of catastrophic failure of the device intra-procedure or post-
procedure, the subjects might undergo open heart surgery. 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 24 of 83 
 
 
Clinical site qualifications will be conducted to ensure that Investigators with 
transapical experience, Heart Teams, and appropriate clinical research staff are 
available to support the study. 
 
Investigators will be required to undergo valve placement training in the animal or 
benchtop model prior to their first implant. 
 
A Central Screening Committee will evaluate each patient to determine eligibility 
which includes anatomical review based on core lab CT findings.  
 
An independent Data Safety Monitoring Board (DSMB)/Clinical Events 
Committee (CEC) will assess the trial in real time. 
Additional details on product handling and procedure guidance should be followed per 
the Instructions For Use (IFU) and Investigator’s Brochure (IB). 
The Sponsor and the Executive Steering Committee (ESC) will help to assess and 
determine site and Investigator eligibility and ability to participate in the study by 
reviewing study progress and CIP compliance on an ongoing basis. 
3.2 
BENEFITS 
The Tiara Mitral Transcatheter Heart Valve is designed to be used in combination with 
the Tiara Delivery System for transapical mitral valve implantation in patients with severe 
mitral regurgitation (both primary and secondary) requiring mitral valve replacement, 
who are deemed to be at high risk for conventional MVR. There are no guaranteed 
benefits from participation in this study. The potential benefits resulting from this study 
fall into the following categories: 
 
Direct benefit subject(s) may receive from participation in the study, 
 
Possible benefit subject(s) may receive from participation in the study, 
 
Possible benefit for future patient(s) receiving the Tiara Mitral Valve based upon 
results of the study. 
Mitral valve replacement with the Neovasc Tiara Mitral Heart Valve with the transapical 
Tiara Delivery System may result in one or more of the following benefits: 
 
improved valvular function, alleviation of symptoms related to mitral 
regurgitation,  
 
improved quality of life and/or improved morbidity and mortality in patients with 
symptomatic severe MR that are high-risk for mitral valve surgery.  

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 25 of 83 
 
Specific potential benefits of the transapical approach include technically easier 
implantation than with a transseptal approach and reduced risk of vascular 
complications.  
The long-term results of using the investigational Tiara Mitral Transcatheter Heart Valve 
are not known at the present time. Alternative treatments include palliative medical 
therapy, high-risk surgical replacement of the mitral valve, and mitral valve plication with 
the MitraClip (Abbott Vascular). 
3.3 
STUDY JUSTIFICATION 
Symptomatic severe mitral regurgitation is associated with high morbidity and mortality 
with impaired quality of life. Surgical mitral valve repair or replacement is the treatment 
of choice. Many patients, due either to comorbidities or to reduced ejection fraction, are 
at high risk for a surgical approach and are therefore not suitable surgical candidates. 
The development of a transcatheter approach which can be accomplished on the 
beating heart without cardiopulmonary bypass may offer an important advance, with the 
possibility of reduction in both mortality and morbidity. The risks of the mitral implantation 
with the novel Tiara valve are therefore justified given the potential benefit of this 
scientific advance. 
4 
STUDY OBJECTIVES 
4.1 
PRIMARY OBJECTIVE 
The objective of this feasibility study is to evaluate the safety and initial performance of 
the Neovasc Tiara Mitral Transcatheter Heart Valve with the Tiara Delivery System.  
Data collected in this clinical study will include short-term safety and performance of the 
device and delivery system as well as up to five-year clinical outcomes.  
4.1.1 PRIMARY ENDPOINT 
 
Freedom from all-cause mortality and major adverse events defined as disabling 
stroke, myocardial infarction (peri-procedural or spontaneous), renal failure 
requiring dialysis, life-threatening bleeding, and cardiac surgical or transcatheter 
reintervention at 30 days from the implant procedure or hospital discharge, 
whichever is later. 
4.1.2 SECONDARY ENDPOINTS 
 
Freedom from all-cause mortality and major adverse events defined as disabling 
stroke, myocardial infarction (peri-procedural or spontaneous), renal failure 
requiring dialysis, life-threatening bleeding, and cardiac surgical or transcatheter 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 26 of 83 
 
reintervention at 90 days, 180 days, one (1) year and annually to five (5) years 
from the implant procedure. 
 
Individual components of the primary endpoint (major adverse events of all-
cause mortality, disabling stroke, myocardial infarction [peri-procedural or 
spontaneous], renal failure requiring dialysis, life-threatening bleeding, and 
cardiac surgical or transcatheter reintervention at 30 days from the implant 
procedure or hospital discharge (whichever is later), 90 days, 180 days, one (1) 
year and annually to five (5) years from the implant procedure. 
 
Individual 30 day rates of the following device/procedure-related major adverse 
events (MAEs): 
a) All mortality 
b) All stroke 
c) Residual MR > mild (1+) 
d) Life threatening bleeding 
e) Acute kidney injury Grade 3 
f) New pacemaker/LBBB 
g) Coronary occlusion/myocardial infarction 
h) Urgent/emergent surgery or reintervention 
 
Composite safety endpoint of the following at 30 days or hospital discharge, 
whichever is later: 
a) Freedom from all-cause mortality 
b) Freedom from MAEs defined as disabling stroke, myocardial infarction, 
renal failure requiring dialysis, life threatening bleeding, and cardiac 
surgical or transcatheter reintervention 
 
Progression of heart failure (HF) (readmission for HF, need for HF device 
implantation, cardiac transplantation or listing for transplantation) at 1 year from 
the implant procedure. 
 
Incidence of mitral valvular insufficiency of  ≥ moderate at post-procedure, 
discharge, 30 days, 90 days, 180 days, 1 year, and annually to 5 years as 
compared to baseline. 
 
Incidence of the composite and of individual components of major adverse 
events (all-cause mortality, disabling stroke, myocardial infarction [peri-
procedural or spontaneous], renal failure requiring dialysis, life-threatening 
bleeding, and cardiac surgical or transcatheter reintervention) at 90 days, 180 
days, 1 year, and annually to year 5 from the implant procedure. 
 
Device migration defined as any movement of any valve structure(s) compared 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 27 of 83 
 
with the final implant location, resulting in hemodynamic or patho-anatomic 
consequences (e.g., mitral paravalvular leak or left ventricular outflow tract 
obstruction). 
 
Device fracture (adjudicated as affecting valve performance or not affecting valve 
performance). 
 
Device success defined as (measured at each assessment interval): 
a) Successful delivery and deployment of the device in the correct position 
and retrieval of the delivery catheter resulting in: 
 
Mitral regurgitation < moderate (2+),  
 
Effective valve orifice area ≥ 1.5 cm2 as assessed by post-
procedural echocardiogram,  
 
MV gradient < 5 mmHg,  
 
no migration, fracture, or endocarditis,  
 
stroke free,  
 
no additional valve/access related interventional or surgical 
procedures. 
 
Procedure success defined as device success without the occurrence of 
procedure/device related major adverse events (defined above) in-hospital or at 
30 days, whichever is later. 
 
Performance (as assessed at 30 days, 90 days, 180 days, and once annually for 
5 years as compared to baseline):  
o Clinical performance as measured by NYHA Functional Class, 6MWT, and 
the KCCQ. 
o Hemodynamic performance as assessed by echocardiography: mean MV 
gradient, mitral regurgitation, effective orifice area of the MV, LV systolic 
and diastolic dimensions as well as volume. 
o Stroke free survival. 
o Original intended device in place. 
o No additional valve/access-related interventional or surgical procedures. 
 
One year non-hierarchical composite of device success and no need for HF 
hospitalization or HF hospitalization equivalent. 
 
Individual patient success (6 months and 1 year) defined as device success and 
all of the following: 
a) No re-hospitalizations or reinterventions for HF (includes HF 
hospitalization equivalents, new listing for heart transplant, need for 
VAD or CRT) 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 28 of 83 
 
b) NYHA class improvement by at least 1 level from baseline 
c) KCCQ improvement >10 vs. baseline  
d) 6MWT improvement >50 meters vs. baseline 
 
Days alive and out of hospital at one (1) year. 
5 
STUDY DESIGN 
This Early Feasibility study is an international, multicenter, single arm, prospective, study 
to evaluate the safety and performance of the Neovasc Tiara Mitral Valve System in 
subjects with symptomatic severe mitral regurgitation requiring mitral valve replacement 
who are at high risk for open chest surgery. 
A maximum of 30 subjects, 18 years of age or older, will be implanted in this study at a 
maximium of 10 sites. A maximum of 15 subjects will be implanted in the United States. 
The other geographies included in this study include Canada and Western Europe. It is 
estimated that 100 subjects will be screened. 
Subjects satisfying the inclusion criteria and exclusion criteria will be  eligible to receive 
the Neovasc Tiara Mitral Transcatheter Heart Valve with the Tiara Delivery System via a 
TMVR procedure. 
6 
STUDY POPULATION 
6.1 
DEMOGRAPHIC AND CLINICAL CHARACTERISTICS 
The study population consists of subjects, greater than 18 years of age, with severe 
symptomatic mitral regurgitation (both primary and secondary) requiring mitral valve 
replacement who are at high risk for open chest surgery and who are deemed 
anatomically eligible for TMVR. 
6.2 
INCLUSION CRITERIA  
The Principal Investigator has the responsibility of screening potential subjects to 
determine if the subject meets all of the following inclusion criteria: 
1. Age 18 years or older. 
2. NYHA Class III or IV heart failure. 
3. Severe symptomatic mitral regurgitation (Stage D) by 2014 AHA/ACC Valvular 
Heart Disease Guidelines [4] classification (several valve hemodynamic 
criteria are required for assessment of MR severity, but not all criteria for 
each category will be present in each subject). 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 29 of 83 
 
Note: Subjects may have either primary (Degenerative) or secondary 
(Functional) MR. As per the guidelines, definition of Stage D varies by primary or 
secondary etiology. 
Stage D Symptomatic Severe Mitral Regurgitation is defined as: 
 
Primary (Degenerative) 
Secondary (Functional) 
Valve Anatomy 
1. Severe mitral valve 
prolapse with loss of 
coaptation or flail leaflet 
2. Rheumatic valve 
changes with leaflet 
restriction and loss of 
central coaptation 
3. Prior Infective 
Endocarditis 
4. Thickening of leaflets 
with radiation heart 
disease 
1.  Regional wall motion 
abnormalities and/or 
LV dilation with severe 
tethering of mitral 
leaflet 
2. Annular dilation with 
severe loss of central 
coaptation of the mitral 
leaflets 
Valve Hemodynamics 
1. Central jet MR > 40% LA 
or holosystolic eccentric 
jet MR 
2. Vena contracta ≥ 0.7 cm 
3. Regurgitant volume ≥ 60 
mL 
4. Regurgitant fraction  
≥ 50% 
5. ERO ≥ 0.40 cm2 
6. Angiographic grade 3–
4+ 
1. ERO ≥ 0.20 cm2 
2. Regurgitant volume  
≥ 30 mL 
3. Regurgitant fraction  
≥ 50% 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 30 of 83 
 
 
Primary (Degenerative) 
Secondary (Functional) 
Hemodynamic 
Consequences/Associated 
Cardiac Findings 
1. Moderate or severe LA 
enlargement 
2. LV enlargement 
3. Pulmonary hypertension 
present 
1. Regional wall motion 
abnormalities with 
reduced LV systolic 
function 
2. LV dilation and 
systolic dysfunction 
due to primary 
myocardial disease 
Symptoms 
1. Decreased exercise 
tolerance 
2. Exertional dyspnea 
1. HF symptoms due to 
MR persist even after 
revascularization and 
optimization of 
medical therapy 
2. Decreased exercise 
tolerance 
3. Exertional dyspnea 
4. High surgical risk for open mitral valve surgery as determined by the examining 
cardiac surgeon and the local institutional Heart Valve Team based on an STS 
mitral valve replacement PROM ≥ 8% and/or the Heart Valve Team assessing 
the risk of operative mortality ≥ 8% (modified from 2014 AHA/ACC Valvular Heart 
Disease Guidelines definition of High Risk [4]). 
5. Subject meets the anatomical eligibility criteria for available size(s) of the Tiara 
Mitral Valve.  Anatomical eligibility (beyond annulus size) will be determined by 
the Central Screening Committee (CSC). 
6. The subject has been informed of the nature of the investigational device, 
required study follow-up procedures and visits, agrees to participate, and has 
provided written informed consent. 
6.3 
EXCLUSION CRITERIA 
Patients must be excluded if any of the following exclusion criteria is present.  
1. Deemed too frail by objective frailty assessments or with severe comorbidities 
such that the subject is unlikely to benefit from the procedure as determined by 
the CSC. 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 31 of 83 
 
2. Subject is listed for cardiac transplantation. 
3. Previous cardiac procedures: 
 
PCI within 30 days of enrollment 
 
Drug Eluting Stent implantation within 3 months of enrollment   
 
Bare Metal Stent implantation within 30 days of enrollment  
 
Coronary artery bypass graft (CABG) within 30 days of enrollment 
 
Any previous mitral valve replacement surgery 
 
Previous TAVR within 30 days of enrollment 
 
Previous mitral valve repair surgery within 30 days of enrollment 
4. Evidence of any myocardial infarction (MI) within 30 days of enrollment. 
5. All cardiac structures will be reviewed and eligibility determined by the CSC: 
 
Degree of mitral stenosis, mitral annular calcification, and other valve 
anatomic pathology 
 
Previously implanted medical devices that may interfere with the 
procedure 
 
Ventricular dysfunction with ejection fraction ≤ 25% within 30 days of 
enrollment 
 
Left ventricular outflow tract (LVOT) obstruction 
 
Evidence of left atrial and/or left ventricular thrombus (within 3 months of 
enrollment), vegetation or cardiac mass 
 
Apex not amenable to transapical access as deemed by the examining 
cardiac surgeon(s) 
 
Right ventricular (RV) dilatation or degree of right-sided heart failure 
 
Severe tricuspid regurgitation (TR)  
 
Presence of an intracardiac shunt 
 
Clinically significant untreated Coronary Artery Disease (CAD) 
6. Cerebrovascular accident and/or TIA within 30 days of enrollment. 
7. Subjects who are on chronic hemodialysis or who have a creatinine value of > 
3.0 mg/dL. 
8. Pregnant or planning pregnancy within next 12 months. 
9. Documented bleeding or coagulation disorders which limits anticoagulant 
therapy. 
10. Documented recent (within 3 months of enrollment) GI bleeding. 
11. Active infections requiring antibiotic therapy. 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 32 of 83 
 
12. Known hypersensitivity or contraindication to: 
 
Aspirin, or heparin, or clopidogrel (Plavix) 
 
Allergy to contrast media, which cannot be managed medically 
 
Nitinol or its components (e.g., nickel or titanium) 
13. Subject is unable to undergo transesophageal echocardiography (TEE) during 
the implantation procedure. 
14. Subject is currently participating in another investigational drug or device clinical 
trial that may interfere with the results of either trial. (Note: Patients enrolled in a 
clinical trial involving products that are now commercially available are eligible.) 
15. Subjects with a life expectancy of less than 12 months outside of mitral valve-
related disease. 
6.4 
EARLY WITHDRAWAL CRITERIA AND PROCEDURES 
The Investigator will make every attempt to follow the subjects at each of the required 
assessment periods. If a subject withdraws (or is withdrawn) from the clinical study, the 
reason for the withdrawal will be documented in the subject’s Case Report Form (CRF) 
and medical records. The Investigator should attempt to complete an unscheduled visit 
prior to the subject’s exit. 
Subjects will be withdrawn from the study for any of the following reasons: 
 
Subject Withdrawal 
The subject may withdraw voluntarily from the study at any time, at their 
request, without penalty or loss of benefits to which they are otherwise entitled. 
 
Physician Withdrawal 
The Principal Investigator also has the right to withdraw a subject if they feel it 
is in the best interest of the subject to do so. 
 
Lost to Follow-up 
If a subject cannot be reached for a follow-up visit, the Investigator will 
document the efforts made to contact the subject and/or efforts made to obtain 
medical records. If the subject cannot be reached, despite multiple modes of 
contacting the subject, or misses a visit, the subject will be considered “unable 
to contact” for that time interval. After three (3) documented unsuccessful 
attempts to contact the subject, a certified letter (or equivalent) will be sent to 
the subject’s residence. If there is no response after the certified letter is sent, 
the subject will be considered “lost to follow-up” and exited from the study. 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 33 of 83 
 
In all cases of study withdrawal, withdrawn subjects will not undergo further 
study follow-up procedures after the time of study exit. Reasons for withdrawal 
will be recorded on the appropriate CRF. A study subject that has been 
withdrawn from the study will not be replaced. 
Death notifications/registries may also be utilized. In the event of a subject 
withdrawal or lost to follow-up, the Sponsor may opt to obtain the death 
certificate/record. 
7 
INVESTIGATIONAL DEVICE MANAGEMENT 
7.1 
DEVICE ACCOUNTABILITY AND RECORDS  
All TMVS shipments will have an Investigational Product Packing List. Any hand-carried 
TMVS devices will be also be accompanied with an Investigational Product Packing List. 
The Principal Investigator or designee will receive the TMVS shipment and take 
inventory comparing it to the Investigational Product Packing List. The Investigational 
Product Packing List will be completed with the shipment receipt date, condition of the 
received devices and the signature of the study personnel. Both the Study Center and 
the Sponsor, Neovasc Medical Inc. (Neovasc) will maintain copies of all Investigational 
Device Records. 
The Investigator will maintain a Device Accountability Log on all received, used and 
returned Neovasc TMVS devices/components for this study. The log will be kept with the 
study documents and will be available for review during Sponsor monitoring visits. 
Documentation on the log will include: 
1. Tiara Mitral Valve serial number and size 
2. Tiara Delivery System serial number and size  
3. Subject study identification number 
4. Date of use - if the device was not used, the date of return and a reason for the 
return will be provided 
The Tiara Mitral Transcatheter Heart Valve and Transapical Delivery System inventory 
will be stored in a controlled, cool, dry and clean area. This area should be secured and 
only accessible to the Principal Investigator(s), and approved Study Personnel. Only 
Cardiovascular Surgeons and Interventional Cardiologists who have been trained on the 
use of the Neovasc TMVS devices and study protocol may implant TMVS investigational 
devices. 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 34 of 83 
 
7.2 
STUDY DEVICE RETURN 
All unused (this includes any device that is opened but not used) Neovasc TMVS 
devices will be returned to Neovasc upon notice from the Sponsor. The Device 
Accountability Log must document any unused devices that have been returned. 
Neovasc will provide instructions and shipping materials for device return as applicable. 
8 
PROCEDURES AND METHODS 
8.1 
TRAINING OF INVESTIGATIONAL CENTER PERSONNEL 
Study Investigator(s), Study Personnel, and study center clinical staff will be trained by 
Neovasc on the use of the Tiara Mitral Valve and Delivery System, the Clinical Protocol, 
and CRFs where applicable. Training will be documented on the “Training Record”, 
which all trainees must sign. Investigators will be required to undergo valve placement 
training in the animal or benchtop model prior to their first implant.  
In addition, a Delegation of Authority Log will be completed at each investigational center 
designating which individuals are allowed to perform specific study-related tasks. 
8.2 
INFORMED CONSENT  
Once the Investigator(s) have identified a patient that may be eligible for the study, the 
background of the proposed study and the benefits and risks of the study and 
procedures must be explained to the patient. Each patient shall be given ample time to 
read the entire Informed Consent Forms (ICFs) and ask questions in order to make an 
informed decision. The patient must sign the Institutional Review Board (IRB)/Ethics 
Committee (EC)/Research Ethics Board (REB) approved ICFs prior to any study 
procedures being performed. Failure to provide informed consent renders the patient 
ineligible for the study. The signed informed consents must be available for review by 
the Sponsor prior to the index procedure. 
Two separate consents will be obtained for this study, a Screening Informed Consent 
and a Study Informed Consent. While the majority, and at times all, the necessary 
screening procedures will likely have been performed as part of standard of care for 
patients with severe symptomatic mitral regurgitation, all patients will be consented 
specifically for the screening process once they have been identified as potential 
candidates for this protocol. The Screening Informed Consent includes the potential 
patients consenting that data (de-identified) may be reviewed by the Central Screening 
Committee. It is noted that some, or even all, of the screening procedures may be part of 
standard of care in specific patients, and may therefore have been obtained prior to the 
signing of the screening consent. 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 35 of 83 
 
The Study Informed Consent should be obtained only after approval of the subject by the 
Central Screening Committee for continuation in the trial. Upon signature of the Study 
Informed Consent, the subject will be eligible for the TMVR procedure and implantation. 
8.3 
SUBJECT ENROLLMENT 
A patient will be considered enrolled into the study and assigned a subject enrollment 
number after the subject has signed and dated the Screening Informed Consent. 
8.4 
SUBJECT SCREENING (UP TO 3 MONTHS PRIOR TO PROCEDURE) 
All symptomatic subjects diagnosed with severe symptomatic mitral regurgitation 
requiring mitral valve replacement seen by the Investigator(s) should be pre-screened 
for eligibility. 
Prior to collection of screening data, all potentially eligible subjects must sign the 
Screening Informed Consent as described in Section 8.2 above. 
Any subject deemed ineligible due to time-window related exclusion criteria may be re-
screened at a later time. If a subject is re-screened at a later date, the subject must 
review and sign the Screening Informed Consent and all enrollment criteria must be 
established based on the most recent information available. Re-screened subjects will 
be issued a new Subject ID. 
The screening procedures must be done no more than three months prior to the 
proposed procedure date, except as noted specifically. 
The following information may be reviewed by the Central Screening Committee (the 
CSC may also request additional information): 
1. History and physical including neurological exam, prior surgeries, and cardiac 
procedures 
2. Medications (including review of guideline directed medical therapy [GDMT] for 
heart failure) 
3. ECG* 
4. STS Risk Score/EuroSCORE II 
5. Canadian Study of Health and Aging (CSHA) 7-Point Clinical Frailty Scale 
6. NIH Stroke Scale/Modified Rankin Scale  
7. NYHA class 
8. Chemistry profile1, CBC with differential, PT/INR/PTT 
9. Pregnancy test in women of childbearing potential 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 36 of 83 
 
10. BNP or NTProBNP (whichever test is completed at screening should be collected 
throughout the duration of study) 
11. Transthoracic echocardiogram (TTE)* 
12. Transesophageal echocardiogram (TEE)* 
13. Dynamic computed tomography (CT) of the chest with contrast (without contrast 
in those with eGFR < 40 ml/min)* 
14. Coronary angiography (may be up to 6 months prior to the procedure)* 
15. Adverse Events 
*Source documents/images will be reviewed for these tests 
1 Na, K, Cl, BUN, Creatinine, Albumin, SGOT/AST, SGPT/ALT, Alkaline Phosphatase, 
Glucose, LDH 
8.5 
STUDY VISITS AND PROCEDURES 
The following visits and study related procedures and tests will take place after the 
subject has been approved by the CSC and provides Study Informed Consent. 
8.5.1 BASELINE VISIT (UP TO 7 DAYS PRIOR TO THE PROCEDURE) 
Any testing conducted at the Screening visit within 7 days of the procedure may be 
utilized as Baseline data and does not have to be repeated for the Baseline visit. 
1. Informed consent for TMVR with Tiara 
2. Physical exam including neurological exam1 
3. Pregnancy test in women of childbearing potential 
4. Listing of current medications 
5. NYHA class 
6. Chemistry panel2  
7. CBC with differential 
8. Reticulocyte count 
9. PT(INR)/PTT 
10. Plasma free hemoglobin  
11. Haptoglobin 
12. NTProBNP or BNP  
13. Troponin I or T 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 37 of 83 
 
14. Optional plasma sample for banking (10 ml of blood) 
15. QoL survey (KCCQ) 
16. NIH Stroke Scale/Modified Rankin Scale 
17. STS Risk Score/EuroSCORE II 
18. Canadian Study of Health and Aging (CSHA) 7-Point Clinical Frailty Scale 
19. 6 Minute Walk Test (6MWT) 
20. ECG 
21. Adverse Events 
1 If a stroke, TIA or change in neurological status has occurred, a neurological exam 
should be performed by a neurologist. 
2 Na, K, Cl, Glucose, BUN, Creatinine, Albumin, SGOT/AST, SGPT/ALT, Alkaline 
Phosphatase, LDH 
8.5.2 PROCEDURE VISIT 
Antibiotic prophylaxis will be given according to standard practice for valve 
implantation at each hospital. 
Transapical access will be conducted per site standard of care to allow for delivery 
system insertion and valve deployment.  The procedure will be done under TEE and 
fluoroscopic/angiographic guidance which will be recorded.  
Neovasc personnel will be present during the procedure to load the valve into the 
delivery system, and a physician proctor will also be present to provide oversight to the 
implanting physician. 
During the procedure all medications and the subject’s vital signs will be monitored as 
per standard catheterization/operating room procedures. The ACT levels will be 
monitored and adjusted to keep > 250 seconds during the procedure (see section 10.1). 
An angiogram to evaluate coronary patency must be completed after implantation of the 
Tiara Mitral Transcatheter Heart Valve prior to exit from the operating/hybrid procedure 
room. 
All intraoperative AEs will be recorded. 
1. Listing of medications administered 
2. TEE 
3. Cine/angiogram of the procedure 
4. Radiation monitoring (fluoroscopy time and radiation exposure) 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 38 of 83 
 
5. Adverse events 
8.5.3 DAY 1 POST-PROCEDURE 
1. Physical exam including neurological exam1 
2. Chemistry panel2 
3. CBC with differential 
4. Reticulocyte count 
5. PT(INR)/PTT 
6. Troponin I or T 
7. ECG 
8. Adverse events 
1 If a stroke, TIA or change in neurological status has occurred, a neurological exam 
should be performed by a neurologist. 
2 Na, K, Cl, Glucose, BUN, Creatinine, Albumin, SGOT/AST, SGPT/ALT, Alkaline 
Phosphatase, LDH 
8.5.4 DISCHARGE OR AT DAY 10 (WHICHEVER IS EARLIER) 
1. Physical exam including neurological exam1 
2. Current medications 
3. NYHA class 
4. Chemistry panel2 
5. CBC with differential  
6. PT/INR 
7. Reticulocyte count 
8. BNP or NTProBNP 
9. ECG 
10. NIH Stroke Scale/Modified Rankin Scale 
11. TTE (may be performed up to 24 hrs prior to discharge if necessary for 
scheduling purposes) 
12. Adverse events 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 39 of 83 
 
1 If a stroke, TIA or change in neurological status has occurred, a neurological exam 
should be performed by a neurologist. 
 2 Na, K, Cl, Glucose, BUN, Creatinine, Albumin, SGOT/AST, SGPT/ALT, Alkaline 
Phosphatase, LDH 
8.5.5 30 DAY VISIT (+ 7 DAYS) 
1. Physical exam including neurological exam1 
2. Current medications 
3. NYHA class 
4. Chemistry panel2 
5. CBC with differential 
6. PT/INR 
7. Reticulocyte count 
8. Plasma free hemoglobin  
9. Haptoglobin 
10. BNP or NTProBNP 
11. Optional plasma sample for banking (10 ml of blood) 
12. ECG 
13. NIH Stroke Scale/Modified Rankin Scale 
14. TTE  
15. QoL survey (KCCQ) 
16. 6MWT 
17. Cine (of the valve) 
18. Examination for radiation injury 
19. Dynamic computed tomography (CT) of the chest with contrast (without contrast 
in those with creatinine clearance < 40 ml/min)*  
20. Adverse Events 
1 If a stroke, TIA or change in neurological status has occurred, a neurological exam 
should be performed by a neurologist. 
 2 Na, K, Cl, Glucose, BUN, Creatinine, Albumin, SGOT/AST, SGPT/ALT, Alkaline 
Phosphatase, LDH 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 40 of 83 
 
8.5.6 90 DAY VISIT (± 14 DAYS) 
1. Physical exam including neurological exam1 
2. Current medications 
3. NYHA class 
4. Chemistry panel2 
5. CBC with differential 
6. Reticulocyte count 
7. BNP or NTProBNP 
8. Plasma free hemoglobin  
9. Haptoglobin 
10. Optional plasma sample for banking (10 ml of blood) 
11. ECG 
12. TTE  
13. QoL survey (KCCQ) 
14. 6MWT 
15. NIH Stroke Scale/Modified Rankin Scale 
16. Adverse events 
1 If a stroke, TIA or change in neurological status has occurred, a neurological exam 
should be performed by a neurologist. 
 2 Na, K, Cl, Glucose, BUN, Creatinine, Albumin, SGOT/AST, SGPT/ALT, Alkaline 
Phosphatase, LDH 
8.5.7 180 DAY VISIT (± 21 DAYS) 
1. Physical exam including neurological exam1 
2. Current medications 
3. NYHA class 
4. Chemistry panel2 
5. CBC with differential 
6. Reticulocyte count 
7. Plasma free hemoglobin  

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 41 of 83 
 
8. Haptoglobin 
9. BNP or NTProBNP 
10. Optional plasma sample for banking (10 ml blood) 
11. ECG 
12. TTE  
13. QoL survey (KCCQ) 
14. 6MWT 
15. NIH Stroke Scale/Modified Rankin Scale 
16. Adverse events 
1 If a stroke, TIA or change in neurological status has occurred, a neurological exam 
should be performed by a neurologist. 
 2 Na, K, Cl, Glucose, BUN, Creatinine, Albumin, SGOT/AST, SGPT/ALT, Alkaline 
Phosphatase, LDH 
8.5.8 ANNUAL (YEARS 1–5) (± 30 DAYS) 
1. Physical exam including neurological exam1 
2. Current medications 
3. NYHA class 
4. Chemistry panel2 
5. CBC with differential  
6. Reticulocyte count 
7. Plasma free hemoglobin  
8. Haptoglobin 
9. BNP or NTProBNP 
10. Optional plasma sample for banking (10 ml of blood) 
11. ECG 
12. TTE  
13. QoL survey (KCCQ) 
14. 6MWT 
15. NIH Stroke Scale/Modified Rankin Scale 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 42 of 83 
 
16. Canadian Study of Health and Aging (CSHA) 7-Point Clinical Frailty Scale (at 1 
Year visit only) 
17. Endpoint-related adverse events (after Year 1 Visit) 
1 If a stroke, TIA or change in neurological status has occurred, a neurological exam 
should be performed by a neurologist. 
 2Na, K, Cl, Glucose, BUN, Creatinine, Albumin, SGOT/AST, SGPT/ALT, Alkaline 
Phosphatase, LDH 
8.5.9 UNSCHEDULED VISITS 
Subjects may also have unscheduled visits if significant medical issues or events occur, 
at the discretion of the Investigator. The following minimum data will be collected for 
unscheduled visits: 
1. Updated history and physical including neurological exam1 
2. Medication update 
3. NYHA class 
4. Adverse events 
1 If a stroke, TIA or change in neurological status has occurred, a neurological exam 
should be performed by a neurologist. 
9 
HEALTH CARE RESOURCE UTILIZATION 
In order to obtain preliminary information regarding health care resource utilization, all 
US sites will be asked to collect hospital bills, third party insurance claims, and 
reimbursement information. All subjects will be consented to allow collection of this 
information and all such records will be deidentified in keeping with the Health Insurance 
Portability and Accountability Act (HIPAA) privacy regulations prior to being sent to the 
Sponsor or CRO. 
10 MEDICATIONS AND FOLLOW-UP VISITS 
10.1 ANTICOAGULATION/ANTIPLATELET THERAPY 
All subjects should receive concomitant anticoagulation and antiplatelet therapy 
medications as outlined in Table 1.  
Intra-procedurally, the activated clotting time (ACT) should be monitored, recorded and 
adjusted to keep the subject’s ACT > 250 sec. 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 43 of 83 
 
Post-procedure: 
 
Subjects in normal sinus rhythm: low-dose aspirin (100 mg or less daily) OR 
clopidogrel (75 mg daily) indefinitely AND warfarin or equivalent vitamin K 
antagonist for three months. 
 
Subjects in atrial fibrillation: low-dose aspirin (100 mg or less daily) OR 
clopidogrel (75 mg daily) AND warfarin or equivalent vitamin K antagonist 
indefinitely. 
Subjects who are within a year post-DES implantation, have an ACS episode during the 
period of mandated warfarin therapy (three months), or have AF and require indefinite 
anticoagulation will receive warfarin plus either ASA + clopidogrel OR clopidogrel alone 
at the physician’s discretion, based upon bleeding risk.  
Note: Novel anticoagulants (e.g., dabigatran, apixaban, rivaroxaban, edoxaban, etc.) 
should not be used in lieu of warfarin during the three months of mandated warfarin 
treatment. 
Note: Prasugrel and Ticagrelor should NOT be used in combination with 
anticoagulation (vitamin K antagonist) in this protocol. 
Table 1: Concomitant Anticoagulation/Antiplatelet Medication Recommendations 
Medication 
Pre-
Procedure 
During 
Procedure 
Post-
Procedure 
Initial 3 
Months 
Post-
Procedure 
After Initial 
3 Months 
Post-
Procedure 
Aspirin 
or 
Clopidogrel* 
ASA: 75–100 
mg if on 
chronic ASA; 
otherwise 
300–325 mg 
loading 
-or- 
Clopidogrel: 
75 mg for 
minimum 
5 days or 
600 mg 
loading 
N/A 
ASA: 75–100 
mg QD 
-or- 
Clopidogrel:75 
mg QD 
ASA 75–100 
mg QD for life 
-or- 
Clopidogrel: 
75 mg QD 
ASA: 75–100 
mg QD for life 
-or- 
Clopidogrel: 
75 mg QD 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 44 of 83 
 
Medication 
Pre-
Procedure 
During 
Procedure 
Post-
Procedure 
Initial 3 
Months 
Post-
Procedure 
After Initial 
3 Months 
Post-
Procedure 
Warfarin 
None  
None 
INR Goal: 2–3 
for 3 mos if in 
NSR 
INR Goal: 2–3 
indefinitely if 
in AF 
INR Goal: 2–
3 for 3 mos if 
in NSR 
INR Goal: 2–
3 indefinitely 
if in AF 
If in NSR: 
none 
INR Goal: 2–
3 indefinitely 
if in AF 
* Note: If the subject has an indication for dual antiplatelet therapy (DAPT) post-PCI or 
post-ACS and is also indicated as above for warfarin, aspirin and clopidogrel may be 
given in combination with warfarin (Triple Therapy) or either aspirin or clopidogrel may 
be held at the Investigator’s discretion due to bleeding risk.  
The following recommendations should be considered: 
 
Ensure no evidence of bleeding from the surgical site prior to starting any 
anticoagulation. 
 
Do not give a loading dose of Coumadin. 
 
Wait 24-48 hours post implant before starting Coumadin. 
 
Closely monitor INRs while administering anticoagulation to achieve an INR Goal 
of 2-3. Continue to monitor INRs closely to ensure stability. 
10.2  GUIDELINE DIRECTED MEDICAL THERAPY 
Guideline directed medical therapy based on AHA/ACC or national guidelines should be 
given post-procedure with particular attention to heart failure and concomitant CAD and 
hyperlipidemia.  
Subjects should receive antibiotic prophylaxis for endocarditis per the recommendations 
of the AHA or ESC (or national guidelines) for heart valve recipients. 
10.3 SCHEDULING FOLLOW-UP VISITS/MISSED SUBJECT VISITS 
At each follow-up assessment, the Investigator(s) or designee will need to determine the 
subject’s availability for future follow-up. If any subject needs to be seen at a time other 
than a regularly scheduled follow-up visit, the same information as described above will 
be documented by the Investigator on the appropriate CRFs and indicated as an 
Unscheduled Visit. Follow-up information obtained by physicians outside of the 
investigational center will be documented and sent to the Investigator. 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 45 of 83 
 
The Investigator(s) or designee will make every attempt to follow the subjects and will 
document the information gathered during the follow-up visits on the CRFs. Subjects will 
be encouraged by the Investigator(s) or designee to report any address or telephone 
number changes to the investigational center. The subject will also be informed of the 
importance of returning for scheduled follow-up visits even if they are not having any 
problems. The Investigator(s) will make every attempt to follow the subject.  
The Investigator or designee should keep a separate log of the subjects’ names and 
current addresses to facilitate their record keeping and ability to contact the subjects for 
future follow-up. If a subject cannot be reached for a follow-up assessment, the 
Investigator(s) will document it on the appropriate CRF for that interval as a ‘missed visit’ 
and will comment on the effort made to contact that subject, the subject’s primary health 
care provider, and/or hospital records. Subjects who miss a visit will not be considered 
withdrawn, and an effort to recontact them will be made by the Investigator(s) or 
designee at the next follow-up interval. 
10.4  CLINICAL STUDY TERMINATION 
The Principal Investigator(s), the EC/IRB/REB and any applicable regulatory authorities 
will be notified in writing upon termination of the study. The Sponsor retains the right to 
suspend or terminate this clinical study at any time. The DSMB/CEC associated with the 
study may recommend termination should safety concerns warrant such action.  
10.5 DATA COLLECTION METHODS  
All required data for this study are to be collected with standardized CRFs for individual 
subjects. The CRFs must be signed by the Principal Investigator or Co-Investigator listed 
on the Clinical Trial Agreement (CTA) for each subject enrolled in the study. Study 
Coordinators or a designee at each clinical site will perform primary data collection 
drawn from source document reviews. Collection and recording of subject data should 
be kept current to reflect subject status during the course of the study. The CRFs will be 
completed prospectively and in a timely manner.  
CRF Instructions will be provided to assist the Investigator(s) and Study Coordinators in 
the completion of the required CRFs.  
Primary data collection on the CRFs will be based on source document reviews 
performed by Study Coordinators or a designee at each clinical site. All applicable CRFs 
will be available to the Study Coordinator as new patients are enrolled in the study. 
All clinical sites will be monitored periodically by the Sponsor or its designee for protocol 
adherence, accuracy of CRFs, and compliance to applicable regulations. Evident 
patterns of non-compliance with respect to these standards will be cause for corrective 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 46 of 83 
 
action. If corrective actions are not subsequently undertaken, the clinical site will be 
asked to withdraw from the trial. 
10.6 SOURCE DOCUMENTATION REQUIREMENTS 
Required study data are to be recorded in the subject’s medical chart or on a study-
specific source documentation form. 
Regulations require that Investigators maintain information in the study subjects’ medical 
records to verify data collected on the CRFs. In order to comply with these regulatory 
requirements, the following information will be verified as required by the Clinical 
Research Associate (CRA), and/or/designee and/or regulatory inspectors: 
1. Medical history and physical condition of the study patient before involvement in 
the study sufficient to verify protocol entry criteria.  
2. Dated and signed notes in the patient’s medical record specifying the date of and 
names of person(s) conducting the informed consent discussions and date of 
consent signature. 
3. Dated and signed notes from each study subject visit with reference to the CRFs 
for further information, if appropriate (for specific results of procedures and 
exams). 
4. Notations on abnormal lab results and adverse events reported and their 
resolution. 
5. Notes regarding concomitant medications taken during the study. 
6. Study subject’s condition upon completion of or withdrawal from the study. 
10.7 QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES 
Because of the potential for errors, inaccuracies, and illegibility in transcribing data, 
originals or photocopies of all relevant procedural records and reports, post-procedural 
examinations, laboratory and other test results may be kept on file. 
11 DATA MANAGEMENT 
Data management will be in charge of collecting and tracking data and instituting quality 
control measures for data entry verification and trial compliance. Data Management will 
query sites when entries in the CRFs are flagged for possible errors. Neovasc will review 
SAEs, SADEs, UADEs and significant protocol deviations from the clinical protocol, and 
ensure that such information is provided to Regulatory Authorities, Investigators, ECs, 
the DSMB and the ESC as required by regulations and this CIP. 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 47 of 83 
 
12 REPORTABLE EVENTS/EFFECTS 
12.1 REPORTING EXPECTATIONS 
Adverse events will be recorded on the applicable CRFs (event, date of onset, severity, 
duration, relationship to device and procedure) by the Investigator or Research 
Coordinator, and will be followed until they are adequately resolved or explained. 
Notification of adverse events to Neovasc may be completed via telephone, fax email, or 
through the electronic database (EDC). Reportable adverse events will be submitted to 
the applicable EC/IRB/REB and regulatory authorities per national and local reporting 
regulations and requirements. 
All adverse events will be collected and reported to the Sponsor through the one year 
follow-up visit. After the one year follow-up visit and through the five year follow-up visit, 
only endpoint-related events will be collected and reported to the Sponsor. Any event 
that is deemed device-related shall be reported to the Sponsor regardless of the event 
severity. 
12.2 ADVERSE EVENT  
An adverse event is defined in ISO 14155:2011 as 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. 
12.3 ADVERSE DEVICE EFFECT  
An adverse device effect is defined in ISO 14155:2011 as an adverse event related to 
the use of an investigational medical device. This definition includes any event resulting 
from insufficient or inadequate instructions for use, deployment, implantation, 
installation, or operation, or any malfunction of the investigational medical device. 
12.4 SERIOUS ADVERSE EVENT  
A serious adverse event (SAE) is defined in ISO 14155:2011 as an adverse event that: 
led to death; led to a serious deterioration in the health of the subject, that either resulted 
in a life-threatening illness or injury, or a permanent impairment of a body structure or a 
body function, or inpatient or prolonged hospitalization, or medical or surgical 
intervention to prevent life-threatening illness or injury or permanent impairment to a 
body structure or a body function; or led to fetal distress, fetal death or a congenital 
abnormality or birth defect. A planned hospitalization for a pre-existing condition, or a 
procedure required by the CIP, without serious deterioration in health, is not considered 
an SAE.  

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 48 of 83 
 
12.5 SERIOUS ADVERSE DEVICE EFFECT 
A serious adverse device effect (SADE) is defined in ISO 14155:2011 as an adverse 
device effect that resulted in any of the consequences characteristic of a serious 
adverse event.  
The Investigator(s) will report any serious device-related adverse event on the applicable 
CRFs and to the Sponsor no later than three days, followed by a written report in ten 
working days after the Investigator(s) first learns of the event.  
It is preferable for the Investigator to notify the Sponsor within 24 hours of occurrence or 
knowledge of the device-related event. 
12.6 UNANTICIPATED ADVERSE DEVICE EFFECT  
Unanticipated adverse device effect (UADE) is defined in 21 CFR 812.3 as 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, Clinical Investigator’s 
Brochure (CIB), Clinical Protocol, or Instructions For Use (IFU), or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, 
or welfare of subjects. 
The Investigator(s) will report any unanticipated device-related adverse event to the 
Sponsor no later than three days, followed by a written report in ten working days after 
the Investigator(s) first learns of the event.  
It is preferable for the Investigator to notify the Sponsor within 24 hours of occurrence or 
knowledge of the device related event. 
12.7 DEATHS AND EXPLANTS  
12.7.1 SUBJECT DEATHS 
In the event of subject death, every effort should be made to obtain a copy of the 
autopsy report and/or death summary and/or death certificate. Information on the cause 
of death and its relationship to the study device will be determined by the Principal 
Investigator and recorded on the appropriate CRFs for study termination. 
If a device is explanted during autopsy, the device should be returned to Neovasc for 
analysis. Return kits for devices will be provided upon request by the Principal 
Investigator or the Sponsor. 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 49 of 83 
 
12.7.2 DEVICE EXPLANTS 
In the event a device is explanted, every effort should be made to obtain a copy of the 
explant procedure report. Information on the cause of explant and its relationship to the 
study device will be determined by the Principal Investigator and recorded on the 
appropriate CRFs. Copies of an explant report, if available, should be included with the 
source documentation. The device should be returned to Neovasc or designee for 
analysis. Return kits for devices will be provided upon request by the Principal 
Investigator or the Sponsor. 
12.8 DEVICE DEFICIENCY, FAILURE, MALFUNCTION, AND MISUSE  
Device Deficiency, Failure, Malfunction, and Misuse information will be collected 
throughout the study. Device Failures (event, date of onset, severity, duration, and 
relationship) will be recorded on the applicable CRFs. 
1. Device Deficiency:  Inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, safety, or performance. Device deficiencies include 
malfunctions, use errors, and inadequate labeling. 
2. Device Failure: A device has failed if it is used in accordance with the Instructions 
For Use (IFU), but does not perform according to the IFU and negatively impacts 
the treatment. 
3. Device Malfunction: A device malfunction is a failure of an investigational medical 
device to perform in accordance with its intended purpose when used in 
accordance with the IFU or CIP. 
4. Device Misuse: A misused device (one that is used by the Investigator in a 
manner that is contradictory to the IFU) will not be considered a malfunction. 
13 STATISTICAL ANALYSIS 
The main objective of this study is to demonstrate the safety of the Neovasc TMVR 
system, while gathering preliminary information on device performance and clinical 
outcomes. The trial is therefore designed to minimize the number of subjects exposed to 
the experimental device while still providing enough information for a preliminary 
indication of safety and performance before proceeding to larger clinical trials. A sample 
size of 30 subjects was chosen based on historical and regulatory experience with 
feasibility studies with transcatheter heart valves. 
13.1 ANALYSIS POPULATIONS 
Intent-to-Treat (ITT) Population: All subjects who have been enrolled in the study. A 
subject is considered enrolled in this population once they have met the 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 50 of 83 
 
inclusion/exclusion criteria and have signed the Study Informed Consent and have had 
the procedure initiated (defined as skin incision). 
NOTE: Subjects who have signed the Study Informed Consent but have not had the 
procedure initiated (defined as skin incision) will not be part of the ITT population but will 
be followed for 30 days for SAEs. 
Treated Population: All subjects who have received the Tiara valve. 
Per Protocol Population: All subjects who have received the Tiara valve and without 
major protocol deviations. 
Screening Safety Population: All subjects who have consented to the screening and 
baseline visit process. SAEs occurring within 30 days of a screening procedure will be 
reported to the Sponsor. 
13.1.1 PRIMARY ENDPOINT 
 
Freedom from all-cause mortality and major adverse events defined as 
disabling stroke, myocardial infarction (peri-procedural or spontaneous), renal 
failure, requiring dialysis,  life-threatening bleeding, and cardiac surgical or 
transcatheter reintervention at 30 days from the implant procedure or hospital 
discharge, whichever is later. 
13.1.2 SECONDARY ENDPOINTS 
 
Freedom from all-cause mortality and major adverse events defined as 
disabling stroke, myocardial infarction (peri-procedural or spontaneous), renal 
failure, requiring dialysis, life-threatening bleeding, and cardiac surgical or 
transcatheter reintervention at 90 days, 180 days, one (1) year and annually to 
five (5) years from the implant procedure. 
 
Individual components of the primary endpoint (major adverse events of all-
cause mortality, disabling stroke, myocardial infarction [peri-procedural or 
spontaneous], renal failure requiring dialysis, life-threatening bleeding, and 
cardiac surgical or transcatheter reintervention) at 30 days from the implant 
procedure or hospital discharge (whichever is later), 90 days, 180 days, 1 year, 
and annually to 5 years from the implant procedure. 
 
Individual 30 day rates of the following device/procedure-related major 
adverse events (MAEs): 
 
All mortality 
 
All stroke 
 
Residual MR > mild (1+) 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 51 of 83 
 
 
Life threatening bleeding 
 
Acute Kidney Injury Grade 3 
 
New pacemaker/LBBB 
 
Coronary occlusion/myocardial infarction 
 
Urgent/emergent surgery or re-intervention 
 
Composite safety endpoint of the following at 30 days or hospital discharge, 
whichever is later: 
 
Freedom from all cause mortality and 
 
Freedom from major adverse events defined as disabling stroke, 
myocardial infarction, renal failure requiring dialysis, life threatening 
bleeding, and cardiac surgical or transcatheter reintervention. 
 
Progression of heart failure (readmission for HF, need for HF device 
implantation, cardiac transplantation or listing for transplantation) at 1 year from 
the implant procedure. 
 
Incidence of mitral valvular insufficiency of ≥ moderate at post-procedure, 
discharge, 30 days, 90 days, 180 days, 1 year, and annually to 5 years as 
compared to baseline. 
 
Incidence of the composite and of individual components of major adverse 
events (all-cause mortality, disabling stroke, myocardial infarction [peri-
procedural or spontaneous], renal failure requiring dialysis, life-threatening 
bleeding, and cardiac surgical or transcatheter reintervention) at 90 days, 180 
days, 1 year, and annually to year 5 from the implant procedure. 
 
Device migration defined as any movement of any valve structure(s) compared 
with the final implant location, resulting in hemodynamic or patho-anatomic 
consequences (e.g., mitral paravalvular leak or left ventricular outflow tract 
obstruction). 
 
Device fracture (adjudicated as affecting valve performance or not affecting 
valve performance). 
 
Device success defined as (measured at each assessment interval): 
o Successful delivery and deployment of the device in the correct position 
and retrieval of the delivery catheter resulting in: 
 
Mitral regurgitation < moderate (2+),  
 
Effective valve orifice area ≥ 1.5 cm2 as assessed by post-
procedural echocardiogram,  
 
MV gradient <5 mmHg,  
 
no migration, fracture, or endocarditis,  
 
stroke free, 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 52 of 83 
 
 
no additional valve/access related interventional or surgical 
procedures. 
 
Procedure success defined as device success without the occurrence of 
procedure/device related major adverse events (defined above) in-hospital or at 
30 days, whichever is later.  
 
Performance (as assessed at 30 days, 90 days, 180 days, and once annually 
for 5 years as compared to baseline): 
 
Clinical performance as measured by NYHA Functional Class, 6MWT, 
and the KCCQ 
 
Hemodynamic performance as assessed by echocardiography: mean MV 
gradient, mitral regurgitation, effective orifice area of the MV, LV systolic 
and diastolic dimensions as well as volume 
 
Stroke free survival 
 
Original intended device in place 
 
No additional valve/access-related interventional or surgical procedures 
 
One (1) year non-hierarchical composite of device success and no need for HF 
hospitalization or HF hospitalization equivalent. 
 
Individual patient success (6 months and 1 year) defined as device success 
and all of the following: 
 
No rehospitalizations or reinterventions for HF (includes HF 
hospitalization equivalents, new listing for heart transplant, need for VAD 
or CRT) 
 
NYHA class improvement by at least 1 level from baseline 
 
KCCQ improvement >10 vs. baseline  
 
6MWT improvement >50 meters vs. baseline 
 
Days alive and out of hospital at one (1) year. 
13.1.3 ANALYSIS OF BASELINE CHARACTERISTICS 
Subject demographics, risk factors, angiographic, echocardiographic and procedural 
characteristics will be summarized. These will be presented as the mean and standard 
deviation for continuous variables and as frequencies and percentages for discrete 
variables. 
13.1.4 ANALYSIS OF ENDPOINTS 
Discrete endpoint variables will be presented in tabular format presenting the frequency 
and percent of each outcome. Continuous variables will be reported by providing their N, 
mean, median standard deviation, minimum and maximum values. 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 53 of 83 
 
For the primary endpoint, a Kaplan-Meier curve will be presented that shows time from 
procedure to first event. Subjects will be censored on the date of discontinuation or the 
final date used for the analysis, whichever occurs first. This same analysis will be used 
for each component of the primary endpoint which is defined as a secondary endpoint. 
Each endpoint that is time-dependent will use this type of analysis. 
For binary outcomes, a one sample Exact binomial test will be used to compare each 
response rate to 0.5. For continuous variables that meet the assumption of normality, the 
change from baseline will be compared to baseline using a one sample t-test. If the 
assumption for normality is not met, then a Wilcoxon signed-rank test will be performed. 
14 MONITORING 
14.1 MONITORING METHODS  
A study monitor (CRA) will be assigned by Neovasc to monitor the progress of the study. 
The study monitor will remain in close contact with each investigational center 
throughout the duration of the study to provide any needed materials (e.g., CRFs) or 
answer any questions. The study monitor will be responsible for reviewing CRFs and 
visiting each investigational center periodically to observe study progress and 
compliance with the study protocol by each center. 
Monitoring visits will be scheduled throughout the duration of the study between the 
monitor and the Investigator at a mutually convenient and available time. These visits 
will ensure that the facilities are still acceptable, the protocol and investigational plan are 
being followed, the IRB/EC/REB has been notified of approved protocol changes as 
required, complete records are being maintained, appropriate timely reports have been 
made to the Sponsor and the IRB/EC/REB, device and device inventory are controlled 
and the Investigator is carrying out all agreed activities. Any personnel changes must be 
reported to the monitor immediately and a training program scheduled and documented. 
Monitoring will be conducted in accordance with each country’s specific requirements. 
To protect subject confidentiality, the subject’s name must not appear anywhere on the 
CRFs, imaging media, or source documentation sent to the Sponsor. Each page should 
be identified with the subject’s study ID number only. All other subject identifiers (e.g., 
medical record number, subject name, date of birth) are to be obscured. 
14.2 MONITORING PLAN 
Prior to patient enrollment, a study initiation visit will be completed at each 
investigational center to ensure the following: 
1. IRB/EC/REB approval has been obtained and documented; 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 54 of 83 
 
2. The Investigators and study personnel are appropriately trained and clearly 
understand the study; 
3. The Investigators and study personnel accept the obligations incurred in 
undertaking this clinical investigation. 
Interim Monitoring Visits will be conducted to ensure the following: 
1. The study is being conducted in accordance with the protocol; 
2. EC/IRB/REB requirements and applicable regulations are being followed;  
3. Managing product supplies, and ensuring ongoing follow-up of open action items; 
4. Resolution of all outstanding site action items.  
Close-out visits are conducted at the end of the study to ensure the following: 
1. Study documentation is complete;  
2. Open action items are closed;  
3. Record retention requirements are understood. 
14.3 PROTOCOL DEVIATION(S)  
A protocol deviation is defined as an event where the Investigator or center personnel 
did not conduct the study according to the clinical protocol (clinical investigation plan) or 
the Investigator Agreement. Investigators shall be required to obtain proper approval 
from the Sponsor before initiating deviations from the clinical protocol, except where 
necessary to protect the life or physical well-being of a subject in an emergency. Such 
approval shall be documented in writing and maintained in study files. Prior approval is 
generally not expected in situations where unforeseen circumstances are beyond the 
Investigator’s control (e.g., subject did not attend scheduled follow-up visit, etc.), 
however the event is still considered a deviation. 
Deviations shall be reported to the Sponsor regardless of whether medically justifiable, 
pre-approved by Neovasc, or taken to protect the subject in an emergency. Subject-
specific deviations will be reported on the CRFs. Investigators will also adhere to 
procedures for reporting study deviations to their institutional review committee in 
accordance with their specific review committee’s reporting policies and procedures. 
For reporting purposes, deviations are classified as major or minor: 
1. Major deviation 
a. Any deviation from patient inclusion and exclusion criteria unless 
approved by the CSC prior to enrollment.  
b. Any deviation from patient informed consent procedures. 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 55 of 83 
 
c. Unauthorized use of an investigational device outside of the study or not 
compliant with the current IFU. 
d. Unauthorized use of an investigational device by a physician who has not 
signed an Investigator Agreement. 
2. Minor deviation 
a. Deviation from a protocol requirement such as incomplete/inadequate 
subject testing procedures.  
b. Follow-up performed outside specified time windows, etc. 
The site will receive a list of study deviations on an annual basis as part of the Annual 
Progress Report and as part of the Final Report. The Sponsor will review all study 
protocol deviations and implement corrective action plans for those deviations and 
investigational sites when necessary. 
14.4 COMMUNICATION PROCEDURES 
During the course of the study, all correspondence (letters, telephone calls, emails and 
faxes) regarding the study must be maintained in the study binder provided by the 
Sponsor. This binder must be made available for monitoring visits or audits. 
15 STUDY COMMITTEES 
15.1 EXECUTIVE STEERING COMMITTEE 
The ESC will be in charge of overall study design and conduct and will be composed of 
key opinion leaders in transcatheter valve replacement. The committee will meet by 
teleconference or in person as frequently as necessary, to monitor subject enrollment, 
clinical site progress, and protocol compliance. This committee will be responsible for 
reviewing the final results, determining the methods of presentation and publication, and 
selection of secondary projects and publications. 
15.2 CLINICAL EVENT COMMITTEE/DATA AND SAFETY MONITORING BOARD 
Given the open label single arm design of this feasibility study, a combined Clinical 
Events Committee/Data and Safety Monitoring Board (CEC/DSMB) will be established to 
adjudicate adverse events and monitor the safety of the study. The CEC/DSMB 
members will be independent of both Neovasc and the study Investigators and will meet 
regularly according to a schedule determined during the first CEC/DSMB meeting. The 
CEC/DSMB will have at least three (3) members and will include at least one 
cardiothoracic surgeon and one interventional cardiologist, and as needed, a 
neurologist. 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 56 of 83 
 
The CEC/DSMB will be responsible for adjudicating endpoint-related events reported 
during the trial. All CEC/DSMB meeting minutes will remain strictly confidential, but open 
session minutes will be made available to regulatory authorities upon request. 
At the onset of the study, the CEC/DSMB will detail explicit rules outlining the minimum 
amount of data required. These rules will be submitted to the Sponsor for final approval. 
Members are provided data summaries from the clinical study.  
The CEC/DSMB will meet prior to initiation of enrollment and periodically or as needed if 
significant safety issues are identified. During the first meeting the CEC/DSMB will 
review, modify as needed, and approve the CEC/DSMB charters. The CEC/DSMB may 
establish criteria (i.e., stopping rules) for recommending study termination. The 
CEC/DSMB will review all adverse events, deaths, explants and unanticipated adverse 
device effects in relation to the role of the device. The CEC/DSMB data review is to 
detect evidence of early dramatic benefit or harm for subjects while the clinical study is 
in progress. The CEC/DSMB will be responsible for recommending if the trial should be 
terminated prior to study completion due to, but not limited to, the observation that the 
serious adverse events outweigh possible clinical benefit.  
Additional duties may be assigned during execution of the study protocol that are 
unforeseen (e.g., input on protocol modifications).  
15.3 CORE LABORATORIES 
Core Laboratories will be utilized throughout the study for review of Angiography, CT, 
and Echocardiography.  
15.4 CENTRAL SCREENING COMMITTEE 
The CSC will review each potential subject in order to make a formal determination of 
whether the subject meets enrollment criteria for the study, taking into account the 
specific screening tests (see Section 8.4) as well as the overall suitability of the subject. 
The committee will include experts in transcatheter valve replacement from the fields of 
cardiothoracic surgery, interventional cardiology, CT, and echocardiography. 
16 ETHICAL AND REGULATORY CONSIDERATIONS 
16.1 APPLICABLE REGULATIONS AND GUIDELINES  
It is the responsibility of the Investigator(s) to comply with the requirements set forth in 
their country-specific and institutional regulations. Furthermore, the Investigator must 
comply with the requirements of the Declaration of Helsinki or with laws of the foreign 
country, whichever will afford greater protection to the subject. 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 57 of 83 
 
The Investigator should also take into consideration guidelines applicable to the study 
population such as the AHA/ACC 2014 Guidelines on Valvular Heart Disease, and the 
ESC/EACTS 2012 Guidelines on Valvular Heart Disease. 
16.2 DATA PROTECTION AND SUBJECT CONFIDENTIALITY 
The confidentiality and privacy of subjects who volunteer to participate in the study will 
be protected to the fullest extent possible. Passwords are issued to appropriate 
personnel to ensure confidentiality and protection of the database by allowing variable 
levels of access to the computer system on a need to know basis. In addition, the study 
Investigator is responsible for maintaining confidentiality throughout the clinical study. 
The hard copies of the CRFs and source documentation are to be maintained in a 
secure area with limited access. All subject identifiers will be obliterated from all 
photocopies of source documents that have been removed from the site. Subject 
identifiers include, but are not limited to: subject’s name, social security number, and 
medical/hospital number. All study documents will identify the subject by a subject study 
identification number assigned by the Sponsor. 
16.3 INFORMED CONSENT AND REVIEW COMMITTEES 
All subjects must provide written informed consent in accordance with the local clinical 
center’s institutional review committee. A copy of the consent form from each center 
must be forwarded to Neovasc for review and approval prior to submitting it to the 
institutional review committee. Each center must provide the Sponsor with a copy of the 
clinical center’s IRB/EC/REB  approval letter (stating the study name, protocol revision 
being approved and an approval date) and the informed consent. IRB/EC/REB 
approvals for the continuation of the trial at each clinical site must also be forwarded to 
the Sponsor. 
16.4 INVESTIGATOR RESPONSIBILITIES 
16.4.1 GENERAL DUTIES 
The Investigator shall ensure that all work and services described herein, or incidental to 
those described herein, shall be conducted in accordance with the highest standards of 
medical and clinical research practice and the applicable regulations. The Investigator 
will provide copies of the current study protocol to all staff responsible for study conduct. 
The role of the Principal Investigator is to implement and manage the day-to-day 
conduct of the clinical investigation as well as ensure data integrity and the rights, safety, 
and well-being of the subjects involved in the clinical investigation. 
The Principal Investigator is responsible for obtaining and maintaining site IRB/EC/REB 
approval. 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 58 of 83 
 
16.4.2 INVESTIGATOR RECORDS 
The Principal Investigator will maintain the accurate, complete, and current records 
relating to participation in this clinical study. Study records including CRFs and 
supporting data (e.g., copies of all labs and diagnostic exams, signed Clinical Trial 
Agreement, protocols and protocol amendments, signed ICFs, device usage, 
IRB/EC/REB approval letters, IRB/EC/REB submissions, correspondence, including 
required reports, and other documents pertaining to the conduct of the study) must be 
kept on file by the Investigator. The Sponsor will ensure that all study sites are trained on 
the requirement to retain and archive all records pertaining to this clinical study as per 
the Clinical Trial Agreement and/or local/national regulations, whichever is longer.  
If the Investigator(s) wishes to assign the files to someone else or remove them to 
another location, the Investigator should consult with the Sponsor in writing as to this 
change. Study files must be maintained in a known location until the Sponsor notifies the 
Investigator in writing that he/she may discard them. 
16.4.3 INVESTIGATOR REPORTS 
The Principal Investigator will prepare and submit the following accurate and complete 
reports to the Sponsor and institutional review committee in a timely manner: 
 
Unanticipated adverse device effects occurring during the study will be reported 
as soon as possible, but no later than 10 working days after the Principal 
Investigator first learns of the event.  
 
Withdrawal of institutional review committee approval will be reported to the 
Sponsor within five (5) working days of review committee withdrawal. Annual 
progress reports will be submitted to the institutional review committee.  
 
Deviation from the clinical protocol (clinical investigation plan) to protect the 
subject’s life or physical well-being in an emergency will be reported to the 
Sponsor and the IRB/EC/REB within five (5) working days. Planned deviations 
from the clinical protocol (investigational plan) require prior approval from the 
Sponsor and as required from the IRB/EC/REB. Use of the TMVR study 
devices without informed consent will be reported to Neovasc and IRB/EC/REB 
within five (5) working days after the use occurs.  
 
A final written report is submitted to the Sponsor and the IRB/EC/REB within 
three months of completion or termination of the trial.  
 
Upon request by a reviewing IRB/EC/REB or the pertinent regulatory agencies, 
the Principal Investigator will provide current information about any aspect of 
the investigation. 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 59 of 83 
 
16.5 SPONSOR RESPONSIBILITIES 
16.5.1 GENERAL DUTIES 
As the Sponsor of this clinical study, Neovasc has the overall responsibility for the 
conduct of the study, including assurance that the study meets the regulatory 
requirements of the pertinent regulatory agencies. In this study, Neovasc will have 
primary responsibility and will delegate some responsibilities to (but not limited to) core 
labs and EDC vendors. 
16.5.2 SELECTION OF INVESTIGATORS  
Neovasc will select qualified Investigators and will ship investigational devices to 
participating Investigators fully trained for the clinical study (e.g., IFU, study manual, 
etc.). Neovasc will obtain signed study agreements and provide the Investigators with 
the information and supplies necessary to conduct the study. 
16.5.3 MONITORING THE STUDY  
The Sponsor will ensure compliance with the signed clinical trial agreement, the protocol 
(clinical investigation plan), the requirements of applicable regulations according to 
geographic investigational site location/jurisdiction, and any conditions of study approval 
by the regulatory authorities. 
Neovasc will conduct an immediate investigation of any unanticipated adverse device 
effects (UADEs) and if an event is found to present an unreasonable risk to study 
subjects. 
16.5.4 SPONSOR RECORDS  
Neovasc will maintain accurate, complete, and current records relating to this clinical 
study. Study records include CRFs, signed clinical trial agreements, financial 
disclosures, protocols and protocol amendments, device usage, IRB/EC/REB approval 
letters and submissions, correspondence, including required reports, and other 
documents. The Sponsor will maintain study documentation during the study and for up 
to two (2) years (or as required by the applicable regulatory requirements) after the study 
is terminated or completed, or the study records are no longer required to support a 
regulatory submission. Storage of the study records may be designated to a third party. 
16.5.5 SPONSOR REPORTS 
The Sponsor will prepare and submit the following accurate and complete reports to the 
investigational site’s IRB/EC/REB and the pertinent regulatory agencies in a timely 
manner: 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 60 of 83 
 
 
Unanticipated adverse device effects reported by an investigational site will be 
evaluated and the IRB/EC/REB and the pertinent regulatory agencies will be 
informed of the results of the evaluation no later than 10 working days after the 
Sponsor first learns of the event. 
 
Withdrawal of IRB/EC/REB approval will be reported to all IRB/EC/REBs and 
the pertinent regulatory agencies within five (5) working days of receipt of 
withdrawal of approval. 
 
Withdrawal of the pertinent regulatory agencies’ approval will be reported to 
investigational centers and IRB/EC/REBs within five (5) working days after 
receiving the notice of approval withdrawal. 
 
A current Investigator list will be submitted to the pertinent regulatory agencies 
at six (6) month intervals, if applicable. 
 
Progress reports will be submitted to the IRB/EC/REBs at least annually and to 
the pertinent regulatory agencies as required. 
 
A final written report is to be completed and submitted to the IRB/EC/REBs and 
the pertinent regulatory agencies within six months after completion or 
termination of the trial. 
 
Use of the investigational TMVR device without informed consent will be 
reported to regulatory authorities within five (5) working days after notification of 
device use. 
 
Upon request by a reviewing IRB/EC/REB or the pertinent regulatory agencies, 
Neovasc will provide current information about any aspect of the investigation. 
16.6 STUDY CHANGES 
Changes in the protocol may be made only by written amendment agreed upon by the 
Sponsor, Investigator, and if pertinent, the IRB/EC/REB. As appropriate, Neovasc will 
submit changes in the protocol to the pertinent regulatory agencies and Investigators to 
obtain IRB/EC/REB re-approval. 
16.7 STUDY SUSPENSION OR PREMATURE TERMINATION 
16.7.1 STUDY 
The study could be suspended or prematurely terminated for the following reasons, 
including but not limited to: 
 
Business decision by Sponsor 
 
DSMB recommendation due to safety concerns 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 61 of 83 
 
16.7.2 SINGLE SITE 
The study could be suspended or prematurely terminated at a clinical investigaton site 
for the following reasons, including but not limited to: 
 
Investigator or site noncompliance 
 
Change in study personnel 
16.7.3 SUBJECT FOLLOW-UP 
In the event that either the study or an investigation site are terminated, subjects should 
continue follow-up care with their primary cardiologist. 
16.8 STUDY COMPLETION OR TERMINATION AND CLOSE-OUT 
The Principal Investigator will be notified in writing upon termination/conclusion of the 
study. Neovasc retains the right to suspend or terminate this clinical study at any time. 
16.9 AUDITS AND INSPECTIONS 
In the event that audits are initiated by the Sponsor or national/international regulatory 
authorities, the Investigator shall allow access to the original medical records and 
provide all requested information. 
16.10  PUBLICATION POLICY 
The Sponsor and the Executive Steering Committee are committed to the timely and 
transparent dissemination of the trial results. A multicenter publication will be prepared 
for publication in a reputable scientific journal. The publication of the principal results 
from any single center experience within the trial is not allowed until the preparation and 
publication of the multicenter results. Exceptions to this rule require prior approval from 
Neovasc. For purposes of abstract presentation and publication, any secondary 
publications will be delegated to the appropriate principal authors, and final analyses and 
manuscript review for all multicenter data will require the approval of Neovasc.  
 
 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 62 of 83 
 
17 REFERENCES 
1. 
Go, A.S., et al., Heart disease and stroke statistics--2013 update: a report from the 
American Heart Association. Circulation, 2013. 127(1): p. e6-e245. 
2. 
Vahanian, A., et al., Guidelines on the management of valvular heart disease (version 
2012): the Joint Task Force on the Management of Valvular Heart Disease of the 
European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic 
Surgery (EACTS). Eur J Cardiothorac Surg, 2012. 42(4): p. S1-44. 
3. 
Nkomo, V.T., et al., Burden of valvular heart diseases: a population-based study. Lancet, 
2006. 368(9540): p. 1005-11. 
4. 
Nishimura, R.A., 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 Thorac Cardiovasc Surg, 2014. 148(1): 
p. e1-e132. 
5. 
Grigioni, F., et al., Ischemic mitral regurgitation: long-term outcome and prognostic 
implications with quantitative Doppler assessment. Circulation, 2001. 103(13): p. 1759-
64. 
6. 
Mirabel, M., et al., What are the characteristics of patients with severe, symptomatic, 
mitral regurgitation who are denied surgery? Eur Heart J, 2007. 28(11): p. 1358-65. 
7. 
De Backer, O., et al., Percutaneous transcatheter mitral valve replacement: an overview 
of devices in preclinical and early clinical evaluation. Circ Cardiovasc Interv, 2014. 7(3): 
p. 400-9. 
8. 
Minha, S., R. Torguson, and R. Waksman, Overview of the 2013 Food and Drug 
Administration Circulatory System Devices Panel meeting on the MitraClip Delivery 
System. Circulation, 2013. 128(8): p. 864-8. 
9. 
Rockwood, K., et al., A Global and Clinical Measure of Fitness and Frailty in elderly 
people. CMAJ 2005; 173(5): 489-495. 
10. 
Kappetein, A. P., et al, Updated standardized endpoint definitions for transcatheter aortic 
valve implantation: The Valve Academic Research Consortium-2 consensus document.  
Eur Heart Journal (2012) 33, p. 2403-2418. 
11. 
Stone, G.W., et al, Clinical Trial Design Principles and Endpoint Definitions for 
Transcatheter Mitral Valve Repair and Replacement: Part 1: Clinical Trial Design 
Principles. JACC (2015) 66, p. 278-307.11.   
 
12. 
Stone, G.W., et al, Clinical Trial Design Principles and Endpoint Definitions for 
Transcatheter Mitral Valve Repair and Replacement: Part 2: Endpoint Definitions. JACC 
(2015) 66, p. 308-321. 
13.  
Association of Thoracic Surgeons Statement: Guidelines for the Six Minute Walk Test. 
Am J Respir Crit Care Med 2002: 166:111-117 
14.  
Mehran, Roxanna et al, Standardized Bleeding Definitions for Cardiovascular Clinical 
Trials. Circulation, 2011; 123: 2736-2747. 
15. 
Thygesen, K. et al, Third Universal Definition of Myocardial Infarction. Circulation 2012; 
126: 2020-2035. 
 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 63 of 83 
 
18 SCHEDULE OF STUDY ACTIVITIES AND TESTS 
Test/Activity 
Screening
1 
Baseline 
(-7–0 days)
2
Procedure
Day 1 
Discharge 
(or up to 
10 days)
3 
30 Days 
(plus up 
to 7 days)
90 Days 
(± 14 days)
180 Days 
(± 21 days)
Annual 
(± 30 days)
Unscheduled 
Visit 
Informed consent 
X 
X 
 
 
 
 
 
 
 
 
Physical exam (including neurological exam
4) 
and subject interview 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test ( for ♀ of reproductive 
potential) 
X 
X 
 
 
 
 
 
 
 
 
Listing of current medications 
X
11 
X 
X
12 
 
X 
X 
X 
X 
X 
X 
NYHA class 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
Blood (serum) chemistry
5 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
CBC with differential 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Reticulocyte count 
 
X 
 
X 
X 
X 
X 
X 
X 
 
PT/INR 
X 
X 
 
X 
X 
X 
 
 
 
 
PTT 
X 
X 
 
X 
 
 
 
 
 
 
Plasma free hemoglobin 
 
X 
 
 
 
X 
X 
X 
X 
 
Haptoglobin 
 
X 
 
 
 
X 
X 
X 
X 
 
NTProBNP or BNP
6 
X 
X 
 
 
X 
X 
X 
X 
X 
 
Troponin I or T 
 
X 
 
X 
 
 
 
 
 
 
Plasma sample
7 
 
X 
 
 
 
X 
X 
X 
X 
 
QoL survey (KCCQ)
8 
 
X 
 
 
 
X 
X 
X 
X 
 
NIH Stroke Scale
9 + Modified Rankin Scale
9 
X 
X 
 
 
X 
X 
X 
X 
X 
 
STS Risk Score/EuroSCORE II 
X 
X 
 
 
 
 
 
 
 
 
Canadian Study of Health and Aging (CSHA) 
X 
X 
 
 
 
 
 
 
X 
 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 64 of 83 
 
Test/Activity 
Screening
1 
Baseline 
(-7–0 days)
2
Procedure
Day 1 
Discharge 
(or up to 
10 days)
3 
30 Days 
(plus up 
to 7 days)
90 Days 
(± 14 days)
180 Days 
(± 21 days)
Annual 
(± 30 days)
Unscheduled 
Visit 
7-Point Clinical Frailty Scale 
Year 1 only
6 Minute Walk Test (6MWT) 
 
X 
 
 
 
X 
X 
X 
X 
 
ECG 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
TTE 
X 
 
 
 
X 
X 
X 
X 
X 
 
TEE 
X 
 
X
14 
 
 
 
 
 
 
 
CT scan (dynamic)
10 
X 
 
 
 
 
X 
 
 
 
 
Angiogram 
X
13 
 
X 
 
 
 
 
 
 
 
Cine 
 
 
X
14 
 
 
X 
 
 
 
 
Radiation monitoring 
 
 
X
15 
 
 
X
16 
 
 
 
 
Adverse events (AEs) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Footnotes: 
1 
Screening procedures must be done no more than three months prior to the proposed procedure date, except as specifically noted in the protocol 
2 
Any testing conducted at the screening visit within seven days of the procedure may be utilized as baseline data and does not have to be repeated for the baseline visit 
3 
Discharge should be at the time of discharge or at day 10, whichever is earlier 
4 
If a stroke, TIA, or change in neurological status has occurred, a neurological exam should be performed by a neurologist 
5 
Glucose, Na, K, Cl, SGOT/AST, SGPT/ALT, BUN, Creatinine, Albumin, LDH, Alkaline Phosphatase 
6 
The test that is completed at the time of screening, either NTProBNP or BNP, should be collected throughout the duration of the study 
7 
Optional test dependent on site (EC/IRB/REB) approvals and subject approval/consent 
8 
Questionnaire completed by the subjects 
9 
Personnel conducting the mRS and NIHSS must have completed certification before conducting each exam 
10 Dynamic CT of the chest with contrast (without contrast in those with eGFR < 40 ml/min) 
11 Medication list to include review of guideline directed medical therapy (GDMT) for heart failure 
12 Listing of medications administered during procedure 
13 Angiogram may be collected within six months of the planned procedure date 
14 TEE and Cine during the procedure should be recorded 
15 Including all fluoroscopy time and radiation exposure 
16 Examination for radiation injury 
 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 65 of 83 
 
19 ABBREVIATIONS AND DEFINITIONS 
ADE 
AE 
ACC 
ACS 
ACT 
AHA 
ARO 
Adverse Device Effect 
Adverse Event 
American College of Cardiology 
Acute Coronary Syndrome 
Activated Clotting Time 
American Heart Association 
Academic Research Organization 
BARC 
CAD 
CBC 
Bleeding Academic Research Consortium 
Coronary Artery Disease 
Complete Blood Cell Count 
CDRH 
Center for Devices and Radiological Health 
CDMS 
CEC 
Clinical Data Management System 
Clinical Events Committee 
CFR 
CIP 
COPD 
CRA 
Code of Federal Regulations 
Clinical Investigation Plan 
Chronic Obstructive Pulmonary Disease 
Clinical Research Associate (monitor) 
CRF 
Case Report Form 
CRO 
CSC 
CSHA 
CT 
cTn 
CTS 
Contract Research Organization 
Central Screening Committee 
Canadian Study of Health and Aging  
Computed Tomography 
Cardiac Troponin 
Cardiothoracic Surgeon 
DAPT 
DSMB 
EACTS 
EC 
ESC 
Dual Antiplatelet Therapy 
Data and Safety Monitoring Board 
European Association of Cardio-Thoracic Surgery 
Ethics Committee 
Executive Steering Committee or European Society of Cardiology 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 66 of 83 
 
FDA 
Food and Drug Administration 
GCP 
GDMT 
GI 
Good Clinical Practices 
Guideline Directed Medical Therapy 
Gastrointestinal 
GLP 
HF 
Good Laboratory Practices 
Heart Failure 
IC 
ICF 
Interventional Cardiologist 
Informed Consent Form 
ICH 
International Conference on Harmonization 
ICU 
Intensive Care Unit 
IDE 
IFU 
Investigational Device Exemption 
Instructions for Use 
IRB 
Institutional Review Board 
ISO 
International Standards Organization 
ITT 
LBBB 
LV 
Intent-to-Treat 
Left Bundle Branch Block 
Left Ventricle 
MedDRA® 
MACCE 
MACE 
MI 
MR 
MV 
mRS 
MVARC 
MVR 
NIHSS 
NYHA 
PCI 
POBA 
PROM 
Medical Dictionary for Regulatory Activities 
Major Adverse Cardiac and Cerebrovascular Event 
Major Adverse Cardiac Event 
Myocardial Infarction 
Mitral Regurgitation 
Mitral Valve 
Modified Rankin Score 
Mitral Valve Academic Research Consortium 
Mitral Valve Replacement 
National Institutes of Health Stroke Scale 
New York Heart Association 
Percutaneous Coronary Intervention 
Plain Old Balloon Angioplasty 
Preoperative Risk of Mortality 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 67 of 83 
 
PVD 
QoL 
RBC 
REB 
RV 
SAE 
SADE 
6MWT 
TAMI 
TEE 
TIA 
TMVR 
TMVS 
TR 
TTE 
U 
UADE 
ULN 
VARC-2 
VKA 
Peripheral Vascular Disease 
Quality of Life 
Red Blood Cells 
Research Ethics Board 
Right Ventricle 
Serious Adverse Event 
Serious Adverse Device Effect 
Six Minute Walk Test 
Transapical Mitral Valve Implantation 
Transesophageal Echocardiogram 
Transient Ischemic Attack 
Transcatheter Mitral Valve Replacement 
Tiara™ Mitral Valve System 
Tricuspid Regurgitation 
Transthoracic Echocardiogram 
Units 
Unanticipated Adverse Device Effect 
Upper Limit of Normal 
Valve Academic Research Consortium-2 
Vitamin K Antagonist 
 
 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 68 of 83 
 
20 STUDY ENDPOINT DEFINITIONS 
The following definitions used for the trial are adapted from VARC-210and MVARC12. 
Term 
Definition 
Acute Kidney 
Injury10 
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) OR 
urine output < 0.5 ml/kg/h for ≥ 6 but < 12 h  
Stage 2 
Increase in serum creatinine to 200–299% (2.0–2.99 × increase 
compared with baseline) OR urine output < 0.5 ml/kg/h for ≥ 12 but 
< 24 h  
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 urine output 
< 0.3 ml/kg/h for ≥ 24 h OR anuria for ≥ 12 h 
NOTE: Patients receiving renal replacement therapy are considered to 
meet Stage 3 criteria irrespective of other criteria. 
Arrhythmias and 
Conduction System 
Disturbances12 
For emerging mitral valve procedures in which the frequency of major 
arrhythmias and conduction system disturbances is unknown, 
continuous rhythm monitoring for at least 48 in the post-procedural 
period is recommended to maximize the detection of arrhythmias and 
conduction system disturbances. 
Data elements to be collected for all patients should include: 
i. Baseline conduction abnormalities, paroxysmal or permanent 
atrial fibrillation (or flutter), ventricular arrhythmias, and the 
presence of permanent pacemaker and implantable 
defibrillators 
ii. Procedure-related new or worsened cardiac conduction 
disturbance (including first-, second- [Mobitz I or Mobitz II], or 
third-degree AV block; incomplete and complete right bundle 
branch block; intraventricular conduction delay; left bundle 
branch block; left anterior fascicular block; or left posterior 
fascicular block, including heart block) requiring a permanent 
pacemaker implant; each subclassified as persistent or 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 69 of 83 
 
Term 
Definition 
transient 
iii. New-onset atrial fibrillation (or flutter) 
iv. New-onset ventricular tachycardia or fibrillation 
v. Pacemaker or defibrillator lead dislodgement 
Arrhythmias and conduction system disturbances are subclassified 
according to: 
i. The occurrence of hemodynamic instability 
ii. Need for therapy including electrical/pharmacological 
cardioversion or initiation of a new medication (oral 
anticoagulation, rhythm, or rate control therapy) 
iii. Need for new permanent pacemaker and/or defibrillator 
implantation, including the indication(s) and the number of 
days post-implant. For patients with defibrillators, the number 
of appropriate and inappropriate shocks should be recorded. 
Bleeding12 
MVARC (Primary Scale)* 
I. Minor 
Any overt†, actionable sign of hemorrhage (e.g., more bleeding than 
would be expected for a clinical circumstance, including bleeding found 
by imaging alone) that meets ≥1 of the following: requiring nonsurgical 
medical intervention by a health care professional; leading to 
hospitalization or increased level of care; prompting evaluation; or 
requires 1 or 2 U of whole blood or packed RBC transfusion and 
otherwise does not meet criteria for major, extensive, or life-threatening 
bleeding. 
II. Major 
Overt bleeding either associated with a drop in the hemoglobin of ≥3.0 
g/dl‡ or requiring transfusion of ≥3 U of whole blood or packed RBCs 
AND does not meet criteria of life-threatening or extensive bleeding. 
III. Extensive 
Overt source of bleeding with drop in hemoglobin of ≥4 g/dl‡ or whole 
blood or packed RBC transfusion ≥4 U within any 24-hour period, or 
bleeding with drop in hemoglobin of ≥6 g/dl‡ or whole blood or packed 
RBC transfusion ≥4 U (BARC type 3b) within 30 days of the procedure. 
IV. Life-threatening 
Bleeding in a critical organ, such as intracranial, intraspinal, intraocular, 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 70 of 83 
 
Term 
Definition 
or pericardial necessitating surgery or intervention, or intramuscular with 
compartment syndrome OR bleeding causing hypovolemic shock or 
hypotension (systolic blood pressure <90 mm Hg lasting >30 min and 
not responding to volume resuscitation) or requiring significant doses of 
vasopressors or surgery. 
V. Fatal 
Bleeding adjudicated as being a proximate cause of death. Severe 
bleeding adjudicated as being a major contributing cause of a 
subsequent fatal complication, such as MI or cardiac arrest, is also 
considered fatal bleeding. 
MVARC Footnotes: 
*Modified with permission from VARC-2
12. 
†“Overt” bleeding is defined by any of the following criteria being met: Reoperation after 
closure of sternotomy for the purpose of controlling bleeding; chest tube output >2 l within 
any 24-h period, >350 ml within the first post-operative hour, ≥250 ml within the second 
post-operative hour, or >150 ml within the third post-operative hour; or visible bleeding 
from the vascular system either at or remote from the access/surgical site.  
‡Adjusted for the number of units of blood transfused (1 U packed red blood cells or whole 
blood is equivalent to 1 g/dl hemoglobin). 
Modified BARC 
Bleeding Scale12 
Type 0 
No bleeding. 
Type 1 
Bleeding that is not actionable and does not cause the patient to seek 
unscheduled performance of studies, hospitalization, or treatment by a 
health care professional. May include episodes leading to self-
discontinuation of medical therapy by the patient without consulting a 
health care professional. 
Type 2 
Any overt†, actionable sign of hemorrhage (e.g., more bleeding than 
would be expected for a clinical circumstance, including bleeding found 
by imaging alone) that does not fit the criteria for type 3, 4, or 5 but does 
meet ≥1 of the following: requiring nonsurgical medical intervention by a 
health care professional, leading to hospitalization or increased level of 
care, or prompting evaluation. 
Type 3a 
 
Overt* bleeding plus hemoglobin drop of 3 to <5 g/dl‡ (provided 
drop is related to bleed) 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 71 of 83 
 
Term 
Definition 
 
Any transfusion with overt bleeding 
Type 3b 
 
Overt bleeding plus hemoglobin drop ≥5 g/dl‡ (provided drop is 
related to bleed) 
 
Cardiac tamponade 
 
Bleeding requiring surgical intervention for control (excluding 
dental/nasal/skin/hemorrhoid) 
 
Bleeding requiring IV vasoactive agents 
Type 3c 
 
Intracranial hemorrhage (does not include microbleeds or 
hemorrhagic transformation but does include intraspinal 
bleeding) 
 
Subcategories confirmed by autopsy, imaging, or lumbar 
puncture 
 
Intraocular bleeding compromising vision 
Type 4 (periprocedural) 
 
Perioperative intracranial bleeding ≤48 h 
 
Reoperation after closure of incision site for the purpose of 
controlling bleeding 
 
Transfusion of ≥5 U whole blood or packed RBCs within 48-h 
period of the index procedure 
 
Chest tube output ≥2 l within 24-h period 
Type 5a: 
 
Probable fatal bleeding. No autopsy or imaging confirmation 
but clinically suspicious. 
Type 5b: 
 
Definite fatal bleeding. Overt bleeding, autopsy, or imaging 
confirmation. 
MVARC Footnotes: 
*Modified  with permission from VARC-2
12. 
†“Overt” bleeding is defined by any of the following criteria being met: Reoperation after 
closure of sternotomy for the purpose of controlling bleeding; chest tube output >2 l within 
any 24-h period, >350 ml within the first post-operative hour, ≥250 ml within the second 
post-operative hour, or >150 ml within the third post-operative hour; or visible bleeding 
from the vascular system either at or remote from the access/surgical site.  
‡Adjusted for the number of units of blood transfused (1 U packed red blood cells or whole 
blood is equivalent to 1 g/dl hemoglobin). 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 72 of 83 
 
Term 
Definition 
Death/Mortality12 
I. Classification of All-Cause Mortality 
A. Cardiovascular mortality 
Any of the following contributing conditions: 
 
Heart failure (subclassified into left ventricular vs. right 
ventricular dysfunction) 
 
Myocardial infarction 
 
Major bleeding 
 
Thromboembolism 
 
Stroke 
 
Arrhythmia and conduction system disturbance 
 
Cardiovascular infection and sepsis (e.g., mediastinitis 
and endocarditis) 
 
Tamponade 
 
Sudden, unexpected death 
 
Other cardiovascular 
 
Device failure 
 
Death of unknown cause (adjudicated as 
cardiovascular) 
B. Noncardiovascular mortality 
 
Any death in which the primary cause of death is clearly 
related to another condition: 
 
Noncardiovascular infection and sepsis (e.g., 
pneumonia) 
 
Renal failure 
 
Liver failure 
 
Cancer 
 
Trauma 
 
Homicide 
 
Suicide 
 
Other noncardiovascular 
II. Periprocedural vs. Nonperiprocedural Mortality 
Death is considered periprocedural if occurring within 30 days of the 
intervention or beyond 30 days in the patient not yet discharged 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 73 of 83 
 
Term 
Definition 
Device Success10 
Absence of procedural mortality  
AND 
Correct positioning of a single prosthetic heart valve into the proper 
anatomical location  
AND 
Intended performance of the prosthetic heart valve (no prosthesis – 
patient mismatch)  
AND  
No moderate or severe prosthetic valve regurgitation 
Hospitalization10 
Hospitalization is defined as admission to an inpatient unit or ward in the 
hospital for ≥24 h, including an emergency department stay.  
Hospitalizations planned for pre-existing conditions are excluded unless 
there is worsening of the baseline condition. 
I. Heart failure hospitalization: 
Both of the following additional criteria are present: 
i. Symptoms, signs and/or laboratory evidence of worsening 
heart failure  
ii. Administration of intravenous or mechanical heart failure 
therapies 
Patients hospitalized with heart failure are further subclassified as: 
IA. Primary (cardiac related) heart failure hospitalization 
IB. Secondary (noncardiac related) heart failure hospitalization 
II. Other cardiovascular hospitalization: such as for coronary artery 
disease, acute myocardial infarction, hypertension, cardiac arrhythmias, 
cardiomegaly, pericardial effusion, atherosclerosis, stroke, or peripheral 
vascular disease without qualifying heart failure 
III. Noncardiovascular hospitalization: not due to heart failure or other 
cardiovascular causes, as defined above 
Myocardial 
Infarction12 
I. Periprocedural MI (≤48 h after the index procedure) 
 
In patients with normal baseline CK-MB (or cTn):  
o 
The peak CK-MB measured within 48 h of the procedure 
rises to ≥10 the local laboratory ULN plus new ST-

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 74 of 83 
 
Term 
Definition 
segment elevation or depression of ≥1 mm in ≥2 
contiguous leads (measured 80 ms after the J-point), or 
to ≥5 ULN with new pathological Q waves in ≥2 
contiguous leads or new persistent LBBB, OR in the 
absence of CK-MB measurements and a normal baseline 
cTn, a cTn (I or T) level measured within 48 h of the PCI 
rises to ≥70 the local laboratory ULN plus new ST-
segment elevation or depression of ≥1 mm in ≥2 
contiguous leads (measured 80 ms after the J-point), or 
≥35 ULN with new pathological Q waves in ≥2 contiguous 
leads or new persistent LBBB. 
 
In patients with elevated baseline CK-MB (or cTn):   
o 
The CK-MB (or cTn) rises by an absolute increment 
equal to those levels recommended above from the most 
recent pre-procedure level plus, new ECG changes as 
described. 
II. Spontaneous MI (>48 h after the index procedure) 
Detection of rise and/or fall of cardiac biomarkers (preferably cTn) with 
at least 1 value above the 99th percentile URL (or ULN in the absence 
of URL) together with at least 1 of the following: 
A. Symptoms of ischemia 
B. ECG changes indicative of new ischemia (new ST-
segment or T-wave changes or newLBBB) or new 
pathological Q waves in ≥2 contiguous leads 
C. Imaging evidence of a new loss of viable myocardium or 
new wall motion abnormality 
III. MI associated with sudden, unexpected cardiac death 
Sudden cardiac death or 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 occurs before blood 
samples could be obtained or at a time before the appearance of cardiac 
biomarkers in the blood 
IV. Pathological findings of an acute myocardial infarction 
MI is defined in pathology as myocardial cell death due to prolonged 
ischaemia. After the onset of myocardial ischaemia, histological cell 
death is not immediate, but takes a finite period of time to develop—as 
little as 20 min, or less in some animal models.4 It takes several hours 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 75 of 83 
 
Term 
Definition 
before myocardial necrosis can be identified by macroscopic or 
microscopic post-mortem examination. Complete necrosis of myocardial 
cells at risk requires at least 2– 4 h, or longer, depending on the 
presence of collateral circulation to the ischaemic zone, persistent or 
intermittent coronary arterial occlusion, the sensitivity of the myocytes to 
ischaemia, pre-conditioning, and individual demand for oxygen and 
nutrients.2 The entire process leading to a healed infarction usually 
takes at least 5– 6 weeks. Reperfusion may alter the macroscopic and 
microscopic appearance 
Stroke and TIA12 
Diagnostic criteria 
I. 
Acute episode of a focal or global neurological deficit with at 
least 1 of the following: 
o 
Change in the level of consciousness 
o 
Hemiplegia, hemiparesis, numbness, or sensory loss 
affecting 1 side of the body 
o 
Dysphasia or aphasia, hemianopia, amaurosis fugax, or 
other neurological signs or symptoms consistent with stroke 
II. 
In addition, there is no other readily identifiable nonstroke cause 
for the clinical presentation (e.g., brain tumor, trauma, infection, 
hypoglycemia, peripheral lesion, pharmacological influences) as 
determined by or in conjunction with the designated neurologist 
The neurological event type classification 
I. 
Stroke: duration of a focal or global neurological deficit ≥24 h 
OR <24 h if available neuroimaging documents a new 
intracranial or subarachnoid hemorrhage (hemorrhagic stroke) 
or central nervous system infarction (ischemic stroke) OR the 
neurological deficit results in death 
II. 
TIA: duration of a focal or global neurological deficit <24 h and 
neuroimaging does not demonstrate a new hemorrhage or 
infarct 
Confirmation of the diagnosis of stroke or TIA requires at least 1 of the 
following 
I. 
Neurologist or neurosurgical specialist, or 
II. 
Neuroimaging procedure (CT scan or brain MRI) 
Stroke/TIA timing classification 
I. 
Periprocedural if it occurs within 30 days of the intervention, or if 
beyond 30 days in the patient not yet discharged. A 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 76 of 83 
 
Term 
Definition 
periprocedural stroke/TIA may be further considered immediate 
if it occurs within 24 h of the procedure or within 24 h of 
awakening from general anesthesia if beyond 24 h. 
II. 
Nonperiprocedural if it occurs beyond 30 days after the 
intervention and after the patient has been discharged. 
Stroke/TIA etiology classification 
I. 
Ischemic: an acute episode of focal cerebral, spinal, or retinal 
dysfunction caused by infarction of the central nervous system 
tissue 
II. 
Hemorrhagic: an acute episode of focal or global cerebral or 
spinal dysfunction caused by intraparenchymal, intraventricular, 
or subarachnoid hemorrhage 
III. 
Undetermined: if there is insufficient information to allow 
categorization as ischemic or hemorrhagic 
Stroke severity is further classified as 
I. 
Disabling stroke: an mRS score ≥2 at 90 days plus an increase 
in ≥1 mRS category from the pre-stroke baseline 
II. 
Nondisabling stroke: an mRS score <2 at 90 days or without an 
increase ≥1 mRS category from the pre-stroke baseline 
Patients with nonfocal global encephalopathy will not be reported as 
having had a stroke without unequivocal evidence of cerebral infarction 
based upon neuroimaging studies (CT scan or cerebral MRI).  
Modified Rankin scale (mRS) assessments should be made by qualified 
individuals according to a certification process. 
Access Site and 
Vascular 
Complications12 
I. Vascular Complications  
A. Major access site vascular complications, including: 
i. Aortic dissection or aortic rupture, or 
ii. Access site-related arterial or venous injury (dissection, 
stenosis, ischemia, arterial, or venous thrombosis including 
pulmonary emboli, perforation, rupture, arteriovenous fistula, 
pseudoaneurysm, hematoma, retroperitoneal hematoma, 
atrial septal defect), irreversible nerve injury, or compartment 
syndrome resulting in death; hemodynamic compromise; life-
threatening, extensive, or major bleeding (MVARC bleeding 
scale); visceral ischemia; or neurological impairment, or 
iii. Distal embolization (noncerebral) from a vascular source 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 77 of 83 
 
Term 
Definition 
requiring surgery or resulting in amputation or irreversible 
end-organ damage, or 
iv. Unplanned endovascular or surgical interventions resulting in 
death; lifethreatening, extensive, or major bleeding (MVARC 
bleeding scale); visceral ischemia; or neurological impairment 
B. Minor access site vascular complications, including: 
i. Access site arterial or venous injury (dissection, stenosis, 
arterial, or venous thrombosis including pulmonary emboli, 
ischemia, perforation, rupture, arteriovenous fistula, 
pseudoaneurysm, hematoma, retroperitoneal hematoma, 
atrial septal defect) not resulting in death; life-threatening, 
extensive, or major bleeding (MVARC scale); visceral 
ischemia; or neurological impairment, or 
ii. Distal embolization treated with embolectomy and/or 
thrombectomy not resulting in amputation or irreversible end-
organ damage, or 
iii. Any unplanned endovascular stenting or unplanned surgical 
intervention not meeting the criteria for a major vascular 
complication, or 
iv. Vascular repair (via surgery, ultrasound-guided compression, 
transcatheter embolization, or stent-graft) 
II. Cardiac structural complications due to access-related issues 
A. Major cardiac structural complications, including: 
i. Cardiac perforation or pseudoaneurysm resulting in death, 
life-threatening bleeding, hemodynamic compromise, or 
tamponade, or requiring unplanned surgical or percutaneous 
intervention 
B. Minor cardiac structural complications, including: 
i. Cardiac perforation or pseudoaneurysm not meeting major 
criteria 
 
 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 78 of 83 
 
21 STUDY-REQUIRED TEST AND EXAMINATION DEFINITIONS 
21.1 DEFINITION OF GRADE D SYMPTOMATIC SEVERE MITRAL 
REGURGITATION 
2014 AHA/ACC Valvular Heart Disease Guideline4 Definition 
 
Primary (Degenerative) 
Secondary (Functional) 
Valve Anatomy 
1. Severe mitral valve prolapse 
with loss of coaptation or flail 
leaflet 
2. Rheumatic valve changes with 
leaflet restriction and loss of 
central coaptation 
3. Prior Infective Endocarditis 
4. Thickening of leaflets with 
radiation heart disease 
1. Regional wall motion 
abnormalities and/or LV dilation 
with severe tethering of mitral 
leaflet 
2. Annular dilation with severe loss 
of central coaptation of the mitral 
leaflets 
Valve 
Hemodynamics 
1. Central jet MR >40% LA or 
holosystolic eccentric jet MR 
2. Vena contracta ≥0.7 cm 
3. Regurgitant volume ≥60 mL 
4. Regurgitant fraction ≥50% 
5. ERO ≥0.40 cm2 
6. Angiographic grade 3–4+ 
1. ERO ≥0.20 cm2 
2. Regurgitant volume ≥30 mL 
3. Regurgitant fraction ≥50% 
Hemodynamic 
Consequences/
Associated 
Cardiac Findings 
1. Moderate or severe LA 
enlargement 
2. LV enlargement 
3. Pulmonary hypertension present 
1. Regional wall motion 
abnormalities with reduced LV 
systolic function 
2. LV dilation and systolic 
dysfunction due to primary 
myocardial disease 
Symptoms 
1. Decreased exercise tolerance 
2. Exertional dyspnea 
1. HF symptoms due to MR persist 
even after revascularization and 
optimization of medical therapy 
2. Decreased exercise tolerance 
3. Exertional dyspnea 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 79 of 83 
 
*Several valve hemodynamic criteria are provided for assessment of MR severity, but not all criteria for each 
category will be present in each patient. Categorization of MR severity as mild, moderate, or severe 
depends on data quality and integration of these parameters in conjunction with other clinical evidence. 
ERO indicates effective regurgitant orifice; IE, infective endocarditis; LA, left atrium/atrial; LV, left ventricular; 
LVEF, left ventricular ejection fraction; LVESD; left ventricular end-systolic dimension; and MR, mitral 
regurgitation 
 
 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 80 of 83 
 
21.2 STS SCORE CALCULATION/DEFINITIONS 
http://riskcalc.sts.org/de.aspx 
The Society of Thoracic Surgeons’ risk models predict the risk of operative mortality and 
morbidity after adult cardiac surgery on the basis of patient demographic and clinical 
variables. The models are primarily used to adjust for case mix when comparing 
outcomes across institutions with different patient populations. Such comparisons are 
provided in the Database reports received by STS Database participants. The STS 
models are also used by physicians and patients as tools for understanding the possible 
risks of surgery. As these risks are solely statistical estimates, they should be 
supplemented by the professional judgment of the patients’ healthcare provider, 
particularly their cardiac surgeon. 
 
Surgical Procedures 
The STS currently has three risk models: CABG, Valve, and Valve + CABG. The models 
apply to seven specific surgical procedure classifications: 
 
CABG model 
1. Isolated Coronary Artery Bypass (CABG Only) 
 
Valve model 
2. Isolated Aortic Valve Replacement (AV Replace) 
3. Isolated Mitral Valve Replacement (MV Replace) 
4. Isolated Mitral Valve Repair (MV Repair) 
 
Valve+CABG model 
5. Aortic Valve Replacement + CABG (AV Replace + CABG) 
6. Mitral Valve Replacement + CABG (MV Replace + CABG) 
7. Mitral Valve Repair + CABG (MV Repair + CABG) 
 
NOTE: A predicted risk value will NOT be calculated for any procedure that does not fall 
into one of these precisely defined categories. 
 
 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 81 of 83 
 
21.1 CSHA CLINICAL FRAILTY 
(A global clinical measure of fitness and frailty in elderly people) 
 
Canadian Study of Health and Aging (CSHA) Clinical Frailty Scale [9] 
 
1. Very fit – Robust, active, energetic, well motivated and fit; these people commonly 
exercise regularly and are in the most fit group for their age  
2. Well – Without active disease, but less fit than people in category 1 
3. Well, with treated comorbid disease – Disease symptoms are well controlled 
compared with those in category 4 
4. Apparently vulnerable – Although not frankly dependent, these people commonly 
complain of being “slowed up” or have disease symptoms 
5. Mildly frail – With limited dependence on others for instrumental activities of daily 
living 
6. Moderately frail – Help is needed with both instrumental and non-instrumental 
activities of daily living 
7. Severely frail – Completely dependent on others for the activities of daily living, or 
terminally ill 
 
IADL (Instrumental Activities of Daily 
Living) 
ADL (Activities of Daily Living) 
 
Activities required to live  
in the community 
 
Meal preparation 
 
Ordinary housework 
 
Managing finances 
 
Managing medications 
 
Phone use 
 
Shopping 
 
Transportation 
 
Mobility in bed 
 
Transfers 
 
Locomotion inside and outside the 
home 
 
Dressing upper and lower body 
 
Eating 
 
Toilet use 
 
Personal hygiene 
 
Bathing 
 
 
 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 82 of 83 
 
21.1 NYHA, MRS, NIHSS, 6MWT, AND KCCQ 
New York Heart 
Association 
Classification 
(NYHA) 
Class I 
Patients with cardiac disease but without resulting limitations of physical 
activity.  
Class II 
Patients with cardiac disease resulting in slight limitation of physical 
activity. Patients are comfortable at rest. Ordinary physical activity 
results in fatigue, palpitation, dyspnoea, or anginal pain. 
Class III 
Patients with cardiac disease resulting in marked limitation of physical 
activity. Patients are comfortable at rest. Less than ordinary physical 
activity causes fatigue, palpitation dyspnoea, or anginal pain. 
Class IV 
Patients 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. 
Modified Rankin 
Scale (mRS) 
0 
No symptoms at all 
1 
No significant disability despite symptoms; able to carry out all usual 
duties and activities 
2 
Slight disability; unable to carry out all previous activities, but able to 
look after own affairs without assistance 
3 
Moderate disability; requiring some help, but able to walk without 
assistance 
4 
Moderately severe disability; unable to walk without assistance and 
unable to attend to own bodily needs without assistance 
5 
Severe disability; bedridden, incontinent, and requiring constant 
nursing care and attention 
6 
Death 
Prior to conducting the mRS, the assessor must be certified in 
completing this neurological assessment. 

TIARATM Early Feasibility Study 
 
Clinical Protocol 
 
047-CPT-001 Revision E:  17 November 2015 
Confidential
Page 83 of 83 
 
National Institutes 
of Health Stroke 
Scale  (NIHSS) 
The National Institutes of Health Stroke Scale, or NIH Stroke Scale 
(NIHSS) is a tool to objectively quantify the impairment caused by a 
stroke.  
The NIHSS is composed of 11 items, each of which scores a specific 
ability. For each item, a score of 0 typically indicates normal function in 
that specific ability, while a higher score is indicative of some level of 
impairment.  The individual scores from each item are summed in order 
to calculate a patient's total NIHSS score.    
Prior to conducting the NIHSS, the asssor must be certified in 
completing this neurological assessment.   
6 Minute Walk Test 
(6MWT) 
This test measures the distance that a patient can quickly walk on a flat, 
hard surface in a period of 6 minutes.  It evaluates the global and 
integrated responses of all the systems involved during exercise, 
including the pulmonary and cardiovascular systems, systemic 
circulation, peripheral circulation, blood, neuromuscular units, and 
muscle metabolism.   
The self-paced 6MWT assesses the submaximal level of functional 
capacity. Most patients do not achieve maximal exercise capacity during 
the 6MWT; instead, they choose their own intensity of exercise and are 
allowed to stop and rest during the test.  
The 6MWT detailed in the “ATS Statement: Guidelines for the Six-
Minute Walk Test13” should be followed to conduct this examination. 
The Kansas City 
Cardiomyopathy 
Questionnaire  
(KCCQ) 
The Kansas City Cardiomyopathy Questionnaire is a 23-item, self-
administered instrument that quantifies physical function, symptoms 
(frequency, severity and recent change), social function, self-efficacy 
and knowledge, and quality of life.  This questionnaire should be given 
to the subject to complete on his or her own.