The SPACER Trial - Repair of Tricuspid Valve Regurgitation Using the Edwards TricuSPid TrAnsCatheter REpaiR System
Phase: NA
Conditions: Tricuspid Valve Regurgitation
Sponsor: Edwards Lifesciences

The SPACER Trial 
 
 
Version C 
December 16 , 2016 
 
Study No. 2015-09 
 Page 1 of 84  
 
 
 
 
 
 
 
 
 
  
The SPACER Trial – Repair of Tricuspid Valve 
Regurgitation using the Edwards  
FORMA TricuSPid TrAnsCatheter REpaiR System 
 
 
CLINICAL PROTOCOL 
(Clinical Investigational Plan) 
 
 
Study Number:  2015-09 
Version:  C 
 
Effective Date:  December 16, 2016 
 
 
 
CONFIDENTIAL 
 
Study Sponsor: 
Edwards Lifesciences LLC 
One Edwards Way 
Irvine, CA 92614  USA 
 
 

The SPACER Trial 
 
 
Version C 
December 16 , 2016 
 
Study No. 2015-09 
 Page 2 of 84  
 
 
 
TABLE OF CONTENTS 
SYNOPSIS........................................................................................................................................................................... 5 
1 
INTRODUCTION...................................................................................................................................................10 
1.1 
CLINICAL BACKGROUND .....................................................................................................................................10 
1.1.1 
Disease Process ....................................................................................................................................10 
1.1.2 
Etiology ..................................................................................................................................................10 
1.2 
ALTERNATIVE TREATMENT/THERAPIES ...............................................................................................................11 
1.2.1 
Surgical Tricuspid Valve Intervention ...............................................................................................11 
1.2.2 
Medical Therapy...................................................................................................................................12 
1.2.3 
Percutaneous Tricuspid Valve Repair ...............................................................................................13 
1.2.4 
Transcatheter Tricuspid Valve Replacement ...................................................................................13 
1.3 
IN-HOSPITAL/30-DAY MORTALITY .....................................................................................................................13 
2 
STUDY PURPOSE .................................................................................................................................................15 
2.1 
INTENDED USE ..................................................................................................................................................15 
2.2 
PRIOR TESTING..................................................................................................................................................15 
2.3 
PRIOR CLINICAL STUDIES....................................................................................................................................15 
2.4 
STUDY DEVICE ...................................................................................................................................................17 
2.4.1 
General Device Description and Components.................................................................................17 
2.4.2 
Edwards FORMA Tricuspid Transcatheter Spacer System: ...........................................................17 
2.4.3 
Edwards FORMA Tricuspid Transcatheter Introducer Sheath Set ...............................................20 
2.4.4 
Edwards FORMA Tricuspid Transcatheter Railing Delivery System ............................................21 
2.4.5 
Edwards FORMA Tricuspid Transcatheter Retrieval System ........................................................22 
3 
RISK ANALYSIS .....................................................................................................................................................23 
3.1 
POTENTIAL RISKS...............................................................................................................................................23 
3.2 
RISK MANAGEMENT ..........................................................................................................................................26 
3.3 
BENEFITS...........................................................................................................................................................26 
3.4 
JUSTIFICATION ...................................................................................................................................................27 
4 
STUDY OBJECTIVES .............................................................................................................................................27 
5 
STUDY ENDPOINTS .............................................................................................................................................27 
5.1 
PRIMARY ENDPOINT ..........................................................................................................................................27 
5.2 
SECONDARY ENDPOINTS & CLINICAL OUTCOMES................................................................................................27 
5.2.1 
Technical Success Endpoint ................................................................................................................27 
5.2.2 
Device Success Endpoint .....................................................................................................................27 
5.2.3 
Procedural Success Endpoint .............................................................................................................28 
5.2.4 
Clinical Outcomes.................................................................................................................................28 
6 
STUDY DESIGN.....................................................................................................................................................28 
7 
SUBJECT POPULATION.......................................................................................................................................29 
7.1 
DEMOGRAPHIC AND CLINICAL CHARACTERISTICS.................................................................................................29 
7.2 
INCLUSION CRITERIA ..........................................................................................................................................29 
7.3 
EXCLUSION CRITERIA .........................................................................................................................................29 
8 
PROCEDURES AND METHODS..........................................................................................................................31 
8.1 
INFORMED CONSENT .........................................................................................................................................31 

The SPACER Trial 
 
 
Version C 
December 16 , 2016 
 
Study No. 2015-09 
 Page 3 of 84  
 
8.2 
SUBJECT ENROLLMENT.......................................................................................................................................31 
8.3 
BASELINE EVALUATION ......................................................................................................................................34 
8.4 
ANTIPLATELET / ANTICOAGULATION THERAPY ....................................................................................................36 
8.5 
DEVICE PREPARATION........................................................................................................................................37 
8.6 
IMPLANT PROCEDURE ........................................................................................................................................37 
8.6.1 
Antibiotic Prophylaxis..........................................................................................................................38 
8.6.2 
Contrast Media.....................................................................................................................................38 
8.6.3 
Discharge...............................................................................................................................................38 
8.7 
FOLLOW-UP VISITS............................................................................................................................................39 
8.7.1 
Follow-Up Visit Windows....................................................................................................................40 
8.8 
MISSED SUBJECT VISITS .....................................................................................................................................43 
8.9 
WITHDRAWAL CRITERIA AND PROCEDURES ........................................................................................................43 
8.10 
SUBJECT STUDY COMPLETION ............................................................................................................................44 
9 
TRAINING..............................................................................................................................................................44 
9.1 
INVESTIGATORS DEVICE TRAINING ......................................................................................................................44 
9.2 
TRAINING OF INVESTIGATIONAL CENTER PERSONNEL...........................................................................................44 
9.3 
TRAINING DOCUMENTATION..............................................................................................................................45 
10 
INVESTIGATIONAL DEVICE MANAGEMENT ..................................................................................................45 
10.1 
DEVICE SHIPMENTS ...........................................................................................................................................45 
10.2 
DEVICE ACCOUNTABILITY ...................................................................................................................................45 
10.3 
DEVICE STORAGE...............................................................................................................................................45 
10.4 
DEVICE RETURN ................................................................................................................................................46 
11 
DATA COLLECTION AND REPORTING .............................................................................................................46 
11.1 
DATA COLLECTION METHODS ............................................................................................................................46 
11.2 
CASE REPORT FORMS ........................................................................................................................................46 
11.3 
SOURCE DOCUMENTATION REQUIREMENTS........................................................................................................47 
11.4 
QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES ...............................................................................47 
12 
REPORTABLE EVENTS / EFFECTS......................................................................................................................48 
12.1 
REPORTING PROCEDURE ....................................................................................................................................48 
12.2 
DEFINITIONS......................................................................................................................................................49 
12.2.1 Adverse Event .......................................................................................................................................49 
12.2.2 Adverse Device Effect ..........................................................................................................................49 
12.2.3 Serious Adverse Event .........................................................................................................................49 
12.2.4 Serious Adverse Device Effect ............................................................................................................49 
12.2.5 Unanticipated Serious Adverse Device Effect..................................................................................50 
12.2.6 Device Deficiency and Malfunction...................................................................................................50 
12.3 
DEATHS AND EXPLANTS .....................................................................................................................................50 
12.3.1 Subject Deaths ......................................................................................................................................50 
12.3.2 Device Explants.....................................................................................................................................51 
13 
STATISTICAL ANALYSIS ......................................................................................................................................51 
13.1 
SAMPLE SIZE .....................................................................................................................................................51 
13.2 
TIMING .............................................................................................................................................................52 
13.3 
ANALYSIS POPULATION ......................................................................................................................................52 
13.4 
PRIMARY ENDPOINT ANALYSIS ...........................................................................................................................53 
13.5 
ADDITIONAL ENDPOINT ANALYSIS ......................................................................................................................53 
13.6 
MISSING DATA ..................................................................................................................................................53 

The SPACER Trial 
 
 
Version C 
December 16 , 2016 
 
Study No. 2015-09 
 Page 4 of 84  
 
13.7 
ANALYSIS SOFTWARE .........................................................................................................................................53 
14 
MONITORING ......................................................................................................................................................54 
14.1 
MONITORING METHODS ...................................................................................................................................54 
14.2 
MONITORING PLAN ...........................................................................................................................................54 
14.3 
PROTOCOL DEVIATION.......................................................................................................................................55 
14.4 
COMMUNICATION PROCEDURES ........................................................................................................................55 
15 
DATA MONITORING COMMITTEE ...................................................................................................................56 
16 
STUDY STOPPING RULES ...................................................................................................................................56 
17 
ETHICAL AND REGULATORY CONSIDERATIONS ...........................................................................................57 
17.1 
APPLICABLE REGULATIONS AND GUIDELINES.......................................................................................................57 
17.2 
DATA PROTECTION AND SUBJECT CONFIDENTIALITY ............................................................................................57 
17.3 
INVESTIGATOR RESPONSIBILITIES ........................................................................................................................57 
17.3.1 General Duties ......................................................................................................................................57 
17.3.2 Investigator Records............................................................................................................................58 
17.3.3 Investigator Reports ............................................................................................................................58 
17.4 
SPONSOR RESPONSIBILITIES ...............................................................................................................................59 
17.4.1 General Duties ......................................................................................................................................59 
17.5 
SELECTION OF INVESTIGATORS ...........................................................................................................................59 
17.5.1 Monitoring the Study ..........................................................................................................................59 
17.5.2 Sponsor Records ...................................................................................................................................59 
17.5.3 Sponsor Reports ...................................................................................................................................60 
17.6 
STUDY CHANGES ...............................................................................................................................................60 
17.7 
STUDY COMPLETION OR TERMINATION AND CLOSE-OUT ....................................................................................60 
17.8 
AUDITS AND INSPECTIONS..................................................................................................................................61 
17.9 
PUBLICATION POLICY .........................................................................................................................................61 
18 
REFERENCES .........................................................................................................................................................62 
19 
DEFINITIONS ........................................................................................................................................................63 
20 
APPENDIX A -  SAMPLE INFORMED CONSENT FORM .................................................................................72 
21 
APPENDIX B - CT ACQUISITION PROTOCOL ..................................................................................................84 
22 
APPENDIX C - ECHO PROTOCOL.......................................................................................................................85 
23 
APPENDIX D – SCREENING COMMITTEE CHARTER......................................................................................86 
 

The SPACER Trial 
 
 
Version C 
December 16 , 2016 
 
Study No. 2015-09 
 Page 5 of 84  
 
SYNOPSIS 
 
Study Number: 
2015-09  
Title: 
The SPACER Trial -  Repair of Tricuspid Valve Regurgitation using the 
Edwards FORMA TricuSPid TrAnsCatheter REpaiR System 
Study Sponsor 
Contacts:  
 
 
 
  
 
 
  
 
 
 
 
 
Principal 
Investigators: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
  
  
 
 

The SPACER Trial 
 
 
Version C 
December 16 , 2016 
 
Study No. 2015-09 
 Page 6 of 84  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study 
Objective: 
The purpose of the study is to assess the safety and device performance 
of the Edwards FORMA Tricuspid Transcatheter Repair System in 
patients with clinically significant, symptomatic, tricuspid regurgitation 
who are at high surgical risk for standard tricuspid repair/replacement. 
Study Devices: 
The Edwards FORMA Tricuspid Transcatheter Repair System: 
 
Edwards FORMA Tricuspid Spacer System,
  
 
Edwards FORMA Tricuspid Introducer Sheath ,
 
 
Edwards FORMA Tricuspid Railing Delivery System, 
  
 
Edwards FORMA Tricuspid Retrieval System ,
 
Intended Use: 
The Edwards FORMA Tricuspid Transcatheter Repair System is intended 
for treatment of subjects with tricuspid regurgitation who are at high 
surgical risk for standard tricuspid repair/replacement due to operative 
risks, long recovery time, and/or significant co-morbidities. 
Study Design: 
This is a multi-center (≤12), international, prospective, single arm, safety 
study. 78 subjects will be enrolled in the study.  All enrolled study 
subjects will be assessed for clinical follow-up at the following intervals:  
1 month, 6 months, 1 year and annually for 3 years post implant 
procedure. 
Study Duration: 
 
 
 
 
 
 

The SPACER Trial 
 
 
Version C 
December 16 , 2016 
 
Study No. 2015-09 
 Page 7 of 84  
 
Study Population: 
Adult subjects with clinically significant, symptomatic, tricuspid 
regurgitation who are at high surgical risk for standard tricuspid repair 
or replacement as assessed by the Heart Team. 
Enrollment Criteria 
(Inclusion): 
1. Signed and dated EC approved study consent form prior to  study 
related procedures  
2. Eighteen years of age or older 
3. Clinically significant, symptomatic (NYHA Functional Class II or 
greater), tricuspid regurgitation (Stage D per 2014 AHA/ACC 
guidelines) requiring tricuspid valve repair or replacement as 
assessed by the Heart Team  
4. Functional tricuspid regurgitation (e.g., EROA ≥ 0.4 cm2 or 
equivalent guideline directed value) as the primary etiology 
5. NYHA Functional Class II or greater or signs of persistent right heart 
failure, despite optimal medical therapy 
6. Determined by the 'HEART Team' (a minimum of one Cardiologist, 
and one Cardiac Surgeon) to be at high surgical risk for tricuspid 
valve repair or replacement and the benefit-risk analysis supports 
utilization of the investigational device  
7. Willing to attend study follow-up assessments for up to 3 years 
Enrollment Criteria 
(Exclusion): 
1. Tricuspid valve/right heart anatomy not suitable for the study 
device:  
a. Native tricuspid annulus area < 2.14 cm2 (9 mm device), < 
2.63 cm2 (12 mm device) or < 3.27cm2 (15 mm device) as 
measured by transthoracic echocardiography or computed 
tomography 
b. Sub-valvular structures/anatomy that would preclude from 
proper anchor or Spacer placement, positioning and retrieval 
c. Access pathway vessel diameter less than 7.1 mm (9, 12 and 
15 mm devices)  
2. Moderate or greater tricuspid valve stenosis 
3. Untreated clinically significant coronary artery disease requiring 
immediate revascularization 
4. Any therapeutic invasive cardiac procedure performed within 30 
days of the scheduled implant procedure  
5. Patients not already receiving dialysis with renal insufficiency 
(eGFR < 25) per lab test ≤ 48 hours prior to scheduled implant 
procedure 
6. Myocardial infarction within 30 days of scheduled implant 
procedure 
7. Hemodynamic instability within 30 days of scheduled implant 
procedure 
8. Patient requiring surgery under general anesthesia for any reason 
within 30 days of scheduled implant procedure 
9. Severe left ventricular dysfunction with ejection fraction < 25% 
within 90 days of scheduled implant procedure 

The SPACER Trial 
 
 
Version C 
December 16 , 2016 
 
Study No. 2015-09 
 Page 8 of 84  
 
10. Patients with pulmonary artery systolic pressure > 70 mmHg via 
transthoracic echocardiography or alternative standard modality 
(e.g., direct pressure measurement) within 90 days 
11. Concomitant clinically significant valve (aortic, mitral, or pulmonic) 
disease requiring immediate ( ± 30 days of study procedure) repair 
or replacement  
12. Active endocarditis or infection within 3 months of scheduled 
implant procedure 
13. Cerebrovascular accident within 3 months of scheduled implant 
procedure 
14. Non-cardiac disease limiting life expectancy to be less than 12 
months at baseline evaluation 
15. Documented history of bleeding diathesis, coagulopathy or 
gastrointestinal bleeding within 3 months of scheduled implant 
procedure 
16. Evidence of right sided intracardiac mass, thrombus, or vegetation 
17. Prior venous stent placed within the access route (e.g., sub-clavian 
vein) that could negatively react with device 
18. Previously treated tricuspid valve which included implantation of a 
bioprosthetic valve or mechanical valve  
19. Known hypersensitivity to cobalt chromium, nitinol or titanium  
20. Known hypersensitivity to anticoagulation therapy or contrast 
agent, which cannot be adequately medicated 
21. Patient is a current intravenous drug user 
22. Female of child-bearing potential is pregnant or lactating 
23. Patient is currently participating or has participated in another 
investigational drug or device clinical study within 30 days of study 
screening activity 
24. Patient requires emergent/emergency treatment for tricuspid 
insufficiency  
25. Patient is under guardianship 
Primary Endpoint: 
The primary endpoint for the study will assess the all-cause mortality 
of the as treated cohort at 30 days compared to a literature derived 
Performance Goal based on high-risk surgical outcomes for tricuspid 
repair/replacement.  
Secondary 
Endpoints and 
Clinical Outcomes: 
The following secondary endpoints and clinical outcomes will also be 
assessed: 
 
Technical Success (at exit from procedure room):   
 
Alive, with  
 
Successful access, delivery and removal of the delivery systems, 
and 
 
Deployment and correct positioning of the intended device, and 
 
No need for additional emergency surgery or re-intervention 
related to the device or access procedure 
 

The SPACER Trial 
 
 
Version C 
December 16 , 2016 
 
Study No. 2015-09 
 Page 9 of 84  
 
Device Success (at 1 month, 6 months & Annually): 
 
Alive, with  
 
Original intended device in place, and   
 
No additional surgical or interventional procedures related to the 
device, and 
 
TR reduction (assessment made by change in EROA) compared to 
baseline and TV gradient ≤ 5mmHg  
 
Procedural Success (at 1 month):  
 
Device Success, and 
 
None of the following device or procedure related SAEs:  
 
Life threatening bleeding   
 
Major vascular or cardiac structural complications requiring 
intervention 
 
Pericardial effusion requiring drainage or surgery (includes 
tamponade) 
 
Stage 2 or 3 acute kidney injury (includes new dialysis). 
 
Severe heart failure or hypotension requiring IV inotrope, 
ultrafiltration or mechanical circulatory support 
 
Prolonged intubation > 48 hours 
 
Clinical Outcomes (at 1 month, 6 months & Annually)    
 
Re-hospitalization rates for the underlying condition (heart failure) 
 
Re-intervention rates for the underlying condition (tricuspid 
regurgitation)  
 
Change in Tricuspid Regurgitation (assessment made by change in 
EROA) from baseline 
 
Change in peripheral edema as assessed by subject weight loss 
(kilograms) from baseline 
 
Change in NYHA Class from baseline 
 
Change in 6 minute walk test distance (meters) from baseline 
 
Change in Quality of Life as assessed by the SF-12 and KCCQ 
questionnaires from baseline 
Study Committee: 
Independent Data Monitoring Committee (DMC)  
 
The DMC will consist of a minimum of 3 members, all members being 
physicians; one cardiothoracic surgeon, one interventional cardiologist 
and one cardiologist  
Echocardiography 
Core Laboratory: 
  
  
 
 

The SPACER Trial 
 
 
Version C 
December 16 , 2016 
 
Study No. 2015-09 
 Page 10 of 84  
 
1 
INTRODUCTION 
1.1 
CLINICAL BACKGROUND 
1.1.1 DISEASE PROCESS 
Tricuspid Regurgitation (TR), tricuspid insufficiency or tricuspid incompetence describes a 
condition in which blood flow through the tricuspid valve flows in the incorrect direction 
during part of the cardiac cycle. Normally, during diastole, the tricuspid valve opens as a 
result of atrial pressure from the right atrium, allowing blood to flow through the tricuspid 
valve, into the right ventricle.  Diastole ends with atrial contraction and the tricuspid valve 
closing to prevent a reversal of blood flow.  However, in patients with TR, the tricuspid 
valve is unable to form a tight seal at diastole end (when it should be closed), allowing 
blood to flow back into the right atrium.  
 
Although TR often accompanies mitral or aortic valve disease, it is usually asymptomatic, 
traditionally considered less clinically significant, and left untreated.  This scenario where 
the tricuspid valve is left untreated has resulted in the tricuspid valve being commonly 
referred to as the “forgotten” valve.  While trace to mild levels of TR are commonly found 
in a large number of patients without clinical consequence, moderate and severe levels 
can have detrimental effects on a patients quality of life [1]. Patients with severe TR 
usually present with signs or symptoms of right heart failure (HF), including peripheral 
edema and ascites [2].  
1.1.2 ETIOLOGY 
TR can have many underlying etiologies, but the majority of these can be divided into two 
major categories: degenerative and functional TR.  Degenerative (primary, organic or 
structural) TR refers to regurgitation resulting from disease processes affecting the 
integrity of the tricuspid valve leaflets and/or valve apparatus, such as in rheumatic heart 
disease, tricuspid valve prolapse or endocarditis.  In contrast, functional (secondary or 
non-structural) TR refers to regurgitation occurring in the absence of significant structural 
disease of the tricuspid valve and/or apparatus.  Functional TR occurs in approximately 
80% of cases of significant TR [2], resulting from annular dilation and right ventricular 
enlargement, which is often secondary to left heart failure from myocardial or valvular 
causes, right ventricular volume and pressure overload, and dilation of cardiac chambers. 
Significant TR may be clinically silent for a prolonged period, during which time 
progressive right ventricle (RV) dilatation and dysfunction may develop, similar to 
changes that can occur with asymptomatic mitral regurgitation (MR) and its’ effect on LV 
function. 
 
 

The SPACER Trial 
 
 
Version C 
December 16 , 2016 
 
Study No. 2015-09 
 Page 11 of 84  
 
Figure 1: Dilation of the Tricuspid Annulus – Dreyfus et al.[3] 
 
 
Tricuspid regurgitation is a common echocardiographic finding that is often considered 
benign unless associated with significant pulmonary hypertension or RV or LV 
dysfunction. It has been shown that increasing TR severity is associated with worse 
survival regardless of LVEF or pulmonary artery pressure [1]. Severe TR is associated with 
a poor prognosis, independent of age, biventricular systolic function, RV size, and IVC 
dilation [1]. 
 
Figure 2: Kaplan-Meier survival curves for all patients  
with tricuspid regurgitation (TR). [1] 
 
 
1.2 
ALTERNATIVE TREATMENT/THERAPIES 
1.2.1 SURGICAL TRICUSPID VALVE INTERVENTION 
The decision to treat TR has been controversial over the years, but has recently become 
recommended in symptomatic patients and in some cases asymptotic patients as 

The SPACER Trial 
 
 
Version C 
December 16 , 2016 
 
Study No. 2015-09 
 Page 12 of 84  
 
prophylactic treatment at the time of MR surgery [4]. The decision as to whether repair 
or replacement is recommended is demonstrated in the diagram below. 
 
Figure 3: 2014 AHA/ACC Indications for Tricuspid Surgery [2] 
 
 
 
Several techniques are available to correct functional tricuspid regurgitation. These 
include the stitch annuloplasty, such as semicircular (classical De Vega repair) or simple 
lateral annuloplasty (Kay), novel techniques such as edge-to-edge or clover technique and 
suture bicuspidization technique, use of flexible and rigid prosthetic rings or 3D rings, 
flexible prosthetic bands, and use of artificial chordae with polytetrafluoroethylene 
sutures for anterior and septal tricuspid leaflet pathology. Whereas the short-term 
outcomes of these techniques are satisfactory, the majority are limited in the mid- and 
long term by unacceptably high rates of residual and/or recurrent regurgitation [5]. 
  
While repair, specifically annuloplasty is considered the procedure of choice, if repair is 
not feasible or unsuccessful, replacement may be considered [6]. For replacement both 
bioprosthetic as well as mechanical valves provide viable options. 
1.2.2 MEDICAL THERAPY 
TR patients may be managed with diuretics for symptoms and only considered for surgery 
after advanced RV dysfunction, liver dysfunction or cirrhosis have developed. 
Additionally, medical therapies may be used to reduce elevated pulmonary artery 
pressures and/or pulmonary resistance [2].  

The SPACER Trial 
 
 
Version C 
December 16 , 2016 
 
Study No. 2015-09 
 Page 13 of 84  
 
For the patient population that would benefit from surgical intervention, but are 
characterized as high-risk or non-surgical, medical management is likely to only provide 
temporary symptom relief. The lack of benefit from medical therapies has prompted the 
search for alternative repair or replacement therapies.   
1.2.3 PERCUTANEOUS TRICUSPID VALVE REPAIR 
Percutaneous tricuspid valve repair therapies have considerable interest due to the 
minimally invasive nature of the procedures, particularly since surgery in functional 
patients is only indicated when they are undergoing concomitant valve surgery [2, 7].   
 
Percutaneous devices are being investigated which mimic surgical repair techniques. 
These devices are targeted for patients which are at high operative risk for surgery. These 
devices aim to approximate the leaflets by anchoring in the annulus and pulling the 
anterior leaflet towards the posterior leaflet, simulating a bicuspidization. Another 
emerging technology is a device which uses pledgets in the annulus to reduce the size of 
the annulus.  
1.2.4 TRANSCATHETER TRICUSPID VALVE REPLACEMENT 
Transcatheter valve replacement with the Edwards Sapien or Medtronic Melody valve has 
been described in the published literature on only single case studies or limited 
retrospective clinical series but primarily for valve-in-valve patients or patients with 
rheumatic disease.  This is not the patient population that the Edwards FORMA Tricuspid 
Transcatheter Repair system is intended for as the Edwards’ device is intended for 
functional tricuspid regurgitation. 
 
Additionally, percutaneous bicaval valve implantation has been used to treat tricuspid 
regurgitation by placing a valve in both the inferior vena cava and the superior vena cava. 
While this does not directly correct the TR it prevents back flow beyond the right atrium 
with the goal of reducing symptoms, normalizing liver function, and improving physical 
capacity. 
1.3 
IN-HOSPITAL/30-DAY MORTALITY 
The most prevalent treatment options for tricuspid regurgitation are surgical repair or 
replacement.  Typically, these procedures are done in conjunction with other cardiac 
surgical procedures (AVR, MVR, CABG,) while interventions performed in an isolated 
tricuspid regurgitation setting are quite rare.  When performed, there are multiple factors 
that determine the success of the surgical intervention.  The literature suggest that the 
most successful surgical interventions occur when tricuspid repair or replacement is 
performed as an elective procedure in conjunction with other cardiac procedures in a  
patient population that has a modest history of prior cardiac surgery.  For example, 
McCarthy et al [8], reported an 8% in-hospital mortality when a large patient population 
with functional tricuspid regurgitation was treated using an annuloplasty approach.  This 

The SPACER Trial 
 
 
Version C 
December 16 , 2016 
 
Study No. 2015-09 
 Page 14 of 84  
 
patient population will most likely represent a lower risk population than what is 
proposed in the SPACER Trial due to their more favorable disposition for cardiac surgery.  
An additional observation that cannot be overlooked, is the mortality rate in patients 
requiring reoperation.  This article reports an alarming in-hospital mortality rate for 
reoperation patients of 37%.  This is not an uncommon finding as Bernal et al [9] reported 
a 35% in-hospital mortality rate for a similar population of reoperation patients.   
 
Ratnatunga et al [10] reported on a large patient population and concluded that for 
patients undergoing tricuspid regurgitation repair “a high mortality rate is universal.”  
Specifically, they suggest an approximate 18% operative mortality rate in a patient 
population with a higher NHYA functional classification distribution than McCarthy [8] as 
well as a blend of isolated TR surgery and TR surgery in conjunction with other cardiac 
surgery procedures.  These results are in line with what Filsoufi et. al. [11] and Moraca et. 
al. [12] reported for a similar patient population (22% and 18%, respectively).  In 
summary, operative mortality (also described as 30-day or in-hospital mortality) is very 
high for patients undergoing tricuspid regurgitation intervention.  The most significant 
predictors of a higher mortality rate are previous cardiac surgery, previous tricuspid 
intervention and high New York Heart Association Classification (NYHA) functional class, 
all of which are inclusion criteria for the SPACER Trial.  This literature review, summarized 
in Table 1 below, was the basis for determining the performance goal to which the safety 
of the Edwards Transcatheter Tricuspid Repair Device will be compared (reference 
Section 13 of this investigational plan). 
 
Table 1 – Tricuspid Regurgitation Mortality Literature Review 
 
Author 
In-Hospital 
Mortality Rate 
Patient 
Population 
(N) 
Reference 
McCarthy 
6% (8% Hospital), 
37% Re-Op 
790 
J Thorac Cariovasc Surg 
2004; 127:674-85 
Bernal 
35.1% Re-Op 
74 
J Thorac Cardiovasc Surg 
2005;130:498-503 
Ratnatunga 
15.6%-18.8% 
425 
Ann Thorac Surg 1998; 
66:1940-7 
Filsoufi 
22% 
81 
Ann Thorac Surg 2005; 
80:845-50 
Moraca 
18% (repair), 13% 
(replacement) 
136 
Ann Thorac Surg 2009; 
87:83-9 
Pfannmuller 
14.6% 
82 
J Thorac Cariovasc Surg 
2013; 146:841-7 
 

The SPACER Trial 
 
 
Version C 
December 16 , 2016 
 
Study No. 2015-09 
 Page 15 of 84  
 
2 
STUDY PURPOSE 
The study of the  Edwards FORMA Tricuspid Transcatheter Repair System is a multi-
center, international, prospective, single arm, safety  study to assess the safety and device 
performance of the Edwards FORMA Tricuspid Transcatheter Repair System in patients 
with clinically significant, symptomatic tricuspid regurgitation who are at high surgical risk 
for standard tricuspid repair/replacement. 
 
Data collected in this clinical study will include safety and device performance of the 
investigational system as well as up to 3 year clinical outcomes.  In addition, the data shall 
be used to obtain regulatory approval. 
2.1 
INTENDED USE 
The Edwards FORMA Tricuspid Transcatheter Repair System is intended for treatment of 
subjects with tricuspid regurgitation who are at high surgical risk for standard tricuspid 
repair/replacement due to operative risks, long recovery time, and/or significant co-
morbidities. 
2.2 
PRIOR TESTING 
A Report of Priors (Clinical Investigator’s Brochure (CIB)) has been prepared for the 
Edwards FORMA Tricuspid Transcatheter Repair System.  This document provides the 
prior testing conducted on the system components. 
2.3 
PRIOR CLINICAL STUDIES 
 
 
   
 

The SPACER Trial 
 
 
Version C 
December 16 , 2016 
 
Study No. 2015-09 
 Page 16 of 84  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

The SPACER Trial 
 
 
Version C 
December 16 , 2016 
 
Study No. 2015-09 
 Page 17 of 84  
 
 
 
 
  
2.4 
STUDY DEVICE 
2.4.1 GENERAL DEVICE DESCRIPTION AND COMPONENTS 
The Edwards FORMA Tricuspid Transcatheter Repair System (herein after referred to as 
the FORMA System) is comprised of four (4) different sub-systems as listed below (Table 
3).   A general device description is provided for all components of the FORMA System.  
Further detailed information such as materials, manufacturing, testing, etc. however, will 
be provided in the Clinical Investigator’s Brochure (CIB).  The FORMA System is not 
currently commercially available.  
 
The following table includes the device names and model numbers of the components 
that make up the FORMA System. 
Table 3 – Device Names and Model Numbers 
 
Product Name 
Models 
Edwards FORMA Tricuspid Transcatheter Spacer 
System  
 
Edwards FORMA Tricuspid Transcatheter Introducer 
Sheath Set  
  
Edwards FORMA Tricuspid Transcatheter Railing 
Delivery System  
  
Edwards FORMA Tricuspid Transcatheter Retrieval 
System  
  
2.4.2 EDWARDS FORMA TRICUSPID TRANSCATHETER SPACER SYSTEM: 
 
 
  
   
2.4.2.1 Spacer Device  
 
 
 
 
 
 

The SPACER Trial 
 
 
Version C 
December 16 , 2016 
 
Study No. 2015-09 
 Page 18 of 84  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 

The SPACER Trial 
 
 
Version C 
 
 
Study No. 2015-09 
 Page 19 of 84  
 
2.4.2.2 Railing System  
 
   
 
 
 
 
   
 
 
 
 
 
  
 
 
2.4.2.3 Locking Mechanisms  
 
  
 

The SPACER Trial 
 
 
Version C 
December 16 , 2016 
 
Study No. 2015-09 
 Page 20 of 84  
 
 
 
  
 
 
 
 
 
 
 
 
 
2.4.3 EDWARDS FORMA TRICUSPID TRANSCATHETER INTRODUCER SHEATH SET  
 
 
 
 
 
  
  
 
 
 
 
  
 

The SPACER Trial 
 
 
Version C 
December 16 , 2016 
 
Study No. 2015-09 
 Page 21 of 84  
 
2.4.4 EDWARDS FORMA TRICUSPID TRANSCATHETER RAILING DELIVERY SYSTEM  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
   
 

The SPACER Trial 
 
 
Version C 
December 16 , 2016 
 
Study No. 2015-09 
 Page 22 of 84  
 
 
 
 
 
2.4.5 EDWARDS FORMA TRICUSPID TRANSCATHETER RETRIEVAL SYSTEM  
 
 
 
  
 
   
 
 
 
 
 
 

The SPACER Trial 
 
 
Version C 
December 16 , 2016 
 
Study No. 2015-09 
 Page 23 of 84  
 
 
 
 
 
3 
RISK ANALYSIS 
A risk analysis has been conducted, in accordance with ISO 14971: “Application of risk 
management to medical devices”. The risks associated with this investigational device 
have been identified by performing Failure Mode and Effect Analysis (FMEA)/Risk 
Analysis. Risks have been proven minimized through appropriate design control, 
confirmed by bench testing, pre-clinical animal testing and clinical surveillance presented 
in the Clinical Investigator’s Brochure.  
 
During the conduct of the clinical study, the existing risk control measures shall be 
reviewed to identify if other hazards have been introduced.  If any new hazards were 
introduced by any risk control measures, the associated risk(s) shall be re-assessed and 
addressed.  
3.1 
POTENTIAL RISKS 
The potential risks of use of the FORMA System are similar to those encountered with 
standard cardiac catheterization and use of anesthesia and have been listed in two 
categories below. First, there are the potential complications associated with the overall 
procedure including standard cardiac catheterization and the use of anesthesia. Second, 
there are the additional potential risks associated with the use of the FORMA System.  

The SPACER Trial 
 
 
Version C 
December 16 , 2016 
 
Study No. 2015-09 
 Page 24 of 84  
 
Estimated occurrence rankings of the potential risks are provided in the Sample Informed 
Consent Form in Appendix A.  
 
Risks related to the overall procedure including standard cardiac catheterization and the 
use of anesthesia may include, but may not be limited to, the following:  
 
 abnormal lab values; 
 access site AV fistula or pseudoaneurysm; 
 allergic reaction to anesthesia or to contrast media; 
 anemia; 
 angina; 
 arrhythmia; 
 bleeding; 
 cardiovascular or vascular injury including perforation, obstruction, or dissection 
of valvular structures that may require intervention, including access sites; 
 conduction system injury (defect) which may require replacement or 
implantation of a pacemaker (temporary or permanent); 
 death; 
 dyspnea (e.g., orthopnea); 
 electrolyte imbalance; 
 embolization including air, particulate, calcific material, or thrombus; 
 exercise intolerance or weakness; 
 fever; 
 heart failure; 
 heart murmur; 
 hematoma; 
 hemorrhage requiring transfusion or intervention; 
 leaflet damage; 
 hypertension/hypotension; 
 infection, including septicemia and endocarditis; 
 inflammation; 
 myocardial infarction; 
 pain or changes at the access site; 
 paralysis; 
 pericardial effusion/cardiac tamponade; 
 permanent disability; 
 pleural effusion; 
 pulmonary edema; 
 renal failure; 
 renal insufficiency; 
 reoperation; 

The SPACER Trial 
 
 
Version C 
December 16 , 2016 
 
Study No. 2015-09 
 Page 25 of 84  
 
 restenosis; 
 retroperitoneal bleed; 
 syncope; 
 systemic peripheral ischemia/nerve injury; 
 thromboembolic events, stroke, transient ischemic attack, clusters, or 
neurological changes; 
 wound dehiscence, delayed or incomplete healing. 
 
In addition to the risks listed above, additional potential risks associated with the use of 
the FORMA System may include, but may not be limited to, the following: 
 
 cardiac arrest; 
 cardiac dysrhythmias requiring replacement or implantation of a pacemaker 
(temporary or permanent); 
 cardiac failure/low cardiac output; 
 cardiogenic shock; 
 chordal damage, rupture; 
 deterioration of native valve (leaflet tear/tearing, leaflet retraction, leaflet 
thickening, leaflet stenosis, or other); 
 device degeneration;  
 device explants;  
 device migration, malposition or embolization potentially requiring intervention;  
 device thrombosis requiring intervention;  
 emergency cardiac surgery;  
 hemolysis;  
 leakage around device; 
 non-emergent reoperation;  
 nonstructural implant dysfunction;  
 papillary muscle damage; 
 pneumothorax; 
 pulmonary artery outflow tract obstruction;  
 skin burn; 
 structural deterioration (wear, fracture, calcification, shaft creep, or other);  
 thromboembolism (permanent or transient pulmonary and/or neurological 
events); 
 transvalvular flow disturbances; 
 valvular regurgitation; 
 ventricular or atrial wall damage, abrasion, or perforation; 
 worsening of heart failure; 
 worsening of valvular insufficiency. 
 

The SPACER Trial 
 
 
Version C 
December 16 , 2016 
 
Study No. 2015-09 
 Page 26 of 84  
 
There may be other risks that are unknown at this time. All safety events will be collected 
and reviewed throughout the entire study and follow-up period. The Investigators will be 
notified of any additional risks identified that could affect the health, safety or welfare of 
the study subjects. 
3.2 
RISK MANAGEMENT 
All efforts will be made to minimize the identified risks by selecting Investigators, team 
members and study sites who meet the following criteria: 
 
 Interventional Cardiologist - must be board certified (or equivalent), experienced with 
performing transcatheter heart valve repair and replacement, and skilled in 
percutaneous coronary interventions and structural heart interventions. 
 Access Management Physician - must be board certified (or equivalent), experienced 
with access management (subclavian/axillary vein access) and right heart 
interventions.  
There will be strong interdepartmental collaboration between interventional cardiology 
and cardiovasculary surgery operators and a designated team of nurses, technicians and 
colleagues from 
supporting 
medical disciplines (e.g., anesthesiologist, echo-
cardiographer, radiologist).  
 
The procedural location is to be an operating room, catheterization lab or hybrid 
operating room with fluoroscopic and echocardiographic imaging capabilities. 
 
All adverse events will be thoroughly reviewed by the Study Sponsor and Data Monitoring 
Committee.  The Study Stopping Rules are outlined in Section 16. 
3.3 
BENEFITS 
The clinical benefits of using the FORMA System for the treatment of tricuspid 
regurgitation are not known at the present time.  There are no guaranteed benefits from 
participation in this clinical study and being treated with the investigational FORMA 
System. 
 
Tricuspid valve repair with the FORMA System may result in one or more of the following 
benefits for subjects typically considered high risk for tricuspid repair or replacement: 
decrease in tricuspid regurgitation, acute alleviation of symptoms related to tricuspid 
insufficiency, and/or improved morbidity and mortality.  
 
Information gained from the conduct of this study may be of benefit to other people with 
the same medical condition in the future as the indication for the system is expanded.  

The SPACER Trial 
 
 
Version C 
December 16 , 2016 
 
Study No. 2015-09 
 Page 27 of 84  
 
3.4 
JUSTIFICATION  
This study, is designed as a multi-center, international, prospective, single arm, safety 
study. This study is designed to assess the safety and device performance of the FORMA 
System in a controlled human population. 
 
The treatments currently available for this patient population include palliative medical 
therapy and high-risk surgical replacement or repair of the tricuspid valve.    Treatment 
with the FORMA System may enable patients with tricuspid regurgitation, to undergo 
tricuspid valve repair via a minimally invasive approach.   
4 
STUDY OBJECTIVES 
The objective of this study is to assess the safety and device performance of the Edwards 
FORMA Tricuspid Transcatheter Repair System in patients with clinically significant, 
symptomatic tricuspid regurgitation who are at high surgical risk for standard tricuspid 
repair/replacement. 
5 
STUDY ENDPOINTS 
5.1 
PRIMARY ENDPOINT 
The primary endpoint for the study will assess the all-cause mortality of the as treated 
cohort at 30 days compared to a literature derived Performance Goal based on high-risk 
surgical outcomes for tricuspid repair/replacement.  
5.2 
SECONDARY ENDPOINTS & CLINICAL OUTCOMES 
The following secondary endpoints and clinical outcomes will also be assessed:  
5.2.1 TECHNICAL SUCCESS ENDPOINT 
Technical Success will be assessed at exit from procedure room and is defined as: 
 
 Alive, with  
 Successful access, delivery and removal of the delivery systems, and  
 Deployment and correct positioning of the intended device, and   
 
No need for additional emergency surgery or re-intervention related to the device or 
access procedure 
5.2.2 DEVICE SUCCESS ENDPOINT 
Device Success will be assessed at 1 month, 6 months and annually and is defined as: 
 
 Alive, with 
 Original intended device in place, and 
 No additional surgical or interventional procedures related to the device, and 

The SPACER Trial 
 
 
Version C 
December 16 , 2016 
 
Study No. 2015-09 
 Page 28 of 84  
 
 TR reduction (assessment made by change in EROA) compared to baseline and TV 
gradient ≤ 5mmHg 
5.2.3 PROCEDURAL SUCCESS ENDPOINT 
Procedural Success will be assessed at 1 month and is defined as: 
 
 Device Success, and  
 None of the following device or procedure related SAEs: 
 Life threatening bleeding 
 Major vascular or cardiac structural complications requiring intervention 
 Pericardial effusion requiring drainage or surgery (includes tamponade) 
 Stage 2 or 3 acute kidney injury (includes new dialysis) 
 Severe heart failure or hypotension requiring IV inotrope, ultrafiltration or 
mechanical circulatory support 
 Prolonged intubation > 48 hours 
5.2.4 CLINICAL OUTCOMES 
Clinical Outcomes will be assessed at 1 month, 6 months & annually and are defined as: 
 Re-hospitalization rates for the underlying condition (heart failure) 
 Re-intervention rates for the underlying condition (tricuspid regurgitation)  
 Change in Tricuspid Regurgitation (assessment made by change in EROA) from 
baseline 
 Change in peripheral edema as assessed by subject weight loss (kilograms) from 
baseline 
 Change in NYHA Class from baseline 
 Change in 6 minute walk test distance (meters) from baseline  
 Change in Quality of Life as assessed by the SF-12 and KCCQ questionnaires from 
baseline 
6 
STUDY DESIGN 
This is a multi-center (≤12), international, prospective, single arm, safety study designed 
to assess the safety and device performance of the FORMA System. 
 
A total of seventy-eight (78) subjects will be enrolled in the study.  All enrolled study 
subjects will be assessed for clinical follow-up at the following intervals:  1 month, 6 
months, 1 year and annually for 3 years post implant procedure.  Centers that do not have 
experience with the investigational device will be allowed a single “roll-in” subject to 
become familiar with the study device and procedure. 
 

The SPACER Trial 
 
 
Version C 
December 16 , 2016 
 
Study No. 2015-09 
 Page 29 of 84  
 
A description of each study visit and required study procedures are included in Section 
8.0, Procedures and Methods.  In addition, a summary of required procedures is listed in 
Table 10.  
7 
SUBJECT POPULATION 
7.1 
DEMOGRAPHIC AND CLINICAL CHARACTERISTICS 
This clinical study is for adult subjects with clinically significant, symptomatic, tricuspid 
regurgitation who are at high surgical risk for standard tricuspid repair or replacement as 
assessed by the Heart Team. 
 
All subjects who meet the initial study eligibility requirements will be evaluated for study 
participation. 
 
Candidates for this study must meet all of the following inclusion criteria and none of the 
exclusion criteria: 
7.2 
INCLUSION CRITERIA  
The Investigator has the responsibility of screening potential subjects to determine if the 
patients meet all the inclusion criteria.  The following are requirements for entry into the 
study:  
 
1. Signed and dated EC approved study consent form prior to  study related 
procedures  
2. Eighteen years of age or older 
3. Clinically significant, symptomatic (NYHA Functional Class II or greater), tricuspid 
regurgitation (Stage D per 2014 AHA/ACC guidelines) requiring tricuspid valve 
repair or replacement  as assessed by the Heart Team 
4. Functional tricuspid regurgitation (e.g., EROA ≥ 0.4 cm2 or equivalent guideline 
directed value) as the primary etiology  
5. NYHA Functional Class II or greater or signs of persistent right heart failure despite 
optimal medical therapy 
6. Determined by the 'HEART Team' (a minimum of one Cardiologist, and one Cardiac 
Surgeon) to be at high surgical risk for tricuspid valve repair or replacement and 
the benefit-risk analysis supports utilization of the investigational device  
7. Willing to attend study follow-up assessments for up to 3 years 
7.3 
EXCLUSION CRITERIA 
The Investigator at the study site must exclude subjects if any of the exclusion criteria are 
present. The following are the criteria for exclusion from participating in the clinical study: 
 

The SPACER Trial 
 
 
Version C 
December 16 , 2016 
 
Study No. 2015-09 
 Page 30 of 84  
 
1. Tricuspid valve/right heart anatomy not suitable for the study device:  
a. 
Native tricuspid annulus area < 2.14 cm2 (9 mm device),  < 2.63 cm2 (12 mm 
device) or< 3.27cm2 (15 mm device) as measured by transthoracic 
echocardiography or computed tomography 
b. 
Sub-valvular structures/anatomy that would preclude from proper anchor or 
Spacer placement, positioning and retrieval 
2. Access pathway vessel diameter less than 7.1 mm (9, 12 and 15 mm devices) 
Moderate or greater tricuspid valve stenosis 
3. Untreated clinically significant coronary artery disease requiring immediate 
revascularization 
4. Any therapeutic invasive cardiac procedure performed within 30 days of the 
scheduled implant procedure  
5. Patients not already receiving dialysis with renal insufficiency (eGFR < 25) per lab 
test ≤ 48 hours prior to scheduled implant procedure 
6. Myocardial infarction within 30 days of scheduled implant procedure 
7. Hemodynamic instability within 30 days of scheduled implant procedure 
8. Patient requiring surgery under general anesthesia for any reason within 30 days 
of scheduled implant procedure 
9. Severe left ventricular dysfunction with ejection fraction < 25% within 90 days of 
scheduled implant procedure 
10. Patients with pulmonary artery systolic pressure >70 mmHg via transthoracic 
echocardiography or alternative standard modality (e.g., direct pressure 
measurement) within 90 days 
11. Concomitant clinically significant valve (aortic, mitral, or pulmonic) disease 
requiring immediate (± 30 days of study procedure) repair or replacement  
12. Active endocarditis or infection within 3 months of scheduled implant procedure 
13. Cerebrovascular accident within 3 months of scheduled implant procedure 
14. Non-cardiac disease limiting life expectancy to be less than 12 months at baseline 
evaluation 
15. Documented history of bleeding diathesis, coagulopathy or gastrointestinal 
bleeding within 3 months of scheduled implant procedure 
16. Evidence of right sided intracardiac mass, thrombus, or vegetation 
17. Prior venous stent placed within the access route (e.g., sub-clavian vein) that could 
negatively react with device 
18. Previously treated tricuspid valve which included implantation of a bioprosthetic 
valve or mechanical valve  
19. Known hypersensitivity to cobalt chromium, nitinol or titanium  
20. Known hypersensitivity to anticoagulation therapy or contrast agent, which 
cannot be adequately medicated 

The SPACER Trial 
 
 
Version C 
December 16 , 2016 
 
Study No. 2015-09 
 Page 31 of 84  
 
21. Patient is a current intravenous drug user 
22. Female of child-bearing potential is pregnant or lactating 
23. Patient is currently participating or has participated in another investigational 
drug or device clinical study within 30 days of study screening activity 
24. Patient requires emergent/emergency treatment for tricuspid insufficiency 
25. Patient is under guardianship 
8 
PROCEDURES AND METHODS 
8.1 
INFORMED CONSENT  
As the study Sponsor, Edwards Lifesciences must approve any modifications to the 
Informed Consent Form prior to submission to the regional ethics investigational review 
board (REB), independent ethics committee (EC) and/or Competent Authority (as 
required).  A sample Informed Consent Form is provided in Appendix A – Sample Informed 
Consent Form.   
Once the patient’s physician has determined the patient’s eligibility for the study, the 
background of the proposed study, and the benefits and risks of the procedures and study 
will be explained to the patient.  The patient must sign the institution’s approved 
Informed Consent Form prior to participation.  Failure to provide informed consent 
renders the patient ineligible for the study. 
The consent form will be written in the native language of the patient and administered 
only by the Investigator or EC approved personnel who speak the native language of the 
patient.  The Principal Investigator or delegated person administering the consent must 
sign and date the Informed Consent Form to indicate that the purpose, risks and benefits 
of the study were explained to the patient and that their signature was witnessed. 
The Investigator will retain the original consent form, a copy will be filed in the patient’s 
medical record, and a copy of the Informed Consent Form will be provided to the patient. 
Informed consent MUST be obtained prior to any study related procedures.  A patient 
will be considered a “subject” and “enrolled” when they have signed the informed 
consent form agreeing to participate in the study and have been deemed eligible for study 
participation by meeting the study criteria (Sections 7.2-7.3).  Subjects who are consented 
to participate in the study but do not fulfill enrollment criteria, will be considered “screen 
failures” as described below (Section 8.2).  Signed informed consent forms must be 
retained by the study site for verification during on-site monitoring visits.  
8.2 
SUBJECT ENROLLMENT  
A Screening/Enrollment Log provided by the Sponsor, will be maintained at the study site 
to document the screening and enrollment of all subjects assessed for study participation.  
The screening of subjects qualifying for this study should be carried out in a sequential, 
prospective manner, such that all patients are offered the possibility of participating in 

The SPACER Trial 
 
 
Version C 
December 16 , 2016 
 
Study No. 2015-09 
 Page 32 of 84  
 
the study and are therefore, evaluated according to the selection criteria defined in this 
protocol (see Figure 16).  If a subject assessed for study participation does NOT enter the 
study, the reason in form of a “screen failure” code will be recorded on the log to ensure 
that a subject selection bias has not been introduced in the study. These reasons may 
include but not limited to: 
 Qualifying patient is not offered an opportunity to participate by Investigator  
 Qualifying subject refuses to participate   
 Potential subject fails the screening criteria    
All subjects assessed for study participation that have signed the informed consent form 
will be at the point of provisional enrollment and entered on the screening log.  All 
subjects assessed for study participation that have signed the informed consent form,  
deemed eligible for study participation by the Screening Committee and have met the 
study criteria, will be at the point of final enrollment and assigned a sequential subject ID 
number by the study sponsor.  The subject ID number together with the subject initials (if 
applicable) shall be used to identify the subject on all study-related documents. 
 
 

The SPACER Trial 
 
 
Version C 
December 16 , 2016 
 
Study No. 2015-09 
 Page 33 of 84  
 

The SPACER Trial 
 
 
Version C 
December 16 , 2016 
 
Study No. 2015-09 
 Page 34 of 84  
 
8.3 
BASELINE EVALUATION  
1. Informed consent will be obtained from all patients who have been determined to 
be eligible study candidates and agreed to participate in the study.  
2. Medical History (includes 6-month prior heart failure hospitalization rate), Clinical 
Evaluation (includes vital signs, weight and height), Concomitant Medication and 
NYHA classification  
3. Administration of Health Status Questionnaires (SF-12, KCCQ) 
4. Administration of Six Minute Walk Test   
5. Clinical Laboratory Tests - 
a. The following lab tests shall be done within 30 days of the scheduled 
implant procedure: 
i. Troponins and/or cardiac enzymes (CK-MB) - MI within 30 days of 
the scheduled implant procedure is an exclusion from study 
participation 
b. The following lab tests shall be done ≤ 2 weeks before implant procedure: 
i. Brain Natriuretic Peptide (BNP) 
ii. CBC and platelet count  
iii. Complete metabolic panel  
iv. Liver panel  
c. The following lab tests shall be done ≤ 48 hours before the implant 
procedure: 
i. Estimated Glomerular Filtration Rate (eGFR) - eGFR result of < 25 is 
an exclusion from study participation for patients not already 
receiving dialysis 
ii. HCG for women who are not sterile or post-menopausal- positive 
result is an exclusion from study participation. 
iii. PTT/aPTT or PT/INR  
6. Standard 12-lead Electrocardiogram (ECG)  
7. Comprehensive  Echocardiograms (Transthoracic [TTE] and Transesophogeal [TEE]), 
if required1, (within 90 days of scheduled implant procedure) including but not 
limited to, annulus size, ventricular size, regurgitant assessment, jet location, mean 
PAP and LVEF.  Analysis will be conducted by the Investigator and Sponsor to certify 
the subject is eligible for the study. 
8. Computed Tomography (CT) (within 902 days of scheduled implant procedure), that 
captures the anatomy of the subclavian and axillary veins, superior vena cava, 
                                                 
1 The primary purpose of the TEE is to confirm the ability to image the tricuspid valve and possible 
anchoring location during the index procedure as this is the method that is used intra-procedure.  If the 
TTE can demonstrate that the imaging of the valve and possible anchoring location is adequate, the TEE 
requirement at the baseline evaluation may be waived. 
2 If a pre-existing CT within 6 months of the scheduled implant procedure captures all the required 
anatomy for necessary measurements and the anatomy has not changed, the baseline CT can be waived 
and is not required to be repeated. 

The SPACER Trial 
 
 
Version C 
December 16 , 2016 
 
Study No. 2015-09 
 Page 35 of 84  
 
tricuspid valve and sub-valvular structures/anatomy, right atrium and right 
ventricle. Analysis will be conducted by the Investigator and Sponsor/designee to 
certify the subject is eligible for the study. 
9. Invasive Hemodynamic Monitoring/Right Heart Catheterization (within 45 days of 
scheduled implant procedure) that includes, but is not limited to, right atrial 
pressure (RAP) and pulmonary artery pressure (PAP) measurements.3  
 
Baseline evaluation data to be collected will include but is not limited to the information 
listed in the following table. 
Table 4 - Baseline Evaluation 
 
General Information 
Clinical Information 
Laboratory Measurements 
 Inclusion/exclusion 
evaluation 
 Informed consent 
 Age 
 Gender 
 Height 
 Weight 
 
 Heart Team determination 
 Medical history (e.g., 
EuroSCORE) /prior 
cardiovascular 
interventions / surgeries  
 Vital signs (Blood pressure, 
heart rate) 
 Concomitant Medication 
 NYHA classification1 
 Echocardiographic 
measurements (TTE & TEE), 
tricuspid regurgitation & 
heart function  
 Computed Tomography 
(CT) 
 Invasive Hemodynamic 
Monitoring/Right Heart 
Catheterization including 
pressure measurements 
 ECG results 
 Six minute walk test (pre & 
post walk data & results) 
 KCCQ & SF-12 
questionnaires 
Within 30 days of procedure: 
 Date of blood draw 
 Troponin2 and/or CK-MB2 
 
Within ≤ 2 weeks of 
procedure: 
 Date of blood draw 
 BNP 
 WBC 
 RBC 
 Hematocrit 
 Hemoglobin 
 Platelets 
 ALT/SGPT 
 AST/SGOT 
 Bilirubin 
 LDH 
 Sodium & potassium 
 Urea  
Within ≤ 48 hours of 
procedure: 
 eGFR3 
 PTT/aPTT or PT/INR 
 HCG, if applicable4 
1. 
Classification of < NYHA II is an exclusion from study participation 
2. 
MI within 30 days of the scheduled implant procedure is an exclusion from study participation 
3. 
eGFR result of < 25 is an exclusion from study participation 
4. 
A positive result is an exclusion from study participation 
                                                 
3 If the screening echo confirms the PAP meets the study criteria, the right heart catheterization/ 
hemodynamic assessment at the baseline evaluation may be waived.   

The SPACER Trial 
 
 
Version C 
December 16 , 2016 
 
Study No. 2015-09 
 Page 36 of 84  
 
8.4 
ANTIPLATELET / ANTICOAGULATION THERAPY  
All subjects will receive aspirin (at least 75 - 100 mg daily) prior to implant procedure.  
Subjects on warfarin will be asked to discontinue use prior to implant procedure.  See 
Table 5.   
 
Heparin will be administered at procedure start.  During the procedure, activated clotting 
time (ACT) will be monitored and recorded on source documentation.  Heparin will be 
administered during the procedure as needed to maintain the subject’s ACT at ≥ 250 sec. 
The sheaths may be removed when ACT level is appropriate (e.g., reaches < 150 sec) after 
implantation of the study devices. 
 
Implanted subjects will receive aspirin (at least 75 - 100 mg daily) post implant procedure 
through the 6 month follow-up visit. Additionally, patients with pre-existing atrial 
fibrillation will continue with their prescribed blood thinning medication (e.g., Coumadin® 
or Jantoven®) (INR > 2.5) post implant procedure through the 6-month follow-up visit.  
For patients not in atrial fibrillation, a second antiplatelet medication of the investigator’s 
choice (e.g., Plavix) shall be prescribed post implant procedure through the 6-month 
follow-up visit.  The antiplatelet regimen past the 6-month follow-up visit will be 
determined at the Investigator’s discretion.   
Table 5 - Summary of Recommended Concomitant Medical Therapy 
Medication 
Pre-
Procedure 
Inter-
Procedure 
Post-
Procedure 
1 Month 
Follow-Up 
6 Month 
Follow-Up 
IV Heparin 
 
X 
X4 
 
 
Aspirin 
75-100 mg daily 
X 
 
X 
X 
X 
Warfarin or alternative 
(AFib Patients) 
 
 
X 
X  
X 
Plavix or alternative 
(Non-AFib Patients) 
 
 
X 
X 
X 
 
NOTE:  The Investigator will determine the antiplatelet/anticoagulation therapy for study 
subjects on an existing dual antiplatelet therapy or with known hypersensitivity to the 
required medications in Table 5.   
                                                 
4 As needed as a bridge to warfarin where applicable 

The SPACER Trial 
 
 
Version C 
December 16 , 2016 
 
Study No. 2015-09 
 Page 37 of 84  
 
8.5 
DEVICE PREPARATION  
A description of device preparation and use is provided in the Instructions for Uses (IFUs), 
(See Clinical Investigator’s Brochure). Investigators must be familiar with the information 
described in the IFU prior to use of the FORMA System.  
 
An Edwards Representative that has been trained on the preparation of the FORMA 
System will be in attendance at all implant procedures.  
8.6 
IMPLANT PROCEDURE  
The implant procedure shall be performed under general anesthesia with hemodynamic 
monitoring in an operating room, catheterization lab or hybrid operating room with 
fluoroscopic and echocardiographic imaging capabilities.  The use of cardiopulmonary 
bypass is not required. 
 
The following study procedures will occur during the implant procedure: 
 
1. Safety Evaluation 
2. Transesophageal Echocardiogram  
3. Angiographic Imaging 
4. Invasive Hemodynamic Monitoring/Right Heart Catheterization including right 
atrial pressure measurements pre and post implant 
5. Heparin administration to achieve (and maintain) an ACT of ≥ 250 during the 
implant procedure 
 
Subjects will be monitored in the operating room as needed with special attention to 
hemodynamic condition and cardiac rhythm. Subsequent monitoring of subjects will be 
continued in the recovery room or ICU.  
 
The date of the implant procedure will be considered as Day 0 for the purpose of 
determining specified time intervals for the follow-up visit for the implanted and non-
implanted cohorts. 
 
Procedure data to be collected will include but is not limited to the information listed in 
the following table. 
 
 
 
 
 
   
 
 

The SPACER Trial 
 
 
Version C 
December 16 , 2016 
 
Study No. 2015-09 
 Page 38 of 84  
 
Table 6 - Procedure Information 
 
General Information 
Clinical Information 
Laboratory Measurements 
 Hospital admission date 
 Subject identification 
number 
 Names of 
Interventional 
Cardiologist & Access 
Management Physician 
 Procedure date 
 Access site 
 Timing of implant 
procedures 
 FORMA System 
identification & 
disposition 
 Fluoroscopy duration & 
contrast volume 
 Heparin administration 
& ACT levels 
 TEE measurements, 
tricuspid regurgitation & 
heart function  
 Angiographic Imaging 
 Invasive Hemodynamic 
Monitoring/Right Heart 
Catheterization and 
pressure measurements 
performed 
 Post-implant antiplatelet 
/ anticoagulation 
regimen 
 Adverse events 
 Device malfunction  
Within 24 hours post 
implant: 
 Troponin1 and/or  
CK-MB1 
 
1. 
If an elevation was noted post implant (within 24 hours), tests must be repeated three times or 
until not clinically significant 
8.6.1 ANTIBIOTIC PROPHYLAXIS  
It is recommended that all recipients be prophylactically treated for endocarditis to 
minimize the possibility of infection. 
8.6.2 CONTRAST MEDIA  
Careful management of contrast media is required for these patients. Accurate 
measurement of the dye used during the implant procedure shall be captured in the 
appropriate case report form.  
8.6.3 DISCHARGE 
The following procedures will be performed prior to discharge from the hospital/unit:  
 
1. Clinical Evaluation and Concomitant Medication  
2. Safety Evaluation 
2. Clinical Laboratory Tests 
a. BNP 
b. CBC and platelet count  
c. Complete metabolic panel  

The SPACER Trial 
 
 
Version C 
December 16 , 2016 
 
Study No. 2015-09 
 Page 39 of 84  
 
d. Liver panel 
e. PTT/aPTT or PT/INR 
f. eGFR 
g. Troponins and/or cardiac enzymes (CK-MB), only required if an elevation 
was noted post implant (within 24 hours) 
3. Standard 12-lead ECG 
4. Comprehensive Transthoracic Echocardiogram, including but not limited to, 
annulus size, ventricular size, regurgitant assessment and jet location 
Discharge data to be collected will include but is not limited to the information listed in 
the following table. 
 
Table 7 - Discharge Information 
 
General Information 
Clinical Information 
Laboratory Measurements 
 Discharge date 
 Weight 
 
 Vital signs (Blood Pressure, 
Heart Rate) 
 NYHA classification 
 TTE measurements, 
tricuspid regurgitation & 
heart function  
 ECG results 
 Post-implant antiplatelet / 
anticoagulation regimen 
 Adverse events 
 
 
 Date of blood draw 
 Troponin and/or CK-MB, if 
applicable 
 BNP 
 WBC 
 RBC 
 Hematocrit 
 Hemoglobin 
 Platelets 
 ALT/SGPT 
 AST/SGOT 
 Bilirubin 
 LDH 
 Sodium & potassium 
 Urea 
 eGFR 
 PTT/aPTT or PT/INR 
 
8.7 
FOLLOW-UP VISITS 
Follow-up visits will be conducted at 1 month, 6 months, and annually for 3 years post 
implant procedure intervals as illustrated in Table 9. The following procedures will be 
conducted during follow-up visits:  
 
1. Clinical Evaluation, Concomitant Medication and NYHA classification 
2. Administration of Health Status Questionnaires (e.g., SF-12, KCCQ) 

The SPACER Trial 
 
 
Version C 
December 16 , 2016 
 
Study No. 2015-09 
 Page 40 of 84  
 
3. Administration of Six Minute Walk Test 
4. Safety Evaluation  
5. Clinical Laboratory Tests : 
a. 
BNP 
b. 
CBC and platelet count  
c. 
Complete metabolic panel  
d. 
Liver panel 
e. 
PTT/aPTT or PT/INR 
f. 
eGFR 
6. Standard 12-lead ECG 
7. Comprehensive Transthoracic Echocardiogram, including but not limited to, 
annulus size, ventricular size, regurgitant assessment and jet location 
Follow-up data to be collected will include but is not limited to the information listed in 
the following table. 
Table 8 - Follow-Up Visit Information 
 
General Information 
Clinical Information 
Laboratory Measurements 
 Visit date 
 Height 
 Weight 
 
 Vital signs (Blood Pressure, 
Heart Rate) 
 NYHA classification 
 TTE measurements, 
tricuspid regurgitation & 
heart function  
 ECG results 
 Six minute walk test (pre & 
post walk data & results) 
 KCCQ & SF-12 
questionnaires 
 Concomitant Medication 
 Adverse events 
 
 Date of blood draw 
 BNP 
 WBC 
 RBC 
 Hematocrit 
 Hemoglobin 
 Platelets 
 ALT/SGPT 
 AST/SGOT 
 Bilirubin 
 LDH 
 Sodium & potassium 
 Urea 
 eGFR 
 PTT/aPTT or PT/INR 
8.7.1 FOLLOW-UP VISIT WINDOWS 
Post-procedure follow-up visits will be performed on all implanted study subjects at 1 
month, 6 months, and annually for 3 years post implant procedure intervals as illustrated 
in Table 9 below: 
 

The SPACER Trial 
 
 
Version C 
December 16 , 2016 
 
Study No. 2015-09 
 Page 41 of 84  
 
Table 9 - Follow-up Visit Windows 
Scheduled Follow-up Interval 
Follow-up Window 
1 month (30 days) 
± 7 days 
6 months (183 days) 
± 30 days 
Annually  (365 days) up to 3 years ± 45 days 
 
 
During the follow-up visits, medical information, findings and results will be entered in 
the appropriate electronic case report forms. 
 
Study subjects who have signed the Informed Consent, are deemed eligible and 
considered enrolled in the study but do not have the study procedure (incision) occur will 
be exited from the study immediately. 
 
Study subjects who have signed the Informed Consent, are enrolled in the study, have the 
study procedure (incision) occur but do not receive the investigational device will be 
classified as “non-implanted” study subjects and exit the study at the 6 month follow-up 
visit.  Non-implanted study subjects must complete safety evaluations but, will be exempt 
from all other study follow-up visit procedures.  
 

The SPACER Trial 
CONFIDENTIAL 
  
 
 
Version C  
December 16, 2016 
Study No. 2015-09  
Page 42 of 84  
 
Table 10 - Summary of Required Study Procedures 
                                                 
1 Implant procedure must be scheduled within 90 days of the baseline transthoracic echocardiogram and 90 days of the pre-implant procedure computed tomography (CT).  If a pre-existing CT within 6 
months of the scheduled implant captures all the required anatomy for necessary measurements & the anatomy has not changed,  the baseline CT can be waived & is not required to be repeated. 
2 Discharge from hospital/unit post implant procedure 
3 HCG for women who are not sterile or post-menopausal 
4 eGFR result of < 25 is an exclusion from study participation 
5 Test will be taken post-implant (within 24 hours).  If an elevation is noted, test must be repeated three times or until not clinically significant.  
6 If an elevation was noted post implant (within 24 hours), test must be repeated three times or until not clinically significant  
7 The primary purpose of the TEE is to confirm the ability to image the tricuspid valve during the index procedure as this is the method that is used intra-procedure.  If the TTE can demonstrate that the 
imaging of the valve is adequate, the TEE requirement at the baseline evaluation may be waived.  
8 If the screening echo confirms the PAP meets the study criteria, the right heart catheterization/hemodynamic assessment at the baseline evaluation may be waived. 
STUDY PROCEDURES 
BASELINE 
IMPLANT 
PROCEDURE1 
(Day 0) 
DISCHARGE2  
1 MONTH 
 (30 ± 7 days ) 
6 MONTHS 
(183 ± 30 days) 
ANNUAL  
 (for 3 yrs)  
(365 ± 45 days) 
Informed Consent 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Clinical Evaluation 
X 
 
X 
X 
X 
X 
NYHA Class Assessment 
X 
 
 
X 
X 
X 
Health Status Questionnaires 
X 
 
 
X 
X 
X 
Six Minute Walk Test 
X 
 
 
X 
X 
X 
Safety Evaluation 
 
X 
X 
X 
X 
X 
Brain Natriuretic Peptide (BNP) 
X 
 
X 
X 
X 
X 
CBC and Platelet Count 
X 
 
X 
X 
X 
X 
Complete Metabolic Panel 
X 
 
X 
X 
X 
X 
Liver Panel 
X 
 
X 
X 
X 
X 
PTT/aPTT or PT/INR 
X 
 
X 
X 
X 
X 
HCG 
X3 
 
 
 
 
 
eGFR 
X4 
 
X 
X 
X 
X 
Troponins and CK-MB 
X 
X5 
X6 
 
 
 
ECG 
X 
 
X 
X 
X 
X 
Transesophageal Echocardiogram 
X7 
X 
 
 
 
 
Transthoracic Echocardiogram 
X 
 
X 
X 
X 
X 
Pre-Implant  Computed Tomography 
X 
 
 
 
 
 
Angiographic Imaging 
 
X 
 
 
 
 
Invasive Hemodynamic Monitoring/Rt Heart Cath. 
X8 
X 
 
 
 
 

The SPACER Trial 
 
Version C  
December 16, 2016 
Study No. 2015-09  
Page 43 of 84 
 
 
 
8.8 
MISSED SUBJECT VISITS 
The Investigator shall inform study subjects of the importance of returning for scheduled 
follow-up visits and reporting any address or telephone number changes.  The 
Investigator shall make every attempt to follow the study subjects. 
 
The Investigator shall keep a separate log of the subjects’ names and current contact 
information 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 will 
document the missed visit and effort made to contact that subject, the subject’s primary 
health care provider, and/or hospital records on the appropriate Case Report Form.  
Subjects who miss a visit will not be considered withdrawn, and an effort to contact them 
at the next follow-up visit interval will be made by the Investigator.   
8.9 
WITHDRAWAL CRITERIA AND PROCEDURES 
The Investigator will make every attempt to follow the subjects at each of the required 
assessment periods. The reason for the withdrawal will be documented on the 
appropriate case report forms and in the medical records for each subject who has 
withdrawn.  
 
Subjects may be withdrawn from the study for any of the following reasons:  
 
• Subject Withdrawal  
The subject may voluntarily withdraw from the clinical study at any time, 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 
contact efforts made to the subject and/or effort to obtain hospital records in the 
appropriate electronic case report form. If the subject cannot be reached in any way, 
or misses a visit, the subject will be considered “unable to contact” for that time 
interval. After three (3) documented unsuccessful attempts to make contact prove 
unsuccessful, a certified letter 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.” 
 

The SPACER Trial 
 
Version C  
December 16, 2016 
Study No. 2015-09  
Page 44 of 84 
 
 
 
In all cases of withdrawal (as described above), withdrawn subjects will not undergo 
further study follow-up procedures after the time of study exit. A study subject that has 
been withdrawn from the study will not be replaced. 
8.10 
SUBJECT STUDY COMPLETION  
Study subjects complete and exit the study when no additional follow-up visits, 
procedures, or data collection are required. Patients will then continue to be followed by 
their primary health care provider as required.   
 
A subject will also be exited from the study in the following instances:  
 
 Subject signs informed consent form, is deemed eligible and considered enrolled but 
does not undergo the study procedure 
 Subject undergoes study procedure and does not receive investigational device (will 
continue in study for safety evaluations only and exit the study at the 6 month follow-
up visit)  
 
Implanted subject requires the investigational device to be explanted for any reason 
(will continue in study for safety evaluations only and exit the study at the 6 month 
follow-up visit)  
 
Subject is lost-to-follow-up  
 
Subject withdraws participation from the study or is withdrawn from the study 
 
Subject expiration 
9 
TRAINING  
9.1 
INVESTIGATORS DEVICE TRAINING 
 
 
 
   
 
 
   
9.2 
TRAINING OF INVESTIGATIONAL CENTER PERSONNEL 
 
 
 
 
 
 
 

The SPACER Trial 
 
Version C  
December 16, 2016 
Study No. 2015-09  
Page 45 of 84 
 
 
 
 
 
9.3 
TRAINING DOCUMENTATION 
 
 
 
 
10 
INVESTIGATIONAL DEVICE MANAGEMENT 
10.1 
DEVICE SHIPMENTS 
Devices will be transported to the study center when the Clinical Study Agreement is in 
place, the study center has obtained applicable regulatory (e.g., EC, Health Canada, MOH) 
approvals, and a subject eligible for implant has been identified.   
 
Devices will be provided to the study center as needed for scheduled implant procedures.  
All investigational devices used in this study for investigational purposes will be labeled 
with regional appropriate clinical investigation labeling and warnings.   
10.2 
DEVICE ACCOUNTABILITY  
All device shipments will have inventory and shipment records. Devices may be hand 
carried to participating study centers by Study Sponsor personnel and will be 
accompanied by delivery of investigational device documentation (packing lists, transfer 
of investigational product form, etc.). The Investigator(s) or designee will take inventory 
of the product and complete the delivery documentation with receipt date and signature. 
Both the study center and the Study Sponsor will retain copies of these documents. The 
Investigator will maintain a Device Accountability Log (as provided by the Sponsor) of all 
investigational devices documenting their receipt, disposition and return during this 
clinical study. The log will be kept with the documents for the clinical study and will be 
available for review during Study Sponsor monitoring visits. 
 
Upon Sponsor request or when enrollment has ended, FORMA System components must 
be returned to Edwards Lifesciences and the date of return must be recorded on the log. 
10.3 
DEVICE STORAGE 
The device inventory will be stored in a locked, controlled, cool and dry area as described 
in the Instructions for Use (IFU) and/or presented on the device labeling.  This secured 
area will be only accessible to the Investigators or approved designee.  Only investigators 
trained and identified in the Delegation of Authority form on file at Edwards Lifesciences 
may use the investigational devices. 

The SPACER Trial 
 
Version C  
December 16, 2016 
Study No. 2015-09  
Page 46 of 84 
 
 
 
10.4 
DEVICE RETURN  
The Investigator will be notified in writing upon termination of the clinical study. All 
unused devices in original package and/or those in opened packages as well as those 
removed from the original package will be returned upon receipt of this notice.  The 
Investigator will receive instructions from the Study Sponsor on the return process. The 
Investigator’s copy of the Device Accountability log must document any unused devices 
that have been returned.  
 
Used devices may be handled and disposed of in the same manner as hospital waste and 
bio-hazardous materials in accordance with local regulations. There are no special risks 
related to the disposal of these devices. Devices that malfunction or are related to a 
serious adverse event or device effects will be returned to the Study Sponsor for further 
investigation (when possible).  All returns and dispositions of devices will be captured on 
the Device Accountability Log Procedure needed. 
11 
DATA COLLECTION AND REPORTING 
11.1 
DATA COLLECTION METHODS 
The Study Sponsor will provide the study center with the clinical protocol, electronic case 
report forms, sample informed consent form, and all other necessary study-related 
documents.  Study Sponsor’s Clinical Affairs Department, or designee, will conduct all 
aspects of data quality control and assurance of the study center including but not limited 
to, data reviewing, data monitoring, and form collection. 
11.2 
CASE REPORT FORMS 
Electronic CRFs will be used to collect all patient data during the trial.  Paper copies will 
be available for printing on the website.  An e-mail notification will be sent to Edwards 
Lifesciences when enrollment data is collected into the website.  Electronic CRFs must be 
fully completed for each patient, and signed electronically by the investigator and/or 
designee. If for any reason the eCRFs are unavailable, or access to the electronic database 
is limited, paper CRF forms must be completed and submitted to study manager. The 
eCRFs should be completed at the first earliest opportunity. 
 
The investigator, or an individual designated by him/her, is responsible for recording all 
data from the trial onto the eCRFs on a dedicated website.  All data entered is subjected 
to data type verification and range checking.  The operator is notified of errors that may 
occur, and depending on the data verification sub-routines, the operator might need to 
resolve that error before moving to the next entry field.  The investigator is required to 
provide an electronic signature on the appropriate eCRF pages to verify that he/she has 
reviewed the recorded data. 
 

The SPACER Trial 
 
Version C  
December 16, 2016 
Study No. 2015-09  
Page 47 of 84 
 
 
 
Completed eCRFs will be reviewed at the investigational site and remotely by authorized 
Edwards Lifesciences personnel at regular intervals throughout the trial.  Each data record 
is evaluated with extensive electronic intra-form and inter-form edit checking at regular 
intervals.  If an error is discovered, the clinical site research Study Coordinator will be 
notified.  Corrections to the eCRFs will be made by the research Study Coordinator, 
approved by the investigator or designee and verified by the sponsor. 
 
Data submission will be monitored closely. Sites that do not complete all data entry tasks 
in a timely manner may be prohibited from enrollment until data submission is current. 
 
The cycle of data editing will be ongoing until all the data are clean.  The sponsor or 
designee will monitor the clinical site for source documentation verification.  If further 
data entry or source documentation errors are discovered during the site visit, additional 
queries will be generated and will have to be addressed by the clinical site. 
11.3 
SOURCE DOCUMENTATION REQUIREMENTS 
The Clinical Research Coordinator (CRC) designated by the Investigator, and documented 
on the Delegation of Authority log, will perform primary data collection drawn from 
source documentation review (subject’s medical record). All data that is entered in the 
eCRFs must have source documentation available in the subject medical records. Data to 
be collected for the study purposes must not be entered directly onto eCRFs. Protocol 
deviation information can be recorded directly on the protocol deviation eCRF.  The data 
must be recorded from original source documents and available for review by the study 
monitor. Regulations require that Investigators maintain information in the study 
subject’s medical records that corroborate data collected on the eCRFs. The source 
documentation may consist of but is not limited to: operative or procedure reports, 
progress notes, discharge summaries, laboratory reports, radiographic reports, 
medication logs, and worksheets. Source Documents may be in electronic form and/or 
hard (paper) copies. 
11.4 
QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES 
Because of the potential for errors and inaccuracies in entering data into eCRFs, originals 
or photocopies of all relevant procedural records and reports, post-procedural 
examinations, laboratory and other test results may be kept on file in the Investigator’s 
subject study files.  Access to eCRFs and copies of test results must be available at all times 
for inspection by the study monitor. 
 
All clinical sites will be audited periodically by a study monitor employed by Edwards for 
protocol 
adherence, 
accuracy 
of 
eCRFs, 
and 
compliance 
to 
applicable 
regulations.  Evident patterns of non-compliance with respect to these standards will be 
cause for the site to be put on probation for a period of one month.  If corrective actions 
are not subsequently undertaken, the clinical site will be asked to withdraw. 

The SPACER Trial 
 
Version C  
December 16, 2016 
Study No. 2015-09  
Page 48 of 84 
 
 
 
 
Operational data is hosted for full security and availability internally by Edwards. Edwards 
data management provides the highest standards of availability and security: 
 
 Hosting facility is a multi-level protected environment. 
 Access is severely restricted with high-end user recognition technology. 
 Multi-points backup of critical data is standard. 
 Firewalls and other undisclosed technologies provide strong data security. 
 Availability all year-round 24 hours a day. 
 
Passwords will be issued to appropriate data management personnel to ensure 
confidentiality and protection of the data by allowing variable levels of access to the 
computer system. 
12 
REPORTABLE EVENTS / EFFECTS 
12.1 
REPORTING PROCEDURE 
Study subjects will be carefully monitored during the clinical study for any possible 
adverse event. All adverse events will be fully investigated by the Investigator. 
Appropriate treatment for the subject will be initiated while the study follow-up 
continues. Adverse events will be followed until they are adequately resolved or 
explained. 
 
The Investigator will attempt to assess the involvement of the investigational device and 
/ or study procedure in the adverse event according to five different levels of causality 
(See Section 19, Definitions, for causality definitions).  All observations and clinical 
findings, including the nature or the severity, will be documented on the appropriate case 
report form.  
 
The Investigator will report any serious adverse event, anticipated or unanticipated, to 
the Study Sponsor within 24 hours after first knowledge of the event. Notification to the 
Study Sponsor will be made as follows: 
 
 
 
 
In addition, the Investigator will report all adverse events to their Ethics Committee 
Institutional Review Board in accordance with their requirements.  Adverse events will be 
reported to the National Regulatory Agency in accordance with the applicable 
requirements, for example as described in the “SAE Documentation, Evaluation and 
Reporting Procedure to the Competent Authorities” document for Germany. 

The SPACER Trial 
 
Version C  
December 16, 2016 
Study No. 2015-09  
Page 49 of 84 
 
 
 
12.2 
DEFINITIONS 
12.2.1 ADVERSE EVENT  
An adverse event (AE) is defined in ISO 14155:2011 as any untoward medical occurrence, 
unintended disease or injury, or untoward clinical signs (including abnormal laboratory 
finding) in subjects, users or other persons, whether or not related to the investigational 
medical device. 
  
Note:  anticipated adverse events are adverse events that have been identified as possible 
adverse events related to the investigational medical device or the study procedure.  The 
anticipated events of this clinical study are outlined in Section 3.1, Potential Risks 
12.2.2 ADVERSE DEVICE EFFECT  
An adverse device effect (ADE) is defined in ISO 14155:2011 as any adverse event related 
to the use of an investigational medical device. This definition includes: 
- 
Adverse event resulting from insufficient or inadequate instructions for use, 
deployment, implantation, installation, or operation, or any malfunction of the 
investigational medical device. 
 
- 
Any event resulting from use error or from intentional abnormal use of the 
investigational medical device. 
12.2.3 SERIOUS ADVERSE EVENT  
A serious adverse event (SAE) is defined in ISO 14155:2011 as an adverse event that: 
1. led to death 
2. led to serious deterioration in the health of the subject that either resulted in: 
a. a life-threatening illness or injury, or 
b. a permanent impairment of a body structure or a body function, or 
c. in-patient or prolonged hospitalization, or 
d. medical or surgical intervention to prevent life threatening illness or injury or 
permanent impairment to a body structure or a body function. 
3. led to fetal distress, fetal death or a congenital abnormality or birth defect (not 
anticipated in this study as pregnant women are excluded from the study). 
12.2.4 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 characteristics of a serious adverse event 
or that might have led to any of these consequences if suitable action had not been taken 
or intervention had not been made or if circumstances had been less opportune.  

The SPACER Trial 
 
Version C  
December 16, 2016 
Study No. 2015-09  
Page 50 of 84 
 
 
 
12.2.5 UNANTICIPATED SERIOUS ADVERSE DEVICE EFFECT  
Unanticipated adverse device effect (USADE) is defined in ISO 14155:2011 as any serious 
adverse device effect which by its nature, incidence, severity or outcome has not been 
identified in the risk analysis section of the study protocol. 
12.2.6 DEVICE DEFICIENCY AND MALFUNCTION  
Device deficiency is defined in ISO 14155:2011 as an inadequacy of a medical device with 
respects to its identity, quality, durability, reliability, safety or performance.  
 
Device deficiencies include malfunctions, use errors and inadequacy in the information 
supplied by the manufacturer. 
 
Device malfunction is defined in ISO 14155:2011 as a failure of an investigational medical 
device to perform in accordance with its intended purpose when used in accordance with 
the Instructions for Use. 
 
Device embolization is defined in ISO 5840-3 as dislodgement from the intended and 
documented original position to an unintended and non-therapeutic location. 
 
Device detachment is defined as separation, under the action of applied stress or strain, 
of any part of the investigational device that was previously intact. 
 
Device migration is defined in ISO 5840-3 as detectable movement or displacement of the 
device from its original position within the implant site, without embolization.  
 
Structural component failure is defined as degradation of structural integrity of the 
support structure (e.g., railing) that results in the functional performance of the implant 
no longer being acceptable and/or that results in adverse events. 
 
Device deficiencies and malfunctions will be reported to the sponsor. 
12.3 
DEATHS AND EXPLANTS 
12.3.1 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.  Information on the cause of death and its relationship to 
the investigational device or study procedure will be determined by the Investigator. 
Copies of an autopsy report, if available, and/or a death summary are to be forwarded to 
the Study Sponsor.  
 

The SPACER Trial 
 
Version C  
December 16, 2016 
Study No. 2015-09  
Page 51 of 84 
 
 
 
If a device is explanted during autopsy, the device should be returned to the Study 
Sponsor for analysis.  Return kits for devices will be provided upon request by the clinical 
monitor.   
12.3.2 DEVICE EXPLANTS 
In the event the study  devices are explanted, in the intra-operative or early post-
operative period a copy of the explant procedure report must be provided to the Study 
Sponsor. Information on the cause of explant and its relationship to the study devices will 
be determined by the Investigator. Explanted study devices during this period must be 
returned to Study Sponsor for analysis.   
 
In the event the study device is explanted, in the late post-operative period, every effort 
should be made to obtain a copy of the explant procedure report, as applicable. 
Information on the cause of explant and its relationship to the study device will be 
determined by the Investigator. Copies of an explant report, if available, are to be sent to 
the Study Sponsor. Explanted study devices during this period should be returned to Study 
Sponsor for analysis. Investigational devices shall be returned to the Study Sponsor as 
described in Section 10.4. 
13 
STATISTICAL ANALYSIS 
13.1 
SAMPLE SIZE  
The primary endpoint is all-cause mortality at 30-days. Survival probabilities and standard 
errors will be estimated using the Kaplan Meier method and Greenwood formula 
respectively. 
 
A performance goal of 18% was pre-specified for the 30-day rate of all-cause mortality in 
TVR (Tricuspid Valve Regurgitation) subjects treated with the Edwards FORMA Tricuspid 
Transcatheter Repair System, which was based on review of literature and early clinical 
studies (reference Section 1.3). The hypothesis for the primary endpoint is as follows: 
 
 
H0:  π    ≥ 18% 
 
HA:  π   < 18% 
 
Where π represents the all-cause mortality rate at 30 days.  
 
The study is powered to detect a clinically significant difference between the expected 
mortality of the treatment group and the 18% Performance Goal.   Based on the initial 
experience of the device (with some additional uncertainty assumptions), the estimated  
true rate was established to be 7.5% or less.  Targeting a clinically significant difference 
of 10.5% (absolute reduction of greater than 50%), a sample size of 63 subjects will yield 

The SPACER Trial 
 
Version C  
December 16, 2016 
Study No. 2015-09  
Page 52 of 84 
 
 
 
at least 80% power to detect this difference at a significant level of 0.05. With a proportion 
of up to 9 investigational centers utilizing a roll-in subject and  with a potential dropout 
rate of approximately 10%, an enrollment target of 78 subjects will ensure a sample size 
of 63 is available for analysis. 
 
 
 
 
 
 
 
13.2 
TIMING 
Subjects will be assessed for clinical follow-up at the following intervals: 1 month, 6 
months, one year and annually thereafter until 3 years after the implant procedure. 
13.3 
ANALYSIS POPULATION 
The analysis population will be grouped into four analysis cohorts that in total comprise 
all subjects enrolled in this study. The analysis cohorts are defined below:  
 
 Enrolled Cohort: all subjects enrolled in the study  
 As Treated (AT) Cohort: all subjects who are enrolled and undergo the study 
procedure (chest incision) 
 Implanted Cohort: all subjects who undergo the study procedure (chest incision), 
receive and retain the investigational device upon leaving the procedure room 
 Roll-In Cohort: first subject enrolled and treated at a center that does not have 
previous device or procedure experience and is classified as a “roll-in” subject 
The primary endpoint will be reported based on the AT cohort. For the secondary 
endpoints and clinical outcomes, technical success analysis will be performed for the AT 
cohort, while device success, procedure success and clinical outcomes analyses will be 
performed for the implanted cohort. Roll-In subjects will be analyzed separately.  Subject 
listings for adverse events, deaths will include all enrolled subjects.   
 
For subjects with major protocol violations, which include but are not limited to study 
criteria and informed consent violations, a secondary analysis will be conducted in which 
those subjects will be excluded from the implanted cohort analyses.  
 
Further analysis plans will be outlined in the statistical analysis plan. 

The SPACER Trial 
 
Version C  
December 16, 2016 
Study No. 2015-09  
Page 53 of 84 
 
 
 
13.4 
PRIMARY ENDPOINT ANALYSIS 
The primary endpoint for this clinical study is all-cause mortality at 30 days post-implant 
procedure in the as treated (AT) cohort population. A one-sided 95% confidence interval 
for 30 day mortality will be computed using the Kaplan-Meier algorithm with the standard 
errors being computed using Greenwood’s formula.  The null hypothesis shall be rejected 
at alpha = 0.05 if the upper confidence limit is less than 0.18. 
13.5 
ADDITIONAL ENDPOINT ANALYSIS 
All statistical analyses will be performed by Edwards Lifesciences. Subject data listings and 
tabular presentations of results will be provided. All clinically relevant baseline and 
follow-up variables will be tabulated. Descriptive statistics will be used for continuous 
variables (e.g., mean, standard deviation, sample size, minimum, and maximum) and 
frequency tables or proportions for discrete variables. 
 
Kaplan Meier estimates will be performed at the pre-specified follow-up times to project 
the estimates for time-related safety endpoints.  The rate of freedom from all-cause 
mortality at 6 month, 1 year, 2 years, and 3 years will be estimated in addition to the 
primary endpoint which is established at 30 days post procedure. 
 
Echocardiographic data will be analyzed by a core laboratory. The improvement from 
baseline items will be presented as shift from baseline for each of the pre-specified 
follow-up periods. Subjects that are missing a baseline or follow-up values will be 
excluded from the analysis. 
 
Subjects that undergo any type of repair or replacement procedure for the tricuspid valve 
will be excluded from the implant cohort analyses at the time of the re-intervention.  
13.6 
MISSING DATA 
All possible steps will be taken to minimize missing data in the study, including monitoring 
of data forms for completeness and efforts to track and maintain contact with study 
subjects during the follow-up period. 
 
All statistical analyses will be performed using available data. No missing value imputation 
will be performed. 
13.7 
ANALYSIS SOFTWARE 
 
 
 

The SPACER Trial 
 
Version C  
December 16, 2016 
Study No. 2015-09  
Page 54 of 84 
 
 
 
14 
MONITORING 
14.1 
MONITORING METHODS  
A study monitor will be assigned to monitor the progress of the study by the Study 
Sponsor.  The study monitor may be either the Study Sponsor or contracted. The study 
monitor will remain in close contact with the study center throughout the duration of the 
study to provide any needed materials, (i.e. study forms, etc.) answer any questions and 
ensure that proper staffing levels are being maintained by the Investigator.  The study 
monitor will be responsible for verifying that subjects have signed the informed consent 
as required by regulations, reviewing the data recorded on the eCRFs and visiting the 
study center periodically to observe study progress and compliance with the study 
protocol and regulations applicable to this clinical study. 
 
Monitoring visits will be scheduled throughout the duration of the clinical study between 
the monitor and the Investigator at a mutually convenient and available time.  These visits 
will assure that the facilities are still acceptable, the study protocol is being followed, the 
EC and regulatory authority have been notified of approved protocol changes as required, 
complete records are being maintained, appropriate timely reports have been made to 
the Study Sponsor and the EC, device and device inventory are controlled and the 
Investigator is carrying out all agreed activities. Any personnel changes must be reported 
to the study monitor immediately and a training program scheduled and documented.  
14.2 
MONITORING PLAN 
Prior to subject enrollment, an initiation visit will be completed at the study center to 
ensure the following:   
 
1. 
EC and applicable regulatory body approvals have been obtained and 
documented,  
2. 
The Investigator(s) and study personnel are appropriately trained and clearly 
understand the study,  
3. 
The Investigator(s) and study personnel accept the obligations incurred in 
undertaking this clinical study, 
4. 
The Delegation of Authority form has been completed properly. 
 
Periodic monitoring visits will be made at the enrolling study center in accordance with 
center enrollment rates. The study center should be visited a minimum of twice per year 
by the study monitor. 
 
Upon termination or conclusion of the study, the study monitor will perform a close-out 
visit.   

The SPACER Trial 
 
Version C  
December 16, 2016 
Study No. 2015-09  
Page 55 of 84 
 
 
 
14.3 
PROTOCOL DEVIATION  
A protocol deviation is defined as an event where the Investigator or a study personnel 
did not conduct the study according to the clinical protocol or the Clinical Study 
Agreement.  Investigators shall be required to obtain proper approval from the Study 
Sponsor before initiating deviations from the study 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 Study Sponsor regardless of whether medically 
justifiable, pre-approved by the Sponsor, or taken to protect the subject in an emergency.  
Subject specific and non-subject specific deviations, (e.g. unauthorized use of an 
investigational device outside the study, unauthorized use of an investigational device by 
a physician who is not listed in the Clinical Study Agreement etc.) will be reported.  Subject 
specific deviation information can be recorded directly on the Protocol Deviation eCRF 
and non-subject specific deviations will be recorded in writing. Investigators will also 
adhere to procedures for reporting study deviations to their EC in accordance with their 
specific reporting policies and procedures. 
 
For reporting purposes, deviations are classified as major or minor: 
 
1. 
Major deviation: 
a. Any deviation from subject inclusion and exclusion criteria;  
b. Any deviation from subject informed consent procedures; 
c. Unauthorized use of an investigational device outside the study; 
d. Unauthorized use of an investigational device by a physician who is not 
listed in the Clinical Study 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.  
14.4 
COMMUNICATION PROCEDURES 
During the course of the study, all correspondence (letters, telephone call, emails and 
faxes) regarding the study must be maintained in the study binder provided by the Study 
Sponsor.  This binder must be made available for monitoring visits or audits. 

The SPACER Trial 
 
Version C  
December 16, 2016 
Study No. 2015-09  
Page 56 of 84 
 
 
 
15 
 DATA MONITORING COMMITTEE 
The Study Sponsor with an independent Data Monitoring Committee (DMC) will monitor 
all serious adverse events.  The DMC will consist of a minimum of 3 members, all members 
being physicians; one cardiothoracic surgeon, one interventional cardiologist and one 
cardiologist.   
 
 
 
 
 
 
 
 
16 
STUDY STOPPING RULES 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
   
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 

The SPACER Trial 
 
Version C  
December 16, 2016 
Study No. 2015-09  
Page 57 of 84 
 
 
 
17 
ETHICAL AND REGULATORY CONSIDERATIONS 
17.1 
APPLICABLE REGULATIONS AND GUIDELINES  
The regulations listed in Table 11 must be observed to comply with the Study Sponsor 
policy for conduct and of clinical studies; they also represent sound research practice.  It 
is the responsibilities of the Investigator(s) to comply with the requirements set forth in 
their country specific regulations.   
 
Table 11 - Applicable Regulations and Guidelines 
Region 
Regulation / Guideline 
United States 
- 93/42/EEC European Medical Device Directive (MDD) 
- EN ISO 13485:2012 Medical Devices - Quality Management 
Systems - Requirements for Regulatory Purposes 
- ISO 14155:2011 (E) (Clinical Investigation of Medical Devices for 
Human Subjects 
- ISO 14971:2012 (Application of risk management to medical 
devices) 
 
Furthermore, the Investigator(s) must comply with the requirements of the Declaration 
of Helsinki (2008) and with of ICH E6 GCP or with laws of the foreign country, whichever 
will afford greater protection to the subject screened for participation in the clinical study 
and subjects who participate in the study. 
17.2 
DATA PROTECTION AND SUBJECT CONFIDENTIALITY 
The Study sponsor is dedicated to maintaining the confidentiality and privacy of subjects 
who volunteer to participate in the study.  Passwords are issued to appropriate personnel 
to insure confidentiality and protection of the database by allowing variable levels of 
access to the computer system. In addition, the Principal Investigator is responsible for 
maintaining confidentiality throughout the clinical study. The hard copies of the 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 study site.  Subject identifiers include, but are not limited to: subject’s 
name, social security number or equivalent, and medical / hospital number.  All study 
documents for the clinical study will identify the subject by a subject study identification 
number assigned by the Sponsor and the subject’s initials (if applicable). 
17.3 
INVESTIGATOR RESPONSIBILITIES 
17.3.1 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 

The SPACER Trial 
 
Version C  
December 16, 2016 
Study No. 2015-09  
Page 58 of 84 
 
 
 
medical and clinical research practice and the applicable regulations.  The Investigator 
shall be responsible for the day to day conduct of the clinical study and for the safety and 
well-being of subjects enrolled. The Investigator will provide copies of the current study 
protocol to all staff responsible for study conduct. 
 
The Investigator is responsible for obtaining and maintaining EC approval for the study at 
his/her study center.   
 
If there is a change or addition of an Investigator, an amended Clinical Study Agreement 
must be completed promptly. 
17.3.2  INVESTIGATOR RECORDS 
The Investigator will maintain the accurate, complete, and current records relating to 
participation in this clinical study.  Study records including CRFs and supporting data, 
signed Clinical Study Agreement, protocols and protocol amendments, signed informed 
consents,  device tracking logs, EC approval letters, EC submissions, correspondence, 
including required reports, and other documents pertaining to the conduct of the study 
must be kept on file by the Investigator.  If the Investigator wishes to assign the 
responsibility of maintaining the study files to someone else or move them to another 
location, he/she should consult with the Study Sponsor in writing regarding the change.   
Upon Study completion, the study files must be maintained in a known location for a 
period in accordance with local regulatory requirements.   
17.3.3  INVESTIGATOR REPORTS 
 
 
 
 
 
   
 
  
 
   
 
 
 
 
 
 
   
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 

The SPACER Trial 
 
Version C  
December 16, 2016 
Study No. 2015-09  
Page 59 of 84 
 
 
 
17.4 
SPONSOR RESPONSIBILITIES 
17.4.1 GENERAL DUTIES 
As the Study Sponsor of this clinical study, Edwards Lifesciences 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 addition, the Study Sponsor declares that no employee/affiliate of the Sponsor or 
Investigator will be included or encouraged to participate in this investigational study. 
 
The Study Sponsor will inform the Investigator of any new information about the study 
that may affect the health, safety or welfare of the subjects or which may influence 
patient’s decision to continue participating in the study. 
 
Additionally, interruptions in the study or recruitment due to significant amendments will 
also be reported to the applicable regulatory authorities. 
17.5 
SELECTION OF INVESTIGATORS   
 
 
 
 
17.5.1 MONITORING THE STUDY  
The Study Sponsor will ensure compliance with the signed clinical agreement, the 
protocol (investigational plan), the requirements of applicable regulations and guidelines 
(see section 17.1) and any conditions of study approval by the EC and regulatory bodies. 
Edwards will conduct an immediate investigation of any unanticipated adverse device 
effects (UADE) and if an event is found to present an unreasonable risk to study subjects, 
the Study Sponsor will inform Investigators, ECs, and regulatory bodies as required. 
17.5.2 SPONSOR RECORDS  
The Study Sponsor will maintain accurate, complete, and current records relating to this 
clinical study.  Study records include CRFs, signed Clinical Study Agreement, signed 
financial disclosure, protocols and protocol amendments, informed consent, device use, 
EC approval letters, submissions, correspondence, including required reports, and other 
documents.  The Study Sponsor will maintain study documentation during the study and 
for a period in accordance with local 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.  

The SPACER Trial 
 
Version C  
December 16, 2016 
Study No. 2015-09  
Page 60 of 84 
 
 
 
17.5.3 SPONSOR REPORTS 
 
 
 
 
 
 
 
   
 
 
     
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
17.6 
STUDY CHANGES 
Changes in the protocol may be made only by written amendment agreed upon by the 
Study Sponsor, the regulatory agency and EC.  As appropriate, the Study Sponsor will 
submit protocol amendments to the pertinent regulatory agencies and Investigators to 
obtain EC approval prior to implementation. 
17.7 
 STUDY COMPLETION OR TERMINATION AND CLOSE-OUT 
The Investigator will be notified in writing upon termination/conclusion of the study.  
Edwards Lifesciences retains the right to suspend or terminate this clinical study at any 
time. 
 
Safety and review committees associated with the study may recommend termination 
should safety concerns warrant such action as described in Section 16. 
 
All study subjects enrolled up to the point of study termination, will continue to be 
followed as per protocol requirements.  

The SPACER Trial 
 
Version C  
December 16, 2016 
Study No. 2015-09  
Page 61 of 84 
 
 
 
17.8 
AUDITS AND INSPECTIONS 
In the event that audits are initiated by the Study Sponsor or national/international 
regulatory authorities, the Investigator shall allow access to the original medical records 
and provide all requested information, as applicable. 
17.9 
PUBLICATION POLICY 
 
 
 
 
  
 
  
 
 
 
 

The SPACER Trial 
 
Version C  
December 16, 2016 
Study No. 2015-09  
Page 62 of 84 
 
 
 
18 
REFERENCES 
 
1. 
Nath, J., E. Foster, and P.A. Heidenreich, Impact of tricuspid regurgitation on long-term 
survival. Journal of the American College of Cardiology, 2004. 43(3): p. 405-409. 
2. 
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. 
3. 
Dreyfus, G.D., S.G. Raja, and K.M.J. Chan, Tricuspid leaflet augmentation to address 
severe tethering in functional tricuspid regurgitation. European Journal of Cardio-
Thoracic Surgery, 2008. 34(4): p. 908-910. 
4. 
Benedetto, U., et al., Prophylactic tricuspid annuloplasty in patients with dilated 
tricuspid annulus undergoing mitral valve surgery. The Journal of thoracic and 
cardiovascular surgery, 2012. 143(3): p. 632-8. 
5. 
Raja, S.G. and G.D. Dreyfus, Surgery for functional tricuspid regurgitation: current 
techniques, outcomes and emerging concepts. Expert Rev Cardiovasc Ther, 2009. 7(1): p. 
73-84. 
6. 
Chang, B.C., et al., Long-term clinical results of tricuspid valve replacement. Annals of 
Thoracic Surgery, 2006. 81(4): p. 1317-1324. 
7. 
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. 
8. 
McCarthy, et al., Tricuspid valve repair: durability and risk factors for failure. J Thorac 
Cariovasc Surg, 2004. 127(3): p. 674-85. 
9. 
Bernal, et al., Reoperations after tricuspid valve repair. J Thorac Cariovasc Surg, 2005. 
130: p. 498-503 
10. 
Ratnatunga, et al., Tricuspid valve replacement: UK heart valve registry mid-term results 
comparing mechanical and biological prostheses. Ann Thorac Surg, 1998. 66(6): p. 1940-
7 
11. 
Filsoufi, et al., Long-term outcomes of tricuspid valve replacement in the current era. 
Ann Thorac Surg, 2005. 80: p. 845-50 
12. 
Moraca, et al., Outcomes of tricuspid valve repair and replacement: a propensity 
analysis. Ann Thorac Surg, 2009. 87: p. 83-9 
13. 
Pfannmuller, et al., Isolated tricuspid valve surgery in patients with previous cardiac 
surgery. J Thorac Cariovasc Surg, 2013. 146: p. 841-7 
 
 
 
 

The SPACER Trial 
 
Version C  
December 16, 2016 
Study No. 2015-09 
Page 63 of 84 
 
 
 
19 
DEFINITIONS  
 
Access Site 
Access site defined as any location (venous) traversed by a 
guidewire, a catheter or a sheath (including the subclavian or 
axillary vein) 
ACT 
Activated clotting time 
Acute Kidney Injury 
(AKI) 
Refer to VARC-2 definition 
Adverse Device Effect 
(ADE) 
Refer to ISO 14155 definition 
Adverse Event (AE) 
Refer to ISO 14155 definition 

The SPACER Trial 
 
 
Version C  
December 16, 2016 
Study No. 2015-09 
Page 64 of 84 
 
 
 
Adverse Event 
Causality 
Not related:  Relationship to the device or procedures can be 
excluded when: 
 The event is not a known side effect of the product category 
the device belongs to or of similar devices and procedures 
 The event has no temporal relationship with the use of the 
investigational device or the procedures 
 The serious event does not follow a known response 
pattern to the medical device (if the response pattern is 
previously known) and is biologically implausible 
 The discontinuation of medical device application or the 
reduction of the level of activation/exposure - when 
clinically feasible – and reintroduction of its use (or increase 
of the level of activation/exposure), do not impact on the 
serious event 
 The event involves a body-site or an organ not expected to 
be affected by the device or procedure 
 The serious event can be attributed to another cause (e.g. 
an underlying or concurrent illness/ clinical condition, an 
effect of another device, drug, treatment or other risk 
factors) 
 Harms to the subject are not clearly due to use error 
 In order to establish the non-relatedness, not all the criteria 
listed above might be met at the same time, depending on 
the type of device/procedures and the serious event 
 
Unlikely: The relationship with the use of the device seems not 
relevant and/or the event can be reasonably explained by 
another cause, but additional information may be obtained. 
 
Possible:  The relationship with the use of the investigational 
device is weak but cannot be ruled out completely. Alternative 
causes are also possible (e.g. an underlying or concurrent 
illness/ clinical condition or/and an effect of another device, 
drug or treatment). Cases were relatedness cannot be assessed 
or no information has been obtained should also be classified 
as possible. 
 
Probable: The relationship with the use of the investigational 
device seems relevant and/or the event cannot reasonably be 

The SPACER Trial 
 
 
Version C  
December 16, 2016 
Study No. 2015-09 
Page 65 of 84 
 
 
 
explained by another cause, but additional information may be 
obtained. 
Causal Relationship: The serious event is associated with the 
investigational device or with procedures beyond reasonable 
doubt when: 
 
The event is a known side effect of the product category the 
device belongs to or of similar devices and procedures 
 
The event has a temporal relationship with investigational 
device use/application or procedures 
 
The event involves a body-site or organ that the 
investigational device or procedures are applied to or have 
an effect on 
 
The serious event follows a known response pattern to the 
medical device (if the response pattern is previously known) 
 The discontinuation of medical device application (or 
reduction of the level of activation/exposure) and 
reintroduction of its use (or increase of the level of 
activation/exposure), impact on the serious event (when 
clinically feasible) 
 
Other possible causes (e.g. an underlying or concurrent 
illness/ clinical condition or/and an effect of another device, 
drug or treatment) have been adequately ruled out 
 
Harm to the subject is due to error in use 
 
In order to establish the relatedness, not all the criteria 
listed above might be met at the same time, depending on 
the type of device/procedures and the serious event 

The SPACER Trial 
 
 
Version C  
December 16, 2016 
Study No. 2015-09 
Page 66 of 84 
 
 
 
Cardiac Tamponade 
 
 
 
 
 
 
 
 
 
 
 
 
Pressure on the heart that occurs when blood or fluid builds up 
in the space between the heart muscle (myocardium) and 
the outer covering sac of the heart (pericardium).  
Cardiovascular 
Mortality 
 
 
 
 
 
 
 
 
Refer to VARC-2 definition 
Cerebrovascular 
Accident (CVA) 
 
 
 
 
 
 
See “Stroke” 

The SPACER Trial 
 
 
Version C  
December 16, 2016 
Study No. 2015-09 
Page 67 of 84 
 
 
 
Clinical Outcomes 
Clinical Outcomes (at 1 month, 6 months & Annually)    
 Re-hospitalization rates for the underlying condition (heart 
failure) 
 Re-intervention rates for the underlying condition (tricuspid 
regurgitation)  
 Change in Tricuspid Regurgitation (assessment made by 
change in EROA) from baseline 
 Change in peripheral edema as assessed by subject weight 
loss (kilograms) from baseline 
 Change in NYHA Class from baseline 
 Change in 6 minute walk test distance (meters) from 
baseline 
 
Change in Quality of Life as assessed by the SF-12 and KCCQ 
questionnaires from baseline 
Death 
All cause mortality 
Device Deficiency 
Refer to ISO 14155 definition 
Device Detachment 
Separation, under the action of applied stress or strain, of any 
part of the investigational device that was previously intact. 
Device Embolization 
Refer to ISO 5840-3 definition 
Device Malfunction 
Refer to ISO 14155 definition 
Device Migration 
Refer to ISO 5840-3 definition 
Device Success 
Device Success (at 1 month, 6-months and annually): 
 Alive, with  
 Original intended device in place, and   
 No additional surgical or interventional procedures related 
to the device, and 
 TR reduction (assessment made by change in EROA) 
compared to baseline and TV gradient ≤ 5mmHg  
 
Embolism 
Free flowing blood clot or lesion material that is located in the 
systemic or pulmonary circulation. 
 
A peripheral embolic event is an operative, autopsy or clinically 
documented embolus that produces symptoms from complete 
or partial obstruction or a peripheral (noncerebral) artery.   

The SPACER Trial 
 
 
Version C  
December 16, 2016 
Study No. 2015-09 
Page 68 of 84 
 
 
 
Emergency Surgery 
Emergent Salvage:  The patient is undergoing CPR en route to 
the operating room or prior to anesthesia induction 
 
Emergent:   
All of the following conditions are met: 
 Not elective status 
 Not emergent salvage status 
 Procedure required before procedure room exit in order to 
minimize chance of further clinical deterioration 
 Any surgical procedure on the previously implanted study 
device (repair, alteration or replacement) or study 
procedure access site post-implant procedure 
 
Elective:  The patient’s cardiac function has been stable in the 
days or weeks prior to the operation. The procedure can be 
deferred without increased risk of compromised cardiac 
outcome. 
Endocarditis  
An inflammation of the inside lining of the heart chambers and 
heart valves (endocardium).  Endocarditis can involve the heart 
muscle, heart valves, or lining of the heart. 
Enrollment 
Subject enrollment in this clinical study is established when a 
subject has signed the informed consent form agreeing to 
participate in the study and has been deemed eligible for study 
participation by meeting the study criteria.   
Explant  
Removal of the study device after completion of the implant 
procedure for any reason. 
Heart Failure 
Heart Failure - A progressive condition that involves loss of 
pumping ability by the heart (heart muscle weakens and 
gradually loses its ability to pump enough blood through the 
body), generally accompanied by fluid accumulation in body 
tissues, especially the lungs. 
 
Heart Failure Hospitalization - An unplanned hospitalization 
that results in at least one overnight stay (i.e., where the 
admission date and the discharge date are different) that 
includes increased signs and/or symptoms of worsening heart 
failure and requires the administration or augmentation of 
existing heart failure therapy. 
 
Severe Heart Failure – See NYHA Class IV 
HEART Team 
The ‘HEART Team', for the purpose of this study, must include a 
minimum of one Cardiologist, and one Cardiac Surgeon. 

The SPACER Trial 
 
 
Version C  
December 16, 2016 
Study No. 2015-09 
Page 69 of 84 
 
 
 
Hemolysis 
(Device Hemolysis) 
Rupturing of red blood cells (erythrocytes) and the release of 
their contents (cytoplasm) into surrounding fluids. 
 
Device hemolysis is defined as hemolysis in or near the 
investigational device that interferes with the function of the 
device.  Device hemolysis related thrombus may be confirmed 
by operation, autopsy, or diagnostically by such methods as 
echocardiography, angiography, or magnetic resonance 
imaging. 
Implant procedure 
Placement of the investigational device in the tricuspid valve 
regurgitant orifice.  
Infection 
Known infection requiring intravenous antibiotics for other than 
prophylaxis, and/or extended hospitalization. 
INR 
International normalized ratio 
IVC 
Inferior vena cava 
KCCQ 
Kansas City Cardiomyopathy Questionnaire is a health-related 
quality-of-life measure for patients with congestive heart 
failure. 
LVEF 
Left ventricular ejection fraction 
Malfunction 
Refer to ISO 14155 definition 
Myocardial Infarction 
Refer to VARC-2 definition 
New York Heart 
Association 
Classification (NYHA 
Class) 
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, 
dyspnea, or anginal pain. 
Class III:     Patients with cardiac disease resulting in marked 
limitation of physical activity.  They are comfortable at rest.  
Less than ordinary physical activity causes fatigue, palpitation 
dyspnea, or anginal pain. 
Class IV:     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. 
Nonstructural 
Dysfunction 
Abnormality extrinsic to the repair device that results in valve 
dysfunction (stenosis, regurgitation or both)  
Patient  
A person with the disease (tricuspid regurgitation) being 
screened to participate in the clinical study. 

The SPACER Trial 
 
 
Version C  
December 16, 2016 
Study No. 2015-09 
Page 70 of 84 
 
 
 
Peripheral 
Thromboembolic 
Event 
See “Embolism” 
Pre-Existing Condition A pre-existing condition is one that is present at the start of 
study treatment. 
Primary Endpoint 
The primary endpoint for the study will assess the all-cause 
mortality of the as treated cohort at 30 days compared to a 
literature derived Performance Goal based on high-risk surgical 
outcomes for tricuspid repair/replacement. 
Procedural Success 
Procedural Success (at 1 month):  
 Device Success, and 
 None of the following device or procedure related SAEs:  
 
Life threatening bleeding   
 
Major vascular or cardiac structural complications 
requiring intervention 
 
Pericardial effusion requiring drainage or surgery 
(includes tamponade) 
 
Stage 2 or 3 acute kidney injury (includes new dialysis). 
 
Severe heart failure or hypotension requiring IV 
inotrope, ultrafiltration or mechanical circulatory 
support 
 
Prolonged intubation > 48 hours 
 
Prosthesis 
An artificial substitute  
QoL 
Quality of Life 
Reintervention 
Any intervention on the previously implanted study device 
(repair, alteration or replacement) or study procedure access 
site post-implant procedure. 
Renal Failure 
See “Acute Kidney Injury (AKI)” 
Screen Failure  
A patient who has signed the consent but, does not meet the 
inclusion criteria or who meets at least one of the exclusion 
criteria. 
Serious Adverse 
Device Effect (SADE) 
Refer to ISO 14155 definition 
Serious Adverse Event 
(SAE) 
Refer to ISO 14155 definition 
SF-12 
A short survey with 12 questions that results in two scales of  
mental and physical functioning and overall health related 
quality of life. 
Six (6) MWT 
Six minute walk test 
Stroke/TIA 
Refer to VARC-2 definition 
Subject  
Refer to ISO 14155 definition 

The SPACER Trial 
 
 
Version C  
December 16, 2016 
Study No. 2015-09 
Page 71 of 84 
 
 
 
Subject Withdrawal 
A subject who decides not to participate in the study after  
signing an informed consent form and being enrolled. 
Technical Success 
Technical Success (at exit from procedure room):   
 Alive, with  
 Successful access, delivery and removal of the delivery 
systems, and 
 Deployment and correct positioning of the intended device, 
and 
 No need for additional emergency surgery or re-
intervention related to the device or access procedure 
 
Thromboembolic 
Event  
See “embolism” 
Thrombus  
(Device Thrombosis) 
An aggregation of platelet, fibrin, clotting factors, and other 
cellular elements exclusive of infection.  
 
Device thrombosis is defined as any thrombus in the absence of 
infection attached to or near the investigational device that 
interferes with function of the device.  An investigational device 
related thrombus may be confirmed by operation, autopsy, or 
diagnostically by such methods as echocardiography, 
angiocardiography, or magnetic resonance imaging. 
Tricuspid 
Regurgitation 
Tricuspid Regurgitation (TR), tricuspid insufficiency or tricuspid 
incompetence describes a condition in which blood flow 
through the tricuspid valve flows in the incorrect direction 
during part of the cardiac cycle. 
Unanticipated Serious 
Adverse Device Effect 
(USADE) 
Refer to ISO 14155 definition 
Valvular Leak  
 
(See Also 
“Nonstructural 
Dysfunction”)  
Any evidence of leakage of blood through the native valve 
leaflets and around the investigational device. Diagnosis of 
valvular leak may be obtained from echo; however definitive 
diagnosis is obtained at reoperation, explant, or autopsy.  
Withdrawal by 
Investigator 
A subject who consents to participate in the study and is  
enrolled but is withdrawn by the Investigator.  
 
 
 
 
 

The SPACER Trial 
 
 
Version C  
December 16, 2016 
Study No. 2015-09 
Page 72 of 84 
 
 
 
 
20 APPENDIX A -  SAMPLE INFORMED CONSENT FORM 
 
 
 
 

The SPACER Trial 
 
 
_ 
  
 
Study No. 2015-09 
 
 Page 84 of 86 
 
21 APPENDIX B - CT ACQUISITION PROTOCOL 
 
 
 

The SPACER Trial 
 
 
 
  
 
Study No. 2015-09 
 
 Page 85 of 86 
 
22 
APPENDIX C - ECHO PROTOCOL 
 

The SPACER Trial 
L 
 
_ 
  
 
Study No. 2015-09 
 
 Page 86 of 86 
 
23 
APPENDIX D – SCREENING COMMITTEE CHARTER