Cross-SealTM IDE Trial: Prospective, Multi-Center, Single Arm Study of the Cross-SealTM Suture-Mediated Vascular Closure Device System
Phase: NA
Conditions: Vascular Closure
Sponsor: Terumo Medical Corporation

Clinical Investigational Plan 
Cross-SealTM IDE Trial 
Protocol Number:  TIS2018-01  
Version 1.4 
  
29 JUL 2020                              CONFIDENTIAL 
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Terumo Study No.:  
 
TIS2018-01 
Version No. 
 
 
1.4 
Date 
 
 
 
29JUL2020 
 
 
 
 
 
 
 
TIS2018-01:   
Cross-SealTM IDE Trial:  Prospective, Multi-Center, Single Arm 
Study of the Cross-SealTM Suture-Mediated Vascular Closure 
Device System 
 
  
 
 
 
SPONSOR:  
Terumo Medical Corporation 
265 Davidson Avenue 
Somerset, NJ 08873  
USA 
 
 
 
 
 
 
 
Confidentiality Statement: 
This protocol, its contents, and the information relating to it are the proprietary 
property of Terumo Medical Corporation. All information is to be kept confidential. 
 
 

Clinical Investigational Plan 
Cross-SealTM IDE Trial 
Protocol Number:  TIS2018-01  
Version 1.4 
  
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Clinical Protocol 
 
 
 
Title: 
Cross-Seal IDETM Trial:  Prospective, Multi-Center, 
Single Arm Study of the Cross-SealTM Suture-
Mediated Vascular Closure Device System 
  
Study Number: 
TIS2018-01 
 
Investigational 
Cross-SealTM Suture-Mediated Vascular Closure 
Device:  
Device System (Cross-SealTM System) 
 
Study Type:  
 
Prospective, multi-center, single arm 
 
Version: 
1.4 
 
Version Date: 
29JUL2020 
 
Sponsor: 
Terumo Medical Corporation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Clinical Investigational Plan 
Cross-SealTM IDE Trial 
Protocol Number:  TIS2018-01  
Version 1.4 
  
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Table of Contents 
 
A. 
Summary Of Changes ................................................................................... 6 
B. 
Protocol Approval Page ................................................................................. 7 
C. Study Roles and Responsibilities ................................................................... 8 
D. Investigator Approval and Agreement .......................................................... 10 
E. 
Study Summary ........................................................................................... 11 
Sample Size Determination ................................................................................ 15 
Primary Efficacy Endpoint ............................................................................... 16 
Primary Safety Endpoint .................................................................................. 16 
F. 
List of Abbreviations and Definition of Terms............................................... 18 
1 
Background.................................................................................................. 19 
1.1 
Need For Large Arteriotomy VCD .......................................................... 20 
1.2 
Current Large Arteriotomy VCDs ........................................................... 21 
1.2.1 Clinical Experience With Suture-Based VCDs ....................................... 22 
1.2.2 Advantages of Suture-based VCDs ....................................................... 22 
1.3 
Cross-SealTM System and Indications For Use ...................................... 23 
1.4 
Description of Device ............................................................................. 23 
1.5 
Summary of Clinical Studies .................................................................. 26 
1.5.1 Clinical Feasibility (FIH) Study ............................................................... 26 
1.5.2 CE Study ................................................................................................ 28 
2 
Study Design, Sample Size and Duration .................................................... 30 
2.1 
Study Design ......................................................................................... 30 
2.2 
Sample Size ........................................................................................... 31 
2.3 
Study Duration ....................................................................................... 31 
3 
Study Objective, Hypothesis, and Endpoints ............................................... 31 
3.1 
Study Objective ...................................................................................... 31 
3.2 
Study Hypothesis ................................................................................... 32 
3.3 
Endpoints ............................................................................................... 32 
3.3.1 Primary Endpoints ................................................................................. 32 
3.3.2 Secondary Endpoints ............................................................................. 33 
3.3.3 Exploratory Endpoints ............................................................................ 35 
4 
Study Design ............................................................................................... 35 
4.1 
Eligibility Criteria .................................................................................... 35 
4.2 
Subject Enrollment ................................................................................. 38 
5 
Ethics ........................................................................................................... 38 

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Protocol Number:  TIS2018-01  
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5.1 
Role of the Sponsor ............................................................................... 38 
5.2 
Role of Clinical Research Organization ................................................. 39 
5.3 
Ethics Review ........................................................................................ 39 
5.4 
Ethical Conduct of the Study .................................................................. 39 
5.5 
Written Informed Consent ...................................................................... 39 
5.6 
Subject Data Protection ......................................................................... 40 
5.7 
Subject Withdrawal ................................................................................ 40 
5.8 
Discontinuing Subject Participation ........................................................ 40 
6 
Device Supply Information ........................................................................... 41 
6.1 
Shipping ................................................................................................. 41 
6.2 
Labeling ................................................................................................. 41 
6.3 
Storage .................................................................................................. 41 
6.4 
Accountability ......................................................................................... 41 
6.5 
Return of a Malfunctioning/Failed Device .............................................. 42 
7 
General Procedures ..................................................................................... 42 
7.1 
Baseline/Pre-Procedure Visit ................................................................. 42 
7.2 
Index Procedure .................................................................................... 43 
7.3 
Investigational Device Set-up and Preparation ...................................... 47 
7.4 
Concomitant Medical Therapy ............................................................... 47 
7.5 
Follow-up Procedures ............................................................................ 47 
7.5.1 Post-Procedure through Hospital Discharge .......................................... 47 
7.5.2 30 Day Follow-Up (30 ± 7 days) ............................................................ 48 
7.5.3 60 Day Follow-Up (60 days ± 14 days) .................................................. 48 
7.6 
Clinical Data Collection .......................................................................... 49 
8 
Adverse Events ............................................................................................ 49 
8.1 
Definitions .............................................................................................. 50 
8.2 
Potential Adverse Events (AEs) ............................................................. 51 
8.3 
Follow-up of Adverse Events ................................................................. 52 
8.4 
Causality Rating ..................................................................................... 52 
8.5 
Severity of Adverse Events .................................................................... 53 
8.6 
Events Requiring Expedited Reporting .................................................. 53 
8.6.1 Expedited Events include:...................................................................... 54 
8.7 
Clinical Events Committee (CEC) .......................................................... 55 
8.8 
Data and Safety Monitoring Board (DSMB) ........................................... 55 
9 
Risk Assessment ......................................................................................... 56 

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Protocol Number:  TIS2018-01  
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9.1 
Risk Management Procedure ................................................................ 56 
9.2 
Potential Benefits ................................................................................... 57 
10 Centers for Medicare and Medicaid Services (CMS) Reimbursement ......... 57 
11 Monitoring .................................................................................................... 58 
12 Image Analysis ............................................................................................ 59 
13 Device Failure and Malfunction .................................................................... 59 
14 Statistical Methods ....................................................................................... 60 
14.1 Sample Size Determination ................................................................... 60 
14.1.1 
Primary Efficacy Endpoint ............................................................... 61 
14.1.2 
Primary Safety Endpoint .................................................................. 62 
14.2 Statistical Analyses ................................................................................ 63 
14.2.1 
General Considerations ................................................................... 63 
14.2.2 
Analysis Populations ....................................................................... 64 
14.2.3 
Poolability Analyses ........................................................................ 65 
14.2.4 
Handling of Missing Data ................................................................ 65 
14.2.5 
Imputation for Endpoints ................................................................. 66 
14.2.6 
Sensitivity Analyses......................................................................... 66 
14.2.7 
Imputation for Dates ........................................................................ 66 
14.2.8 
Subject Disposition .......................................................................... 67 
14.2.9 
Demographics and Baseline Characteristics ................................... 67 
14.2.10 
Analysis of Study Endpoints ............................................................ 67 
14.2.11 
Subgroup Analyses ......................................................................... 68 
14.2.12 
Interim Analyses .............................................................................. 68 
14.2.13 
Protocol Deviations ......................................................................... 69 
14.2.14 
Additional Changes to Planned Analyses ........................................ 69 
15 Reporting ..................................................................................................... 69 
Appendix 1 
References ................................................................................... 70 
 
 
 

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Protocol Number:  TIS2018-01  
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A.  Summary Of Changes 
 
CIP 
Version 
CIP Date 
Description of change and rationale 
1.0 
01 Jun 2018 
Initial Release 
1.1 
14 Aug 2018 • Eligibility criteria updated 
• Study Endpoints updated  
• Abbreviations and Definitions of Terms updated 
• Baseline visit assessments amended to include laboratory 
requirements and targeted groin exam 
• General and Procedural sections updated for additional 
requirements 
• Schedule of Events Table updated to reflect protocol changes 
• Concomitant Medication requirements updated regarding 
anticoagulants/anti-platelet use during index procedure 
• Potential Adverse Events updated 
• Minor clarification to text 
1.2 
27Sep2018 
• Update to hypotension definition in procedural section 
1.3 
30Oct2018 
• Update to statistical methods including performance goal for 
primary safety endpoint 
• Update of images and description for generation 2.2 knot tyer 
• Minor clarification to text 
1.4 
29JUL2020 
• Change Sponsor address and study personnel update 
• For consistency across protocol and SAP - Clarified definition 
of “adjunctive treatment.” 
• Addition of unscheduled visit sand telephone assessment to 
assess safety of patients whose follow up visits were affected 
by COVID-19 
• Update to statistical analysis sections to reflect imputation of 
data points and potential use of roll-in subjects if needed 
• Minor clarification to text 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Clinical Investigational Plan 
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Protocol Number:  TIS2018-01  
Version 1.4 
  
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C. Study Roles and Responsibilities 
 
Principal Investigators:       Prakash Krishnan, MD 
 
Mazin Foteh, MD 
 
Medical Monitor: 
    
Mike Martinelli, MD 
 
 
 
 
Terumo Medical Corporation 
 
Sponsor Contact: 
 
Robert Gash 
Director of Clinical Operations 
Terumo Medical Corporation 
265 Davidson Avenue 
Somerset, NJ 08873 
Phone:  908-914-1045 
 
CRO:    
 
 
Syntactx 
 
Core Laboratory: 
 
Syntactx 
 
Proprietary Notice: 
This document contains mainly unpublished data and is 
the sole property of the Sponsor. Therefore, it is provided 
to you in strict confidence as an investigator, potential 
investigator, or consultant. The information may be 
reviewed by you, your staff, and your institutional review 
board/independent ethics committee. It is understood that 
this information will not be disclosed to others without 
written authorization from the study Sponsor except to the 
extent necessary to obtain informed consent from those 
persons in whom the investigational device may be 
implanted. 
 
Ethics Statement: 
The study will be completed in accordance with applicable 
regulations and standards to provide public assurance that 

Clinical Investigational Plan 
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Protocol Number:  TIS2018-01  
Version 1.4 
  
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the rights, safety, and well-being of study subjects are 
protected, consistent with the principles that have their 
origin in the Declaration of Helsinki. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page Section Intentionally Blank 
 
 

Clinical Investigational Plan 
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Protocol Number:  TIS2018-01  
Version 1.4 
  
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D. Investigator Approval and Agreement 
 
PROTOCOL SIGNATURE PAGE 
 
The signature below constitutes the receipt, review and understanding of the protocol 
entitled, “Cross-SealTM IDE Trial:  Prospective, Multi-Center, Single Arm Study of the 
Cross-SealTM Suture-Mediated Vascular Closure Device System ” and any attachments, 
and provides the necessary assurances that this study will be conducted according to all 
stipulations of the signed Clinical Trial Research Agreement (CTRA), protocol, including 
all statements regarding confidentiality, and according to local legal and regulatory 
requirements and applicable U.S. federal regulations.    
 
 
 
 
 
________________________________                              _______________________                               
Investigator Signature 
 
 
Date (DD/MMM/YYYY) 
 
 
______________________________________________________________________ 
Investigator Name (please print) 
 
 
______________________________________________________________________ 
Investigator Institution (please print) 
 
 

Clinical Investigational Plan 
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Protocol Number:  TIS2018-01  
Version 1.4 
  
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E. Study Summary 
 
Study Design 
This is a prospective, multi-center, single arm, clinical study to investigate the safety and 
efficacy of the Cross-SealTM System.  
 
Investigational Device and Indications for Use 
The Cross-SealTM System is indicated for the percutaneous delivery of sutures for 
closing the common femoral artery access site of subjects who have undergone 
interventional catheterization procedures using 8Fr to 18Fr sheaths.  
 
Target Subject Population 
The target population is comprised of subjects scheduled for elective percutaneous 
intervention with introducer sheath sizes of 8-18Fr  and planned percutaneous 
arteriotomy closure. Applicable procedures include Transcatheter Aortic Valve 
Replacement (TAVR), Endovascular Aneurysm Repair (EVAR). Thoracic Endovascular 
Aneurysm Repair (TEVAR) and Balloon Aortic Valvuloplasty (BAV). 
 
Study Center(s) and Number of Subjects Planned 
A minimum of 3 sites and up to 25 sites in the US are expected to participate in the 
study with approximately 100 pivotal subjects enrolled. No more than 15% of the pivotal 
subjects may be enrolled at a single investigational site. 
 
The first 1-2 subjects enrolled by each investigator will be considered roll-in subjects to 
allow for physician experience with the investigational device. A maximum of 3 study 
investigators and 6 roll-in subjects will be permitted at each investigational site.  
 
In total, up to 250 subjects will receive the investigational device as part of the clinical 
study. 
 
Study Duration 
Study enrollment is expected to occur over a 10 to 12-month period. Imaging and follow-
up procedures will continue through 30 days post-procedure. Subjects with an abnormal 
Duplex Ultrasound (DUS) at 30 days will have a repeat DUS at 60 days post-procedure 

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Protocol Number:  TIS2018-01  
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(all DUS will be analyzed by an independent core laboratory). The total study duration is 
expected to be approximately 24 months. 
 
Note: Due to the COVID-19 pandemic, some patient follow-up visits have been delayed 
greater than 6 months or completely missed; therefore, making data collection extremely 
difficult (e.g., missed DUS assessments) to support some of the secondary endpoints. 
To evaluate safety, we have added an unscheduled visit and telephone assessment (if 
needed) to be conducted as soon as possible based on physician and hospital 
regulatory discretion. 
 
Study Objective 
The study objective is to demonstrate the safety and efficacy of the investigational 
device to achieve hemostasis of common femoral artery access site in subjects 
undergoing percutaneous endovascular procedures utilizing 8-18Fr introducer sheath. 
 
Study Hypothesis 
Safety: 
The freedom from major complications at the target limb access site within 30 days post-
procedure will be greater than the specified Performance Goal (PG). 
 
Efficacy: 
Following use of the investigational device, the mean Time-to-Hemostasis (TTH) will be 
less than the specified PG. 
 
Endpoints 
The following study endpoints will be evaluated:  
 
Primary Safety Endpoint: 
• 
Freedom from major complications of the target limb access site within 30 days 
post-procedure which includes the following: 
 
Major Complications:  
• 
Vascular injury attributable to the investigational device that requires surgical 
repair, stent-graft, or balloon angioplasty  

Clinical Investigational Plan 
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Protocol Number:  TIS2018-01  
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• 
Access site-related bleeding attributable to the investigational device that 
requires transfusion 
• 
Any new access site-related ipsilateral lower extremity ischemia attributable to 
the investigational device and documented by patient symptoms, physical exam, 
and/or decreased or absent blood flow on lower extremity angiogram 
• 
Surgery for access site-related nerve injury attributable to the investigational 
device 
• 
Permanent (lasting > 30 days) access site-related nerve injury attributable to the 
investigational device 
• 
Access site infection requiring intravenous antibiotics and/or extended 
hospitalization  
 
Primary Efficacy Endpoint:   
• 
The mean TTH in the Common Femoral Artery (CFA) of the target limb access 
site with use of the investigational device. 
 
TTH will be evaluated from time of procedural sheath removal to first 
observed cessation of CFA bleeding (excluding cutaneous or 
subcutaneous oozing at access site) in the target limb for subjects not 
requiring adjunctive intervention.  
 
If a sheathless system is used during the procedure, TTH will be 
calculated from final introducer sheath removal to first observed cessation 
of CFA bleeding (excluding cutaneous or subcutaneous oozing at access 
site) in the target limb for subjects not requiring adjunctive intervention. 
 
Adjunctive Intervention is defined as any use of surgical or endovascular 
intervention OR firm/occlusive manual pressure needed to achieve 
access site hemostasis (light/non-occlusive pressure to control cutaneous 
or subcutaneous oozing at the access site is excluded).  
 
Secondary Safety Endpoints: 
• 
The freedom from minor complications at the target limb access site within 30 
days post-procedure including the following: 
 

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Protocol Number:  TIS2018-01  
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Minor Complications:  
o Non-treated pseudoaneurysm attributable to the investigational device 
and documented by DUS 
o Pseudoaneurysm attributable to the investigational device and treated 
with ultrasound-guided compression, ultrasound-guided thrombin 
injection. or ultrasound-guided fibrin adhesive injection 
o Non-treated or treated arteriovenous (AV) fistula attributable to the 
investigational device and documented by DUS 
o Access site hematoma greater than or equal to 10 cm in diameter, 
attributable to the investigational device, and confirmed by DUS 
o Late (following hospital discharge) access site-related bleeding in target 
limb 
o Lower extremity arterial emboli attributable to the investigational device 
o Vein thrombosis attributable to the investigational device 
o Transient access site-related nerve injury attributable to the 
investigational device 
o Access site wound dehiscence 
o Access site infection treated with intramuscular or oral antibiotics  
• 
Device Related Complications (DRCs) and procedural complications within 30 
days post-procedure 
• 
Evaluation of all Adverse Events (AEs) from time of investigational device 
use within 30 days post-procedure, and through 60 days post-procedure 
for subject’s requiring a repeat DUS, including major and minor 
complications 
 
Secondary Efficacy Endpoints: 
• 
Technical Success:  defined as achievement of hemostasis with the 
investigational device without the need for any access-site-related adjunctive 
surgical or endovascular intervention (target limb only).  
• 
Access site closure success:  defined as technical success and freedom from 
major complications within 48 hours of the index procedure or hospital discharge, 
whichever occurs first (target limb only). 
• 
Treatment Success:  defined as technical success and freedom from major 
complications through 30 days follow-up. 

Clinical Investigational Plan 
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Protocol Number:  TIS2018-01  
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• 
Subjects requiring adjunctive surgical or endovascular intervention to achieve 
hemostasis of the access site (target limb only) including type of adjunctive 
intervention. 
• 
Subjects receiving adjunctive manual compression following use of the 
investigational device to achieve hemostasis of the access site (target limb only). 
o Type of compression applied (light or firm, where light compression is 
defined as non-occlusive (i.e., “patent hemostasis”) allowing distal blood 
flow, and firm compression defined as occlusive prohibiting distal blood 
flow.  
• 
Time-to-Ambulation:  defined as elapsed time from final procedural sheath 
removal to time when the subject stands and walks at least 20 feet without 
re-bleeding. 
• 
Time-to-Discharge (i.e., time of actual discharge defined as the elapsed time 
between final procedural sheath removal and when the subject is actually 
discharged from the hospital) 
• 
Occurrence of device failure as defined in Section 13.0 
 
Exploratory Endpoints: 
• 
Time-to-Device-Deployment defined as time of guidewire removal during device 
insertion to time of guidewire reinsertion during device removal, and overall 
procedure time defined as time of first skin nick/incision to achievement of 
hemostasis in the access site (target limb only) 
• 
Time-to-Dischargeability (i.e., discharge eligibility defined as the elapsed time 
between final procedural sheath removal and time when the subject is medically 
able to be discharged based solely on the assessment of the access site as 
determined by the investigator. 
 
Statistical Methods 
Sample Size Determination 
The sample size calculations were performed using PASS 2020 Version 20.0.2i.  The 
appendix included the output from the software.  The sample size for the study is 
based on power considerations for the primary effectiveness endpoint. As will be 
described below, this sample size should also provide adequate power for the 
primary safety endpoint. 

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Protocol Number:  TIS2018-01  
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Primary Efficacy Endpoint 
The primary effectiveness hypothesis will be tested by comparing the primary 
effectiveness endpoint, mean time-to-hemostasis (TTH), against a performance goal 
(PG) of 15 minutes. 
The comparison to the performance goal will be based on the following statistical 
hypothesis test: 
𝐻𝑂: 𝜇𝑇𝑇𝐻   ≥ 15 
𝐻𝐴: 𝜇𝑇𝑇𝐻   < 15 
where 𝜇𝑇𝑇𝐻is the mean time-to-hemostasis in minutes. 
The test will be based on whether the upper one-sided 97.5% confidence limit (based 
on a t-distribution)ii is less than 15. Assuming similar performance to Perclose 
ProGlide®, with a mean time-to-hemostasis of 9.8 minutes and a standard deviation 
of 17 minutes the sample sizes for power levels from 80 to 90% 
a Table 1: Primary Efficacy Endpoint Sample Sizes for Various levels of Power 
Power 
Sample Size 
Maximum Observed Time 
(minutes) and still reject H0 
80.0% 
86 
10.8 
81.4% 
89 
10.9 
82.3% 
91 
10.9 
83.1% 
93 
10.9 
84.3% 
96 
11.0 
85.0% 
98 
11.1 
Successful rejection of the null hypothesis will mean that the PG has been met. 
 
Primary Safety Endpoint 
The primary safety hypothesis will be tested by comparing the primary safety 
endpoint, freedom from major complications of the target limb access site within 30 
days post-procedure, against a performance goal.   

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The comparison to the performance goal will be based on the following statistical 
hypothesis test: 
𝐻𝑂: 𝑝 ≤ 85.2% 
𝐻𝐴: 𝑝 > 85.2% 
where p is the safety endpoint rate for the test device. 
Assuming similar performance as ProGlide (an event-free rate of 94%), one-sided 
alpha = 0.05, the sample sizes for various levels of power are: 
Table 2: Primary Safety Endpoint Sample Sizes for Various levels of Power 
Power 
Sample Size 
Minimum # of Event Free 
Patients needed to reject the 
H0 
81.3% 
78 
72 
85.6% 
86 
79 
88.3% 
95 
87 

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F. List of Abbreviations and Definition of Terms 
AE: 
Adverse Event 
ACT: 
Activated Clotting Time 
AV: 
Arteriovenous 
BAV:  
Balloon Valvuloplasty 
BMI:  
Body Mass Index 
CE: 
Conformité Européene  
CEC: 
Clinical Events Committee 
CFA: 
Common Femoral Artery 
CFR: 
Code of Federal Regulations 
CIP: 
Clinical Investigational Plan 
CRO: 
Clinical Research Organization 
CTRA: 
Clinical Trial Research Agreement 
CVD: 
Cardiovascular Disease 
DRC:  
Device Related Complication 
DSMB: 
Data Safety Monitoring Board 
DUS: 
Duplex Ultrasound 
eCRF: 
Electronic Case Report Form 
EVAR: 
Endovascular Aneurysm Repair 
FIH: 
First-in-Human 
GMP: 
Good Manufacturing Practice 
HIPAA: 
Health Care Portability and Accountability Act 
ICF:   
Informed Consent Form 
ICH: 
International Conference on Harmonization 
IFU: 
Instructions for Use 
IRB: 
Institutional Review Board 
LVEF 
Left Ventricular Ejection Fraction 
MI: 
Myocardial Infarction 
PC: 
Percutaneous 
PG:  
Performance Goal 
SAE: 
Serious Adverse Event 
SC :  
Surgical Cut-down 
SDV : 
Source Document Verification 
STEMI : 
ST Elevated Myocardial Infarction 
TAVR:  
Transcatheter Aortic Valve Replacement 
TEVAR: 
Thoracic Endovascular Aneurysm Repair 
TTH: 
Time to Hemostasis 
UADE: 
Unanticipated Adverse Device Effect 
VCD: 
Vascular Closure Device 

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1 
Background  
Cardiovascular disease (CVD) is the number one cause of death in the United States 
and worldwide. In 2012 an estimated 17.5 million people worldwide died from CVD and 
by 2030 more than 23 million people will die annually.1 The older population is growing 
faster than the total population in almost all regions of the world and the difference in 
growth rates is increasing. According to the US Census Bureau there will be 71 million 
people above the age of 65 years, and 19.5 million above the age of 80 in 2030.2 People 
age 85 and over are now the fastest growing portion of many national populations.3 As 
the aging population continues to rise, there is a corresponding increase in the number 
of percutaneous radiologic and endovascular procedures to address CVD. As a result, 
there are continued efforts to improve patient outcomes while reducing procedural 
related complications and health care utilization. As procedure complexity rapidly 
increases, often involving multiple access points needed for advanced disease 
treatment, efforts to improve outcomes and reduce complications are increasingly 
focused on improvements of vascular access closure. 
 
One area of percutaneous vascular interventions that has received considerable focus in 
the past decade relates to technologies to achieve rapid and effective control of femoral 
arterial access. Traditionally, cardiac and peripheral interventions have involved 5–8Fr 
sheaths with hemostasis achieved with manual compression at the vascular access 
site.4 Manual compression is associated with extended bed rest/hospital stay and patient 
discomfort. Arteriotomy closure devices were introduced in 1995 as adjuncts or 
alternatives to manual compression in an attempt to reduce vascular complications, 
reduce time to hemostasis and ambulation and improve patient comfort.5 Currently, a 
number of vascular closure devices (VCD) exist for closure of small femoral arterial 
access sites. These devices are categorized by mechanism that include collagen plug 
devices such as Angio-Seal™ (Terumo Corporation, Tokyo, JP); clip-based closure : 
StarClose SE® (Abbott Vascular, Santa Clara, CA, USA); sealing agents: Mynx® 
(AccessClosure, Mountain View, CA, USA); and sutures for placement around the 
femoral artery: Prostar XL® Percutaneous Vascular Surgical Device and Perclose 
ProGlide® Suture-Mediated Closure System (Abbott Vascular, CA, USA).6 These 
closure devices have primary been developed for peripheral interventions. 
 

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1.1 Need For Large Arteriotomy VCD 
An increasing number of interventional procedures require large-sheath technology (> 
12 Fr), including abdominal aortic aneurysm repair, thoracic aortic aneurysm repair, 
balloon valvuloplasty, percutaneous aortic valve replacement, and a variety of 
percutaneous ventricular-assist devices. These procedures create challenges for 
hemostasis and minimization of vascular complications. The ability to achieve access 
and closure without surgical cut-down has become an important part of the vascular 
closure device arena.  
 
Aortic stenosis is a disease with a long latency period followed by rapid progression after 
the appearance of symptoms - approximately 50% of untreated patients will die within 
the first 2 years after symptoms appear.7,8 Surgical replacement of the aortic valve in the 
absence of serious co-morbidities is associated with low operative mortality. However, 
approximately 30% of patients with severe symptomatic aortic stenosis do not undergo 
surgery due to advanced age, left ventricular dysfunction, and/or presence of multiple 
co-existing conditions.4, 5 For these high-risk patients, a less invasive treatment, such as 
percutaneous aortic balloon valvuloplasty (BAV), introduced in 1985 by Dr. Cribier, is a 
less invasive alternative to surgical aortic valve replacement (SAVR) for severe aortic 
stenosis in high risk patients.9 The procedure, generally carried out from a transfemoral 
artery approach, involves placement of one or more balloons across a stenotic valve 
followed by inflation to increase the aortic valve area.10 Despite symptomatic benefit, 
early enthusiasm for BAV was tempered due to high restenosis rates and a failure to 
improve survival rates.11, 12 Echocardiographic restenosis rates at 1 year were reported 
to be > 80% while mortalities ranged from 25-45%.9 Over the last decade BAV is 
experiencing a resurgence largely due to improvements in BAV techniques, changing 
patterns and indications for use, and outcome improvements from initial reports.8, 13 
 
The development of the TAVR/TAVI technique in clinical practice has also generated the 
need for VCD capable of accomplishing effective hemostasis after large diameter 
arteriotomies (up to 24Fr, recently down to 14Fr) as vascular access and closure 
remains a challenge.14 Initially, open surgical access was routinely used to introduce 
large sheaths and catheters. Subsequently, percutaneous techniques have  emerged as 
the new standard, resulting in a less invasive, fully percutaneous procedure.15 One of the 
first reported randomized studies to compare the safety and efficacy of percutaneous 
access with surgical cutdown in transfemoral TAVR demonstrated no difference in the 

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primary endpoint of VARC-2 major and minor complications.16 The overall rate of VARC-
2 major vascular complications in the study was 13%. A recent meta-analysis of studies 
reporting on percutaneous (PC) versus surgical cut-down (SC) access in TAVR resulted 
in the inclusion of 2,513 patients in PC and 1,767 patients in SC.17 Major and minor 
vascular complications, as well as bleeding complications, were comparable between 
the two approaches. The need for surgical intervention for vascular complications was 
comparable between PC and SC groups and there was no difference in perioperative all-
cause mortality. The authors concluded PC and SC have similar safety profiles and 
outcomes when used appropriately in selected patients. 
 
Minimally invasive approaches for the treatment of other forms of aortic pathology such 
as endovascular aortic repair procedures are now also very common. Endovascular 
aneurysm repair (or endovascular aortic repair/EVAR), is a type of endovascular surgery 
used to treat pathology of the aorta, most commonly an abdominal aortic aneurysm 
(AAA). EVAR, invented in the early 1990’s, involves placing a stent graft into the 
aneurysm. Over the years the procedure has been refined to include new generation 
stent-graft and delivery systems. Studies have shown that patients treated with EVAR or 
traditional open surgery demonstrated fewer early complications with the minimally 
invasive approach and some studies have also observed a lower mortality rate with 
EVAR.18, 19 
 
When used to treat thoracic aortic disease, the procedure is termed thoracic 
endovascular aortic/aneurysm repair (TEVAR). Originally developed by Dake in 1984 
using the same principles as EVAR20, TEVAR also involves the percutaneous placement 
of an expandable stent graft within the aorta. 
 
1.2 Current Large Arteriotomy VCDs 
Although BAV, TAVR/TAVI, EVAR, and TEVAR are less invasive alternatives to 
conventional surgical approaches, large sized delivery sheaths are still required. 
Management of the arterial access sites often represent a challenge and usually 
requires prolonged manual compression or alternatively suture-mediated closure 
techniques, two of which are commercially available. The Prostar XL was originally 
approved in the US and EU for closure of 5–8Fr access sites and has since gained a CE 
mark for up to 24Fr. The Perclose ProGlide® was originally approved for 5-8Fr and now 
is approved for up to 21Fr. The ProStar® XL, which provides four suture needles but, as 

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some have suggested, has a somewhat challenging platform, or two ProGlides placed at 
a 40º angle are placed at the beginning of the procedure leaving knots untied. The 
puncture site is then dilated to the appropriate size and the sutures are tied once the 
endovascular procedure is complete. For sheath sizes greater than 8Fr, at least two 
devices are required. More recently, a technique has been described using three 
ProGlides; this presumably grabs more segments of the arterial wall and provides 
redundancy in case one of the closures fails.21 In the ProGlide® US FDA approval study, 
the majority of cases used two (74%) or three (18%) devices and some 
used four (4%) and five (2%) closure devices in the procedure.22 
 
1.2.1 Clinical Experience With Suture-Based VCDs 
Extensive published clinical experience with the suture based ProGlide and Prostar XL 
for percutaneous closure of large arterial access sites demonstrate relatively high rate of 
technical success and low access-related complication rates with ranges of 81-100% 
and 6-19% respectively.15, 23-34 This data suggests that there is the possibility that use of 
the device in large arterial access sites could result in clinically meaningful savings in 
procedural time, patient recovery time and patient length of stay, which may lead to 
improved safety outcomes and reduced resource use as compared to surgical cut-
down.2, 19 
 
1.2.2 Advantages of Suture-based VCDs 
Several advantages of suture-based closure devices have been suggested. An analysis 
of a database of 23,813 consecutive interventional coronary procedures that used either 
a collagen plug-based, nitinol clip-based or suture-based VCD, found that suture-based 
VCDs demonstrated a lower risk of vascular complications when compared with other 
VCDs irrespective of the success of VCD deployment. Although the collagen plug-based 
VCDs showed lowest failure rate (2.1%), when deployment was unsuccessful, it was 
associated with the highest vascular complication rate as compared to unsuccessful 
deployment of suture-based or nitinol clip-based VCDs. Deployment failure of suture 
based VCDs did not impact the vascular complication rate as compared with its 
successful deployment. It was proposed by the author that it was due, in part, to the 
availability of a “bailout” mechanism in the event of deployment failure that permits 
control of the arteriotomy site with sheath replacement or a second attempt at closure 
with VCDs. No bailout mechanism is readily available for the collagen plug-based or the 
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Others have suggested percutaneous closure devices such as the Prostar XL might 
have advantages over surgical cut-down. The smaller scar reaction at the level of the 
groin increases the potential for repeat puncture of the femoral artery, allowing further 
vascular access when necessary.2 Additionally, the complications associated with use of 
the Prostar® XL device, while similar in frequency to the rate of complications associated 
with surgical cut-down, can differ markedly in their seriousness and ease of resolution.2 
 
1.3 Cross-SealTM System and Indications For Use 
The Cross-SealTM System is indicated for the percutaneous delivery of sutures for 
closing the common femoral artery access site of patients who have undergone 
interventional catheterization procedures using 8Fr to 18Fr sheaths. The Cross-SealTM 
System includes the Cross-SealTM Device and three accessories (Cross-SealTM Knot 
Tyer, Cross-SealTM Knot Pusher, and Cross-SealTM Suture Trimmer). The concept is 
similar to the suture-based VCDs described above but is designed to reduce the 
possible number of devices needed to close the arteriotomy and to reduce the steps 
required. One device deploys two (2) sutures in three (3) steps. Therefore, in addition to 
the aforementioned potential advantages of suture-based VCDs, other potential 
advantages of the Cross-SealTM System include reduction in number of devices required 
and ease of use. 
 
1.4 Description of Device 
The Cross-SealTM Suture Mediated Vascular Closure Device System (Cross-SealTM 
System) includes the Cross-SealTM Device and three accessories (Cross-SealTM Knot 
Tyer, Cross-SealTM Knot Pusher, and Cross-SealTM Suture Trimmer). The Cross-SealTM 
Device (Figure 1) is composed of a Catheter, Suture Delivery System and Handle. The 
device tracks over a standard 0.038” or 0.035” (minimum length 130 cm) guidewire. A 
HEMOSTASIS VALVE located in the middle of the CATHETER limits blood flow from the 
GUIDEWIRE PORT through the CATHETER with or without the guidewire in place.  The 
Suture Delivery System contains NEEDLES, LOCATOR WINGS, and the NEEDLE 
BARREL that control suture placement around the arteriotomy. The Handle contains the 
SLIDER, BLEEDING INDICATOR, PLUNGER, RESET 1 BUTTON (SLIDER 
RETRACTOR), and RESET 2 BUTTON (LOCATOR WINGS RETRACTOR). The 
SLIDER triggers a mechanism that opens the LOCATOR WINGS and creates a 
sandwich configuration to stabilize the delivery system within the vessel wall. The 

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BLEEDING INDICATOR connects to a lumen that has an intraluminal port positioned at 
the distal end of the Suture Delivery System to allow back bleeding  which ensures the 
Suture Delivery System is positioned properly in the femoral artery. The NEEDLE 
BARREL keeps the Cross-SealTM Device from moving deeper inside the vessel, 
stabilizes the device once the LOCATOR WINGS are open and retrieves the disengaged 
suture-carrying NEEDLES. The PLUNGER triggers the NEEDLES to deploy the sutures 
and simultaneously closes the LOCATOR WINGS. 
 
 
                             Figure 1: Cross-SealTM Device 
 
The Cross-SealTM System includes the following three accessories:  
 
1) Cross-SealTM Knot Tyer is used to provide pre-tie fisherman’s knots (also 
named Improve Clinch Knot) in the suture. 
2) Cross-SealTM Knot Pusher is used to advance pre-tied knots percutaneously 
to the top of the arteriotomy and secure the knots. 
3) Cross-SealTM Suture Trimmer is used to cut sutures after knots are 
delivered and secured to the top of the arteriotomy. 
 
The Cross-SealTM Knot Tyer (Figure 2) is used for making a Fisherman’s knot.  
• 
The TOP and SIDE HOOK are used to hook the two ends of suture.  
• 
The RING TAB, which is connected to PRELOAD STRING, is pulled to trigger 
the process of making the knot. The non-rail end of suture will be brought into 
a preconfigured PRELOAD STRING on the ROTOR.  
• 
The SLIDER is activated to release the loops and slide down the knot. 
 

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Figure 2: Cross-SealTM Knot Tyer 
 
The Cross-SealTM Knot Pusher (Figure 3) is used for delivering the knot to the top of the 
arteriotomy. The SNARE WIRE is used to load the rail suture onto the PUSHER BODY, 
which is then pushed to advance the knot percutaneously to the top of arteriotomy. 
 
 
Figure 3: Cross-SealTM Knot Pusher 
 
The Cross-SealTM Suture Trimmer (Figure 4) is used for trimming the suture ends 
percutaneously. The SLIDER controls the suture HOOK by advancing the HOOK for 
loading the sutures. The TRIGGER controls the cutting mechanism located at distal end 
of the CUTTING BARREL. 
 
  
Figure 4: Cross-SealTM Suture Trimmer 
The Cross-SealTM and Accessories are provided sterile to the user as single-use, 
disposable devices. 

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Cross-SealTM System Specifications 
Feature 
Specification 
Cross-SealTM Device 
 
Guidewire Compatibility 
0.038” or 0.035” 
Catheter Diameter 
9Fr 
Interventional Device Compatibility 
8-18Fr  
Overall Device Length 
555 mm 
Catheter Length 
232 mm 
Locator Wings Length 
17.4 mm 
Needle Barrel Length 
66 mm 
Needle Barrel Outer Diameter 
7 mm 
Cross-SealTM Knot Tyer 
Overall Device length 
162 mm 
Cross-SealTM Knot Pusher 
Overall Device length 
143 mm 
Cross-SealTM Suture Trimmer 
Overall Device length 
185 mm 
 
 
 
1.5 Summary of Clinical Studies 
 
1.5.1 Clinical Feasibility (FIH) Study 
A First-in-Human clinical study was conducted to assess the initial safety and 
feasibility of the Cross-SealTM System GEN 1.0 to facilitate hemostasis in patients 
undergoing percutaneous transcatheter interventions involving access through the 
femoral artery using an 8-18Fr introducer sheath. Results are demonstrated as 
shown in Table 1. A total of ten (10) subjects were enrolled at a single site in 
Asuncion, Paraguay between October 26 and 27, 2015. A total of 10 patients 
completed the study. As shown in Table 1, the patient population consisted of 6 
(60%) men and 4 (40%) women with a mean age of 66.0 years (range 56.3 to 80.2 
years) and mean BMI of 29.2 kg/m2 (range 24.2 to 36.7). The mean estimated 
diameter of femoral artery lumen at the closure site was 9.0 mm and ranged from 
7.1 to 11.0 mm as measured via duplex ultrasound. Size 14Fr introducers were 
utilized in 2 patients and 18Fr introducers were used in 8 patients. The mean 

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Cross-SealTM System procedure time was 4 minutes (range 1-8) and mean TTH 
was 3 minutes and 5 seconds (range 0-13:00). Total estimated blood loss 
including the interventional procedure was 97.2 mL (range 50-150). The mean 
Time-to-Ambulation was 3 hours and 12 minutes (range 1:25-9:12) and mean 
time-to-hospital-discharge was 18 hours and 17 minutes (range 14:05 to 22:22). 
Four adverse events occurred in 3 patients; 2 hematomas, 1 vessel spasm, and 1 
post obstructive flow in the femoral artery. None of the adverse events were 
serious or unanticipated. All of the events reported were related to the procedure 
and not to the device and were resolved without any further action required. 100% 
of patients met the Cross-SealTM System success defined as closure of the 
arteriotomy without the need for any access site related adjunctive surgical or 
endovascular procedures stemming from hemorrhagic, infectious, or ischemic 
complications. 100% of the patients met the primary and secondary safety 
endpoints - none had a major or minor vascular complication directly related to the 
Cross-SealTM System as defined by VARC-2 (Valve Academic Research 
Consortium-2). The results of this feasibility study demonstrated that the Cross-
SealTM System is safe and performed as intended. 
 
Table 1. Summary of First-In-Human Clinical Study of the Cross-SealTM System 
(GEN 1.0) 
Patient Population 
Gender 
6 (60%) men and 4 (40%) women 
Age 
Mean age = 66.0 years (range 56.3 - 80.2 years) 
BMI 
Mean BMI = 29.2 (range 24.2 - 36.7) 
Diameter of femoral artery 
lumen 
Mean = 9.0 mm (range 7.1 - 11.0 mm) 
Procedure 
Introducer size 
14 Fr, n = 2 
18 Fr, n = 8 
Cross-SealTM System 
procedure time 
Mean = 4 minutes (range 1-8 minutes) 
TTH 
Mean = 3:05 minutes (range 0 - 13:00) 
Total estimated blood loss 
Mean = 97.2 mL (range 50-150 mL) 
Technical Success 
100% 
Post-procedure 
Time-to-Ambulation 
Mean = 3:12 hours (range 1:25-9:12) 
Time-to-Hospital-Discharge Mean = 18:17 hours (range 14:05 - 22:22) 
Adverse Events 
N = 3 patients; 2 hematoma, 1 vessel spasm, 1 
post obstructive flow 
 

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1.5.2  CE Study 
The CE study was a prospective, multi-center, and single arm study conducted in 
OUS countries. The primary endpoint of effectiveness was technical success 
defined as closure of the arteriotomy without the need for any access-site-related 
adjunctive surgical or endovascular procedures. The primary endpoint of safety 
was freedom from major VARC-2 events within 30 days of the procedure. Results 
are demonstrated as shown in Table 2. 
 
A total of twenty-six (26) subjects were enrolled across 5 sites in Australia (1), New 
Zealand (3), and Taiwan (1), between May 30, 2017 and January 12, 2018.  Study 
results from the total of 26 patients’ data were monitored and shown in Table 2. 
The patient population consisted of 20 (77%) men and 6 (23%) women with a 
mean age of 76.5 years (range 33 – 91 years) and mean BMI is 25.7 (range 20.7-
36.7). The mean estimated diameter of femoral artery lumen at the closure site 
was 8.3 mm and ranged from 6 mm to 11 mm as measure by ultrasound or CT 
scan. The introducer sheath utilized in study subjects ranged from 8Fr to 18Fr. An 
8Fr introducer sheath was utilized in 1 (3.85%) subject, 9Fr introducer sheath was 
utilized in 1 (3.85%) subject, 10Fr introducer sheaths were utilized in 3 (11.54%) 
subjects, 12Fr introducer sheaths were utilized in 5 (19.23%) subjects, 14Fr 
introducer sheaths were utilized in 7 (26.92%) subjects, 16Fr introducer sheaths 
were utilized in 3 (11.54%) subjects and 18Fr introducer sheaths were utilized in 6 
(23.08%) subjects. The mean TTH was 1 minute and 11 seconds (range 00:01 – 
11:54). The mean estimated total blood loss including the interventional procedure 
was 158 ml (range 5 – 600 ml). 
 
A successful ipsilateral “pre-close” percutaneous technique, defined as closure 
with the Cross-SealTM System, was achieved in 100% of the subjects with no major 
ipsilateral access site vascular complication at 30 days follow-up. 
 
Table 2. Summary of CE Clinical Study of the Cross-SealTM System (GEN 2.0) 
Patient Population 
Gender 
20 (77%) men and 6 (23%) women 
Age 
Mean age = 76.5 years (range 33 - 91 years) 
BMI 
Mean BMI = 25.7 (range 20.7 - 36.7) 

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Diameter of femoral artery 
lumen 
Mean = 8.3 mm (range 6.0 - 11.0 mm) 
Procedure 
Introducer size 
8 Fr, n = 1 
9 Fr, n = 1 
10 Fr, n = 3 
12 Fr, n = 5 
14 Fr, n = 7 
16 Fr, n = 3 
18 Fr, n = 6 
TTH 
Mean = 1:11 minutes (range 00:01 - 11:54) 
Total estimated blood loss 
Mean = 158 mL (range 5 -600 mL) 
Technical Success* 
100% 
Post-procedure 
Adverse events 
N = 12 subjects ( 35 adverse events) 
1 Device related 
1 Device probably related 
33 Non-Device related 
 
* In one case, user exceeded 90 degrees over guidewire and damaged the catheter, successful 
closure was achieved using a second device. 
 
There were 35 adverse events which occurred in 12 subjects. Among the events, 
one is device related, one is probably device related, and 33 are non-device 
related. All adverse events related to access sites complications are in freedom 
from major VARC-2 events within 30 days of the procedure. 
 
One (1) “device related” adverse event occurred as the operators passed the 
device between the catheter too quickly at > 90 degrees that led to pre-damage of 
the guidewire catheter port. The device was then withdrawn from the tortuous 
vessel resulting in catheter breakage. The broken portion was successfully 
removed and access site closure was achieved using a second Cross-SealTM 
device. The IFU and training materials were updated accordingly to reinforce the 
importance of passing the device coaxially with an angle less than 60 degrees to 
prevent catheter bending or cracking. Additional on-site trainings were provided to 
the operators with agreement that under normal use conditions, catheter breakage 
should not occur. After training, no catheter bending or kinking was observed in the 
following 21 cases.  
 
One “probably device related” adverse event, a small pseudoaneuysm, was 
observed. Such events are expected potential adverse events from suture-
mediated vascular closure device.  
 

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Other adverse events related to access sites complications also were observed. 
They were non-occlusive thrombus and false aneurysm which are expected 
potential adverse events from suture-mediated vascular closure devices. 
An independent Medical Monitor was appointed to review and adjudicate all SAEs 
that occurred during the course of the study. The results of this CE study 
demonstrated that the Cross-SealTM System is safe and performed as intended. 
 
In summary, the 10 subjects enrolled in FIH study and 26 subjects enrolled in CE 
study demonstrated a safety and effectiveness profile of Cross-SealTM system. The 
patient population in the study underwent a variety of procedures including 19 
BAV, 10 TAVI, and 7 TEVAR. The mean of TTH for total 36 subjects (FIH study 
and CE study) is 1 min 10 seconds. The mean TTH observed by sheath size are 
provided in Table 3. 
 
Table 3. TTH vs Sheath Size in FIH Study and CE Study 
 
Cross-SealTM System GEN 
1.0, FIH Study 
Cross-SealTM System GEN 
2.0, CE Study 
Sheath Size 
Closure 
Number 
Mean TTH 
(min) 
Closure 
Number 
Mean TTH 
(min) 
8Fr 
N/A 
N/A 
N=1 
0.23 
9Fr 
N/A 
N/A 
N=1 
0.63 
10Fr 
N/A 
N/A 
N=3 
0.47 
12Fr 
N/A 
N/A 
N=5 
0.55 
14Fr 
N=2 
2.5 
N=7 
2.26 
16Fr 
N/A 
N/A 
N=3 
1.95 
18Fr 
N=8 
3.23 
N=6 
0.7 
 
Total (10) 
3.08 
Total (26) 
1.19 
 
 
2 
Study Design, Sample Size and Duration 
 
2.1 Study Design 
This is a prospective, multi-center, single arm, clinical study to investigate the safety and 
efficacy of the Cross-SealTM System.  
 
The target population is comprised of subjects scheduled for elective percutaneous 
intervention with introducer sheath sizes of 8-18Fr and planned percutaneous 
arteriotomy closure. Applicable procedures include Transcatheter Aortic Valve 

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Replacement (TAVR), Endovascular Aneurysm Repair (EVAR). Thoracic Endovascular 
Aneurysm Repair (TEVAR) and Balloon Aortic Valvuloplasty (BAV). 
 
2.2 Sample Size 
A minimum of 3 sites and up to 25 sites in the US are expected to participate in the 
study with approximately 100 pivotal subjects enrolled. No more than 15% of the pivotal 
subjects may be enrolled at a single investigational site.  
 
The first 1-2 subjects enrolled by each investigator will be considered roll-in subjects to 
allow for physician experience with the investigational device. A maximum of 3 study 
investigators and 6 roll-in subjects will be permitted at each investigational site.  
 
In total, up to 250 subjects will receive the investigational device as part of the clinical 
study. 
 
2.3 Study Duration 
Study enrollment is expected to occur over a 10 to 12 month period. Imaging and follow-
up procedures will continue through 30 days post-procedure. Subjects with an abnormal 
DUS at 30 days will have a repeat DUS at 60 days post-procedure (all DUS will be 
analyzed by an independent core laboratory). The total study duration is expected to be 
approximately 24 months. 
 
Note: Due to the COVID-19 pandemic, some patient follow-up visits have been delayed 
greater than 6 months or completely missed; therefore, making data collection extremely 
difficult (e.g., missed DUS assessments) to support some of the secondary endpoints. 
To evaluate safety, we have added an unscheduled visit and telephone assessment (if 
needed) to be conducted as soon as possible based on physician and hospital 
regulatory discretion. 
 
3 
Study Objective, Hypothesis, and Endpoints 
 
3.1 Study Objective 
The study objective is to demonstrate the safety and efficacy of the investigational 
device to achieve hemostasis of common femoral artery access site in subjects 
undergoing percutaneous endovascular procedures utilizing 8-18Fr introducer sheath. 

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3.2 Study Hypothesis 
Safety: 
The freedom from major complications at the target limb access site within 30 days post-
procedure will be greater than the specified PG. 
 
Efficacy: 
Following use of the investigational device, the mean TTH will be less than the specified 
PG. 
 
3.3 Endpoints 
This clinical study will evaluate the primary and secondary endpoints described below.  
 
3.3.1 Primary Endpoints   
Primary Safety Endpoint: 
• 
Freedom from major complications of the target limb access site within 30 days 
post-procedure which includes the following: 
 
Major Complications:  
• 
Vascular injury attributable to the investigational device that requires surgical 
repair, stent-graft, or balloon angioplasty  
• 
Access site-related bleeding attributable to the investigational device that 
requires transfusion 
• 
Any new access site-related ipsilateral lower extremity ischemia attributable to 
the investigational device and documented by patient symptoms, physical exam, 
and/or decreased or absent blood flow on lower extremity angiogram 
• 
Surgery for access site-related nerve injury attributable to the investigational 
device 
• 
Permanent (lasting > 30 days) access site-related nerve injury attributable to the 
investigational device 
• 
Access site infection requiring intravenous antibiotics and/or extended 
hospitalization  
 
 
 
 

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Primary Efficacy Endpoint: 
• 
The mean TTH in the Common Femoral Artery (CFA) of the target limb access 
site with use of the investigational device. 
 
TTH will be evaluated from time of procedural sheath removal to first 
observed cessation of CFA bleeding (excluding cutaneous or 
subcutaneous oozing at access site) in the target limb for subjects not 
requiring adjunctive intervention.  
 
If a sheathless system is used during the procedure, TTH will be 
calculated from final introducer sheath removal to first observed cessation 
of CFA bleeding (excluding cutaneous or subcutaneous oozing at access 
site) in the target limb for subjects not requiring adjunctive intervention. 
 
Adjunctive Intervention is defined as any use of surgical or endovascular 
intervention OR firm/occlusive manual pressure needed to achieve 
access site hemostasis (light/non-occlusive pressure to control cutaneous 
or subcutaneous oozing at the access site is excluded).  
 
3.3.2 Secondary Endpoints 
Secondary Safety Endpoints: 
• 
The freedom from minor complications at the target limb access site within 30 
days post-procedure which includes the following: 
 
Minor Complications:  
o Non-treated pseudoaneurysm attributable to the investigational device 
and documented by DUS 
o Pseudoaneurysm attributable to the investigational device and treated 
with ultrasound-guided compression, ultrasound-guided thrombin 
injection. or ultrasound-guided fibrin adhesive injection 
o Non-treated or treated arteriovenous (AV) fistula attributable to the 
investigational device and documented by DUS 
o Access site hematoma greater than or equal to 10 cm in diameter, 
attributable to the investigational device, and confirmed by DUS 

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o Late (following hospital discharge) access site-related bleeding in target 
limb 
o Lower extremity arterial emboli attributable to the investigational device 
o Vein thrombosis attributable to the investigational device 
o Transient access site-related nerve injury attributable to the 
investigational device 
o Access site wound dehiscence 
o Access site infection treated with intramuscular or oral antibiotics  
• 
Device Related Complications (DRCs) and procedural complications within 30 
days post-procedure 
• 
Evaluation of all Adverse Events (AEs) from time of investigational device 
use within 30 days post-procedure, and through 60 days post-procedure 
for subject’s requiring a repeat DUS, including major and minor 
complications 
 
Secondary Efficacy Endpoints: 
• 
Technical Success:  defined as achievement of hemostasis with the 
investigational device without the need for any access-site-related adjunctive 
surgical or endovascular intervention (target limb only).  
• 
Access site closure success:  defined as technical success and freedom from 
major complications within 48 hours of the index procedure or hospital discharge, 
whichever occurs first (target limb only). 
• 
Treatment Success:  defined as technical success and freedom from major 
complications through 30 days follow-up. 
• 
Subjects requiring adjunctive surgical or endovascular intervention to achieve 
hemostasis of the access site (target limb only) including type of adjunctive 
intervention. 
• 
Subjects receiving adjunctive manual compression following use of the 
investigational device to achieve hemostasis of the access site (target limb only). 
o Type of compression applied (light or firm, where light compression is 
defined as non-occlusive (i.e., “patent hemostasis”) allowing distal blood 
flow, and firm compression defined as occlusive prohibiting distal blood 
flow.  
• 
Time-to-Ambulation:  defined as elapsed time from final procedural sheath 
removal to time when the subject stands and walks at least 20 feet without 

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re-bleeding. 
• 
Time-to-Discharge (i.e., time of actual discharge defined as the elapsed time 
between final procedural sheath removal and when the subject is actually 
discharged from the hospital) 
• 
Occurrence of device failure as defined in Section 13.0 
 
3.3.3 Exploratory Endpoints 
• 
Time-to-Device-Deployment defined as time of guidewire removal during device 
insertion to time of guidewire reinsertion during device removal, and overall 
procedure time defined as time of first skin nick/incision to achievement of 
hemostasis in the access site (target limb only) 
• 
Time-to-Dischargeability (i.e., discharge eligibility defined as the elapsed time 
between final procedural sheath removal and time when the subject is medically 
able to be discharged based solely on the assessment of the access site as 
determined by the investigator. 
 
4 
Study Design 
This is a prospective, multi-center, single arm, clinical study to investigate the safety and 
efficacy of the Cross-SealTM System. The safety and efficacy will be evaluated 
immediately post-procedure, prior to hospital discharge, through 30 days post-
procedure, and through 60 days post-procedure for subjects requiring a repeat DUS.  
 
Study sites will make every attempt to conduct a telephone assessment for patients 
whose follow-up visits have been affected COVID-19. The assessment will evaluate 
AEs, concomitant medications and groin health status (which would otherwise be 
evaluated by a physical exam and DUS). 
 
A subject is considered enrolled into the study if the subject has signed the ICF and 
meets all eligibility criteria. 
 
4.1 Eligibility Criteria 
Inclusion Criteria 
1. Subject is ≥ 18 years old 
2. Subject is scheduled for elective or planned (i.e., not emergent or urgent) 
percutaneous transcatheter interventional procedures involving access through 

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the femoral artery using 8-18 Fr introducer sheaths (i.e. BAV, TAVR/TAVI, 
EVAR, TEVAR) 
3. Subject is able to undergo emergent vascular surgery if a complication related to 
the vascular closure necessitates such surgery 
4. Subject is willing and able to complete follow-up requirements 
5. Subject has the mental capacity to consent for themselves (i.e., does not require 
the use of a Legally Authorized Representative), and signs a written Informed 
Consent Form (ICF) prior participating in the study 
 
Subjects will not be permitted to participate in the study if they meet any of the following 
general exclusion criteria and/or intra-procedure exclusion criteria: 
 
General Exclusion Criteria 
1. Prior intra-aortic balloon pump at access site 
2. Subjects with severe inflow disease (iliac artery diameter stenosis > 50%) and/or 
severe peripheral arterial disease (Rutherford Classification 5 or 6), as confirmed 
with prior standard of care CT Imaging, duplex ultrasound, and/or intra-
procedural fluoroscopy 
3. Common femoral artery lumen diameter is < 5 mm  
4. In opinion of the investigator, significant scarring of the target access site which 
would preclude use of the device in accordance with the IFU 
5. Prior target artery closure with any closure device < 90 days, or closure with 
manual compression ≤ 30 days prior to index procedure 
6. Prior vascular surgery, vascular graft, or stent in region of access site  
7. Subjects receiving glycoprotein IIb/IIIa inhibitors before, during, or after the 
catheterization procedure 
8. Subjects with significant anemia (Hgb < 10 g/dL, Hct < 30%) 
9. Subject with known bleeding disorder including thrombocytopenia (platelet count 
< 100,000), thrombasthenia, hemophilia or Von Willebrand’s disease  
10. Subject with renal insufficiency (serum creatinine level > 221µmol/L or 2.5 
mg/dL), on dialysis therapy, or with renal transplant 
11. Known severe allergy to contrast reagent that cannot be managed with 
premedication 
12. Inability to tolerate aspirin and/or other anticoagulation/antiplatelet treatment 

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13. Planned anticoagulation therapy post-procedure such that ACT is expected to be 
elevated above 350 seconds for more than 24 hours after the procedure 
14. Connective tissue disease (e.g., Marfan's Syndrome) 
15. Thrombolytics (e.g. t-PA, streptokinase, urokinase), Angiomax (bivalirudin) or 
other thrombin-specific anticoagulants ≤ 24 hours prior to the procedure 
16. Recent (within 8 weeks) cerebrovascular accident or Q-wave myocardial 
infarction 
17. Subjects who are morbidly obese (BMI > 40 kg/m2) 
18. Planned major intervention or surgery, including planned endovascular 
procedure in the target leg, within 30 days following the interventional procedure  
19. Subject unable to ambulate at baseline (i.e., confined to wheelchair or bed) 
20. Currently participating in a clinical study of an investigational device or drug that 
has not completed its primary study endpoint 
21. Known allergy to any device component  
22. Subject is known or suspected to be pregnant or lactating 
23. Evidence of active systemic or local groin infection 
24. Subject has other medical, social or psychological problem that in the opinion of 
the investigator precludes them from participating 
25. Subject is mentally incompetent or a prisoner 
26. New York Heart Association (NYHA) Class IV heart failure that is uncontrolled 
and requires treatment in the Intensive Care Unit within 24 hours prior to the 
index procedure 
27. Left Ventricular Ejection Fraction (LVEF) < 20% 
28. Unilateral or bilateral lower extremity amputation 
29. Known existing nerve damage in the target leg 
30. Subjects who have already participated in this IDE study 
 
Intra-Procedure Exclusion Criteria 
31. Access site above the most inferior border of the inferior epigastric artery (IEA) 
and/or above the inguinal ligament based upon bony landmarks 
32. Access site in the profunda femoris or superficial femoral arteries, or the 
bifurcation of these vessels 
33. Ipsilateral femoral venous sheath during the catheterization procedure 
34. Common femoral artery calcium at the arteriotomy site (i.e., target access site), 
which is visible with prior CT Imaging and/or duplex ultrasound 

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35. Subject in which there is difficulty inserting the introducer sheath or need for 
greater than 2 ipsilateral arterial punctures at the start of the catheterization 
procedure 
36. Difficulty in obtaining vascular access resulting in multiple arterial punctures 
and/or posterior arterial puncture 
37. Evidence of a pre-existing hematoma (> 1.5 cm in diameter), arteriovenous 
fistula, pseudoaneurysm, or intraluminal thrombosis at the access site 
38. Marked tortuosity (at the investigator’s discretion) of the femoral or external iliac 
artery in the target leg based on prior CT imaging, fluoroscopy, and/or duplex 
ultrasound 
39. Angiographic evidence of arterial laceration, dissection, or stenosis in the femoral 
artery that would preclude use of the investigational device 
40. Target arteriotomy >18F sheath 
 
The inclusion of subjects using other medications will be left to the discretion of the 
treating investigator. All such medication use, dose, and schedule will be recorded and 
documented. 
 
4.2 Subject Enrollment 
A minimum of 3 sites and up to 25 sites in the US are expected to participate in the 
study with approximately 100 pivotal subjects enrolled. No more than 15% of the pivotal 
subjects may be enrolled at a single investigational site. 
 
The first 1-2 subjects enrolled by each investigator will be considered roll-in subjects to 
allow for physician experience with the investigational device. A maximum of 3 study 
investigators and 6 roll-in subjects will be permitted at each investigational site.  
 
In total, up to 250 subjects will receive the investigational device as part of the clinical 
study. 
 
5 
Ethics 
 
5.1 Role of the Sponsor 
The Sponsor has the overall responsibility for the conduct of the study, including 
assurance that the study meets all regulatory requirements. In this study, the Sponsor 

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will have certain direct responsibilities and will delegate other responsibilities to the 
Clinical Research Organization (CRO). The Sponsor will conduct all its responsibilities in 
compliance with the Code of Federal Regulations (CFR).  
 
5.2 Role of Clinical Research Organization  
The Clinical Research Organizations (CROs) will support the data management and 
safety oversight throughout study conduct which includes, but is not limited to, safety 
review boards (DSMB, CEC), informing the Sponsor of any unanticipated adverse 
device effects (UADEs), serious adverse events (SAEs), and deviations from the 
protocol as appropriate. The CRO will conduct all its responsibilities in compliance with 
the Code of Federal Regulations (CFR).  
 
5.3 Ethics Review 
The final study protocol and written Informed Consent Form must be approved in writing 
by an Institutional Review Board (IRB). The principal investigator is responsible for 
informing the IRB of any amendments to the protocol in accordance with local 
requirements. In addition, the IRB must approve all advertising used to recruit subjects 
to the study. The protocol must be re-approved by the IRB annually, as local regulations 
require.   
Progress reports and notification of serious, unexpected adverse events will be provided 
to the IRB according to local regulations and guidelines. 
5.4 Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in 
the Declaration of Helsinki and are consistent with the ICH/Good Clinical Practice, and 
applicable regulatory requirements. 
 
5.5 Written Informed Consent 
Written Informed Consent must be obtained prior to any study-related procedures*. The 
principal investigator will ensure that proper informed consent is provided, including 
ensuring the subject is given full and adequate oral and written information about the 
nature, purpose, possible risks and benefits of the study. Subjects must also be notified 
that they are free to discontinue/withdraw from the study at any time. The subject must 
be given the opportunity to ask questions and allowed time to consider the information 

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provided. The principal investigator will ensure that the subject has met all eligibility 
criteria prior to enrollment in the study. 
 
The principal investigator must store the original, signed written ICF.  A copy of the 
written ICF must be given to the subject. Any modifications made to the ICF must be 
approved by the IRB, Sponsor, and FDA if applicable.   
 
*Pre-procedure assessments considered standard of care completed prior to obtaining 
informed consent do not need to be repeated if performed within 30 days of the 
procedure unless the investigator feels it is medically necessary, or unless otherwise 
specified (e.g., pregnancy test). 
 
5.6 Subject Data Protection 
In accordance with the Health Information Portability and Accountability Act (HIPAA), the 
written Informed Consent Form must include a subject authorization to release medical  
information to the study Sponsor and or allow the Sponsor or their designate, a 
regulatory authority, or IRB access to subject’s medical information that includes all 
hospital records relevant to the study, including subjects’ medical history. 
 
5.7 Subject Withdrawal 
A subject’s participation in the study is voluntary. Subjects may withdraw their consent 
from participation in the study at any time. A subject may withdraw completely or may 
withdraw but leave the authorization to access their medical records in effect. The 
investigator will take every reasonable measure to follow the subject for vital status and 
clinical events. Should a subject exit the study for any reason, the investigator will 
document the reason for study exit, if known, and record in the study database.   
 
5.8 Discontinuing Subject Participation 
A subject’s continued participation in the study may be terminated for the following 
reasons: 
 
 
1. Serious or severe adverse event or unanticipated adverse device effect. 
 
2. Termination of study by the Sponsor. 
 
3. Investigator determines that continued participation is not in the best interest of 
the subject.  

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4. Subject withdrawal of consent at any time. 
 
6 
Device Supply Information 
 
6.1 Shipping 
An initial supply of the investigational device will be shipped to investigational site when 
the site is approved by the Sponsor after all requirements, such as IRB approval and 
conduct of a Site Initiation Visit, are completed. Resupply of investigational devices 
during the study will be facilitated by the Sponsor, and/or designate.  
 
6.2 Labeling 
Labelling of investigational devices will be performed in accordance with the Good 
Manufacturing Practices (GMP) for Medical Devices of the Quality System Regulations 
(QSR). The devices will be packaged in individual trays with a peel-pack design. Each 
individual device tray will be packaged in a pouch within a cardboard box and will be 
labeled with the statement:  “CAUTION Investigational Device. Limited by Federal Law 
to Investigational Use”. Information on the investigational device label will indicate the 
identity, quantity, and storage conditions.  
 
6.3 Storage 
All investigational devices must be kept in a secure place under appropriate storage 
conditions. A description of the appropriate storage and shipment conditions will be 
specified on the device label and/or in the IFU. The stored device supplies must be 
accessible to authorized staff only, who must have adequate control of storage area 
temperature in order to maintain stability of the device supplies as specified in the IFU. 
The investigational devices should be stored in the original pack including tray, pouch, 
and box, until use. For further information, investigators should refer to the 
investigational device label and/or IFU.  
 
6.4 Accountability 
The investigator and delegated study personnel are responsible for maintaining accurate 
dispensing records of the investigational device. All devices must be accounted for, 
including devices accidentally or deliberately destroyed. All records for number of 
devices received, dispensed, and returned must be documented. Under no 

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circumstances will the investigator allow the investigational device to be used other than 
as directed by the protocol without prior Sponsor approval.  
 
6.5 Return of a Malfunctioning/Failed Device 
In the case where a device has malfunctioned and/or failed, the investigator must make 
every possible effort to return the device to the Sponsor, unless there is a known 
contamination with an infectious disease (i.e. Hepatitis B, C or HIV). Upon completion of 
the appropriate electronic Case Report Form (eCRF) for failed device, the Sponsor will 
contact the site with complete return instructions.   
 
7 
General Procedures 
 
7.1 Baseline/Pre-Procedure Visit 
Prior to the procedure, subjects must sign the informed consent form, meet all of the 
inclusion and none of the exclusion criteria and complete the following assessments:  
 
The following baseline evaluations are required within 30 days prior to the Index 
Procedure unless otherwise specified: 
• 
Informed Consent Form 
• 
Eligibility Criteria 
• 
Blood Tests including Complete Blood Count (CBC), Platelet Count, Serum 
Creatinine, Hemoglobin (HGB), Blood Urea Nitrogen (BUN), and Hematocrit 
(HCT) to assess eligibility criteria (collected within 2 weeks prior to index 
procedure) 
• 
Medical History/Demographics 
• 
Pregnancy test if female of child-bearing potential (within 7 days prior to 
procedure according to site standard of care) 
• 
Target limb standard of care CT Imaging to document eligibility criteria 
requirements for CFA diameter and stenosis (performed up to 6 months prior to 
index procedure) 
• 
Concomitant Medications (Anticoagulation / Antiplatelets Only) 
 
Note:  For subjects that do not have a standard of care CT Imaging modality, a micro 
puncture and angiogram intra-procedure, may be utilized to confirm eligibility criteria. 
 

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7.2 Index Procedure 
Subjects that meet the general eligibility criteria and have signed the informed consent 
will have their scheduled interventional procedure (i.e., index procedure) performed in 
accordance with investigator/investigational site standard practices. Subjects on warfarin 
or anti-Xa inhibitors must be managed per institutional pre-interventional procedure 
standard of care. 
 
Prior to the use of the investigational device, the investigator will assess the subject for 
the intra-procedure eligibility criteria to confirm enrollment in the study. If the subject is 
enrolled (i.e., signed informed consent and meets all eligibility criteria, including intra-
procedural), the investigational device will be utilized for femoral artery closure according 
to the IFU. Enrolled subjects must also receive anticoagulant and/or antiplatelet 
medication during the index procedure in accordance with the IFU. 
 
If the subject does not meet all eligibility criteria, the subject cannot be enrolled. The 
subject will be considered a screening failure and will not have the investigational device 
utilized. The investigator will perform the femoral artery closure according to their 
standard practice and the subject will not be followed as part of the study protocol. After 
completion of the interventional procedure, subjects will be treated in accordance with 
hospital standard of care and the study protocol.   
 
Note:  Only one single access site per subject will be eligible for use of the 
investigational device and any additional access sites will be managed according to the 
operator’s standard of care. It is recommended the investigational device be used on the 
primary access site (i.e., ipsilateral) as on the side with the intended larger procedural 
sheath size.  Should the procedure require a sheath that exceeds 18Fr at the primary 
access site (i.e., does not meet the eligibility criteria), the subject may still be enrolled if 
the secondary access site (i.e., contralateral to the primary access site) is within the 
acceptable range of 8-18Fr and meets the eligibility criteria.  
 
At the end of the index procedure and prior to closure of the arteriotomy with the 
investigational device, the Activated Clotting Time (ACT) for heparinized subjects will be 
determined. It is required that the ACT < 350 seconds immediately prior to sheath 
removal to minimize the risk of bleeding; the investigator may use their standard of care 
and/or medication to control the ACT.  In addition, if uncontrolled hypertension (systolic 

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blood press > 180 mm Hg or diastolic blood pressure > 110 mm Hg) or hypotension 
(Systolic blood pressure < 90 mm Hg) is observed just prior to planned vascular closure, 
every effort should be made to appropriately manage according to the investigator’s 
standards of care. 
 
After the vascular closure has been completed, cutaneous or subcutaneous oozing may 
be treated with light (non-occlusive) pressure applied to the access site manually, with a 
dressing, or as per the investigator’s standard procedure for suture-mediated closure 
devices. Such oozing will not affect the TTH assessment or be considered an adverse 
event unless severe enough to require further treatment (i.e. surgery or other 
intervention). TTH, defined as elapsed time from procedural sheath removal to the first 
observed cessation of CFA bleeding (excluding cutaneous or subcutaneous oozing at 
access site), will be recorded. If a sheathless system is used during the procedure, TTH 
will be calculated from final introducer sheath removal to first observed cessation of CFA 
bleeding (excluding cutaneous or subcutaneous oozing at access site) in the target limb. 
 
In the event of failure to achieve hemostasis following use of the investigational device 
and based on the investigator’s assessment of bleeding, a bail-out method such as 
manual compression, compression assisted devices, secondary closure device and/or a 
surgical repair to obtain hemostasis should be performed according to the investigator’s 
standard practice and the subject will be followed per the protocol.  Should a secondary 
closure device be utilized for the bail-out method, it must be commercially available and 
cannot be the investigational device. 
 
The following will be conducted during the index procedure: 
• 
Eligibility Criteria (including intra-procedure) 
• 
Femoral artery angiography to assess femoral artery and puncture site prior to 
utilizing the investigational device and after procedure for assessment of major 
and/or minor complications 
• 
Activated Clotting Time (ACT) 
• 
Time-to-Hemostasis (TTH) 
• 
Concomitant Medications (Anticoagulation / Antiplatelets Only) 
• 
Adverse Events (observed from time of enrollment) 
 
 

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Table 2:  
Schedule of 
Events 
Assessment 
Screening / 
Baseline 
Index 
Procedure 
Post Procedure to 
Hospital 
Discharge 
30 Day Follow-
up 
60 Day Follow-
up∞ 
Unscheduled 
Visit ⁂        
Informed Consent 
X 
 
 
 
 
 
Eligibility Criteria 
X 
X 
 
 
 
 
Medical History/Demographics 
X 
 
 
 
 
 
Pregnancy Test¶  
X 
 
 
 
 
 
Blood Testsµ 
X 
 
 
 
 
 
Femoral Artery Imaging (CT scan)– within 6 months prior to 
index procedure§ 
X 
 
 
 
 
 
Femoral Artery Angiography± 
 
X 
 
 
 
 
Activated Clotting Time (ACT) 
 
X 
 
 
 
 
Time-to-Hemostasis (TTH)≠ 
 
X 
 
 
 
 
Time-to-Ambulation† 
 
 
X 
 
 
 
Time-to-Dischargeability‡ 
 
 
X 
 
 
 
Time-to-Discharge (TTD)¥ 
 
 
X 
 
 
 
Targeted Physical Exam, including groin exam 
 
 
 
X 
X 
Xa 
Femoral Duplex Ultrasound (DUS)* 
 
 
 
X 
X 
Xa 
Concomitant Medications (Anticoagulation / Antiplatelets Only) 
X 
X 
X 
X 
X 
X 
Adverse Events ⌘ 
 
X 
X 
X 
X 
X 
Phone Call assessment of AEs and patient condition 
 
 
 
 
 
X 
µ Blood Tests include Complete Blood Count (CBC), Platelet Count, Serum Creatinine, Hemoglobin (HGB), Blood Urea Nitrogen (BUN), and Hematocrit (HCT) to   
  assess eligibility criteria (collected within 2 weeks prior to index procedure) 
¶ Pregnancy test if female of child-bearing potential (collected within 7 days prior to index procedure according to site standard of care) 
* Femoral Duplex Ultrasound is required for assessment of groin/access site related complications. If subject has an abnormal 30 day DUS, subject will be required to return for an additional DUS at 
60 days post-index procedure. 
§ Standard of care CT Imaging modality performed to assess femoral artery quality per trial criteria (collected within 6 months prior to index procedure). Note: If subject does not have a previous CT 
imaging modality, a micro puncture and angiogram intra-procedure may be utilized to confirm eligibility criteria. 
± Femoral Angiography for assessment of quality of femoral artery and puncture site prior to utilizing investigational device. 
⌘ Adverse events should be recorded at any time during the course of the study from time of enrollment through 30 days post-index procedure. Should a subject require a repeat DUS, AEs will be 
collected through 60 days post-index procedure.  
† Time-to-Ambulation is defined as elapsed time from final procedural sheath removal and time when the subject stands and walks without re-bleeding.  
‡Time-to-Dischargeability (i.e., discharge eligibility defined as the elapsed time between procedural sheath removal and time when the subject is medically able to be discharged based solely on the 
assessment of the access site as determined by the investigator. 
 ¥Time-to-Discharge defined as the elapsed time between final procedural sheath removal and when the subject is actually discharged from the hospital 
≠TTH will be evaluated from time of procedural sheath removal to first observed cessation of CFA bleeding (excluding cutaneous or subcutaneous oozing) in the target limb for subjects not requiring 
adjunctive intervention. If a sheathless system is used during the procedure, TTH will be from final introducer sheath removal to first observed cessation of CFA. 
∞ 60 Day Follow-Up Visit assessments are only required if the subject returns to complete a repeat DUS following an abnormal 30 Day DUS 
⁂ Unscheduled visits can occur at any time. Ensuring the safety of trial participants is paramount. Surveillance for adverse events and concomitant medications can be collected via telephone 
contact or similar if the patient is unable to make an in-person visit. 
a If clinically indicated. 

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7.3 Investigational Device Set-up and Preparation  
Please refer to the IFU for additional guidance for the investigational device. 
 
7.4 Concomitant Medical Therapy 
Subjects enrolled in this study should be medicated according to investigator’s standard of 
care prior to, during, and after the interventional procedure. Enrolled subjects must also 
receive anticoagulation and/or antiplatelet medication during the index procedure in 
accordance with the IFU.  
 
Any medications should be recorded on the appropriate eCRF. 
 
7.5 Follow-up Procedures 
Subjects will be evaluated prior to discharge and through 30 days post-procedure. Subjects 
with an abnormal 30 Day DUS will be required to complete a repeat DUS at 60 days post-
procedure. All follow-up visit dates will be calculated based on a 30 day calendar.  
 
7.5.1 Post-Procedure through Hospital Discharge 
The subject may ambulate or be discharged when clinically stable, at the investigator’s 
discretion.  
 
The following information will be collected from procedure through hospital discharge: 
• 
Time-to-Ambulation, defined as elapsed time from final procedural sheath removal 
to time when the subject stands and walks at least 20 feet without re-bleeding 
• 
Time-to-Dischargeability, i.e., discharge eligibility defined as the elapsed time 
between procedural sheath removal and time when the subject is medically able to 
be discharged based solely on the assessment of the access site as determined 
by the investigator 
• 
Time-to-Discharge (i.e., time of actual discharge defined as the elapsed time 
between final procedural sheath removal and when the subject is actually 
discharged from the hospital) 
• 
Concomitant Medications (Anticoagulation / Antiplatelets Only) 
• 
Adverse Events  

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7.5.2 30 Day Follow-Up (30 ± 7 days) 
All subjects will be asked to return to the investigational site 30 days post-procedure. This 
visit will conclude the subject’s participation in the study unless the subject has an abnormal 
30 day DUS in which case the subject will return for a repeat DUS at 60 days post-
procedure. 
 
The following data will be collected:    
• 
Femoral Duplex Ultrasound (DUS) for assessment of groin/access site related 
complications (target limb only) 
• 
Targeted physical exam, including groin exam 
• 
Concomitant Medications (Anticoagulation / Antiplatelets Only) 
• 
Adverse Events  
 
7.5.3 60 Day Follow-Up (60 days ± 14 days) 
All subjects with an abnormal DUS at 30 days post-procedure will be asked to return to the 
investigational site at 60 days post-procedure to complete a repeat DUS.   
 
The following data will be collected:    
• 
Repeat DUS for assessment of groin/access site related complications (target limb 
only) 
• 
Targeted physical exam, including groin exam 
• 
Concomitant Medications (Anticoagulation / Antiplatelets Only) 
• 
Adverse Events  
 
7.5.4 Unscheduled Visit 
 
The unscheduled visit is designed to evaluate the ongoing safety of enrolled patients 
outside the protocol defined 30-day and/or 60-day visits.  
 
Patients with missed or incomplete in-person protocol defined visits due to the COVID-19 
pandemic will not be considered lost-to-follow-up/withdrawn by the Sponsor. Rather, the 
unscheduled visit can be used to reconsent the patient for this extended follow up to 

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evaluate their safety. The Interim follow up visit will be available for up to 12 months from 
the primary study index procedure and subjects should return as soon as reasonably 
possible unless the patient wishes to be withdrawn from the study. 
 
The following data will be collected during the unscheduled visit:    
• 
DUS for assessment of groin/access site related complications in target limb only (if 
not completed already or if repeat is needed (e.g., missed 30-day and/or 60-day 
visit)) 
• 
Targeted physical exam, including groin exam (if not completed already or if repeat 
is needed (e.g., missed 30-day and/or 60-day visit)) 
• 
Concomitant Medications (Anticoagulation / Antiplatelets Only) 
• 
Adverse Events  
 
If the patient will not or cannot return for an unscheduled visit, the study site should 
contact the patient via telephone to determine AEs and patient condition.  
 
7.6 Clinical Data Collection 
Information about subject demographics, eligibility requirements, procedure summary, 
concomitant mediations as well as any procedure complications and/or adverse events will 
be collected on eCRFs provided by the Sponsor. The eCRFs should accurately reflect data 
contained in the subject’s medical records (i.e. source documents). 
 
8 
Adverse Events 
The reporting and recording of adverse events is crucial to the evaluation of an 
investigational device, and to the development of labeling information that appears in the 
IFU. During a clinical study, the reporting of adverse experience information can lead to 
important design changes in the new device, as well as provide integral safety data. The 
investigator will monitor each subject for clinical and laboratory evidence of adverse events 
on a routine basis throughout the procedure.  
Subject safety will be monitored via the reporting of adverse events occurring from the time 
of enrollment through study completion. Any pre-existing condition known to the investigator 
will not be reportable as an adverse event unless that condition worsens during the study.   

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Where an adverse event has, by its nature, a prolonged course, the event will be considered 
a single event and not multiple events. For example, if a subject develops end-stage renal 
failure requiring regular dialysis, the event is considered as end stage renal failure, not 
multiple single renal events.   
 
The investigator is not obligated to actively seek adverse events from a subject once a 
subject has completed/exited the study. If the investigator learns of any adverse event at 
any time after a subject’s exit from the study, and there is a reasonable possibility that it is 
related to investigational device, the investigator should promptly report it to the Sponsor. 
 
8.1 Definitions 
An adverse event (AE) is defined as an unwanted medical occurrence in a subject. This 
definition does not imply that there is a relationship between the AE and the device 
under investigation. This can include, but is not limited to, a change in the subject’s 
health status from baseline that is related to the disease process, interventional 
procedures, investigational device, and/or side effects to medications.   
 
An adverse device effect is defined as those adverse events that are caused by, or 
related to, the investigational device. 
 
An unanticipated adverse device effect (UADE) is an adverse device effect that is not 
described in the study risk assessment or the informed consent.  “Any serious adverse 
effect on health or safety or any life-threatening problem or death caused by, or 
associated with, a device, if that effect, problem, or death was not previously identified 
in nature, severity, or degree of incidence in the investigational plan or application 
(including a supplementary plan or application), or any other unanticipated serious 
problem associated with a device that relates to the rights, safety, or welfare of subjects” 
(21 CFR 812.3(s)). 
A serious adverse event (SAE) is an adverse event that led to a death or led to a 
serious deterioration in the health of a subject that: 
1. Resulted in a life-threatening illness or injury, 
2. Resulted in a permanent impairment of a body structure or body function, 

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3. Required in-subject hospitalization or prolongation of existing 
hospitalization, 
4. Resulted in medical or surgical intervention to prevent impairment to body 
structure or a body function, or 
5. Led to fetal distress, fetal death or a congenital abnormality or birth 
defect.   
 
Each AE will be assessed by the investigator to determine whether it is serious or non-
serious.  (Note:  The term serious is not synonymous with severity, which is used to 
describe the intensity of an event experienced by the subject).   
 
A serious adverse device effect is an adverse event that is both serious and device 
related. 
 
8.2 Potential Adverse Events (AEs) 
Potential complications associated with the investigational device as with all other suture 
mediated closure devices may include, but are not limited to, the following:  
 
• 
Allergic reaction or hypersensitivity to device components  
• 
Anemia  
• 
Arterial stenosis/occlusion  
• 
Arteriovenous fistula  
• 
Bleeding/hemorrhage  
• 
Bruising  
• 
Death  
• 
Deep vein thrombosis  
• 
Device entrapment  
• 
Device failure/malfunction/misplacement  
• 
Diminished pulses distal to closure site  
• 
Embolism  
• 
Extended Hospitalization / Delayed time to ambulation  
• 
Hematoma 
• 
Infection/sepsis  

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• 
Inflammation  
• 
Intimal tear/dissection  
• 
Ischemia distal to closure site  
• 
Nerve injury  
• 
Numbness  
• 
Pain  
• 
Perforation  
• 
Pseudoaneurysm  
• 
Retroperitoneal hematoma/bleeding  
• 
Superficial vein thrombosis 
• 
Surgical exposure/closure of common femoral artery  
• 
Thrombus formation  
• 
Vascular injury  
• 
Vasovagal episode  
• 
Vasoconstriction/vasospasm  
• 
Wound dehiscence 
 
8.3 Follow-up of Adverse Events 
All adverse events observed from the time of enrollment throughout the duration of the study 
must be reported on the eCRF. All adverse events will be followed until resolution or 
stabilization of symptoms through study completion and/or the subject withdraws consent. 
Resolution means that the subject has returned to a baseline state of health. Stabilization 
means that the investigator does not expect any further improvement or worsening of the 
adverse event.   
 
8.4 Causality Rating 
The causal relationship of an adverse event to the investigational device will be rated as 
follows: 
 
Not Related:   An event for which an alternative explanation is conclusively identified - e.g., 
concomitant drug(s), concomitant disease(s), and/or the relationship in time suggests that a 
causal relationship is highly unlikely. 
 

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Possible:  An event that is unlikely due to the use of the investigational device. An 
alternative explanation - e.g., concomitant drug(s), concomitant disease(s) - is inconclusive. 
The relationship in time is reasonable; therefore, the causal relationship cannot be excluded. 
 
Probable:   An event that might be due to the use of the investigational device. An 
alternative explanation is less likely - e.g., concomitant drug(s), concomitant disease(s). The 
relationship in time is suggestive. 
 
Definitely:  An event that is due to the use of the investigational device. The event cannot be 
reasonably explained by an alternative explanation - e.g., concomitant drug(s), concomitant 
disease(s). 
 
8.5 Severity of Adverse Events 
The severity of an AE will be rated as follows: 
Mild 
An adverse event that is easily tolerated by the subject, causes minimal 
discomfort and does not interfere with everyday activities.  
Moderate 
An adverse event that is sufficiently discomforting to interfere with normal 
everyday activities; intervention may be needed. 
Severe 
An adverse event that prevents normal everyday activities; treatment or 
other intervention usually needed. 
 
 
8.6 Events Requiring Expedited Reporting 
Expedited Events refer to events that the site principal investigator should report to the 
CRO/Sponsor within twenty-four (24) hours of knowledge of the event. The appropriate 
eCRF and related documents should be completed in the data management system.  
 
If a non-serious AE becomes serious, this and other relevant follow-up information must 
also be reported using the appropriate eCRF. 
 
The Sponsor will immediately conduct an evaluation of any unanticipated adverse device 
effects (UADEs). If the effect is determined by the Sponsor to present an unreasonable risk 
to the subject, all investigations or parts of the investigation presenting that risk will be 

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terminated as soon as possible. Termination will occur not later than five working days after 
the Sponsor makes this determination, and not later than 15 working days after first 
receiving notice of the effect. 
 
The Sponsor will not resume an investigation terminated under these conditions without 
an additional IRB approval. 
 
8.6.1 Expedited Events include: 
1. 
Unanticipated Adverse Device Effects (as defined in section 8.1) will include 
events meeting either A or B as stated below: 
A. Events meeting ALL of the following criteria: 
• 
Not included in the list of Anticipated Events (refer to section 8.2) 
• 
Possible, probable, or definitely related to the investigational device per 
the site principal investigator 
• 
Serious (meets any of the following criteria): 
1. Resulted in a life-threatening illness or injury 
2. Resulted in a permanent* impairment of a body structure or body 
function 
3. Required in-patient hospitalization or prolongation of existing 
hospitalization 
4. Resulted in medical or surgical intervention to prevent impairment to 
body structure or a body function 
 *(Permanent means irreversible impairment or damage to a body structure or 
function, excluding trivial impairment or damage) 
B. Any other unanticipated serious problem associated with the investigational 
device that relates to the rights, safety, or welfare of subjects 
2. 
Device Failures as defined in Section 13 
3. 
Device Malfunctions as defined in Section 13 
4. 
User Errors:  A device is used by the investigator in a manner that is contrary 
to the IFU 
5. 
All Deaths 
 

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8.7 Clinical Events Committee (CEC) 
The CEC is composed of physicians who are interventional and/or non-interventional 
cardiologists, who are not participating in this study, and who do not have any investment 
with the study Sponsor. The CEC is charged with the review and classification of adverse 
events (AEs), including deaths. The CEC will establish rules outlining the minimum amount 
of data required and the algorithm followed in order to classify AEs. All members of the CEC 
will meet regularly to review and classify AEs. All appropriate data will be reviewed by the 
CEC. The CEC will forward a report of event reviews and classifications as outlined in the 
CEC charter. 
 
8.8 Data and Safety Monitoring Board (DSMB) 
The DSMB will be appointed to monitor the conduct of the study and subject safety by 
periodically reviewing data from the study. The DSMB will oversee the overall safety of 
current and future study subjects by protecting them from avoidable harm. The DSMB will 
review adverse events and other relevant study data and will recommend study termination 
if safety concerns warrant such action. The DSMB will also establish guideline criteria for 
recommending study termination, to the extent possible that the DSMB can predict adverse 
events or outcomes, before the proposed study begins. 
 
The DSMB will be an independent committee with no direct involvement in the day-to-day 
undertaking of the study and no investment in the Sponsor. DSMB members and activities 
may overlap with the CEC as appropriate. The DSMB will consist of physicians, including 
one chairperson and a statistician who will provide an independent review of the data. The 
physicians will include an interventional cardiologist and vascular surgeon experienced in 
vascular closure to ensure appropriate review of vascular complications in the study. The 
DSMB report will detail all serious and unexpected adverse events or other unanticipated 
problems that involve potential risk to future study participants. If the DSMB has concerns 
regarding the study, the DSMB will notify the Sponsor, who will provide the relevant 
summaries to local IRBs. Actions taken by any IRB in response to safety concerns will be 
reported to the DSMB.  
 

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The DSMB will meet periodically throughout the study in order to assure close and timely 
monitoring of adverse events and outcomes. The operational details of the DSMB will be 
determined early in the study and formalized in the DSMB Charter.  
The Sponsor and/or CRO will be responsible for working with the DSMB to ensure the 
DSMB Charter is developed. After the DSMB Charter has been finalized and approved by 
the DSMB, any changes or deviations to the plans in the charter will be documented in the 
minutes of the DSMB meetings.  
 
Reports will be prepared by the Sponsor and/or CRO as requested by the DSMB Chairman 
and as required per the charter. In addition to safety data, the reports may include 
recruitment and retention rates, interim analyses and other information as requested by the 
DSMB Chairperson. 
 
9 
Risk Assessment 
 
9.1 Risk Management Procedure 
Subjects will be monitored closely throughout the study duration. Risks will be further 
mitigated through selection of qualified physicians, appropriate training, and study 
monitoring ensured by the following: 
• 
Investigators who participate in the study will be experienced and skilled in 
endovascular techniques. Additionally, investigators, in conjunction with the 
investigational site, will have adequate resources for participation in a clinical 
study. 
• 
The study has been designed to ensure treatment and follow-up of subjects are 
consistent with current medical practice. 
• 
Each investigator will ensure oversight and approval of the study by their IRB prior to 
initiation of the clinical study at his/her investigational site. 
• 
The investigator and study personnel will be trained on the clinical protocol and IFU 
for the investigational device. 
• 
Subjects will be carefully evaluated against the eligibility criteria prior to entering the 
clinical study to ensure that their diagnosis and medical status are appropriate for 
participation. 

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• 
Subjects will be monitored throughout the follow-up period as defined in the study 
protocol. Subjects will have visits with the investigator or his/her designee to monitor 
the subjects’ status pre-procedure, intra-procedure, and post-procedure. 
• A DUS will be performed at 30 days post-procedure and repeated at 60 days if 
subject had an abnormal 30 day ultrasound to ensure adequate evaluation of the 
target limb access site. 
 
9.2 Potential Benefits 
Subjects enrolled in this clinical study will be monitored closely throughout the study and 
have regular assessments according to the investigator’s standards of care. The data 
collected during the clinical study will provide further understanding how the Cross-SealTM 
System is clinically beneficial. Potential benefits may include: 
• 
Reduced Time-to-Ambulation (TTA) 
• 
Reduced Time-to-Hemostasis (TTH) 
• 
Improved quality of life 
 
10 Centers for Medicare and Medicaid Services (CMS) Reimbursement 
The Sponsor will seek applicable Medicare coverage in compliance with CMS requirements 
for this study. Based on the target study population including mean age, approximately 
70% of subjects enrolled in this study will utilize CMS/Medicare reimbursement during their 
participation.   
 
The study will be conducted in compliance with all applicable Federal regulations concerning 
the protection of human subjects found at 21 CFR parts 50, 56, and 812, and 45 CFR part 
46. In addition, the study will be registered with the National Institutes of Health National 
Library of Medicine’s ClinicalTrials.gov.  
 
The Sponsor has a legal responsibility to the regulatory authorities to fully report all results 
of sponsored clinical studies. No investigational procedures other than those in this protocol 
shall be undertaken. The sponsor intends to submit a formal report to FDA following 
completion of the last subject visit required for primary endpoint analysis. Should the study 
be terminated early, the Sponsor will make every effort to expedite reporting of study 

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results to the FDA database for public review. Any use of the investigational device by an 
investigator that is contradictory to the application described in the IFU will be categorized 
as device misuse. 
 
11 Monitoring 
The Sponsor will perform monitoring functions within this clinical study and may be 
delegated to a CRO designate as needed. Study monitors will work in accordance with 
standard operating procedures (SOPs) and the approved Monitoring Plan. Any CRO 
monitors have the same rights and responsibilities as monitors from the Sponsor 
organization.  
 
At the site, monitors will perform and verify the following: 
• 
The adequacy and experience of the study center including Sponsor notification of 
any problems relating to facilities, technical equipment or medical staff 
• 
Written Informed Consent has been obtained from all subjects prior to any study 
related procedures being performed and that data is recorded correctly and 
completely 
• 
Source Document Verification (SDV):  comparing data in the eCRFs to ensure they 
correspond with applicable source data, and to inform the Sponsor and investigator 
of any discrepancies, errors or omissions 
• 
Ensure adherence to the protocol and applicable regulations at the investigational 
site and notify the Sponsor promptly of any deviations  
• 
Evaluate subject compliance and support subject retention efforts at the site 
• 
Device accountability and appropriate storage conditions are maintained according 
to the IFU   
 
Data will be collected using eCRFs for this study. Investigative sites will enter data directly 
into the eCRFs via a web-based system. A Sponsor representative will provide training and 
technical assistance to the investigator and site staff on the procedural application, intended 
use, and performance characteristics of the investigational device. In addition, a Sponsor 
representative will schedule periodic, on-site visits to observe clinical procedures, under 

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supervision of the investigator, and to answer questions or concerns regarding the 
investigational device. 
 
Given that on-site monitoring at some trial locations may be impacted due to the COVID-19 
pandemic, the Sponsor has implemented both central and remote monitoring to maintain 
oversight of the clinical study and sites. This includes, but is not limited to, telephone and/or 
email contacts with the sites (to review study procedures, trial participant status, and study 
progress), remote review of de-identified source, remote access to electronic medical 
records (EMR), and frequent eCRF reviews. Given the ongoing and unpredictable nature of 
the COVID-19 pandemic, individual site variability on permitting remote EMR and/or the 
transmission of de-identified source, as well as continually changing local and state 
mandates governing travel, the Sponsor may have to adapt its monitoring processes 
regularly to fulfill its obligations as a Sponsor under federal law and regulations. The 
Sponsor will continuously assess each site and will monitor study data at the earliest 
possible opportunity, either in person or remotely. 
 
12 Image Analysis 
Duplex Ultrasound (DUS) of the femoral artery will be obtained at 30 days post-procedure 
(target limb only). In the instance of an abnormal DUS at 30 days, the subject will be 
required to conduct a repeat DUS at 60 days post-procedure.  
 
All Duplex Ultrasound images obtained during the study will be anonymized and sent to a 
central core laboratory for independent analysis.  
 
13  Device Failure and Malfunction 
A device failure has occurred when the device is used in accordance with the IFU, but does 
not perform as described in the IFU, and also negatively impacts treatment of the study 
subject. Device Failures may include the following:   
• 
Device used in study subject resulting in the occurrence of a major complication 
• 
Unable to use RESET 1 Button 
• 
Unable to deploy PLUNGER on device 
• 
Unable to use RESET 2 Button 

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A device malfunction occurs when the device is used in accordance with the IFU and an 
unexpected change to the device contradictory to the IFU is observed, which may or may 
not affect device performance. Device Malfunctions may include the following: 
• 
Device(s) with which insertion attempts were made, but was not used in the 
subject. 
• 
Unable to observe bleeding back after sufficient dissection is performed 
• 
Unable to deploy slider of Cross-SealTM Device 
• 
Needle dislodged after device deployment 
• 
Unable to cut suture with Suture Trimmer 
• 
Device is damaged in packaging  
• 
Issues with use of Knot Tyer and/or Knot Pusher 
• 
Suture break during device, Knot Tyer and/or Knot Pusher use 
• 
Device packaging issue 
• 
Device Sterility issue 
 
Device malfunctions occurring in roll-in subjects will be additionally evaluated  for potential 
relationship with the learning curve of the investigational device (e.g., operator applies 
excess tension to suture during pre-closure causing break) 
 
In the case where a device has malfunctioned/failed, the investigator must make every 
possible effort to return the device to the Sponsor, unless there is a known contamination 
with an infectious disease (i.e. Hepatitis B, C or HIV).  
 
14 Statistical Methods  
14.1 Sample Size Determination 
The sample size calculations were performed using PASS 2020 Version 20.0.2iii.  The 
appendix included the output from the software.  The sample size for the study is based 
on power considerations for the primary effectiveness endpoint. As will be described 
below, this sample size should also provide adequate power for the primary safety 
endpoint. 

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14.1.1 Primary Efficacy Endpoint 
The primary effectiveness hypothesis will be tested by comparing the primary 
effectiveness endpoint, mean time-to-hemostasis (TTH), against a performance goal 
(PG) of 15 minutes. 
The comparison to the performance goal will be based on the following statistical 
hypothesis test: 
𝐻𝑂: 𝜇𝑇𝑇𝐻   ≥ 15 
𝐻𝐴: 𝜇𝑇𝑇𝐻   < 15 
where 𝜇𝑇𝑇𝐻is the mean time-to-hemostasis in minutes. 
The test will be based on whether the upper one-sided 97.5% confidence limit (based on 
a t-distribution)iv is less than 15. Assuming similar performance to Perclose ProGlide®, 
with a mean time-to-hemostasis of 9.8 minutes and a standard deviation of 17 minutes 
the sample sizes for power levels from 80 to 90% 
a Table 3: Primary Efficacy Endpoint Sample Sizes for Various levels of Power 
Power 
Sample Size 
Maximum Observed Time 
(minutes) and still reject H0 
80.0% 
86 
10.8 
81.4% 
89 
10.9 
82.3% 
91 
10.9 
83.1% 
93 
10.9 
84.3% 
96 
11.0 
85.0% 
98 
11.1 
Successful rejection of the null hypothesis will mean that the PG has been met. 
 

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14.1.1.1 
Development of the Performance Goal 
The PG was derived from literature for the Perclose ProGlide® (Abbott Vascular, Inc., 
Redwood City, CA, USA), a suture-mediated device indicated for the closure of large 
arterial access sites. 
14.1.2 Primary Safety Endpoint 
The primary safety hypothesis will be tested by comparing the primary safety endpoint, 
freedom from major complications of the target limb access site within 30 days post-
procedure, against a performance goal.   
The comparison to the performance goal will be based on the following statistical 
hypothesis test: 
𝐻𝑂: 𝑝 ≤ 85.2% 
𝐻𝐴: 𝑝 > 85.2% 
where p is the safety endpoint rate for the test device. 
Assuming similar performance as ProGlide (an event-free rate of 94%), one-sided alpha 
= 0.05, the sample sizes for various levels of power are: 
Table 4: Primary Safety Endpoint Sample Sizes for Various levels of Power 
Power 
Sample Size 
Minimum # of Event Free 
Patients needed to reject the 
H0 
81.3% 
78 
72 
85.6% 
86 
79 
88.3% 
95 
87 
 
14.1.2.1 Development of the Performance Goal 
The observed rate of major complications for ProGlide was 6% (3/50), with a one-sided 
exact binomial upper 95% confidence bound of 14.8%. In terms of an event-free rate, 
these quantities are mathematically equivalent to an observed event-free rate of 94% 

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with a lower confidence bound of 85.2%. Accordingly, for the current study, a value of 
85.2% is proposed for a performance goal for the primary safety endpoint based on the 
event-free rate. 
14.2 Statistical Analyses 
 
14.2.1 General Considerations 
Except where otherwise specified, the following general principles apply to the planned 
statistical analyses. All statistical analyses will be conducted using {SAS version 9.3 or 
later (SAS Institute Inc., Cary, NC)} or other widely accepted statistical or graphical 
software as required. 
14.2.1.1 Descriptive Statistics 
Continuous data will be summarized with mean, standard deviation, median, minimum, 
maximum, and number of evaluable observations. Categorical variables will be 
summarized with frequency counts and percentages. Confidence intervals may be 
presented, where appropriate, using the t-distribution for continuous data and exact 
binomial method for categorical variables. 
14.2.1.2 Study Visit 
Study visit Day 0 is the date of the index procedure. Day in the study will be calculated 
relative to the index procedure as follows: 
Study Day = Assessment Date – Index Procedure Date 
Each subject duration in the study will be based on the last study contact date, which is 
the latest date of all follow-up visits, assessments, adverse event onset or resolution, 
and study exit, including date of death. 
Duration will be calculated as follows: Duration Days = Start Date – End Date 
14.2.1.3 Visit Windows 
Unless otherwise specified, visit assessments will be analyzed for each analysis time 
point according to the visit entered in the electronic Case Report Form (eCRF). 
14.2.1.4 Statistical Significance 
Unless otherwise specified, hypothesis testing will be performed at the two-sided 0.05 
significance level. P-values will be rounded to three decimal places. If a p-value is less 

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than 0.001 will be reported as "<0.001". If a p-value is greater than 0.999, it will be 
reported as ">0.999". 
14.2.1.5 Reporting Precision 
Unless otherwise specified, the following conventions will apply for data display. In 
general, percentages will be displayed to 1 decimal place. Percentages <0.05% will be 
reported to 2 decimal places. For continuous parameters, means and medians will be 
reported to 1 additional decimal place than the measured value. In contrast, the standard 
deviation will be reported to 2 additional decimal places than the measured value. 
Minimum and maximum values will be reported to the same precision as the measured 
value. 
14.2.2 Analysis Populations 
14.2.2.1 Full Analysis Set 
The full analysis set (FAS) as defined by the ICH E9v as "The set of subjects that is as 
close as possible to the ideal implied by the intention-to-treat principle." The guideline 
also defined the Intention-To-Treat Principle as the effect of a treatment policy can be 
best assessed by evaluating based on the intention to treat a subject (i.e., the planned 
treatment regimen) rather than the actual treatment given.  Therefore, the FAS includes 
all patients that were consented, enrolled, and met the inclusion/exclusion criteria. 
14.2.2.2 Per-Protocol Analysis Set 
The protocol definition of the TTH endpoint includes only those patients that received the 
test device and did not have adjunctive therapy other than light compression applied to 
the access site manually, with a dressing, or as per the investigator's standard procedure 
for suture-mediated closure devices.  Therefore, the per-protocol analysis set (PPS) 
includes those patients in the FAS where the patient received the test device and did not 
have adjunctive therapy other than light compression.  
14.2.2.3 Full Roll-In Analysis Set 
The full roll-in analysis set (FAS_RI) are those patients that meet the same criteria as the 
FAS but are identified as roll-in patients. 
14.2.2.4 Per-Protocol Roll-In Analysis Set 
The per-protocol roll-in analysis(PPS_RI) set are those patients that meet the same 
criteria as the PPS but are identified as roll-in patients. 

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14.2.2.5 Efficacy Analysis Set 
Due to the challenges during the pandemic, the number of patients in a non-missing 
primary efficacy endpoint may drop below the lowest accepted power (80%) for approval 
trial design (< 86 patients).  If the number of patients in the PPS is <= 86, the efficacy 
analysis set will include the patients in the PPS and the last 18 sequentially enrolled 
patients from the PPS_RI.  If the number of patients in the PPS is > 86, then the efficacy 
analysis set will only include PPS patients. 
14.2.2.6 Safety Analysis Set 
Due to the challenges during the pandemic, the number of patients in a non-missing 
primary safety endpoint may drop below the lowest accepted power (80%) for approval 
trial design (< 78 patients). If the number of patients in the FAS is <= 78, the safety 
analysis set will include the patients in the FAS and the last 18 sequentially enrolled 
patients from the FAS_RI.  If the number of patients in the FAS is > 78, then the safety 
analysis set will only include FAS patients. 
14.2.3 Poolability Analyses 
All investigational sites will follow the requirements of a common protocol and 
standardized data collection procedures and forms. The primary endpoints will be 
presented separately (major and minor complications will be presented separately for the 
primary safety endpoint) for each site using descriptive statistics. Poolability of the 
primary endpoints across the investigational site will be evaluated using a regression 
model with fixed effects for the site using the FAS for the primary safety endpoint and 
PPS for primary efficacy endpoint. Sites enrolling less than five subjects will be 
combined with the geographically nearest site. If the p-value for the site effect is <0.15, 
additional exploratory analyses will be performed to understand any variations in 
outcomes by site. 
14.2.4 Handling of Missing Data 
All attempts will be made to limit the amount of missing data. For all analyses of the 
primary endpoints, the number of observations available, patients with no primary safety 
endpoint information, and patients with imputed results will be reported so the reader can 
assess the impact of missing data. 

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14.2.5 Imputation for Endpoints 
Due to the challenges related to the COVID-19 pandemic faced during the enrollment, 
some 30-day follow-up visits were outside of the protocol specified window.  Therefore, 
for those patients whose 30-day visit was outside the window, the primary safety 
endpoint will be imputed based on the on visits that occurred at a minimum of 23 days 
post-discharge and is the closest to the 30-day visit. If there were no post-discharge 
visits, the primary safety endpoint will be imputed based on the site contacting the 
patient by phone as well as reviewing their records to determine the patient's primary 
safety endpoint status at 30 days. If even that information is not available, then the 
patient will be considered as missing the primary safety endpoint data. 
14.2.6 Sensitivity Analyses 
Sensitivity analyses will be performed to assess the impact of missing data for the 
primary safety endpoint; a tipping point analysis will be conducted in which subjects 
censored without a 30 days follow-up visit are sequentially imputed as failures at the 
time of censoring. The primary safety endpoint analysis will be repeated after each 
sequentially imputed failure. 
Sensitivity analyses will be performed to assess the impact of missing data for the 
primary efficacy endpoint; a tipping point analysis will be conducted in which subjects 
without a TTH are sequentially imputed as 15 minutes (the performance goal). The 
primary efficacy endpoint analysis will be repeated after each sequentially imputed 
value. 
14.2.7 Imputation for Dates 
More generally, in the case of partial adverse event onset date or date of death, the 
unknown portion of the date of the event will be imputed. If the month and year are 
known, the 15th of the month will be used for analysis. If only the year is known, the 
event will be analyzed as if it occurred on June 30th of the known year. In the rare case 
that the date is fully unknown, the date will be imputed as the index procedure date. 
Imputation of partial dates is subject to the condition that it must occur on or after the 
index procedure date. In the case where the imputed date is before the index procedure 
date, the date of the index procedure will be used. As death cannot occur before any 
documented subject contact, for date of death, the imputed date of death must occur on 

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or after the last known contact in the study. 
14.2.8 Subject Disposition 
Subjects who are screened and signed an informed consent form, but do not meet all 
protocol eligibility criteria (i.e., screening failure), will be excluded from the statistical 
analyses. These subjects will be summarized in a subject accountability table only. 
Subject accountability will be summarized by visit for those in the FAS.  The number of 
subjects who are enrolled, eligible for follow-up, and number completing clinical follow-up 
will be summarized for each protocol-required visit. 
14.2.9 Demographics and Baseline Characteristics 
Descriptive statistics will be presented for clinically relevant baseline demographic, 
medical history, and clinical characteristic variables. 
14.2.10 Analysis of Study Endpoints 
Study success is defined as the successful rejection of the corresponding null 
hypotheses for each of the primary safety and effectiveness endpoints. 
14.2.10.1 Primary Efficacy Endpoint 
The primary efficacy endpoint will be evaluated using the using the efficacy analysis set.  
The mean and standard error will be reported for the primary efficacy endpoint.  A one-
sample t-distribution will be used for calculating the upper 97.5% confidence limit.   
14.2.10.1.1 Sensitivity Analyses 
There will be three sensitivity analyses: 
1. The primary efficacy endpoint analysis will be repeated with the PPS patients only if 
PPS_RI patients are added to the efficacy analysis set 
2. Tipping analysis based on missing data in the efficacy analysis set as described in 
section 14.2.6 
3. The primary efficacy endpoint analysis will be repeated with the PPS_RI and the 
efficacy analysis set combined. 
14.2.10.2 Primary Safety Analysis 
The primary safety endpoint will be evaluated using the FAS or the safety analysis set if 
roll-ins are needed.  The endpoint will be presented as the proportion of subjects with 

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freedom from primary safety endpoint and the lower 95% confidence limit using the 
Clopper-Pearson exact methodvi.  If the one-sided 95% confidence limit is greater than 
85.2%, then the device will have met the performance goal for safety. 
14.2.10.2.1 
Sensitivity Analyses 
There will be three sensitivity analyses: 
1. The primary safety endpoint analysis will be repeated with the FAS patients only if 
FAS_RI patients are added to the safety analysis set 
2. Tipping analysis based on missing data in the safety analysis set, as described in 
section 14.2.6. 
3. The primary efficacy endpoint analysis will be repeated with the FAS_RI and the 
safety analysis set combined. 
14.2.10.3 Secondary Endpoints  
No formal hypothesis tests for the secondary and exploratory endpoints will be 
performed; endpoints will be summarized using the FAS with descriptive statistics. 
14.2.11 
Subgroup Analyses 
Subgroup analysis of the primary safety (major and minor complications analyzed 
separately) and efficacy endpoints will be performed for the following subgroups: gender, 
age (Age<65, Age≥65), and race (white vs. non-white). These analyses are intended to 
assess the consistency of results across subgroups. 
Subgroup analyses will be performed using the efficacy analysis set for the primary 
efficacy endpoint and the safety analysis set for the primary safety endpoint. For each 
subgroup, a regression model will be fit that includes fixed effects for subgroup 
membership.  
14.2.12 
Interim Analyses 
There are no formal plans for interim analyses for the purposes of early stopping for 
effectiveness or sample size adjustments. Interim safety reports will be performed as 
requested by the DSMB Charter. Unless otherwise specified, methods for such reports 
may follow those outlined in this document. 

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14.2.13 
Protocol Deviations 
Investigational sites will report deviations from the procedures outlined in the CIP on the 
eCRF. Protocol deviations will be summarized for all deviations and by type with event 
counts and number of subjects with at least one deviation. 
14.2.14 
Additional Changes to Planned Analyses 
Any additional changes to planned statistical analyses determined necessary before 
performing the analyses will be documented in an amended Statistical Analysis Plan 
Version 1.4 and approved before the analysis when possible. Any other deviations or 
changes from the planned analyses deemed necessary due to violation of critical 
underlying statistical assumptions, data characteristics, or missing data will be clearly 
described in the clinical study report with justification and rationale. 
15 Reporting 
A final integrated clinical/statistical report will be prepared and provided to the FDA for the 
purposes of fulfilling the requirements of the IDE and PMA submission.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 1 References 
 
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429–435. 

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14. Dencker D, Taudorf, M, Luk V, et al. Frequency and effect of access-related vascular injury 
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device closure. Catheter Cardiovasc Interv. 2015 Dec 1;86(7):1255-61. 

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27. Thomas C, Steger V, Heller S, et al. Safety and Efficacy of the Prostar XL Vascular Closing 
Device for Percutaneous Closure of Large Arterial Access Sites. Radiol. Res. Pract. 
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28. Kodama A, Yamamoto M, Shimura T, et al. Comparative data of single versus double 
proglide vascular preclose technique after percutaneous transfemoral transcatheter aortic valve 
implantation from the optimized catheter valvular intervention (OCEAN-TAVI) japanese 
multicenter registry. Catheter Cardiovasc Interv. 2016 Oct 27. doi: 10.1002/ccd.26686. 
29. Pratesi G, Barbante M, Pulli R, et al. Italian Percutaneous EVAR (IPER) Registry: outcomes 
of 2381 percutaneous femoral access sites' closure for aortic stent-graft. J Cardiovasc Surg 
(Torino). 2015 Dec;56(6):889-98. 
30. van Dorp M, Ruyssers M, Amajoud Z, et al. Preclose Percutaneous Endurant™ Endografting 
with the Proglide™ Device: a Safe and Feasible Combination. Acta Chir Belg. 2015 May-
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31. Ichihashi T, Ito T, Kinoshita Y, et al. Safety and utility of total percutaneous endovascular 
aortic repair with a single Perclose ProGlide closure device. J Vasc Surg. 2016 Mar;63(3):585-8. 
32. Griese DP, Reents W, Diegeler A, et al. Simple, effective and safe vascular access 
siteclosure with the double-ProGlide preclose technique in 162 patients receiving transfemoral 
transcatheter aortic valve implantation. Catheter Cardiovasc Interv. 2013 Nov 1;82(5):E734- 
33. Hu G, Chen B, Fu W, et al. Predictors and Treatments of Proglide-Related Complications in 
Percutaneous Endovascular Aortic Repair. PLoS ONE 2015 10(4):e0123739. doi:10.1371. 
34. Rijkée MP, Statius van Eps RG, Wever JJ, et al. Predictors of Failure of Closure in 
Percutaneous EVAR Using the Prostar XL Percutaneous Vascular Surgery Device. Eur J Vasc 
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35. Vidi VD MM et al. Vascular Closure Device Failure in Contemporary Practice. JACC. 
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36. PASS 14 Power Analysis and Sample Size Software (2015). NCSS, LLC Kaysville, Utah, 
USA. ncss.com/software/pass. 
 
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iii PASS 2020 Power Analysis and Sample Size Software (2020). 
NCSS, LLC. Kaysville, Utah, USA, ncss.com/software/pass. 
 

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iv Dawson, B., & Trapp, R. G. (2004). Basic & clinical 
biostatistics (4th ed.). New York: Lange Medical Books-McGraw-
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(1998), ICH Harmonised Tripartite Guideline Statistical 
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vi Clopper, C.; Pearson, E. S. (1934). The use of confidence or 
fiducial limits illustrated in the case of the binomial. 
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