Global, Post-Market, Prospective, Multi-Center, Randomized Controlled Trial of the VenaSeal™ Closure System vs. Surgical Stripping or Endothermal Ablation (ETA) for the Treatment of Early & Advanced Stage Superficial Venous Disease
Phase: NA
Conditions: Venous Reflux
Sponsor: Medtronic Endovascular

 
 
Cover page for Study Protocol 
 
Sponsor name: 
Medtronic Endovascular 
NCT number 
NCT03820947 
Sponsor trial ID: 
MDT18034 
Official title of study: 
Global, Post-Market, Prospective, 
Multi-Center, Randomized 
Controlled Trial of the VenaSeal™ 
Closure System vs. Surgical 
Stripping or Endothermal Ablation 
(ETA) for the Treatment of Early & 
Advanced Stage Superficial 
Venous Disease 
Document date 
31 August 2022 
 

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Clinical Investigation Plan 
Clinical Investigation Plan/Study Title  VenaSeal Spectrum: Global, Post-Market, Prospective, Multi-
Center, Randomized Controlled Trial of the VenaSeal™ 
Closure System vs. Surgical Stripping or Endothermal Ablation 
(ETA) for the Treatment of Early and Advanced Stage 
Superficial Venous Disease 
Clinical Investigation Plan Identifier 
MDT18034 
Study Product Name 
VenaSeal™ Closure System 
Sponsor/Local Sponsor 
Medtronic Vascular Inc. 
3576 Unocal Place, 
Santa Rosa, California 95403, United States  
Medtronic Bakken Research Center B.V. – EU legal 
representative 
Endepolsdomein 5, 6229 GW Maastricht,  
The Netherlands 
Medtronic Korea Co. Ltd. 
17F, Glass Tower, #534,  
Teneran-ro, Gangnam-gu, Seoul, 06181,  
South Korea 
Medtronic Australasia Pty Ltd  
2 Alma Road, Macquarie Park NSW 2113,  
Australia 
Medtronic Canada ULC  
99 Hereford St, Brampton Ontario, L6Y 0R3, 
Canada 
Telephone number: (905) 460-3800 
Document Version 
5.0 / 31-AUG-2022 
Lead Principal Investigator(s) 
Kathleen Gibson, MD 
1135 116th Avenue NE, Suite 305 
Bellevue, Washington 98004, United States  
 
Manjit Singh Gohel, MD 
Addenbrooke’s Hospital, Hills Road, 
Cambridge, CB2 0QQ, United Kingdom 
Confidentiality Statement 
The information contained in this document is confidential and the proprietary property of Medtronic. 
Any distribution, copying, or disclosure without the prior written authorization of Medtronic is strictly 
prohibited. Persons to whom the information is disclosed must know that it is confidential and that it 
may not be further disclosed by them. 

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1. Investigator Agreement and Signature Page 
Study Product Name 
VenaSeal™ Closure System 
Sponsor 
Medtronic Vascular Inc. 
3576 Unocal Place 
Santa Rosa, California 95403, United States  
Clinical Investigation Plan Identifier 
MDT18034 
Version Number/Date  
5.0 / 31-AUG-2022 
I have read the clinical investigation plan, including all appendices, and I agree that it contains all 
necessary details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time designated. 
 
I agree to comply with the Declaration of Helsinki, the Clinical Investigation Plan, and Good Clinical 
Practice, as well as local laws, regulations, and standards, and internal institutional requirements as 
specified in section 15 of the Clinical Investigation Plan. I agree to ensure that the confidential 
information contained in this document will not be used for any purpose other than the evaluation and 
conduct of the clinical investigation without the prior written consent of Medtronic. 
 
I will provide all study personnel under my supervision copies of the clinical investigation plan and 
access to all information provided by Medtronic. I will discuss this material with them to ensure that 
they are fully informed about the products and the study. 
Investigator’s Signature: 
 
 
 
 
 
Investigator’s Name: 
 
Institution: 
 
Date: 
 
 
 

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Table of Contents  
 
1. 
Investigator Agreement and Signature Page .................................................................... 2 
Table of Contents ...................................................................................................................... 3 
2. 
Glossary .............................................................................................................................. 8 
3. 
Synopsis ........................................................................................................................... 12 
4. 
Introduction ..................................................................................................................... 24 
4.1. Background ........................................................................................................................... 24 
4.2. Purpose ................................................................................................................................. 30 
5. 
Objectives and Endpoints ................................................................................................. 30 
5.1. Objectives ............................................................................................................................. 30 
5.1.1. 
Primary Objectives ................................................................................................................ 30 
5.1.2. 
Secondary Objectives ............................................................................................................ 31 
5.2. Endpoints .............................................................................................................................. 31 
5.2.1  
Primary Endpoints ................................................................................................................. 31 
5.2.2 
Key Secondary Endpoints ...................................................................................................... 31 
5.2.3 
Secondary Endpoints ............................................................................................................. 32 
6. 
Study Design .................................................................................................................... 35 
6.1. Duration ................................................................................................................................ 36 
6.2. Rationale ............................................................................................................................... 37 
7. 
Product Description.......................................................................................................... 38 
7.1. General ................................................................................................................................. 38 
7.2. Manufacturer ......................................................................................................................... 41 
7.3. Packaging .............................................................................................................................. 41 
7.4. Intended Population ............................................................................................................... 41 
7.5. Equipment ............................................................................................................................. 42 
7.6. Product Use ........................................................................................................................... 42 
7.7. Product Training Materials ...................................................................................................... 42 
7.8. Product Accountability ............................................................................................................ 42 
8. 
Study Site Requirements ................................................................................................. 43 

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8.1. Investigator/Investigation Site Selection .................................................................................. 43 
8.2. Study Site Activation .............................................................................................................. 44 
8.3. Role of the Sponsor Representatives ....................................................................................... 45 
9. 
Selection of Subjects ........................................................................................................ 45 
9.1. Study Population .................................................................................................................... 45 
9.2. Subject Screening and Enrollment ........................................................................................... 45 
9.3. Target Veins and Target Limb ................................................................................................. 49 
9.4. Target Ulceration on the Target Limb ...................................................................................... 49 
9.5. Inclusion Criteria .................................................................................................................... 50 
9.6. Exclusion Criteria ................................................................................................................... 50 
10. Study Procedures ............................................................................................................. 51 
10.1. 
Schedule of Events and Data Collection ............................................................................. 51 
10.2. 
Scheduled Follow-up Visit Windows ................................................................................... 54 
10.3. 
Subject Consent ............................................................................................................... 55 
10.4. 
Randomization and Treatment Assignment (CEAP 2-5) ....................................................... 57 
10.5. 
Study Assessments ........................................................................................................... 58 
10.6. 
Screening ........................................................................................................................ 62 
10.7. 
Prior and Concomitant Medications .................................................................................... 63 
10.8. 
Baseline (within 30 days prior to index procedure) ............................................................. 63 
10.9. 
Index Procedure ............................................................................................................... 64 
10.10. 
Follow-Up Visits: All Subjects ............................................................................................ 67 
10.11. 
Unscheduled Visits ........................................................................................................... 72 
10.12. 
Additional Follow-Up Visits: VLU Study Active Ulcers ........................................................... 72 
10.13. 
Assessment of Effectiveness ............................................................................................. 73 
10.14. 
Assessment of Safety ....................................................................................................... 74 
10.15. 
Recording Data ................................................................................................................ 74 
10.16. 
Deviation Handling ........................................................................................................... 75 
10.17. 
Subject Exit, Withdrawal or Discontinuation ....................................................................... 78 
10.17.1. Study Exit ............................................................................................................................... 78 
10.17.2. Study Completed ................................................................................................................... 78 

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10.17.3. Lost to Follow-up ................................................................................................................... 79 
10.17.4. Subject Chooses to Exit (i.e. Revokes Consent) .................................................................... 79 
10.17.5. Investigator Withdraws Subject ............................................................................................ 79 
10.17.6. Conditional Disengagement .................................................................................................. 80 
11. Risks and Benefits ............................................................................................................ 80 
11.1 Potential Risks ....................................................................................................................... 80 
11.2. Potential Risks of the Procedure............................................................................................. 81 
11.3. Risk Minimization .................................................................................................................. 82 
11.4. Potential Benefits .................................................................................................................. 82 
11.5. Risk-Benefit Rationale ........................................................................................................... 83 
12. Adverse Events and Device Deficiencies .......................................................................... 83 
12.1. 
Definitions/Classifications .................................................................................................. 83 
12.1.1. Definitions ............................................................................................................................. 83 
12.1.2. Classification of Causal Relationships ................................................................................... 86 
12.2. 
Foreseeable Adverse Events and Foreseeable Adverse Device Effects .................................. 88 
12.3. 
Recording and Reporting of Adverse Events ....................................................................... 89 
12.4. 
Recording and Reporting of Device Deficiencies ................................................................. 91 
12.5. 
Adverse Event and Device Deficiency Review Process ......................................................... 92 
12.6. 
Reporting of Adverse Events ............................................................................................. 92 
12.7. 
Emergency Contact for Reporting Events and Device Deficiencies........................................ 93 
12.8. 
Processing Updates and Resolution ................................................................................... 93 
12.9. 
Subject Death .................................................................................................................. 93 
13. Data Review Committees ................................................................................................. 94 
13.1. 
Clinical Events Committee (CEC) ....................................................................................... 94 
13.2. 
Lead Principal Investigators .............................................................................................. 95 
13.3. 
Ulcer Assessment Core Laboratory .................................................................................... 95 
14. Statistical Design and Methods ........................................................................................ 95 
14.1. 
Randomized Studies ......................................................................................................... 96 
14.1.1. Sample Size Evaluation on Primary Endpoints ...................................................................... 97 
14.1.2. Sample size evaluation on key secondary endpoints .......................................................... 100 

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14.1.3. Interim Analysis ................................................................................................................... 105 
14.1.4. Analysis Sets ........................................................................................................................ 105 
14.2. 
VLU Study (Single-Arm Study) ......................................................................................... 105 
14.2.1. Sample Size Consideration .................................................................................................. 105 
14.2.2. Interim Analysis ................................................................................................................... 106 
14.2.3. Analysis Sets ........................................................................................................................ 106 
14.3. 
Analysis of Safety Events ................................................................................................ 107 
14.4. 
Analysis of Baseline Characteristics .................................................................................. 107 
14.5. 
Safety Event Analysis and Reporting of Results ................................................................ 107 
14.6. 
Health Economics Analysis .............................................................................................. 107 
14.7. 
Missing Data .................................................................................................................. 107 
15. Ethics .............................................................................................................................. 108 
15.1. 
Statement(s) of Compliance ............................................................................................ 108 
16. Study Administration ..................................................................................................... 110 
16.1. 
Clinical Trial Agreement .................................................................................................. 110 
16.2. 
Subject Compensation .................................................................................................... 110 
16.3. 
Site Activation / Supply of Trial Materials ......................................................................... 110 
16.4. 
Monitoring ..................................................................................................................... 111 
16.5. 
Data Management .......................................................................................................... 112 
16.6. 
Direct Access to Source Data/Documents ......................................................................... 113 
16.7. 
Confidentiality ................................................................................................................ 113 
16.8. 
Liability .......................................................................................................................... 114 
16.9. 
CIP Amendments ........................................................................................................... 114 
16.10. 
Record Retention ........................................................................................................... 115 
16.10.1. Investigator Records............................................................................................................ 115 
16.10.2. Sponsor Records .................................................................................................................. 116 
16.11. 
Reporting Requirements ................................................................................................. 116 
16.11.1. Investigator Reports ............................................................................................................ 116 
16.11.2. Sponsor Reports .................................................................................................................. 118 

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16.12. 
Publication and Use of Information .................................................................................. 121 
16.13. 
Transparency ................................................................................................................. 122 
16.14. 
Suspension or Early Termination ..................................................................................... 122 
17. References ..................................................................................................................... 124 
18. Appendices ..................................................................................................................... 127 
Appendix A: Patient Questionnaires and Assessments ......................................................... 127 
1. AVVQ .......................................................................................................................................................... 127 
2. EQ-5D-5L .................................................................................................................................................. 131 
3. rVCSS ......................................................................................................................................................... 134 
4. SF-36 .......................................................................................................................................................... 136 
5. CEAP Classification ............................................................................................................................... 138 
6. VenousTSQ ............................................................................................................................................... 139 
7. VenousDQoL Overview items ............................................................................................................ 144 
8. Patient Reported Symptoms Table ................................................................................................. 145 
9. Patient Prior History Table................................................................................................................. 146 
Appendix B: Definitions .......................................................................................................... 148 
19. Version History ............................................................................................................... 152 
 
 
 

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2. Glossary 
Term 
Definition 
AASV 
Anterior Accessory Saphenous Vein 
ABI 
Ankle-brachial Index 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
AT 
As treated  
AVVQ 
Aberdeen Varicose Vein Questionnaire 
BfArM 
Bundesinstitut für Arzneimittel und Medizinprodukte  
(English: Federal Institute for Drugs and Medical Devices) 
CA 
Competent Authority 
CE 
Conformité Européenne (European Conformity) 
CEAP 
Clinical, Etiological, Anatomical, and Pathophysiological Classification 
CEC 
Clinical Events Committee 
CFR 
Code of Federal Regulations   
CIP 
Clinical Investigation Plan 
CRF 
Case Report Form 
CTA 
Clinical Trial Agreement 
CVD 
Chronic Venous Disease 
DRF 
Data Release Form 
DTL 
Delegated Task List 

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Term 
Definition 
DUS 
Duplex Ultrasound 
DVT 
Deep Vein Thrombosis 
EC 
Ethics Committee 
EDC 
Electronic Data Capture 
EGIT 
Endovenous glue induced thrombosis 
EHIT 
Endovenous heat induced thrombosis 
EQ-5D-5L 
EuroQoL 5 Dimensions Standardized Quality of Life Survey 
EVLA 
Endovenous Laser Ablation 
ETA 
Endovenous Thermal Ablation 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GSV 
Great Saphenous Vein 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
IDE 
Investigational Device Exemption 
IFU 
Instructions for Use 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
ISO 
International Organization for Standardization 
ITT 
Intention-to-treat 

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Term 
Definition 
MPSV 
Medizinprodukte-Sicherheitsplanverordnung 
(English: BfArM’s Ordinance on the Medical Device Safety Plan) 
NRS 
Numeric rating scale 
NSAID 
Non-Steroidal Anti-Inflammatory Drug 
NTNTNS 
Non-Thermal, Non-Tumescent and Non-Sclerosant 
OUS 
Outside of the United States 
PAD 
Peripheral Artery Disease 
PASV 
Posterior Accessory Saphenous Vein 
PE 
Pulmonary Embolism 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PP 
Per-Protocol 
PPE 
Personal Protective Equipment 
QoL 
Quality of Life  
RDC 
Remote Data Capture 
RFA 
Radiofrequency Ablation 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event  
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System software  
SF-36 
Short Form-36 Quality of Life Survey  

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Term 
Definition 
SFJ 
Sapheno-femoral Junction 
SoC 
Standard of Care 
SOP 
Standard Operating Procedure 
SPJ 
Sapheno-popliteal Junction 
SSV 
Small Saphenous Vein 
UADE 
Unanticipated Adverse Device Effect 
US 
United States 
USADE 
Unanticipated Serious Adverse Device Effect 
rVCSS 
revised Venous Clinical Severity Score 
VenousDQoL 
Venous Dependent Quality of Life 
VenousTSQe 
Venous Treatment Satisfaction Questionnaire- early 
VenousTSQs 
Venous Treatment Satisfaction Questionnaire- status 
VLU 
Venous Leg Ulcer 
VRD 
Venous Reflux Disease 
 
 
 

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3. Synopsis 
VENASEAL SPECTRUM Study Synopsis 
Title 
VENASEAL SPECTRUM: Global, Post-Market, Prospective, Multi-Center, Randomized 
Controlled Trial of the VenaSeal™ Closure System vs. Surgical Stripping or 
Endothermal Ablation (ETA) for the Treatment of Early and Advanced Stage 
Superficial Venous Disease 
Clinical Study 
Type 
Global, post-market, prospective, multi-center, randomized controlled trial  
Product Name 
VenaSeal™ Closure System, Surgical Stripping and Endothermal Ablation (ETA) 
Sponsor/Local 
Sponsor  
Medtronic Vascular Inc. 
3576 Unocal Place 
Santa Rosa, California 95403 
United States 
Medtronic Bakken Research Center B.V. 
Endepolsdomein 5 
6229 GW Maastricht 
The Netherlands 
Medtronic Korea Co. Ltd. 
17F, Glass Tower, #534 
Teneran-ro, Gangnam-gu, Seoul, 06181 
South Korea 
Medtronic Australasia Pty Ltd  
2 Alma Road 
Macquarie Park NSW 2113 
Australia 
Medtronic Canada ULC  
99 Hereford St 
Brampton Ontario, L6Y 0R3 
Canada 
Telephone number: (905) 460-3800 
Indication in 
Study 
 
The VenaSeal™ closure system will be used according to the instructions for use (IFU) 
criteria as applicable per geography. 
o United States (U.S.) Indication (VS-402, VS-404): The VenaSeal™ system is 
indicated for use in the permanent closure of lower extremity superficial 
truncal veins, such as the great saphenous vein (GSV), through endovascular 
embolization with coaptation. The VenaSeal™ system is intended for use in 
adults with clinically symptomatic venous reflux as diagnosed by duplex 
ultrasound (DUS). 

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o Outside of the United States (OUS) Indication (VS-403, SP-101): The VenaSeal™ 
system is intended for the permanent, complete, endovascular adhesive 
closure of the GSV and associated varicosities in the treatment of venous reflux 
disease (VRD). 
o South Korea Indication (SP-101): The VenaSeal™ system is intended for use in 
patients with venous reflux disease as diagnosed by duplex ultrasound (DUS). 
The VenaSeal™ system is indicated for use in the permanent closure of lower 
extremity superficial truncal veins, such as the great saphenous vein (GSV), 
through endovascular adhesive closure. 
The indications listed here are at the time of protocol finalization. Please refer to the 
respective Instructions for Use for current and applicable indications. 
Product Status 
The VenaSeal™ system is commercially available in all countries selected for 
participation in this study. Surgical stripping or ETA will be designated comparators 
when commercially available at a site. 
Investigation 
Purpose 
Randomized Studies (CEAP 2-5): To evaluate the patient’s experience and clinical 
improvement after treatment with the VenaSeal™ system compared to standard of 
care treatments, surgical stripping or ETA, in the treatment of symptomatic 
superficial venous disease (CEAP 2-5). Patient-centered outcomes, vein closure, 
ability to return to work, and clinical improvement will be measured after treatment 
of symptomatic venous reflux in the superficial truncal veins by the VenaSeal™ 
system or the comparator treatments. 
VLU Study (CEAP 6): To evaluate the patient’s experience and clinical improvement 
after treatment with the VenaSeal™ system in the treatment of active venous leg 
ulcer (VLU) (CEAP 6) subjects.  
Target 
Population 
Randomized Studies (CEAP 2-5): Adults with symptomatic venous reflux in the 
superficial truncal veins (CEAP 2-5) appropriate for treatment with the VenaSeal™ 
system and ETA in VenaSeal vs. ETA Study, and appropriate for treatment with the 
VenaSeal™ system and surgical stripping in the VenaSeal vs. Surgical Stripping Study. 
A trial center should provide VenaSeal™ system treatment, and surgical stripping or 
ETA as part of their standard of care. 
VLU Study (CEAP 6): Adults with symptomatic venous reflux in the superficial truncal 
veins (CEAP 6) appropriate for treatment with the VenaSeal™ system. 
Patients will be enrolled globally at up to 40 centers.  
Study Design 
Global, post-market, prospective, multi-center randomized controlled trial of 
patients with symptomatic superficial venous disease, with a single arm embedded 
ulcer subgroup.  
Expected total enrollment of approximately 500 subjects in VenaSeal Spectrum 
Study. Approximately 375 subjects will be enrolled in CEAP clinical classifications 2-5 

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in the Randomized Studies (108 subjects in VenaSeal vs. Surgical Stripping Study and 
about 264 subjects in VenaSeal vs. ETA Study), and up to 125 CEAP 6 subjects with 
VLUs will be treated with the VenaSeal™ system. Enrollment of the VenaSeal vs. 
Surgical Stripping Study was closed on 22-Feb-2022. 
Primary 
Objective(s) 
 
For the CEAP 2-5 Randomized Studies, the primary objectives are to compare the 
VenaSeal™ system to surgical stripping and ETA regarding patient experience and 
satisfaction, through a validated, patient-centered 2-part venous treatment 
satisfaction questionnaire (VenousTSQ-early [VenousTSQe] and VenousTSQ-status 
[VenousTSQs]) at 30 days, and the ability to achieve elimination of clinically relevant 
superficial truncal disease in the target veins at the index procedure. 
For the VLU Study, the primary objective is to evaluate time to ulcer healing through 
12 months. 
Secondary 
Objective(s) 
 
The key secondary objectives are to compare the VenaSeal™ system to surgical 
stripping and ETA in achieving the anatomical closure of superficial truncal veins at 6 
months, and the ability to return to work post-index procedure. 
The secondary objective of the study is to evaluate the VenaSeal™ system in the 
treatment of symptomatic venous reflux in the superficial truncal veins. Specific areas 
of analysis include: effectiveness, safety, healthcare utilization, patient experience, 
and treating physician experience. 
In addition, secondary objectives in the VLU Study include ulcer healing rate, ulcer 
recurrence, and ulcer-free time. 
Primary 
Endpoints  
The CEAP 2-5 Randomized Studies have three primary endpoints comparing the 
VenaSeal™ system to surgical stripping or ETA.  
1. Peri-procedural patient satisfaction as measured by a validated, patient-centered 
venous treatment satisfaction questionnaire (VenousTSQe) at 30 days. 
2. Patient satisfaction as measured by a validated, patient-centered venous 
treatment satisfaction questionnaire (VenousTSQs) at 30 days. 
3. Elimination of clinically relevant superficial truncal disease in each target vein at 
the time of index procedure as measured by the percentage of target vein length 
successfully treated.  
The primary endpoint for the VLU Study is time to ulcer healing, calculated through 
healing confirmation and verified by an independent core laboratory through 12 
months.  
Key Secondary 
Endpoints 
Data supporting the following endpoints will be collected for both the Randomized 
Studies as well as the VLU Study. The following endpoints will be compared for the 

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Randomized Studies and will be evaluated for the VenaSeal™ system for the VLU 
Study.  
1. Anatomic closure of the primary target superficial truncal vein at 6 months, 
defined as DUS showing vein closure along the entire treated vein segment with 
no discrete segments of patency exceeding 5 cm after VenaSeal™ system and ETA 
procedures, or the absence of refluxing or residual primary target vein after 
surgical stripping procedures. 
2. Time to return to work as reported by the patient. 
Secondary 
Endpoints 
Data supporting the following endpoints will be collected for both the CEAP 2-5 
Randomized Studies as well as the VLU Study. When appropriate, data will be 
evaluated for the CEAP 2-5 Randomized Studies to compare the VenaSeal™ system 
to surgical stripping or ETA. Data may also be pooled for all VenaSeal™ system 
subjects from the CEAP 2-5 Randomized Studies and VLU Study as appropriate.  
Data from VenaSeal vs. Surgical Stripping Study will be collected through the 12 
months visit.  
Effectiveness secondary endpoints 

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1. Anatomic closure of primary target vein at 30 days, and 12, 24, 36, 48 and 60 
months:  
• 
For subjects treated with the VenaSeal™ system or ETA it is defined as 
DUS showing vein closure along the entire treated vein segment with no 
discrete segments of patency exceeding 5 cm. 
• 
For subjects treated with surgical stripping this is defined as absence of 
refluxing or residual vein at 30 days and 12 months only. 
2. Anatomic closure of target vein at 30 days, and 6, 12, 24, 36, 48 and 60 months: 
• 
For subjects treated with the VenaSeal™ system or ETA this is defined as 
DUS showing vein closure along the entire treated vein segment with no 
discrete segments of patency exceeding 5 cm. 
• 
For subjects treated with surgical stripping this is defined as absence of 
refluxing or residual vein at 30 days, 6 and 12 months only. 
3. Technical success of each target vein immediately post-index procedure: 
• 
For subjects treated with the VenaSeal™ system or ETA this is defined as 
DUS showing vein closure along the entire treated vein segment with no 
discrete segments of patency exceeding 5 cm. 
• 
For subjects treated with surgical stripping this is defined as absence of 
refluxing or residual vein. 
4. Reintervention of any target vein (including primary target vein) through 60 
months, assessed at each follow-up visit. Subjects enrolled in the VenaSeal vs. 
Surgical Stripping Study will be followed through the 12 months visit only.  
5. Time to reintervention of any target vein (including primary target vein) through 
60 months, as measured by the time between the index procedure and the first 
reintervention procedure. Subjects enrolled in the VenaSeal vs. Surgical Stripping 
Study will be followed through the 12 months visit only.  
Safety secondary endpoints 
6. Adverse events (AEs) occurring in the target limb, evaluated from index 
procedure through 12 months: 
• 
Hypersensitivity to VenaSeal™ adhesive  
• 
Phlebitis 
• 
Granuloma 

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• 
Endovenous glue induced thrombosis (EGIT) or endovenous heat induced 
thrombosis (EHIT) 
• 
Symptomatic deep vein thrombosis (DVT) events 
7. Additional events evaluated through 60 months (through 12 months for VenaSeal 
vs. Surgical Stripping Study) 
• 
Symptomatic Pulmonary embolism (PE) 
• 
Serious adverse events (SAEs)  
Healthcare utilization secondary endpoints 
8. Number and type of adjunctive treatments conducted through 12 months post-
index procedure. 
9. Healthcare utilization related to the target limb VRD, as determined by the 
number of healthcare visits conducted, and other health-related resources 
utilized (e.g., home healthcare services) between study visits through 60 months 
(through 12 months for VenaSeal vs. Surgical Stripping Study). 
10. Procedures, tests and treatment of AEs related to the treatment modality or 
index procedure through 60 months (through 12 months for VenaSeal vs. Surgical 
Stripping Study). 
11. VLU Study: Healthcare utilization and routine wound care treatments between 
study visits through 60 months. 
Patient Experience secondary endpoints 
12. Time to return to normal activities as reported by the patients. 
13. Intra-procedural and post-procedural pain at the index procedure, and pain at 7 
and 30 days as reported by the patient using the numeric rating scale (NRS) with 
a scale of 0-10. 
14. Change in venous disease symptoms at 7 and 30 days, and at 6, 12, 24, 36, 48, 
and 60 months compared to baseline (7 and 30 days, 6 and 12 months only for 
VenaSeal vs. Surgical Stripping Study), as measured by the revised Venous Clinical 
Severity Score (rVCSS) and subject self-reporting. 
15. Change in AVVQ score at 30 days, and 6, 12, 24, 36, 48, and 60 months (30 days, 
6 and 12 months only for VenaSeal vs. Surgical Stripping Study) compared to 
baseline. 
16. Change in EuroQoL Group 5-Dimension Self-Report Questionnaire (EQ-5D-5L) at 
30 days, and 6, 12, 24, 36, 48 and 60 months (30 days, 6 and 12 months only for 
VenaSeal vs. Surgical Stripping Study) compared to baseline. 

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17. Change in the 36-Item Short Form Health Survey (SF-36) reported by the patient 
at 30 days, and 6 and 12 months compared to baseline. 
18. Change in the Venous Dependent Quality of Life (VenousDQoL) reported by the 
patient at 30 days, and 6, 12, 24, 36, 48, and 60 months (30 days, 6 and 12 months 
only for VenaSeal vs. Surgical Stripping Study) compared to baseline. 
Provider Experience secondary endpoint 
19. Provider experience will be assessed post-index procedure, evaluating overall 
satisfaction with the procedure. 
VLU Study: 
The primary endpoint of the VLU Study is referenced above. 
The following ulcer-specific effectiveness endpoints will be evaluated: 
20. Ulcer healing rate, as measured by the percentage of the ulcer area healed per 
given time period, according to an independent core laboratory through 24 
months or until ulcer healing has been confirmed. 
21. Ulcer recurrence on the target limb, assessed at all follow-up timepoints 
following ulcer healing through 60 months. 
22. Ulcer-free time, calculated as days between initial ulcer healing and first ulcer 
recurrence, as applicable, through 60 months. 
In addition, the primary endpoints and any other applicable endpoints of the 
Randomized Studies will be also assessed for the VLU Study: 
23. Peri-procedural patient satisfaction as measured by a validated patient-centered 
venous treatment satisfaction questionnaire (VenousTSQe) at 30 days. 
24. Patient satisfaction as measured by a validated patient-centered venous 
treatment satisfaction questionnaire (VenousTSQs) at 30 days. 
25. Elimination of clinically relevant superficial truncal disease in target vein at the 
time of index procedure as measured by the percentage of target veins 
successfully treated. 
Follow-up 
Follow-up will occur at 7 and 30 days and 6, 12, 24, 36, 48, and 60 months post-index 
procedure (7 and 30 days, 6 and 12 months for VenaSeal vs. Surgical Stripping Study). 
 
CEAP 6 subjects will have additional follow-up visits until healing verification at: 2, 3, 
4, 5, 8, and 10 months. If healing has not occurred by 24 months, subjects will 
continue to follow standard wound care and remaining study visits. Subjects will 

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come in for ulcer healing verification visit up to 24 months, after which no core 
laboratory ulcer assessment for wound healing will be required. 
Study Duration Approximately 8 years, including up to 60-month follow-up post-procedure. 
Randomization CEAP 2-5 subjects will be enrolled via randomization in one out of the two 
Randomized Studies: 
1. VenaSeal vs. ETA Study: subjects will be 1:1 randomized to VenaSeal™ system or 
the ETA treatment. 
2. VenaSeal vs. Surgical Stripping Study: subjects will be 1:1 randomized to 
VenaSeal™ system or surgical stripping treatment. 
Each site will be designated as participating in only one of the two Randomized 
Studies and cannot participate in both. Which study the site will enroll into is pre-
determined by geographical region and device/treatment availability. 
CEAP 6 subjects will not be randomized.  
Sample Size  
~375 CEAP 2-5 subjects (randomized to VenaSeal™, surgical stripping or ETA 
treatment) and up to ~125 CEAP 6 subjects (VenaSeal treatment only) at up to 40 
global sites. 
Inclusion/ 
Exclusion 
Criteria 
 
 
Inclusion: 
1. Patient is ≥18 years of age. 
2. Patient has venous reflux in superficial truncal vein(s) (e.g., GSV, SSV, accessory 
saphenous veins) with CEAP category 2 (symptomatic) or CEAP category 3, 4a, 4b, 
5, 6 based on the American Venous Forum CEAP classification (2004), appropriate 
for treatment, as confirmed by DUS. 
3. Eligibility for treatment:  
• 
VenaSeal vs ETA Study: Patient is eligible for treatment with the 
VenaSeal™ system and ETA. 
• 
VenaSeal vs Surgical Stripping Study: Patient is eligible for treatment with 
the VenaSeal™ system and surgical stripping. 
• 
VLU Study: patients should be eligible for treatment with the VenaSeal™ 
system. 
4. Treatable refluxing segment of target vein(s) 10 cm in length or longer. 
5. Patient has a target vein diameter of ≥3 mm throughout the intended treated 
segment of the target vein as measured by DUS while patient is standing. 
6. Patient is willing and capable of complying with specified follow-up evaluations 
at the specified times. 
7. Patient has an ability to understand the requirements of the study and to provide 
informed consent. 
 
Exclusion: 

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1. Patient has a known history of allergic sensitivities (including but not limited to 
cyanoacrylate adhesives), or any other condition, which in the opinion of the 
investigator may make the patient more susceptible to cyanoacrylate adhesive 
hypersensitivity. 
2. Patient has known deep vein obstruction in the target limb, as identified by the 
site’s standard of care. 
3. Patient has abnormal pulse exam or ABI <0.8. 
4. Patient has acute superficial thrombophlebitis. 
5. Patient requires any non-target vein treatments in the contralateral or ipsilateral 
limb, or any other surgical procedure up to 30 days pre-procedure and through 3 
months post-procedure. 
6. Patient has any co-morbid conditions, which in the investigator’s opinion may 
interfere with the patient’s compliance with study visits and procedures, or may 
confound interpretation of study data (e.g., congestive heart failure Class III and 
IV, non-ambulatory patients, severe hepatic dysfunction, life expectancy < 1 
year). 
7. IFU contraindications:  
• 
VenaSeal vs. ETA Study: Patient has VenaSeal™ system and/or ETA 
product’s IFU contraindication(s). 
• 
VenaSeal vs Surgical Stripping Study: Patient has surgical stripping and/or 
VenaSeal™ system IFU contraindication(s). 
• 
VLU Study: Patient has VenaSeal™ system IFU contraindication(s). 
8. Patient is non-ambulatory. 
9. Patient is a female of childbearing potential who may be pregnant or 
breastfeeding at the time of the index procedure. *  
10. Patient belongs to a vulnerable population per investigator's judgment or patient 
has any kind of disorder that compromises his/her ability to give written informed 
consent and/or to comply with study procedures. 
11. Patient is currently participating in an investigational drug or device study when 
the data collected could be conflicting or biased due to participation in another 
study. 
12. Patient has documented COVID-19 infection currently or within the past 3 
months. Patient is not completely recovered from past COVID-19 infection, per 
physician's discretion. 
13. VLU Study: Patient has target ulceration identified to be of non-venous etiology, 
as confirmed by the independent core laboratory. 
14. VLU Study: Patient has target circumferential ulceration that cannot be captured 
in a single photograph (any ulcer curvature around the leg that goes out of sight). 
Note: CEAP 6 patients are excluded at sites not identified as VLU sites. 
*Pregnancy to be assessed per treating physician’s routine practice; testing is not 
required if verbal confirmation is preferred. Breastfeeding patients may be included 
if mother’s expressed milk is discarded surrounding the index procedure, per the 

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treating physician’s standard instructions. Sites must document routine methods 
utilized for such patients. 
 
 

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Study 
Procedures and 
Assessments 
Table 1: Schedule of Assessments – All Subjects  
Data Collection 
Requirement 
Screening 
Baseline 
(<30 days before procedure) 
Index Procedure  (Day 0) 
Day 7  (± 2 days) 
Day 30  (± 7 days) 
3+ Months Adjunctive 
Therapy (Optional) 
6 Months  (± 4 weeks) 
12 Months  (± 8 weeks)1 
24, 36, 48 and 60 Months (± 
8 weeks) 
Unscheduled2 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
CEAP Clinical 
Classification 
(2004 and 2020) 
X 
 
 
 
 
 
X 
X 
X 
X 
Randomization 
X 
 
 
 
 
 
 
 
 
 
Demographics, 
Medical History 
 
X 
 
 
 
 
 
 
 
 
Concomitant 
Medications 
 
X 
X 
 
 
 
 
 
 
 
rVCSS 
 
X 
 
X 
X 
 
X 
X 
X 
X 
Patient-Reported 
Symptoms  
 
X 
 
X 
X 
 
X 
X 
 
 
EQ-5D-5L QoL 
 
X 
 
 
X 
 
X 
X 
X 
 
AVVQ QoL 
 
X 
 
 
X 
 
X 
X 
X 
 
SF-36 QoL 
 
X 
 
 
X 
 
X 
X 
 
 
VenousTSQ3 
 
 
 
 
X 
 
X 
X 
 
 
Duplex 
Ultrasound 
 
X4 
X 
X 
X 
 
X 
X 
X 
X 
Procedure-
related Data & 
Outcome 
 
 
X 
 
 
 
 
 
 
 
Physician 
Satisfaction with 
Procedure 
 
 
X 
 
 
 
 
 
 
 
Patient-Reported 
Outcomes 
 
 
 
X 
X 
 
X 
X 
X 
 
Reintervention 
Review 
 
 
 
X 
X 
 
X 
X 
X 
 
Healthcare 
utilization 
 
 
 
X 
X 
 
X 
X 
X 
 
Adjunctive 
Therapy 
Assessment 
 
 
 
 
 
X 
X 
X 
X 
 
Adverse Event 
Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 

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Device Deficiency 
Assessment 
 
 
X 
 
 
 
 
 
 
 
1Subjects in VenaSeal vs. Surgical Stripping Study will be followed through 12 months only.  
2AE assessments at unscheduled visits are required. Additional assessments are per investigator’s 
discretion; see section 10.11 for additional detail 
3VenousTSQe captured at 30 Days; VenousTSQs captured at 30 Days, 6 Months and 12 Months 
4Sites to utilize their standard of care DUS to assess screening criteria, within 6 months of the 
Screening/Baseline visit; if not conducted in a standing position, sites will need to re-image patient for 
target vein measurements only 
 
Data will be collected at the timepoints specified in Table 1 for all subjects and 
collected at the timepoints specified in Table 2 for VLU subjects only. 
Table 2: Additional Schedule of Assessments – VLU Study  
Data Collection  
Requirement 
Screening 
Baseline 
Procedure 
7 & 30 Days 
2, 3, 4, & 5 Months 
(+/- 7 days) 
6 Months 
8 & 10 Months 
(+/- 2 weeks) 
12 Months 
24, 36, 48, & 60 Months 
Healing Verification 
(<2 weeks of healing) 
All-Subject 
Requirements and Visit 
Windows from Table 1 
X 
X 
X 
X 
 
X 
 
X 
X 
 
Etiology Photograph 
X 
 
 
 
 
 
 
 
 
 
Target Active Ulcer 
Assessment 
 
X 
 
X 
X 
X 
X 
X 
 
 
Ulcer-specific 
Healthcare Utilization 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Active Ulcer or Healing 
Verification 
Photograph 
 
X1 
 
Photographs captured at each visit 
until healing is demonstrated 
through 24 months. 
 
X2 
Adverse Event 
Assessment 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Ulcer Healing and/or 
Recurrence Assessment 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Active Ulcer Wound 
Care 
Wound care and compression therapy to proceed per routine care until 
healing is demonstrated. 
 
1Index procedure should occur within 7 days of baseline ulcer photograph. If the baseline visit is more 
than 7 days out from the index procedure, photographs should instead be taken on the day of the index 
procedure, prior to the start of the procedure. 
2Healing verification to be captured through 24 months, as applicable. 

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Statistics 
This evaluation has been designed as a global, post-market, prospective, multi-center, 
randomized controlled study of patients with symptomatic superficial venous disease, 
with a single arm embedded ulcer study. The study is designed with two Randomized 
Studies (VenaSeal vs. Surgical Stripping Study and VenaSeal vs. ETA Study) for CEAP 2-
5 subjects and one single arm active VLU Study with CEAP 6 subjects. Each study will 
be individually assessed and analyzed for the overall study objectives. 
 
The three primary endpoints in the Randomized Studies will be measured to compare 
VenaSeal vs. the treatment of ETA or surgical stripping on VenousTSQe and 
VenousTSQs (separately) at 30 days, and elimination of clinically relevant superficial 
truncal disease in the target vein at the time of index procedure. The primary endpoint 
of the VLU Study is time to ulcer healing and will be measured until healing has 
occurred through 12 months.  
 
Subjects randomized within the VenaSeal vs. Surgical Stripping Study will be followed 
through the 12 months visit. In this study, the elimination of clinically relevant 
superficial truncal disease in the target vein at the time of index procedure will be 
summarized between two treatment arms but there is no formal hypothesis to be 
tested. 
 
The Statistical Analysis Plan (SAP) will be developed prior to data analysis and will 
include a comprehensive description of the statistical methods used to analyze the 
study objectives. Any change to the data analysis methods described in the CIP will 
require an amendment only if it changes a principal feature of the CIP. Any other 
change to the data analysis methods described in the CIP, and the justification for 
making the change, will be described in the clinical study report. 
 
All statistical analyses will be performed using Statistical Analysis System (SAS) 
software (version 9.2 or higher) or other widely accepted statistical or graphical 
software. 
4. Introduction  
4.1. Background  
Venous Reflux Disease 
Venous reflux disease (VRD) is a type of chronic venous disease (CVD) also known as venous insufficiency, 
a medical condition which affects the circulation of blood through the venous system of the lower 
extremities.  

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VRD of the lower extremities is a chronic and progressive disorder that is influenced by genetic and 
mechanical factors. It is believed to result from abnormal distensibility of the connective tissue present in 
the vein wall which ultimately results in venous dilatation and the failure of one-way valves present within 
the veins that direct the return of blood up the lower limb.1 Incompetence of the valves and hypertrophy 
of the vein wall result in backflow, or venous reflux, and a pooling of the blood in the superficial veins. 
Reflux in the superficial venous system, commonly known as varicose veins, is estimated to affect 23% of 
all adults in the U.S.2,3 The Framingham study (1988) found that VRD was twice as prevalent as coronary 
heart disease and five times as prevalent as Peripheral Arterial Disease (PAD), and that up to 90% with 
symptomatic venous reflux are untreated.4 The more advanced stages of the disease affect approximately 
5% of the population, with active ulcerative end stage disease present in about 1-2%.5,6 Great Saphenous 
Vein (GSV) insufficiency is the most common manifestation of varicose veins, although small saphenous 
(SSV), accessory saphenous, and duplicate veins that travel in parallel with the great and small saphenous 
veins (SSV) may also be affected.7 
CVD is considered a major socioeconomic burden throughout the world with a budgetary impact greater 
than that of arterial disease.8 At least 63.9% of over 90,000 subjects in a Vein Consult Program, providing 
data from Europe, Latin America, the Middle East and the Far East, were diagnosed with CVD.9 It was 
recently described that in Western Europe, 2% of the annual healthcare budget is spent on chronic venous 
conditions (900 million Euros). Venous ulcers, which could be prevented by early therapy, contribute to 2 
million lost workdays annually in the US.10,11 
Diagnosis and Classification of Disease Severity  
Primary varicose veins initially develop in subcutaneous veins with diameters ≤ 3 mm and are at first 
accompanied by few signs of CVD.12 As the disease progresses, patients with varicose veins develop one 
or more symptoms that might include heaviness, aching or throbbing pain in the lower legs, cramps, 
restless leg syndrome, pruritus (itchiness), fatigue, swelling, and tenderness along the varicosity.13 
Thrombophlebitis or bleeding from superficial varicose veins may be evident at diagnosis, as might the 
changes indicative of more advanced CVD such as edema, eczema, pigment changes, and ulcerations.6,14,15 
The skin changes occur due to sustained venous hypertension concomitant with CVD.16 
To adequately manage and treat venous reflux, the patient’s CVD must be accurately diagnosed and 
classified, with a focus on the underlying venous problem. Patients typically undergo non-invasive Duplex 
Ultrasound (DUS) scanning in accordance with guidelines for investigation of lower limb disease. DUS is 
considered the gold standard in diagnosis of VRD and is used in pre- and postoperative assessment as well 
as during therapy for minimally invasive procedures. The GSV, Anterior Accessory Saphenous Vein (AASV), 
Posterior Accessory Saphenous Vein (PASV), thigh extension, and the SSV are the main superficial conduits 
imaged and tested for possible reflux prior to therapy.  

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One of the most well-accepted methods to evaluate the clinical signs of VRD is the Clinical, Etiological, 
Anatomical, and Pathophysiological (CEAP) classification system.2,6,17 The CEAP includes four categories of 
assessment: the clinical signs of the disease (C), the etiology or cause of the disease (E), the anatomy of 
the disease (A), and its underlying pathophysiology (P). Based upon these assessments, the severity of the 
disease can be classified. Stages range from CEAP 0 to CEAP 6. The clinical signs range from no visible signs 
of the disease to venous disease with multiple symptomology and active venous ulcerations.12 
Treatment of VRD 
Traditional surgical removal of the incompetent varicose veins was for many years considered a gold 
standard for the treatment of superficial venous reflux. Such an approach is generally achieved by surgical 
ligation and stripping of incompetent superficial truncal veins. This procedure may require use of general 
anesthesia and has been associated with significant perioperative morbidity including postoperative pain 
18,19 and slow recovery to normal daily activities.20 
Therapies are often combined for maximum treatment benefit. Sclerotherapy is a minimally invasive 
endovenous treatment option in which a sclerosing compound (foam or liquid) is delivered directly into 
the target vein. The injected compound produces endothelial damage and inflammation which lead to 
"sclerotic changes" in the vein wall and eventual fibrosis across the vein lumen.21 Sclerotherapy is often 
used adjunctively with other primary treatments and is allowable in this study as described in section 10, 
study procedures. Disadvantages of sclerotherapy as a primary treatment include poor efficacy requiring 
multiple treatments and prolonged compression hose therapy following treatment.22 General risks 
associated with sclerotherapy are similar to other endovenous therapies and include thrombophlebitis, 
localized phlebitis, hyperpigmentation, telangiectatic matting, and transient pain.21, 22, 23, 24 
In response to the complications associated with the surgical treatment, minimally invasive procedures 
have been developed. Interventions such as endothermal ablation (ETA) are minimally invasive 
procedures and include endovenous laser ablation (EVLA) that uses laser or radiofrequency ablation (RFA) 
that uses radiofrequency heating to seal the vessel. Heat is applied in both the therapies to ablate the 
target vein via a different medium. The underlying goal for all thermal ablation procedures is to deliver 
sufficient thermal energy to the wall of the incompetent vein segment to coapt the vein wall and achieve 
occlusion, and fibrosis. RFA involves delivery of controlled radiofrequency energy through a generator 
which heats a segment of the catheter which is inserted into the diseased vein. A tumescent anesthetic is 
administered around the vein, the catheter is inserted, and the radiofrequency energy is delivered to 
occlude the vein. The heat causes the vein to contract and occlude. EVLA involves use of a laser catheter 
and is inserted into the venous system via percutaneous access using duplex ultrasound (DUS) guidance 
or by open venotomy. A tumescent anesthetic is also administered around the vein, laser energy is applied 
to the inside of the vein and the vein is sealed. Despite EVLA and RFA being minimally invasive, there are 

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disadvantages and risks with ETA, including hematoma, thrombophlebitis, venous thrombosis, vessel 
perforation, skin burns, paresthesia of the leg, the need for multiple needle sticks to apply large volumes 
(150-1000 cc) of perivenous anesthetic (i.e., tumescent anesthesia), or injury to the sural or saphenous 
nerve.25 Tumescent anesthesia is painful during administration and can lead to ecchymosis and longer 
recovery time. 
The VenaSeal™ closure system was developed as a non-thermal, non-tumescent and non-sclerosant 
(NTNTNS) alternative to other available treatment options, specifically thermal and tumescent options 
which require the usage of tumescent anesthesia and involve risk of thermal injury.25 The VenaSeal™ 
system uses a medical grade adhesive to eliminate the primary source of reflux by coapting the vein walls. 
Closure of the insufficient vein is accomplished through polymerization of a cyanoacrylate-based adhesive 
delivered via a catheter, and the resultant acute coaptation of blood flow is followed by eventual 
encapsulation of the blockage.  
Summary of VenaSeal™ Closure System Clinical Studies 
Feasibility Study 
The Feasibility Study was a prospective, single center study performed in the Dominican Republic to assess 
safety and VenaSeal™ effectiveness to treat VRD in the GSV. Effectiveness results of the Feasibility Study 
indicated a 94.7% closure rate at 6 months following the index procedure. Subjects were followed for 36 
months in total. There were 4 Serious Adverse Events (SAEs) reported in 3 subjects, with 1 of the 4 
determined to be related to the study device or study procedure. An additional 24 Adverse Events (AEs) 
were reported in 17 subjects. Finally, 1 Deep Vein Thrombosis (DVT) was observed at 31 months post-
treatment in a hypercoagulable subject (unknown device relationship, not related to the procedure). 
eSCOPE Post-Market Study 
The eSCOPE Post-Market Study was a multicenter, prospective, single arm study conducted in Europe 
designed to record the clinical outcomes of the CE-marked VenaSeal™ closure system for its approved 
indications. The primary objective was to assess the role of the VenaSeal™ system in closure of 
incompetent GSVs in a routine clinical setting. Effectiveness and safety (AEs) were compared to 
appropriate literature reports as per individual study protocols to determine if the results of the 
treatment of reflux disease with the VenaSeal™ system were consistent with or better than the 
expectations of the medical community for alternative treatments, specifically endovenous laser thermal 
ablation and RFA. Effectiveness results indicated a 91.4% closure rate at 6 months, declining to 88.5% 
closure at 36 months. At 6 months, safety analysis observed 32 AEs, one of which was an unrelated serious 
adverse event.  

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VeClose IDE Pivotal Study 
The VeClose Study was a randomized, prospective, multicenter study conducted to demonstrate safety 
and effectiveness of the VenaSeal™ system for the treatment of lower-extremity truncal reflux compared 
to RFA performed using the ClosureFast™ System. This study was conducted in the United States under 
Investigational Device Exemption (IDE) G120204, data from the study was used to support a premarket 
approval (PMA) application.  The PMA Application was approved by the FDA on February 20, 2015. 
The study’s primary effectiveness endpoint was at 3 months. The primary safety assessment was 
performed at 1 month. The study was originally completed on April 10, 2017. The    original results of the 
study, including 3-year follow-up data are summarized below. 
A total of 242 subjects from 10 US clinical sites were treated in the study. There were 20 subjects 
treated and analyzed in the roll-in cohort and 222 subjects in the randomized cohorts (108 in VenaSeal™ 
system and 114 in RFA). The overall mean age was 50 years (range 25 – 70) and the study population was 
consistent with the known female predominance of venous disease, with primarily female subjects (80%). 
The majority of subjects (56.6%) entered the study with venous disease in the study limb classified as 
CEAP 2. Aching and pain were the 2 most frequently reported dominant symptoms, with over 25% of 
subjects reporting these symptoms. There were no statistically significant differences in the 
demographics or baseline parameters between the randomized groups (VenaSeal™ system and RFA).  
Effectiveness was measured as vein closure at 3, 12, 24 and 36 months. At 3 months, the closure rate 
observed was 99.0% for the cyanoacrylate group and 96% for the RFA group decreasing to 94.4% by 36 
months for the cyanoacrylate group and 91.9% for the RFA group.26 There were no statistically significant 
differences in rates of any individual AEs between the randomized VenaSeal™ system group and the RFA 
group through 36 months. For both groups, the majority of subjects reported no AEs, and of those who 
reported AEs, the majority had only one event. A total of 156 AEs were reported in 100 subjects; 78 AEs 
in 47 VenaSeal™ system subjects, 15 AEs in 11 roll-in subjects, and 63 AEs in 42 RFA subjects. A total of 15 
serious adverse events (SAEs) were reported in 12 subjects (5 VenaSeal™ system, 1 roll-in, and 6 RFA). All 
were assessed as unrelated to the study device or study procedure.26,27,28,29 
There was one report of death (due to liver cancer) in a VenaSeal™ system subject. The liver cancer death 
at Day 1098 post-procedure was assessed as unrelated to the study device or study procedure. There was 
one report of deep venous thrombosis (DVT) in the non-index limb in an RFA subject. There were no 
reports of Pulmonary Embolism (PE), no reports of allergic reactions to the VenaSeal™ adhesive 
(cyanoacrylate), and no reports of Unanticipated Adverse Device Effects (UADEs). 
 

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VeClose Five-Year Follow-up Extension Study 
The VeClose Five-Year Follow-up Extension study was conducted to gain additional follow-up data from 
the patients enrolled in the VeClose IDE pivotal study described above. Patients treated in both the 
experimental and control study arms as well as in the roll-in cohort were assessed for a 60-month follow-
up visit. The study was conducted under a separate protocol and no further intervention occurred under 
this protocol. A total of 89 subjects completed the 60-month visit, 9 subjects were from the roll-in cohort 
and 80 subjects from randomization cohort (47 subjects in VenaSeal™ system and 33 subjects in RFA). 53 
subjects treated with the VenaSeal™ system (subjects enrolled in VenaSeal™ system + roll-in subjects) 
maintained a closure rate of 94.6% at 60 months. The closure rate for 33 subjects treated with RFA was 
100%. Kaplan-Meier freedom-from-recanalization analysis demonstrated non-inferiority of the 
VenaSeal™ system compared to the RFA group at a significance level of 0.025 (non-inferiority based on 
one-sided 97.5% confidence interval with lower limit = -3.5%, and margin of -10%), through the 60-month 
follow-up period (91.4% vs. 85.2%, respectively). These rates remained unchanged from the 36-month 
follow-up visit, indicating that no new GSV failures occurred between the 36- and 60-month visits in either 
group. No SAE, PE, DVT or treatment limb AEs were reported in both the VenaSeal™ system cohort and 
the RFA cohort between 36-month and 60-month follow-up.30 
WAVES 
In addition to the above industry-initiated studies, the Lake Washington Vascular VenaSeal™ Post-Market 
Evaluation (WAVES) study was a single-center multiple-investigator, single-arm prospective study 
investigating the use of the VenaSeal™ system in patients with symptomatic VRD. The study assessed the 
use of the VenaSeal™ system in GSVs (n=48), SSVs (n=8), and accessory saphenous veins (n=14).31 Diseased 
veins of up to 20 mm diameter were included. The WAVES protocol did not allow adjunctive tributary 
treatment at the time of the index procedure which were staged at 3 months post-index procedure. 
There were 70 veins treated in 50 subjects. All primary target veins (48 GSV, 14 ASV, and 8 SSV) showed 
100% closure using DUS at 7 days and 1 month. Complete closure at 3 months was achieved in 70 (99%) 
of the treated veins. By 3 months, the revised Venous Clinical Severity Score (rVCSS) (6.5 ± 2.4 at baseline 
to 1.8 ± 1.4 at 1 month and 3 month; p<0.001), Aberdeen Varicose Vein Questionnaire (AVVQ) (17.3 ± 7.9 
at baseline to 8.9 ± 6.6 at 1 month and 6.5 ±7.2 at 3 month; p<0.001), and the EQ VAS (84 ± 12 at baseline 
to 88.3 ± 8.7 at 1 month and 88.6 ± 10.6 at 3 month; p = 0.002) all showed statistical improvement 
between baseline and 1 month, and baseline and 3 month visits. The percentage of patients who required 
adjunctive treatments at three months was lower than had been predicted by the treating physicians (65% 
versus 96%, p=.0002).32 Procedural pain was mild with a Nominal Pain Rating (NPR) of 2.2 ± 1.8, and the 
mean time to return to work and normal activities was 0.2 ± 1.1 and 2.4 ± 4.1 days, respectively.  

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Phlebitis was the most common AE, occurring in the treatment area or side branches in 10 patients (20%), 
but resolving in all but one subject (2%) by one month. One patient developed body hives within the first 
week of the procedure which was resolved following antihistamine and steroid treatment, this was said 
to be consistent with a cyanoacrylate allergy. There were no DVTs or other SAEs. One patient had a 
thrombus extension at the seven-day DUS which was no longer evident at the one-month DUS. Between 
the 1-month and 3-month visits, there was one AE, knee bursitis in the treatment limb which was 
determined as unrelated to the procedure.32 
4.2. Purpose 
The purpose of the VENASEAL SPECTRUM study is to evaluate the patient’s experience and clinical 
improvement after treatment with the VenaSeal™ system compared to Standard of Care (SoC) 
treatments, surgical stripping or ETA, in the treatment of symptomatic superficial venous disease (CEAP 
2-5). Patient-centered outcomes, vein closure, ability to return to work, and clinical improvement will be 
measured after treatment of symptomatic venous reflux in the superficial truncal veins by the VenaSeal™ 
system or the comparator treatments. Additionally, in a separate single-arm study, CEAP 6 patients with 
at least one active venous leg ulcer will be enrolled, treated with the VenaSeal™ system and evaluated for 
wound healing. This study will complement the available clinical evidence for the VenaSeal™ system. 
There will be approximately 500 subjects enrolled in the VenaSeal Spectrum Study. Approximately 375 
subjects will be enrolled in CEAP clinical classifications 2-5 in the Randomized Studies (108 subjects in 
VenaSeal vs. Surgical Stripping Study and about 264 subjects in VenaSeal vs. ETA Study), and up to 125 
CEAP 6 subjects with VLUs will be treated with the VenaSeal™ system. Enrollment of the VenaSeal vs. 
Surgical Stripping Study was closed on 22-Feb-2022. All subjects participating in the VenaSeal vs ETA Study 
or in the VLU Study (CEAP 2-6) will be followed up to 60 months post-index procedure, all subjects 
participating in the VenaSeal vs. Surgical Stripping Study will be followed up to 12 months post-index 
procedure. 
5. Objectives and Endpoints 
5.1. Objectives 
5.1.1. 
Primary Objectives 
For the CEAP 2-5 Randomized Studies, the primary objectives are to compare the VenaSeal™ system to 
surgical stripping and ETA regarding patient experience and satisfaction, through a validated, patient-
centered 2-part venous treatment satisfaction questionnaire (VenousTSQ-early [VenousTSQe] and 

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VenousTSQ-status [VenousTSQs]) at 30 days, and the ability to achieve elimination of clinically relevant 
superficial truncal disease in the target veins at the index procedure.  
For the VLU Study, the primary objective is to evaluate time to ulcer healing through 12 months. 
5.1.2. 
 Secondary Objectives 
The key secondary objectives are to compare the VenaSeal™ system to surgical stripping and ETA in 
achieving the anatomical closure of superficial truncal veins at 6 months, and the ability to return to work 
post-index procedure. 
For all subjects, the secondary objective of the study is to evaluate the VenaSeal™ system in the treatment 
of symptomatic venous reflux in the superficial truncal veins. Specific areas of analysis include: 
effectiveness, safety, healthcare utilization, patient experience, and treating physician experience.   
In addition, secondary objectives in the VLU Study include ulcer healing rate, ulcer recurrence, and ulcer-
free time.  
5.2. Endpoints 
5.2.1  
Primary Endpoints 
The CEAP 2-5 Randomized Studies have three primary endpoints comparing the VenaSealTM system to 
surgical stripping or ETA: 
1. Peri-procedural patient satisfaction as measured by a validated, patient-centered venous treatment 
satisfaction questionnaire (VenousTSQe) at 30 days. 
2. Patient satisfaction as measured by a validated, patient-centered venous treatment satisfaction 
questionnaire (VenousTSQs) at 30 days. 
3. Elimination of clinically relevant superficial truncal disease in each target vein at the time of index 
procedure as measured by the percentage of target vein length successfully treated. 
The Primary endpoint for the VLU Study is time to ulcer healing, calculated through healing confirmation 
and verified by an independent core laboratory through 12 months.  
5.2.2 
Key Secondary Endpoints 
Data supporting the following endpoints will be collected for both the Randomized Studies as well as the 
VLU Study. The following endpoints will be compared for the Randomized Studies and will be evaluated 
for the VenaSeal™ system for the VLU Study.  

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1. Anatomic closure of the primary target superficial truncal vein at 6 months, defined as DUS showing 
vein closure along the entire treated vein segment with no discrete segments of patency exceeding 5 
cm after VenaSeal™ system and ETA procedures, or the absence of refluxing or residual primary target 
vein after surgical stripping procedures. 
2. Time to return to work as reported by the patient. 
5.2.3 
Secondary Endpoints 
Data supporting the following endpoints will be collected for both the CEAP 2-5 Randomized Studies as 
well as the VLU Study. When appropriate, data will be evaluated for the CEAP 2-5 Randomized Studies to 
compare the VenaSeal™ system to surgical stripping or ETA. Data may also be pooled for all VenaSeal™ 
system subjects from the CEAP 2-5 Randomized Studies and VLU Study as appropriate. The surgical 
stripping data will be collected up to the 12 months’ time point. 
Effectiveness secondary endpoints 
1. Anatomic closure of primary target vein at 30 days, and 12, 24, 36, 48 and 60 months:  
2. Anatomic closure of target vein at 30 days, and 6, 12, 24, 36, 48 and 60 months: 
3. Technical success of each target vein immediately post-index procedure: 
5. Time to reintervention of any target vein (including primary target vein) through 60 months, as 
measured by the time between the index procedure and the first reintervention procedure (through 
12 months for subjects enrolled in the VenaSeal vs. Surgical Stripping Study).  
• 
For subjects treated with the VenaSeal™ system or ETA it is defined as DUS showing vein closure 
along the entire treated vein segment with no discrete segments of patency exceeding 5 cm. 
• 
For subjects treated with surgical stripping this is defined as absence of refluxing or residual vein 
and it will be collected at 30 days and 12 months only. 
• 
For subjects treated with the VenaSeal™ system or ETA this is defined as DUS showing vein 
closure along the entire treated vein segment with no discrete segments of patency exceeding 5 
cm. 
• 
For subjects treated with surgical stripping this is defined as absence of refluxing or residual vein 
and it will be collected at 30 days, 6 and 12 months only. 
• 
For subjects treated with the VenaSeal™ system or ETA this is defined as DUS showing vein 
closure along the entire treated vein segment with no discrete segments of patency exceeding 
5 cm. 
• 
For subjects treated with surgical stripping this is defined as absence of refluxing or residual vein. 
4. Reintervention of any target vein (including primary target vein) through 60 months, assessed at each 
follow-up visit (through 12 months for subjects enrolled in the VenaSeal vs. Surgical Stripping Study). 

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Safety secondary endpoints 
6. Adverse events (AEs) occurring in the target limb, evaluated from index procedure through 12 
months: 
7. Additional events evaluated through 60 months (through 12 months for subjects enrolled in the 
VenaSeal vs. Surgical Stripping Study): 
Healthcare utilization secondary endpoints 
8. Number and type of adjunctive treatments conducted through 12 months post-index procedure. 
9. Healthcare utilization related to the target limb VRD, as determined by the number of healthcare visits 
conducted, and other health-related resources utilized (e.g., home healthcare services) between 
study visits through 60 months (30 days, 6 and 12 months only for subjects enrolled within the 
VenaSeal vs. Surgical Stripping Study). 
10. Procedures, tests and treatment of AEs related to the treatment modality or index procedure. 
11. VLU Study: Healthcare utilization and routine wound care treatments between study visits through 
60 months. 
Patient Experience secondary endpoints 
12. Time to return to normal activities as reported by the patients. 
13. Intra-procedural and post-procedural pain at the index procedure, and 7 days and 30 days as reported 
by the patient using the numeric rating scale (NRS) with a scale of 0-10. 
14. Change in venous disease symptoms at 7 and 30 days, and at 6, 12, 24, 36, 48, and 60 months 
compared to baseline (7 days, 30 days, 6 and 12 months only for subjects enrolled in the VenaSeal vs. 
Surgical Stripping Study), as measured by the revised Venous Clinical Severity Score (rVCSS) and 
subject self-reporting. 
• 
Hypersensitivity to VenaSeal™ adhesive  
• 
Phlebitis 
• 
Granuloma 
• 
Endovenous glue induced thrombosis (EGIT) or endovenous heat induced thrombosis 
(EHIT) 
• 
Symptomatic deep vein thrombosis (DVT) events 
• 
Symptomatic pulmonary embolism (PE) 
• 
Serious adverse events (SAEs) 

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15. Change in AVVQ score at 30 days, and 6, 12, 24, 36, 48, and 60 months (30 days, 6 and 12 months only 
for subjects enrolled in the VenaSeal vs. Surgical Stripping Study) compared to baseline. 
16. Change in EuroQoL Group 5-Dimension Self-Report Questionnaire (EQ-5D-5L) at 30 days, and 6, 12, 
24, 36, 48 and 60 months (30 days, 6 and 12 months only for subjects enrolled in the VenaSeal vs. 
Surgical Stripping Study) compared to baseline. 
17. Change in the 36-Item Short Form Health Survey (SF-36) reported by the patient at 30 days, and 6 and 
12 months compared to baseline. 
18. Change in the Venous Dependent Quality of Life (VenousDQoL) reported by the patient at 30 days, 
and 6, 12, 24, 36, 48, and 60 months (30 days, 6 and 12 months only for subjects enrolled in the 
VenaSeal vs. Surgical Stripping Study) compared to baseline. 
Provider Experience secondary endpoint 
19. Provider experience will be assessed post-index procedure, evaluating overall satisfaction with the 
procedure. 
VLU Study: 
The primary endpoint of the VLU Study is referenced in section 5.2.1, Primary endpoints. 
The following ulcer-specific effectiveness endpoints will be evaluated: 
20. Ulcer healing rate, as measured by the percentage of the ulcer area healed per given time period, 
according to an independent core laboratory through 24 months or until ulcer healing has been 
confirmed. 
21. Ulcer recurrence on the target limb, assessed at all follow-up timepoints following ulcer healing 
through 60 months. 
22. Ulcer-free time, calculated as days between initial ulcer healing and first ulcer recurrence, as 
applicable, through 60 months. 
In addition, the primary endpoints and any other applicable endpoints of the Randomized Studies will be 
also assessed for the VLU Study: 
23. Peri-procedural patient satisfaction as measured by a validated patient-centered venous treatment 
satisfaction questionnaire (VenousTSQe) at 30 days. 
24. Patient satisfaction as measured by a validated patient-centered venous treatment satisfaction 
questionnaire (VenousTSQs) at 30 days. 
25. Elimination of clinically relevant superficial truncal disease in target vein at the time of index 
procedure as measured by the percentage of target veins successfully treated.  

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6. Study Design  
The study design is a global, post-market, prospective, multi-center, randomized-controlled study of 
patients with symptomatic superficial venous disease, with a single-arm embedded ulcer group. The study 
is designed with two Randomized Studies (VenaSeal vs. Surgical Stripping Study and VenaSeal vs. ETA 
Study) for CEAP 2-5 subjects and one single arm active VLU Study for CEAP 6 subjects. Each study will be 
individually assessed and analyzed for the overall study objectives. The two Randomized Studies 
(VenaSeal vs. Surgical Stripping Study and VenaSeal vs. ETA Study) will not be blinded due to the significant 
differences between the treatments and after care which would prevent the patient from being able to 
be blinded. For example: surgical stripping subjects will undergo a surgical procedure with several possible 
types of anesthesia including general anesthesia, whereas VenaSeal and ETA subjects will undergo a 
minimally invasive intervention with limitations in allowed anesthesia; these different anesthesia types 
require significantly different post-treatment care. In addition, due to the post-market nature of the study, 
where allowable within regions, patient insurance will be utilized to cover the cost of the procedure, 
however each procedure may result in differing financial impacts to the patient. Due to these inherently 
different aspects, blinding of treating physicians or patients would not be possible, and patients could 
potentially be put at higher risk due to blinding. 
There will be approximately 500 subjects enrolled in the VenaSeal Spectrum Study. Approximately 375 
subjects will be enrolled in CEAP clinical classifications 2-5 in the Randomized Studies (108 subjects in 
VenaSeal vs. Surgical Stripping Study and about 264 subjects in VenaSeal vs. ETA Study), and up to 125 
CEAP 6 subjects with VLUs will be treated with the VenaSeal™ system.  
On 22-Feb-2022, enrollment closed to participating VenaSeal vs. Surgical Stripping Study sites within the 
VenaSeal Spectrum clinical study. Subjects randomized in this study will be followed up to and including 
the 12 months visit.  
Enrollment will take place at up to 40 sites globally. A list of participating investigational sites which 
includes the name, position, emergency contact details and address of the investigators responsible for 
conducting the study will be available under a separate cover (including additional regions that may be 
added to the study).  
Currently, ETA and surgical stripping are the most common health insurance-covered treatments for VRD 
in a global setting. ETA is standard of care both in the United States and outside of the United States. 
Surgical stripping is not standard of care in the United States and is practiced as primary treatment outside 
of the United States. Hence, in the United States, sites will only participate in VenaSeal vs. ETA Study 
and/or the VLU Study. Outside of the United States, sites will participate in either the VenaSeal vs. ETA 
Study or the VenaSeal vs. Surgical Stripping Study, and/or the VLU Study. Beginning with version 4.0 of 

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the VenaSeal Spectrum CIP, no new sites will be activated for participation in the VenaSeal vs. Surgical 
Stripping Study and no additional VenaSeal vs. surgical stripping subjects will be enrolled. Sites in all 
geographies may participate in the VLU and VenaSeal vs. ETA Study. Site designation for all studies will be 
indicated in the Site Selection Letter provided by Medtronic. 
To avoid introduction of bias to the study results due to disproportionate enrollment, enrollment at any 
individual site shall not exceed 20% of any single study (approximately 50 subjects for the Randomized 
Studies and 25 subjects for the VLU Study, excluding screen failures) of the total sample size. It is expected 
that sites enroll a minimum of 10 subjects per individual study the site is participating in. 
The study methods include the following measures to minimize potential sources of bias: 
6.1. Duration 
It is anticipated that enrollment will take approximately 36 months following enrollment of the first 
subject. The estimated study duration is approximately 8 years, including up to 60-month follow-up post-
procedure and excluding the time required for preparing the final report. The expected duration of each 
subject’s participation is up to 60 months after the index procedure, apart from subjects who were 
enrolled in the VenaSeal vs. Surgical Stripping Study. The latter will be followed through 12-months only.  
Data will be recorded in the Case Report Form (CRF) at screening, baseline, index procedure (day 0), and 
during follow-up at 7 days (± 2 days), 30 days (± 7 days), 6 months (± 4 weeks), 12 months (± 8 weeks), 24 
months (± 8 weeks), 36 months (± 8 weeks), 48 months (± 8 weeks) and 60 months (± 8 weeks). Additional 
routine care visits can be conducted to accommodate adjunctive procedures 3 or more months following 
the index procedure (data for adjunctive procedures will be collected through 60 months), per the treating 
physician’s discretion; these will not be considered study visits. 
• 
An external, independent Clinical Events Committee (CEC) will review and adjudicate, at minimum, 
SAEs, target limb AEs including hypersensitivity, phlebitis, granuloma, and EGIT or EHIT. Safety results 
for these events will be reported based on CEC adjudication. 
• 
An ulcer core laboratory will evaluate all CEAP 6 subjects who are enrolled into the study with active 
VLUs. VLU size measurements will be based on ulcer core laboratory evaluation as well as final 
confirmation of ulcer healing. 
• 
Study monitors will verify subject data and ensure compliance with the clinical investigation plan and 
other study requirements per the monitoring plan. 
• 
Statistical analysis plan (SAP) will be developed prior to the analysis of the objectives. 
• 
To avoid bias during randomization: Oracle Clinical will be used for randomization of subjects, 
stratified by study site and CEAP classification (2004).  

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Data of subjects who were enrolled in the VenaSeal vs. Surgical Stripping Study will be recorded in the 
CRF at screening, baseline, index procedure (day 0), and during follow up at 7 days (± 2 days), 30 days (± 
7 days), 6 months (± 4 weeks), and 12 months (± 8 weeks).  
CEAP 6 subjects will have additional study visits until healing verification and data will be recorded in the 
CRFs at: 2 months (± 7 days), 3 months (± 7 days), 4 months (± 7 days), 5 months (± 7 days), 8 months (± 
2 weeks), 10 months (± 2 weeks). If the healing has not occurred by 12 months, subjects will continue to 
follow standard wound care and remaining study visits. Subjects will come in for ulcer healing verification 
visit up to 24 months, after which no core laboratory ulcer assessment for wound healing will be required.  
6.2. Rationale  
Currently, ETA and surgical stripping (outside of the US) are the most common treatments of VRD. This 
study is being conducted to evaluate the patient’s experience and clinical improvement after treatment 
with the VenaSeal™ system compared to standard of care treatments, surgical stripping or ETA, in the 
treatment of symptomatic superficial venous disease (CEAP 2-5). Patient-centered outcomes, vein 
closure, ability to return to work and clinical improvement will be measured after treatment of 
symptomatic venous reflux in the superficial truncal veins by the VenaSeal™ system or the comparator 
treatments. In a separate single-arm VLU Study, CEAP 6 patients with at least one active venous leg ulcer 
will be enrolled and treated with the VenaSeal™ system and evaluated for wound healing. 
By collecting additional data regarding the provider experience, patient experience, safety, quality of life, 
patient satisfaction, ability to return to normal activities, procedural experience and healthcare resource 
utilization, this study will provide foundational evidence for further characterizing the VenaSeal™ system. 
In addition, this study represents the first VenaSeal™ system study focusing on the active VLU (CEAP 6) 
population, evaluating time to ulcer healing, ulcer healing rate, ulcer recurrence, and ulcer-free time.  
The justification of the study design is based on a clinical evaluation and is aligned with the risk assessment 
done for the study, given the post market nature of all the devices and procedures involved.  
The decision of closure of the VenaSeal vs. Surgical Stripping Study enrollment was made due to significant 
delays and challenges recruiting sites and subjects during the global COVID-19 pandemic. The subjects 
enrolled in VenaSeal vs. Surgical Stripping Study will still be followed through 12 months to ensure follow-
up through the first year following procedure. 
The primary endpoint for the VLU study for time to ulcer healing is updated from 24 months to 12 months 
to align with landmark clinical trials in superficial venous space.  

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The hypothesis test was removed for the primary endpoint of elimination of clinically relevant superficial 
truncal disease in each target vein at the time of index procedure for the VenaSeal vs. Surgical Stripping 
Study as the endpoint is no longer powered with the reduced sample size. However, results will still be 
summarized between study arms.  
Subjects may also complete 48 and 60 months visit remotely per physician’s discretion if subjects cannot 
return to the site for follow-up. The long-term follow-up visits, 48 and 60 months may have higher attrition 
rate. The remote visit is permitted in the study for 48 and 60 months to keep the attrition rate minimal 
and be able to collect long term study data as much as possible.  
Data for adjunctive therapies and additional treatments will be collected till 60 months to ensure accuracy 
of data on healthcare utilization. 
Data on perforating veins for CEAP 4b or 5 on the target limb are collected from 3 months through study 
end to perform an accurate healthcare utilization analysis. 
The exclusion criterion on COVID-19 has been updated to reflect the current understanding and 
guidelines. 
7. Product Description 
The primary product in the study is the VenaSeal™ closure system and is described below. The use of 
comparator products that will be included in ETA are per the study site’s standard of care or the treating 
physician’s discretion. The comparator products are not described in this protocol and the current version 
of the Instructions for Use (IFU) available at the time of the study procedure with the appropriate product 
should be utilized. The surgical stripping procedure should be performed per treating physician’s standard 
of care.  
7.1. General 
The VenaSeal™ system is a medical device kit consisting of delivery tools and proprietary VenaSeal™ 
adhesive used to treat venous reflux insufficiency in lower-extremity superficial truncal veins. The 
VenaSeal™ system offers an outpatient treatment option for permanently occluding superficial truncal 
veins.  
The VenaSeal™ system includes one 5 cc vial of VenaSeal™ adhesive and the VenaSeal™ Delivery System 
components. 

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 Figure 1: VenaSeal™ adhesive                                                Figure 2: VenaSeal™ Components in a Tray                               
The VenaSeal™ Delivery System consists of 7 delivery tools used to facilitate endovascular placement and 
delivery of VenaSeal™ adhesive in the target vessel during the delivery procedure: 
All materials that may contact tissues and/or body fluids are presented in the Table 3:  
Table 3: Materials in contact with tissues and/or body fluids 
VenaSeal™ system device 
component 
Materials 
VenaSeal adhesive 
• 
Proprietary Cyanoacrylate adhesive 
Introducer 
• 
Extrusion: Polyethylene homopolymer, Filler, Pigment, Color 
Concentrate High Density Polyethylene  
Dilator 
• 
High Density Polyethylene Extrusion: Polyethylene hexene 
copolymer, Filler, Color Concentrate  
• 
Introducer  
• 
Dilator  
• 
Catheter  
• 
Dispenser gun  
• 
Dispenser tips  
• 
3 cc syringes  
• 
Guidewire 

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VenaSeal™ system device 
component 
Materials 
Catheter 
• 
Extrusion: Polytetrafluoroethylene Extruded 
• 
Extrusion: Polytetrafluoroethylene Extruded Unfilled, Natural 
• 
Hub: High Density Polyethylene  
.035" Guide Wire 
• 
Core: Stainless Steel Medical Grade 
• 
Coating: Polytetrafluoroethylene  
3mL Monoject Luer Lock 
Syringe 
• 
Barrel: Polypropylene Copolymer 
• 
Plunger Tip: SSBR Rubber Compound (Silicon-free rubber) 
14 Gauge SS Dispensing Tip 
• 
Hub: Polypropylene, proprietary stabilizers/colorant 
• 
Cannula: Stainless Steel 
• 
Adhesive: UV Adhesive 
Captive J-Straightener 
• 
Polypropylene, Pantone 264-U Purple 
All tools are provided sterile and are intended for single patient use. Designs are based on applicable 
standards for similar devices.  
Current VenaSeal™ System model numbers information is listed below in Table 4: 
Table 4: Current VenaSeal™ System model numbers 
Model Number  Product (Manufacturer) 
Investigational or Market-released 
SP 101 
VenaSeal™ System (Medtronic Inc.) 
Market-released 
VS 402 
VenaSeal™ System (Medtronic Inc.) 
Market-released 
VS 403 
VenaSeal™ System (Medtronic Inc.) 
Market-released 
VS 404 
VenaSeal™ System (Medtronic Inc.) 
Market-released 
In the event that additional model numbers become available during the study, an updated model number 
list will be made available under a separate cover. 

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7.2. Manufacturer 
The VenaSeal™ closure system is manufactured in accordance with standard procedures and 
specifications under 21 Code of Federal (CFR) 820 and International Organization for Standardization (ISO) 
13485:2016. The legal manufacturer is listed below: 
Medtronic Inc. 
710 Medtronic Parkway  
Minneapolis, Minnesota 55432 USA 
7.3. Packaging 
The study will be conducted in geographies where the VenaSeal™ closure system is commercially 
available. The packaging and labeling are in accordance with local regulations and available in local 
languages as applicable. The VenaSeal™ system is delivered in a sterile package for single use only. 
7.4. Intended Population 
The VenaSeal™ closure system will be used according to the IFU criteria as applicable per region. The 
indications listed here are at time of protocol finalization. Please refer to the respective IFU for current 
and applicable indications.  
The VenaSeal™ system achieved European Conformity (CE) mark status in September 2011, Food and 
Drug Administration (FDA) approval in the United States in February 2015, and approval in South Korea in 
October 2016.  
United States (U.S.) Indication (VS-402, VS-404): The VenaSeal™ system is indicated for use in the 
permanent closure of lower extremity superficial truncal veins, such as the GSV, through endovascular 
embolization with coaptation. The VenaSeal™ system is intended for use in adults with clinically 
symptomatic venous reflux as diagnosed by DUS. 
Outside of the United States (OUS) Indication (VS-403, SP-101): The VenaSeal™ system is intended for the 
permanent, complete, endovascular adhesive closure of the GSV and associated varicosities in the 
treatment of VRD. 
South Korea Indication (SP-101): The VenaSeal™ system is intended for use in patients with venous reflux 
disease as diagnosed by duplex ultrasound (DUS). The VenaSeal™ system is indicated for use in the 
permanent closure of lower extremity superficial truncal veins, such as the great saphenous vein (GSV), 
through endovascular adhesive closure. 

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If any additional regions are added to the study, the current IFU applicable to the region should be 
followed.  
The use of the VenaSeal™ system is contraindicated when any of the following conditions exist: 
7.5. Equipment 
Any test equipment critical to be used for assessing endpoints (e.g., DUS) will be maintained/calibrated 
and documented according to the site’s standard protocol. The maintenance and calibration report should 
be made available to monitors upon request.  
7.6. Product Use  
The device should be used within the intended use described in the IFU for subjects who meet the 
eligibility criteria for the study. The VenaSeal™ closure system will be obtained by the study sites according 
to their standard procedures for commercial products. The site must store devices as labelled. The 
identification number of the VenaSeal™ system used for enrolled subjects will be captured in the study 
database.  
7.7. Product Training Materials 
Treating physician training for the study products is to be completed per local regulations prior to study 
participation. Additional, study-driven training is not required as the products used in the study are 
commercially available. However, all treating physicians are required to have minimum experience with 
the study product as explained in section 8.1. 
7.8. Product Accountability 
Commercially available product supply will be managed in a manner consistent with other market-
released products. All products used in this study will be market released in the geographies they are 
used. Device Traceability may be required per local laws and regulations. If there are additional local 
requirements related to the VenaSeal™ system beyond what is collected by Medtronic on the CRF, this is 
the Investigator’s responsibility and should be recorded in the subject’s medical records, but will not be 
• 
Previous hypersensitivity reactions to the VenaSeal™ adhesive or cyanoacrylates 
• 
Acute superficial thrombophlebitis 
• 
Thrombophlebitis migrans 
• 
Acute sepsis. 

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collected by Medtronic (e.g., national registration card number, identification code linked to names and 
contact information, log of all subjects enrolled in the study, lot or batch number). Full device tracking as 
required by ISO 14155:2020 will not be performed due to the post-market nature of the study. 
8. Study Site Requirements 
8.1. Investigator/Investigation Site Selection  
All investigators managing the subject’s superficial venous disease must be qualified practitioners and 
experienced in the diagnosis and treatment of subjects with superficial venous disease. All treating 
physicians must be experienced and/or trained in the handling of the VenaSeal™ system if they are 
delegated to treating VenaSeal subjects and, depending on the randomized study they will participate in, 
either in a standard of care ETA treatment modality or the surgical stripping procedure. In addition, only 
a physician is allowed to carry out the index procedure, regardless of local laws governing endovenous 
procedures. The investigator’s experience with superficial venous treatment will be documented on a 
separate physician experience form prior to the individual’s activation for the study.  
Additional, qualifying treating physicians may be added to a site and activated at any point in the study, 
following meeting all the above requirements, all appropriate training and study team approval.  
The role of the Principal Investigator (PI) is to implement and manage the day-to-day conduct of the 
clinical investigation as well as to ensure data integrity and the rights, safety and well-being of the subjects 
involved in the clinical investigation. 
The Principal Investigator shall: 
- 
Be qualified by education, training, and experience to assume responsibility for the proper 
conduct of the clinical investigation. 
- 
Be experienced in the field of application and training in the use of the VenaSeal™ system. 
- 
Disclose potential conflicts of interest, including financial, that interfere with the conduct of the 
clinical investigation or interpretation of results. 
- 
Be able to demonstrate that the proposed investigational study site has: 
• 
The required number of eligible subjects needed within the recruitment period. 
• 
One or more qualified investigators, a qualified investigational study site team, and 
adequate facilities for the foreseen duration of the clinical investigation. 
Study site personnel training will be completed and documented prior to participation in this study. 

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8.2. Study Site Activation  
During the activation process (prior to subject enrollment), Medtronic will train study site personnel on 
the current version of the clinical investigation plan (CIP), relevant standards and regulations (as needed), 
informed consent, and data collection and reporting tools. If new members join the study site team, they 
will receive training on the applicable study requirements relevant to their role before being activated by 
Medtronic and contributing to the study. The PI and study site personnel who are trained to the study 
protocol and all relevant documents can also train other study site personnel in accordance to their role 
as needed. All participating study site staff must be delegated by the PI to perform study related activities. 
Medtronic will provide each study site with documentation of study site readiness. PI, Sub-Investigators 
and research coordinators participating in the study will also receive a Site Activation Letter; this letter 
must be received prior to performing study related activities. DUS technicians will not receive a Site 
Activation Letter but are required to provide training documentation and listing on the site’s delegation 
task list prior to commencing study related activities.   
Prior to performing study related activities, all regulatory requirements shall be fulfilled, including, but 
not limited to the following: 
• 
Institutional Review Board (IRB)/Ethics Committee (EC)/Competent Authority (CA) approval (and 
voting list, as required by local law) of the current version of the CIP and Informed Consent Form (ICF). 
• 
Regulatory Authority approval or notification (as required per local law). 
• 
Fully executed Clinical Trial Agreement (CTA). 
• 
Complete site documentation including but not limited to Financial Disclosure, CV of Investigators and 
key members of investigation study site team, Delegated Task List, and Training Record. 
Due to the COVID-19 global pandemic, a COVID-19 site activation assessment shall be completed with the 
site in order to assess a site’s readiness to be activated, and to ensure the protection of subjects in 
accordance to the study CIP. The assessment consists of a checklist that provides recommended criteria 
to be assessed and to be verified prior to resuming study-related activities. Consideration should be made 
to minimize risk to subjects due to COVID-19 including all study-specific non-standard of care activities 
and post-procedural care (i.e., location, travel, etc.). Sites should evaluate if a subject is suitable for 
enrollment based on their individual situation including the applicable IRB/EC, local, and country guidance 
to reduce associated COVID-19 risks and to maintain adherence to the CIP including index procedures, 
subject follow-up visits, medical assessments, and imaging compliance. Sites should also be able to 
support either on-site or remote monitoring prior to activation. If, during the conduct of the trial, a site’s 
COVID-19 impact changes, Medtronic reserves the right to re-assess the site’s ability to continue with 
subject enrollment and follow-up at any point following site activation. 

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8.3. Role of the Sponsor Representatives  
Sponsor representatives may provide support at the study site as required for the study under supervision 
of the PI, including: 
• 
Provide study training relevant and pertinent to the involvement of personnel conducting study 
activities and investigator responsibilities. 
• 
Technical support during the procedure under the supervision of a study investigator, but no data 
entry, shall be performed by Medtronic personnel or their representatives at study sites. 
• 
Monitoring and auditing activities. 
Representatives from Medtronic may provide technical support during the procedures to the treating 
physicians and study site staff relative to the use of the VenaSeal™ system and in relation to the collection 
of data during the index procedure. This will not bias the data integrity in any way. Initial technical support 
may be provided by Medtronic during the first few VenaSeal procedures at a site to ensure that the 
technique is carried out consistently according to the device’s IFU by all treating physicians. In addition, 
the technical support will also have the purpose to ensure that the necessary study datapoints are 
considered and collected for all procedures that are part of this study. This is expected to lead to high 
quality data that is consistently collected among all global sites. Technical support for the comparator 
therapy procedures will only be provided in relation to data collection, as participating sites will have more 
experience with comparator therapies being SoC.    
9. Selection of Subjects 
9.1. Study Population 
Patients 18 years of age or older requiring treatment of symptomatic venous reflux within the superficial 
truncal veins may be considered for this study if they meet all of the inclusion and none of the exclusion 
criteria outlined in this clinical investigation plan. Patients with CEAP 2-5 will be screened for the 
Randomized Study; VenaSeal vs. ETA Study. As of February 22, 2022, enrollment closed in the VenaSeal 
vs. Surgical Stripping Study. Patients with CEAP 6 will be screened for the active VLU Study. Due to the 
post-market nature of the study, the investigational population is almost identical to the device’s target 
population except for the exclusion of the non-ambulatory patients.  
9.2. Subject Screening and Enrollment 
Patients with symptomatic venous reflux (2004 CEAP 2-6) in the superficial truncal veins (GSV, SSV, 
accessory saphenous vein) will be screened for possible inclusion in the study. Patients with CEAP 2-5 will 

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be screened for the Randomized Studies. CEAP 6 patients with symptomatic reflux in the superficial 
truncal veins eligible for vein closure using the VenaSeal™ system will be screened only at designated VLU 
sites for the VLU Study; these subjects will not be randomized.  
During the study, Medtronic may limit enrollments of specific CEAP classifications, if needed to achieve a 
balanced distribution across clinical severity subgroups. 
A combination of medical records, history and physical examinations, as well as standard of care DUS 
examination may be utilized for screening and identification of potential target veins. 
Patients who meet all eligibility criteria and sign and date the ICF will be considered ‘screened’ from the 
point they have signed and dated the ICF. Information needed to assess eligibility will, in most cases, 
already be captured via routine care prior to consent. If the routine diagnostic DUS is older than 6 months, 
this will need to be redone in order to verify eligibility. In the instance that a screened subject no longer 
meets all eligibility criteria, the screened patient will be considered a ‘screen failure’. 
All patients that will be identified for the potential screening in the study will be added to the ‘Pre-
Screening Log’. In the ‘Pre-Screening Log’, sites will document the general reason for why a patient was 
not consented in the pre-specified categories. All subjects that sign and date the informed consent will be 
added to the Oracle database and hence there will be no need to maintain an additional ‘Subject Screening 
Log’ unless it is the site’s preference to do so. All subjects that are enrolled will be documented in the 
‘Subject Identification and Enrollment Log’ (subject name, date of birth, subject identification number, 
enrollment date and randomization arm as applicable), which will not be collected by Medtronic but 
should be available for monitor review while on site. 
CEAP 2-5 Subjects 
After the patient has signed the ICF, met all of the inclusion and none of the exclusion criteria, the CEAP 
2-5 subjects will be randomized to one of the treatment arms, refer to section 10.4, Randomization and 
Treatment Assignment (CEAP 2-5) for more details. CEAP 2-5 subjects will be considered ‘enrolled’ from 
the moment of randomization.  
CEAP 6 Subjects 
CEAP 6 subjects that have met all of the inclusion and none of the exclusion criteria and sign the ICF will 
be considered ‘enrolled’ from the moment the first component of the VenaSeal™ delivery system enters 
the body. Study sites that are not identified at site selection as VLU sites will not be allowed to enroll CEAP 
6 patients.  
 

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Treatment Outcome Groups: 
The subjects will be included in one of the below treatment groups; the required follow-up schedule for 
all outcome groups is indicated in Table 5. In the event that the assigned treatment for the subject is not 
successfully completed on the first attempt, the reattempt of the procedure can be done on the same day 
or within 14 days of attempted index procedure per treating physician’s discretion. After 14 days, the site 
should contact the study team to determine next steps. 
Table 5: Treatment Outcome Groups 
Treatment Outcome 
Required Follow-Up 
Successful Treatment*:  
Completion of the assigned treatment including any 
reattempt to complete the index procedure. 
Follow subject schedule per schedule of events and 
data collection in section 10.1. 
Incomplete Treatment*:  
The index procedure was commenced where the device 
entered the vasculature, or the surgical stripping 
procedure was initiated but for any reason full target 
vein length was not treated. 
Follow subject schedule per schedule of events and 
data collection in section 10.1. 
*Subjects with more than one target vein can have a resulting outcome of successful treatment in one vein and 
incomplete treatment in another. These differing outcomes should be reported on separate Procedure Target 
Vein CRFs. 
Aborted Procedure:  
Failed completion of the assigned treatment where the 
subject was prepped for the index procedure, but the 
device did not enter the vasculature or surgical 
stripping was not initiated for any target vein. 
Follow subject for 30 days from the date of the 
attempted index procedure for AE assessment only, 
which can be completed as a phone call visit if deemed 
appropriate by the treating physician.  
Any data collected prior to and during the attempted 
index procedure, including AE and device deficiency, 
should be reported on applicable CRFs. 
No Procedure (CEAP 2-5):  
Subject is randomized (considered enrolled) but 
withdraws from the study after randomization without 
any attempt to conduct the procedure (e.g., COVID-19 
exclusion, subject withdrawal, etc.). 
Subject will not be followed in the study for any 
duration and can exit the study. Complete Study Exit 
CRF. 
Randomization Procedure Not Followed (CEAP 2-5; 
major protocol deviation): 
Subject treated with a modality they were not 
randomized to. 
Follow subject schedule per schedule of events and 
data collection in section 10.1. Report protocol 
deviation as “randomization procedure not followed”. 

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Figure 3: Flow-Diagram from Subject Screening to Follow-up 

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9.3. Target Veins and Target Limb 
Multiple refluxing superficial truncal veins (e.g., GSV, SSV, accessory saphenous veins) in the same target 
limb that are each at least 10 cm in length may be enrolled and treated in the study. During screening and 
prior to randomization, sites will identify at least one incompetent target vein. The primary target vein 
should be the saphenous vein which at the investigator’s discretion is most likely responsible for the 
greatest portion of the patient’s symptoms or pathology. The investigator will identify the primary target 
vein and any additional qualifying target veins to be treated prior to the randomization for CEAP 2-5 
subjects and prior to the index procedure for CEAP 6 subjects. The primary target vein will be treated first 
during the index procedure, and the remaining target veins will be treated in succession.  
If more than one vein requires treatment in the target limb, the treating physician will indicate which vein 
is the primary target vein in the CRFs and track the veins accordingly throughout the study.  In the case of 
bilateral disease with both limbs meeting study eligibility criteria, the investigator should designate the 
more severe limb (higher CEAP score or most symptomatic according to patient, per treating physician’s 
discretion) target limb. Treatment of the contralateral limb must be staged at least 30 days prior to or at 
least 3 months post-index procedure. 
9.4. Target Ulceration on the Target Limb 
At designated VLU sites, patients may be enrolled as CEAP 6 only if ulceration of venous etiology has been 
identified. Venous etiology will be verified at Screening by the independent core laboratory. The 
ulceration must be on the target limb. In case of multiple potential wounds within the ulceration, the 
physician should designate each wound in succession using the image capture equipment provided to 
sites. Instructions and training will be provided to sites for this purpose. 
Circumferential ulcers are not eligible to be included in the study, and the ulcer type will be assessed 
during the screening visit. It is acceptable for included ulcers to have some curvature, however any 
curvature around the leg that goes out of sight would be classified as a circumferential ulcer.  
Photographs of the target ulceration will be taken at each visit and sent to the core laboratory for 
assessment. Any ulcer that cannot be captured by one photograph (any ulcer curvature around the leg 
that goes out of sight) will be considered as a circumferential ulcer and these subjects will not be included 
in the study. Screening etiology photographs captured as part of routine care within 60 days can also be 
utilized and sent to the core lab, as deemed appropriate by the treating physician. All wounds on the 
target limb, as well as any new wounds that develop during the course of the study, should be treated per 
the investigator’s standard of care using approved devices or procedures including wound care, 
compression therapy, additional superficial vein treatment, and treatment of additional varicosities and 
incompetent perforating vein(s) required to heal the ulcer. 

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9.5. 
 Inclusion Criteria  
1. Patient is ≥18 years of age. 
2. Patient has venous reflux in superficial truncal vein(s) (e.g., GSV, SSV, accessory saphenous veins) with 
CEAP category 2 (symptomatic) or CEAP category 3, 4a, 4b, 5, 6 based on the American Venous Forum 
CEAP classification (2004), appropriate for treatment, as confirmed by DUS. 
3. Eligibility for treatment: 
• 
VenaSeal vs ETA Study: Patient is eligible for treatment with the VenaSeal™ system and ETA. 
• 
VenaSeal vs Surgical Stripping Study: Patient is eligible for treatment with the VenaSeal™ system 
and surgical stripping. 
• 
VLU Study: patients should be eligible for treatment with the VenaSeal™ system. 
4. Treatable refluxing segment of target vein(s) 10 cm in length or longer. 
5. Patient has a target vein diameter of ≥3 mm throughout the intended treatment segment of the 
target vein as measured by DUS while patient is standing. 
6. Patient is willing and capable of complying with specified follow-up evaluations at the specified times. 
7. Patient has an ability to understand the requirements of the study and to provide informed consent. 
9.6. Exclusion Criteria  
1. Patient has a known history of allergic sensitivities (including but not limited to cyanoacrylate 
adhesives), or any other condition, which in the opinion of the investigator may make the patient 
more susceptible to cyanoacrylate adhesive hypersensitivity. 
2. Patient has known deep vein obstruction in the target limb, as identified by the site’s standard of care. 
3. Patient has abnormal pulse exam or ABI <0.8. 
4. Patient has acute superficial thrombophlebitis. 
5. Patient requires any non-target vein treatments in the contralateral or ipsilateral limb, or any other 
surgical procedure up to 30 days pre-procedure and through 3 months post-procedure. 
6. Patient has any co-morbid conditions, which in the investigator’s opinion may interfere with the 
patient’s compliance with study visits and procedures, or may confound interpretation of study data 
(e.g., congestive heart failure Class III and IV, non-ambulatory patients, severe hepatic dysfunction, 
life expectancy < 1 year). 
7. IFU contraindications:  
• 
VenaSeal vs. ETA Study: Patient has VenaSeal™ system and/or ETA product’s IFU 
contraindication(s). 
• 
VenaSeal vs. Surgical Stripping Study: Patient has surgical stripping and/or VenaSeal™ system IFU 
contraindication(s). 
• 
VLU Study: Patient has VenaSeal™ system IFU contraindication(s). 

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8. Patient is non-ambulatory. 
9. Patient is a female of childbearing potential who may be pregnant or breastfeeding at the time of the 
index procedure. * 
10. Patient belongs to a vulnerable population per investigator's judgment or patient has any kind of 
disorder that compromises his/her ability to give written informed consent and/or to comply with 
study procedures. 
11. Patient is currently participating in an investigational drug or device study when the data collected 
could be conflicting or biased due to participation in another study. 
12. Patient has documented COVID-19 infection currently or within the past 3 months. Patient is not 
completely recovered from past COVID-19 infection, per physician's discretion.  
13. VLU Study: Patient has target ulceration identified to be of non-venous etiology, as confirmed by the 
independent core laboratory. 
14. VLU Study: Patient has target circumferential ulceration that cannot be captured in a single 
photograph (any ulcer curvature around the leg that goes out of sight). 
Note: CEAP 6 VLU patients are excluded at sites not identified as VLU Study sites. 
*Pregnancy to be assessed per treating physician’s routine practice; testing is not required if verbal 
confirmation is preferred. Breastfeeding patients may be included if mother’s expressed milk is discarded 
surrounding the index procedure, per the treating physician’s standard instructions. Sites must document 
routine methods utilized for such patients. 
10. Study Procedures  
10.1. Schedule of Events and Data Collection 
An overview of all data collection requirements is given in Table 6 and Table 7 below. All subjects (in the 
Randomized Studies as well as the VLU Study) will follow the assessment schedule in Table 6, and VLU 
Study subjects will also follow the assessment schedule in Table 7, until healing per the CIP definition has 
occurred. Study-specific assessments may not occur until the ICF has been obtained, and only 
trained/delegated personnel may conduct study specific assessments. Subjects should return to the study 
site for their study visits; other local hospitals or clinics should not be used as an alternative.  
Some study follow-up visits are not routine care. Routine care post-procedure differs from site to site. 
However, follow-up visits that are not routine care are not considered burdensome and/or invasive. 

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Table 6: Schedule of Assessments – All Subjects 
Data Collection 
Requirement 
Screening 
Baseline 
(<30 days before 
procedure) 
Index Procedure  
(Day 0) 
Day 7  
(± 2 days) 
Day 30  
(± 7 days) 
 
3+ Months Adjunctive 
Therapy (Optional) 
6 Months  
(± 4 weeks) 
12 Months 1  
(± 8 weeks) 
24, 36, 48 and 60 
Months  
(± 8 weeks) 
Unscheduled2 
Informed Consent 
X 
 
 
 
 
 
 
 
 
CEAP Clinical 
Classification (2004 and 
2020) 
X 
 
 
 
 
 
X 
X 
X 
X 
Randomization 
X 
 
 
 
 
 
 
 
 
 
Demographics, Medical 
History 
 
X 
 
 
 
 
 
 
 
 
Concomitant 
Medications 
 
X 
X 
 
 
 
 
 
 
 
rVCSS 
 
X 
 
X 
X 
 
X 
X 
X 
X 
Patient-Reported 
Symptoms  
 
X 
 
X 
X 
 
X 
X 
 
 
EQ-5D-5L QoL 
 
X 
 
 
X 
 
X 
X 
X 
 
AVVQ QoL 
 
X 
 
 
X 
 
X 
X 
X 
 
SF-36 QoL 
 
X 
 
 
X 
 
X 
X 
 
 
VenousTSQ3 
 
 
 
 
X 
 
X 
X 
 
 
Duplex Ultrasound 
 
X4 
X 
X 
X 
 
X 
X 
X 
X 
Procedure-related Data 
& Outcome 
 
 
X 
 
 
 
 
 
 
 
Physician Satisfaction 
with Procedure 
 
 
X 
 
 
 
 
 
 
 
Patient-Reported 
Outcomes 
 
 
 
X 
X 
 
X 
X 
X 
 
Reintervention Review 
 
 
 
X 
X 
 
X 
X 
X 
 
Healthcare utilization 
 
 
 
X 
X 
 
X 
X 
X 
 
Adjunctive Therapy 
Assessment 
 
 
 
 
 
X 
X 
X 
X 
 
Adverse Event 
Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
Device Deficiency 
Assessment 
 
 
X 
 
 
 
 
 
 
 
1 Subjects in VenaSeal vs. Surgical Stripping Study will be followed through 12 months only. 

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2AE assessments at unscheduled visits are required. Additional assessments are per investigator’s discretion; see section 10.11 
for additional detail 
3 VenousTSQe captured at 30 Days; VenousTSQs captured at 30 Days, 6 Months and 12 Months 
4 Sites to utilize their standard of care DUS to assess screening criteria, within 6 months of the Screening/Baseline visit; if not 
conducted in a standing position, sites will need to re-image patient for target vein measurements only 
Table 7: Additional Schedule of Assessments – VLU Study 
Data 
Collection  
Requirement 
Screening 
Baseline 
Procedure 
7 & 30 Days 
2, 3, 4, & 5 Months  
(+/- 7 days) 
6 Months 
8 & 10 Months  
(+/- 2 weeks) 
12 Months 
24, 36, 48, & 60 
Months 
Healing Verification 
(<2 weeks of healing) 
All-Subject 
Requirements 
and Visit 
Windows from 
Table 6 
X 
X 
X 
X 
 
X 
 
X 
X 
 
Etiology 
Photograph 
X 
 
 
 
 
 
 
 
 
 
Target Active 
Ulcer 
Assessment 
 
X 
 
X 
X 
X 
X 
X 
 
 
Ulcer-specific 
Healthcare 
Utilization 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Active Ulcer or 
Healing 
Verification 
Photograph 
 
X1 
 
Photographs captured at each visit until healing is 
demonstrated through 24 months. 
 
X2 
Adverse Event 
Assessment 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Ulcer Healing 
and/or 
Recurrence 
Assessment 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Active Ulcer 
Wound Care 
Wound care and compression therapy to proceed per routine care until healing is demonstrated. 
1 Index procedure should occur within 7 days of baseline ulcer photograph. If the baseline visit is more than 7 days out from the 
index procedure, photographs should instead be taken on the day of the index procedure, prior to the start of the procedure. 
2 Healing verification to be captured through 24 months, as applicable. 

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10.2. Scheduled Follow-up Visit Windows 
The target visit dates for the subject that gets enrolled in the study can be obtained via ‘Visit Scheme’ CRF 
from the study database. Should a subject miss a visit or if the visit falls outside of the pre-specified 
window, a study deviation must be reported, and the original follow-up schedule should be maintained 
for subsequent visits.  
Data analyses include follow-up visits, regardless of whether the visit occurs within the window. 
Therefore, a late visit is preferred over a missed visit but must be accompanied by a deviation report. 
Follow-up visit windows are listed in Table 8 and Table 9 and are based on days post-procedure. 
Table 8: Follow-up Visit Window – All Subjects, VenaSeal vs Surgical Stripping Study will follow this 
schedule to 12 months 
Study Follow-up 
Visit 
Window 
(Calculated days post index procedure) 
Window Start 
(days post-
procedure) 
Target 
(days post-
procedure) 
Window End 
(days post-
procedure) 
Day 7 
5  
7  
9  
Day 30 
23  
30 
37  
6 Months 
154  
182 
210  
12 Months 
309  
365  
421  
24 Months 
674  
730 
786 
36 Months 
1039 
1095 
1151 
48 Months 
1404 
1460 
1516 
60 Months 
1769 
1825 
1881 
 
 
 

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Table 9: Additional Follow-up Visit Window – VLU Study 
Study Follow-up 
Visit 
Window 
(Calculated days post index procedure) 
Window Start 
(days post-
procedure) 
Target 
(days post-
procedure) 
Window End 
(days post-
procedure) 
2 Months 
53 
60 
67 
3 Months 
83 
90 
97 
4 Months 
113 
120 
127 
5 Months 
143 
150 
157 
8 Months 
226 
240 
254 
10 Month 
286 
300 
314 
10.3.  Subject Consent 
Informed consent is defined as a legally effective documented confirmation of a subject’s voluntary 
agreement to participate in a particular study after information has been given and explained to the 
subject on all aspects of the study that are relevant to the subject’s decision to participate. This process 
includes obtaining an ICF that has been approved by the study site’s IRB/EC/CA and signed and dated by 
the subject. A subject may only consent after information has been given and explained to the subject on 
all aspects of the clinical investigation that are relevant to the subject’s decision to participate.  
Prior to enrolling subjects, the informed consent along with the Authorization to Use and Disclose 
Personal Health Information/Research Authorization/other privacy language as required by law must be 
approved by the IRB/ EC/CA. The document must be controlled (i.e., versioned and/or dated) to ensure it 
is clear which version(s) were approved by the IRB/EC/CA. Any adaptation of the template ICF must be 
reviewed and approved by Medtronic and the IRB/EC/CA reviewing the application prior to enrolling 
subjects.  
The investigator must notify the subject of any significant new findings about the study that become 
available during the course of the study which are pertinent to the safety and well-being of the subject, 
as this could impact a subject’s willingness to participate in the study. If relevant, consent may be 
requested from subjects to confirm their continued participation. 
The study informed consent is available under a separate cover. Prior to initiation of any study-specific 
procedures, informed consent must be obtained from the subject. Likewise, privacy or health information 
protection regulation may require subjects to sign additional forms to authorize study sites to submit 

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subject information to the study sponsor. The informed consent process must be conducted by the PI or 
an authorized designee, and the ICF along with Authorization to Use and Disclose Personal Health 
Information/Research Authorization/other privacy language as required by law must be given to the 
subject in a language he/she is able to read and understand. The process of informed consent must be 
conducted without using coercion or undue improper influence on or inducement of the subject to 
participate by the investigator or other study site personnel. The informed consent process shall not waive 
or appear to waive subject’s legal right. The language used shall be as non-technical as possible and must 
be understandable to the subject and the impartial witness, where applicable.  
The subject must have ample time and opportunity to read and understand the ICF, to inquire about 
details of the study, and to decide whether or not to participate in the study. All questions about the study 
should be answered to the satisfaction of the subject. 
When the subject decides to participate in the study, the ICF must be signed and personally dated by the 
subject and investigator or authorized designee, as required by the ICF, and ensured by the PI or his/her 
authorized designee.  
A copy of the ICF along with the Authorization to Use and Disclose Personal Health Information/Research 
Authorization/other privacy language, signed and dated as required by law, must be provided to the 
subject. 
If the informed consent is obtained the same day the subject begins participating in study-related 
procedures, it must be documented in the subject’s case history that consent was obtained prior to 
participation in any study-related procedures. It is best practice for the informed consent process to be 
documented in the subject’s case history, regardless of circumstance. 
In the event the subject cannot read and/or write, the informed consent process shall be obtained through 
a supervised oral process. An independent and impartial witness must be present during this process. The 
ICF and any other information must be read aloud to the prospective subject or his/her legally designated 
representative. Whenever possible, either the subject or his/her legally designated representative shall 
sign and personally date the ICF. The witness signs and personally dates the ICF attesting that the 
information was accurately explained and that informed consent was freely given. 
The original of the signed ICF must be filed in the hospital/clinical chart and/or with the subject’s study 
documents.  
The ICF along with Authorization to Use and Disclose Personal Health Information/Research 
Authorization/other privacy language as required by law must be available for monitoring and auditing.  

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Consistent with the Declaration of Helsinki, vulnerable adults (i.e., those subjects mentally incapable of 
giving consent) are excluded from this protocol.  Any subjects with mental incompetence (e.g., 
Alzheimer’s, dementia, psychiatric disorders, developmental disorders) should be assessed for vulnerable 
status. If the ICF is signed by an individual other than the subject, the monitor may discuss whether the 
Investigator believes the subject meets the definition of a vulnerable adult.  This protocol defines 
vulnerable adult as those subjects mentally incapable of giving consent, in the Investigator’s opinion.  The 
Investigator should consider the definition of vulnerable adult per ISO 14155, which defines vulnerable 
adults as: “individuals who are unable to fully understand all aspects of the investigation that are relevant 
to the decision to participate, or who could be manipulated or unduly influenced as a result of a 
compromised position, expectation of benefits or fear of a retaliatory response.” For example, this could 
include Individuals with loss of autonomy due to immaturity or through mental disability, persons in 
nursing homes, children, impoverished persons, subjects in emergency situations, ethnic minority groups, 
homeless persons, nomads, refugees, and those incapable of giving informed consent. Other vulnerable 
subjects could include, for example, members of a group with a hierarchical structure such as university 
students, subordinate hospital and laboratory personnel, employees of the sponsor, members of the 
armed forces, and persons kept in detention. 
10.4. Randomization and Treatment Assignment (CEAP 2-5) 
After a patient has signed the ICF, the CEAP assessment has been completed, and the eligibility criteria 
are verified, the patient will be enrolled via randomization. There are two Randomized Studies:  
Each site will be designated as participating in only one of the two Randomized Studies and cannot 
participate in both. Which study the site will enroll into is pre-determined by geographical region and 
device/treatment availability (i.e., regulatory approval and reimbursable status). Randomization will be 
accomplished using the Oracle Clinical system (or paper back-up if the system is down) prior to the 
collection of Baseline visit data and will be stratified by the site and by CEAP (2004) clinical category to 
ensure balanced arms. Site personnel will obtain the subject’s randomization sequence on the 
Randomization CRF which will be generated from the database. Randomization schedules will be prepared 
for each site using a random permuted block design stratified by site and CEAP (2004) (grouping categories 
2-3 vs. 4-5).  
1. VenaSeal vs. ETA Study: subjects will be 1:1 randomized to VenaSeal™ system or ETA treatment. 
2. VenaSeal vs. Surgical Stripping Study: subjects were randomized 1:1 to VenaSeal™ system or surgical 
stripping treatment.  VenaSeal vs Surgical Stripping Study was closed to enrollment as of 22-Feb-
2022. 

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If a subject is inadvertently randomized twice or more, the first assigned treatment arm will be used for 
the intention-to-treat analysis, and investigators should treat subjects according to the first 
randomization. Knowledge of the development of randomization lists may lead to selection bias, 
therefore these details will be described in a separate document. If a subject is inadvertently treated with 
the wrong treatment modality, this will be recorded as a protocol deviation. 
Randomization may be done during the screening visit as applicable or may be completed closer to the 
Baseline visit if there will be a significant delay between Screening and Baseline.  
CEAP 6, active VLU subjects will not be randomized and will be treated with the VenaSeal™ system.  
10.5. Study Assessments 
CEAP Classification 
At screening and at 6, 12, 24, 36, 48 and 60 months, the American Venous Forum CEAP classification 
(2004) will be used to provide a comprehensive objective classification of the severity of the target limb 
(CEAP Classification). CEAP describes the clinical manifestations (C), etiologic factors (E), anatomic 
distribution of disease (A), and underlying pathophysiologic findings (P). This study will only collect the 
clinical manifestations classification. This assessment must be performed for the target limb. The CEAP 
Classification needs to be assessed by a physician or qualified delegated person. Alternatively, it can be 
assessed by a nurse practitioner per their license or training. Recently, an updated CEAP classification 
(2020) was published by Lurie et al.17 The 2020 clinical manifestation of the CEAP classification will be 
collected for analysis purposes but will not be used to determine the patient’s eligibility as part of this 
study. 
Revised Venous Clinical Severity Score (rVCSS) 
The revised VCSS will be used to assess baseline venous disease status as well as changes in venous disease 
severity over time (rVCSS). As such, the rVCSS should be assessed for the target limb at baseline and at 7 
days, 30 days, 6, 12, 24, 36, 48 and 60 months. At Unscheduled visits, the rVCSS should be taken before 
an intervention in the target vein takes place; if an intervention is not occurring, it can be completed at 
the treating physician’s discretion. The rVCSS needs to be assessed by a physician or qualified delegated 
investigator. Alternatively, the rVCSS can be assessed by a nurse practitioner per their license or training. 
Duplex Ultrasound 
It is expected that patients approached for study enrollment will have undergone a standard of care DUS 
to diagnose the patient’s VRD; this routine imaging can be utilized up to 6 months prior to the Screening 
visit. DUS images will be performed by DUS technicians or investigators trained and delegated to the 
study. Target vein measurements will be collected from this DUS if conducted while the patient was 

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standing; if not, the DUS must be repeated solely to measure the target vein(s) diameter at the proximal, 
mid, and distal points, as well as the widest part of the vein. Additional instructions for target vein 
measurements will be provided under a separate cover. 
Post-index procedure, DUS evaluation is required to assess target vein (including primary target vein) 
closure after VenaSeal™ system or ETA treatment and absence of refluxing vein or residual vein after 
surgical stripping. DUS is also used for thrombus assessment. This DUS assessment will also be performed 
at 7 days, 30 days, 6, 12, 24, 36, 48 and 60 months. This DUS assessment could be completed on the day 
of the follow-up visit or anytime during the follow-up visit window, as applicable to the site’s standard 
scheduling process. 
Patient-Reported Symptoms 
Subjects will be asked to report symptoms related to their target limb: pain, aching, itching, burning, 
sensitivity, heaviness and swelling, and asked to identify their dominant symptom from this list. This will 
be assessed at baseline and at follow-up visits through 12 months. These questions must be completed 
by the subject and a translation will be available in each of the applicable languages; however, designated 
site staff may verbally read the symptom list to the patient. 
Venous Treatment Satisfaction Questionnaire (VenousTSQ) 
The two components of the VenousTSQ are evaluated as two separate primary endpoints in this study. 
The questionnaire needs to be completed either by the subject or by a delegated person who asks the 
questions to the subject and completes the questionnaire on behalf of the subject. This should be the first 
subject-reported assessment at all study visits when administered. 
The Venous Treatment Satisfaction Questionnaire (VenousTSQ) is a new Patient Reported Outcome 
Measure (PROM). Via a qualitative design approach involving patient interviews and clinical expert 
reviews, the process resulted in an independently developed tool for venous patients. The tool consists 
of two components, the peri-procedural early component of treatment satisfaction which will be 
measured at 30 days post index-procedure (VenousTSQe), and the longer-term status component of 
treatment satisfaction which can be measured at 30 days, 6 and 12 months (VenousTSQs). Questions focus 
on topics relevant for patients with varicose veins who have undergone a venous treatment and include 
items 
on 
treatment 
satisfaction/dissatisfaction, 
symptoms 
such 
as 
pain, 
and 
outcome 
satisfaction/dissatisfaction. 
At the time of the finalization of this investigation plan, partial validation of the VenousTSQ has taken 
place while the remaining validation steps are being carried out during a psychometric analysis. Part of 
the development and validation process of the VenousTSQ is a quantitative psychometric analysis that is 
carried out independently to determine the internal consistency and reliability of the tool and that will 

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ultimately lead to the scoring guidelines. The quantitative psychometric analysis will be carried out within 
the study on the 30-day data of at least 100 subjects from predominately English-speaking countries (e.g., 
US, UK, Australia, and Canada) who are enrolled as part of this study. In addition, confirmatory linguistic 
validation on other languages may be performed. Where applicable, subjects will be asked for their 
consent for this separately because part of their non-identifying data may be shared with the independent 
developer of this questionnaire. 
Quality of Life 
Health-related Quality of Life (QoL) outcomes will be assessed at baseline, day 30 and months 6, 12, 24, 
36, 48, and 60 using the AVVQ, EQ-5D-5L and SF-36 questionnaires (Appendix A: Patient Questionnaire 
and Assessments). These questionnaires need to be completed either by the subject or by a delegated 
person who asks the questions to the subject and completes the questionnaire on behalf of the subject.  
• 
AVVQ: a venous-disease specific QoL measure including 13 questions that each correspond to one of 
four clinically recognizable aspects of health, being 1) pain and dysfunction, 2) cosmetic appearance, 
3) extent of varicosity, 4) complications. 
• 
EQ-5D-5L: a two-component tool consisting of a descriptive part that evaluates five dimensions 
(mobility, self-care, usual activities, pain/discomfort, anxiety/depression) and the EQ-VAS, a vertical, 
visual analog scale, used for self-reporting on health. 
• 
SF-36: a 36-item generic QoL tool measuring health across three dimensions and including eight 
separate scales: 1) functional status (including physical functioning, social functioning, role limitations 
attributed to physical problems, and role limitations attributed to emotional problems), 2) wellbeing 
(including mental health, energy and fatigue, and pain), and 3) overall evaluation of health (including 
general health perception).  
Other Patient-Reported Outcomes 
• 
Pain score will be collected during the index procedure and at 7 days and 30 days. 
• 
Return to work and return to normal activities will be assessed at follow-up visits until the subject has 
returned to each. 
• 
The VenousDQoL consists of two stand-alone questions at baseline, 7 and 30 days, 6, 12, 24, 36, 48 
and 60 months (data will be collected through 12 months for subjects enrolled in VenaSeal vs. Surgical 
Stripping Study). 
Questionnaire completion by delegated site personnel 
The required study questionnaires such as EQ-5D-5L, VenousTSQ, patient reported symptoms, etc. should 
be completed in a consistent manner throughout the study. Selecting to complete the required 
questionnaire on behalf of the subjects should only be if the subjects require it (e.g., vision or literacy 
issues) and not simply by site or patient preference. The site personnel completing the questionnaire 

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cannot be the treating physician or the PI in order to avoid any bias. If site personnel are assigned to 
complete the questionnaire on behalf of the subject for one visit, then site personnel should complete for 
all the remaining visits. Site personnel have to read the complete questionnaire including all the response 
options. Ideally, the same person will complete the questionnaire with the same subject each time, if at 
all possible. The questionnaires completed by site personnel may differ from subject questionnaires and 
may require IRB/EC approval. If necessary, due to COVID-19 restrictions, these questionnaires could also 
be completed and signed by the subject within 24 hours prior to the follow-up visit. If captured in this 
manner, care must be taken to ensure the questionnaires are completed and returned to the site prior to 
the completion of the rest of the visit. 
Healthcare Utilization 
This study will collect healthcare utilization data related to subject’s VRD and care related to the 
VenaSeal™ closure system to demonstrate total costs over the follow-up period. Specifically, this study 
will collect: 
• 
Number and type of adjunctive treatments (phlebectomy and sclerotherapy) conducted through 60 
months post-index procedure. 
• 
Subject’s healthcare utilization related to their target limb VRD, as determined by medical record 
review and/or subject’s report of healthcare visits conducted and other health-related resources 
utilized (e.g. home healthcare services) between study visits. 
• 
Procedures, tests and treatment of AEs related to the VenaSeal™ system or the index procedure, as 
reported by sites in AE reporting. 
• 
VLU Study: Subject’s healthcare utilization and routine wound care treatments between follow-up 
visits through 60 months. 
VLU Assessment on the target limb 
Patients who enter the study at designated VLU sites with an active VLU (CEAP 6) on the target limb will 
receive wound care and compression therapy per the site’s standard of care for their VLUs, and undergo 
ulcer assessments at screening, baseline and each follow-up visit until the ulcer is healed.   
At the Screening visit, after consent has been obtained, target limb ulceration will be photographed by 
the provided eKare imaging equipment to assess etiology and if circumferential. Any ulcer curvature 
around the leg that extends out of sight and that cannot be captured in a single photograph would be 
considered as a circumferential ulcer and such subjects will not be included in the study. These 
photographs captured as part of routine care within 60 days can also be utilized, as deemed appropriate 
by the treating physician. Photographs will be submitted to the core laboratory to assess venous etiology 
within 3 business days. If the core laboratory concludes that the ulcer is of non-venous etiology, then the 
subject will be considered as a screen failure and exited from the study. The baseline ulceration 

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photographs must be taken within 7 days of the index procedure. If the baseline visit is scheduled more 
than 7 days from the index procedure, the site may collect all remaining baseline data and hold off on 
taking the photographs until the day of the index procedure, prior to the start of the procedure. The 
baseline photographs will be sent to the core laboratory for assessments.  
Follow-up target limb ulcer assessments will take place at Day 7, Day 30, Months 2, 3, 4, 5, 6, 8, 10, and 
12 or until healing has occurred. If the healing has not occurred at 12 months, subjects will revert to the 
annual visit schedule and continue to follow standard wound care unless healing occurs, and a healing 
verification visit is necessary. If healing occurs past 24 months, subjects will no longer undergo a healing 
verification visit. When all target limb ulceration has healed, subjects will have an ulcer healing verification 
visit (up to 24 months) as outlined in section 10.12.  
Photographs will be taken of active ulcers and at the healing verification visit using the eKare insight® 3D 
wound imaging system provided to VLU sites. Multiple photographs will be captured: 1) one 3-
dimensional photo for the measurements and 2) a standard, 2-dimensional photo of a wider view of the 
index limb. The ulcer size will be assessed, and complete healing will be confirmed by the wound core 
laboratory via these photographs provided by the study site. Core laboratory assessment is also described 
in section 13.3.  
If the ulcer on the target limb recurs, this will be reported in the CRF during study follow-up visits. The 
ulcer status compared to the last study visit (e.g., healed, recurred, or healed and recurred) will be 
collected at each visit. In addition, type of the wound care received since last visit including debridement, 
skin graft, dressing change, Unna boots or any other treatment will be recorded in the CRFs at each follow-
up visit until initial ulcer healing is confirmed. An ulcer core laboratory manual and site training will be 
provided to sites for further details on the photograph process.   
New ulcers not related to the original ulceration that develop post-index procedure but prior to initial 
healing may need to be reported as AEs (if considered worsening of disease) and will undergo ulcer 
assessments as described here for all ulcers. New ulceration that develops following healing confirmation 
will be considered ulcer recurrence and will not be assessed as described here, however may need to be 
reported as AEs. 
10.6. Screening 
During the screening visit, the site will conduct the following: 
1. Informed consent. 
2. Subject evaluation for inclusion/exclusion criteria: Sites should utilize their routine care diagnostic 
DUS from within 6 months of the screening visit, or repeat this DUS if greater than 6 months old. 

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Sites may randomize the patients in the Randomized Studies following the Screening Visit data collection 
and confirmation of inclusion/exclusion criteria. 
10.7. Prior and Concomitant Medications 
The current use of the following medications will be collected at the Baseline visit: 
Medications given as part of the index procedure will also be documented. Medications used for 
treatment of any AEs will be tracked during the AE assessment. Additional concomitant medications will 
not be recorded for study purposes. 
10.8. Baseline (within 30 days prior to index procedure) 
The Baseline visit may be combined with the index procedure visit if the site chooses, so long as the 
Baseline data is collected prior to the index procedure.  
VLU Study: wound care and compression therapy should be initiated per the site’s standard of care and 
as early as possible (e.g., after confirmation of venous etiology by the core laboratory), if it is not ongoing 
already.   
During the Baseline visit, the site will collect the following: 
 
1. Demographics, as able to be collected per the site’s regional regulations. 
2. Targeted medical history and concomitant medications, limited to items potentially related to the 
subject’s VRD as indicated in the CRF specifications provided separately. 
3. Baseline DUS: If routine care DUS was not conducted in a standing position, sites will need to re-image 
patient for target vein measurements only. 
4. rVCSS 
5. AVVQ QoL questionnaire 
3. CEAP clinical classification. 
4. VLU Study: Photographs to assess ulcer venous etiology and exclude circumferential ulcers. These 
photographs captured as part of routine care within 60 days can also be utilized as deemed 
appropriate by treating physician. Photos must be submitted to the core laboratory and confirmed as 
venous etiology prior to moving on to the Baseline visit. 
1. Anticoagulants (e.g., Warfarin, NOAC, Lovenox) 
2. Antiplatelets/Aspirin/P2Y12-inhibitors 
3. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) 
4. Other pain medication. 

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6. EQ-5D-5L QoL questionnaire 
7. SF-36 QoL questionnaire 
8. Venous DQoL 
9. Patient-reported symptoms and indication of their dominant symptom. 
10. VLU Study: Ulcer assessment on target limb including ulcer photograph for submission to core 
laboratory. The baseline ulcer photograph must be taken within 7 days prior to the index procedure. 
If the Baseline visit is more than 7 days prior to the index procedure, then photographs should be 
collected at the index procedure before the start of the procedure. 
10.9. Index Procedure 
For the Randomized Studies, subjects must undergo the procedure for which they were randomized to. 
Subjects treated with a modality they were not randomized to will be considered a major protocol 
deviation. CEAP 6 subjects in the VLU Study will not be randomized and will all be treated with the 
VenaSeal™ system. 
The index procedure should be performed according to the current and applicable version of the 
manufacturer’s IFU (if applicable) to the region of the study site. AE reporting for all subjects (Randomized 
Studies and VLU Study) will begin from the moment the index procedure is initiated, in line with the 
reporting requirements described in section 12: Adverse Events and Device Deficiencies of the protocol. 
All Subjects: 
The primary target vein must be treated first during the index procedure, and the remaining target veins 
will be treated in succession.   
Procedure for VenaSeal™ closure system (CEAP 2-5 subjects in Randomized Studies assigned to 
VenaSeal™, or CEAP 6 subjects in VLU Study):  
Prophylactic medications for potential allergic reaction to VenaSeal™ adhesive may be administered to 
the subject per the treating physician’s discretion. Compression therapy and wound care dressings (VLU 
subjects) will be removed prior to the start of the procedure, if applicable. 
Local anesthetic including tumescent and light sedation (including but not limited to oral Xanax and 
Valium) may be utilized. All other types of anesthesia including general, regional, and heavy sedation are 
not permitted for the VenaSeal™-treated subjects.   
The IFU for the VenaSeal™ system applicable per region should be referred to for the procedure.  

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Procedure for surgical stripping (CEAP 2-5 subjects in Randomized Studies assigned to surgical 
stripping):  
All types of anesthesia including general, heavy and light sedation, regional or local anesthesia may be 
used, per site’s standard practice. Compression therapy will be removed prior to the start of the 
procedure, if applicable.  
Surgical stripping was performed per physician’s or site’s standard practice. Enrollment was closed as of 
22-Feb-2022 in the VenaSeal vs. Surgical Stripping Study. 
Procedure for ETA (CEAP 2-5 subjects in Randomized Studies assigned to ETA): 
Local anesthetics including tumescent and light sedation (including but not limited to oral Xanax and 
Valium) may be utilized. All other types of anesthesia including general, regional, and heavy sedation are 
not permitted for the ETA-treated subjects. Compression therapy use will be removed prior to the start 
of the procedure, if applicable.  
The subject can be treated with either RFA or EVLA per site’s standard practice and treating physician’s 
discretion. Also, any RFA or EVLA device approved in the site’s region can be used per site’s standard 
practice. The manufacturer’s current IFU applicable per region should be referred to for the procedure.  
Adjunctive Therapies & Treatments 
If the target limb is CEAP 4b, or 5, incompetent perforating veins may be treated per the investigator’s 
standard of care using approved devices or procedures during the index procedure. If any other devices 
are used during the index procedure to treat the incompetent perforating veins, then data will be 
collected on other devices as applicable. The devices used for the incompetent perforating veins 
procedure should have regulatory approval applicable per region. If the incompetent perforating veins 
are treated post index procedure (permitted 3 months after index procedure) for CEAP 4b or 5 target limb, 
then data will be collected from 3 months through study end.  
VLU Study: For CEAP 6 subjects, incompetent perforating veins may be treated per the investigator’s 
standard of care using approved devices or procedures during the index procedure or at any time after 
the index procedure. If any other devices are used during or after the index procedure to treat the 
incompetent perforating veins, then data will be collected on other devices as applicable throughout the 
study. The devices used for the incompetent perforating veins procedure should have regulatory approval 
applicable per region.  

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VLU Study: Foam sclerotherapy may be injected into the ulcer bed, per site’s standard of care. Subjects 
with VLUs will continue with ongoing wound care therapy, or have it initiated, as directed by a wound 
care physician until wound healing has been verified by the core laboratory. 
For subjects undergoing surgical stripping, adjunctive procedures such as phlebectomy of tributaries can 
be performed during the index procedure, per the treating physician’s discretion. For ETA or VenaSeal™ 
subjects, any adjunctive treatment of varicosities in the target limb such as phlebectomy or sclerotherapy 
cannot be performed along with the index procedure. 
Subjects for all studies may return to the site after 3 months (calculated as 90 days) following the index 
procedure to complete additional adjunctive therapies of target limb varicosities per the treating 
physician’s discretion; these treatments will be considered routine care. The data for the adjunctive 
therapy treatment will be collected through 60 months.  
Other truncal veins in the non-target limb may not be treated at the time of the index procedure or within 
30 days prior to or 3 months post-index procedure. 
Post-Procedure 
At the completion of the procedure, when treatment of all target veins has been completed, vessel 
occlusion (VenaSeal™ or ETA) or absence of refluxing target vein or residual target vein (surgical stripping) 
will be confirmed by DUS. Subjects should be provided pain, allergy and/or anti-coagulant medication at 
the treating physician’s discretion as appropriate for the treatment received. Upon discharge, subjects 
should follow the site’s standard post-operative instructions.  
At the index procedure visit, the following procedural data shall be recorded for each subject in the study: 
1. 
Date of procedure. 
2. 
Code for physician conducting the procedure, as indicated in a coded log provided to sites. 
3. 
VenaSeal-randomized and CEAP 6 subjects: Number of VenaSeal™ system procedures the treating 
physician has completed to date. 
4. 
VenaSeal-randomized and CEAP 6 subjects: Identification data of the VenaSeal™ kits utilized for 
treatment. 
5. 
Procedure times as described in the CRF specifications. 
6. 
Medications: anesthetic, prophylactic, and post-procedural medications. 
7. 
Pre-procedure length measurement of clinically relevant superficial truncal disease in target veins 
with a tape measure applied outside of the target limb prior to sterile field. 
8. 
Chosen vein access sites for each target vein as well as type of access utilized. 
9. 
Distance of vein access from the tibial tuberosity, if below the knee. 

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10. VenaSeal-treated subjects: points of aneurysm, tributaries, or perforators per target vein when 
multiple VenaSeal™ aliquots are utilized. 
11. Post-procedure DUS: assessment of patency, stump length, reflux along treatment area, evidence of 
thrombus. 
12. Post-procedure measurement of actual treatment length using a tape measure to measure the 
difference between the clinically relevant lowest point of reflux to the access point. 
13. Physician satisfaction with the procedure. 
14. AE assessment from the moment the index procedure was initiated. 
15. VenaSeal™ system treated subjects: Device deficiencies related to the VenaSeal™ system. 
16. Treatment issues experienced by the treating physician. 
17. Subject’s use of compression stockings upon discharge. 
10.10. 
Follow-Up Visits: All Subjects 
The VenaSeal vs Surgical Stripping Study patients will stop any follow-up assessments after the 12-month 
visit.  
Day 7 (+/- 2 days) 
Patients will return to the site for follow-up for the following assessments (limb-specific assessments are 
of the target limb only): 

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1. DUS: 
a. Areas of patency, if any 
b. Reflux along treatment area 
c. Evidence of thrombus 
2. rVCSS 
3. Patient reported outcomes:  
a. Pain score measured by using NRS scale of 0-10 
b. Patient-reported symptoms 
c. Ability to return to work/normal activities 
d. VenousDQoL 
4. AE assessment 
5. Healthcare utilization since last study visit 
6. VLU Study: 
a. Active ulcers: ulcer assessment, ongoing wound care, photographs for core laboratory, healing 
status 
b. Post-healing confirmation: recurrence status. 
 
 

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Day 30 (+/-7 days) 
 
If COVID-19 prevents patients from returning for follow-up visits at 7 or 30 days (due to subject contracting 
COVID-19 or due to site policy), these visits may be conducted through telehealth or other alternative 
methods to be discussed with the Medtronic study team prior to execution.  
 
 
1. DUS: 
a. Areas of patency, if any 
b. Reflux along treatment area. 
c. Evidence of thrombus 
2. rVCSS 
3. Peri-procedural Venous Treatment Satisfaction Questionnaire (VenousTSQe) and Venous Treatment 
Satisfaction Questionnaire (VenousTSQs) 
4. EQ-5D-5L 
5. AVVQ 
6. SF-36 
7. Patient reported outcomes:   
a. Pain score measured by using NRS scale of 0-10 
b. Ability to return to work/normal activities (only if not returned to work/normal activities by 7-day 
visit) 
c. VenousDQoL  
d. Patient-reported symptoms 
8. AE assessment 
9. Healthcare utilization since last study visit 
10. VLU Study: 
a. Active ulcers: ulcer assessment, ongoing wound care, photographs for core laboratory, healing 
status 
b. Post-healing confirmation: recurrence status. 

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3+ Months (calculated as 90 days): Optional for all subjects 
6 months (+/- 4 weeks), 12, 24, 36(+/-8 weeks) 
Subjects will return to the site for follow-up to conduct the following assessments (limb-specific 
assessments are of the target limb only). VenaSeal vs Surgical Stripping Study subjects will be followed up 
to and including 12 months: 
 
 
1. Adjunctive therapy: Number of phlebectomy sites and/or sclerotherapy injections administered 
(data collected through 60 months). 
2. AE Assessment. 
1. DUS: 
a. Areas of patency, if any 
b. Reflux along treatment area 
c. Evidence of thrombus 
2. CEAP classification  
3. rVCSS 
4. Venous Treatment Satisfaction Questionnaire (VenousTSQs) (up to 12 months visit) 
5. EQ-5D-5L 
6. AVVQ  
7. SF-36 (up to 12-month visit) 
8. Patient reported outcomes: 
a. VenousDQoL  
b. Patient-reported symptoms (up to 12-month visit) 
9. Adjunctive therapy assessment  
10. AE assessment  
11. Healthcare utilization since last study visit 
12. VLU Study: 
a. Active ulcers: ulcer assessment, ongoing wound care, photographs for core laboratory, healing 
status 
b. Post-healing confirmation: recurrence status. 

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48, 60 months (+/-8 weeks) 
Subjects will return to the site for follow-up to conduct the following assessments (limb-specific 
assessments are of the target limb only). Subjects may also complete 48 and 60 months visit remotely per 
physician’s discretion if subjects cannot return to the site for follow-up.  
 
If remote visit occurs, the following assessments can be completed via telehealth and/or hard-copy of 
questionnaires required to be completed via mail. Questionnaires can be sent to subjects via mail and 
subjects can complete and return it back to the site via mail. 
1. DUS: 
a. Areas of patency, if any 
b. Reflux along treatment area 
c. Evidence of thrombus 
2. CEAP classification  
3. rVCSS 
4. EQ-5D-5L 
5. AVVQ  
6. Patient reported outcomes: 
a. VenousDQoL  
7. Adjunctive therapy assessment 
8. AE assessment  
9. Healthcare utilization since last study visit 
10. VLU Study: 
a. Active ulcers: ulcer assessment, ongoing wound care, healing status 
b. Post-healing confirmation: recurrence status. 

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10.11. 
Unscheduled Visits 
A visit outside of the study follow-up schedule will be reported as unscheduled study visit if it was 
conducted for the evaluation of an AE per the AE reporting requirements in this study. In addition to any 
applicable AE treatment or diagnostic testing, the following additional assessments may be completed, 
per the treating physician’s discretion (limb specific assessments are of the target limb only): 
10.12. 
Additional Follow-Up Visits: VLU Study Active Ulcers 
2, 3, 4, 5 (+/- 7 days), 8, 10 Months (+/- 2 weeks) until Healing Verification 
Ulcer assessments on the target limb will take place at standard study visits (Screening visit, Baseline visit, 
Day 7, Day 30, and 6, 12, 24, 36, 48 and 60 months). In addition, visits at 2, 3, 4, 5, 8, and 10 Months will 
be conducted for active ulcers, until healing has occurred and been verified. If complete healing has not 
occurred by 24 months, subjects will continue to follow standard wound care and remaining study visits. 
At these active ulcer visits, sites will conduct the following assessments: 
1. EQ-5D-5L 
2. AVVQ  
3. Patient reported outcomes: 
a. VenousDQoL  
4. AE assessment  
5. Healthcare utilization since last study visit 
6. VLU Study: 
a. Active ulcers: ulcer assessment, ongoing wound care, healing status 
b. Post-healing confirmation: recurrence status 
1. Required: AE assessment  
2. CEAP classification 
3. rVCSS 
4. DUS. 

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5. Healing and/or recurrence assessment 
6. AE assessment. 
 
Ulcer Healing Verification Visit 
Once the site research team has been informed of all wounds healing on the target ulceration by the 
wound care center, the subject will undergo an ulcer healing verification visit within 2 weeks of ulcer 
healing to confirm healing and collect photographs of the ulcer. The ulcer assessment core laboratory will 
verify healing. If core laboratory does not confirm healing with the first set of photographs, the subject 
will return in 1 week for additional photographs to be collected and sent to the core laboratory. If the core 
laboratory does not confirm healing after the second set of photographs, but the treating physician 
believes the ulcer has healed, the ulcer will be classified as healed. The ulcer healing verification visit may 
occur up to 24 months, after which core lab ulcer imaging for wound healing will not be required. Data 
will continue to be collected for healing and recurrence status changes through 60 months. 
10.13. 
Assessment of Effectiveness 
Procedure effectiveness will be measured as primary target vein and target vein closure, defined as DUS 
showing closure along the entire treated vein segment with no discrete segments of patency exceeding 5 
cm after ETA or VenaSeal™ system treatment and absence of refluxing vein or residual vein after surgical 
stripping. It will also be measured as elimination of clinically relevant superficial truncal disease in target 
vein at the time of index procedure in addition to reintervention and time to reintervention of a target 
vein (including primary target vein) through 60 months (through 12 month visit for subjects randomized 
to the VenaSeal vs. Surgical Stripping Study) assessed at each follow-up visit (except 7 days) until 
reintervention occurs or the study ends. 
Ulcer healing effectiveness will be measured by time to ulcer healing, percent area healing per month and 
absolute healing, as verified by the independent core laboratory. 
 
1. Active ulcer assessment 
2. Ongoing wound care 
3. Ulcer-specific healthcare utilization 
4. Photographs for core laboratory 

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10.14. 
Assessment of Safety 
An AE assessment will take place at each follow-up visit (from the moment the index procedure is initiated 
until completion of follow-up or study exit). Reports of AEs and device deficiencies (refer to section 12) 
will be evaluated by Medtronic. The CEC will review and adjudicate events in accordance with section 13.1 
Additional details are outlined in the CEC Charter. 
10.15. 
Recording Data 
This study will utilize a Clinical Remote Data Capture (RDC) system that is the property of Medtronic. Each 
enrolled subject will be assigned a unique study ID number, which is pre-configured in the RDC system. 
Records of the subject/subject ID relationship will be maintained by the study site. Individual subject 
medical information obtained for this study will be considered confidential. The subject’s medical charts 
must be clearly marked to indicate that subjects are enrolled into the study, per the site’s Standard 
Operating Procedures (SOPs). 
Required data will be recorded on electronic case report forms (CRFs) by authorized site personnel as 
indicated on the Delegated Task List (DTL), which can be found in the Investigator Site File (ISF). Study 
personnel delegated for CRF completion will be trained on the use of the RDC system and thereafter 
provided with a username and password to access the system. The CRFs must be completed and/or 
updated to reflect the latest observations on the subjects participating in the study. The investigator (or 
delegated co-investigator) will electronically sign the appropriate pages of each CRF. 
The RDC system maintains an audit trail of entries, changes, and corrections in CRFs. If a person only 
authorized to complete CRFs makes changes to an already signed CRF, the investigator shall re-approve 
that CRF. 
The investigator must ensure accuracy, completeness, legibility and timeliness of the data reported in the 
CRFs and in all other required reports. Data entered must be traceable to source documents. Source 
documentation is defined as the first-time data appear, and may include original documents, data, and 
records (e.g., hospital records, clinical and office charts, procedure reports, subject worksheets). 
In general, CRFs may not serve as source documents, aside from the data elements listed below. Source 
documentation for data elements not routinely captured in medical records may vary from study site to 
study site; the study site may use source document worksheets if identified as source documents. Data 
reported on the CRFs which are derived from source documents must be consistent with the source 
documents or the discrepancies need to be justified in a documented rationale, signed and dated by an 
Investigator and filed in the subject’s research records at the site. 

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The investigator must ensure the availability of source documents from which the information on the CRFs 
was derived. The type and location of source documents should be documented. Where printouts of 
electronic medical records, are provided as source documents, or where copies of source documents are 
retained as source documents, those should be certified. Certification must contain (1) the signature of 
the individual making the copy, (2) the date the copy was made and (3) a statement attesting to the 
accuracy and completeness of the copy. 
The source documents must be made available for monitoring or auditing by Medtronic’s representative 
or representatives of the competent authorities and other applicable regulatory agencies. 
The CRF may be considered source for the following data collection elements: 
• 
Study Assignment CRF 
 
Target vein assignments 
• 
Procedure General CRF 
 
Number of VenaSeal treatments completed by treating physician to date 
 
VenaSeal kit usage: Product number, lot number, and why the kit was utilized 
 
Physician satisfaction with procedure 
 
Would the treating physician have preferred to use a secondary therapy 
• 
AE CRF 
 
Date study site became aware of event 
 
Procedure relatedness and device relatedness 
• 
DD CRF 
 
Date study site became aware of event 
 
DD led to Serious adverse device event (SADE) 
• 
Subject Death 
 
Date study site became aware of death 
• 
Deviations 
 
Reason for deviation. 
10.16. 
Deviation Handling 
A CIP and/or study deviation is defined as an event where the investigator or investigational site personnel 
did not conduct the clinical study according to the clinical investigation plan or CTA. Prior approval by 
Medtronic is expected in situations where the investigator anticipates, contemplates, or makes a 
conscious decision to deviate. Prior approval is not required when a deviation is necessary to protect the 
safety, rights or well-being of a subject in an emergency or in unforeseen situations beyond the 
investigator’s control (e.g., subject failure to attend scheduled follow-up visits, inadvertent loss of data 
due to computer malfunction, inability to perform required procedures due to subject illness). 

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For medically justifiable conditions which preempt a subject’s ability to complete a study-required 
procedure, it may be permitted to report only one deviation which will apply to all visits going forward. 
This may also apply for other unforeseen situations (e.g., the subject permanently refuses to complete a 
study required procedure and the data will not contribute to the primary end point analysis). However, 
prior approval from Medtronic is required for such situations.  
All study deviations must be reported on the CRF regardless of whether medically justifiable, pre-
approved by Medtronic, an inadvertent occurrence, or taken to protect the subject in an emergency. 
Multiple deviations of the same type at the same visit may be reported on one case report form. 
In the event the deviation involves a failure to obtain a subject’s consent, or is made to protect the life or 
physical well-being of a subject in an emergency, the deviation must be reported to the IRB/EC/CA within 
time period required by the regulations and reported to Medtronic as well. Reporting of all other study 
deviations should comply with IRB/EC policies and/or local laws and must be reported to Medtronic as 
soon as possible upon the study site becoming aware of the deviation.  
Medtronic is responsible for analyzing deviations, assessing their significance, and identifying any 
additional corrective and/or preventive actions (e.g., amend the CIP, conduct additional training, 
terminate the investigation). Repetitive or serious investigator compliance issues may result in initiation 
of a corrective action plan with the investigator and study site, and in some cases, may necessitate 
suspending enrollment until the problem is resolved or ultimately terminating the investigator's 
participation in the study. Medtronic may provide study site-specific reports to investigators summarizing 
information on deviations that occurred at the investigational study site on a periodic basis.  
 Examples of CIP deviations include but are not limited to the following: 

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Investigators may not deviate from the CIP and waivers cannot be used for this study, unless the deviation 
is necessary to protect the rights, safety and wellbeing of the subject in an emergency situation. Deviations 
should be reported to Medtronic regardless of whether medically justifiable or taken to protect the 
subject in an emergency. Study deviations should be reported to Medtronic via the study deviation CRF.  
Investigators are required to adhere to local IRB/EC procedures and CA procedures (if applicable) for 
reporting deviations. In addition, investigators should report the following deviations to Medtronic and 
their reviewing IRB/EC and CA (as applicable) without any delay (per the timelines required by IRB/EC/CA): 
• 
Failure to obtain written informed consent. 
• 
Deviations to protect the life or physical well-being of a subject in an emergency. 
1. Failure to obtain informed consent from patient prior to study participation. 
2. Incorrect version of the ICF used. 
3. Failure to obtain IRB/EC approval and CA approval, if applicable, before the start of the study. 
4. Treated subject did not meet inclusion/exclusion criteria. 
5. Subject not treated per the treatment assigned by randomization. 
6. Required assessment(s) during visit not done. 
7. Subject failure to attend a follow-up visit 
8. Adjunctive therapy visits occurring prior to 3 months post-index procedure for subjects assigned to 
ETA and VenaSeal™ treatment arm. For subjects in the surgical stripping arm, any additional 
adjunctive therapy occurring (excluding the adjunctive treatment completed along with the index 
procedure) prior to 3 months. 
9. Subject attends a follow-up visit which occurred outside the visit window (data is still to be entered in 
the CRF of the applicable visit). 
10. AEs and device deficiencies not reported in the required time to Medtronic or the EC/IRB in the frame 
as required by regulation or as specified in the CIP (according to section 12.3). 
11. Source data permanently lost. 
12. Enrollment of patients during lapse of IRB/EC approval and CA, if applicable. 
13. Enrollment limits exceeded. 

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10.17. 
Subject Exit, Withdrawal or Discontinuation  
10.17.1. Study Exit 
A study exit CRF is required for all subjects. Prior to exiting a subject from the study, it is recommended 
to follow the subject until all ongoing system and/or procedure related AEs are resolved or unresolved 
with no further actions planned.  Following exit, subjects will continue to receive standard medical care.  
Upon exiting from the study, no further study data will be collected, or study visits will occur for the 
subject. All data available through the time of the subject’s exit will be used for analysis.  
Subjects are urged to remain in the study as long as possible but may be exited from the study for any of 
the following situations: 
• 
Study completed 
• 
Subject lost to follow-up 
• 
Subject death 
• 
Screen Failure 
• 
Subject didn’t receive treatment for any of the target vein 
• 
Subject chooses to withdraw (e.g., consent withdrawal, relocation to another geographic location)  
• 
Investigator deems withdrawal necessary (e.g., medically justified, failure of subject to maintain 
adequate study compliance). 
The following information is required to be collected at study exit: 
• 
Date of the exit 
• 
Reason for exit. 
If discontinuation is because of safety, the subject may be asked to be followed for collecting safety data 
outside the clinical investigation.  
10.17.2. Study Completed  
The study will be considered completed when the last subject is exited and the database is locked. The 60 
months follow-up visit and exit visit should be combined, as applicable and both CRFs need to be 
completed. The subject will continue to be followed as per standard of care after study completion and 
no specific assessments are needed post study completion. VenaSeal vs. Surgical Stripping Study subjects 
will be exited following the 12 month visit. 

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10.17.3. Lost to Follow-up 
The study site will make every effort to have all subjects complete the follow-up visit schedule. A subject 
will not be considered lost to follow-up unless all efforts to obtain compliance are unsuccessful and the 
site should contact the study team before exiting the subject. At a minimum, the effort to obtain follow-
up information must include three attempts to make contact via telephone and if contact via phone is not 
successful, a traceable letter from the investigator should be sent to the subject’s last known address, a 
copy of which should be maintained in the subject’s study record. All contact efforts to obtain follow-up 
must be documented in the subject’s medical records.  
10.17.4. Subject Chooses to Exit (i.e. Revokes Consent) 
A study subject has the right to discontinue participation in the study at any time without penalty or loss 
of benefits to which the subject is otherwise entitled. A withdrawn subject will be treated according to 
standard of medical care and will not be replaced. If the subject no longer wants to participate in the 
study, no further personal data will be collected. Subjects will be included in the analyses up to the time 
that consent was withdrawn. The subject can also withdraw the consent to process the personal data. In 
that case, Medtronic may not delete the data to comply with legal obligations (such as storage periods) 
and/or to the extent that processing these data is necessary to ensure the validity of the study results. 
If the subject decides to withdraw from the study, the investigator will document the reason for 
withdrawal, if known, and indicate any rationale for the withdrawal from the study in the subject’s file 
and a Study Exit CRF must be completed. If a subject is withdrawn from the study due to problems related 
to the device or for safety reason, permission may be requested to follow up with the subject outside of 
the study due to withdrawal based on problems related to the safety or device performance. The site shall 
request permission from the subject to collect safety data up to 30 days from the day of exit (Safety data 
can be collected during the 30 days visit in-hospital or by phone as deemed appropriate by Investigator. 
Follow-up of any ongoing events will be done according to normal hospital practice and in accordance 
with local requirements). In all other cases, no additional data will be captured after the subject withdraws 
or is removed from the study, unless the information is publicly available. Subjects have the right to 
withdraw from the study at any time without explaining why and without any consequences. 
10.17.5. Investigator Withdraws Subject 
No subjects should be withdrawn by investigators unless compelling medical justification is present. It is 
recommended investigators discuss any withdrawals with the study team prior to withdrawing subjects. 
If the subject was randomized, it is preferred to keep the subject in the study and perform study 

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procedures/collect data to the extent possible. If an Investigator withdrawal is necessary, the reason for 
subject withdrawal should be collected prior to subject withdrawal if possible. 
10.17.6. Conditional Disengagement 
After a subject is enrolled/randomized every effort should be made to keep the subject in the study. 
However, it is recognized that there are circumstances where limited data may be collected, or study exit 
will need to occur. In these cases, we will consider either modified data collection requirements where 
subjects may conditionally disengage in study procedures but data from the subject can still be collected 
because the subject has not revoked consent or exit when study participation is completely ended. In 
randomized subjects, modified data collection is always preferred over exit. 
Subjects may be conditionally disengaged from study procedures for any of the following reasons: 
• 
Subject chooses to disengage (e.g., follow-up schedule cannot be adhered to, study burden too 
large, relocation to another geographic location). 
• 
Investigator deems conditional disengagement necessary (e.g., medically justified). 
If the subject wishes to disengage from the study, or the investigator deems it necessary, the study site is 
required to document the reason. Prior approval from the study team is required and a Limited Data 
Collection CRF needs to be completed. Data collection requirements no longer apply, but study sites are 
encouraged to collect as much data as possible on the regular CRFs. 
11. Risks and Benefits 
11.1 Potential Risks 
This study assesses the use of the VenaSeal™ Closure Device in comparison with surgical stripping or ETA 
treatment. The risk analysis process for the VenaSeal Spectrum study is being performed in accordance 
with ISO 14971 and will ensure that the level of risk is acceptable prior to starting the study. None of the 
treatment devices, materials, and techniques related to standard diagnostic and treatment procedures 
will be changed in this study. The device designs used in this study are commercially available and have a 
proven safety record. Standard risks associated with medical devices used in this study and risks 
associated with superficial venous disease treatment procedures are provided in the respective device 
IFUs. Additional risks, which are not known at this time, may also exist. In addition, the study design will 
minimize the risks through center and investigator selection criteria, careful subject selection and 
management, adherence to the schedule of assessments and adverse event monitoring.  

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11.2. Potential Risks of the Procedure  
Below are a list of the potential adverse effects and additional precautions associated with the use of the 
VenaSeal™ closure system, according to the IFU at time of protocol finalization.  Potential AEs that may 
be associated with the VenaSeal™ closure system are similar to those associated with other endovenous 
treatments that close the diseased vein. Please refer to the respective IFU as applicable per region for 
current and applicable information. 
The potential AEs (e.g., complications) associated with the use of the VenaSeal™ system include, but are 
not limited to, the following list: 
• 
Arteriovenous fistula  
• 
Bleeding from the access site 
• 
Deep Vein Thrombosis (DVT)  
• 
Edema in the treated leg  
• 
Embolization, including PE 
• 
Foreign body reactions (including, but not limited to, hypersensitivity or allergic reactions to 
cyanoacrylates, such as hives, asthma, anaphylactic shock, and nonspecific inflammation of the 
cutaneous and subcutaneous tissue) 
• 
Hematoma  
• 
Hyperpigmentation  
• 
Infection at the access site  
• 
Pain 
• 
Paresthesia  
• 
Phlebitis  
• 
Superficial thrombophlebitis  
• 
Urticaria or ulceration may occur at the injection site  
• 
Vascular rupture and perforation  
• 
Visible scarring. 
Additional Precautions for the VenaSeal™ Closure System: 
• 
The safety and effectiveness of the VenaSeal™ system in pregnant women and in pediatric 
patients have not been established.  
• 
The VenaSeal™ system is sterile unless the package is opened or damaged. The package should 
be examined prior to use. If the package is damaged DO NOT USE.  
• 
The VenaSeal™ system is intended for single patient use only. DO NOT REUSE or RE-STERILIZE.  

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• 
Prior to use, carefully examine the VenaSeal™ system components and verify they, and their 
packaging, have not been damaged during shipment. If the components show any sign of damage 
DO NOT USE.  
• 
Do not use after the expiration date.  
• 
Verify that the VenaSeal™ adhesive is a clear and free-flowing liquid prior to use. Material that is 
discolored should be discarded.  
• 
The VenaSeal™ adhesive will adhere to most surfaces. Avoid contact with non-disposable 
surfaces.  
• 
Gloves and eye/face protection are recommended when handling the VenaSeal™ adhesive.  
• 
The VenaSeal™ adhesive is intended to be delivered via the VenaSeal™ delivery system 
components only. 
11.3. Risk Minimization  
The potential risks associated with the therapies in this study were identified and have been successfully 
mitigated. Any potential risks associated with this study are further minimized by selecting qualified 
investigators and training study personnel on the CIP.  
In addition, investigators will be actively involved in the treatment and follow-up of the subjects treated 
with the study therapies. 
Risks will be minimized by careful assessment of each subject prior to, during, and after treatment with 
any of the study therapies.  
The products used for this study are the devices that are approved in the regions they are used. Medtronic 
has further minimized the possibility of risks by implementing quality control measures into production 
processes, providing guidelines for subject selection and evaluation, and providing adequate instructions 
and labeling. 
After treatment, subjects in the VenaSeal Spectrum study will be followed at regular intervals to monitor 
their condition following the therapy. At each protocol required follow-up, the investigator must assess 
any adverse events. 
11.4. Potential Benefits 
Surgical stripping has long been the gold standard for successful removal of incompetent varicose truncal 
veins. ETA is a minimally invasive method that uses thermal ablation, either through radiofrequency or 
laser, for closure of incompetent varicose truncal veins. The VenaSeal™ closure system is also a minimally 
invasive method and provides vein closure through injection of cyanoacrylate glue without the 

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administration of heat.  Improvements from treatment include reduction in rVCSS and AVVQ scores at 
follow-ups from 1 week to 36 months.27 All three treatments have high rates of closure and lead to clinical 
improvement.  
11.5. Risk-Benefit Rationale 
The probable benefits of the VenaSeal™ closure system are based on outcomes reported in the VeClose 
Pivotal IDE study as well as the Feasibility and eSCOPE studies described in section 4.1, Background. These 
data were used to support regulatory approval of the VenaSeal™ system. The use of the VenaSeal™ system 
to treat VRD in the GSV, a superficial truncal vein, resulted in high closure rates, and these results are 
consistent with the reported closure success rates with ETA treatments (i.e., RFA, EVLA). In addition, the 
VenaSeal™ system addresses some challenges associated with current ETA technologies such as less 
bruising (ecchymosis) and rapid return to normal activities without the need for compression stockings 
following treatment.33,34  The risks are similar to RFA, which is currently a commonly-used and comparative 
treatment modality that will be allowed as part of the ETA arm in this study.  
Regarding study participation, subjects are not put at any additional risk for participating in the study, as 
compared to being treated with the VenaSeal™ system, through ETA, or a surgical stripping treatment as 
part of their routine care. Subjects for whom it is unethical to be randomized to one of the treatment 
arms, should not be included in this study. Subjects who are included in this study will receive an increased 
level of care from their physicians as a result of participation, specifically additional follow-up visits and 
AE assessments. 
Given the available information above, the data support that for use in the treatment of lower extremity 
symptomatic varicose veins, the probable benefits of treatment with the VenaSeal™ system, treatment 
with ETA, or treatment through a surgical stripping procedure outweigh the probable risks. 
12. Adverse Events and Device Deficiencies 
12.1. Definitions/Classifications 
12.1.1. 
 Definitions 
For the purposes of the clinical report, Medtronic will classify each AE and device deficiency according to 
ISO 14155:2020 where applicable (Table 10). Where the definition indicates “device” for the VenaSeal™ 
system, it refers to any component of the VenaSeal™ closure system used in the study. Surgical 
instruments used as part of the surgical stripping or ETA procedures other than Medtronic’s ClosureFast™ 
device will not be considered for device deficiency assessment.  

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In situations where country-specific definitions and safety reporting regulations are stricter than those 
mandated per ISO14155:2020, reporting will be performed in compliance with the country-specific safety 
regulations.  
Table 10:  Adverse Event and Device Deficiency Definitions 
Adverse Event (AE): (ISO 14155:2020 3.2) 
Untoward medical occurrence, unintended disease or injury, or untoward clinical signs (including 
abnormal laboratory findings) in subjects, users or other persons, whether or not related to the 
investigational medical device and whether anticipated or unanticipated. 
NOTE 1:  This definition includes events related to the investigational medical device or the comparator. 
NOTE 2:  This definition includes events related to the procedures involved. 
NOTE 3:  For users or other persons, this definition is restricted to events related to the use of investigational medical devices or 
comparators. 
Adverse Device Effect (ADE): (ISO 14155:2020 3.1) 
AE related to the use of an investigational medical device. 
 
NOTE 1: This definition includes AEs resulting from insufficient or inadequate instructions for use, deployment, implantation, 
installation, or operation, or any malfunction of the investigational medical device. 
NOTE 2: This definition includes any event resulting from user error or from intentional misuse of the investigational medical 
device. 
NOTE 3: This includes ‘comparator’ if the comparator is a medical device. 
 
Serious Adverse Event (SAE): (ISO 14155:2020 3.45) 
AE that led to any of the following 
a) death, 
b) serious deterioration in the health of the subject, users, or other persons as defined by one or 
more of the following:  
1. a life-threatening illness or injury, or 
2. a permanent impairment of a body structure or a body function including chronic 
disease, or 
3. in-patient or prolonged hospitalization, or  
4. medical or surgical intervention to prevent life-threatening illness or injury, or 
permanent impairment to a body structure or a body function, 

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c) fetal distress, fetal death, a congenital abnormality, or birth defect including physical or mental 
impairment.   
 
NOTE 1:  Planned hospitalization for a pre-existing condition, or a procedure required by the CIP, without serious deterioration 
in health, is not considered an SAE. 
 
Serious Adverse Device Effect (SADE): (ISO 14155:2020 3.44) 
Adverse device effect that has resulted in any of the consequences characteristic of a serious adverse 
event.   
 
Device deficiency (DD): (ISO 14155:2020 3.19) 
Inadequacy of a medical device with respect to its identity, quality, durability, reliability, usability, safety 
or performance. 
 
NOTE 1: DD include malfunctions, use errors, and inadequacy in the information supplied by the manufacturer including labelling. 
NOTE 2: This definition includes DD related to the investigational medical device or the comparator. 
 
Unanticipated Serious Adverse Device Effect (USADE) (ISO 14155:2020 section 3.51) 
SADE which by its nature, incidence, severity or outcome has not been identified in the current risk 
assessment. 
Note: Anticipated Serious Adverse Device Effect (ASADE) is an effect which by its nature, incidence, severity or outcome has 
been identified in the risk assessment. 
Serious Health Threat (ISO 14155:2020, 3.46) 
Signal from any adverse event or device deficiency that indicates an imminent risk of death or a serious 
deterioration in the health in subjects, users or other persons, and that requires prompt remedial 
action for other subjects, users or other persons. 
 
NOTE 1: This would include events that are of significant and unexpected nature such that they become alarming as a potential 
serious health hazard or possibility of multiple deaths occurring at short intervals.  
SAE definition and reporting in Germany will be in conformance with Verordnung über die Erfassung, 
Bewertung und Abwehr von Risiken bei Medizinprodukten (Medizinprodukte-
Sicherheitsplanverordnung- MPSV) and with the rules of the electronic reporting procedures published 
on the Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM) homepage. 

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Serious Adverse Event (SAE) definition: (MPSV § 2 Definitions Abs 5) 
In accordance with this regulation – 
A serious adverse event (SAE) is an event that occurs in a clinical investigation subject to approval or 
occurring in a performance evaluation which led, might have led or could lead directly or indirectly to 
death or serious deterioration of health of the subject, the user or a third party, without consideration 
if the event has been caused by the medical device itself; this applies accordingly to serious adverse 
events occurring in a clinical investigation or performance evaluation. 
An event is not considered an AE if it has been identified as a pre-existing condition, unless there is a 
change in nature, severity or degree of incidence of the event.  
12.1.2. 
 Classification of Causal Relationships  
For each reported AE, the causal relationship between the AE and the study device (for VenaSeal™ and 
ETA treatment only) and index-procedure will be classified as not related, unlikely, possible, probable or 
causal relationship (Table 11). 
Table 11: Causality Assessment 
Not related 
Relationship to the device or procedures can be excluded when: 
• 
the event is not a known side effect of the product category the device 
belongs to or of similar devices and procedures; 
• 
the event has no temporal relationship with the use of the investigational 
device or the procedures; 
• 
the serious event does not follow a known response pattern to the medical 
device (if the response pattern is previously known) and is biologically 
implausible; 
• 
the discontinuation of medical device application or the reduction of the level 
of activation/exposure - when clinically feasible – and reintroduction of its use 
(or increase of the level of activation/exposure), do not impact on the serious 
event; 
• 
the event involves a body-site or an organ not expected to be affected by the 
device or procedure; 
• 
the serious event can be attributed to another cause (e.g. an underlying or 
concurrent illness/ clinical condition, an effect of another device, drug, 
treatment or other risk factors); 

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• 
the event does not depend on a false result given by the investigational device 
used for diagnosis, when applicable; 
• 
harms to the subject are not clearly due to use error; 
In order to establish the non-relatedness, not all the criteria listed above might be 
met at the same time, depending on the type of device/procedures and the serious 
event. 
Unlikely 
The relationship with the use of the device seems not relevant and/or the event can 
be reasonably explained by another cause, but additional information may be 
obtained. 
Possible 
The relationship with the use of the investigational device is weak but cannot be 
ruled out completely. Alternative causes are also possible (e.g., an underlying or 
concurrent illness/ clinical condition or/and an effect of another device, drug or 
treatment). Cases were relatedness cannot be assessed or no information has been 
obtained should also be classified as possible. 
Probable 
The relationship with the use of the investigational device seems relevant and/or 
the event cannot reasonably be explained by another cause, but additional 
information may be obtained. 
Causal relationship 
The event is associated with the investigational device or with procedures beyond 
reasonable doubt when: 
• 
the event is a known side effect of the product category the device belongs to 
or of similar devices and procedures; 
• 
the event has a temporal relationship with investigational device 
use/application or procedures; 
o the event involves a body-site or organ that  
 
the investigational device or procedures are applied to; 
 
the investigational device or procedures have an effect on: 
o the serious event follows a known response pattern to the medical 
device (if the response pattern is previously known); 
• 
the discontinuation of medical device application (or reduction of the level of 
activation/exposure) and reintroduction of its use (or increase of the level of 
activation/exposure), impact on the serious event (when clinically feasible); 
• 
other possible causes (e.g. an underlying or concurrent illness/clinical 
condition or/and an effect of another device, drug or treatment) have been 
adequately ruled out; 
• 
harm to the subject is due to error in use; 

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• 
the event depends on a false result given by the investigational device used for 
diagnosis, when applicable; 
In order to establish the relatedness, not all the criteria listed above might be met 
at the same time, depending on the type of device/procedures and the serious 
event. 
 
The following definitions (Table 12) are intended as guidelines for classifying causal relationships between 
the event and the VenaSeal™ or ETA system and the index- procedure (Timeframe for assessing implant 
procedure relationships begins when subject is being prepared for the procedure). 
Table 12: Adverse Event Relationship Definitions 
Related to 
Definition 
Procedure with the VenaSeal™ closure system, 
ETA, or surgical stripping (procedure relatedness)  
Any AE that occurs within 30 days of the index 
procedure unless specifically shown not to be 
related to that procedure. 
VenaSeal™ closure system (product relatedness) 
 
Any AE involving the function of the product, or 
the presence of the product in the body. Included 
in this category are events that are directly 
attributed to the product. 
ETA devices (product relatedness)  
Any AE involving the function of the laser or RF 
generator used in a treatment with the ETA arm. 
Included in this category are events that are 
directly attributed to the product.  
12.2. Foreseeable Adverse Events and Foreseeable Adverse Device 
Effects 
A list of adverse events or complications associated with the use of the applicable devices that may occur 
or require intervention can be found in the applicable IFU.  These expected events are considered 
anticipated adverse events that can be predicted to occur with some frequency, irrespective of how low 
that frequency is expected to be. For the list of anticipated AEs and anticipated adverse device effects 
associated with the treatments in this study refer to the applicable IFUs. 

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Medical occurrences that are inherent to an intervention and expected to occur in the majority of subjects 
for a projected duration may be considered unavoidable. Such events include those listed in Table 13. 
These medical occurrences should not be reported as AEs during this study. 
12.3. Recording and Reporting of Adverse Events 
Events will be recorded on the appropriate CRFs entering information as documented in the subject’s 
medical records. Events will be reported throughout the course of study (from the moment the index 
procedure is initiated until completion of follow up or exit). Due to the post market nature of this study, 
only adverse events meeting the below criteria will be reported).   
For all reportable AEs, investigators should assess and record at least the following information on the AE 
CRF: 
1. All AEs occurring in the target limb, including but not limited to the following specific events: 
• 
Hypersensitivity 
• 
Phlebitis 
• 
Granuloma 
• 
Endovenous glue induced thrombosis (EGIT) or endovenous heat induced thrombosis (EHIT) 
• 
Symptomatic DVT. 
2. Symptomatic PEs  
3. Serious adverse events (SAE) 
4. Non-subject (users) adverse events: AEs occurring to the users or other site personnel related to the 
device or the procedure. 

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Events described in Table 13 are considered unavoidable events inherent to surgical procedure that is 
expected to occur in all subjects for a projected duration according to the Investigator’s opinion 
Unavoidable events should not be reported unless the event worsens or is present outside the stated 
timeframe from the index procedure. 
Table 13: Expected and Unavoidable not to be reported adverse events 
Event Description  
Timeframe from the 
procedure 
Anesthesia related nausea/vomiting 
24 hours 
Low-grade fever (<100°F or <37.8°C) 
48 hours 
Incisional pain (with or without standard treatment and patient not returning 
to clinic to have additional treatment) 
72 hours 
Mild to moderate bruising / ecchymosis * 
7 days 
Back pain related to laying on table 
72 hours 
1. Date the event started (if full date is not available, partial date is allowed) 
2. Date site became aware of event 
3. Date event first determined to be a Serious Adverse Event, if applicable 
4. Event term 
5. Event description 
6. Action taken/treatment 
7. Which seriousness criteria did the event meet, if applicable 
8. Relationship of the event to the procedure 
9. Relationship of the event to the device (for VenaSeal™ and ETA treatment only)  
10. Narrative (describe any additional details relevant to the AE)  
11. Outcome of the event. 

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Bleeding at access site (not requiring treatment) 
24 hours 
Emergency room visits and procedures not meeting the SAE definition** 
NA 
* Ecchymosis events will not be considered AEs unless they are classified as significant by the Investigator due to the 
more serious nature of it. 
**Emergency room visits and procedures will not be considered collectable AEs unless there is a potential 
relationship with the VenaSeal™ system. 
12.4. Recording and Reporting of Device Deficiencies 
Device deficiency information will be collected and recorded throughout the study. The Device 
Deficiencies related to the VenaSeal™ system and Medtronic ClosureFast™ system (ETA treatment 
modality) will need to be reported in the CRF. 
The Device Deficiencies related to any other products used in the study should be reported per site’s 
standard practice of reporting to their manufacturer. This reporting requirement is a deviation from ISO 
14155:2020 due to the post-market nature of the study.  
It is the responsibility of the investigator to report all product complaint(s) associated with a medical 
device distributed by Medtronic, regardless whether they are related to intended use, misuse or abuse of 
the product. In addition to study requirements outlined above, additional reporting of product complaints 
by the site must be done according to the local Standard Operating Procedures. Medtronic will notify the 
Regulatory Authority (e.g., CA) as applicable for the following incidents immediately upon learning of 
them and is not limited to AEs and DDs only: 
• 
Device deficiencies that lead to an AE by study definition will be reported on the AE CRF only.   
• 
Device deficiencies that did not lead to an AE will be reported on a Device Deficiency CRF (one for 
each device deficiency). 
• 
Device deficiencies that did not lead to an AE but might have led to a SADE if  
a. a suitable action had not been taken, or  
b. an intervention had not been made, or  
c. circumstances had been less fortunate, should be reported to Medtronic on a Device Deficiency 
CRF. 
• 
Device deficiencies that did not meet any of the above criteria will be reported to Medtronic through 
normal complaint process. 

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• 
Any malfunction or deterioration in the characteristics and/or performance of a device, as well as any 
inadequacy in the labeling or instructions for use which led or might have led to the death or serious 
deterioration in the state of health of a patient, user, or other person. 
• 
Any technical or medical reason resulting in withdrawal of a device from the market by the 
manufacturer. 
• 
Any serious deterioration in the state of health, including: 
 
Life-threatening illness or injury. 
 
Permanent impairment of a body function or permanent damage to a body structure. 
 
A condition necessitating medical or surgical intervention to prevent permanent impairment 
of a body function or permanent damage to a body structure. 
12.5. Adverse Event and Device Deficiency Review Process 
AEs/Device Deficiencies will be reviewed by Medtronic Study Management and/ or designee. This review 
will include the determination whether the AE/Device Deficiency meets regulatory reporting 
requirements. The sponsor will ensure timely AE/Device Deficiency reporting to meet global and country 
specific regulatory requirements.  
12.6. Reporting of Adverse Events 
The information below outlines the AE reporting requirements from the investigator to Medtronic (Table 
14). Investigators and Medtronic are obligated to report AEs to their EC/IRB in accordance with the 
requirements and local regulations. Refer to section 12.3 and section 12.4 for a list of types of AEs that 
are required to be reported during the study. 
Table 14: Investigator reporting requirements 
Timeframe for Reporting 
Event Type 
Immediately, but no later than 3 calendar 
days of the investigator’s / site’s first 
knowledge of the event (or sooner if 
required by local regulation) 
• 
Adverse Device Effect (ADE) or Device Related 
Adverse Event. Device Deficiency (DD).  
• 
Device Deficiency that might have led to a SADE 
• 
Serious Adverse Device Effect (SADE) 
• 
Serious Adverse Event (SAE) 
In a timely manner from the investigator’s / 
site’s first knowledge of the event 
Adverse Event (AE): only those that are required to 
be reported according to CIP. 

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12.7. Emergency Contact for Reporting Events and Device 
Deficiencies 
Investigators should contact their Medtronic clinical representative if they have any questions regarding 
AEs and/or device deficiencies. Sponsor contact information is subject to change and will be maintained 
in a document separate from the clinical investigation plan and provided to sites.  
If the CRF is not available for immediate recording, the paper AE or Device Deficiency Form in the ISF must 
be completed and submitted to the email box specified in the ISF and to the Medtronic clinical study 
monitor. In due time, the AE or device deficiency needs to be entered in the CRF as well. 
12.8. Processing Updates and Resolution 
For any changes in status of a previously reported adverse event or DD (i.e., change in actions taken, 
change in outcome, change in relatedness), information needs to be updated on, or added to the original 
AE or DD form. All AEs must be followed until the AE has been resolved, is unresolved with no further 
actions planned, the subject dies or exits the study, or until study closure, whichever occurs first.  
In the event that a subject is exited from the study prior to study completion, all efforts should be made 
to continue following the subject until all unresolved procedure related AEs, as classified by the 
investigator, are resolved or unresolved with no further actions planned. Additionally, if there are 
procedure related AEs at the time of study completion, the subject should not be exited, but should 
continue to be followed for up to 30 days to assess the ongoing AE. Once the ongoing system or procedure 
AE(s) is/are resolved, or the subject has been followed for 30 days whichever occurs first, the subject 
should be exited. If AEs are still ongoing 30 days post study completion, it should be noted on the AE CRF 
that the AE is unresolved at time of study exit. 
At the time of study exit, all collected adverse events that are unresolved must be reviewed and an update 
to the original AE must be reported. 
12.9. Subject Death 
All subject deaths must be reported by the investigator to Medtronic on an AE form (AE with outcome of 
death) as soon as possible after the investigator first learns of the death.  In case of death, there should 
be one AE with the outcome of death.  
A copy of the death certificate, if available and allowed by state/local law, should be sent to the Medtronic 
clinical study team. When a death occurs in a hospital, a copy of the death summary report and all relevant 
hospital records, if available should be sent to the Medtronic clinical study team. If an autopsy is 
conducted, a copy of the autopsy report should also be sent to the Medtronic clinical study team if 

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available and allowed by state/local law. When the death occurs at a remote study site, it is the 
investigative study site’s responsibility to attempt retrieval of information about the death.  
In summary, the following data will be collected: 
• 
Date of death 
• 
Detailed description of death 
• 
Cause of death 
• 
Relatedness to system and/or procedure 
• 
Death summary/hospital records (if available and allowed by state/local law) 
• 
Autopsy report (if available and allowed by state/local law) 
• 
Death certificate (if available and allowed by state/local law). 
13. Data Review Committees  
13.1. Clinical Events Committee (CEC) 
A Clinical Events Committee will provide independent medical review and adjudication of AE data.  The 
CEC will adjudicate only the safety endpoint events specified in the CEC Charter reported by the 
investigators. Source documents to support adjudication may be requested. Further AEs may be reviewed 
and adjudicated upon request of the sponsor. The CEC will follow the definitions for classifying AEs that 
relate to clinical safety endpoints as described in the CEC Charter. 
The CEC members will be free from bias towards the study and will be independent from the study 
investigators, Medtronic and regulatory authorities. The committee will consist of experts (non-Medtronic 
employed physicians) with training or experience relevant to the study.  
Events for all three Studies requiring at minimum adjudication include the following through 12 months 
post-index procedure: 
In addition, any Serious Adverse Events (SAEs) will be adjudicated through 12 months post-index 
procedure.  
 
1.  Specific target limb adverse events (AEs): 
• 
Hypersensitivity to VenaSeal™ adhesive 
• 
Phlebitis 
• 
Granuloma 
• 
EGIT or EHIT 

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The CEC will be established and led by: 
NAMSA (previously Syntactx) 
150 Greenwich Street 
Floor 44 
New York, NY 10007 
13.2. Lead Principal Investigators 
The lead principal investigators will take responsibility for the scientific validity of the clinical investigation 
plan, assessment of the study quality and conduct as well as for the scientific quality of the data analysis 
and reporting.  
13.3. Ulcer Assessment Core Laboratory 
The ulcer assessment core laboratory is responsible for assessing target limb VLU size, healing, recurrence 
and other applicable measurements. VLU photographs and select data points (e.g., ulcer origin date, date 
of visit) will be provided to the core laboratory by designated VLU Study sites through imaging systems 
provided to the site by the ulcer core laboratory. The core laboratory will report all ulcer data to Medtronic 
per a standardized process. Additional details are available under separate cover. 
The ulcer assessment core laboratory will be established and led by: 
Syntropic Core Lab 
3545 Olentangy River Rd #514 | 
Columbus, OH 43214 |  
Office: 614-788-5830 
14. Statistical Design and Methods 
This evaluation has been designed as a global, post-market, prospective, multi-center, randomized 
controlled study of patients with symptomatic superficial venous disease, with a single arm embedded 
ulcer study. The study is designed with two Randomized Studies (VenaSeal vs. Surgical Stripping Study and 
VenaSeal vs. ETA Study) for CEAP 2-5 subjects and one single arm active VLU Study with CEAP 6 subjects. 
Each study will be individually assessed and analyzed for the overall study objectives.   
The three primary endpoints in the Randomized Studies will be measured to compare VenaSeal vs. the 
treatment of ETA or surgical stripping on VenousTSQe and VenousTSQs (separately) at 30 days, and 
elimination of clinically relevant superficial truncal disease in the target vein at the time of index 

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procedure. The primary endpoint of the VLU Study is time to ulcer healing and will be measured until 
healing has occurred.  
The Statistical Analysis Plan (SAP) will be developed prior to data analysis and will include a comprehensive 
description of the statistical methods used to analyze the study objectives. Any change to the data analysis 
methods described in the CIP will require an amendment only if it changes a principal feature of the CIP. 
Any other change to the data analysis methods described in the CIP, and the justification for making the 
change, will be described in the clinical study report.   
All statistical analyses will be performed using Statistical Analysis System (SAS) software (version 9.2 or 
higher) or other widely accepted statistical or graphical software. 
Statistical analysis methods are discussed separately for the Randomized Studies and the single-arm VLU 
Study below. 
14.1. Randomized Studies 
Analyses will be performed on all patients who pass the point of enrollment (randomization), according 
to the intention-to-treat (ITT) principle. Patients will be analyzed in the arm they are randomized to 
regardless of the treatment received. There are three primary endpoints and two key secondary endpoints 
with formal hypothesis testing for the Randomized Studies. Multiplicity adjustment needs to be 
considered to control the overall type I error. Each randomized study will have a family-wise type I error 
rate of 0.05. Within each study, a Hochberg procedure (Benjamini & Hochberg, 1995) will be used to 
control the family-wise type I error rate to 0.05 for the primary endpoints. Type I error preserved from 
the primary endpoints will be used for the key secondary endpoints.  
A type I error of 0.0167 will be used in the following sample size calculations for this purpose.  
In the two Randomized Studies, three primary endpoints will be assessed: 1) Peri-procedural patient 
satisfaction as measured by a validated patient-centered venous treatment satisfaction questionnaire 
(VenousTSQe) at 30 days; 2) Patient satisfaction as measured by a validated patient-centered venous 
treatment satisfaction questionnaire (VenousTSQs) at 30 days, and 3) elimination of clinically relevant 
superficial truncal disease in each target vein at index procedure. The two key secondary endpoints 
include achieving the anatomical closure of superficial truncal veins at 6 months and the ability to return 
to work post-index procedure.  
For VenaSeal vs Surgical Stripping Study, 108 patients randomized before 22-Feb- 2022 will be included in 
the analysis. These patients will be followed for 12 months after index procedure. Since the enrollment 
was stopped for VenaSeal vs. Surgical Stripping Study with up to 108 subjects, there is still reasonable 

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power for the two TSQs and key secondary objectives. Therefore, the VenaSeal vs Surgical Stripping Study 
will test two primary endpoints (Venous TSQe and TSQs at 30 days) and key secondary endpoints. The 
elimination of truncal reflux at the index procedure will be summarized but not tested for hypothesis 
testing. 
14.1.1. 
Sample Size Evaluation on Primary Endpoints 
VenousTSQ 
Subject experience and satisfaction will be measured through a new, patient-centered venous treatment 
satisfaction questionnaire (VenousTSQ). The VenousTSQ is designed to have two components, the 
VenousTSQe and the VenousTSQs. As a result of the different content of both components of the 
VenousTSQ, the related endpoints are split into two separate primary endpoints, being: 
While the VenousTSQ is a newly-developed PROM and its scoring guidelines are currently under 
development at the time of finalization of this protocol, the final versions of the questionnaires provide 
sufficient insight in the eventual scoring scales. Each of the two parts consists of 8-11 items in total.  
VenousTSQe consists of 8 items (13 including sub-items) with items being able to be scored with yes/no 
or from 6 – 0. VenousTSQs consists of 11 items (15 including sub-items) and items can similarly be scored 
with yes/no or from 6 – 0. Consequently, VenousTSQe and Venous TSQs have a potential scale that range 
runs from 0 - 78 and 0 – 90, respectively. Final scoring guidelines will be evaluated via psychometric 
analysis utilizing data from approximately 100 English-speaking enrolled patients. Sample sizes are 
provided in Table 15 for different scenarios with a varying final scoring.   
To determine the variance (SD), a comparison was made to other treatment satisfaction questionnaires 
(TSQs) that were developed by the same expert group. The Macular TSQ (MacTSQ) was designed as a 
measure of patient satisfaction with treatment for macular disease. The questionnaire consists of two 
subscales with each a maximum score of 36 (6 questions each) and a single scale with a maximum score 
of 72 (12 questions). The SD was reported as 3.56 for subscale 1, 5.04 for subscale 2, and 7.30 for the 
single scale35. The Diabetes TSQ (DTSQ) was designed as a measure of patient satisfaction with treatment 
for diabetes. The questionnaire consists of a scale with a maximum score of 48 (8 questions) and a typical 
SD is around 5.036,37. To determine the SD for the two VenousTSQ endpoints, an overestimate was made 
in comparison with literature findings. As such, the SD was selected to be 10 for VenousTSQe and 
VenousTSQs endpoints, respectively.  
1. Peri-procedural patient satisfaction as measured by a validated, patient-centered venous treatment 
satisfaction questionnaire (VenousTSQe) at 30 days. 
2. Patient satisfaction as measured by a validated, patient-centered venous treatment satisfaction 
questionnaire (VenousTSQs) at 30 days.  

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The null hypothesis on the primary endpoints of VenousTSQe and VenousTSQs at 30 days is that the 
VenaSeal™ system arm will have same PROM scale as that of the control (ETA or surgical stripping) arm. 
The alternative hypothesis is that the VenaSeal™ system arm will have a different PROM scale from that 
of the control arm. Rejection of the null hypothesis in favor of the VenaSeal™ system will signify that the 
treatment satisfaction with the VenaSeal™ system is superior to the treatment with ETA or surgical 
stripping. A minimum difference of 0.5 points per item, as a total score, is utilized as the minimum 
meaningful difference between comparison groups. 
Specifically, the null (Ho) and alternative (Ha) hypotheses are: 
Ho: pA = pC 
Ha: pA ≠ pC 
Where pA and pC are the true PROM scale for the VenaSeal™ system arm and ETA or surgical stripping 
arm, respectively. 
The parameter assumptions are: 
With these assumptions, a total of 237 subjects (220 evaluable, 110 in each arm) will yield 90% power to 
reject the null hypothesis in favor of the alternative hypothesis of superiority on VenousTSQe and 
VenousTSQs at 30 days, in each study.  
Assuming the standard deviation increases with the number of questions and the minimum clinical 
difference of 0.5 points per question, the sample size calculations are not impacted by the number of 
questions. Therefore, sample size adjustments are not anticipated if the number of questions varies from 
8 or 11.   
 
 
• 
pA - pC =4 and 5.5 PROM points for VenousTSQe and VenousTSQs, respectively 
• 
Common standard deviation of 8 and 11 PROM points for VenousTSQe and VenousTSQs, respectively 
• 
T test with two sided α 0.0167 
• 
1:1 randomization 
• 
7% attrition rate for VenousTSQ at 30 days 

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Table 15: VenousTSQ Sample Size Evaluation 
Number of Venous TSQ 
questions 
Difference of PROM 
Points 
SD of PROM points 
(assuming equal in 
both arms) 
Sample size (1:1 
evaluable) 
6 
3 
6 
110:110 
8 
4 
8 
110:110 
10 
5 
10 
110:110 
11 
5.5 
11 
110:110 
12 
6 
12 
110:110 
Elimination of truncal reflux 
The third primary endpoint is the elimination of clinically relevant superficial truncal disease in target veins 
at the index procedure. This endpoint will be measured as a percentage of treated vein vs. diseased vein 
for each target vein.  
Based on clinical experience, the minimal clinically relevant difference in mean percentage of truncal 
disease elimination between treatment modalities is expected to be 10%. To calculate the sample size, a 
combination of the smallest minimal clinically relevant difference and the largest variance (SD) are 
justified being the conservative assumptions. An SD of 20% was estimated as being the maximum likely 
seen and is therefore used to calculate the sample sizes.  
The null hypothesis on this primary endpoint is that the VenaSeal™ system arm will have the same 
percentage of reflux eliminated at the index procedure as that of the control (ETA or surgical stripping) 
arm. The alternative hypothesis is that the VenaSeal™ system arm will have a different percentage of 
reflux eliminated at the index procedure from the control arm. Rejection of the null hypothesis will signify 
that the treatment with the VenaSeal™ system is superior to the treatment with ETA or surgical stripping. 
Specifically, the null (Ho) and alternative (Ha) hypotheses are: 
Ho: µA = µC 
Ha: µA ≠ µC 
Where µA and µC are the true percentage of reflux treated at the index procedure for the VenaSeal™ 
system arm and ETA or surgical stripping arm. 
The parameter assumptions are: 

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With these assumptions, a total of 227 subjects (220 evaluable, 110 in each arm) will yield 90% power to 
reject the null hypothesis in each study.  
14.1.2. 
Sample size evaluation on key secondary endpoints 
Return to work 
Return to work is defined as the time in days patients need following a procedure to return to work. 
Return to work time can be influenced by factors that are independent of the type of work they are 
employed to do (e.g., including physical effort), the type of anesthesia that is used with or without 
hospitalization, and other regional/cultural differences.  
To minimize the effects of independent factors that may influence the return to work time, several 
measures will be taken into account. Employment status will be captured for all patients. Only patients 
who have an active employment status (employed or independent worker, including stay at home 
parents) will be included in the analysis for return to work time. Information will be captured on the 
category of occupation to be able to distinguish between physical and sedentary work. The analysis may 
correct for weekends and part-time work as applicable.  
A literature search on historical data for return to work time following treatment of venous reflux disease 
was conducted using the PubMed database of clinical literature. Publications describing return to work 
times for treatment of venous reflux disease with the VenaSeal™ closure device, any type of endovenous 
laser ablation and radiofrequency ablation, or surgical stripping were considered.   
The resulting return to work times are summarized in Table 16. Where applicable, the return to normal 
activities time is included. The corresponding sample size (based on ITT) and measure of return time 
(mean vs. median) are included in the table. The results of the first five rows were used to estimate sample 
sizes for the return to work endpoint because these studies specifically report the mean and SD. Using a 
conservative approach, the resulting SDs for the three treatment groups (ETA, VenaSeal™ treatment, and 
surgical stripping) were compared against the median and IQR of the remaining findings to make sure the 
used estimations were justified compared to existing data. With this approach, the smallest differences 
between treatment with the VenaSeal™ device and the other treatments are utilized to calculate the final 
sample size.    
• 
µa µC = 10%  
• 
Common standard deviation of 20% 
• 
Two-sided t test with α = 0.0167 
• 
1:1 randomization 
• 
3% attrition 

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Table 16: Return to work/normal activity time post treatment 
AUTHOR 
YEAR 
TREATMENT 
TYPE 
SAMPLE 
SIZE  
(# PTS, ITT) 
MEASURE 
TIME IN DAYS 
TO RETURN 
TO NORMAL 
ACTIVITIES 
TIME IN 
DAYS TO 
RETURN TO 
WORK  
PRONK 
2010 
ETA: Laser 
62 
Mean (SD) 
3.2 (4.3) 
4.4 (5.4) 
LURIE 
2003 
ETA: RFA 
45 
Mean (95% CI) 1.15 (0.05-
2.34) 
4.7 (1.16-
8.17) 
GIBSON  
2017 
VenaSeal™ 
50 
Mean (SD) 
2.4 (+/- 4.1) 
0.2 (+/- 1.1)   
LURIE 
2003 
Surgical 
stripping 
40 
Mean (95% CI) 3.89 (2.67-
5.12)  
12.4 (8.66-
16.23) 
PRONK 
2010 
Surgical 
stripping 
68 
Mean (SD) 
3.2 (4.0) 
4.2 (3.7) 
SAMUEL 
2013 
ETA: Laser 
38 
Median (IQR) 
4 (1-14)       
4 (0-12) 
2013 
ETA: Laser 
38 
Median (IQR) 
3 (1-14)  
3 (1-8) 
RASMUSSEN  
2011 
ETA: Laser 
125 
Median 
(range) 
2 (0–25)  
3.6 (0–46) 
COTTON 
2016 
ETA: Laser 
212 
Median 
7.7  
LATTIMER 
2012 
ETA: Laser 
56 
Median (IQR) 
7.5 (2-15) 
 
CARRADICE 
2011 
ETA: Laser 
140 
Median (IQR) 
3 (1-10) 
4 (2-14) 
RASMUSSEN  
2011 
ETA: RFA 
125 
Median 
(range) 
1 (0–30)  
2.9 0–14) 
LANE 
2016 
ETA: RFA 
83 
Median (IQR) 
2 (1-7) 
2 (2-7)    
SUBRAMONIA  2010 
ETA: RFA 
48 
Median (IQR) 
3 (2-5) 
10 (4-13)  
CHAN 
2017 
VenaSeal™ 
29 
Median 
(range)  
1 (1-16) 
The null hypothesis for the key secondary endpoint is that the VenaSeal™ system arm will have the same 
days to return to work as that of the control (ETA or surgical stripping) arm. The alternative hypothesis is 
that the VenaSeal™ system arm will have different days to return to work than that of the control arm. 
Rejection of the null hypothesis in favor of VenaSeal will signify that the ability to return to work after 
treatment with the VenaSeal™ system is superior to ETA or surgical stripping. 
Specifically, the null (Ho) and alternative (Ha) hypotheses are: 
Ho: rA = rC 
Ha: rA ≠ rC 
Where rA and rC are the true days to return work for the VenaSeal™ system arm and ETA or surgical 
stripping arm, respectively. 
The parameter assumptions are: 

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With these assumptions, a total of 22 subjects (evaluable; 11 in each arm) in the VenaSeal vs ETA Study 
and 10 subjects (evaluable; 5 in each arm) in Surgical Stripping Study will yield 90% power to reject the 
null hypothesis in favor of the alternative hypothesis of superiority in each study. 
Closure rate 
Closure rate is a generally used measure to determine the short and long-term success of venous reflux 
disease treatment. Literature may report on closure rate, occlusion rate, or recanalization rate at various 
moments in time. The endpoint used in this study focuses on the closure rate measured at 6 months.  
To calculate the sample size based on historical data on closure rate, a literature search was conducted 
using
 the
 PubMed
 database
 of
 clinical
 literature.
 Any
 literature
 older
 than
 10 years
 was
 excluded
 from
 the
 
analysis. Six-month closure rates for treatment of venous reflux disease with the VenaSeal™ closure 
device, any type of endovenous laser ablation and radiofrequency ablation, or surgical stripping were 
considered.  
Closure rates were weighted within a treatment arm by multiplying the closure rate for that treatment 
with the sample size of the treatment arm. Table 17 shows an overview of the literature that was used to 
calculate weighted closure rates that were used for sample size calculations.  
Table 17: Closure rates for treatment of venous reflux disease 
AUTHOR 
YEAR 
TREATMENT 
FOLLOW-
UP 
SAMPLE SIZE  
(# PTS, ITT) 
CLOSURE/OCCLUSION 
RATE 
BRITTENDEN  2015 
ETA: Laser 
6M 
212 
83.0% 
BOZOGLAN 
2016 
ETA: Laser 
6M 
60 
100.0% 
EROGLU 
2018 
ETA: Laser 
6M 
175 
95.1% 
SYDNOR 
2017 
ETA: Laser 
6M 
100 
100% 
WOZNIAK 
2016 
ETA: Laser 
6M 
56 
100% 
MESE 
2015 
ETA: Laser 
6M 
60 
100% 
ATASOY 
2015 
ETA: Laser 
6M 
44 
100% 
CALIK 
2019 
ETA: Laser 
6M 
200 
95.6% 
LANE  
2016 
ETA: RFA 
6M 
82 
93.0% 
BETELI 
2017 
ETA: RFA 
6M 
43 
95.3% 
• rA = 0.2 in the VenaSeal™ system arm and rC = mean 3 and 8 in ETA arm and surgical stripping arm, 
respectively 
• standard deviation of 1.1 in the VenaSeal™ system arm, 2 in ETA arm and 3 in surgical stripping arm 
• Two-sided t test with  = 0.0167 
• 1:1 randomization. 

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AUTHOR 
YEAR 
TREATMENT 
FOLLOW-
UP 
SAMPLE SIZE  
(# PTS, ITT) 
CLOSURE/OCCLUSION 
RATE 
EROGLU 
2018 
ETA: RFA 
6M 
175 
94.1% 
SYDNOR 
2017 
ETA: RFA 
6M 
100 
97.3% 
MENDES 
2016 
ETA: RFA 
6M 
18 
80.0% 
WOZNIAK 
2016 
ETA: RFA 
6M 
54 
100% 
MESE 
2015 
ETA: RFA 
6M 
60 
95.0% 
YANG 
2013 
ETA: RFA 
6M 
100 
99.0% 
MORRISON 
2018 
ETA: RFA 
6M 
114 
96.2% 
CRETON 
2010 
ETA: RFA 
6M 
295 
98.6% 
CHAN 
2017 
VenaSeal™ 
6M 
57 
90.3% 
ALMEIDA 
2013 
VenaSeal™ 
6M 
38 
92.1% 
GIBSON 
2016 
Venaseal™ 
6M 
70 
98.0% 
PROEBSTLE 
2015 
VenaSeal™ 
6M 
70 
91.4% 
MORRISON 
2018 
VenaSeal™ 
6M 
108 
99.0% 
BRITTENDEN 
2015 
Surgical 
stripping 
6M 
294 
84.4% 
JIA 
2010 
Surgical 
stripping 
6M 
26 
89.5% 
 
Table 18 shows an overview of the weighted average closure rates at 6 months that were used to calculate 
the sample size for this endpoint.   
Table 18: Weighted Average Closure Rate 
COMPARATOR  
TOTAL NUMBER OF 
CONSIDERED 
STUDIES 
TOTAL SAMPLE SIZE IN 
CONSIDERED STUDIES 
WEIGHTED AVERAGE 
CLOSURE RATE AT 6M 
VENASEAL™ 
5 
343 
95.0% 
ETA 
14 
1948 
95.4% 
SURGICAL STRIPPING 
2 
320 
84.8% 
 
The null hypothesis on this key secondary endpoint is that the closure rate at 6 months in the VenaSeal™ 
system arm will have less than or equal to that in the control (ETA or surgical stripping) arm minus a 
clinically relevant difference of 10%. The alternative hypothesis is that the closure rate at 6 months in the 
VenaSeal™ system arm will be greater than that in the control arm minus a clinically relevant difference 
of 10%. Rejection of the null hypothesis will signify that the treatment with the VenaSeal™ system is not 
inferior to the treatment with ETA or surgical stripping. 

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Specifically, the null (Ho) and alternative (Ha) hypotheses are: 
Ho: πA ≤ πC - 10% 
Ha: πA > πC - 10% 
Where πA and πC are the closure rate at 6 months in the VenaSeal™ system arm and the ETA or surgical 
stripping arm. 
The parameter assumptions are: 
With these assumptions, a total of 264 subjects (238 evaluable, 119 in each arm) will yield 80% power to 
reject the null hypothesis in favor of the alternative hypothesis of non-inferiority to the ETA arm. A total 
of 98 subjects (88 evaluable, 44 in each arm) will yield 80% power to reject the null hypothesis in favor of 
the alternative hypothesis of non-inferiority to the surgical stripping arm. 
Overall Sample Size Evaluation 
Power Analysis and Sample Size (PASS) was used to compute sample size. Based on the above fixed sample 
size calculations, the total sample size in the VenaSeal vs ETA study will be 264 to demonstrate the success 
on each primary endpoint with at least 90% power Table 19. 
The total sample size in the VenaSeal vs Surgical Stripping Study will be 108 subjects due to the enrollment 
closure on 22-Feb-2022. 
Table 19: Sample Size for Randomized Studies 
Primary or Key Secondary 
Endpoint 
Total Sample Size: VenaSeal 
and ETA Arms  
Total Sample Size: VenaSeal 
and Surgical Stripping Arms 
VenousTSQe at 30 days 
237 
237 
VenousTSQs at 30 days 
237 
237 
Elimination of truncal reflux at 
index procedure 
227 
220 
Return to work 
22 
10 
• 
πA = 95% in the VenaSeal™ system arm and πC = 95.4% and 84.8% in ETA and surgical stripping arm, 
respectively 
• 
Likelihood Score (Farrington & Manning) test with one sided α 0.0167 
• 
1:1 randomization 
• 
10% attrition rate. 

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Closure rate at 6 months 
264 
98 
Overall Sample Size (Including 
Attrition) 
264 
237 
14.1.3. 
Interim Analysis 
No interim analysis for early stopping is planned for the VenaSeal vs. ETA Study or the VenaSeal vs. Surgical 
Stripping Study.   
14.1.4.  Analysis Sets 
The primary analysis set for Randomized Studies will be the ITT analysis set.  Per-protocol (PP) analyses 
may be performed as a sensitivity analysis. All analysis sets have been defined with the intent of 
minimizing bias in the data analysis.  
Intent-to-Treat (ITT): All patients who are randomized in the arms in each study will be included in the 
analysis regardless of the treatment received or the outcome of the treatment.  
Per-Protocol (PP): The ITT population excluding failed and no procedure treatment outcomes, subjects 
that are treated with the modality they were not randomized to and/or have not met the 
inclusion/exclusion criteria. 
As treated (AT): Includes subjects in the arm they are treated with according to the treatment actually 
received, regardless of the arm they were randomized to. 
14.2. VLU Study (Single-Arm Study)  
Analyses will be performed on all enrolled patients with CEAP 6 as according to the inclusion/exclusion 
criteria.  
Descriptive statistics will be presented for the study endpoints.  
14.2.1. 
Sample Size Consideration 
The primary endpoint in the VLU Study is time to ulcer healing. For reference, the EVRA study38 evaluated 
clinical and cost effectiveness of early endovenous treatment and standard care vs. deferred intervention 
in patients with chronic venous ulceration. As there are no statistically powered hypotheses in the VLU 
Study, precision estimates (distance from point estimate to the max of lower or upper 95% two-sided 
confidence bound) were used to derive the sample size based on the outcomes of the EVRA study.  

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In comparison to the EVRA study, criteria for VLU Study inclusion is less restrictive, which may result in an 
ulcer population which is older and heals more slowly than the EVRA early-intervention group. Precision 
calculations utilized an assumed median time to healing of 70 days which is the approximate average of 
the median healing time between the EVRA early-intervention and deferred-intervention groups (56 and 
82 days, respectively). Precision estimates for a range of sample sizes are provided in Table 20. A 
simulation is run 10,000 times on the assumption of exponential distribution of 70 days median time to 
healing. The simulation result shows the precision of less than 23 days can be obtained with a sample size 
of 125 subjects enrolled into the VLU Study. 
Table 20: Sample Size for the VLU Study 
Sample size  
Evaluable Sample Size 
(10% attrition) 
Precision 
80 
72 
<30 days 
90 
81 
<28 days 
100 
90 
<26 days 
110 
99 
<25 days 
115 
104 
<24 days 
120 
108 
<24 days 
125 
113 
<23 days 
14.2.2. 
Interim Analysis 
No interim analysis is planned for this CEAP 6 single arm study.   
14.2.3. 
Analysis Sets 
Intention-to-Treat (ITT):  All patients with CEAP 6 who are enrolled in this study (either successful, 
incomplete or failed treatment outcome) will be counted in the ITT population, which will be the primary 
analysis set. 
Per-Protocol (PP):  The ITT population excluding failed treatment outcome and/or subjects that have not 
met the inclusion/exclusion criteria 
The primary analysis for this CEAP 6 single arm study will be on intention-to-treat (ITT) population.  All 
analysis sets have been defined with the intent of minimizing bias in the data analysis. 

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14.3. Analysis of Safety Events  
Descriptive statistics for the safety events will be provided. Quantitative variables will be presented with 
mean and standard deviation or median, minimum and maximum as appropriate. Qualitative variables 
will be presented with frequency and percentage. The time-sensitive nature of any response variable may 
be displayed by using a Kaplan-Meier plot. AEs will be tabulated and reported using the current version 
of MedDRA dictionary. SAEs will be tabulated and reported up to 60 months. 
14.4. Analysis of Baseline Characteristics 
All clinically relevant baseline variables will be tabulated and reported. Quantitative variables will be 
presented with mean and standard deviation or median, minimum and maximum as appropriate. 
Qualitative variables will be presented with frequency and percentage. 
14.5. Safety Event Analysis and Reporting of Results 
Patient data listings and tabular and graphical presentations of results will be provided if needed.  
14.6. Health Economics Analysis 
This study will collect healthcare utilization data related to subject’s VRD and care related to the 
VenaSeal™ closure system to demonstrate total costs over the follow-up period.  
US cost and global effectiveness data collected in the study will be used to validate and update VenaSeal™ 
system US cost-effectiveness model developed by Medtronic. The healthcare utilization data from non-
US countries will then be transformed to identified regional costs which will then be used as model 
parameters for global regional cost-effectiveness and/or budget impact model adaptations.  
Specific analysis will focus on additional VLU healthcare utilization for all ulcers on the target limb, 
including routine wound care treatment through ulcer healing. The additional VLU healthcare utilization 
will not be only limited to routine wound care treatments but also any other unscheduled healthcare 
utilizations including office visits and emergency room visits. 
14.7. Missing Data 
Every effort will be undertaken to minimize missing data. Unless otherwise specified, no statistical 
techniques will be used to impute missing data for continuous or categorical outcomes. The number of 
patients included in each analysis will be reported so that the reader can assess the potential impact of 
missing data. 

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15. Ethics 
15.1. Statement(s) of Compliance 
The VenaSeal Spectrum study will be conducted in compliance with international ethical and scientific 
quality standards, known as Good Clinical Practice (GCP). GCP includes review and approval by an 
independent EC before initiating a study, continuing review of an ongoing study by an EC, and obtaining 
and documenting the freely given informed consent of a subject before initiating the study. This study is 
designed to reflect the GCP principles outlined in ISO 14155:2020 and other international clinical 
requirements outlined below. These include the protection of the rights, safety and well-being of human 
subjects, controls to ensure the scientific conduct and credibility of the clinical investigation and the 
definition of responsibilities of Medtronic and investigators. In accordance with ISO 14155:2020, 
Medtronic shall avoid improper influence on, or inducement of, the subject, monitor, any investigator(s) 
or other parties participating in, or contributing to, the clinical investigation. All investigators shall avoid 
improper influence on or inducement of the subject, sponsor, monitor, other investigator(s) or other 
parties participating in or contributing to the clinical investigation. The process of reporting AE and DD 
handling in this study is ISO 14155:2020 compliant for all participating geographies. 
The study will be conducted according to the Clinical Investigation Plan, CTA, federal, national and local 
laws, regulations, standards, and requirements of the countries/geographies where the study is being 
conducted.  
The study will also be conducted in accordance with the Declaration of Helsinki. The principles of the 
Declaration of Helsinki are implemented in this study by means of the patient informed consent process, 
IRB/EC/CA approval, study training and clinical study registration, risk-benefit assessment and publication 
policy.  
Ultimately, all study sites in all geographies will follow and comply with: 
• 
Principles of Declaration of Helsinki 
• 
21 CFR Part 11 (Electronic Records, Electronic Signatures) 
• 
21 CFR Part 54 (Financial Disclosure by Clinical Investigators) 
• 
The CTA 
• 
The procedures described within this CIP 
• 
Local EC Requirements. 
In addition to the regulatory requirements outlined above, the study will be conducted according to 
federal, national and local laws, regulations, standards, and requirements of the countries/geographies 
where the study is being conducted. These include but are not limited to:  

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• 
In the US, the study will be conducted in compliance with 21 CFR Parts 50 (Protection of Human 
Subjects) and 56 (IRBs). 
• 
In Canada, SOR/98-282, Section 59-88 will be followed and Mandatory Problem Reporting 59(1), 
59(2), 60(1). 
• 
In Europe the study will be conducted in compliance with the MDD 93/42/EEC, EU MDR 2017/745. 
The study will be publicly registered prior to in accordance with 42 CFR part 11 and Declaration of 
Helsinki on http://clinicaltrials.gov. In addition, the study may be registered in local regulatory databases 
where required by local law.  
Approval of the CIP and CIP amendments is required from the following groups prior to any study 
procedures at a study site: 
• 
Medtronic 
• 
Principal Investigators (where required by local law/regulations) 
• 
Geography-specific regulatory authorities (if regulatory approval is required) 
• 
An independent EC or IRB. 
Similarly, approval of subsequent revisions to the CIP is required at each study site from the above 
mentioned groups prior to implementation of the revised CIP at the study site. 
Due to the post-market nature of this study and because this study does not include a primary safety 
endpoint, the scope of AE reporting in this study has been limited to reporting of events listed in section 
12 and no device accountability is required with exception of documenting a reference to the used device 
in the CRF (this is a deviation from ISO 14155:2020). The subject enrollment definition for this study is ‘the 
moment of randomization’ for CEAP 2-5 subjects and ‘the moment the first component of VenaSeal™ 
system enters the body’ for CEAP 6 subjects; this is also a deviation from ISO 141155:2020. 
The EUDAMED generated single identification number of the clinical investigation will be provided under 
a separate cover when available. 
 
 
• 
In all geographies except US, the study will be conducted in compliance with ISO 14155:2020, with 
an exception that this study only collects a subset of adverse events. 

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16. Study Administration 
16.1. Clinical Trial Agreement 
Medtronic contracts with participating institutions/investigators through a CTA that defines the scope and 
responsibilities and associated compensation related to carrying out the obligations under a clinical study 
sponsored by Medtronic. A CTA shall be in place, signed by the participating investigational site and/or PI 
of each investigational site, as per the local legal requirements, and returned to Medtronic prior to the 
commencement of any clinical study activities. The investigator is indicating approval of this clinical 
investigation plan and subsequent amendments, with a fully executed agreement. 
16.2. Subject Compensation 
Subjects will receive a fixed amount of compensation as applicable/allowed per region for the time spent 
completing the questionnaires and other documentation, and for transportation to and from the study 
visits and other related costs that may be incurred for study participation. Medtronic may provide 
reimbursement for subjects who will incur extraordinary travel costs related to their participation in the 
study, including airfare, mileage, or hotel expenses. The participating institution will make such request(s) 
in writing to Medtronic (de-identified of participant information), detailing the unusual circumstances and 
the excessive costs that the participant will incur. Medtronic will evaluate requests on a case-by-case basis 
and will notify the participating institution of its decision. 
16.3. Site Activation / Supply of Trial Materials 
Investigational sites will receive a formal letter of site activation, upon receipt of or completion of the 
following: 
• 
Clinical Trial agreement 
• 
CA approval (as applicable to the geography) 
• 
Ethic Boards approval 
• 
Medtronic and Ethic Boards approved ICF/Data release form (DRF) document, and other 
information provided to the subject 
• 
Curriculum vitae of the PI, Sub-Investigators, and all key site staff  
• 
Financial Disclosure from the investigators 
• 
Delegated Task List 
• 
Documented training of the investigative team  

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• 
It is expected that product training per standard Medtronic requirements will be completed by 
all treating physicians prior to his/her enrolling subjects into the study. A treating physician may 
be included in the clinical study if compliant with the following:  
16.4. Monitoring  
Monitoring and monitoring oversight will be provided by Medtronic and detailed in a Monitoring Plan 
separate from this CIP. 
A site qualification visit may be conducted by Medtronic personnel (or designees) in person or remotely 
to review the clinical investigational plan and, regulatory and study requirements with the investigator 
and study personnel. 
Medtronic will conduct a site initiation visit prior to first enrollment to prepare the site to conduct the 
study, as outlined in the Monitoring Plan. Medtronic may conduct investigator meetings in place of, or in 
addition to on-site initiation visits. These visits may be in person or remotely, as allowable per local site 
regulations.  
Monitoring visits will be conducted at the start, during and at the closure of the clinical study in 
accordance with the Monitoring Plan, either in person or remotely, as allowable per local site regulations.  
Findings from each monitoring visit will be provided to the clinical study personnel at the site. Corrective 
action will be taken to resolve any issues of noncompliance. If Medtronic finds that an investigator is not 
complying with the executed CTA, this Investigational Plan, the applicable laws and regulations, or the 
requirements of the reviewing IRB/EC/CA, prompt action will be taken to secure compliance. Medtronic 
will reserve the right to suspend or terminate the participation of the investigator or the investigational 
site. 
During the routine monitoring visit, it may be verified whether signed and dated ICF/DRF forms have been 
obtained from each subject before any clinical study related procedures are undertaken. Medtronic or 
designee will conduct site monitoring visits to monitor compliance with the protocol and adherence to 
the data collection procedures, to assess the accuracy and completeness of submitted clinical data, and 
to verify that records and documents are being properly maintained for the duration of the study. 
o Physician is an appropriately qualified practitioner legally authorized to practice in 
his/her respective region, and experienced in the diagnosis and endovascular treatment 
of patients requiring superficial truncal vein treatment. 
o Physician has demonstrated experience with conducting clinical trials that comply with 
applicable regulatory standards. 

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A risk-based monitoring plan will be followed, this is outlined in further detail within the Monitoring Plan. 
When source data verification is performed, the monitor must have direct access to original source 
documentation or certified copies of the original source must be provided. 
If electronic source documentation is used at the site, the site must provide to the monitor, either on-site 
or remotely, as per regulatory requirements: 
16.5. Data Management 
Data will be collected using an electronic data management system for studies.  CRF data will be stored in 
a secure, password-protected database which will be backed up nightly.  Data will be reviewed using 
programmed and manual data checks.  Data queries will be made available to study sites for resolution.  
Study management reports may be generated to monitor data quality and study progress.  At the end of 
the study, the data will be frozen and will be retained by Medtronic in accordance with applicable 
regulations. 
All records and other information about subjects participating in this study will be treated as confidential. 
Data will be transferred and processed by Medtronic or a third party designated by Medtronic in a key 
coded form.  
Procedures in the CIP require source documentation. Source documentation will be maintained at the 
study site. Source documents, which may include worksheets and subject medical records must be 
created and maintained by the investigational study site team.  
The investigator will clearly mark clinical records to indicate that the subject is enrolled in this clinical 
investigation.  
The data reported on the CRFs shall be derived from source documents and be consistent with these 
source documents, and any discrepancies shall be explained in writing. See section 10.15 for CRFs and 
data collection elements that may be considered source. 
• 
Direct access to the electronic source document(s) with Monitor’s login details and limited access to 
study subjects. 
• 
Direct access to the electronic medical record(s), or direct access to the electronic medical record(s) 
by reviewing alongside appropriate study staff. 
• 
Copies of the electronic medical record signed and dated by a member of the investigation site team 
with a statement that it is a true reproduction of the original source document. 

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It is recommended to complete CRFs no later than 10 working days after each procedure or follow-up 
visit, except for CRFs documenting AEs or device deficiencies that require immediate reporting (refer to 
Table 14 for the reporting requirements). Medtronic will be responsible for the processing and quality 
control of the data. Data review, database cleaning and issuing and resolving data queries will be done 
according to Medtronic internal SOPs and the Data Management Plan for this study. The study database 
will employ validation programs (e.g., range and logic checks) on entered data to identify possible data 
entry errors and to facilitate data validation.  
16.6. Direct Access to Source Data/Documents  
The PI and the study team shall be accessible to Medtronic representative, monitoring team and the 
clinical study manager. This accessibility is of particular importance for reviewing data in the CRF.  
The investigator and/or institution shall permit Medtronic and regulatory bodies direct access to source 
data and documents or be approached to upload source documents into a secure system, taking into 
account any restrictions due to local law, to perform clinical study-related monitoring, audits, IRB/EC 
review, and regulatory inspections.  
As soon as the Investigator is notified of a planned inspection by the authorities, he/she will inform 
Medtronic and authorize Medtronic to participate in this inspection.  
16.7. Confidentiality 
All information and data sent to parties involved in study conduct concerning subjects or their 
participation in this study will be considered confidential. Each enrolled subject will be assigned to a 
unique subject ID number (SID), which is pre-configured in Electronic Data Capture (EDC) system.  Records 
of the subject/SID relationship will be maintained by the study site. The SID is to be recorded on all study 
documents to link them to the subject’s medical records at the site. To maintain confidentiality, the 
subjects’ name or any other personal identifiers should not be recorded on any study document other 
than the subject’s ICF. In the event a subject’s name is included for any reason, it will be immediately 
blinded as applicable. In the event of inability to blind the identification (e.g., digital media), it will be 
handled in a confidential manner by the authorized personnel. Data relating to the study might be made 
available to third parties (for example in case of an audit performed by RA), provided the data are treated 
as confidential and that the subject’s privacy is guaranteed. No identifiable subject information will be 
published. 

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Confidentiality of data will be observed by all parties involved at all times throughout the clinical study. 
All data shall be secured against unauthorized access. The privacy of each subject and confidentiality of 
his/her information shall be preserved in reports and when publishing any data. 
In general, Sponsor’s representatives, IRB/EC and CA members, European or other international public 
regulatory authorities may have access to subject confidential information. 
In the US, “Protected Health Information” (PHI) will be maintained in compliance with the Health 
Insurance Portability and Accountability Act of 1996 (HIPAA). To maintain confidentiality, the subject’s 
name or any other PHI should not be recorded on any study document other than the ICF. This scenario 
will be covered in the Patient Information-Informed Consent Form. In the event a subject’s name/PHI is 
included for any reason, it will be blinded as applicable. In the event of inability to blind the identification 
(e.g., digital media), it will be handled in a confidential manner by the authorized personnel. 
16.8. Liability 
The sponsor and local sponsors are wholly owned subsidiaries of Medtronic. Medtronic (including all 
wholly owned subsidiaries companies) maintains appropriate clinical study liability insurance coverage as 
required under applicable laws and regulations and will comply with applicable law and custom 
concerning specific insurance coverage. If required, a Clinical Study Insurance statement or certificate will 
be provided to the EC/IRB and CA, if applicable. 
Medtronic will provide subject indemnification according to local laws where this study will be conducted. 
16.9. CIP Amendments 
The investigator will propose any appropriate modification(s) of the clinical investigation plan or product 
use when needed. Medtronic will review this proposal and decide whether the modification(s) will be 
implemented.  
Medtronic will submit any significant amendment to the clinical investigation plan, including a justification 
for this amendment, to the appropriate regulatory authorities, IRBs/ECs and to the investigators. The 
investigator will only implement the amendment after approval of the IRB/EC, regulatory authority (if 
applicable) and sponsor. Furthermore, investigators shall sign any approved amendment for agreement. 

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16.10. 
Record Retention 
All study-related documents must be retained for a period of at least 2 years after study closure or longer 
if required by local law. Medtronic will inform the investigator/study site when these documents are no 
longer required to be retained. 
No study document or image will be destroyed without prior written agreement between Medtronic and 
the investigator. The investigator should take measures to prevent accidental or premature destruction 
of documents. Should the investigator wish to assign the study records to another party or move them to 
another location, advance written notice must be given to Medtronic. 
Medtronic will retain the study records per local regulations. 
 
16.10.1. Investigator Records 
The investigator is responsible for the preparation and retention of the records cited below. All of the 
below records, with the exception of case history records and case report forms, should be kept in the 
Investigator Site File or Subject Study Binder. CRFs must be maintained and signed electronically within 
the electronic data capture system during the study. The following records are subject to inspection and 
must be retained for a period of two years or longer as required by local law: 
• 
All correspondence between the IRB/EC/CA, sponsor, monitor, regulatory authority and the 
investigator that pertains to the investigation, including required reports.  
• 
Subject’s case history records, including:  
o Signed and dated ICF. 
o Observations of AEs/ADEs/DDs. 
o Medical history. 
o Procedure and follow-up data (if applicable). 
o Documentation of the dates and rationale for any deviation from the protocol. 
• 
Randomization list (for the Randomized Studies). 
• 
List of investigation study sites. 
• 
Financial Disclosure as applicable. 
• 
Subject Pre-screening log and Subject Identification & Enrollment log. 
• 
All approved versions of the CIP, ICF. 
• 
Signed and dated CTA.  
• 
CV of PI and key members of investigation study site team (as required by applicable regulations. 
• 
Documentation of delegated tasks.  
• 
Regulatory Approval notification, correspondence and approval, where required per local law. 

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• 
Study training records for study site staff.  
• 
Insurance certificates as applicable. 
• 
Final Study Report including the statistical analysis. 
 
16.10.2. Sponsor Records 
Medtronic shall maintain the following accurate, complete, and current records: 
• 
All correspondence which pertains to the investigation. 
• 
Signed Investigator Trial Agreements, Financial Disclosure and current signed and dated CV of PI 
and key members of the investigation study site team (as required by local law), delegated task 
list. 
• 
All approved ICF templates, and other information provided to the subjects and advertisements, 
including translations. 
• 
Randomization records (for the Randomized Studies). 
• 
Copies of all IRB/EC approval letters and relevant IRB/EC correspondence and IRB/EC voting 
list/roster/letter of assurance. 
• 
Names of the institutions in which the study will be conducted. 
• 
RA correspondence, notification and approval as required by national legislation. 
• 
Insurance certificates as applicable. 
• 
Names/contact addresses of monitors. 
• 
Monitoring visit reports. 
• 
Statistical analyses and underlying supporting data. 
• 
Final report of the study. 
• 
The CIP, and study related reports, and revisions. 
• 
Study training records for study site personnel and Medtronic personnel involved in the study. 
• 
Any other records that local regulatory agencies require to be maintained.  
Medtronic records and reports will be maintained in a password-protected document management 
system. After closure of the study Medtronic will archive records and reports per local regulations. 
16.11. 
Reporting Requirements 
16.11.1. Investigator Reports 
The investigator is responsible for the preparation (review and signature) and submission to the sponsor 
of all case report forms, adverse events and adverse device effects, device deficiencies, deaths, and any 
deviations from the clinical investigation plan.  If any action is taken by IRB/EC/CA with respect to this 

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study, copies of all pertinent documentation must be forwarded to Medtronic in a timely manner. Reports 
are subject to inspection and to the retention requirements as described above for investigator records.  
Safety data investigator reporting requirements are listed in section 12. The investigator shall prepare and 
submit in a complete, accurate and timely manner the reports listed in this section. 
Table 21: Investigator reports applicable for all geographies per Medtronic requirements 
Report  
Submit to 
Description/Constraints 
Withdrawal of 
IRB/EC/CA approval 
Sponsor and 
Relevant 
Authorities 
The investigator must report a withdrawal of approval by the 
reviewing IRB/EC of the investigator’s part of the investigation 
within 5 working days. 
Study Deviations  
Sponsor and 
IRB/EC 
Any deviation from the clinical investigational plan shall be 
recorded together with the explanation of the deviation. 
Notice of deviations from the CIP to protect the life or physical 
well-being of a subject in an emergency shall be given in a 
timely manner after the emergency occurred.  Except in such 
emergency, prior approval is required for changes in the plan 
or deviations.  
Final Report 
IRBs/ECs and  
Relevant 
Authorities 
This report must be submitted within 3 months of study 
completion or termination. 
 

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Table 22 : Investigator reports applicable to Europe and Middle East per ISO 14155 
Report  
Submit to 
Description/Constraints 
Withdrawal of IRB/EC 
approval 
Sponsor 
Report if required by local law. 
Progress Report  
Sponsor and 
IRB/EC 
Provide if required by local law or IRB/EC.  
Study Deviations  
Sponsor, CA and 
IRB/EC 
Any deviation from the CIP shall be recorded together with an 
explanation for the deviation.  Deviations shall be reported to 
the sponsor who is responsible for analyzing them and 
assessing their significance.   
Note: When relevant, ethics committees, CAs or the 
appropriate RAs should be informed. (ISO 14155:2020) 
Failure to obtain IC 
Sponsor and 
IRBs/ECs 
IC shall be obtained in writing and documented before a 
subject is enrolled into the clinical investigation.  (ISO 
14155:2020) 
 
16.11.2. Sponsor Reports 
Medtronic shall prepare and submit the following complete, accurate, and timely reports listed in the 
tables below (by geography).  In addition to the reports listed below, Medtronic shall, upon request of the 
reviewing IRB/EC, RA or FDA, provide accurate, complete and current information about any aspect of the 
investigation. Safety data Medtronic reporting requirements are listed in section 12. 
Table 23: Sponsor reports for Australia 
Report  
Submit to 
Description/Constraints 
Premature 
termination or 
suspension of the 
clinical investigation 
Investigators, 
IRB/EC, and 
relevant 
authorities 
Provide prompt notification of termination or suspension and 
reason(s). (ISO 14155:2020). 
Recall and device 
disposition 
Investigators, 
Head of 
Institution, 
IRB/EC, and 
relevant 
authorities 
Notification as per the local requirements in Australia.  

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Report  
Submit to 
Description/Constraints 
Study deviation  
Investigators 
Ensure that all deviations from the CIP are reviewed with the 
appropriate clinical investigator(s), are reported on the CRFs 
and the final report of the clinical investigation.  (ISO 
14155:2020) 
Study site specific study deviations will be submitted to 
investigators periodically.   
Table 24: Sponsor reports for Canada 
Report  
Submit to 
Description/Constraints 
Premature 
termination or 
suspension of the 
clinical investigation 
Investigators, 
IRB/EC, 
Relevant 
authorities, and  
Head of the 
Institution 
Provide prompt notification of termination or suspension and 
reason(s).  
Recall and device 
disposition 
Investigators, 
Head of 
Institution, 
IRB/EC, 
relevant 
authorities 
 
Notification within 30 working days and will include the 
reasons for any request that an investigator return, repair, or 
otherwise dispose of any devices.   
Study deviation  
Investigators 
Ensure that all deviations from the CIP are reviewed with the 
appropriate clinical investigator(s), are reported on the CRFs 
and the final report of the clinical investigation.  
Study site specific study deviations will be submitted to 
investigators periodically.   

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Table 25: Sponsor reports for Europe and Middle East 
Report  
Submit to 
Description/Constraints 
Premature 
termination or 
suspension of the 
clinical investigation 
Investigators, 
IRB/EC, 
Relevant 
authorities and 
Head of the 
Institution 
Provide prompt notification of termination or suspension and 
reason(s). (ISO 14155:2020) 
Withdrawal of IRB/EC 
approval 
Investigators, 
Head of 
Institution, 
IRB/EC and  
relevant 
authorities 
Investigators, IRBs/ECs will be notified only if required by 
local laws or by the IRB/EC. 
Withdrawal of CA 
approval 
Investigators, 
Head of 
Institution, 
IRB/EC, and 
relevant 
authorities 
Investigators, IRBs/ECs will be notified only if required by 
local laws or by the IRB/EC. 
Progress Reports 
IRB/EC and 
RAs 
This will be submitted to the IRB/EC only if required by the 
IRB//EC). 
Final report 
Investigators,  
IRB/EC, and 
RAs if required 
For studies with study sites complying to ISO 14155: 
• 
The investigator shall have the opportunity to review 
and comment on the final report.   
• 
If a clinical investigator does not agree with the final 
report, his/her comments shall be communicated to 
the other investigator(s).   
• 
The coordinating investigator shall sign the report. If 
no coordinating investigator is appointed, then the 
signature of the PI in each study site should be 
obtained.    (ISO 14155:2020) 

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Report  
Submit to 
Description/Constraints 
Study deviation  
Investigators 
Ensure that all deviations from the CIP are reviewed with the 
appropriate clinical investigator(s), are reported on the CRFs 
and the final report of the clinical investigation.  (ISO 
14155:2020) 
Study site specific study deviations will be submitted to 
investigators periodically.   
16.12. 
Publication and Use of Information 
Publications and presentations referring to this clinical study will be coordinated by Medtronic to allow 
the use of all available data. Publications from this study will be handled according to Standard 
Operating Procedures and as indicated in the CTA. 
The following publication policy will apply to all participating investigational sites: 
 
• 
Medtronic may use the study data for regulatory authority submission, may publish the results in 
peer reviewed scientific journal(s) and present the data at major congresses. 
• 
Authorship on any publication(s) resulting from this clinical study will be assigned according to 
substantial contributions to conception and design, acquisition of data, or analysis and 
interpretation of data, drafting the article or revising it critically for important intellectual content, 
and final approval of the version to be published. This is in accordance with the Vancouver 
principles (The Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Writing 
and Editing for Biomedical Publication, ICMJE, October 2008), as agreed upon by the editors of all 
major medical journals. 
• 
The number of authors will be dependent on the regulations of the concerning journal. Names of 
all participating investigators will appear in the Acknowledgment of the paper, if allowed by the 
journal. 
• 
Based on the principle that Medtronic owns the data of this clinical study, a single investigational 
site may access and use the data provided by itself for scientific publications following prior 
approval by Medtronic. 
• 
Pooling data from several investigational sites for publication purposes, national projects and 
international projects all require prior approval from Medtronic. 
• 
Medtronic as the owner of the data can use the data and/or any results derived from the data or 
publications based on that data for marketing purposes, further research and development of 
devices or educational use. 

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The study sponsor will collect data in such way that no subject can be identified. Participating subjects 
will not be identified by name in any published reports about the clinical study. 
16.13. 
Transparency 
Transparency of clinical study results will be maintained by the following means: 
- 
A final report, describing the results of all objectives and analysis, will be distributed to all 
investigators, IRB, ECs and CAs of participating countries when required by local law. 
- 
Registering and posting the study results on a publicly accessible database, e.g., ClinicalTrials.gov 
based on the posting rules stipulated. 
- 
Submitting for publication the primary study results when available. 
- 
Disclosing conflicts of interest (e.g., financial) of the co-authors of publications according to the 
policies set forth by the corresponding journals and conferences. 
- 
Making an individual study site study data accessible to the corresponding investigator after the 
completion of the study, if requested. 
16.14. 
Suspension or Early Termination 
Early study suspension or termination 
Medtronic reserves the right to complete the study earlier (i.e., longer-term follow-up visits may not be 
completed). Early Termination is the closure of a study that occurs prior to meeting defined endpoints. 
This is possible for the whole study or a single study site. Suspension is a temporary postponement of 
study activities related to enrollment and distribution of the product. This is possible for the whole study 
or a single study site. Medtronic also reserves the right to suspend or terminate the study for any other 
reason than the ones listed above.  
Early investigational site suspension or termination 
Medtronic, IRB/EC or regulatory authority may decide to suspend or prematurely terminate an 
investigational site. If an investigational site is suspended or prematurely terminated, Medtronic shall 
promptly inform the investigator(s) of the termination or suspension and the reason(s) for this. The 
investigator shall then promptly inform the reviewing IRB/EC and the study subjects.  
When the risks are found to outweigh the potential benefits or when there is conclusive proof of definite 
outcomes, investigators must assess whether to continue, modify or immediately stop the clinical study 
in the respective investigational site and immediately inform the sponsor and IRB/EC, if applicable. 
Criteria for Investigator/center Termination or Suspension 

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Possible reasons for clinical investigator or center termination or suspension include but are not limited 
to: 
 
Subject follow-up in case of termination 
In case of early termination, all subjects should be followed by their physicians per standard care and no 
further patient data will be collected under this clinical investigation plan. 
 
 
• 
Failure to obtain initial IRB/EC/CA approval or annual renewal of the study. 
• 
Consistent non-compliance to the CIP (e.g., failure to adhere to inclusion/exclusion criteria, failure to 
follow subjects per scheduled follow-ups, etc.). 
• 
Lack of enrollment. 
• 
Noncompliance to regulations and the terms of the Clinical Study Agreement (e.g., failure to submit 
data in a timely manner, failure to follow-up on data queries and monitoring findings in a timely 
manner, etc.). 
• 
IRB/EC/CA suspension of the center. 
• 
Fraud or fraudulent misconduct (as defined by local law and regulations). 
• 
Investigator request (e.g., no longer able to support the study). 

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17. References 
1. Lee BB, Nicolaides AN, Myers K, et al. Venous hemodynamic changes in lower limb venous disease: The 
UIP consensus according to scientific evidence. International Angiology. 2016;35(3):236-352. 
2. Gloviczki P, Comerota AJ, Dalsing MC, et al. The care of patients with varicose veins and associated 
chronic venous diseases: clinical practice guidelines of the Society for Vascular Surgery and the American 
Venous Forum. J Vasc Surg. 2011;53(5 Suppl):2s-48s. 
3. Kaplan RM, Criqui MH, Denenberg JO, Bergan J, Fronek A. Quality of life in patients with chronic venous 
disease: San Diego population study. J Vasc Surg. 2003;37(5):1047-1053. 
4. Brand FN, Dannenberg AL, Abbott RD, Kannel WB. The epidemiology of varicose veins: the Framingham 
Study. Am J Prev Med. 1988;4(2):96-101. 
5. Graham ID, Harrison B, Nelson EA, Lorimer K, Fisher A. Prevalence of lower-limb ulceration: a systemic 
review of prevalence studies. Adv Skin Wound Care. 2003;16:305-316. 
6. Wittens C, Davies AH, Bækgaard N, et al. Editor's choice - Management of chronic venous disease: 
Clinical practice guidelines of the European Society for Vascular Surgery (ESVS). Eur J Vasc Endo Surg. 
2015;49(6):678-737. 
7. National Institute for Health and Clinical Excellence. Cyanoacrylate glue occlusion for varicose veins.  26 
June 2015 2015. (IPG526). 
8. Bozkurt AK, Rabe E, Sharkawy MI. Chronic Venous Insufficiency: Management and Treatment. EMJ 
Dermatol. 2017;5(Suppl 2):2-13. 
9. Rabe E, Guex JJ, Puskas A, Scuderi A, Fernandez Quesada F. Epidemiology of chronic venous disorders 
in geographically diverse populations: results from the Vein Consult Program. Int Angiol. 
2012;31(2):105-115. 
10. McGuckin M, Waterman R, Brooks J, et al. Validation of venous leg ulcer guidelines in the United States 
and United Kingdom. Am J Surg. 2002;183(2):132-137. 
11. Ruckley CV. Socioeconomic impact of chronic venous insufficiency and leg ulcers. Angiology. 
1997;48(1):67-69. 
12. Eklof B, Rutherford RB, Bergan JJ, et al. Revision of the CEAP classification for chronic venous disorders: 
consensus statement. J Vasc Surg. 2004;40(6):1248-1252. 
13. Perrin M, Eklof B, A VANR, et al. Venous symptoms: the SYM Vein Consensus statement developed 
under the auspices of the European Venous Forum. Int Angiol. 2016;35(4):374-398. 
14. Gloviczki P, Dalsing MC, Henke P, et al. Report of the Society for Vascular Surgery and the American 
Venous Forum on the July 20, 2016 meeting of the Medicare Evidence Development and Coverage 
Advisory Committee panel on lower extremity chronic venous disease. J Vasc Surg. 2017;5(3):378-398. 
15. Min RJ, Khilnani N, Zimmet SE. Endovenous laser treatment of saphenous vein reflux: long-term results. 
J Vasc Interv Radiol. 2003;14(8):991-996. 
16. Serra R, Grande R, Butrico L, Fugetto F, De Franciscis S. Epidemiology, diagnosis and treatment of chronic 
venous disease: A systematic review. Chirurgia (Turin). 2016;29(2):34-45. 
17. Lurie F, et al.  The 2020 update of the CEAP classification system and reporting standards. Journal of 
Vascular Surgery: Venous and Lymphatic Disorders. 2020;8(3):341–352.  

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26. Morrison N, et al. Comparison of cyanoacrylate closure and radiofrequency ablation for the treatment 
of incompetent great saphenous veins: 36-Month outcomes of the VeClose randomized controlled trial. 
Phlebology. 2018. DOI: 10.1177/0268355518810259 
27. Morrison N, Kolluri R, Vasquez M, Madsen M, Jones A, Gibson K.  Randomized trial comparing 
cyanoacrylate embolization and radiofrequency ablation for incompetent great saphenous veins 
(VeClose). Journal of Vascular Surgery. 2015;61(4):985–994. 
29. Gibson K, Morrison N, Kolluri R, Vasquez M, Weiss R, Cher D, Madsen M, Jones A. Twenty-four month 
results from a randomized trial of cyanoacrylate closure versus radiofrequency ablation for the 
treatment of incompetent great saphenous veins. In Journal of Vascular Surgery: Venous and Lymphatic 
Disorders. September 2018 6(5):606-613 
18. Schwaiger N, Wu J, Wright B, Morrissey L, Harris M, Rohanizadeh R. BioWeld((R)) Tube and surgical glue 
for experimental sutureless venous microanastomosis. Br J Surg. 2010;97(12):1825-1830. 
19. Song HH, Won YD, Kim YJ. Transcatheter N-butyl cyanoacrylate embolization of pseudoaneurysms. J 
Vasc Interv Radiol. 2010;21(10):1508-1511. 
20. Nesbitt C, Bedenis R, Bhattacharya V, Stansby G. Endovenous ablation (radiofrequency and laser) and 
foam sclerotherapy versus open surgery for great saphenous vein varices. The Cochrane database of 
systematic reviews. 2014;7:CD005624. 
21. Wittens C, Davies AH, Bækgaard N, et al. Editor's choice - Management of chronic venous disease: 
Clinical practice guidelines of the European Society for Vascular Surgery (ESVS). Eur J Vasc Endo Surg. 
2015;49(6):678-737  
22. Hamel-Desnos CM, Guias BJ, Desnos PR, Mesgard A. Foam sclerotherapy of the saphenous veins: 
randomised controlled trial with or without compression. Eur J Vasc Endovasc Surg. 2010;39(4):500-
507. 
23. Eberhardt RT, Raffetto JD. Chronic venous insufficiency. Circulation. 2014;130(4):333-346. 
24. Serra R, Grande R, Butrico L, Fugetto F, De Franciscis S. Epidemiology, diagnosis and treatment of chronic 
venous disease: A systematic review. Chirurgia (Turin). 2016;29(2):34-45 
25. Goodyear SJ, Nyamekye IK. Radiofrequency ablation of varicose veins: Best practice techniques and 
evidence. Phlebology. 2015;30(2):9-17 
28. Morrison N, Gibson K, Vasquez M, Weiss R, Cher D, Madsen M, Jones A. VeClose trial 12-month 
outcomes of cyanoacrylate closure versus radiofrequency ablation for incompetent great saphenous 
veins. In Journal of Vascular Surgery: Venous and Lymphatic Disorders. May 2017 5(3):321-330 
30. Morrison N, Gibson K, Vasquez M, Weiss R, Jones A. Five year extension study of patients from a 
randomized clinical trial (VeClose) comparing cyanoacrylate closure versus radiofrequency ablation for 
the treatment of incompetent great saphenous veins. Journal of Vascular Surgery: Venous and 
Lymphatic Disorders. 2020. DOI: 10.1016/j.jvsv.2019.12.080 

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31. Gibson K, Ferris B. Cyanoacrylate closure of incompetent great, small and accessory saphenous veins 
without the use of post-procedure compression: initial outcomes of a post-market evaluation of the 
VenaSeal System (the WAVES Study). Vascular. 2017;25(2):149-156. 
 
 
 
 
32. Gibson K, Minjarez R, Gunderson K, Ferris B. Need for adjunctive procedures following 
cyanoacrylate closure of incompetent great, small and accessory saphenous veins without the use 
of postprocedure compression: Three-month data from a postmarket evaluation of the VenaSeal 
System (the WAVES Study). Phlebology 2019, Vol 34(4) 231-237 
33. European Multicenter Study on Cyanoacrylate Embolization of Refluxing Great Saphenous Veins 
without Tumescent Anesthesia and without Compression Therapy. Presented at: Charing Cross; 
April 28, 2016; London, UK. 
34. Almeida JI, Javier JJ, Mackay EG, Bautista C, Cher DJ and Proebstle TM. Thirty-sixth-month follow-
up of first-in-human use of cyanoacrylate adhesive for the treatment of saphenous vein 
incompetence. JVS: Venous and Lymphatic Disorders. 2017;5(5):658-666. 
35. Mitchell J and Bradley C. Design and development of the MacTSQ measure of satisfaction with 
treatment for macular conditions used within the IVAN trial. Journal of Patient-Reported 
Outcomes (2018) 2:5. 
36. Ashwell SG et al. Treatment satisfaction and quality of life with insulin glargine plus insulin lispro 
compared with NPH insulin plus unmodified human insulin in individuals with type 1 diabetes. 
Diabetes Care: 31:1112–1117, 2008. 
37. DAFNE Study Group. Training in flexible, intensive insulin management to enable dietary freedom 
in people with type 1 diabetes: dose adjustment for normal eating (DAFNE) randomized controlled 
trial.  BMJ: 2002;325:746. 
38. Gohel M, et al. A randomized trial of early endovenous ablation in venous ulceration. NEJM 2018; 
378:2105-114  

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18. Appendices 
Appendix A: Patient Questionnaires and Assessments 
1. AVVQ 
1. Were your varicose veins present in 1 or more segments? If yes, please specify the segments 
 
 
Check off segments below that were shaded by patient 
 No segments were shaded by patient   
 
ANTERIOR 
 
POSTERIOR 
 
Right 
 
 
Left 
 
 
Left 
 
 
Right 
A 
1 2  3  4 
 
I 
1 2  3  4 
 
Q 
1 2  3  4 
 
Y 
1 2  3  4 
B 
1 2  3  4 
 
J 
1 2  3  4 
 
R 
1 2  3  4 
 
Z 
1 2  3  4 
C 
1 2  3  4 
 
K 
1 2  3  4 
 
S 
1 2  3  4 
 
AA 
1 2  3  4 
D 
1 2  3  4 
 
L 
1 2  3  4 
 
T 
1 2  3  4 
 
BB 
1 2  3  4 
E 
1 2  3  4 
 
M 
1 2  3  4 
 
U 
1 2  3  4 
 
CC 
1 2  3  4 
F 
1 2  3  4 
 
N 
1 2  3  4 
 
V 
1 2  3  4 
 
DD 
1 2  3  4 
G 
1 2  3  4 
 
O 
1 2  3  4 
 
W 
1 2  3  4 
 
EE 
1 2  3  4 

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H 
1 2  3  4 
 
P 
1 2  3  4 
 
X 
1 2  3  4 
 
FF 
1 2  3  4 
 
 
2. In the last two weeks for how many days did your veins cause you pain or ache? 
 
Right Leg 
Left Leg 
None at all 
О 
О 
Between 1 and 5 days 
О 
О 
Between 6 and 10 days 
О 
О 
For more than 10 days 
О 
О 
 
3. During the last two weeks, how many days did you take painkilling tablets for your varicose veins? 
 
Right Leg 
Left Leg 
None at all 
О 
О 
Between 1 and 5 days 
О 
О 
Between 6 and 10 days 
О 
О 
For more than 10 days 
О 
О 
 
4. In the last two weeks, how much ankle swelling have you had? 
О  None at all 
О  Between 1 and 5 days 
О  Between 6 and 10 days 
О  For more than 10 days 
 
5. In the last two weeks, have you worn support stockings or tights? 
 
Right Leg 
Left Leg 
No 
О 
О 
Yes, those I bought myself without prescription 
О 
О 
Yes, those prescribed by my doctor which I wear occasionally 
О 
О 
Yes, those prescribed by my doctor which I wear every day 
О 
О 
 
6. In the last two weeks, have you had any itching in association with your varicose veins? 
 
Right Leg 
Left Leg 

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No 
О 
О 
Yes, above the knee only 
О 
О 
Yes, below the knee only 
О 
О 
Yes, above and below the knee 
О 
О 
 
7. Do you have purple discoloration caused by tine blood vessels in the skin, in association with your 
varicose veins? 
 
Right Leg 
Left Leg 
No 
О 
О 
Yes 
О 
О 
 
8. Do you have a rash or eczema in the area of your ankle? 
 
Right Leg 
Left Leg 
No 
О 
О 
Yes, but it does not require treatment from a doctor or district nurse 
О 
О 
Yes, and it requires treatment from a doctor or district nurse 
О 
О 
 
9. Do you have a skin ulcer associated with your varicose veins? 
 
Right Leg 
Left Leg 
No 
О 
О 
Yes 
О 
О 
 
10. Does the appearance of your varicose veins cause you concern? 
О  None at all 
О Yes, their appearance causes me slight concern 
О Yes, their appearance causes me moderate concern 
О Yes, their appearance causes me a great deal of concern 
 
11. Does the appearance of your varicose veins influence your choice of clothing including tights? 
О  No 
О  Occasionally 
О  Often 
О  Always 

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12. During the last two weeks, have your varicose veins interfered with your work/housework or other 
activities? 
О  No 
О  I have been able to work but my work has suffered to a slight extent 
О  I have been able to work but my work has suffered to a moderate extent 
О  My veins have prevented me working one day or more 
13. During the last two weeks, have your varicose veins interfered with your leisure activities?  
       (Including sports, hobbies, and social life) 
О  No 
О  Yes, my enjoyment has suffered to a slight extent 
О  Yes, my enjoyment has suffered to a moderate extent 
О  Yes, my veins have prevented me taking part in any leisure activities 
 
 
 

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2. EQ-5D-5L 
 
 
 
 
 
 
 
 
Health Questionnaire 
 
 
English version for the USA 
 
 
 

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Under each heading, please check the ONE box that best describes your health TODAY. 
MOBILITY 
 
I have no problems walking 
 
I have slight problems walking 
 
I have moderate problems walking 
 
I have severe problems walking 
 
I am unable to walk 
 
SELF-CARE 
 
I have no problems washing or dressing myself 
 
I have slight problems washing or dressing myself 
 
I have moderate problems washing or dressing myself 
 
I have severe problems washing or dressing myself 
 
I am unable to wash or dress myself 
 
USUAL ACTIVITIES (e.g. work, study, housework, family or leisure activities) 
 
I have no problems doing my usual activities 
 
I have slight problems doing my usual activities 
 
I have moderate problems doing my usual activities 
 
I have severe problems doing my usual activities 
 
I am unable to do my usual activities 
 
PAIN / DISCOMFORT 
 
I have no pain or discomfort 
 
I have slight pain or discomfort 
 
I have moderate pain or discomfort 
 
I have severe pain or discomfort 
 
I have extreme pain or discomfort 
 
ANXIETY / DEPRESSION 
 
I am not anxious or depressed 
 
I am slightly anxious or depressed 
 
I am moderately anxious or depressed 
 
I am severely anxious or depressed 
 
I am extremely anxious or depressed 
 

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The worst 
health you can 
imagine 
 
 
We would like to know how good or bad your health is TODAY.  
This scale is numbered from 0 to 100. 
100 means the best health you can imagine. 
0 means the worst health you can imagine. 
Mark an X on the scale to indicate how your health is TODAY. 
Now, please write the number you marked on the scale in the box below. 
 
 
 
 
 
 
  
 
 
YOUR HEALTH TODAY = 
10
0 
20
30
40
50
60
80
70
90
100 
5 
15
25
35
45
55
75
65
85
95
The best 
health you 
can imagine 

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3. rVCSS 
Venous disease severity measurement intended to evaluate the responses to changes in disease severity over time 
and in response to treatment.   
 
None: 0 
Mild: 1 
Moderate: 2 
Severe: 3 
Pain 
or other discomfort (i.e. 
aching, heaviness, 
fatigue, soreness, 
burning) 
 
Presumes venous origin 
 
Occasional pain or 
other discomfort 
(i.e. not restricting 
regular daily 
activities) 
Daily pain or other 
discomfort (i.e. 
interfering with 
but not preventing 
regular daily 
activities) 
Daily pain or 
discomfort (i.e., 
limits most regular 
daily activities) 
Varicose Veins 
“Varicose” veins must 
be ≥3 mm in diameter 
to qualify in the 
standing position 
 
Few: scattered (i.e., 
isolated branch 
varicosities or 
clusters) 
Also includes 
corona 
phlebectatica 
(ankle flare) 
Confined to calf or 
thigh 
Involves calf and 
thigh 
Venous Edema 
Presumes venous origin 
 
Limited to foot and 
ankle area 
Extends above 
ankle but below 
knee 
Extends to knee 
and above 
Skin Pigmentation 
Presumes venous origin 
 
Does not include focal 
pigmentation over 
varicose veins or 
pigmentation due to 
other chronic diseases 
(i.e., vasculitis purpura) 
None or focal 
Limited to 
perimalleolar area 
Diffuse over lower 
third of calf 
Wider distribution 
above lower third 
of calf 
Inflammation 
More than just recent 
pigmentation (i.e., 
erythema, cellulitis, 
venous eczema, 
dermatitis) 
 
Limited to 
perimalleolar area 
Diffuse over lower 
third of calf 
Wider distribution 
above lower third 
of calf 
Induration 
Presumes venous origin 
of secondary skin and 
subcutaneous changes 
(i.e., chronic edema 
with fibrosis, 
hypodermitis) 
 
 
Limited to 
perimalleolar area 
Diffuse over lower 
third of calf 
Wider distribution 
above lower third 
of calf 

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Includes white atrophy 
and ipodermatosclerosis 
Active Ulcer Number 
0 
1 
2 
≥3 
Active Ulcer Duration 
(longest active) 
N/A 
<3 mo 
>3 mo but <1 y 
Not healed for >1 y 
Active Ulcer Size 
(largest active) 
N/A 
Diameter <2 cm 
Diameter 2-6 cm 
Diameter >6 cm 
Use of Compression 
Therapy 
0 
 
Not used 
1 
 
Intermittent use of 
stockings 
2 
 
Wears stockings 
most days 
3 
 
Full compliance: 
stockings 
 
 
 

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4. SF-36 
 

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5. CEAP Classification 
 
The CEAP classification is a method for evaluating venous disease of the leg based on clinical, etiologic, anatomic, 
and pathophysiologic data. 
The CEAP system consists of two parts: classification and severity scoring: 
Classification 
C- clinical manifestation 
E- etiologic factors 
A- anatomic distribution 
P- pathophysiologic dysfunction 
Severity Scoring 
1. Number of anatomic segments affected 
2. Grading of signs and symptoms 
3. Disability 
CLINICAL CLASSIFICATION per 2004 guidelines 
C0: no visible or palpable signs of venous disease 
C1: telangiectasies or reticular veins 
C2: varicose veins 
C3: edema 
C4a: pigmentation and eczema 
C4b: lipodermatosclerosis and atrophie blanche 
C5: healed venous ulcer 
C6: active venous ulcer 
 
CLINICAL CLASSIFICATION per 2020 guidelines 
C0: no visible or palpable signs of venous disease 
C1: telangiectasies or reticular veins 
C2: varicose veins 
C2r: recurrent varicose veins 
C3: edema 
C4a: pigmentation and eczema 
C4b: lipodermatosclerosis and atrophie blanche 
C4c: corona phlebectatica 
C5: healed venous ulcer 
C6: active venous ulcer 
C6r: recurrent active venous ulcer 
 
 

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6. VenousTSQ 
Both components of the VenousTSQ, the peri-procedural early component of the venous treatment 
satisfaction (VenousTSQe) and the status component of the venous treatment satisfaction questionnaire 
(VenousTSQs) are provided below. 
 

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7. VenousDQoL Overview items 
 
 

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8. Patient Reported Symptoms Table 
 
ACHING 
o NO       o YES     
☐ DOMINANT SYMPTOM 
BURNING 
o NO       o YES     
☐ DOMINANT SYMPTOM 
HEAVINESS 
o NO       o YES     
☐ DOMINANT SYMPTOM 
ITCHING 
o NO       o YES     
☐ DOMINANT SYMPTOM 
PAIN 
o NO       o YES     
☐ DOMINANT SYMPTOM 
SENSITIVITY 
o NO       o YES     
☐ DOMINANT SYMPTOM 
SWELLING 
o NO       o YES     
☐ DOMINANT SYMPTOM 
 

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9. Patient Prior History Table 
 
Superficial and deep venous treatment history  
Medical History Term 
Prior History 
Limb 
Level of Satisfaction with Treatment 
How many years ago? 
Thermal ablation (laser, RF) 
o NO    
 o YES 
o Right     
o Left 
o Very dissatisfied          o Somewhat dissatisfied    
o   Somewhat satisfied   o Very satisfied 
o Last year    o 1-2 years     
o 3+ years 
Non-thermal ablation 
(MOCA, PEM) 
o NO    
 o YES 
o Right    
o Left 
o Very dissatisfied          o Somewhat dissatisfied    
o   Somewhat satisfied   o Very satisfied 
o Last year    o 1-2 years     
o 3+ years 
CAC 
o NO     
o YES 
o Right     
o Left 
o Very dissatisfied          o Somewhat dissatisfied    
o   Somewhat satisfied   o Very satisfied 
o Last year    o 1-2 years     
o 3+ years 
Ultrasound-guided foam 
sclerotherapy 
o NO     
o YES 
o Right    
o Left 
o Very dissatisfied          o Somewhat dissatisfied    
o   Somewhat satisfied   o Very satisfied 
o Last year    o 1-2 years     
o 3+ years 
Stripping 
o NO     
o YES 
o Right     
o Left 
o Very dissatisfied          o Somewhat dissatisfied    
o   Somewhat satisfied   o Very satisfied 
o Last year    o 1-2 years     
o 3+ years 

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Cosmetic sclerotherapy 
o NO    o YES 
o Right     
o Left 
o Very dissatisfied          o Somewhat dissatisfied    
o   Somewhat satisfied   o Very satisfied 
o Last year    o 1-2 years     
o 3+ years 
Ambulatory phlebectomy 
o NO     
o YES 
o Right     
o Left 
o Very dissatisfied          o Somewhat dissatisfied    
o   Somewhat satisfied   o Very satisfied 
o Last year    o 1-2 years     
o 3+ years 
Deep venous stent 
o NO     
o YES 
o Right     
o Left 
o Very dissatisfied          o Somewhat dissatisfied    
o   Somewhat satisfied   o Very satisfied 
o Last year    o 1-2 years     
o 3+ years 
Other (specify) 
o NO     
o YES 
o Right     
o Left 
o Very dissatisfied          o Somewhat dissatisfied    
o   Somewhat satisfied   o Very satisfied 
o Last year    o 1-2 years     
o 3+ years 

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Appendix B: Definitions 
 
Term 
Definition 
Aborted Treatment 
Failed completion of the assigned treatment where the subject was 
prepped for the index procedure, but the device did not enter the 
vasculature or surgical stripping was not initiated. 
Acute superficial 
thrombophlebitis 
Thrombus induced inflammation of a vein in a time period <14 days from 
symptom onset.  It presents with skin redness and tenderness around the 
hardened vein due to the associated inflammation. It is also commonly 
referred as superficial vein thrombosis. 
Adjunctive treatment 
Secondary treatment (phlebectomy and/or sclerotherapy) used to treat 
remaining varicosities after index procedure for cosmesis, to lessen the risk 
of superficial thrombophlebitis or because it may enhance primary 
treatment effectiveness.  
As Treated (Analysis set for 
CEAP 2-5 subjects) 
Includes subjects in the arm they are treated with according to the 
treatment actually received, regardless of the arm they are randomized to.  
Circumferential ulcer  
An ulcer that extends around the circumference of the leg and out of sight 
and, or an ulcer that cannot be captured in a single photograph with 
equipment provided by ulcer core laboratory.  
COVID-19  
Corona Virus Disease 2019, a new contagious disease caused by the Severe 
Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2). 
Endothermal Ablation 
Treatment (ETA) 
Radiofrequency or laser ablation treatment available per site standard 
practice for the treatment of superficial venous reflux. 
Granuloma 
A grouping of macrophages. Non-specific.  
Hypersensitivity reaction  
An allergic reaction to a foreign body/substance.  
Incomplete Treatment 
The index procedure was commenced where the device entered the 
vasculature, or the surgical stripping procedure was initiated but for any 
reason full target vein length was not treated. 

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Intent to Treat (ITT) 
(Randomized studies; CEAP 
2-5 subjects) 
All patients who are randomized in the study will be included in the 
randomized arm in the analysis regardless of the treatment received.  
Intent to Treat (ITT) (VLU 
Study; CEAP 6 subjects) 
All patients with CEAP 6 who are enrolled in this study and successfully 
treated with VenaSeal™ system, will be counted in the ITT population. 
No Procedure treatment 
outcome (CEAP 2-5) 
Subject is randomized (considered enrolled) but withdraws from the study 
after randomization without any attempt to conduct the procedure (e.g. 
COVID-19 exclusion, subject withdrawal, etc.). 
Per-Protocol (PP) (CEAP 2-
6) 
The ITT population excluding subjects that are not treated with the 
assigned treatment modality and/or have not met the inclusion/exclusion 
criteria.  
Phlebectomy 
Surgical procedure to remove small varicose veins through a series of small 
(1-3 cm) incisions in the leg along the GSV and its tributaries.  
Phlebitis 
Inflammation of a vein, the grading of the phlebitis are as follows and 
subject may have more than one grading:  
P1:  Inflammation of truncal or epifascial vein post-treatment, with 
palpable and/or non-palpable (Superficial thrombophlebitis) areas. Located 
within the treatment zone. It is caused due to Damage to treated vein by 
prescribed treatment with and without thrombus. 
P2:   Superficial thrombophlebitis in residual varicosities/tributaries. 
Located outside of treatment zone. It is caused due to thrombosis of 
draining varices or tributaries secondary to closure of truncal vein 
P3:  Inflammation of cutaneous and subcutaneous tissue. Located within or 
outside of treatment zone and adjacent tissues. It is caused due to tissue 
reaction to treatment or hypersensitivity.  
Point of Enrollment (CEAP 
2-5) 
Subjects will be considered enrolled from the moment of randomization.  
Point of Enrollment (CEAP 
6) 
Subjects will be considered enrolled from the moment the first component 
of the VenaSeal™ delivery system enters the body. 

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Pre-Screen Failure 
Patients that were identified for screening (consenting in the study) but 
were not consented in the study 
Pre-Screening 
The process of identifying patients for potential inclusion in the study, prior 
to obtaining informed consent from the patient.   
Primary Target Vein 
The primary target vein should be the saphenous vein (GSV, SSV, accessory 
saphenous veins) which at the investigator’s discretion is most likely 
responsible for the greatest portion of the patient’s symptoms or 
pathology. This vein will be treated first. 
Reintervention 
Retreatment of any segment of the target vein in the target limb previously 
treated as part of the study at the index procedure.  
Sclerotherapy 
Non-surgical procedure where an irritant (i.e. sclerosant) is directly injected 
into the vein, leading to irreversible endothelial injury and causing the vein 
to spasm and collapse. 
Screen Failure 
Subjects who signed and dated the Informed Consent Form, but who no 
longer meet all eligibility criteria before the point of enrollment. 
Screened 
Subjects who meet all eligibility criteria will be considered screened from 
the moment they have signed and dated the ICF  
Successful treatment 
Completion of the assigned treatment including any reattempt to complete 
the index procedure. 
Target limb 
Target limb is the limb identified to be treated limb in the study. In case of 
bilateral disease with both limbs meeting study eligibility criteria, the 
treating physician designating the more severe limb depending on the 
higher CEAP score or most symptomatic according to the patient will be the 
target limb. 
Target Vein (s) 
Any additional superficial truncal vein (s) in the target limb beyond the 
primary target vein which will be treated after the PTV during the index 
procedure.  
Treatment zone 
Broad and linear area surrounding the target vein and access site. 

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Thrombophlebitis migrans 
Advancing or migratory thrombophlebitis that involves multiple vessels at 
the same time.  
Thrombus extension:  
a. Endothermal Heat 
Induced Thrombus 
extension (EHIT) 
b. Endothermal Glue 
Induced Extension 
(EGIT) 
 Extensions of a thrombus that extend from the treated vein (GSV, SSV, 
ASV) into the deep venous system.  
Three different types of extension with VenaSeal to be distinguished: 
1. A pure glue extension – this looks like a very thin line and is rigid, 
and is detected immediately after the procedure.  
2. A glue/thrombus combination: This glue/thrombus combination is 
detected immediately after the procedure like pure glue extension. 
3. Thrombus extensions: This could be detected at all intervals/follow 
up periods after the procedure.  
Ulcer healing rate 
Percent of the ulcer area healed and calculated per given time period on 
the target limb.  The percent healed is determined by an independent core 
laboratory. 
Ulcer recurrence 
First occurrence of ulcer re-appearance after it has healed. 
Ulcer-free time 
Calculated as time between ulcer healing and first instance of ulcer 
recurrence. 
VenaSeal vs. ETA Study 
One of the two Randomized Studies in the protocol comparing the 
VenaSeal™ closure system to endothermal treatment modality 
VenaSeal vs. Surgical 
Stripping Study 
One of the two Randomized Studies in the protocol comparing the 
VenaSeal™ closure system to surgical stripping treatment modality 
Venous leg ulcer (VLU) site 
The site that is invited to enroll CEAP 6 subjects.  This will be indicated in 
the Site Selection Letter. 
VLU Study 
Single-arm venous leg ulcer study within the protocol; no comparator 

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19. Version History 
 
Version 
Summary of changes 
Justification of 
changes 
Potential impact 
of the change on 
performance, 
effectiveness, or 
safety or other 
endpoints 
Identification 
of the 
affected study 
documents 
Author(s)/ 
Title 
     1.0 
Not applicable, New document 
NA to this version of 
the template 
NA to this 
version of the 
template 
NA to this 
version of the 
template 
Stephanie Geerts-
Hulshof/Sr. Clinical 
Research Specialist 
Sara Ortiz/ Sr. Clinical 
Research Specialist 
2.0 
Extensive revisions changing the study design from a 
single-arm study to 3 separate studies: 
1. Randomized Studies 
• 
VenaSeal vs. ETA Study 
• 
VenaSeal vs. Surgical Stripping Study 
NA to this version of 
the template  
 
 
NA to this 
version of the 
template 
NA to this 
version of the 
template 
Sara Ortiz/Sr. Clinical 
Research Specialist 
Shital Patel/Clinical 
Research Specialist 

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2. VLU Study 
Language updated throughout document to indicate 
differences and similarities between the 3 studies. A 
redline version of this document is available upon 
request. 
Specific updates by section: 
1. Investigator Statement: No changes. 
2. Glossary: Updates based on language in current 
version. 
3. Synopsis: Updates to reflect changes in subsequent 
sections. 
4. Introduction: Addition of comparator therapy 
information. 
5. Objectives and Endpoints: Updates based on 
changed study design 
6. Study Design: Updates to reflect changes in study 
design, total expected enrollment numbers, total 
expected site number, follow-up visit schedule and 
rationale.  
7. Product Description: Updates reflects reference to 
comparator product’s IFU for product description 
 
 
 
 
 
 
 
 
Awaz Ali/ Clinical 
Research Specialist 

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and site’s standard practice for surgical stripping 
procedure.  
8. Selection of Subjects: Updates reflects changes in 
subject identification and screening process along 
with updates related to target vein/target ulcer 
selection. Inclusion and Exclusion criteria are 
updated based on revised study design. 
9. Study Procedures: Updates reflect changes related 
schedule of events, study assessments, screening, 
baseline, index procedure and follow-up visits. 
Randomization details added.  
10. Risks and Benefits: Updates reflects reference to 
comparator product’s IFU for risk details and risk-
benefit rationale updated based on revised study 
design.  
11. Adverse Events and Device Deficiencies: Recording 
and reporting of adverse events and device 
deficiencies (device deficiency reporting only for 
VenaSeal™ system) updated. 
12. Data Review Committees:  Updates to include CEC 
and ulcer core laboratory details. 
13. Statistical Design and Methods: Updates based on 
revised study design related to sample size 
evaluation and data analysis. 

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14. Ethics: Updates to include study registration on 
clinicaltrials.gov, EUDAMED identifier, and 
deviations from ISO 14155:2011.  
15. Study Administration: Updates to include language 
related to randomized and single arm study design 
and subject compensation details. 
16. References: Updates to include references as they 
are used throughout the document. 
3.0 
Specific Updates by Section: 
1. Investigator Statement: No changes. 
2. Glossary: Updates based on language in current 
version. 
3. Synopsis: Updates to reflect changes in subsequent 
sections. 
4. Introduction: Reference update for CEAP 
assessment. 
5. Objectives and Endpoints: Error related to 
healthcare utilization data for VLU study corrected 
to accurately reflect 6 months prior to the index 
procedure data will not be collected. VenousDQoL 
added under patient experience secondary 
endpoints. 
6. Study Design: Language updated to clarify the 
rationale for non-blinded study. The maximum 
• Changes to reflect 
ISO 14155:2020 
updates and 
Version B CIP 
template in 
applicable 
sections. 
• Changes to clarify 
study procedures, 
treatment groups, 
and timing of 
data capture. 
• Changes to 
accommodate 
potential impact 
of COVID 19. 
• No potential 
impact on the 
performance, 
effectiveness, 
or safety.  
• One additional 
secondary 
endpoint 
added. 
• Informed 
Consent 
Form 
• Case Report 
Forms 
 
 
Sara Ortiz/Pr. Clinical 
Research Specialist 
Shital Patel/Clinical 
Research Specialist 
Awaz Ali/Clinical 
Research Specialist 

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enrollment allowed per site updated to accurately 
reflect maximum allowed per study per site.  
7. Product Description: Updates reflects new CIP 
template requirements. 
8. Study Site Requirements: New section added per 
new CIP template requirement and to reflect ISO 
14155:2020 updates. 
9. Selection of Subjects: Updates reflects changes in 
patient follow-up for different treatment outcome 
category. Allowing usage old ulcer photograph for 
etiology confirmation added for VLU study. Exclusion 
criteria updated to add COVID-19 specific exclusion. 
10. Study Procedures: Updates reflect changes related 
to new CIP template and ISO 14155:2020 updates. 
Added requirement for collecting 2020 CEAP 
assessment along with 2004 CEAP assessment. 
Adjunctive therapies and treatment allowed for VLU 
study modified.   
11. Risks and Benefits: Updates reflects changes related 
to new CIP template and ISO 14155:2020 updates. 
The potential AE list for VenaSeal™ system modified 
to reflect the updated VenaSeal IFU.  
12. Adverse Events and Device Deficiencies: Updates 
reflect changes in the Adverse event and device 
• New release of 
CEAP 2020 and 
VenousDQoL. 
• Administrative 
changes. 

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deficiency definitions per ISO 14155:2020 updates 
along with updates in expected and unavoidable 
adverse events.  Recording and reporting of adverse 
events and device deficiencies (device deficiency 
reporting only for VenaSeal™ system and Medtronic 
ClosureFast™ system) updated. 
13. Data Review Committees:  Administrative changes 
to update CEC address. 
14. Statistical Design and Methods: Updates related to 
VenousTSQ language and analysis set definitions 
clarified.  
15. Ethics: Updates reflects changes related to new CIP 
template and ISO 14155:2020 updates. 
16. Study Administration: Updates reflects changes 
related to new CIP template 
4.0 
Updates by section: 
1. Cover Page: OU for Sponsor Medtronic Bakken 
Research Center B. V. deleted, added sponsor 
Medtronic Canada 
2. Document version and date updated throughout the 
document 
3. Section 1: section updated to reflect current internal 
CIP template 
• 
Per CIP 4.0, the 
decision of 
closure of the 
VenaSeal vs. 
Surgical 
Stripping Study 
enrollment was 
made due to 
significant 
delays and 
• 
No potential 
impact on 
the 
performance, 
effectiveness
, or safety 
endpoints for 
the VenaSeal 
vs ETA study.  
• 
Informed 
Consent 
Form 
• 
Case 
Report 
Forms 
 
Shital Patel, Sr. Clinical 
Research Specialist 
Mariapaola Loda, Sr. 
Clinical Research 
Specialist 
 

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4. Section 2 (Glossary): added SAP, UADE, USADE, 
updated VCSS with phrase “revised” 
5. Section 3 (Synopsis): OU for Sponsor Medtronic 
Bakken Research Center B. V. deleted, added sponsor 
Medtronic Canada. Updated indication codes for US 
and OUS. Updated details for enrollments in section 
Study Design. Updated Primary Objective section for 
VLU. Updated Primary Endpoint section for VLU. 
Updated secondary endpoints section for Surgical 
Stripping Study. Updated sample size. Updated 
exclusion criteria #12. Updated Table 1 (Schedule of 
Assessments – All Subjects) and added a new 
footnote related to the follow-up for Surgical 
Stripping Study. Updated Table 2 (Additional 
Schedule of Assessments – VLU Study) and added the 
term “active” to “Target Active Ulcer Assessment”. 
Updated statistics section and specified that primary 
endpoint for VLU study will be measured through 12 
months and added a paragraph about surgical 
stripping study. 
6. Section 4.2 (Purpose): Updated number of subjects 
that will be enrolled as well as the follow-up for all 
studies. 
7. Section 5.1.1 (Primary Objective): specified that 
primary objective for VLU study is measured through 
12 months. 
challenges 
recruiting sites 
and patients 
during the 
global COVID-19 
pandemic. The 
subjects 
enrolled in 
VenaSeal vs. 
Surgical 
Stripping Study 
will still be 
followed 
through the 12 
month follow-
up visit to 
ensure follow-
up through the 
first year 
following 
procedure.  
• 
The primary 
endpoint for the 
VLU study for 
time to ulcer 
healing is 
updated from 
• 
Primary 
endpoint for 
VLU study 
changed to 
12 months 
from 24 
months. 
• 
The 
performance, 
effectiveness
, and safety 
objectives 
with follow-
up greater 
than 1 year 
were 
reduced to 
12 months 
follow-up in 
the VenaSeal 
vs. Surgical 
Stripping 
Study.  

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8. Section 5.2.1 (Primary Endpoints): updated primary 
endpoint for VLU study from 24 to 12 months. 
9. Section 5.2.3 (Secondary Endpoints): updated all 
secondary endpoints for the Surgical Stripping Study 
through 12 months. 
10. Section 6 (Study Design): updates related to the 
closure of Surgical Stripping Study, follow-up through 
12 months for Surgical Stripping Study, number of 
patients enrolled in the study, maximum number of 
subjects to be enrolled by each site for VLU study, 
SAEs have been added to the events that require CEC 
adjudication. 
11. Section 6.1 (Duration): updated enrollment and study 
duration. Updated duration and collection of data for 
Surgical Stripping Study. 
12. Section 6.2 (Rationale): updated to reflect changes 
for Surgical Stripping and VLU study. 
13. Section 7.1 (Product Description, General): added 
new VenaSeal system model numbers. 
14. Section 
7.4 
(Product 
Description, 
Intended 
Population): updated VenaSeal system numbers for  
US and OUS. 
24 months to 12 
months to align 
with landmark 
clinical trials in 
superficial 
venous space.  
• The hypothesis 
test for the 
primary endpoint 
of elimination of 
clinically relevant 
superficial truncal 
disease in each 
target vein at the 
time of index 
procedure in 
VenaSeal vs. 
Surgical Stripping 
Study is removed 
as the endpoint is 
no longer 
powered with the 
reduced sample 
size. However, 
results will still be 
summarized 

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15. Section 
8.1 
(Investigator/Investigation 
Site 
Selection): updated language related to treating 
physicians. 
16. Section 9.1 (Study Population): added language on 
closure of enrollment for Surgical Stripping Study. 
17. Section 9.6 (Exclusion Criteria): updated exclusion 
criteria #12 on COVID-19. 
18. Section 10.1 (Schedule of events and data collection): 
Updated Table 6 (Schedule of Assessments – All 
Subjects) and added a new footnote related to the 
follow-up for Surgical Stripping Study. Data collection 
language has been updated according to the changes 
made to the tables. Updated language on standard of 
care procedures. 
19. Section 10.2 (Scheduled Follow-up visit windows): 
title of table 8 updated for Surgical Stripping Study. 
Word “implant” changed into procedure. 
20. Section 10.3 (Subject Consent): deleted reference to 
consent templates. 
21. Section 
10.4 
(Randomization 
and 
treatment 
assignment (CEAP 2-5)): updated language on 
Surgical Stripping Study. 
22. Section 
10.5 
(Study 
Assessments): 
added 
“investigators” to the paragraph on personnel that 
between study 
arms. 
• Per CIP 4.0, 
subjects may also 
complete 48 and 
60 months visit 
remotely per 
physician’s 
discretion if 
subjects cannot 
return to the site 
for follow-up.  
The long-term 
follow-up visits, 
48 and 60 months 
may have higher 
attrition rate. The 
remote visit is 
permitted in the 
study for 48 and 
60 months to 
keep the attrition 
rate minimal and 
be able to collect 
long term study 
data as much as 

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can perform Duplex Ultrasound. Updated section on 
Other Patient- Reported Outcomes on timelines to 
collect Venous DQoL and timelines for Surgical 
Stripping Study. Updated section “Questionnaire 
completion by delegated site personnel” to specify 
that questionnaires completed by a delegated person 
might be different and may require EC/IRB approval. 
23. Section 10.9 (Index Procedure): updated section 
Procedure for surgical stripping (CEAP 2-5 subjects in 
Randomized Studies assigned to surgical stripping). 
Added language in section Adjunctive Therapies & 
Treatments on adjunctive therapy and additional 
treatments as well as on perforating veins. 
24. Section 10.10 (Follow-up visits: all Subjects): updated 
language on Surgical Stripping Study. Added Patient 
Reported Outcomes and Venous DQoL to the list of 
assessments, where applicable. Updated language on 
adjunctive therapies and additional treatments. 
Added language to perform follow-up at 48 and 60 
months remotely. 
25. Section 10.12 (Additional Follow-Up Visits: VLU Study 
Active 
Ulcers): 
updated 
timeline 
for 
ulcer 
assessment. Replaced word “assessment” with 
“imaging” in section Ulcer Healing Verification Visit. 
possible 
remotely. 
• Per CIP 4.0 all 
SAEs will be 
adjudicated by 
CEC to ensure 
better safety 
oversight. 
• Per CIP 4.0, the 
exclusion criteria 
on COVID-19 has 
been updated to 
reflect the 
current 
understanding 
and guidelines. 
• Data for 
adjunctive 
therapies and 
additional 
treatments will be 
collected till 60 
months to ensure 
accuracy of data. 
• Data on 
perforating veins 
for CEAP 4b or 5 

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26. Section 10.13 (Assessment of Effectiveness): updated 
timelines for Surgical Stripping Study. 
27. Section 10.15 (Recording Data): updated section on 
the CRFs that may be considered source; added 
VenaSeal system details and AE relatedness. 
28. Section 
10.17.2 
(Study 
Completed): 
updated 
language on Surgical Stripping Study. 
29. Section 12.1.1 (Definitions): added definition of 
U(S)ADE. 
30. Section 12.3 (Recording and Reporting of Adverse 
Events): updated language on reportable events. 
31. Section 12.6 (Reporting of Adverse Events): updated 
language 
and 
table 
on 
events 
reporting 
requirements. 
32. Section 13.1 (Clinical Event Committee): added 
language on adjudication of SAEs and updated name 
of CRO leading CEC adjudications. 
33. Section 14.1.2 (Sample size evaluation on key 
secondary endpoints): updated text and sample size 
for Surgical Stripping Study. 
34. Section 14.1.3 (Interim Analysis): updated language 
on Surgical Stripping Study. 
target limb are 
collected from 3 
months through 
study end to 
perform an 
accurate 
healthcare cost 
analysis. 
• Investigator 
reporting 
requirements 
updated to reflect 
the requirements 
from each 
country involved 
in the study. 
• U(S)ADE 
definitions was 
added since this 
type of events 
need to be 
reported 
according to 
specific EC/IRB 
requirements. 

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35. Section 14.2.1 (Sample Size Consideration): language 
and sample size numbers updated. 
36. Section 16.5 (Data Management): changed word 
“indefinitely” with “in accordance with applicable 
regulations”. 
37. Section 18 (Appendices): updated language of 
question 1 from AVVQ. 
38. Administrative updates 
5.0 
Updates by section: 
1. Cover page:  added that Medtronic Bakken Research 
Center B.V. is EU legal representative. 
2. Corrections in table numbering throughout the 
document. 
3. Synopsis: correction in bullet point numbering 
Secondary Endpoints. 
4. Section 6.2 (Rationale): changed “healthcare cost 
analysis” to “healthcare utilization analysis”. 
5. Section 9.6 (Exclusion Citeria): correction in bullet 
point numbering. 
6. Section 10.1 (Schedule of Events and Data 
Collection): Updated Table 7 (Additional Schedule of 
Assessments – VLU Study) and added the term 
Administrative 
corrections. 
 
Clarification of 
definition 
Medtronic Bakken  
Research Center 
B.V. – EU legal 
representative. 
NA to this 
version of the 
template 
NA to this 
version of the 
template 
Marlies de Ligt, Sr. 
Clinical Research 
Specialist 

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“active” to “Target Active Ulcer Assessment”. This 
was not implemented in version 4.0.