Investigator Initiated Safety Study Using the Venclose Vestico (Commercial Name TBD) Radiofrequency (RF) Ablation System for the Treatment of Incompetent Perforator Veins (IPVs)
Phase: NA
Conditions: Chronic Venous Insufficiency
Sponsor: Venclose, Inc.

 
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INVESTIGATION PLAN 
 
Investigator Initiated Safety Study Using the Venclose 
Vestico (commercial name TBD) Radiofrequency (RF) 
Ablation System for the Treatment of Incompetent 
Perforator Veins (IPVs) 
 
Protocol No.: CL-VAV-001 
Principal Investigator:  Jeffrey G. Carr, MD 
Sponsor: Venclose, Inc. 
2570 N. First Street 
2nd Floor, #221 
San Jose, CA. 95131 
 
Version Number:  4.0 
14-April-2020 
STATEMENT OF COMPLIANCE 
The study will be conducted in accordance with the International Conference on Harmonization 
guidelines for Good Clinical Practice (ICH E6) and the Code of Federal Regulations on the 
Protection of Human Subjects (45 CFR Part 46). All personnel involved in the conduct of this 
study have completed Good Clinical Practice (GCP).  
 
 
NCT04386785

 
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Reference Documents 
 
Investigational Device Exemptions (IDEs) for Early Feasibility Medical Device Clinical 
Studies, Including First in Human (FIH) Studies, Guidance for Industry and Food and 
Drug Administration Staff, October 1, 2013. 
 
Guidance for Industry, E9 Statistical Principles for Clinical Trials, FDA, 1998. 
 
Draft Guidance for Clinical Trial Sponsors, On the Establishment and Operation of 
Clinical Trial Data Monitoring Committees, FDA, 2001. 
 
Clinical Investigation of Medical Devices for Human Subjects – Good Clinical Practice 
ISO 14155:2011). 
 
ICH GCP E6. 
 
U.S. CFR Title 21 Parts 50 and 56 and CFR Title 45 Part 46.  
 
U.S. 21 CFR 812.25 and 812.27 
 
Guidance for Industry and Food and Drug Administration Staff, Collection of Race and 
Ethnicity Data in Clinical Trials, FDA, October 26, 2016 
 
Guidance for Industry and Food and Drug Administration Staff, Evaluation and 
Reporting of Age-, Race-, and Ethnicity-Specific Data in Medical Device Clinical 
Studies, FDA, September 12, 2017 
 
 

 
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PROTOCOL SIGNATURE PAGE 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and ICH guidelines. 
Principal Investigator and Sponsor’s Point of Contact: 
Signed: 
Signature on File 
Date: 
 
 
Name: Dr. Jeffrey G. Carr 
 
Title: 
Principal Investigator 
Signed: 
Signature on File 
Date: 
 
 
Name: Arthur Macaraeg 
 
Title: 
Sponsor Representative 
 
Venclose, Inc. 
 
. 
 

 
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TABLE OF CONTENTS 
 
PAGE 
STATEMENT OF COMPLIANCE ................................................................................................ 1 
PROTOCOL SIGNATURE PAGE ............................................................................................... 3 
TABLE OF CONTENTS .............................................................................................................. 4 
LIST OF ABBREVIATIONS ......................................................................................................... 6 
SECTION 3 – INVESTIGATION PLAN ....................................................................................... 7 
CLINICAL PROTOCOL SUMMARY ............................................................................................ 7 
1 
KEY ROLES AND CONTACT INFORMATION ................................................................. 11 
2 
INTRODUCTION .............................................................................................................. 12 
2.1 
Background Information ........................................................................................ 12 
2.2 
Study Outline ........................................................................................................ 13 
 
Device Name ............................................................................................. 13 
 
Intended Use ............................................................................................. 13 
 
Indication for Use ...................................................................................... 13 
 
Device Description .................................................................................... 13 
2.3 
Potential Risks and Benefits ................................................................................. 15 
 
Potential Risks .......................................................................................... 16 
 
Potential Benefits to Subjects .................................................................... 18 
 
Alternatives to Participation ....................................................................... 18 
CLINICAL PROTOCOL ............................................................................................................. 20 
3 
OBJECTIVES ................................................................................................................... 21 
3.1 
Study Objectives and Outcome Measures ............................................................ 21 
3.2 
Overview ............................................................................................................... 22 
4 
STUDY ENROLLMENT AND WITHDRAWAL .................................................................. 24 
4.1 
Subject Inclusion Criteria ...................................................................................... 24 
4.2 
Subject Exclusion Criteria ..................................................................................... 24 
4.3 
Strategies for Recruitment and Retention ............................................................. 25 
4.4 
Subject Withdrawal ............................................................................................... 25 
 
Reasons for Withdrawal ............................................................................ 25 
 
Handling of Subject Withdrawals or Subject Discontinuation of Study 
Intervention ............................................................................................... 25 
4.5 
Premature Termination or Suspension of Study .................................................... 26 
5 
STUDY INTERVENTION .................................................................................................. 27 
5.1 
Concomitant Medications/Treatments ................................................................... 27 
5.2 
Administration of Intervention ................................................................................ 27 
5.3 
Accountability Procedures for the Study Product .................................................. 27 
 
Deficient Product ....................................................................................... 27 
5.4 
Procedures for Training Investigators and Study Monitoring ................................. 27 
6 
STUDY PROCEDURES ................................................................................................... 29 
6.1 
Subject Recruitment.............................................................................................. 29 
6.2 
Informed Consent ................................................................................................. 29 
6.3 
Costs to Subjects and Payment for Participation ................................................... 29 
6.4 
Consultation / Enrollment ...................................................................................... 29 

 
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6.5 
Baseline / Intervention .......................................................................................... 30 
6.6 
3-day Post-Intervention Safety Assessment .......................................................... 30 
6.7 
15-day Post-Intervention Safety Assessment ........................................................ 30 
6.9 
Withdrawal Visit .................................................................................................... 31 
6.10 
Unscheduled Visit ................................................................................................. 31 
7 
STUDY SITE SELECTION ............................................................................................... 32 
7.1 
Site Selection ........................................................................................................ 32 
8 
ASSESSMENT OF SAFETY ............................................................................................ 33 
8.1 
Reporting Procedures ........................................................................................... 33 
 
Reportable Events and Unanticipated Problems, Reporting to IRB ........... 33 
8.2 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 34 
9 
STUDY OVERSIGHT ....................................................................................................... 35 
10 
CLINICAL SITE MONITORING ........................................................................................ 36 
11 
ANALYTICAL METHODS ................................................................................................. 37 
11.1 
Data Analysis ........................................................................................................ 37 
11.2 
Lost to Follow-up .................................................................................................. 37 
11.3 
Sample Size Estimate ........................................................................................... 37 
12 
QUALITY CONTROL (QC) AND QUALITY ASSURANCE (QA) PROCEDURES ............. 39 
12.1 
Quality Management System ................................................................................ 39 
12.2 
Clinical Quality ...................................................................................................... 39 
12.3 
Study Conduct and Agreements ........................................................................... 39 
12.4 
Quality Control ...................................................................................................... 39 
12.5 
Essential Documents ............................................................................................ 40 
12.6 
Study Data ............................................................................................................ 40 
13 
ETHICS/PROTECTION OF HUMAN SUBJECTS ............................................................. 41 
13.1 
Ethical Standard ................................................................................................... 41 
13.2 
Institutional Review Board (IRB) ........................................................................... 41 
13.3 
Informed Consent Process ................................................................................... 41 
13.4 
Exclusion of Women, Minorities, and Children (Special Populations) .................... 41 
13.5 
Subject Confidentiality .......................................................................................... 41 
14 
DATA HANDLING AND RECORD RETENTION / KEEPING ............................................ 43 
14.1 
Data Management Responsibilities ....................................................................... 43 
14.2 
Data Capture Methods .......................................................................................... 43 
14.3 
Study Records Retention ...................................................................................... 43 
14.4 
Protocol Deviations ............................................................................................... 44 
15 
PUBLICATION / DATA SHARING .................................................................................... 45 
APPENDIX A:  TRAINING GUIDE AND CHECKLIST ............................................................... 46 
APPENDIX B:  INFORMED CONSENT FORM ......................................................................... 46 
 
 
 
 

 
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LIST OF ABBREVIATIONS 
Term 
Explanation 
ABI 
Ankle-Brachial Index 
BMI 
Body Mass Index 
CEAP 
Clinical-Etiology-Anatomy-Pathophysiology classification 
CFR 
Code of Federal Regulations 
CVI 
Chronic Venous Insufficiency  
DUS 
Duplex Ultrasound 
DVT 
Deep Venous Thrombosis 
EC 
Ethics Committee 
GCP 
Good Clinical Practices 
GSV 
Great Saphenous Vein 
IPV 
Incompetent Perforator Vein 
IV 
Intravenous 
PI 
Perforator Incompetency 
PV 
Perforator Vein 
RF 
Radiofrequency 
RFA 
Radiofrequency Ablation  
SEPS 
Subfascial Endoscopic Perforating Vein Surgery 
SFJ 
Sapheno-Femoral Junction 
SPJ 
Sapheno-Popliteal Junction 
 
 
 

 
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Section 3 – INVESTIGATION PLAN 
CLINICAL PROTOCOL SUMMARY 
Title: 
Investigator Initiated Safety Study Using the Venclose 
Vestico (commercial name TBD) Radiofrequency (RF) 
Ablation System for the Treatment of Incompetent Perforator 
Veins (IPVs) 
Synopsis: 
An Investigator Initiated study  conducted to evaluate the safety of 
the Venclose digiRF Generator with Vestico Catheter System 
(“Vestico”) treating incompetent perforator veins (IPVs).  The 
study will be conducted in compliance with IDE requirements 
under local IRB approval(s). Study data will be summarized and 
submitted to FDA in a premarket notification once all subjects 
have completed 30-day follow-up.  
Venclose’s venous ablation technology is already cleared by FDA 
for use in treating chronic venous insufficiency, especially treating 
saphenous and branching veins, and has been in clinical practice 
since 2017 with extremely low adverse events.  The study’s 
working hypothesis is that using the Venclose Vestico Catheter 
System will safely treat incompetent perforator veins (IPVs) 
without resulting in any adverse outcomes related to use of the 
device.  
A physician with extensive clinical background and experience in 
treating vascular and venous diseases and a medical license to 
practice in the United States will use the Vestico device to treat a 
minimum of 30 IPVs on at least twenty (≥ 20) and a maximum of 
thirty (≤ 30) subjects. 
Description of 
Intervention: 
Following informed consent, the physician operator will gain 
access to the IPV in the leg using ultrasound guidance. The 
Vestico device will be inserted into the vein lumen also with 
ultrasound imaging guidance and the target treatment position 
confirmed. After providing local anesthesia to the vein and 
surrounding tissues, the Vestico device will be activated to deliver 
the thermal ablation energy to the vessel.  Once the treatment 
cycle has been completed the device will be withdrawn and 
closure confirmed with duplex ultrasound. A bandage and  
compression hose will be applied. The patient will then 
immediately ambulate.             
Number of Sites: 
Single Site 
Objectives: 
1) The study’s working hypothesis is that using the Venclose 
Vestico Catheter System for treating incompetent perforator 
veins (IPVs) will not result in significant adverse outcomes 
related to use of the device. 

 
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2) The study will be conducted in compliance with IDE 
requirements and labeling (21 CFR 812.2(b)) under local IRB 
approval(s). 
 
3) Multiple limbs and IPVs may be treated. All IPVs treated will 
be followed according to the study schedule. 
Population: 
At least twenty (≥ 20) and a maximum of thirty (≤ 30) ambulatory 
subjects diagnosed with Incompetent Perforator Veins (IPVs) who 
meet the inclusion and exclusion criteria, both males and females 
over the age of 18, will be enrolled at one clinic.  
Primary Endpoints: 
1) Safety - Procedure related adverse events (AE), serious 
adverse events (SAE), adverse device effects (ADE), serious 
adverse device effects (SADE) and unanticipated adverse 
device effects (UADE) will be monitored 3 days, 15 days (+/- 3 
days), and 30 days (+/- 3 days) post-procedure and analyzed 
for acceptability post study . 
 
Monitored events include: 
 
Edema 
 
Skin changes 
 
Venous ulcers 
 
Deep vein thrombosis 
 
Superficial vein thrombosis 
 
Pulmonary embolism 
 
Venous thromboembolism 
 
Skin burn 
 
Thermal injury of adjacent tissues 
 
Paresthesia 
 
Infection/cellulitis 
 
AV Fistula 
 
Need for re-operation 
 
Death 
2) Effectiveness - Technical success, defined as successful 
access and entry into the IPV to be ablated and the ability to 
deliver the intended energy to the target vein segment, will be 
evaluated. 
Secondary Endpoints: 
1) The acute ablation success endpoint is defined as complete 
lack of flow or IPV disappearance in the treated segment 
(vessel occlusion).  Success will be measured by Duplex 
Ultrasound imaging performed 3 days, 15 days (+/- 3 days), 
and 30 days (+/- 3 days) post-procedure.  
 
2) Presence of reflux in the treated IPV will be recorded at each 
time point (3, 15, and 30 days post intervention) and an overall 

 
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absence of reflux rate (i.e. reflux free rate) will be documented 
at each follow-up time point 
Subject Participation 
Duration: 
Five Visits: An Informed Consent / Consultation visit;  
Intervention visit; routine follow-up within 3 days post-intervention, 
follow-up visit at 15 days post-intervention, and final follow-up visit 
at 30 days post-intervention. Total duration: three - five hours. 
Study Duration: 
Three to four months 

 
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Schematic of Study Design: 
 
Visit 1 
Informed  
Consent /  
Consultation 
 
 
 
 
 
 
 
 
 
 
Visit 2  
Intervention 
 
 
 
 
 
 
Visit 3 
3 day  
Follow-up  
 
 
 
 
Visit 4 
15 day 
Follow-up 
 
 
 
 
 
 
Visit 5 
30 day 
Follow-up 
 
 
 
Intervention 
 
Safety assessments, successful access and entry into the IPV to be ablated and 
the ability to deliver the intended energy to the target vein segment, as well as 
pre- and post-treatment presence of reflux (assessed by Duplex Ultrasound) will 
be evaluated.  
Consultation for the ablative procedure including medical history and physical 
exam, pre-operative venous Duplex Ultrasound imaging. Subjects are screened for 
inclusion/exclusion criteria. Patients are identified as eligible to participate as a 
study subject during consultation for treatment of a diagnosed pathologic IPV(s).  
 
Study explained by investigator and consent form provided. Patient can review and 
sign or return later. Baseline and intervention visits can be scheduled once 
informed consent and enrollment has been confirmed. 
Total N ≥ 30 IPVs (on a minimum of 20 and a maximum of 30 subjects) 
15 day- Safety and Success Assessments 
 
Safety assessments and presence of reflux in the treated IPV based on Duplex 
Ultrasound imaging performed 15 days (+/- 3 days) post intervention will be 
recorded with reporting of the overall absence of reflux (reflux free rate). 
3 day- Post-Intervention Assessments 
 
Safety assessments and presence of reflux based on Duplex Ultrasound imaging 
performed within 3 days post intervention.  
30 day- Safety and Success Assessments 
 
Safety assessments and presence of reflux in the treated IPV based on Duplex 
Ultrasound imaging performed 30 days (+/- 3 days) post intervention will be 
recorded with reporting of the overall absence of reflux (reflux free rate). 

 
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1 KEY ROLES AND CONTACT INFORMATION 
Principal 
Investigator: 
Jeffrey G. Carr, M.D., F.A.C.C., F.S.C.A.I. 
Medical Director, Vein Center of East Texas at CardioStream  
Chief Medical Officer, Venclose, Inc. 
 
Clinical Site: 
Vein Center of East Texas at CardioStream 
1783 Troup Highway 
Tyler, Texas 75701 
 
 
Coordinating 
Center: 
Discovery Statistics. 
31434 West Nine Drive 
Laguna Niguel, CA 92677 
Contact:  John Carlow, EdD MPH, President 
760-519-7395  
Email: jcarlow.discovery@gmail.com 
 
Other Key 
Personnel: 
Arthur Macaraeg 
Venclose, Inc. 
2570 N. First Street 
2nd Floor, #221 
San Jose, CA. 95131 
408-674-9438 
Email: amacaraeg@VENCLOSE.com 
 
 
 
 

 
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2 INTRODUCTION 
2.1 
Background Information 
As stated by the Society of Vascular Surgery in 2011, in the Western adult population, the 
prevalence of varicose veins is > 20% (range, 21.8%-29.4%), with about 5% (range, 3.6%-
8.6%) have advanced disease manifesting as lower extremity venous edema, skin changes or 
venous ulcerations. Active venous ulcers are present in up to 0.5%, and between 0.6% and 
1.4% have healed ulcers. On the basis of estimates of the San Diego epidemiologic study, more 
than 11 million men and 22 million women between the ages of 40 and 80 years in the United 
States have varicose veins, and 2 million adults have advanced CVD, with skin changes or 
ulcers. The incidence of post-thrombotic venous ulcers has not changed in the past two 
decades for women, and it recently increased in men. In the United States each year, at least 
25,000 patients receive a new diagnosis of venous ulcers.  Chronic venous insufficiency (CVI) is 
prevalent worldwide.(12) 
As the primary established mode of endovenous therapy for CVI in the US for over 20 years, 
thermal ablation for venous reflux via a time-temperature based thermal injury produces 
collagen denaturation and vein diameter reduction resulting in safe and efficacious fibrotic 
occlusion of the vessel. 
Incompetent perforator vein treatment using the Venclose Vestico Catheter System uses the 
same mechanism of action (MOA) as the Medtronic RFS procedure cleared by FDA (K number) 
for IPVs as well as the same MOA as the Venclose EVSRF procedure previously cleared by the 
FDA (K number) for thermally ablating Saphenous reflux. The only difference between the RFS 
and the Vestico/EVSRF technology is the mode of thermal energy delivery which is bipolar 
energy delivered directly to the patient tissues for RFS vs. patient isolated resistive heating for 
the Vestico/EVSRF technology.  Thermal energy (i.e., heat energy; time-at-temperature) is what 
effects successful collagen denaturation and vessel occlusion.  Both bipolar and resistive 
technologies accomplish the same result (i.e., both impart heat energy to occlude the vessel). In 
the case of the Vestico system, the resistive heating technology is inherently safer since the 
patient (i.e., patient’s tissues) is not used as part of the electrical circuit which is the case for the 
FDA cleared RFS device currently in use today.  Additionally, resistive heating technologies like 
the Venclose EVSRF and Medtronic ClosureFAST technologies have proven to be the standard 
of care for much larger diameter vessels than required for treating perforator veins.  
Consequently, based on the understanding of the thermal effects on collagen, and on the typical 
size of the target vein anatomy, these resistive heating technologies are well-suited for 
successful treatment of incompetent perforators. 
 
 

 
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2.2 
Study Outline 
The study’s working hypothesis is that using the Venclose Vestico Catheter System for treating 
incompetent perforator veins (IPVs) will not result in significant adverse outcomes related to use 
of the device.  
There will be an informed consent/consultation visit and an intervention visit. A pre-operative 
Duplex Ultrasound imaging will be obtained prior to or during the consultation visit. The Vestico 
device will be used to treat IPVs during the intervention visit. Safety assessments and pre- and 
post-treatment Duplex Ultrasound imaging will be obtained measuring reflux during the primary 
intervention. Safety assessments and post-operative Duplex Ultrasound images will be obtained 
within 3 days after the intervention. All subjects will be followed up at 15 days and 30-days 
post-operatively for a safety assessment and Duplex Ultrasound. No further study intervention, 
study visits or study-specific data collection will follow the 30-day follow-up. The subject 
population will be patients in need of treatment for Chronic venous insufficiency (CVI) and 
disease due to IPVs.  
 
Device Name 
Device Trade Name: Venclose Vestico System 
Regulation Description: Electrosurgical cutting and coagulation device and 
accessories 
Product Code:  GEI  
Regulation Number: 21CFR 878.4400 
 
Intended Use 
The Venclose VESTICO (commercial Name TBD) Catheter is intended to be 
used with the Venclose digiRF Generator as a system. 
 
 
Indication for Use 
The Venclose VESTICO (commercial Name TBD) Catheter is intended for 
endovascular coagulation of blood vessels in patients with perforator and 
tributary vein reflux. 
 
Device Description 
The Venclose Vestico System uses resistive radiofrequency ablation (via energy 
delivered to heat the wall of an incompetent vein) with temperature-controlled RF 
energy, and an already widely accepted procedure to cause irreversible luminal 
occlusion. This is followed by fibrosis and ultimately resorption of the vein.  
 
Venclose Vestico System consists of two (2) main components:  

 
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1) Vestico catheter with integrated cable connector which treats the vein in 
0.5 cm segments (Figure 1) and 
2) Venclose digiRF generator (model VC-RFG-1) which delivers 
radiofrequency (RF) energy to the Vestico catheter (digiRF generator 
already cleared under, K160754) (Figure 2).   
 
               
 
         Figure 1: Vestico Catheter  
 
Figure 2: Venclose digiRF Generator 
 
The Vestico catheter is a slight modification to the sponsor’s already cleared 
EVSRF catheter (K160754) for the treatment of superficial veins. The primary 
components of the catheter, as illustrated in Figure 3, include the shaft, handle 
and integrated connector cable. The catheter shaft is 6 French (6F = 2.0 mm in 
diameter) in profile, with an insertable length of 40 cm and a 0.5 cm heating coil, 
which is energized by the digiRF generator. The shaft’s lumen allows passage of 
a guidewire 0.025” or smaller in diameter to help steer the catheter into position 
within the vasculature, as needed.    
 
The technology and design used in the Vestico catheter is identical to the EVSRF 
catheter and developed based on special considerations for human factors and 
usability engineering with features included to provide easy handling for the 
operator. The parent technology of EVSRF catheter used in Vestico with human 
factors testing has been reviewed and cleared by the FDA. Briefly, the catheter 
handle includes a manual start/stop button, the circuitry for communication with 
the generator, and a luer connector for flushing of the guidewire lumen prior to 
catheter insertion into the vein (Figure 3). The button on catheter gives full 
control of the device operation to the user, such as to activate or terminate 
treatments, or to pause and re-start as necessary.  
 
In addition, all treatment parameters for the Vestico catheter are provided with no 
user-selectable adjustments.  The graphical user interface uses icons and digits 
for readability from distances of up to eight feet away and with symbols for 
understanding across users with different primary languages. The procedure can 
be performed in an outpatient setting, without the need for general anesthesia, 
allowing for a walk-in/walk-out procedure with minimal post-operative recovery 
time.  

 
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Figure 3:  Vestico Catheter 
 
The tip of the Vestico catheter where the heating coil is located is covered with a non-stick outer 
layer, which enables thermal control and prevents the device from tissue burns because of 
residual heating. The catheter is also fully shielded by several non-conductive polymer layers 
(including the non-stick outer jacket) to prevent delivery of electric current into patient tissues  
. 
2.3 
Potential Risks and Benefits 
The risks associated with participation in this study present no greater probability or magnitude 
of harm or discomfort than those ordinarily encountered as standard of care for endovenous 
thermal ablation.  
The following explanation is offered as the rationale for this risk determination under Title 21 
CFR 812.150(b)(10).  
Under 21 CFR 812.3(m), a Significant Risk (SR) device means an investigational device that:  
1. Is intended as an implant and presents a potential for serious risk to the health, safety, 
or welfare of a subject.  
 
The Vestico Device is not an implant, nor does it present serious risk to the health, 
safety or welfare of the subject. 
2. Is purported or represented to be for use supporting or sustaining human life and 
presents a potential for serious risk to the health, safety, or welfare of a subject.  
 
The Vestico Medical Device does not support or sustain human life. 
3. Is for a use of substantial importance in diagnosing, curing, mitigating, or treating 
disease, or otherwise preventing impairment of human health and presents a potential 
for serious risk to the health, safety, or welfare of a subject; or  
 
Vestico Device is used for treating IPVs; however, does not present a potential for 
serious risk to the health, safety, or welfare of a subject. 

 
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4. Otherwise presents a potential for serious risk to the health, safety, or welfare of a 
subject.  
 
The Vestico Device does not present a serious risk for health, safety, or welfare of a 
patient 
In order to determine if a particular risk is considered serious, FDA guidance regarding serious 
adverse event was reviewed. In this guidance document, OHRP defines serious adverse 
event as any adverse event that: 
1. results in death; 
2. is life-threatening (places the subject at immediate risk of death from the event as it 
occurred); 
3. results in inpatient hospitalization or prolongation of existing hospitalization; 
4. results in a persistent or significant disability/incapacity; 
5. results in a congenital anomaly/birth defect; or 
6. based upon appropriate medical judgment, may jeopardize the subject’s health and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
this definition (examples of such events include allergic bronchospasm requiring 
intensive treatment in the emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse). 
If the Vestico Device fails, it will not lead to death, won’t create a life-threatening situation, would 
not lead to additional patient hospitalization, would not disable the patient, and would not lead to 
additional surgical procedures of the patient. 
 
Potential Risks 
Risks from undergoing endovenous thermal ablation: 
The Vestico ablation procedure will be performed by trained and registered medical 
doctors who follow standard of care for RFA. While thermal ablation procedures 
have inherent risks, problems with the procedure are considered rare, and when 
they do occur, they are usually minor and easily treated.  
Some of the potential risks identified are: 
 
Edema 
 
Skin changes 
 
Venous ulcers 
 
Deep vein thrombosis 
 
Superficial vein thrombosis 

 
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 
Pulmonary embolism 
 
Venous thromboembolism 
 
Skin burn 
 
Thermal injury of adjacent tissues 
 
Paresthesia 
 
Infection/cellulitis 
 
AV Fistula 
 
Need for re-operation 
 
Death 
 
Before undergoing ablation procedure, subjects will be informed by the treating 
clinician of these potential side effects using the clinical informed consent form, in 
addition to a separate informed consent form for the research study. 
Known risks from use of the subject device: 
During the development of the device, a Risk Management process compliant with 
ISO 14971 Medical devices - Application of risk management to medical devices 
was undertaken. Upon completion of this process it has been determined that 
known device related risks that may result in patient’s harm have been either 
mitigated or reduced to a level that is as low as reasonably possible.  
The approaches followed by the sponsor to mitigate the occurrence of device 
related risk include designing the device for inherent safety and providing 
information for safety. Specific risk controls implemented to protect patients from 
harm are respectively described below: 
 
Injury to electric shock – designed the device to make it compliant with all 
applicable requirements regarding electrical safety as defined in IEC 60601-1 
Medical electrical equipment - Part 1: General requirements for basic safety 
and essential performance. 
 
Injury from sharp edges - designed the device to make it compliant with all 
applicable requirements regarding mechanical safety as defined in IEC 60601-1 
Medical electrical equipment - Part 1: General requirements for basic safety 
and essential performance. 
 
Infection due to use of contaminated patient contacting components – Single-
patient use components are provided sterile while for reusable components, 
users are provided with cleaning and sterilization instructions which had been 
validated per national and international standards on reprocessing of reusable 
medical equipment. 
 
Patient contacting components provoke a biocompatibility response – designed 
the device to make it compliant with all applicable requirements of ISO 10993-1 
Biological evaluation of medical devices -- Part 1: Evaluation and testing within 
a risk management process 

 
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 
Training – All study investigators and their staff will receive GCP training and 
attend an Investigator meeting to be trained on the study protocol and 
procedures. Prior to use, clinicians and assistants receive training according to 
the commercial training program on the use of the Vestico Device and all of its 
components.   
Duplex Ultrasound:  
Duplex ultrasound is a non-invasive evaluation of blood flow through the arteries 
and veins. This test provides information to help the vascular interventionist make 
a sound diagnosis and outline an appropriate treatment plan. Accuracy is critical, 
so ultrasound testing should be performed by a credentialed sonographer in an 
experienced vascular laboratory. There are typically no side effects or 
complications associated with duplex ultrasound examinations. 
Pregnant women, children and adolescents have been excluded from the study. 
 
Potential Benefits to Subjects  
From undergoing ablation procedures: 
There are several potential benefits to patients undergoing thermal ablation 
therapy to IPVs including some or all of the following: Partial or complete (active) 
ulcer healing, reduced likelihood of ulcer recurrence, pain reduction at the site of or 
adjacent to the active or healed ulcer, prevention or reduction of complications 
from untreated or undertreated vein leg ulcers such as infections (cellulitis, 
phlebitis, osteomyelitis, sepsis), hospitalizations, minor or major leg or foot 
amputations and death. Other potential health benefits included reduction in 
edema, focal pain at the site of active skin changes and inflammation, and 
improved appearance and health of the skin in the legs. In addition there are 
potential non-medical benefits to the patients which include reduction in extended 
wound care visits and therapies, travel costs and time to multiple doctor or care 
providers visits, time away from work and loss of income for the patient and/or 
primary caretakers, costs of medications and supplies, side effects from 
medications, potential for opiate addiction due to relief of chronic pain and mental 
distress from a chronic medical problem. 
 
Alternatives to Participation  
Participation is voluntary. Alternatives to vein leg ulcer therapy include non- 
operative management including compression garment therapy (graduated hose, 
stockings, pneumatic pumps, etc.), leg elevation, and exercise. Although these are 
important as adjunctive therapies, they are overall ineffective at healing active 
ulcers in a timely fashion.  Other interventional treatments include surgical therapy 
such as SEPS (subfascial endoscopic perforator surgery) which is more invasive 

 
RA-0007.A 
 
 
 
19
and rarely utilized, thermal ablation therapy with a laser or radiofrequency device, 
and ultrasound-guided foam sclerotherapy.  These techniques have technical and 
efficacy challenges due to the variances and complexities of perforator anatomy. 

 
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CLINICAL PROTOCOL 
A study  conducted to evaluate the safety and effectiveness of the Venclose digiRF Generator 
with Vestico Catheter System (“Vestico”) treating incompetent perforator veins (IPVs).  The 
study will be conducted in compliance with IDE requirements under local IRB approval(s). Study 
data will be summarized and submitted to FDA in a premarket notification once all subjects have 
completed 30-day follow-up.  
 
The study working hypothesis is that using the Venclose Vestico Catheter System for treating 
incompetent perforator veins (IPVs) will not result in any adverse outcomes related to use of the 
device. 
No significant risk is posed by either the use of the Vestico Device or the study process. 
While safety can never be taken lightly, this study is not meant to measure, monitor or 
analyze any significant disease or disorder for which medical treatment is mandatory. 

 
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3 OBJECTIVES  
3.1 
Study Objectives and Outcome Measures 
Objectives 
1) 
The study’s working hypothesis is that using the Venclose Vestico Catheter System 
for treating incompetent perforator veins (IPVs) will not result in significant adverse 
outcomes related to use of the device. 
2) 
The study will be conducted in compliance with IDE requirements and labeling (21 
CFR 812.2(b)) and under local IRB approval(s). 
3) 
Multiple limbs and IPVs may be treated. All IPVs treated will be followed according to 
the study schedule. 
Outcome Measures 
Primary Endpoints: 
1) 
Safety - Procedure related adverse events (AE), serious adverse events (SAE), 
adverse device effects (ADE), serious adverse device effects (SADE) and 
unanticipated adverse device effects (UADE) will be monitored and analyzed for 
acceptability post study. 
Monitored events include: 
 Edema 
 Skin changes 
 Venous ulcers 
 Deep vein thrombosis 
 Superficial vein thrombosis 
 Pulmonary embolism 
 Venous thromboembolism 
 Skin burn 
 Thermal injury of adjacent tissues 
 Paresthesia 
 Infection/cellulitis 
 AV Fistula 
 Need for re-operation 
 Death 
2) 
Effectiveness - Technical success, defined as successful access and entry into the 
IPV to be ablated and the ability to deliver the intended energy to the target vein 
segment, will be evaluated. 
Secondary Endpoints: 
1) 
The acute ablation success endpoint is defined as complete lack of flow or IPV 
disappearance in the treated segment (vessel occlusion).  Success will be measured 
by Duplex Ultrasound imaging performed 3 days, 15 days (+/- 3 days), and ), and 30 
days (+/- 3 days)  post-procedure. 

 
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2) 
Presence of reflux in the treated IPV will be recorded at each time point (3, 15, and 
30 days post intervention) and an overall absence of reflux rate (i.e. reflux free rate) 
will be documented at each follow-up time point 
3.2 
Overview 
A. 
Subjects 
At least twenty (≥ 20) and a maximum of thirty (≤ 30) subjects eligible for endovenous thermal 
ablation, specifically IPVs, will be enrolled in this study. 
B.  
Protocol 
i. 
Enrollment: At least twenty (≥ 20) and a maximum of thirty (≤ 30) subjects requiring 
thermal ablation will be asked to participate in this study. Exclusion criteria will include 
any factors excluding a patient from having RFA (e.g. medical conditions, psychological 
conditions, or vascular conditions) and/or exclude the use of the Vestico Device (See 
Section 4 for detailed inclusion/exclusion criteria). 
ii. 
Clinical Procedures: There will be an informed consent/consultation visit and an 
intervention visit. A pre-operative Duplex Ultrasound imaging will be obtained prior to or 
during the consultation visit. The Vestico device will be used to treat IPVs during the 
intervention visit. Safety assessments and pre- and post-treatment Duplex Ultrasound 
imaging will be obtained measuring reflux during the primary intervention. Safety 
assessments and post-operative Duplex Ultrasound images will be obtained within 3 
days after the intervention. All subjects will be followed up at 3-days, 15-days and 30-
days post-operatively for a safety assessment and Duplex Ultrasound. No further study 
intervention, study visits or study-specific data collection will follow the 30-day follow-up. 
The subject population will be patients in need of treatment for Chronic venous 
insufficiency (CVI) and disease due to IPVs. 
iii. 
The Investigator proceeds with the Vestico Device procedure and will take a post-
operative Duplex Ultrasound Scan following the ablation procedure.  
iv. 
Data and Imaging Collection and Study Monitoring: On the day of surgery, Screening 
and Baseline Visit Case Report Forms (CRFs) will be completed by the Investigator or 
their delegate. The clinical study monitor will confirm that Pre- and Post-Operative 
Duplex Ultrasound Scans are taken. 
v. 
Analysis: The treatment plan, including the pre-operative Duplex Ultrasound Scan, and 
post-operative Duplex Ultrasound Scan images are collected by the clinical study 
monitor. Cessation of flow and cessation of flow reflux through the perforator vein(s) will 
be recorded, thoroughly investigated, documented and included in the study analysis. 
All adverse events related to the device will be handled and reported to regulatory 
authorities as per this study protocol.  

 
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D.  
Data Collection 
Data will be collected using case report forms (CRFs).  The following describes the data being 
collected: 
 
Imaging and surgical preplanning information 
 
De-identified subject data (e.g. age, gender, medications and medical conditions) 
 
Device related data 
 
Surgical site data (e.g. location), blood flow, etc. 
 
Surgical Information (date and reason for the surgery, complications) 
 
Duplex Ultrasound Scans from pre- and immediately post-intervention. 
 
All adverse events 
E.  
Investigators 
One investigator with a wide range of endovascular interventional experience and his assistants 
will be trained on the protocol, investigator and sponsor responsibilities, study procedures and 
the instructions for use of the Vestico device. (See Appendix A). The investigators and staff will 
be certified with GCP training. 
A qualified clinical study monitor will verify data collection. 
F. 
Oversight (see Section 15.2, Institutional Review Board)  
This study will be subjected to review by an Institutional Review Board in addition to the 
oversight provided by the principal investigator and the clinical study monitor to ensure that the 
rights, welfare and safety of subjects are protected. 

 
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4 STUDY ENROLLMENT AND WITHDRAWAL 
4.1 
Subject Inclusion Criteria 
In order to be eligible to participate in this study, an individual must meet all of the following 
criteria: 
1. Patient is >= 18 years. 
2. IPVs to be treated have an outward flow duration of >= 0.5 seconds immediately 
after release of manual distal compression with patient standing or in Reverse 
Trendelenburg. 
3. IPV(s) to be treated have a diameter of ≥ 3.5 mm located caudal edge of ankle. 
4. Has been diagnosed with refractory symptomatic disease attributable to the IPV to 
be treated. 
5. Is able to ambulate. 
6. Is able to comprehend and has signed the Informed Consent Form (ICF) to 
participate in the study. 
7. Is willing and able to comply with the Clinical Investigation Plan and follow-up 
schedule. 
 
4.2 
Subject Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
1. Has venous insufficiency secondary to venous obstruction proximal to the intended 
treatment site. 
2. Has thrombus in the vein segment to be treated. 
3. Has untreated critical limb ischemia from peripheral arterial disease. 
4. Is undergoing active anticoagulant therapy for Deep Vein Thrombosis or other 
conditions (e.g., warfarin, direct oral anticoagulant or low molecular weight heparin) 
or has a history of Deep Vein Thrombosis within the last 6 months or 
hypercoagulable state. 
5. Patients with known bleeding or clotting disorders or unwilling or unable to frequently 
ambulate post-operatively. 
6. Has had prior venous procedures in the study limb within the last 30 days (including 
thrombolysis, thrombectomy, stenting, ablation, phlebectomy, visual or foam 
sclerotherapy). 
7. Has undergone or is expected to undergo any major surgery within 30 days prior to 
or following the study procedure. 
8. Has a condition, judged by the treating physician, that may jeopardize the patient's 
well-being and/or confound the results or the soundness of the study. 

 
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9. Is pregnant or lactating at the time of the study procedure or is intending on 
becoming pregnant within 30 days following the study procedure. 
10. Is participating in another clinical study that is contraindicated to the treatment or 
outcomes of this investigation 
4.3 
Strategies for Recruitment and Retention 
At least twenty (≥ 20) and a maximum of thirty (≤ 30) subjects who desire treatment for their 
varicose veins will be recruited and enrolled from one clinical site. Study advertising in the form 
of an accredited IRB approved flyer will be posted in each clinic in high visibility areas as 
necessary. Patients interested in obtaining further information will be invited to inquire at the 
clinic reception to receive study information and arrange for the consent process to be started. 
Patients who are being consulted for treatment of varicose veins may also be informed by their 
attending physician that the study is taking place. Recruitment and screening efforts will 
continue until the target number of subjects has been reached. 
4.4 
Subject Withdrawal 
Since final follow-up will be at 30 days post-intervention, it is unlikely subjects will withdraw                                 
from the study. However, subjects may withdraw voluntarily from the study or the investigator 
may terminate a subject's participation at any time. Withdrawals will be reported to an 
accredited IRB. In the case of a withdrawal of an enrolled subject, a new subject will be enrolled 
in order to reach the target enrollment of a minimum of thirty (≥ 30) IPVs across at least twenty 
(≥ 20) and a maximum of thirty (≤ 30) subjects. 
 
Reasons for Withdrawal 
Subjects are free to withdraw from participation in the study at any time upon his 
or her request without prejudice to medical care. An investigator has a duty to 
terminate a study subject’s participation in the study if: 
 
Any clinical adverse event (AE), other medical condition or situation 
occurs such that continued participation in the study would not be in the 
best interest of the subject. 
 
The subject meets an exclusion criterion (either newly developed or not 
previously recognized) that precludes further study participation. 
 
Handling of Subject Withdrawals or Subject Discontinuation of Study 
Intervention 
Subjects who are removed from the study as a result of clinical conditions during 
surgery that prevent implant placement will be included in the study analysis of 
data. For the purposes of analyzing accuracy, it will be necessary to enroll 
another implant patient so that study results are not affected.  

 
RA-0007.A 
 
 
 
26
Subjects may be removed from the study at their request. In the event that a 
subject wants to be withdrawn from the study, reasonable effort will be made to 
ascertain the reason for the withdrawal which will be documented in the subject’s 
CRF. However, the study subject is not obligated to provide a reason for their 
withdrawal. In the case of a withdrawal of an enrolled subject, a new subject will 
be enrolled in order to reach the target enrollment. 
4.5 
Premature Termination or Suspension of Study 
This study may be suspended or prematurely terminated if there is sufficient reasonable cause 
as described in the circumstances below. If the study is prematurely terminated or suspended, 
the principal investigator will promptly inform FDA and the IRB and will provide the reason(s) for 
the termination or suspension.  
Circumstances that may warrant termination include, but are not limited to: 
 
Determination of unexpected, significant, or unacceptable risk to subjects. 
 
Insufficient adherence to protocol requirements. 
 
Data that is not sufficiently complete and/or evaluable.  
 
Determination of futility. 

 
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5 STUDY INTERVENTION 
5.1 
Concomitant Medications/Treatments 
All concomitant medications will be recorded on a study CRF for each subject. The information 
about these medications will be collected and recorded prior to enrollment. If subjects are 
enrolled on a date prior to the ablation procedure, the concomitant medications will be reviewed 
and updated with the subject for accuracy during the first study visit and prior to the surgical 
intervention utilizing the Vestico Device. 
5.2 
Administration of Intervention 
The Vestico device will be utilized during the RFA at the one clinic in the United States and the 
intervention will be performed by the qualified study investigators trained in the use of the 
Vestico device. This intervention will occur at one visit only and should take approximately two 
hours. 
5.3 
Accountability Procedures for the Study Product 
The sponsor, Venclose, Inc., will supply the Vestico Devices to the clinical site at no charge. 
Supply of the consumable (Vestico Catheter) and reusable (Vestico Generator) components will 
also be provided at no charge in sufficient quantity to meet the requirements of the study.  
The study CRFs include capture of serial, batch/lot numbers of components used for each study 
subject. These will be compared to unused and returned supply at study close to ensure that 
each consumable and reusable component is accounted for. 
 
Deficient Product 
If a device deficiency is detected, the investigator will discontinue use of the 
affected component and report this deficiency immediately to the study sponsor.  
The study sponsor will investigate and determine corrective or preventive actions if 
required. 
Additional supplies may be requested in writing to the study sponsor if deficiencies 
require replacement of the device or its consumable or reusable components. 
5.4 
Procedures for Training Investigators and Study Monitoring 
Investigators will have documented certification of GCP training.  
Investigators will receive practical training for the Vestico Device that will be conducted by 
qualified Venclose training personnel according to Venclose’s approved customer training 
procedure. Prior to site initiation, training of the investigators and assistants will be provided by 
the sponsor and Principal Investigator and will cover the following: study protocol, Investigator 

 
RA-0007.A 
 
 
 
28
and Sponsor responsibilities, and site procedures. A follow up training session to review these 
materials will be conducted at site initiation by the clinical study monitor and Venclose Training 
personnel. Training records will be created for each trainee.  
Only registered investigators and assistants who have documented training in GCP, have 
received the required study related training, and are determined to be proficient in the use of the 
Vestico device will participate in the conduct of the study. 
A qualified clinical study monitor will verify collection of data, and monitor compliance to the 
protocol and study procedures. The monitor is required to report any deviations from the site 
procedures or study protocol to the sponsor and Principal Investigator.   
Venclose Service and Support technicians may be on-site to provide technical support to the 
clinician, should they request it. The Service and Support personnel will not be involved in the 
planning or be present in the operatory during the procedure to ensure that data recorded is not 
compromised.  

 
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6 STUDY PROCEDURES  
6.1 
Subject Recruitment 
Potential study subjects may be identified through in-clinic advertising in the form of a flyer 
posted in high visibility areas. Interested potential participants may approach clinic staff to 
express their interest and receive Informed Consent information. Patients who are being 
consulted for treatment of their varicose veins may also be informed by their attending physician 
that the study is taking place and if interested, an Informed Consent appointment can be booked 
with the Investigator or his/her designate. 
6.2 
Informed Consent 
The informed consent visit will be conducted by the Investigator or their designated study staff 
at the time of the consultation for intervention visit and may occur up to one month before the 
scheduled intervention. 
 
Review all aspects of the clinical investigation that are relevant to the possible 
subject’s decision to participate 
 
Care is to be taken not to coerce or unduly influence possible subject participation 
 
Provide ample time for the possible subject to read and understand the informed 
consent form and to consider participation  
 
Answer all questions asked to the satisfaction of the possible subject 
 
Provide a copy of the signed informed consent to the possible subject, if signed 
 
Arrange for Screening / Enrollment Visit  
A copy of the IRB approved Informed Consent Form is located in Appendix B of this document. 
6.3 
Costs to Subjects and Payment for Participation 
There will be no cost to subjects as a result of participating in this study. Participants will receive 
a $75-$150 pre-loaded gift card for each completed study visit to cover travel and out-of-pocket 
expenses related to the study. 
6.4 
Consultation / Enrollment 
Consultation Visit (up to two months before the scheduled intervention)   
 
Confirm documented informed consent from potential subject 
 
Obtain/review medical/clinical history (standard of care) 
 
Assess/review eligibility based on inclusion/exclusion criteria 
 
Review concomitant medications history to determine eligibility based on 
inclusion/exclusion criteria (standard of care) 

 
RA-0007.A 
 
 
 
30
 
Perform medical/clinical examinations needed to determine eligibility (standard of care) 
 
Obtain demographic information (standard of care) 
 
Determine surgical site(s) 
 
Pre-operative Duplex Ultrasound Scan 
 
Schedule study intervention visit for individuals who are eligible and available for the 
study (standard of care)  
 
Complete Screening CRF 
 
Provide potential subjects with instructions and possible prescriptions needed to 
prepare for the intervention visit (standard of care) 
6.5 
Baseline / Intervention 
Baseline Visit (Day of intervention) 
 
Verify inclusion/exclusion criteria   
 
Review concomitant medications (standard of care) 
 
Record results of physical and clinical examinations (standard of care) 
 
Complete Baseline CRFs 
 
Perform ablation procedure (standard of care) using the Vestico Device  
 
Post-operative Duplex Ultrasound Scan (same day and within 3 days of Intervention) 
 
Record AEs and SAEs and report to sponsor immediately (if applicable) 
6.6 
3-day Post-Intervention Safety Assessment 
Follow-up Visit (3-days post-intervention) 
 
Document all adverse events, if any 
 
Post-operative Duplex Ultrasound Scan (same day or within 3 days of 3-day Follow-
up) 
6.7 
15-day Post-Intervention Safety Assessment 
Follow-up Visit (15-days post-intervention) 
 
Document all adverse events, if any  
 
Post-operative Duplex Ultrasound Scan (same day or within 3 days of 15-day Follow-
up) 
 
6.8 
30-day Post-Intervention Safety Assessment 
Follow-up Visit (30-days post-intervention) 
 
Document all adverse events, if any 

 
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31
 
Post-operative Duplex Ultrasound Scan (same day or within 3 days of 30-day Follow-
up) 
6.9 
Withdrawal Visit 
Any subjects wishing to withdraw or be withdrawn by the clinician will be scheduled for a 
withdrawal visit. Reasonable efforts will be made to ascertain the reason for withdrawal which 
will be documented in the subject’s CRF. However, the study subject is not obligated to provide 
a reason for their withdrawal. Withdrawals will be reported to an accredited IRB per their 
guidelines.  
6.10 
Unscheduled Visit 
Subjects in need of a visit between the screening and baseline visits will be scheduled and any 
treatment or evaluation will be documented in a study CRF if they have not completed the 
baseline visit.   

 
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7 STUDY SITE SELECTION 
7.1 
Site Selection 
Site will be selected based on the following criteria: 
i. 
Geographic location;  
ii. 
Expertise in therapeutic area; 
iii. 
Level of experience and training (clinic, research, etc.); 
iv. 
Availability of appropriate type and number of subjects;  
v. 
Adequate facilities, staff, resources; including an on-site Duplex Ultrasound 
Scanner; 
vi. 
No undisclosed financial or professional conflict of interest with the proposed study; 
and 
vii. 
The investigator is not the subject of current investigation or review by their 
licensing organization or other regulatory body.   

 
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8 ASSESSMENT OF SAFETY 
8.1 
Reporting Procedures 
 
Reportable Events and Unanticipated Problems, Reporting to FDA and 
IRB 
A reportable event is defined as anything that could significantly impact the 
conduct of the research or alter the Institutional Review Board’s (IRB) approval or 
favorable opinion to continue the research.  
An unanticipated problem is defined as any incident, experience, or outcome 
(including an adverse event) that meets all of the following criteria:  
 
Event is unexpected (in terms of nature, severity, or frequency) given (a) the 
research procedures that are described in the protocol-related documents, such 
as this IRB approved research protocol and informed consent document, or the 
Device Instructions for Use; (b) the event is not associated with the expected 
natural progression of any underlying disease, disorder, predisposing risk factor, 
or condition of the participant(s) experiencing the adverse event; and  
 
Related or possibly related to participation in the research (possibly related 
means there is a reasonable possibility that the incident, experience, or outcome 
may have been caused by the investigational product(s) or procedure involved in 
the research); and  
 
Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized.  
Should an unanticipated problem, or reportable event occur due to participation 
in this study, the information will be recorded in the subject CRFs and reviewed 
by the sponsor. 
Adverse Events or Serious Adverse Events that are Unanticipated 
Problems 
NOTE: Report to the IRB only adverse events that in the opinion of the 
investigator may represent unanticipated problems involving risks to the other 
subjects in the research.   
The investigator must immediately inform the sponsor of any unanticipated 
problems, adverse events and/or serious adverse events. The investigator is 
responsible for reporting adverse events without delay to the IRB that fit the 
above criteria. 

 
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8.2 
Time Period and Frequency for Event Assessment and Follow-Up 
Any unanticipated problems, adverse events and/or serious adverse events will be recorded in 
the subject CRF during the study. The PI will record all reportable events with start dates 
occurring any time after informed consent is obtained until 30 days after the last day of the study 
participation. The investigator will inquire about the occurrence of AE/SAEs since the last visit. 
Events will be followed for outcome information until resolution or stabilization. 

 
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35
9 STUDY OVERSIGHT 
In addition to the responsibility of the principal investigator to oversee study conduct, an 
independent clinical study monitor will conduct routine monitoring visits to minimize the 
instances of errors or missing data, to provide assurance that the study documentation is 
completed according to procedures and to assess compliance with the protocol, GCPs and 
intended use of the device. (See section 11.)  

 
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10 CLINICAL SITE MONITORING 
Clinical site monitoring is conducted to ensure that the rights of human subjects are protected, 
that the study is implemented in accordance with the protocol and/or other operating 
procedures, and that the quality and integrity of study data and data collection methods are 
maintained. Monitoring for this study will be performed by a qualified individual independent of 
the study. The monitor will evaluate study processes and documentation based on International 
Conference on Harmonization (ICH), E6: Good Clinical Practice guidelines (GCP). 
Some monitoring activities may be performed remotely, while others will take place at the study 
site(s). The independent monitor will conduct monitoring activities and provide reports of the 
findings and associated action items to the site study team, the study PI and the sponsor. The 
clinical study monitor will conduct routine monitoring visits and will verify the collection of 
required data elements. Additional monitoring will be done at the discretion of the Sponsor and 
clinical study monitor. 

 
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37
11 ANALYTICAL METHODS 
11.1 
Data Analysis 
Appropriate analytical methods will be used to interpret the study results.  Techniques may 
include: 
 
Descriptive statistics and graphical plots (i.e., box and whisker plots) to assess the 
central tendency and variability of the raw data 
 
Distribution diagnostics and outlier test to determine degree of nonlinearity and other 
systematic error. All missing data will be assumed to be missing-at-random, unless trends 
are detected. 
 
Any statistical analysis will be performed using JMP Statistical Software, Version 15.0 
(SAS Institute Inc., Cary, NC.) 
11.2 
Lost to Follow-up 
Data on subjects who are lost to follow-up or who withdraw from the study will be maintained 
and analyzed up to the point at which they discontinued.  The reason for withdrawal will be 
recorded if known.  Subjects who discontinue participation, for whatever reason, will remain in 
the study and be subject to follow-up in the same manner as those who complete the study 
except as noted above.  The only confirmed lost to follow-up subject will be the subject who dies 
or refuses to continue to participate in the study and withdraws. 
11.3 
Sample Size Estimate 
This is an Investigator Initiated Study; there is no formal sample size calculation. A minimum of 
thirty (≥ 30) IPVs on at least twenty (≥ 20) and a maximum of thirty (≤ 30) subjects will be 
enrolled. 
1) Along with the available Real-World Evidence data, the number of IPVs proposed is 
satisfactory  compared with number of IPVs used in other early studies performed for 
“Substantial Equivalence” 510k pathways requiring human data in the field of thermal 
ablation for venous reflux. 
2) Based on Real World Evidence and MAUDE database review, the number of AEs and 
MDRs, respectively, is very low. If a study is designed to evaluate what is already observed 
in RWE, it would drive sample sizes for statistical justification to be extremely high, which is 
overly burdensome to demonstrate “substantial equivalence”. 
3) Based on review of the technical features of the predicate device vs. subject device, the set-
point temperature and thermal ablation size are “substantially equivalent”. This means the 
thermal spread is the same providing reasonable level of assurance of safety and 
effectiveness. The proposed sample size for this study is large enough to understand any 
differences in performance between subject and predicate devices. 
4) Post-hoc review of the study results will be performed on any AEs and/or occlusion data to 
determine if results provide an acceptable level of substantial equivalence. 

 
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38
DIRECT ACCESS TO SOURCE DATA / DOCUMENTS  
Study staff will maintain appropriate clinical and research records for this study, in compliance 
with ICH E6, Section 4.9 and regulatory and institutional requirements for the protection of 
confidentiality of subjects. Study staff will permit authorized representatives of regulatory 
agencies to examine (and when required by applicable law, to copy) research records for the 
purposes of quality assurance reviews, audits, and evaluation of the study safety, progress and 
data validity.   

 
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12 QUALITY CONTROL (QC) AND QUALITY ASSURANCE (QA) 
PROCEDURES 
12.1 
Quality Management System 
The sponsor, Venclose, Inc. maintains a quality system that is Certified to ISO 13485 CMDCAS 
and ISO 9001 standards and is in compliance with FDA ‘s 21 CFR 820, Medical Device 
Regulation. Clinical Quality Assurance and Quality Control will be integrated in the sponsor’s 
overall quality system and will be overseen by the Sponsor’s Department of Quality Assurance 
and Regulatory Affairs. All members of this department have received training and certification 
in GCP by an accredited GCP training institution. 
12.2 
Clinical Quality 
The sponsor maintains written Clinical Quality procedures for the design, conduct and 
monitoring of clinical studies. This includes written procedures to ensure that trials are 
conducted and data are generated, recorded and reported in compliance with the approved 
study protocol, GCP and applicable regulatory requirements.  
For activities related to the use of the subject device in the Clinical study, the sponsor’s 
established Quality Management System procedures will be utilized e.g. Quality System 
Procedures for Adverse Event Reporting and Corrective and Preventive Action. 
12.3 
Study Conduct and Agreements 
A written Clinical Trial Agreement (CTA) between and among the Institution, Principal 
Investigator and the sponsor includes agreement to allow direct access to all trial related sites, 
source data/documents, and reports for the purposes of monitoring and auditing by the sponsor, 
as well as for inspection by domestic and foreign regulatory authorities.  
12.4 
Quality Control 
The sponsor employs a clinical study monitor who is responsible for overseeing the progress, 
conduct, records and reporting in accordance with the protocol, SOPs, GCP and other identified 
regulatory requirements. The activities of the monitor are documented in the sponsor’s SOP for 
Clinical Study Monitoring. The sponsor assures that the monitor is appropriately trained to 
perform these activities. Training is documented according to QSP 6.2-1. (See section 6.4.). 
The study CRFs and regulatory files will be reviewed for verification and agreement to the study 
protocol by the Clinical Monitor, Principal Investigator, and the sponsor’s Quality Assurance and 
Regulatory Affairs Department. 

 
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12.5 
Essential Documents 
The quality management of essential documents (i.e. CRFs, informed consent forms; refer to 
Section 8 of the ICH for a complete list of documents) will be conducted by the clinical study 
monitor with oversight of the Principal Investigator. 
12.6 
Study Data 
The sponsor will be provided de-identified data only.  
The sponsor’s document control coordinator is responsible for the quality management of 
subject/participant data (study CRFs and de-identified radiographs).  Once the sponsor has 
received these documents from the site(s), the clinical study monitor initiates an internal review 
by the sponsor’s Quality Assurance and Regulatory Affairs department to ensure that records 
are accurate, complete, legible and timely. Any data queries that result from this review must be 
resolved. The Principal Investigator must review and approve each study CRF that has been 
completed by investigator(s) before the data can be used.  

 
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13 ETHICS/PROTECTION OF HUMAN SUBJECTS 
13.1 
Ethical Standard 
The investigator will ensure that this study is conducted in full conformity with the principles set 
forth in the Declaration of Helsinki and The Belmont Report: “Ethical Principles and Guidelines 
for the Protection of Human Subjects of Research”, as drafted by the US National Commission 
for the Protection of Human Subjects of Biomedical and Behavioral Research (April 18, 1979) 
and codified in 45 CFR Part 46 and/or the ICH E6.  
13.2 
Institutional Review Board (IRB) 
The protocol and informed consent form will be submitted to an accredited IRB for review and 
approval prior to beginning the study and before enrolling subjects. Any amendment to the 
protocol will require review and approval by an accredited IRB before the changes are 
implemented in the study.   
The IRB, in addition to the oversight provided by the principal investigator and the clinical study 
monitor, serves to ensure that the rights, welfare, and safety of patients is protected. 
13.3 
Informed Consent Process 
A consent form describing in detail the study procedures and risks will be given to the subject. 
Consent forms will be approved by an accredited IRB. 
The subject is required to read and review the document or have the document read to him or 
her. The investigator or designee will explain the research study to the subject and answer any 
questions that may arise. The subject will sign the informed consent document prior to any 
study-related assessments or procedures. Subjects will be given the opportunity to consider the 
risks and benefits prior to agreeing to participate. They may withdraw consent at any time 
throughout the course of the study. A copy of the signed informed consent document will be 
given to subjects for their records. The rights and welfare of the subjects will be protected by 
emphasizing to them that the quality of their clinical care will not be adversely affected if they 
decline to participate in this study. The consent process will be documented in the clinical or 
research record. 
13.4 
Exclusion of Women, Minorities, and Children (Special Populations) 
Individuals, 18 years and older, of any gender or racial/ethnic group may participate. Pregnant 
women will be excluded. Children are excluded from the study as they are still developing and 
are typically not candidates for this procedure. 
13.5 
Subject Confidentiality 
Subject confidentiality is strictly held in trust by the investigators, study staff, and the sponsor(s) 
and their agents. At the time of screening and enrollment, study subjects will be assigned a 

 
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unique subject ID which will be used for study documentation. Personal information collected for 
study purposes will be identified only by their assigned subject ID. The screening and 
enrollment log will be held in electronic form on a password protected and secured server and 
maintained by the Principal Investigator. The personal identification of study subjects will be 
accessible only by the PI and will not be shared with the sponsor. Study records are retained 
according to ICH and FDA guidelines. 
The study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any 
unauthorized third-party without prior written approval of the sponsor. 
The clinical study monitor or other authorized representatives of the sponsor may inspect all 
study documents and records required to be maintained by the investigator, including but not 
limited to, medical records (office, clinic, or hospital) for the study subjects. The clinical study 
site will permit access to such records. 

 
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14 DATA HANDLING AND RECORD RETENTION / KEEPING 
The investigators are responsible for ensuring the data reported is attributable, legible, 
contemporaneous, original and accurate (ALCOA). All source documents are to be completed in 
a neat, legible manner to ensure accurate interpretation of data. The investigators will maintain 
adequate case histories of study subjects, including accurate case report forms (CRFs), and 
source documentation. All original study CRFs and de-identified scans will be securely 
transferred to and maintained by the sponsor via Venclose personnel or insured parcel service 
(requiring receipt signature). Records will be stored in locked boxes in secure, fire-safe cabinets 
accessible only to authorized study team members.   
The sponsor will retain original records related to the study for at least two years after the last 
subject’s study visit date. Some examples of study records include device use instructions, all 
versions of the protocol and informed consents, CRFs etc.   
14.1 
Data Management Responsibilities 
Data collection and accurate documentation are the responsibility of the study staff and clinical 
study monitor under the supervision of the investigator and study sponsor. The study sponsor 
maintains policies and procedures to support the generation of high-quality, reliable, and 
statistically sound data and results from the study. 
De-identified data from paper CRFs and accuracy measurements taken from radiographs will be 
transcribed by qualified individuals into a validated study database developed and maintained 
by the study sponsor. All data will be verified for accuracy and reconciled by the sponsor’s 
quality assurance team. 
14.2 
Data Capture Methods 
All data will be captured on paper study CRFs. All original CRFs will be transferred to the 
sponsor via insured parcel service (requiring receipt signature), within seven days of completion 
of each subject’s study participation. A copy of these documents will be maintained at the study 
site until the sponsor has verified receipt of the original documents. Once the sponsor confirms 
receipt of the originals, a site study team member will be instructed by the sponsor to destroy 
the CRF copy (e.g. shred).   
Shipment of documents to sponsor will occur as follows: 
John J. Carlow, EdD, MPH 
Discovery Statistics 
31434 West Nine Drive 
Laguna Niguel, CA. 92677 
14.3 
Study Records Retention 
Study records will be retained by the sponsor per the sponsor's Clinical Quality procedures. 

 
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14.4 
Protocol Deviations 
All deviations from the protocol must be addressed in study subject source documents and 
promptly reported to an accredited IRB, according to their requirements.   

 
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15 PUBLICATION / DATA SHARING 
The Investigator may not publish or otherwise disseminate the results of its investigative 
findings without written authorization of the Sponsor. 
 

 
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APPENDIX A:  TRAINING GUIDE AND CHECKLIST 
APPENDIX B: INFORMED CONSENT FORM