Observational Study of the Effect of VarIthena® on Wound Healing in the Treatment of Venous Leg Ulcers Resulting From Chronic Venous Insufficiency
Conditions: Venous Leg Ulcer
Sponsor: Boston Scientific Corporation

Protocol BTG-001652-01 (VIEW-VLU) 
Version 1.1, 14Aug2017 
 
 
 
 
 
 
Page 1 of 50 
Provensis Ltd 
CONFIDENTIAL 
 
A BTG International group company 
 
Protocol Number: 
BTG-001652-01 
Protocol Short Title: 
VIEW-VLU 
Protocol Name: 
Observational Study of the Effect of VarIthEna® on Wound Healing in 
the Treatment of Venous Leg Ulcers Resulting from Chronic Venous 
Insufficiency 
Sponsor: 
Provensis Ltd 
A BTG International group company  
5 Fleet Place 
London EC4M 7RD 
Coordinating 
Principal Investigator: 
Michael Shao, MD 
Swedish Covenant Hospital 
5140 N. California Ave. Suite 780 
Chicago, IL  60625 
P: 773.781.6352 
Medical Monitor: 
Simon Hogan, MD 
Provensis Ltd, a BTG International group company 
Lakeview, Riverside Way, Watchmoor Park 
Camberley, Surrey, GU15 3YL, UK 
P: +44.1276.902.020 
Investigational 
Product (IP) 
Commercially distributed Varithena® (polidocanol injectable foam) 1%  
This document is the confidential property of Sponsor. No part of it may be transmitted, reproduced, published, or 
used by other persons without prior written permission. 
 
 
VERSION 
NUMBER 
APPROVAL 
DATE 
BRIEF DESCRIPTION OF CHANGES 
1.0 
18May2017 
Original protocol 
1.1 
14Aug2017 
Protocol amended to include Canadian sites 
 
 
 
 
 
 
 
 
 
 
 
 

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Provensis Ltd 
CONFIDENTIAL 
 
A BTG International group company 
 
Registry Contacts 
 
BTG International Ltd 
Leslie Cass, MA, CCRA 
Manager Clinical Development 
11911 North Creek Parkway S. 
Bothell, WA  98011-8809, USA 
P: 425.415.3186 
F: 425.415.3107 
M: 206.641.4529 
E-mail:  Leslie.Cass@btgplc.com 
 
Simon Hogan, MD 
Project Physician 
Lakeview, Riverside Way, Watchmoor Park 
Camberley, Surrey, GU15 3YL, UK 
P: +44.1276.902.020 
F: +44.1276.537.162 
M: +44.7972.638.647 
E-mail: Simon.Hogan@btgplc.com 
 
 
Tissue Analytics® Technical Support 
Phone Support: 443.491.8241 
Email Support: support@tissue-analytics.com 
 

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Provensis Ltd 
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INVESTIGATOR PROTOCOL REVIEW STATEMENT 
Protocol Number: 
BTG-001652-01 
Protocol Short Title: 
VIEW-VLU 
Protocol Name: 
Observational Study of the Effect of VarIthEna® (polidocanol injectable 
foam) 1% on Wound Healing in the Treatment of Venous Leg Ulcers 
Resulting from Chronic Venous Insufficiency 
Protocol Version: 
1.1 
Protocol Approval 
Date: 
14Aug2017 
 
The investigational site Principal Investigator (undersigned) hereby declares that he/she has 
read this protocol and agrees to its contents. 
The undersigned confirms that the registry will be conducted and documented in accordance 
with the Declaration of Helsinki, this protocol, standards of Good Clinical Practice, applicable 
laws and regulatory requirements specified in the protocol, and the stipulations of the Clinical 
Trial Agreement (CTA). 
By written consent to this protocol, the Principal Investigator agrees to the above and to fully co-
operate with all monitoring and audits in relation to this registry by allowing direct access to all 
documentation, including source data, by authorized individuals representing Provensis Ltd, BTG 
International, the institutional review board (IRB) and/or by regulatory authorities. 
 
Investigator Name (please print):   _________________________________________ 
 
Investigator Signature:   _________________________________________ 
 
Date (DD/MMM/YYYY):   _________________________________________ 
 
 
 
 

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TABLE OF CONTENTS, LISTS OF TABLES & FIGURES 
Registry Contacts_____________________________________________________ 2 
PROTOCOL APPROVAL & RELEASE SIGNATURE PAGE ____________________ 3 
INVESTIGATOR PROTOCOL REVIEW STATEMENT _________________________ 4 
TABLE OF CONTENTS, LISTS OF TABLES & FIGURES ______________________ 5 
1. TERMS, ACRONYMS, ABREVIATIONS ________________________________ 8 
2. PROTOCOL SYNOPSIS ____________________________________________ 10 
3. SCHEDULE OF REGISTRY ASSESSMENTS ___________________________ 14 
4. BACKGROUND __________________________________________________ 15 
4.1 
Venous Leg Ulcers from Chronic Venous Insufficiency ____________________ 15 
4.2 
Varithena® Product Description ________________________________________ 17 
4.3 
Varithena® Clinical Summary __________________________________________ 17 
5. REGISTRY OBJECTIVE AND PURPOSE ______________________________ 20 
5.1 
Objective(s) ________________________________________________________ 20 
5.2 
Design _____________________________________________________________ 20 
5.3 
Primary Endpoint(s) _________________________________________________ 21 
5.4 
Secondary Endpoint(s) _______________________________________________ 22 
6. SUBJECT SELECTION ____________________________________________ 22 
6.1 
Registry Population __________________________________________________ 22 
6.2 
Subject Selection ____________________________________________________ 22 
6.2.1 Inclusion Criteria __________________________________________________________ 22 
6.2.2 Exclusion Criteria _________________________________________________________ 23 
6.3 
Subject Completion __________________________________________________ 23 
6.4 
Withdrawal _________________________________________________________ 23 
7. TREATMENT OF SUBJECTS ________________________________________ 23 
7.1 
Varithena® (polidocanol injectable foam) 1% _____________________________ 23 
7.1.1 Dosage & Administration ____________________________________________________ 23 
7.1.2 Additional Treatment _______________________________________________________ 24 
7.1.3 Post-treatment Management _________________________________________________ 24 
7.1.4 Duration of Treatment and Follow-up __________________________________________ 24 
7.1.5 Concomitant Therapies or Interventions ________________________________________ 24 
8. MEASUREMENTS AND EVALUATIONS _______________________________ 25 
8.1 
Time and Event Schedule _____________________________________________ 25 
8.1.1 Screening/Baseline Visit (can occur up to 14 days prior to treatment) (Clinic) ___________ 25 
8.1.2 Enrollment/Treatment Visit (Day 0) (Clinic) ______________________________________ 25 
8.1.3 Week 1 Visit (1st Follow-up Visit Per SoC) (Clinic) ________________________________ 25 
8.1.4 Week 2 through Wound Closure (at WCC) ______________________________________ 26 

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8.1.5 Week 12 Visit (±1wk) (Clinic) ________________________________________________ 26 
8.1.6 3 Months (±1wk) Post-Wound-Closure (Telephone) _______________________________ 26 
8.1.7 6 Months (±1wk) Post-Treatment (Telephone) ___________________________________ 26 
8.1.8 Month 12 Visit (±1wk) Post-Treatment (Clinic) ___________________________________ 27 
8.2 
Evaluations and Procedures __________________________________________ 27 
8.2.1 Informed Consent Process __________________________________________________ 27 
8.2.2 Eligibility Review __________________________________________________________ 27 
8.2.3 Assignment of Subject Idendification Code (SIC) _________________________________ 27 
8.2.4 Demographics ____________________________________________________________ 28 
8.2.5 Physical Examination ______________________________________________________ 28 
8.2.6 Wound History and Prior Treatments __________________________________________ 28 
8.2.7 Wound Photographs _______________________________________________________ 28 
8.2.8 Varithena® Treatment Record ________________________________________________ 29 
8.2.9 Numeric Pain Rating Scale __________________________________________________ 29 
8.2.10 
Venous Clinical Severity Score (Revised) ____________________________________ 29 
8.2.11 
EQ-5D-5L Quality of Life Assessment _______________________________________ 29 
9. ADVERSE EVENTS _______________________________________________ 30 
9.1 
Definitions _________________________________________________________ 30 
9.2 
Reporting Adverse Events ____________________________________________ 30 
10. 
STATISTICAL CONSIDERATIONS __________________________________ 31 
10.1 Statistical Analysis __________________________________________________ 31 
10.2 Determination of Sample Size _________________________________________ 31 
10.2.1 
Analysis Populations _____________________________________________________ 31 
10.3 Primary Efficacy Analyses ____________________________________________ 31 
10.4 Secondary Efficacy Analyses __________________________________________ 32 
10.5 Additional Efficacy Analyses __________________________________________ 32 
10.6 Sub-group Analyses _________________________________________________ 33 
10.7 Safety Analyses _____________________________________________________ 33 
10.8 Interim Analyses ____________________________________________________ 33 
11. 
DATA MANAGEMENT ___________________________________________ 33 
12. 
LEGAL/ETHICS AND ADMINISTRATIVE PROCEDURES ________________ 34 
12.1 Good Clinical Practice/Regulatory Compliance ___________________________ 34 
12.2 Site and Investigator Qualification _____________________________________ 34 
12.2.1 
Investigator Curriculum Vitae (CV) __________________________________________ 34 
12.2.2 
Statement of Investigator _________________________________________________ 34 
12.3 Institutional Review Board (IRB) _______________________________________ 35 
12.3.1 
Institutional Approval of the Protocol_________________________________________ 35 
12.3.2 
IRB Membership Roster __________________________________________________ 35 
12.4 Informed Consent – Ethical Compliance _________________________________ 35 
12.5 Subject Privacy and Confidentiality ____________________________________ 35 
12.6 Monitoring _________________________________________________________ 36 

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12.7 Modification of the Protocol ___________________________________________ 36 
12.8 Suspension or Termination of Registry _________________________________ 36 
12.8.1 
Protocol Deviations/Violations ______________________________________________ 36 
12.9 Recording, Access to and Retention of Source Data_______________________ 37 
12.10 Final Data __________________________________________________________ 37 
12.11 Publications ________________________________________________________ 37 
12.12 Audit/Inspections ___________________________________________________ 37 
13. 
SUPPLEMENTS/APPENDICES ____________________________________ 38 
13.1 Appendix A: CEAP Classification ______________________________________ 38 
13.2 Appendix B: Venous Duplex Assessment _______________________________ 40 
13.3 Appendix C: Varithena® (polidocanol injectable foam) 1% Full Prescribing 
Information ______________________________________________________________ 43 
13.4 Appendix D: Varithena® (polidocanol injectable foam) 1% Instructions for Use 44 
13.5 Appendix E: Use of Varithena® to manage patients with GSV-derived venous 
hypertension and chronic venous leg ulcer ___________________________________ 45 
13.6 Appendix F: Venous Clinical Severity Score (VCSS) _______________________ 46 
13.7 Appendix G: EQ-5D-5L _______________________________________________ 49 
13.8 Apendix H: Adverse Event Form _______________________________________ 50 
LIST OF TABLES 
Table 1: Schedule of Registry Assessments 
 
LIST OF FIGURES 
Figure 1: Study Schematic 
 

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1. 
TERMS, ACRONYMS, ABREVIATIONS 
The following abbreviations and specialist terms are used in this protocol. 
AASV 
Anterior Accessory Saphenous Vein 
ABPI 
Ankle-Brachial Pressure Index 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
CEAP 
Clinical Etiologic Anatomic Pathophysiologic  
CFR 
Code of Federal Regulation 
CI 
Confidence Interval 
CRA 
Clinical Research Associate 
CTA 
Clinical Trial Agreement 
CV 
Curriculum Vitae 
CVD 
Chronic Venous Disorders 
DCF 
Data Clarification Form 
DCT 
Data Capture Tool 
DMP 
Data Management Plan 
DM 
Data Management  
DVT 
Deep Vein Thrombosis 
EQ-5D-5L 
EuroQol five dimension five level questionnaire 
FDA 
Food and Drug Administration 
FPI 
Full Prescribing Information 
GCP 
Good Clinical Practice 
GSV 
Great Saphenous Vein 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
iDCT 
Investigator Data Capture Tool 
IFU 
Instructions for Use 
IRB 
Institutional Review Board 
IP 
Investigational Product 
NPRS 
Numeric Pain Rating Scale 
PE 
Pulmonary Embolism 
RCT 
Randomized-Controlled Trial 
QOL 
Quality of Life 
REB 
Research Ethics Board 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
sDCT 
Subject Data Capture Tool 
SEPS 
Sub-fascial Endoscopic Perforator Vein Surgery 
SIC 
Subject Identification Code 
SFJ 
Saphenofemoral Junction 
SoC 
Standard of Care 
SPJ  
Saphenopopliteal Junction 
SSV 
Small Saphenous Vein 
SW 
Source Worksheet 
USWR 
United States Wound Registry 

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VAS 
Visual Analogue Scale 
VCSS 
Venous Clinical Severity Score 
VLU 
Venous Leg Ulcer 
WCC 
Wound Care Center 
WHI 
Wound Healing Index 
 
 

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2. 
PROTOCOL SYNOPSIS  
Protocol Number 
BTG-001652-01 
Protocol Short Title 
VIEW-VLU 
Protocol Title 
Observational Study of the Effect of VarIthEna® on Wound Healing 
in the Treatment of Venous Leg Ulcers Resulting from Chronic 
Venous Insufficiency 
Investigational Product 
Commercially distributed Varithena® (polidocanol injectable foam) 
1% (Approved 25 Nov 2013 NDA 205098)  
Type of Protocol 
Phase 4 Registry 
Rationale 
The purpose of this registry is to observe the effects of Varithena® 
on venous leg ulcer (VLU) healing in patients who have symptoms 
of chronic venous insufficiency. The impact of treatment on rate of 
healing, rate of recurrence, subject’s pain and quality of life will be 
observed. 
Objective(s) 
To evaluate VLU healing rate, recurrence rate, and patient reported 
outcomes for Varithena® in C6 disease per Clinical Etiologic 
Anatomic Pathophysiologic (CEAP) classification 
Primary Endpoint (s) 
 
Rate of epithelial migration (mm/week) measured by wound 
perimeter on photograph taken using the data capture tool 
(DCT) and submitted to Tissue Analytics® for analysis 
 
Wound closure at 12 weeks (±1wk) post-treatment 
 
Time from initial treatment with Varithena® to wound closure 
Secondary Endpoint (s) 
 
Percent of wounds remaining closed at 3 months post-wound 
closure 
 
VLU recurrence (at same site) at 6 months and 12 months post-
treatment 
 
Change in pain at ulcer location on numeric pain rating scale 
(NPRS) compared to baseline at 12 weeks, 6 months, and 12 
months post-treatment 
 
Change on EuroQol five dimension five level questionnaire (EQ-
5D-5L) quality of life assessment compared to baseline at 12 
weeks and 12 months post-treatment 
 
Change in Venous Clinical Severity Score (VCSS) of treated leg 
from Screening/Baseline to 12 weeks and 12 months post-
treatment 
 
Number of ulcer free weeks defined as weeks from closure 

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(complete epithelialization is recorded) to date of recurrence (at 
same site) or last contact if no recurrence 
Duration 
Enrollment will take place over approximately a 12 month period. 
For each subject, the registry lasts about 12 months. 
Design 
Multicenter, open-label, 12-month registry. Enrollment is performed 
by Investigator who plans to treat subject’s great saphenous vein 
(GSV) system and/or anterior accessory saphenous vein (AASV) 
incompetence and resulting VLU using Varithena®. VLU recurrence 
information is collected for those with healed wounds during the 12 
month follow-up period.  
Note: In cases of cluster wounds, Investigator collects data for a 
single, primary wound. If more than one wound meets eligibility 
criteria, Investigator determines which wound to evaluate as the 
primary. All endpoint measurements are collected for the primary 
wound. 
Population 
Patients classified C6 on CEAP classification with active VLU 
resulting from venous insufficiency of the GSV system and/or AASV  
Subject Sample and 
Investigational Sites 
Up to 200 subjects scheduled to receive Varithena® for active VLU 
(C6) resulting from venous insufficiency of the GSV system and/or 
AASV will be enrolled at up to 40 investigational sites in the United 
States and Canada. 
Treatment 
Subjects scheduled for treatment with Varithena® are treated in 
accordance with the Investigator’s standard of care (SoC), including 
treatment of varicose tributaries in the proximity of the ulcer bed. 
Administration procedures and volume are per SoC, full prescribing 
information (FPI) and instructions for use (IFU). Additional 
treatment(s) with Varithena® can be administered at Investigator’s 
discretion and according to FPI.    
Post-procedure care, including compression dressing, should be 
used and prescribed in accordance with Investigator’s SoC. 
 
 
 

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Eligibility Criteria 
Inclusion Criteria 
1. Men and women; age ≥18  
2. Investigator has selected Varithena® to treat patients classified 
C6 with chronic (≥ 3 months) VLU resulting from GSV and/or 
AASV incompetence 
3. Wound can be visualized in one plane to allow for image 
collection of the entire wound in one photograph, or if wound 
is circumferential, subject must be able to capture the entire 
wound using multiple photographs taken from directly above 
the wound (straight on) 
4. Reflux >500ms on duplex ultrasound 
5. Willing and able to collect wound photographs and data using 
an application installed on a tablet 
6. Willing and able to return for scheduled follow-up and wound 
care visits 
7. Ability to comprehend and sign informed consent form (ICF) 
and complete questionnaires 
Exclusion Criteria    
8. Contraindications to Varithena® 1% in accordance with the FPI 
9. Any serious concomitant disease, per physician’s discretion, 
that confounds wound healing, including malignant changes of 
wound  
10. Concomitant heat ablation, or heat ablation of index leg within 
6 weeks prior to treatment with Varithena®  
11. Significant arterial disease or ankle-brachial pressure index 
(ABPI) ≤ 0.8 
12. In the opinion of Investigator, wound would close within 12 
weeks without additional treatment 
Statistical Power and 
Sample Size 
No formal statistical hypotheses are being tested and no formal 
sample size calculation has been performed. The aim of the registry 
is to collect additional data on treatment effects of a specific 
indication for which Varithena® is approved but has not been 
examined in detail. Previous feasibility metrics indicate 
approximately 200 subjects can be enrolled within one year. 
 
 
 

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Statistical Methods 
Wound area and perimeter will be measured at baseline and each 
week up to 12 weeks in order to assess rate of epithelial migration, 
wound closure at 12 weeks and time to wound closure.  
Secondary endpoints, VCSS, NPRS, and EQ-5D-5L will be 
calculated as difference from baseline at each visit. Recurrence will 
be defined as wounds that were reported to have closed, but did not 
remain so.  
Summary statistics of the primary and secondary endpoints will be 
reported with 95% confidence intervals (CI). CIs will be estimated 
using the Kaplan-Meier method for time to event analyses and the 
exact (e.g., Clopper-Pearson) method for binomial proportion 
analyses.  
Additionally, distribution of continuous endpoints will be evaluated 
for skewness. Missing data will not be imputed. 
Registry Procedures 
See Table 1: Schedule of Registry Assessments below 
Data Collection 
All Investigator and subject data is collected via a DCT. There are 
two versions of the DCT: physician-facing, referred to as 
Investigator data capture tool (iDCT), and subject-facing, referred to 
as subject data capture tool (sDCT). Investigator data can be 
entered into the iDCT through an application downloaded on a 
Sponsor-provided tablet or by using the web portal. Subjects collect 
wound photographs and answer an NPRS question on a Sponsor-
provided tablet via the sDCT at designated time points. This allows 
for photograph and data collection between clinic visits.  
Data is maintained in a Health Insurance Portability and 
Accountability Act (HIPAA) compliant database. Subject data is 
linked to Investigator data by the subject identification code (SIC). 
Central Imaging  
All wound photographs collected for this registry are submitted via 
the iDCT and sDCT. Tissue Analytics® analyzes each photograph, 
or set of photographs for circumferential wounds, and provides 
wound color and size data for statistical analyses. 
 
 
 

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3. 
SCHEDULE OF REGISTRY ASSESSMENTS 
Table 1 
acompleted within 14 days of Screening/Baseline visit. Screening/Baseline and Enrollment/Treatment visit measurements and evaluations may occur at the same visit if subject is 
provided adequate time to consider and have all questions answered. 
bnot required within first week; should be scheduled per SoC for first follow-up 
cshould be completed prior to treatment with Varithena® 
dadditional treatment with Varithena® cannot occur sooner than 5 days after index treatment 
ecollected/completed by subject using sDCT 
fInvestigator or designee to request during phone follow- up 
Registry Visit 
Screening/ 
Baseline 
Enrollment/ 
Treatmenta 
(Day 0) 
Week 1 
Follow-Up 
Visitb 
Week 2 through 
Wound Closure 
(at WCC) 
Weekly 
Week 12 
(±1wk) 
Follow-Up 
Visit 
3 Months 
(±1wk)  
Post-Closure 
(phone call) 
6 Month 
(±1wk) 
Follow-Up 
(phone call) 
Month 12 
(±1wk) 
Follow-Up 
Visit 
Informed consent 
X 
 
 
 
 
 
 
 
Duplex ultrasound of 
superficial and deep veins 
X 
 
X  
(as necessary) 
 
 
 
 
 
Screening: eligibility criteria 
X 
 
 
 
 
 
 
 
Demographics, 
comorbidities, wound history 
X 
 
 
 
 
 
 
 
Wound Characteristics 
 
X
 c 
 
 
 
 
 
 
Varithena® treatment 
 
X 
X  
(as necessary)d 
 
 
 
 
 
Hospitalizations for wound? 
 
X 
X 
 
X 
X 
X 
X 
Subject training to use sDCT 
 
 
X 
 
 
 
 
 
Review of VLU recurrence  
(if applicable) 
 
 
 
 
 
X 
X 
X 
Photograph(s) of wound  
(or closed wound area) 
X 
X c 
Xe 
Xe 
X 
Xe,f  
Xe,f  
X  
Numeric Pain Rating Scale 
 
X c 
Xe 
Xe 
X 
Xe,f  
Xe,f  
X  
VCSS 
 
X c 
 
 
X 
 
 
X 
EQ-5D-5L quality of life 
assessment 
 
X c 
 
 
X 
 
 
X 

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4. 
BACKGROUND 
4.1 Venous Leg Ulcers from Chronic Venous Insufficiency 
VLUs are the most common chronic wounds in ambulatory elderly population accounting for 60-
70% of all lower extremity wounds. There is higher prevalence of VLUs in individuals with fewer 
economic resources and years of education. VLUs also result in reduced quality of life and 
social isolation.1 VLUs are also known to have high recurrence rates ranging from 54-78%.2 
Symptomatic venous disease prevalence is estimated to be 5% of the population.3 Prevalence 
of VLUs in the population older than 60 years of age is 1-3%4,5 with annual treatment costs 
reaching $14.9 billion.6 
It is well known that compression therapy results in healing of VLUs, but there is a challenging 
subset of the ulcer population that does not respond to standard compression therapy alone. 
The landmark ESCHAR trial by Gohel et al compared compression therapy (multilayered 
compression bandage wraps) to superficial venous surgery plus compression therapy. There 
was no significant improvement in the ulcer healing between both the groups (89% versus 93%) 
at 48 months.7,8 The ESCHAR trial also reported a reduction in 12-month ulcer recurrence rates 
in the surgery plus compression group versus those with compression therapy alone (12% 
versus 28%; CI 1.78-4.27; p < 0.0001). This difference in ulcer recurrence rates persisted at 4 
years. The recurrence rates with surgery were similar to the results reported earlier by Barwell 
et al.9 A weakness of the trial was that there was no surgical arm without compression. It is also 
important to note that this study did not include treatment of pathologic perforators. Conversely, 
Scriven et. al. studied patients with normal deep venous system and demonstrated 
improvement in venous ulcer healing with saphenous vein stripping, even without compression 
bandaging.10 
The association of incompetent perforators and venous ulcers is well-known. In the 1990s and 
mid-2000s, sub-fascial endoscopic perforator vein surgery (SEPS) was widely used for the 
treatment of perforator reflux.11 However, minimally invasive thermal ablations and ultrasound 
guided sclerotherapy have made SEPS obsolete in the western hemisphere. The North 
                                               
1 Abbade LP, Lastoria S. Venous ulcer: epidemiology, physiopathology, diagnosis and treatment. International journal of 
dermatology. 2005;44(6):449-56. 
2 Phillips T, Stanton B, Provan A, Lew R. A study of the impact of leg ulcers on quality of life: financial, social, and psychologic 
implications. J Am Acad Dermatol. 1994;31(1):49-53. 
3 Graham ID, Harrison MB, Nelson EA, Lorimer K, Fisher A. Prevalence of lower-limb ulceration: a systematic review of prevalence 
studies. Adv Skin Wound Care. 2003;16(6):305-16. 
4 Graves N, Zheng H. The prevalence and incidence of chronic wounds: a literature review. 2014. 
5 Margolisa DJ, Bilkerb W, Santannab J. Venous leg ulcer: incidence and prevalence in the elderly. Journal of the American 
Academy of Dermatology. 2002;46(3):381-6. 
6 Rice JB, Desai U, Cummings AKG, Birnbaum HG, Skornicki M, Parsons N. Burden of venous leg ulcers in the United States. 
Journal of medical economics. 2014;17(5):347-56. 
7 Barwell JR, Davies CE, Deacon J, Harvey K, Minor J, Sassano A, et al. Comparison of surgery and compression with compression 
alone in chronic venous ulceration (ESCHAR study): randomised controlled trial. Lancet. 2004;363(9424):1854-9. 
8 Gohel MS, Barwell JR, Taylor M, Chant T, Foy C, Earnshaw JJ, et al. Long term results of compression therapy alone versus 
compression plus surgery in chronic venous ulceration (ESCHAR): randomised controlled trial. Bmj. 2007;335(7610):83. 
9 Barwell JR, Taylor M, Deacon J, Ghauri AS, Wakely C, Phillips LK, et al. Surgical correction of isolated superficial venous reflux 
reduces long-term recurrence rate in chronic venous leg ulcers. Eur J Vasc Endovasc Surg. 2000;20(4):363-8. 
10 Scriven J, Hartshorne T, Thrush A, Bell P, Naylor A, London N. Role of saphenous vein surgery in the treatment of venous 
ulceration. British journal of surgery. 1998;85(6):781-4. 
11 Gloviczki P, Comerota AJ, Dalsing MC, Eklof BG, Gillespie DL, Gloviczki ML, 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. Journal of vascular surgery. 2011;53(5 Suppl):2S-48S. 

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American SEPS registry (17 U.S. centers, 155 limbs, 85% with class C5 and C6 disease) 
included SEPS procedure along saphenous vein ablation in severe venous disease. Ulcer 
healing at one year was 88%, with the median time to ulcer healing of 54 days.12 Other studies 
demonstrated similar results.13,14,15 A systematic review of one randomized-controlled trial (RCT) 
and 19 case series’ reported results of the SEPS procedure performed with or without 
superficial ablation on 1140 limbs. Ulcer healing was noted in 88% of limbs with a recurrence 
rate of 13%, at a mean time of 21 months.16 Although minimally invasive percutaneous ablation 
of perforators has replaced SEPS in the management of perforator reflux, most studies 
unfortunately reported occlusion rates of the perforators as opposed to ulcer healing.17 
Ultrasound-guided sclerotherapy is the least invasive of the available treatments for perforating 
reflux. Ultrasound-guided injection of morrhuate sodium in 80 limbs with perforator 
incompetence was shown to result in significant improvement in VCSS, and rapid healing in 
86.5% of the VLUs, with a mean time to heal of 36 days. The ulcer recurrence rate was 32% at 
a mean of 20 months, despite poor compliance (15%) with compression therapy 
recommendations.18 Rojas et al compared ultrasound-guided polidocanol foam with 
compression therapy. One group received conservative treatment (37 patients) with layered 
compression therapy and the other group received ultrasound-guided polidocanol foam (33 
patients). In a follow-up period of 21 weeks, 72.8% of all ulcers closed. There was a statistically 
significant higher healing rate of 84.8% in polidocanol group compared to 62.1% in the 
compression therapy group.19 
Harlander-Locke et. al. evaluated the impact of radiofrequency ablation of incompetent GSV, 
small saphenous vein (SSV) and posterior tibial perforator vein on the healing rates of venous 
leg ulcers. One-hundred forty radiofrequency ablations were performed on 110 venous ulcers in 
88 limbs (74 on superficial veins and 66 on perforator veins). The mean ulcer duration prior to 
ablation was 71 months. After at least 6 months follow-up, 76 of 110 ulcers (69 %) had healed. 
The mean time-to-healing was 142 days (± 14 days). The healing rate improved from 1.0 
cm2/month (standard error 0.1 cm2/month) prior to ablation to -4.4 cm2/month (standard error 0.1 
cm2/month; p < 0.05) after ablation. Six of the healed ulcers (7.1%) recurred within 1 year.20 
O’Hare et.al. attempted to assess the value of adding foam sclerotherapy to four layer bandage 
system in speeding venous ulcer healing. This trial failed to recruit sufficient patients for formal 
comparison. However, at 12 weeks, 13/21 (62%) in the control group and 12/13 (92%) who had 
additional foam sclerotherapy healed. At 24 weeks, healing rates were 17/ 20 (85%, 1 died) in 
                                               
12 Kalra M, Gloviczki P, Noel AA, Rooke TW, Lewis BD, Jenkins GD, et al. Subfascial endoscopic perforator vein surgery in patients 
with post-thrombotic venous insufficiency--is it justified? Vascular and endovascular surgery. 2002;36(1):41-50. 
13 Bianchi C, Ballard JL, Abou-Zamzam AM, Teruya TH. Subfascial endoscopic perforator vein surgery combined with saphenous 
vein ablation: results and critical analysis. Journal of vascular surgery. 2003;38(1):67-71. 
14 Rabe E, Pannier-Fischer F, Bromen K, Schuldt K, Stang A, Poncar C, et al. Bonner Venenstudie der Deutschen Gesellschaft für 
Phlebologie. Phlebologie. 2003;32(1):1-14. 
15 Tawes RL, Barron ML, Coello AA, Joyce DH, Kolvenbach R. Optimal therapy for advanced chronic venous insufficiency. Journal 
of vascular surgery. 2003;37(3):545-51. 
16 Tenbrook JA, Jr., Iafrati MD, O'Donnell T F, Jr., Wolf MP, Hoffman SN, Pauker SG, et al. Systematic review of outcomes after 
surgical management of venous disease incorporating subfascial endoscopic perforator surgery. Journal of vascular surgery. 
2004;39(3):583-9. 
17 O'Donnell T. The role of perforators in chronic venous insufficiency. Phlebology / Venous Forum of the Royal Society of Medicine. 
2010;25(1):3-10. 
18 Masuda EM, Kessler DM, Lurie F, Puggioni A, Kistner RL, Eklof B. The effect of ultrasound-guided sclerotherapy of incompetent 
perforator veins on venous clinical severity and disability scores. Journal of vascular surgery. 2006;43(3):551-7. 
19 Rojas JCM, Lozano JAS, Sánchez NE, Mijangos F, Ferreira JLG, Moreno CR. Tratamiento conservador versus escleroterapia 
segmentaria de vena safena y de venas perforantes guiada por ultrasonido para el manejo de la úlcera venosa crónica. 
ANGIOLOGIA. 2009;37(2). 
20 Harlander-Locke M, Lawrence PF, Alktaifi A, Jimenez JC, Rigberg D, DeRubertis B. The impact of ablation of incompetent 
superficial and perforator veins on ulcer healing rates. Vasc Surg 2012;55:458-64. 

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the control group and 12/13 (92%) who received foam sclerotherapy. There were no significant 
thrombotic complications of deep vein thrombosis (DVT) or pulmonary embolism (PE) in either 
group. This study suggests that addition of early foam sclerotherapy to compression bandaging 
may be safe and effective in occlusion of the saphenous vein.21 
4.2 Varithena® Product Description 
Varithena® (polidocanol injectable foam) 1% is a low-nitrogen, microfoam with uniform density, 
size, and stability, dispensed from a proprietary canister device. It is formulated with a gas 
mixture (carbon dioxide/oxygen) designed to maintain physical foam characteristics while 
allowing rapid bubble absorption following injection. The foam remains coherent, displacing the 
blood in the vein and efficiently delivering the sclerosant to the venous endothelium. It is 
echogenic and therefore can be directed to the intended segments of incompetent vein using 
duplex ultrasound. The net effect is that with a small total dose of active sclerosant, a large vein 
can be emptied of blood. The sclerosant, neither diluted nor de-activated, acts on the 
endothelium and in combination with adequate post-treatment compression can successfully 
sclerose large veins. 
Varithena® is indicated for the treatment of incompetent great saphenous veins, accessory 
saphenous veins and visible varicosities of the GSV system above and below the knee. 
Varithena® improves the symptoms of superficial venous incompetence and the appearance of 
visible varicosities.  
A complete description of Varithena® may be found in the FPI (Appendix C) and IFU (Appendix 
D). 
4.3 Varithena® Clinical Summary 
Varithena® (polidocanol injectable foam) has been evaluated in 12 clinical studies. The two 
pivotal studies supporting approval of Varithena® were randomized, blinded, multicenter clinical 
trials designed to assess the efficacy and safety of Varithena® 0.5%, 1.0% and 2.0% (VANISH-
1) and Varithena® 0.5% and 1.0% (VANISH-2) compared with placebo in the treatment of both 
symptoms and appearance of varicose veins in patients with saphenofemoral junction (SFJ) 
incompetence as evidenced by reflux of the GSV or major accessory veins. In both studies, a 
Varithena® 0.125% treatment group was included as a control for blinding of the duplex 
ultrasound assessment. Patients with a history of deep vein thrombosis or pulmonary embolism, 
inability to comply with post-treatment compression due to severe peripheral arterial disease or 
leg obesity, incompetence of the small saphenous vein or deep venous reflux as a major source 
of reflux, reduced mobility, major surgery, pregnancy, or prolonged hospitalization within three 
months were excluded. In these clinical trials, the maximum volume of injectable foam or 
placebo to be administered per treatment session was 15mL. 
In VANISH-1, patients received one blinded treatment and in VANISH-2, patients received one 
blinded treatment with an option for a second blinded treatment 1 week later. In VANISH-2, 
patients in the Varithena® 1.0% treatment group received an average of 1.4 blinded treatments. 
All patients received post-procedure compression therapy for 14 days following treatment. 
Of the 519 patients randomized into VANISH-1 and VANISH-2, a total of 511 were treated with 
either Varithena® 0.5% (n=111), 1.0% (n=110), or 2.0% (n=63), Varithena® 0.125% as control 
(n=114), or placebo (n=113).  
                                               
21 O’Hare JL, Earnshaw JJ. Randomised clinical trial of foam sclerotherapy for patients with a venous leg ulcer. Eur J Vasc 
Endovasc Surg (2010) 39, 495e499. 

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For both VANISH-1 and VANISH-2, treatment with 1.0% was superior to placebo in improving 
symptoms as measured by VVSymQ® (Varicose Vein Symptom Questionnaire), when either a 
duration or an intensity scale was used to measure patients’ symptoms. 
VCSS is a clinician rating of severity of chronic venous insufficiency ranging from 0 to 30, where 
higher scores indicate more severe venous disease. In VANISH-1 and VANISH-2, the adjusted 
mean changes from baseline in VCSS in the 1% Varithena® treatment groups were 3.70 and 
5.05, respectively, at Week 8 compared with 0.75 and 1.52 points in the placebo groups, 
respectively. For both studies, the differences between these improvements were statistically 
significant (P<0.0001). 
The physiological response to treatment as measured by duplex ultrasound (duplex response) 
was defined as elimination of reflux through the SFJ and/or complete occlusion of all 
incompetent GSV and major accessory veins at baseline. The primary comparison for duplex 
response in both studies was the pooled Varithena® groups vs. the Varithena® 0.125% (control) 
group. For both studies, the pooled Varithena® groups were statistically superior to the 0.125% 
(control) group. In VANISH-1 and VANISH-2, in the pooled groups, 75% and 85% of patients 
respectively, compared with 42% of patients and 60% of patients, respectively, in the 0.125% 
(control) groups, met the criteria for response to treatment. These differences were statistically 
significant (P≤0.0002).  
VEINES-QOL (Venous Insufficiency Epidemiological and Economic Study Quality of Life) is a 
disease-specific quality of life instrument, ranging from 0 (worst possible quality of life) to 100 
(best possible quality of life). In VANISH-1 and VANISH-2, the adjusted mean changes from 
baseline in VEINES-QOL in the pooled Varithena® treatment groups were 21.2 and 21.6, 
respectively, at Week 8 compared with 7.7 and 7.4 points in the placebo groups, respectively. 
For both studies, the differences between these improvements are statistically significant 
(P<0.0001). 
For efficacy endpoints, Varithena® treatment effects were consistent across subgroups of age, 
sex, BMI (up to 48 kg/m2), CEAP clinical class, GSV diameter (up to 25.9 mm) and VCSS. 
A total of 1333 patients in 12 clinical trials were evaluated for safety when treated with 
Varithena® at dose concentrations of 0.125%, 0.5%, 1.0% or 2.0%, including 437 patients 
treated with Varithena® in placebo-controlled clinical trials. 
The AEs most commonly observed in the clinical studies of Varithena® are manageable events 
that would be expected in patients undergoing a minimally-invasive medical procedure for the 
treatment of GSV incompetence. These include infusion site thrombosis (retained coagulum), 
injection site hematoma, contusion, pain in extremity, limb discomfort, and superficial 
thrombophlebitis. Post-procedural pain resolved within 1 week in 80% of the cases reported, 
and very few Varithena®-treated patients were treated with opioid analgesics within 10 days of 
the study treatment procedure. 
In the 1333 patients treated with Varithena® in the clinical studies, there were no anaphylaxis or 
major hypersensitivity reactions, no deaths or non-fatal SAEs attributed to the study treatment, 
and only a small number of patients with severe AEs or withdrawals due to AE. The following 
venous thrombus AEs occurred: common femoral vein thrombus extension (2.9%), proximal 
DVT (1.7%), distal DVT (1.1%), isolated gastrocnemius and soleal vein thrombosis (1.4%). 
Proximal symptomatic venous thrombi occurred in <1% of patients treated with Varithena®. 
Approximately half (49%) of patients with thrombi received treatment with anticoagulants. 
Neurologic adverse events (e.g., cerebrovascular accident, migraines) have been reported in 
patients following administration of physician-compounded foam sclerosants. None of the 1333 
patients in the Varithena® trials experienced clinically important neurological or visual adverse 

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events suggestive of cerebral gas embolism. The incidence of neurologic and visual adverse 
events within one day of treatment in the placebo-controlled studies was 2.7% in the pooled 
Varithena® group and 4.0% in the placebo groups.  
Skin discoloration adverse events were reported in 1.1% of the pooled Varithena® group and 
0.7% of the placebo group in the placebo-controlled studies. 
The VANISH-2 trial (22) compared 0.5% and 1% Varithena® concentration to placebo in 232 
patients (placebo n=57; 0.125% control n=57; 0.5% Varithena® n=60; 1% Varithena® n=58). 
94.8% of the patients enrolled were in the Clinical, Etiological, Anatomical, and 
Pathophysiological (CEAP) clinical class C2 through C4 [C2 (varicose veins) 31.9%; C3 
(edema) 40.1%; C4 (skin changes) 22.8%], while C5 (healed venous ulcer) and C6 (active 
venous ulcer) class accounted only to 5.2%. The primary and secondary endpoints included 
improvement in the varicose vein related symptoms and appearance. These parameters were 
tested with 3 newly validated clinical outcome assessments and patient reported outcome 
measures; the Varicose Vein Symptoms Questionnaire (VVSymQ), a patient self-assessment 
score of 5 most important symptoms of varicose veins; the Patient Self-Assessment of Visible 
Varicose Veins (PA-V3); and, the Independent Photography Review of Visible Varicose Veins 
(IPR-V3) by experts in venous disease. At 8 weeks, Varithena® in concentrations of 0.5% and 
1% demonstrated statistically significant superior results when compared to placebo with larger 
improvements of symptoms and greater improvements in physician and patient assessments of 
the appearance as compared to placebo. 60% of the Varithena® patients demonstrated at least 
one adverse event compared with 39% of placebo. However, 95% of these were mild or 
moderate. No pulmonary emboli were detected and no clinically significant neurologic or visual 
adverse events were reported. The most common adverse events with Varithena® were 
retained coagulum, limb pain, and superficial thrombophlebitis most of which resolved at end of 
study. Of the 232 patients that were treated at baseline visit, 230 patients completed the eighth 
week follow-up visit. These 230 patients then entered the one-year extension study. Of these, 
87.9% received additional open label Varithena®, within 2 to 3 weeks after the 8-week follow-up 
visit. These results were reported in a subsequent study (23). At 1 year, there was improvement 
in symptoms as measured by reductions in mean VVSymQ score, IPR-V3 and PA-V3. There 
were also reductions in disease severity, as measured by the Venous Clinical Severity Score 
(VCSS) and quality of life measures. There were no new venous thrombotic events. There were 
no clinically important long term adverse sequelae in patients who had thrombophlebitis at the 
8-week visit, including recurrence of thrombosis or evidence of post-thrombotic syndrome at 1 
year. The proportion of patients with a duplex ultrasound response was 89% at 8 weeks and 
73% at 1 year. 
In a separate study (VANISH-1),   Varithena® was tested in patients with patients with moderate 
to severe symptoms of superficial venous incompetence and visible varicosities of the GSV 
system (24). 279 were randomized to either placebo (n=56), 0.125% Varithena® (n=57), 0.5% 
Varithena® (n=51), 1% Varithena® (n=52), or 2% Varithena® (n=63). The primary endpoint was 
similar to the VANISH-2 trial. Patient-reported venous symptom improvement was measured as 
a change from baseline to week 8 in the VVSymQ score. Secondary endpoints included 
appearance measures tested with IPR-V3 and PA-V3 scores. Tertiary endpoints measured 
included duplex ultrasound response, changes in VCSS, and the modified Venous Insufficiency 
Epidemiological and Economic Study. At week 8, VVSymQ scores for the pooled Varithena® 
group (0.5% + 1% + 2%; p < 0.0001) and individual dose concentrations (p < 0.001) were 
significantly superior to placebo. Mean changes from baseline to week 8 in IPR- V3 and PA-V3 
scores were also significantly greater for pooled Varithena® than for placebo (p < 0.0001). The 
tertiary end point of duplex ultrasound response was defined as the elimination of sapheno-
femoral junction (SFJ) reflux and/or complete occlusion of the incompetent GSV and/or major 

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saphenous accessory vein. This Duplex ultrasound response rates for patients treated with 
Varithena® 0.5%, 1%, and 2% foam (pooled and individually) ranged from 59% to 83%. There 
were no pulmonary emboli noted. No patient discontinued the study due to an adverse event. 15 
patients (5.5%) had a common femoral vein thrombus extension. 5 patients had proximal DVTs 
(popliteal vein or above), 4 had distal DVTs, and 3 had isolated gastrocnemius and soleal DVTs. 
The total of 27 patients with DVTs accounted for a DVT rate of 9.8% with this technique. In 
summary,   Varithena® has been studied in more than 1300 patients and has demonstrated 
consistent improvement in patient-reported clinical outcomes and in clinical appearance. 
Varithena® has a distinct advantage over other non-thermal techniques in the treatment of 
patients with severe venous disease, as the foam can reach the veins under the diseased and 
lipodermatosclerotic skin as well as the feeder veins in close proximity to the venous ulcers, 
without any concern for nerve injury. Neovascularized veins, tortuous veins, and post-thrombotic 
(scarred) veins are extremely difficult to navigate with thermal technologies and other non-
thermal technologies. Varithena® is again advantageous in these settings as foam can traverse 
through these areas.  
Varithena® treatment has been shown to result in both hemodynamic and symptomatic benefit 
for patients. The Varithena® studies have had equivalent pooled benefit to alternative therapies 
(surgery and sclerotherapy) so it can be anticipated that, as with other studies, there will be 
improved ulcer healing following Varithena® treatment. Varithena® can uniquely extend therapy 
to the most distal varicose tributaries, close or even under the ulcer bed. It is possible the 
treatment may confer greater advantage, as it did with a few C5 and C6 patients. It is therefore 
appropriate to investigate the benefit Varithena® may provide in accelerating ulcer healing and 
reduction of ulcer recurrence. Given the paucity of treatment availability for this patient 
population, there is great value in better understanding the effects of Varithena® on healing, 
recurrence rates and quality of life for patients with venous insufficiency resulting in VLUs. This 
registry is designed to provide insights into treating this difficult indication.  
5. 
REGISTRY OBJECTIVE AND PURPOSE 
5.1 Objective(s) 
The purpose of this registry is to observe the effects of Varithena® on VLU healing in patients 
who have the symptoms of chronic venous insufficiency. The objective of the registry is to 
evaluate VLU healing rate, recurrence rate, and patient reported outcomes for Varithena® in C6 
disease per Clinical Etiologic Anatomic Pathophysiologic (CEAP) classification 
5.2 Design 
This 12 month, multicenter, open-label registry is designed to collect treatment and outcome 
data related to subjects treated with Varithena® for GSV system and/or AASV incompetence 
resulting in VLU. Subjects are treated per Investigator’s SoC and in accordance with the FPI 
and IFU. For subjects with healed ulcers during the 12 month follow-up period, VLU recurrence 
information is collected. Wound recurrence is defined as the reopening of a wound that was 
previously closed; recurrence must occur at same location.  
Note: In cases of cluster wounds, Investigator collects data for a single, primary wound. If more 
than one wound meets eligibility criteria, Investigator determines which wound to evaluate as 
the primary. All endpoint measurements are collected for the primary wound. 
 
 

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For each subject, participation in the registry lasts approximately 12 months. Subjects are seen 
at the investigational site for initial treatment, about one week after treatment for initial follow-up 
visit (and retreatment if necessary), 12 weeks (±1wk) and 12 months (±1wk) after initial 
treatment. Between follow-up visits, and until wound closure, subjects are asked to collect 
weekly photographs of the wound via the sDCT during dressing changes at the wound care 
center (WCC).  
Additionally, follow-up phone calls are placed at 3 months (±1wk) post-closure and 6 months (±1 
week) post-treatment. At that time, subjects are asked to take a picture of the wound area and 
complete the NPRS using the sDCT. (Figure 1) 
 
Figure 1. Study Schematic 
 
5.3 Primary Endpoint(s) 
 
Rate of epithelial migration (mm/week) measured by wound perimeter on photograph 
taken using the DCT and submitted to Tissue Analytics® for analysis 
 
Wound closure at 12 weeks (±1wk) post-treatment 
 
Time from initial treatment with Varithena® to wound closure 
 
 

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5.4 Secondary Endpoint(s) 
 
Percent of wounds remaining closed at 3 months (±1wk) post-wound closure date, 
determined via photograph assessed by Tissue Analytics®; non-healed wounds are not 
included in percent calculation  
 
For healed wounds, rate of VLU recurrence collected via phone calls and subject-
collected photographs at 6 months (±1wk) and 12 months (±1wk) post-treatment  
 
Change in pain on NPRS compared to baseline at 12 weeks (±1wk), 6 months (±1wk), 
12 months (±1wk) post-treatment 
 
Change on EQ-5D-5L quality of life assessment compared to baseline at 12 weeks 
(±1wk) and 12 months (±1wk) post-treatment 
 
Change in VCSS from Baseline to 12 week (±1wk) and 12 month (±1wk) follow-up 
 
Number of ulcer free weeks defined as weeks from time of closure (complete 
epithelialization is recorded) to date of recurrence or last contact if no recurrence (at 
study completion or withdrawal)  
6. 
SUBJECT SELECTION  
6.1 Registry Population 
This registry is designed to collect data related to treatment with Varithena® in patients 
experiencing symptoms of chronic venous insufficiency of the GSV or AASV system who are 
classified C6 on the CEAP with active VLU. 
Data is collected for up to 200 subjects selected by their physician to receive Varithena®. 
Enrollment is to occur at up to 40 investigational sites in the United States and Canada. 
6.2 Subject Selection 
6.2.1 Inclusion Criteria 
Subjects must meet all of the following inclusion criteria: 
1 Men and women; age ≥18  
2 Investigator has selected Varithena® to treat patients classified C6 with chronic (≥ 3 
months) VLU resulting from GSV and/or AASV incompetence 
3 Wound can be visualized in one plane to allow for image collection of the entire wound in 
one photograph, or if wound is circumferential, subject must be able to capture the entire 
wound using multiple photographs taken from directly above the wound (straight on)  
4 Reflux >500ms on duplex ultrasound 
5 Willing and able to collect wound photographs and data using an application downloaded 
on a tablet 
6 Willing and able to return for scheduled follow-up and wound care visits 
7 Ability to comprehend and sign ICF and complete questionnaires 
 
 

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6.2.2 Exclusion Criteria 
Subjects must not meet any of the following exclusion criteria: 
8 Contraindications to Varithena® in accordance with the FPI 
9 Any serious concomitant disease, per physician’s discretion, that confounds wound 
healing, including malignant changes of wound  
10 Concomitant heat ablation, or heat ablation of index leg within 6 weeks prior to treatment 
with Varithena®  
11 Significant arterial disease or ABPI ≤ 0.8 
12 In the opinion of Investigator, wound would close within 12 weeks without additional 
treatment 
6.3 Subject Completion 
A subject is considered to have successfully finished the registry upon completion of the 12 
month follow-up phone call.  
6.4 Withdrawal 
For cases in which the subject does not complete all assessments and follow-up visits, the 
subjects are classified as follows: 
 
Investigator withdrawal – Investigator can withdraw a subject from the registry for a 
safety concern, non-compliance, or for any other concern warranting withdrawal of the 
subject in the judgment of Investigator. Reason for Investigator withdrawal of a subject 
and last date of contact for the registry are documented on the Completion Log.  
 
Subject withdrawal – Subjects may withdraw from participation at any time during the 
registry. All data collected prior to withdrawal shall remain part of the registry data. 
Reasonable effort should be made to encourage the subject to remain in the registry. If 
the subject declines, determine and document the reason for withdrawal on the 
Completion Log.  
 
Lost to follow-up – A subject is considered lost to follow-up if there have been at least 
three documented attempts to contact the subject for follow-up without success. Last 
date of contact is documented on the Completion Log. 
7. 
TREATMENT OF SUBJECTS 
7.1 Varithena® (polidocanol injectable foam) 1% 
Treatment with Varithena® is selected and administered per SoC and the FPI. Varithena® is 
commercially available. As such, investigational product (IP) accountability and tracking is not 
necessary.  
7.1.1 Dosage & Administration 
Subject is treated on Day 0 with up to 15mL of Varithena®, above and below the knee as 
needed, per Investigator’s clinical judgement and the FPI. Each injection should not exceed 
5mL. Date of treatment, number of injection sites, and volume above and below the knee is 
recorded in the iDCT. Appendix E: Use of Varithena® to manage patients with GSV-derived 
venous hypertension and chronic venous leg ulcer is provided as a guide to best practices in 
treating this indication. 

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7.1.2 Additional Treatment 
Additional treatment(s) of Varithena® can be administered at Investigator’s discretion and 
according to FPI. Note that additional treatment should not be administered sooner than 5 days 
after previous treatment. Date of additional treatment, number of injection sites, and volume 
above and below the knee is recorded in the iDCT.  
7.1.3 Post-treatment Management 
Following treatment with Varithena®, subjects should be treated with compression dressing per 
Investigator’s SoC. Subjects are referred to a local WCC. The WCC does not need to be 
affiliated with the investigational site. Subjects’ compression dressing is checked and changed 
at the WCC. Subjects are asked to continue to visit the WCC weekly for continuing care until the 
wound is healed. At each WCC when the wound area is exposed, the patient should make 
every effort to take a photograph of the wound, or the wound area if the wound has healed, 
using the sDCT. The pain rating should also be recorded in the sDCT by response to the NPRS. 
The staff at the WCC are not delegated under the investigational site, so the subject should 
understand that they are responsible for collecting the photograph and answering the NPRS 
question independently. 
 
If the wound is not healed at the 12 Week Follow-up visit, the subject continues to visit the WCC 
for continuing care until wound closure, collecting a wound photograph and answering the 
NPRS question at each appointment.  
7.1.4 Duration of Treatment and Follow-up 
Following the initial treatment with Varithena®, each subject is followed for 12 months. Additional 
treatment can be administered following the initial treatment; however, it is recommended that 
re-treatment occur as close to the time of the initial treatment as is possible, but not sooner than 
5 days, according to FPI and IFU. Date of re-treatment, number of injection sites, and volume 
above and below the knee is recorded in the iDCT. 
During the follow-up period, subjects are followed for VLU-related hospitalizations, wound 
recurrence, and other clinical outcomes. Subjects are assessed at the investigational site at 
Week 1 Follow-up visit (about one week after treatment), 12 weeks (±1wk) post-treatmentand 
12 months (±1wk) post-treatment. Subjects are contacted by telephone for follow-up 3 months 
(±1wk) post wound-closure, and 6 months (±1wk) post-treatment. Subjects collect wound 
photographs between follow-up visits when the wound dressing is being changed at the WCC.    
7.1.5 Concomitant Therapies or Interventions  
Subjects should not be enrolled in the registry if they were treated for venous insufficiency in the 
index leg with heat ablation above the knee within the 6 week period prior to enrollment. 
Treatment with heat ablation could confound the outcome of treatment with Varithena®. For 
subjects who have had recent heat ablation treatment (greater than 6 weeks but less than 6 
months), it should be clear to Investigator that ulcer is not healing or would not heal were 
subject not to receive additional treatment. 
It is suggested that heat ablation not be used after treatment until the primary endpoint data 
have been collected at Week 12 Follow-up visit. This allows for assessment of the effects of 
Varithena® without heat ablation as a confounding factor.  
 
 

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8. 
MEASUREMENTS AND EVALUATIONS 
8.1 Time and Event Schedule 
8.1.1 Screening/Baseline Visit (can occur up to 14 days prior to treatment) (Clinic) 
The screening phase begins when the ICF is fully signed and dated and ends at the initiation of 
initial treatment with Varithena® (Day 0).  
The following evaluations are performed at Screening/Baseline: 
 
Review and signing of the ICF 
 
Review and confirmation of eligibility to participate in the registry 
 
Collection of demographic information, wound history (including prior treatments), and 
physical examination to assess venous and wound characteristics 
 
Collection of photograph (photographs if wound is circumferential) in iDCT 
8.1.2 Enrollment/Treatment Visit (Day 0) (Clinic) 
Screening/Baseline and Enrollment/Treatment visit measurements and evaluations may occur 
at the same visit if subject is provided adequate time to consider and have all questions 
answered.  
The following are performed at this visit: 
 
Collection of data prior to treatment: 
- 
Photograph(s) of wound in iDCT 
- 
VCSS 
- 
NPRS 
- 
EQ-5D-5L quality of life assessment 
 
Varithena® Treatment – treatment procedure and collection of treatment details 
8.1.3 Week 1 Visit (1st Follow-up Visit Per SoC) (Clinic) 
This visit is not required to occur within first week after initial treatment but should be the first 
follow-up visit per SoC. If retreatment is expected, this visit should occur no sooner than 5 days 
after initial treatment. Date of visit is documented in the iDCT.  
The following are performed at the Week 1 visit: 
 
Subject is trained to use sDCT 
- 
Subject collects photograph(s) of wound using sDCT (additional training required 
for circumferential wounds) 
- 
Subject enters NPRS response into sDCT 
 
Assessment of medical compression therapy compliance 
 
Documentation of re-treatment details, if applicable 
 
 

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8.1.4 Week 2 through Wound Closure (at WCC) 
The subject does not return to the investigational site at this time. The subject presents to a 
WCC for wound care and dressing changes on about a weekly basis. During each visit to the 
WCC, subject is asked to take a photograph (multiple photographs for circumferential wounds) 
of the wound and answer the NPRS question using the sDCT. It is important that the subject 
understands that the WCC staff may not be aware of the registry, so collection of the 
photograph(s) and answering the NPRS question should be completed independently. The 
subject should refer questions about the sDCT and data collection to the investigational site, or 
contact Tissue Analytics® for technical support.  
If the wound is not healed at the Week 12 Follow-up visit, subject continues to collect 
photograph(s) and answer NPRS questions at weekly WCC visits until wound closure.  
8.1.5 Week 12 Visit (±1wk) (Clinic) 
The following are performed and entered into the iDCT at this visit: 
 
Collection of wound photograph(s) or photograph of wound area if wound is healed 
 
VCSS 
 
NPRS 
 
EQ-5D-5L quality of life assessment 
 
Assessment of medical compression therapy compliance 
8.1.6 3 Months (±1wk) Post-Wound-Closure (Telephone) 
Once the subject’s wound is determined to be healed, Tissue Analytics® schedules a reminder 
for Investigator or delegate to contact the subject by phone at 3 months (±1 week) to perform 
the following: 
 
Assessment for VLU recurrence 
 
Assessment of medical compression therapy compliance 
 
Request that subject collects the following using the sDCT: 
- 
Photograph of wound area, or wound if reccurred 
- 
NPRS 
8.1.7 6 Months (±1wk) Post-Treatment (Telephone) 
Investigator or delegate contacts the subject by phone to perform the following:  
 
Assessment for VLU recurrence 
 
Assessment of medical compression therapy compliance 
 
Request that subject collects the following using the sDCT: 
- 
Photograph of wound area, or wound if reccurred 
- 
NPRS 
 
EQ-5D-5L quality of life assessment (only collected at 12 Months) 
 
 

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8.1.8 Month 12 Visit (±1wk) Post-Treatment (Clinic) 
The following are performed and entered into the iDCT at this visit: 
 
Assessment for VLU recurrence 
 
Collection of photograph of wound area, or wound if recurred 
 
VCSS 
 
NPRS 
 
EQ-5D-5L quality of life assessment 
 
Assessment of medical compression therapy compliance 
8.2 Evaluations and Procedures 
Evaluations and procedures performed to establish eligibility and baseline may be performed 
within the 14 days prior to treatment, inclusive of day of treatment, provided subject has 
adequate time to consider and have all questions answered before treatment is initiated. 
8.2.1 Informed Consent Process 
Patients with the potential to meet eligibility criteria may be offered the opportunity to be 
evaluated for participation in this registry. All such patients must sign an ICF approved by the 
relevant Institutional Review Board (IRB) or Research Ethics Board (REB) before any trial-
related evaluations can be performed. 
Investigator or qualified delegate reviews the treatment plans with the patient and the patient 
has an opportunity to ask questions about trial procedures, the follow-up schedule, risks and 
benefits of the treatment and alternative treatment options prior to signature. The patient 
receives a copy of the signed ICF to keep for their records.  
Subjects will be informed of any revisions of the ICF and relevant revisions are signed and kept 
in the subject’s file.  
The consenting process, acquisition of the ICF and any revisions should be documented in the 
subject’s medical record and the ICF should be signed and dated by the individual who 
conducted the informed consent discussion. 
8.2.2 Eligibility Review 
A physical evaluation of the wound as well as data regarding venous insufficiency, medical 
history and prior treatment are reviewed against the eligibility criteria to determine eligibility of 
the subject for the registry. Subjects who complete a consent form and are found to be ineligible 
for the registry are recorded on the Screening Log with the exclusionary criteria indicated. 
Subjects who are found to meet all inclusion criteria and no exclusion criteria are entered into 
the iDCT.  
8.2.3 Assignment of Subject Idendification Code (SIC) 
Subjects who meet all inclusion and no exclusion criteria for the registry are assigned an SIC by 
Investigator or delegate. The SIC is used to deidentify subject data and should be used on 
source worksheets and for data entry purposes. The Investigator or delegate maintains an SIC 
list, a confidential list of subjects’ names and associated SICs which allows Investigator to 
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The SIC is formatted as a six digit number: a three digit assigned site code followed by 
consecutive three digit numbers, beginning with 001 (e.g., 321-001). The site code is provided 
to investigational site during site inititation. 
8.2.4 Demographics 
For each subject, date of birth and gender are collected.  
8.2.5 Physical Examination 
All patients undergo a physical examination at screening, in accordance with Investigator’s 
current practice, to include height and weight. 
The venous evaluation includes: 
 
Examination of the external appearance of the leg to be treated 
 
Confirmation of CEAP classification (Appendix A) 
 
Venous duplex ultrasound to review for duplex reflux duration, GSV, AASV, major 
perforator, and SSV incompetence 
The wound examination includes: 
 
Location of index wound 
 
Number of current ulcers 
 
Signs of infection or bioburden 
8.2.6 Wound History and Prior Treatments 
Information is collected regarding wound age at first encounter (defined as time since current 
episode began), total previous episodes of current ulcer and other ulcers, duration of 
compression therapy for current wound, and medical compression therapy compliance. 
The following information is recorded for previous treatments (e.g., heat ablation, grafting) for 
the current ulcer. Treatment should only be listed for the current location of venous insufficiency 
and the resulting current ulcer: 
 
Procedure type 
 
Date (start date in the case of a long term treatment, like compression therapy) 
 
Outcome (i.e. Healed/Non Healed) 
8.2.7 Wound Photographs 
Wound photographs for the registry are collected via the iDCT and sDCT. Photographs are 
analyzed for wound characteristics by Tissue Analytics®. Wound photographs are collected by 
Investigator or delegate at Baseline/Screening, Day 0 before treatment and Week 12 Follow-up 
visit using iDCT. Wound photographs are collected by subject via sDCT at Week 1 Follow-up 
visit, weekly during dressing changes at the WCC and at the 3, 6 and 12 month follow-up 
assessment time points. All photographs for a given subject are linked back to Investigator data 
using the SIC and are accessible by Investigator or delegate within the iDCT. 
Investigator or delegate provides Tissue Analytics® sDCT training module to subject during 
Week 1 Follow-up visit and ensures subject can use sDCT. The photograph(s) collected at this 
visit should be collected by subject using the sDCT.  
 
 

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If the wound is circumferential, wound can be captured using two or more photographs. The 
subject should be able to view and photograph the entire wound using multiple photographs. 
The photographs should be taken from directly above and perpendicular to the wound (straight 
on). As this may be difficult for wounds that reach the back of the leg, it should be confirmed at 
screening that the subject is able.    
8.2.8 Varithena® Treatment Record 
The following data is recorded in the iDCT for the initial treatment with Varithena® and any touch 
up treatment: 
 
Treatment date 
 
Volume injected above the knee 
 
Volume injected below the knee 
 
Total number of injection sites (for specified treatment date) 
8.2.9 Numeric Pain Rating Scale 
An 11-point NPRS is used to assess subject’s level of pain. Subject is asked “What was your 
pain level at the ulcer location over the last 24 hours?” and selects a score between 0 and 10, 
with 0 meaning no pain and 10 meaning the worst pain. Investigator or delegate assesses and 
records this directly into the iDCT. The subject answers this question in the sDCT at Week 1 
Follow-up visit, at each weekly WCC visit during dressing changes and at 3 months post wound 
closure, and 6 and 12 month follow-up assessment time points (phone contacts). 
8.2.10 Venous Clinical Severity Score (Revised) 
The VCSS assesses nine common signs/symptoms of venous disease: skin changes and 
pigmentation, inflammation and induration, and ulcers (including number, size, and duration). A 
tenth item assesses compression compliance. Each item is scored individually on a 0-3 point 
scale. The revised VCSS clarifies ambiguities in category descriptions and contains an 
additional category for compression. Investigator or delegate should complete assessment on 
source worksheet (SW) and enter data into iDCT.  
8.2.11 EQ-5D-5L Quality of Life Assessment 
The EQ-5D-5L is a validated, widely used quality of life assessment. It is a patient reported 
outcome that provides a simple descriptive profile and single index value for health status. The 
questionnaire consists of 5 questions pertaining to specific health dimensions, including 
mobility, self-care, usual activities, pain/discomfort, anxiety/depression, and overall health status 
rating scale. Subjects should complete questionnaire on SW and data is entered into iDCT.  
 
 

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9. 
ADVERSE EVENTS 
9.1 Definitions 
Adverse Event (AE)  any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with the treatment22  
An undesirable event can be, but is not limited to, symptoms experienced by a subject or 
objective findings, such as significant clinical laboratory abnormalities. 
Serious Adverse Event (SAE)  any untoward medical occurrence that at any dose: 
 
results in death, 
 
is life-threatening (Note: The term “life-threatening” refers to an event in which the 
patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe), 
 
requires inpatient hospitalization or prolongation of existing hospitalization, 
 
results in persistent or significant disability/incapacity, 
 
is a congenital anomaly/birth defect, 
 
is an important medical event that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention to 
prevent one of the other outcomes listed above22 
Adverse Drug Reaction (ADR)  a response to a drug which is noxious and unintended and 
which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease or 
for modification of physiological function.22 
Unexpected Adverse Event an AE for which the nature or severity is not consistent with 
information in the relevant source document(s).22 
9.2 Reporting Adverse Events 
AEs can occur from the time of initiation of treatment until the subject completes the registry or 
withdraws. If Investigator or delegate becomes aware of an AE and wishes to report it to the 
Sponsor/Manufacturer, Investigator or delegate should report the event by sending an Adverse 
Event Form (Apendix H) via email to vigilance@btgplc.com. Questions about AEs or other 
safety-related concerns can also be sent via the same email address.  
In some cases, Sponsor/Manufacturer may need additional information from investigational site 
in order to provide a report to the Food and Drug Administration (FDA) to comply with 
mandatory regulatory reporting. Sponsor will request additional medical information about 
subject as needed.  
If additional safety information becomes available during the course of the registry, Sponsor will 
amend protocol and ICF as necessary.  
 
 
                                               
22 ICH E2A Clinical Safety Data Management: Definitions and Standards for Expedited Reporting. 1994. 

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10. 
STATISTICAL CONSIDERATIONS 
10.1 Statistical Analysis  
The statistical analysis plan (SAP) will be a separate document and will be updated as required, 
in association with any protocol amendments prior to database lock. The SAP will include 
detailed descriptions of statistical methodology. 
Summary statistics for continuous variables will include number of patients, means, medians, 
standard deviations, standard errors, minima and maxima. For categorical variables, 
frequencies and percentages will be given; 95% CI will be calculated using the Clopper-Pearson 
(exact) method for binary proportions. For time to event variables, the number of patients, 
number of events, the median and 95% CI of the median, and quartiles will be provided by the 
Kaplan Meier (KM) method. 
Missing data will not be imputed.  
Baseline is defined as the last available measurement taken before the first treatment. 
10.2 Determination of Sample Size 
No formal statistical hypotheses are being tested and no formal sample size calculation has 
been performed. The aim of the registry is to collect additional data on treatment of a specific 
indication for which Varithena® is approved but has not been examined in detail. Previous 
feasibility metrics indicate approximately 200 subjects can be enrolled within one year. 
10.2.1 Analysis Populations  
The Efficacy Population will include all patients who are treated with Varithena® and who have 
at least one post treatment primary endpoint assessment. 
10.3 Primary Efficacy Analyses  
The three primary endpoints are: 
 
Rate of epithelial migration (mm/week) by perimeter 
 
Wound closure at 12 weeks post-treatment 
 
Time to wound closure 
Summary statistics with 95% CI will be provided for all primary endpoints. The Clopper-Pearson 
method will be used for binary proportions (wound closure at 12 weeks post-treatment). 
Additionally, distribution of time to wound closure will be estimated using the Kaplan Meier (KM) 
method and the 25th percentile, median, and 75th percentile will be presented along with 95% 
CIs.  
The primary endpoint, rate of epithelial migration, will be evaluated for skewness using the 
Kolmogorov Smirnov test. In the event of significant skewness, the interquartile range will be 
reported in addition to the 95% CI. 
 
 

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10.4 Secondary Efficacy Analyses 
The secondary endpoints are: 
 
Wounds remaining closed at 3 months post-wound closure 
 
VLU recurrence (at same site) at 6 months and 12 months post-treatment 
 
Change in pain on NPRS compared to baseline at 12 weeks, 6 months, 12 months post-
treatment 
 
Change on EQ-5D-5L quality of life assessment compared to baseline at 12 weeks and 
12 months post-treatment 
 
Change in VCSS from Baseline to 12 week and 12 month follow-up 
 
Number of ulcer free weeks 
The proportion of wounds remaining closed at 3 months post-wound closure will be presented 
with frequencies and percentages with 95% CIs based on Clopper-Pearson. Similarly, 
recurrence at 6 months and 12 months post-treatment will be presented with frequencies and 
percentages with 95% CIs. 
Change from baseline for pain on the NPRS, the index health state based on EQ-5D-5L and 
VCSS will be presented by summary statistics with 95% CIs.  
Summary statistics for the number of ulcer free weeks will be presented along with the 
distribution of the number of ulcer free weeks (time to recurrence) estimated using the KM 
method and the 25th percentile, median and 75th percentile will be presented along with 95% 
CIs. 
10.5 Additional Efficacy Analyses 
A cox regression model will be presented for the time to wound closure investigating effects of 
subject age, wound age, presence of infection, ambulatory method and total wounds/ulcers of 
any type. The NPRS scale will be grouped into categories by severity (no pain, mild pain, 
moderate pain and severe pain) and presented in a shift table. Similarly, each EQ-5D-5L 
dimension will be summarized by a shift table. The overall visual analogue scale (VAS) and 
change from baseline will be descriptively summarized. 
The Wound Healing Index (WHI)23 is the predicated probability of a specified wound becoming 
healed and is created from multiplying the logistic regression parameter estimates by the values 
of the significant variables for a wound category type. The WHI will be calculated by entering 
eight pre-specified parameters into a portal via the US Would Registry to get a score per 
patient. The eight pre-specified parameters are: 
1) Patient age in years at first treatment 
2) VLU age (duration) in days at first encounter 
3) VLU area in cm2 at first encounter 
4) Signs of infection or bioburden 
5) Wound on lateral leg? 
6) Patient’s primary ambulatory method 
7) Total wounds or ulcers of any type 
8) Encounter ends with patient being sent to emergency department or hospital 
                                               
23 Horn S, Fife C, Smout R, Barrett R, Thomson B. Development of a wound healing index for patients with chronic wounds. Wound 
Rep Reg 2013;21:823-32. 

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The WHI will be used to stratify ulcers into simple, complex and severe categories.  
Additionally, Varithena® outcomes from this study will be compared to historical data from the 
US Wound Registry.  
10.6 Sub-group Analyses 
Sub-group analyses will be performed for the rate of epithelial migration, wound closure at 12 
months post-treatment and time to treatment. The following sub-group analyses will be 
performed: 
 
Ulcer severity (simple, complex, severe) 
 
Wound area (< median, ≥ median)  
 
Largest circle area (< median, ≥ median) 
 
Largest circle perimeter (< median, ≥ median) 
 
An additional sub-group analyses will be performed on all analyses by wound type (single plane 
and circumferential). 
10.7 Safety Analyses 
No safety analyses are planned.  
10.8 Interim Analyses 
An interim futility analysis will be performed on the primary endpoints when approximately 50 – 
75 subjects have enrolled. 
11. 
DATA MANAGEMENT 
Data from the registry is collected via the Tissue Analytics® tablet application and website, 
collectively referred to as the data capture tool (DCT). There are two versions of the DCT: 
physician-facing, referred to as Investigator data capture tool (iDCT), and subject-facing, 
referred to as subject data capture tool (sDCT). All data is transferred to Sponsor Clinical 
Development and Data Management (DM) groups in a secured format on a weekly basis, or as 
requested if needed more frequently. All processes are documented in the Data Management 
Plan (DMP). Delegated personnel are trained to use the iDCT and enter data on the 
observations, tests and assessments specified in this protocol and according to the data entry 
instructions. Each user has an individual login and password and is assigned a specific 
permission level, based on their study function. A Clinical Research Associate (CRA) reviews 
the data to check for missing, inconsistent or illogical data.  
Data entered in the DCTs are immediately saved to a central database and changes tracked to 
provide an audit trail. Data validation checks are performed by Sponsor DM utilizing electronic 
edit checks comprised of validated computer programs and manual data review. Any data 
discrepancies are referred back to Investigator.  
When data have been entered, reviewed and edited, as necessary, Investigator is notified and 
asked to sign the data electronically via the Investigator Signature section in the iDCT. After the 
database has been declared clean, it will be locked to prevent further editing. Editing in the 
database will only be allowed with the proper documentation. Each investigational site will 
receive a copy of the data for each subject they enrolled for archiving. 

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After database lock, data will be extracted to SAS® (SAS Institute, Inc., Cary, NC, USA) for 
analysis as defined in the SAP. 
12. 
LEGAL/ETHICS AND ADMINISTRATIVE PROCEDURES 
12.1 Good Clinical Practice/Regulatory Compliance 
The procedures set out in the this protocol, pertaining to the conduct, evaluation, and 
documentation of this registry, are designed to ensure that Sponsor and Investigators abide by 
the Declaration of Helsinki and International Conference on Harmonisation (ICH) Guideline E6 
(R1): Good Clinical Practice (GCP). 
It is Investigator’s responsibility to ensure that adequate time and appropriate resources are 
available at the investigational site prior to commitment to participate in this registry. Investigator 
should also be able to estimate or demonstrate the potential for recruiting the required number 
of suitable subjects within the agreed recruitment period. Investigator maintains a list of 
appropriately qualified persons to whom Investigator has delegated significant registry-related 
tasks. 
12.2 Site and Investigator Qualification 
All participating investigational sites are assessed by Sponsor to verify that they are able to 
conduct the registry. Each participating institution must have an established IRB/REB and 
clinical protocol review process that is compliant with the code of federal regulation (CFR): 21 
CFR 56, ensuring the clinical protocol can be adequately evaluated and approved at the 
institutional level. A centralized IRB is available to sites who do not have an established 
IRB/REB, or those who receive a deferral from their local IRB/REB. 
The Institution must have appropriately qualified investigators, and clinical and administrative 
support staff in place to adequately conduct the registry according to ICH GCP in general and 
must have the adequate expertise and staff to conduct this registry in compliance with the 
relevant guidelines and regulations and to treat chronic venous insufficiency with resulting leg 
ulcers with Varithena®. 
This registry is scheduled to be performed by qualified, experienced investigators at up to 40 
research facilities in the United States and Canada. Given that the registry is intended to collect 
data related to SoC treatment with Varithena®, special care will be taken to select investigators 
with extensive experience in the treatment of venous insufficiency with Varithena®.  
Site and Investigator qualification is primarily accomplished through a Site Qualification Form 
and a qualification phone interview. In some cases, an on-site qualification visit may be 
performed.  
12.2.1 Investigator Curriculum Vitae (CV) 
Investigator and all investigational site staff provide Sponsor with his/her current (dated within 
two years) curriculum vitae and any revisions/updates.  
12.2.2 Statement of Investigator 
Investigator must sign and date the Statement of Investigator/Protocol Signature Page (page 4) 
of this protocol for the original and each subsequent amendment of the protocol and return a 
signed copy to Sponsor.  

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12.3 Institutional Review Board (IRB) 
12.3.1 Institutional Approval of the Protocol 
It is the responsibility of Investigator or delegate to submit this protocol (submitted by Sponsor 
for sites using centralized IRB), the ICF (approved by Sponsor), relevant supporting information 
and all types of subject recruitment information to the IRB/REB for review and approval prior to 
investigational site initiation. A copy of the written approval of the protocol and ICF must be 
received by Sponsor prior to recruitment of subjects.  
Investigator or delegate is responsible for keeping the IRB/REB apprised of the progress of the 
registry, any changes to the protocol, deviations from the protocol and reportable adverse 
events. 
12.3.2 IRB/REB Membership Roster  
Investigator or delegate must submit a complete and current roster of the IRB/REB to Sponsor. 
Some institutions, due to reasons of confidentiality, may not release their roster. In such 
instances, the institution’s General Assurance Number, assigned by the Department of Health 
and Human Services, is an acceptable substitute. 
12.4 Informed Consent – Ethical Compliance 
Investigator or delegate provides Sponsor with a copy of the IRB or REB-approved consent 
forms and a copy of the IRB/REB written approval, prior to investigational site initiation. 
Additionally, if the IRB/REB requires modifications to the sample ICF provided by Sponsor, the 
documentation supporting this requirement must be provided to Sponsor. 
It is the responsibility of Investigator or delegate to obtain written informed consent from 
subjects prior to the conduct of any trial procedures. All consent documentation must in 
accordance with applicable regulations and ICH GCP Guidelines. Each subject or the subject’s 
legally authorized representative is requested to sign the ICF after the subject has received and 
read written information and received an explanation of the registry, including but not limited to: 
the objectives, treatment plan, potential benefits and risk, inconveniences, alternative treatment 
options and the subject’s rights and responsibilities. A copy of the ICF must be given to the 
subject or the subject’s legally authorized representative. If applicable, it is provided in a 
certified translation of the subject’s local language.  
Acquisition of the informed consent should be documented in the subject medical record and 
the ICF should be signed and personally dated by the subject and the individual who conducted 
the informed consent discussion. Signed consent forms must remain in each subject’s registry 
file and must be available for review by CRA or auditor at any time. 
12.5 Subject Privacy and Confidentiality  
Sponsor and Investigator affirm and uphold the principle for the subject’s right to protection 
against invasion of privacy. Throughout this registry, all data collected and analyzed by Sponsor 
is treated confidentially and identified by a SIC.  
To verify compliance, Sponsor may require access to the subject’s primary medical record to 
review those portions that directly concern this registry (including but not limited to radiology 
images and hospital and outpatient records).  
 
 

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As part of required content of the ICF, the patient must be informed that his/her records may be 
reviewed by Sponsor, Sponsor representative and/or a representative of the appropriate 
regulatory agency. The ICF or related document must also state that patient privacy will be 
maintained pursuant to the HIPAA and 21 CFR 21. Should access to such medical records 
require a waiver or authorization separate from the statement of informed consent, Investigator 
obtains such permission in writing from the subject before the subject is entered in the registry. 
Data collected during this registry may be used to support the development or marketing of 
Varithena®. Collected data may be reviewed by Sponsor and/or its representatives, independent 
auditors who validate the data on behalf of Sponsor, national or local regulatory authorities and 
the IRB/REB which granted approval for this registry to proceed. 
12.6 Monitoring 
Monitoring the subject data is preformed using three methods: centralized, remote and on-site. 
All monitoring activities are performed by qualified personnel from Sponsor. Investigator and 
his/her staff are expected to cooperate with the CRA and be available during the visit to answer 
questions and resolve action items.  
Monitoring activities are documented through various means, which include monitoring visit 
reports and documentation of centralized monitoring activities. For on-site visits, the CRA 
records the date, a summary of the status and progress of the registry, and proposed actions. 
12.7 Modification of the Protocol 
All amendments to this protocol must be documented in writing, reviewed and approved by 
Investigator, Sponsor, and IRB/REB prior to implementation. If the protocol amendment 
substantially alters the design or potential risk to the subject, new written informed consent must 
be obtained from each subject for continued participation in the registry. 
12.8 Suspension or Termination of Registry 
If conditions arise requiring further clarification before the decision can be reached to proceed 
with or terminate the registry, the registry will be suspended until the situation has been 
resolved.  
Sponsor has the right to terminate this registry at any time. Examples of situations where this 
might occur include: 
 
It becomes apparent that enrollment is unsatisfactory with respect to quality and/or 
quantity or data recording is chronically inaccurate and/or incomplete. 
 
The incidence and/or severity of adverse events in the registry indicate a potential health 
hazard caused by the treatment. 
12.8.1 Protocol Deviations/Violations 
Protocol deviations/violations not related to the informed consent process or eligibility are not 
required to be reported to Sponsor for this registry. Every attempt should be made to perform 
procedures and collect data according to this protocol. Protocol deviations/violations related to 
informed consent or eligibility should be reported to the IRB/REB, per reporting requirements. 
Copies of these reports and IRB/REB notification of receipt of these reports shall be submitted 
to Sponsor.  
 
 

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12.9 Recording, Access to and Retention of Source Data 
Investigators are required to prepare and maintain adequate source documentation which 
includes: 
 
Documents that verify eligibility criteria 
 
Records covering subject participation in the registry including basic identification 
information, results of physical examinations and diagnostic tests, treatment 
administration, and visit/consult notes 
All key data must be recorded in the subject’s source documents including the informed consent 
acquisition. 
The CRA, auditors, IRB/REB, or regulatory inspectors may check data entered against the 
source documents. The consent form must include a statement by which the subjects allow the 
above-named access to source data that substantiate data entered in the iDCT. These 
personnel, bound by privacy laws and professional secrecy, will not disclose any personal 
information or personal medical information.  
As described in the ICH GCP Guidelines, ‘essential documents’, including final data set, source 
documents and consent forms should be retained by Investigator until at least two years have 
elapsed since the formal discontinuation of the registry. These documents should be retained 
for a longer period however if required by the applicable regulatory requirements or by an 
agreement with Sponsor. Investigator must obtain written permission from Sponsor prior to 
destruction of any registry document. 
12.10 Final Data 
Investigator is responsible for maintaining adequate and accurate source documents from which 
accurate information is transcribed into iDCT, which is designed to capture all pertinent data for 
the registry. Data entry should be completed by Investigator or delegate, as delegated on the 
Delegation of Authority Log.  
Once the data have been reviewed by the CRA, queries may be raised if the data are missing, 
unclear or contradictory. Queries are documented on data clarification forms (DCFs) and 
provided to the investigational site for timely resolution. Once all data is entered and all queries 
resolved, Investigator signs the completed data electronically via the Investigator Signature 
section of the iDCT and the database is locked. The final data set is provided to the site by 
Sponsor for archiving. 
12.11 Publications 
No individual Investigator may publish results from his/her investigational site until after 
publication of the primary manuscript describing the full population. 
The detailed obligations regarding the publication of any data, material results or other 
information that is generated or created in relation to the registry is set out in the CTA between 
Investigator and Sponsor. 
The registry is listed in a publicly accessible registry of trials, clinicaltrials.gov.  
12.12 Audit/Inspections 
To ensure compliance with relevant regulations, data generated by this registry must be 
available for inspection upon request by representatives of Sponsor and the IRB/REB for each 
investigational site. 
 

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13. 
SUPPLEMENTS/APPENDICES 
13.1 Appendix A: CEAP Classification 
 
 
 
Revised CEAP Classification of Venous Disorders 
Bo Eklöf, MD et al for the American Venous Forum International Ad Hoc Committee for 
Revision of the CEAP Classification7 
 
The CEAP classification for chronic venous disorders (CVD) was originally 
developed in 1994 by an international ad hoc committee of the American Venous 
Forum, endorsed by the Society for Vascular Surgery, and incorporated into 
“Reporting Standards in Venous Disease” in 1995. This classification system was 
designed to more clearly and accurately describe the form and severity of the 
venous disease being discussed.  
Rather than allowing it to stand as a static classification system, an ad hoc 
committee of the American Venous Forum recommended a number of changes in 
2004. These included refinement of several definitions; refinement of the C classes 
of CEAP; addition of the descriptor “n” (no venous abnormality identified); 
elaboration of the date of classification and level of investigation; and introduction 
of a basic CEAP version. The authors noted that CEAP is a descriptive 
classification, whereas venous severity scoring and quality of life scores are 
instruments for longitudinal research to assess outcomes.  
The letter "C" is based on the clinical findings, usually easily seen on 
physical examination.  
C0 = no visible or palpable signs of venous disease  
C1 = telangiectasies or reticular veins  
C2 = varicose veins  
C3 = edema  
C4a = pigmentation or eczema 
C4b = lipodermatosclerosis or strophie blanche 
C5 = healed venous ulcer  
C6 = active venous ulcer 
After this number, the letter "a" is assigned if the patient is asymptomatic, and the 
letter "s" is assigned if the patient experiences symptoms. An additional number 
may follow the "s" to denote the severity of the symptom. More than one number 
may be assigned if the patient has several findings on clinical examination.  

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The "E" stands for etiology, and the options are "c" for congenital disease, 
"p" for primary disease (not due to another cause), and "s" for secondary 
venous disease (postthrombotic), and “n” is for no venous cause identified.  
The "A" refers to anatomic findings, and is usually based on Duplex 
ultrasound examination. The options are as follows:  
 
Superficial veins (As)  
1. Telangiectasias or reticular veins  
2. Greater saphenous vein - above the knee  
3. Greater saphenous vein - below the knee  
4. Lesser (short) saphenous vein  
5. Nonsaphenous  
Deep veins (Ad)  
6. Inferior vena cava  
7. Common iliac  
8. Internal iliac  
9. External iliac  
10. Pelvic: gonadal, broad ligament, etc.  
11. Common femoral  
12. Deep femoral  
13. Superficial femoral  
14. Popliteal  
15. Crural: anterior tibial, posterior tibial, peroneal  
16. Muscular: gastrocnemius, soleus, etc.  
Perforator Veins (Ap) 
17. Thigh  
18. Calf  
No venous location identified (An) 
"P" refers to the pathophysiologic component, and the notations "r" for 
reflux, "o" for obstruction, or "r,o" for both reflux and obstruction may be 
used.  
To improve the assignment of designations under E, A, and P, a new descriptor, n, 
has been added and is now recommended for use where no venous abnormality is 
identified. The n can be added to E (En, no venous cause identified), A (An, no 
venous location identified), and P (Pn, no venous pathology identified).  
Using the CEAP classification routinely in your patient records and in the medical literature 
will allow us to compare the efficacy of our treatments and to follow the progress of 
patients in an intelligent and meaningful way. Implementation of this classification is an 
easily achieved goal, and all phlebologists are encouraged to use this tool in their daily 
practice. 
 
Reference: Eklöf B, Rutherford RB, Bergan JJ, et al for the American Venous Forum 
International Ad Hoc Committee for Revision of the CEAP Classification. Revision of the CEAP 
classification for chronic venous disorders: Consensus statement. J Vasc Surg. 2004;40:1248-
1252. 
 
 

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13.2 Appendix B: Venous Duplex Assessment 
1.  
Guidelines for Duplex Venous Assessment 
1.1 
Position of patient: Where possible, patients are assessed while standing, with the 
majority of weight on the opposite limb. The limb being scanned is slightly flexed at 
the knee and the foot is turned outwards. The patient should be observed throughout 
the procedure for possible syncope. When assessing the proximal deep veins for 
compressibility, the patient should be semi-supine (upper body raised to 30o to 
promote vein filling in the leg); however, when assessing the distal deep veins the 
patient should be in the sitting position.  
1.2 
Ultrasound settings, choice of probes, assessment criteria: The selected 
ultrasound device should have color flow and pulsed Doppler available. The operator 
has the right to select their choice of probe frequency, but a linear array is essential 
for accurate measurements. A venous default setting is selected on the machine, or 
color flow velocity maps are selected to identify low velocity blood flow. 
 
Calf compression and release and Valsalva are used to assess venous flow in both 
the deep and superficial veins. The normal color setting is blue for proximal flow and 
red for reflux. All veins should fill from wall to wall; if the vein does not fill wall-to-wall 
thrombus may be present, but different steering angles and lower color flow velocity 
profiles should be used to optimize color filling. On release of the calf pressure, reflux 
is indicated by red color filling in excess of 0.5 seconds. 
1.3  
Assessment of deep veins: A transducer is placed in the groin and the common 
femoral vein is identified medial to the common femoral artery. Turning the transducer 
by 90 degrees to view the common femoral vein in a cross-section (grayscale image) 
the patient is asked to perform a Valsalva maneuver. This should result in an increase 
in common femoral diameter. If no increase is seen, a proximal obstruction should be 
considered. Proximal obstruction can be confirmed by placing the Doppler sample 
volume in the lumen (longitudinal section); common femoral venous flow will be 
continuous and aphasic, a Valsalva maneuver will not result in a movement of blood 
towards the probe (i.e., in the same direction as arterial flow). If there is absence of 
phasicity of flow with respiration, detailed proximal vein scanning is to be undertaken 
(i.e., iliac veins). 
 
The Doppler sample volume is steered to a 60-degree Doppler angle, with the 
common femoral vein flow and the sample volume size increased across the full 
diameter of the lumen. Augmentation of flow by calf compression will result in venous 
return and a negative deflection on the spectral display. On release of the calf 
pressure, reflux will be seen as a positive deflection of greater than 0.5 seconds. A 
positive deflection of less than 0.5 seconds is probably due to valve closure and 
should be ignored. Moving distally a deep junction is identified. The deeper vein is the 
profunda femoris vein and should be assessed for competency using color flow and 
Doppler assessment. The more superficial vein is the femoral vein and should be 
traced along its length to assess competency and patency. 
 
Viewing the common femoral vein in cross-section, pressure is applied by the probe 
on the medial aspect of the leg and at the same time pressure is applied by the hand 
on the lateral aspect of the leg. This procedure is repeated at regular intervals (2-3 
cm) along the length of the common femoral and femoral veins. Failure to fully 
compress the veins indicates the presence of thrombus. The echogenicity of the 
thrombus indicates its age, with fresh thrombus appearing as a similar echogenicity to 

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the blood and old thrombus appearing as a similar echogenicity to the surrounding 
muscle tissue. 
 
The transducer is placed over the popliteal fossa and the popliteal vein is identified. 
As before, it is checked for competency and compressibility. It is important to note 
that proximal to an incompetent small saphenous vein, a segment of the popliteal vein 
may appear incompetent. This can be excluded by rechecking for popliteal vein 
incompetence when the small saphenous vein (SSV) is occluded by external 
compression. Distally a deep vein just within the fascia may be seen to extend down 
the posterior aspect of the leg this is the gastrocnemius vein. The soleal veins are 
embedded in the soleus muscle and are less easily identified than the gastrocnemius 
veins. Several soleal veins can be present. They are laterally orientated and are lower 
in the calf than the gastrocnemius veins. 
 
The anterior tibial vein may be seen as the first deep communication with the popliteal 
vein. Distal to this junction the tibio-peroneal trunk veins divide to form the posterior 
tibial and peroneal veins. It is easier to trace the deep calf veins from the ankle 
proximally. Placing the transducer posterior to the medial malleolus the posterior tibial 
artery and two veins can be visualized. Augmentation of flow by compressing the sole 
of the foot with a hand should result in good color filling. The posterior tibial veins 
should be traced proximally ensuring both are viewed along their length with no 
evidence of deep vein thrombosis. If the probe is angled slightly posterior the 
peroneal artery and veins should be visualized deep to the posterior tibial vessels. 
Placing your thumb and first finger on the anterior-medial and anterior-lateral aspects 
of the ankle and applying pressure can augment the peroneal vein flow. Placing the 
transducer on the anterior aspect of the ankle the anterior tibial artery and veins can 
be visualized and traced to the proximal calf. 
 
All deep calf veins should be checked for patency, competency and compressibility 
and details recorded. 
1.4 
Assessment of superficial veins: Returning to the groin and moving distally along 
the common femoral vein, the great saphenous vein will appear as a superficial 
medial tributary. Care should be taken to view both color flow and perform Doppler 
assessment to determine whether the saphenofemoral junction is competent or 
incompetent. The sample volume should be placed immediately distal to the SFJ 
within the first 3 cm of the great saphenous vein (GSV). As for the deep veins 
augmentation of flow by calf compression will result in venous return and a negative 
deflection on the spectral display. On release of the calf pressure, reflux will be seen 
as a positive deflection of greater than 0.5 seconds. A positive deflection of less than 
0.5 seconds is probably due to valve closure and should be ignored. The great 
saphenous should be traced along its length as isolated segments of incompetence 
and perforators may be identified. Any incompetent tributaries/perforators should be 
noted. The probe should be regularly turned to cross-section as perforators may be 
missed in longitudinal views. The great saphenous vein diameter (mm)) should be 
measured 5 cm below the saphenofemoral junction. 
 
The SSV can be viewed either with the patient sitting or standing facing away from 
the operator. When sitting on the edge of the bed, the patient places their foot on the 
technologist’s lap and the leg is slightly flexed at the knee and relaxed. When 
standing the leg must be slightly flexed and this position makes identification of the 
superior branch and posterior thigh connections and incompetence easier to identify. 

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The SSV is identified in the popliteal fossa, where it is usually deep to the deep 
fascia. It is then traced distally into the calf and the point at which it becomes 
superficial, perforating the deep fascia, is noted. The SSV is checked for competency 
and patency and then traced proximal to its junction with the popliteal vein. The 
popliteal vein must be viewed proximal and distal to the saphenopopliteal junction 
(SPJ) to determine whether the junction is incompetent. Incompetence can be 
proximal into the superior branch of the small saphenous. In some cases a SPJ may 
not be identified and the SSV may communicate with the vein of Giacomini, which lies 
just beneath the fascia and extends into the proximal posterior thigh. The diameter of 
the SSV should be measured 5cm distal to the junction. 
 
 

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13.3 Appendix C: Varithena® (polidocanol injectable foam) 1% Full Prescribing 
Information 
 
 
 

  
 
 
 
 
 
 
 
 
 
 
 
 
  __________________ 
 _________________  
 
 
 
 
 
 
 
 
 
  
  
 
 ______________  
 
 
 
 
 
 
 
 
 
  ______________ 
 _____________  
 
 
 
 
 
 
  ___________________ 
 ___________________  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  ______________ 
 _______________  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
      
 
 
 
 
 
 
 
HIGHLIGHTS OF PRESCRIBING INFORMATION 
These highlights do not include all the information needed to use 
VARITHENA™ safely and effectively.  See full prescribing information 
for VARITHENA™. 
Varithena™ (polidocanol injectable foam), for intravenous use 
Initial U.S. Approval: 2013 
INDICATIONS AND USAGE 
Varithena™ (polidocanol injectable foam) is a sclerosing agent indicated for 
the treatment of incompetent great saphenous veins, accessory saphenous 
veins and visible varicosities of the great saphenous vein system above and 
below the knee.  Varithena™ improves the symptoms of superficial venous 
incompetence and the appearance of visible varicosities. (1) 
_______________DOSAGE AND ADMINISTRATION 
For intravenous use under ultrasound guidance only. Use up to 5 ml per  
injection and 15 ml per treatment session (2)  
Separate treatments sessions by a minimum of 5 days (2)  
DOSAGE FORMS AND STRENGTHS 
Injectable foam delivering a 1% polidocanol solution. (3)  
Each mL of Varithena™ injectable foam contains 1.3 mg of polidocanol. (3)  
CONTRAINDICATIONS 
• 
Known allergy to polidocanol (4) 
• 
Acute thromboembolic disease (4) 
_______________WARNINGS AND PRECAUTIONS _______________ 
• 
Be prepared to treat anaphylaxis. (5.1) 
• 
Tissue ischemia and necrosis: Do not inject intra-arterially. (5.2) 
• 
Venous Thrombosis (5.3) 
___________________ ADVERSE REACTIONS ___________________ 
In clinical trials, the most common related adverse events (occurring in ≥3% 
of patients treated with Varithena™) were pain/discomfort in extremity, 
infusion site thrombosis (retained coagulum), injection site hematoma or pain, 
thrombophlebitis superficial, and extravasation.(6.1) 
To report SUSPECTED ADVERSE REACTIONS, contact 
Biocompatibles Inc. at 1-855-971-VEIN or FDA at 1-800-FDA-1088 
or www.fda.gov/medwatch. 
___________________ DRUG INTERACTIONS____________________ 
There are no known drug interactions with Varithena™. (7) 
USE IN SPECIFIC POPULATIONS 
Do not use Varithena in pregnant women. (8.1) 
See 17 for PATIENT COUNSELING INFORMATION 
Revised: 11/2013 
FULL PRESCRIBING INFORMATION: CONTENTS* 
1 
INDICATIONS AND USAGE 
2 
DOSAGE AND ADMINISTRATION 
3 
DOSAGE FORMS AND STRENGTHS 
4 
CONTRAINDICATIONS 
5 
WARNINGS AND PRECAUTIONS 
5.1 Anaphylaxis 
5.2 Tissue Ischemia and Necrosis 
5.3 Venous Thrombosis 
6 
ADVERSE REACTIONS 
6.1 Clinical Trials Experience 
7 
DRUG INTERACTIONS 
8 
USE IN SPECIFIC POPULATIONS 
8.1 Pregnancy 
8.2 Labor and Delivery 
8.3 Nursing Mothers 
8.4 Pediatric Use 
8.5 Geriatric Use 
10 
OVERDOSAGE 
11 
DESCRIPTION 
12 
CLINICAL PHARMACOLOGY 
12.1 Mechanism of Action 
12.2 Pharmacodynamics 
12.3 Pharmacokinetics 
13 
NONCLINICAL TOXICOLOGY 
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 
13.2 Animal Toxicology and/or Pharmacology 
14 
CLINICAL STUDIES 
16 
HOW SUPPLIED/STORAGE AND HANDLING 
16.1 How Supplied 
16.2 Storage and Handling 
17 
PATIENT COUNSELING INFORMATION 
*Sections or subsections omitted from the full prescribing information are not 
listed. 
Reference ID: 3412964 

 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
   
 
 
 
  
 
 
 
   
FULL PRESCRIBING INFORMATION  
1 
INDICATIONS AND USAGE 
Varithena™ (polidocanol injectable foam) is indicated for the treatment of incompetent great saphenous 
veins, accessory saphenous veins and visible varicosities of the great saphenous vein (GSV) system 
above and below the knee.  Varithena™ improves the symptoms of superficial venous incompetence and 
the appearance of visible varicosities. 
2 
DOSAGE AND ADMINISTRATION 
For intravenous use only. 
Varithena™ is intended for intravenous injection using ultrasound guidance, administered via a single 
cannula into the lumen of the target incompetent trunk veins or by direct injection into varicosities.  Use 
up to 5 ml per injection and no more than 15 mL per session. 
Physicians administering Varithena™ must be experienced with venous procedures, possess a detailed 
working knowledge of the use of the duplex ultrasound in venous disease and be trained in the 
administration of Varithena™. 
Activate Varithena™ using the Varithena™ Oxygen Canister and Polidocanol Canister (see Instructions 
for Use). Once a Varithena™ Transfer Unit is in place, foam can be generated and transferred to a 
syringe. Discard the syringe contents if there are any visible bubbles.  Administer the injectable foam 
within 75 seconds of extraction from the canister to maintain injectable foam properties. Use a new 
sterile syringe after each injection. Use a new Varithena™ Transfer Unit for each treatment session. 
Local anesthetic may be administered prior to cannula insertion but neither tumescent anesthesia nor 
patient sedation is required.  Cannulate the vein to be treated using ultrasound guidance to confirm 
venous access. 
Inject freshly generated Varithena™ slowly (approximately 1 mL/second in the GSV and 0.5 mL/second 
in accessory veins or varicosities) while monitoring using ultrasound.  Confirm venospasm of the treated 
vein using ultrasound. 
When treating the proximal GSV, stop the injection when Varithena™ is 3-5 cm distal to the 
Saphenofemoral Junction (SFJ). 
Apply compression bandaging and stockings and have the patient walk for at least 10 minutes, while 
being monitored. Maintain compression for 2 weeks after treatment. 
Repeat treatment may be necessary if the size and extent of the veins to be treated require more than 15 
mL of Varithena™. Separate treatment sessions by a minimum of 5 days. 
Retained coagulum may be removed by aspiration (microthrombectomy) to improve comfort and reduce 
skin staining. 
3 
DOSAGE FORMS AND STRENGTHS 
Polidocanol Solution, 180 mg/18 mL (10 mg/mL) must be activated before use. 
Reference ID: 3412964 

 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
Once activated, Varithena is a white, injectable foam delivering a 1% polidocanol solution. 
Each mL of Varithena™ injectable foam contains 1.3 mg of polidocanol. 
4 
CONTRAINDICATIONS 
The use of Varithena™ is contraindicated in patients with: 
• known allergy to polidocanol [see Warnings and Precautions (5.1)] 
• acute thromboembolic disease 
5 
WARNINGS AND PRECAUTIONS 
5.1 
Anaphylaxis 
Severe allergic reactions have been reported following administration of liquid polidocanol, including 
anaphylactic reactions, some of them fatal. Observe patients for at least 10 minutes following injection 
and be prepared to treat anaphylaxis appropriately. 
5.2 
Tissue Ischemia and Necrosis 
Intra-arterial injection or extravasation of polidocanol can cause severe necrosis, ischemia or gangrene 
Patients with underlying arterial disease, such as marked peripheral arteriosclerosis or thromboangiitis 
obliterans (Buerger’s Disease) may be at increased risk for tissue ischemia. If intra-arterial injection of 
polidocanol occurs, consult a vascular surgeon immediately. 
5.3 
Venous Thrombosis 
Varithena™ can cause venous thrombosis [see Adverse Reactions (6)]. Follow administration 
instructions closely and monitor for signs of venous thrombosis after treatment. Patients with reduced 
mobility, history of deep vein thrombosis or pulmonary embolism, or recent (within 3 months) major 
surgery, prolonged hospitalization or pregnancy are at increased risk for developing thrombosis. 
6 
ADVERSE REACTIONS 
6.1 
Clinical Trials Experience 
Because clinical trials are conducted under controlled but widely varying conditions, adverse reaction 
rates observed in clinical trials of Varithena™ cannot be directly compared to rates in the clinical trials 
of other drugs or procedures and may not reflect the rates observed in practice. 
A total of 1333 patients in 12 clinical trials were evaluated for safety when treated with Varithena™ at 
dose concentrations of 0.125%, 0.5%, 1.0% or 2.0%, including 437 patients treated with Varithena™ in 
placebo-controlled clinical trials. 
Adverse reactions occurring in 3% more patients receiving Varithena™ 1% than receiving placebo are 
shown in Table 1. 
Reference ID: 3412964 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 1: 
Treatment-emergent adverse reactions (3% more on Varithena™ 1% than on 
placebo) through Week 8 (n=588) 
Adverse Reaction 
Placebo 
(N=151) 
VarithenaTM 1.0% 
(N=149) 
Pooleda Varithena™ 
(N=437) 
Pain in extremity 
14 (9.3) 
25 (16.8) 
65 (14.9) 
Infusion site thrombosisb 
0 
24 (16.1) 
46 (10.5) 
Contusion/injection site hematoma 
9 (6.0) 
23 (15.4) 
38 (8.7) 
Limb discomfort 
5 (3.3) 
18 (12.1) 
32 (7.3) 
Tenderness/injection site pain 
5 (3.3) 
16 (10.7) 
30 (6.9) 
Venous thrombosis limbc 
0 
12 (8.1) 
24 (5.5) 
Thrombophlebitis superficial 
2 (1.3) 
8 (5.4) 
40 (9.2) 
Deep vein thrombosis 
0 
7 (4.7) 
10 (2.3) 
a Includes Varithena™ 0.125%, 0.5%, 1.0%, and 2.0% from the placebo-controlled trials.  
b Retained coagulum.  
c Common femoral vein thrombus extension (non-occlusive thrombi starting in the superficial vein and extending into the  
common femoral vein). 
In Varithena™-treated patients, 80% of pain events in the treated extremity resolved within 1 week. 
In the 1333 patients treated with Varithena™, the following venous thrombus adverse events occurred: 
common femoral vein thrombus extension (2.9%), proximal deep vein thrombosis (DVT) (1.7%), distal 
DVT (1.1%), isolated gastrocnemius and soleal vein thrombosis (1.4%). 
Proximal symptomatic venous thrombi occurred in 0.9% of patients treated with Varithena™ 49% 
(n=35) of these patients required treatment with anticoagulants.  
Since Varithena™ induces thrombosis in the treated superficial veins, D-dimer is commonly elevated 
post-treatment and is not useful diagnostically to assess patients for venous thrombus following 
treatment with Varithena™. 
Neurologic adverse events (cerebrovascular accident, migraines) have been reported in patients 
following administration of physician compounded foam sclerosants. None of the 1333 patients in the 
Varithena™ trials experienced clinically important neurological or visual adverse events suggestive of 
cerebral gas embolism. The incidence of neurologic and visual adverse events within 1 day of treatment 
in the placebo-controlled studies was 2.7% in the pooled Varithena™ group and 4.0% in the placebo 
groups. 
Skin discoloration adverse events were reported in 1.1% of the pooled Varithena™ group and 0.7% of 
the placebo group in the placebo-controlled studies. 
7 
DRUG INTERACTIONS 
No specific drug interaction studies have been performed.  There are no known drug interactions with 
Varithena™. 
Reference ID: 3412964 

 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
   
8 
USE IN SPECIFIC POPULATIONS 
8.1 
Pregnancy 
Pregnancy Category C. 
There are no adequate and well-controlled studies of Varithena™ in pregnant women.  Do not use 
Varithena™ during pregnancy.  
Animal Studies 
Developmental reproductive toxicity testing was performed in rats and rabbits using intravenous 
administration of polidocanol solution.  In rabbits, dose levels up to and including 10 mg/kg/day 
(approximately 12 times the proposed maximum human dose of 15 mL of 1% Varithena™ based on 
body surface area) did not produce any indication of adverse effects on embryo-fetal mortality, fetal 
weight or the incidences of fetal abnormalities and variants.  In rats administered 27 mg/kg/day of 
polidocanol solution (approximately 13.5 times the human dose based on body surface area), there were 
no adverse effects on pregnancy performance or fetal development. In a peri- and post-natal study in 
rats, dose levels of polidocanol up to 9 mg/kg/day (approximately 4.5 times the human dose based on 
body surface area) were without effects on the development of the conceptus and offspring, and at a 
dose level of 27 mg/kg/day of polidocanol solution (approximately 13.5 times the human dose based on 
body surface area), effects were confined to an equivocal reduction in body weights of first-generation 
males, and an associated equivocal delay in the age of preputial separation.  
8.2 
Labor and Delivery 
The effects of Varithena™ on labor and delivery in pregnant women are unknown. 
8.3 
Nursing Mothers 
It is not known whether polidocanol, the active pharmaceutical ingredient in Varithena™, is excreted in 
human milk.  Because many drugs are excreted in human milk and because of the potential for serious 
adverse reactions in nursing infants, avoid administering Varithena™ to a nursing woman. 
8.4 
Pediatric Use 
Safety and effectiveness in pediatric patients have not been established. 
8.5 
Geriatric Use 
Of the 1333 subjects in clinical studies treated with Varithena™, 9.1% (n=121) were ≥65 years of age.   
No clinically important differences in safety or efficacy were observed between older and younger 
patients in all studies. 
10 
OVERDOSAGE 
There are no known cases of overdosage with Varithena™.  In clinical studies, total volumes of up to 
60 mL of Varithena™ per treatment session have been administered. 
Reference ID: 3412964 

 
 
 
 
 
 
 
 
 
 
  
 
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11 
DESCRIPTION 
Varithena™ injectable foam contains the sclerosant, polidocanol.  It is intended for intravenous use 
only. 
Chemically, polidocanol is polyoxyl lauryl ether.  The structural formula is represented below: 
Polidocanol structural formula – 9-mole adduct 
Polidocanol has the molecular formula CH3(CH2)11 (OCH2CH)nOH and molecular weight 582.9 when 
the average ethylene glycol moieties is nine (n = 9).  Polidocanol is a white to almost white, waxy, 
hygroscopic solid that is soluble in water and alcohol and melts at temperatures above 20oC. 
Varithena™ is a sterile, injectable foam of an aqueous polidocanol solution (1%) containing the 
following inactive ingredients:  ethanol (4.2% w/w), disodium hydrogen phosphate dihydrate (0.24% 
w/w), and potassium dihydrogen phosphate (0.085% w/w) with pH adjustment using 0.1 M sodium 
hydroxide solution and 0.1 M hydrochloric acid solution to achieve a pH of 6.0-7.5. 
Activate the Varithena canister to enable foam generation from polidocanol solution, 180 mg/18 mL (10 
mg/mL). Once activated, Varithena is a white, injectable foam delivering a 1% polidocanol 
solution. Each mL of Varithena™ injectable foam contains 1.3 mg of polidocanol. An activated 
canister of Varithena™ generates 90 mL of injectable foam which, following purging instructions 
contained in the IFU, is sufficient to yield 45 mL of usable injectable foam for intravenous injection. 
The polidocanol solution is stored under a carbon dioxide atmosphere in an aluminum canister prior to 
use.  
The injectable foam is generated after activation of the polidocanol canister with oxygen from a second 
aluminum canister, resulting in a final gas mixture of oxygen:carbon dioxide in a ratio of 65:35 with low 
(<0.8%) nitrogen content.  At the time of use, Varithena™ is generated as an injectable foam of 
controlled density and bubble size.  The foam is then transferred to a syringe through the Varithena™ 
Transfer Unit.  The injectable foam has a liquid to gas ratio of approximately 1:7 by volume. The 
median bubble diameter is less than 100 µm and no bubbles are greater than 500 µm. 
Reference ID: 3412964 

 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12 
CLINICAL PHARMACOLOGY 
12.1 
Mechanism of Action 
Varithena™ is drug/device combination product that generates injectable foam.  The injectable foam is 
composed of a liquid and gas phase, both of which are necessary to have its therapeutic effect.  
Varithena™ is intended to act as follows: (1) the foam displaces blood from the vein to be treated, (2) 
thepolidocanol then scleroses the endothelium. 
The active pharmaceutical ingredient of Varithena™ is polidocanol, a non-ionic surfactant sclerosing 
agent. The hydrophobic pole of the polidocanol molecule attaches to the lipid cell membrane of the 
venous endothelium, resulting in disruption of the osmotic barrier, destruction of the venous 
endothelium, and vasospasm. Following exposure to polidocanol, the interior surface of the vein 
becomes thrombogenic, which leads to thrombus formation and venous occlusion. The occluded vein is 
eventually replaced by fibrous connective tissue. Polidocanol is deactivated upon contact with 
blood, thus limiting the sclerosant action to the endothelium near the site of injection. 
12.2 
Pharmacodynamics 
The active pharmaceutical ingredient in Varithena™ is polidocanol.  Polidocanol has a concentration 
dependent damaging effect on the endothelium of blood vessels. 
12.3 
Pharmacokinetics 
The pharmacokinetics of Varithena™ (as a weighted sum of 4 oligomers: E5, E9, E12 and E14) were 
evaluated at two concentrations (1% and 2%) randomly assigned within gender in 20 patients with GSV 
incompetence. 
When administered as an intravenous injectable foam as two fixed 5 mL doses separated by 10 minutes, 
polidocanol was rapidly detected in plasma, reaching maximum concentration of drug in the body after 
dosing (Cmax ) within 15 minutes of the first injection and within 5 mins of receiving the second injection 
of Varithena™ 1% or Varithena™ 2%. The mean volume of distribution (Vd) of polidocanol ranged 
from 35L to 82L. 
Mean systemic clearance (CL) of polidocanol ranged from 0.2 to 0.4 L/min. The clearance of E5 was 
significantly greater than is that of longer oligomers. Mean terminal elimination half-life (t 1/2 ) ranged 
from 102 to 153 minutes, with most plasma samples below the limit of quantitation (BLQ) at the end of 
the 8 hour collection period. The increase in plasma polidocanol concentrations was less than 
proportional with increasing Varithena™ concentration. Weight normalized data demonstrated no 
consistent differences in C max or AUC between males and females. 
13 
NONCLINICAL TOXICOLOGY 
13.1 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
Long term studies in animals have not been performed to evaluate carcinogenic potential of 
Varithena™.  No mutagenic activity was observed in the in vitro bacterial reverse mutation assay at non-
toxic concentrations.  No mutagenic activity was observed in the in vitro mouse lymphoma assay in the 
absence of S9 mix and was weakly mutagenic in the presence of S9 close to the limit of acceptance for 
Reference ID: 3412964 

 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
the accompanying level of toxicity.  No micronucleus induction was detected in the in vivo assay on 
mouse bone marrow cells up to the maximum tolerated dose of 80 mg/kg. 
There was no adverse effect on fertility in both male and female rats at 27 mg/kg/day.  This dose level is 
approximately 13.5 times the proposed maximum human dose based on body surface area. 
13.2 
Animal Toxicology and/or Pharmacology 
The pharmacological effects of polidocanol solution on the renal function of the rat were evaluated and 
at the highest dose tested (10 mg/kg) hematuria occurred in 67% of animals.  This dose is 5 times higher 
than the proposed maximum human dose based on body surface area. Blood was no longer detectable in 
urine 24 hours after dosing.  In the 28 day repeated dose toxicity study in rat blood pigments were noted 
in the urine for animals in all treatment groups, including male controls, at the end of the 4 week 
treatment period with up to 27 mg polidocanol/kg/day. Following the 2 week recovery period there was 
still evidence that blood pigments were present in the urine but the incidence and severity was decreased 
when compared to the main study animals.  There were no histopathological findings in the urinary 
bladder in any study animals.  
In a cardiovascular pharmacology study in the anesthetized dog at 20 mg/kg (approximately 33 times the 
human dose based on body surface area) statistically significantly higher values for P-Q interval were 
measured before and during dosing and at all time points up to 30 minutes after dosing. An increase in 
QRS interval was also measured after dosing of 20 mg/kg and at 5 and 10 minutes after dosing. This 
effect was short lived and was no longer seen at 15 minutes after dosing.  In addition, there was an 
increase in diastolic pressure with increasing dose of polidocanol.  This increase became significantly 
greater (p<0.05) than baseline before injection of the final and highest dose (20 mg/kg). 
In a further cardiovascular pharmacology study conducted with a once weekly, for four weeks, 
intravenous bolus injection of Varithena™ in the conscious dog, dose levels of up to 8.0 mL/kg 
(approximately 17 times the human dose based on body surface area) to beagle dogs caused only a 
transient, but consistent, effect on respiration, evidenced by a decrease in tidal volume and RMV at 15 
minutes post-dose, resolving by one hour post-dose. Histopathology of the lung at the end of the 3 
month follow-up period showed no abnormalities. 
14 
CLINICAL STUDIES 
Varithena™ was evaluated in two randomized, blinded, multicenter clinical trials designed to assess the 
efficacy and safety of VARITHENA 0.5%, 1.0% and 2.0% (VANISH-1) and Varithena™ 0.5% and 
1.0% (VANISH-2) compared with placebo in the treatment of both symptoms and appearance in 
patients with SFJ incompetence as evidenced by reflux of the GSV or major accessory veins. In both 
studies, a Varithena™ 0.125% treatment group was included as a control for blinding of the duplex 
ultrasound assessment.  Patients with history of deep vein thrombosis or pulmonary embolism, inability 
to comply with post-treatment compression due to severe peripheral arterial disease or leg obesity, 
incompetence of the small saphenous vein or deep venous reflux as a major source of reflux, or reduced 
mobility, or major surgery, pregnancy, or prolonged hospitalization within 3 months were excluded. 
Patients were randomized in an equal distribution to each treatment group; the primary time point for 
analyses of the primary, secondary and tertiary efficacy endpoints was Week 8. 
Reference ID: 3412964 

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VANISH-1 
VANISH-2 
Placebo 
Varithena™ 
1.0% 
Pooled 
Varithena™* 
Placebo 
Varithena™ 
1.0% 
Pooled 
Varithena™* 
PA-V3 
N 
55 
50 
164 
56 
57 
117 
Baseline Score, mean 
3.49 
3.46 
3.54 
3.30 
3.49 
3.54 
Adjusted mean 
change from baseline 
at Week 8 
-0.15 
-1.60 
-1.58 
-0.32 
-1.79 
-1.82 
Clinically meaningful 
improvement  in 
Appearance at Week 8† 
3.6% 
(n=56) 
54.9% 
(n=51) 
64.2% 
(n=165) 
7.1% 
(n=56) 
69.0% 
(n=58) 
74.6% 
(n=118) 
Comparison vs. 
Placebo, P-value at 
Week 8, Adjusted Mean 
Change 
<0.0001 
<0.0001 
<0.0001 
<0.0001 
*VANISH-1 Varithena™ (pooled): 0.5% + 1.0% + 2.0%; VANISH-2 Varithena™ (pooled): 0.5% + 1.0%.
†Percent who reported the appearance of varicose veins had “moderately improved” or “much improved” compared with 
baseline. 
Tertiary endpoints in VANISH-1 and VANISH-2 included response to treatment as determined by 
change from baseline in Venous Clinical Severity Score (VCSS), by duplex ultrasound, and by change 
from baseline in Venous Insufficiency Epidemiologic and Economic Study – Quality of Life/Symptoms 
(VEINES-QOL) score. 
VCSS is a clinician rating of severity of chronic venous insufficiency ranging from 0 to 30, where 
higher scores indicate more severe venous disease. In VANISH-1 and VANISH-2, the adjusted mean 
changes from baseline in VCSS in the 1% Varithena™ treatment groups were 3.70 and 5.05, 
respectively, at Week 8 compared with 0.75 and 1.52 points in the placebo groups, respectively. For 
both studies, the differences between these improvements are statistically significant (P<0.0001). 
The physiological response to treatment as measured by duplex ultrasound (duplex response) was 
defined as elimination of reflux through the SFJ and/or complete occlusion of all incompetent GSV and 
major accessory veins at baseline. The primary comparison for duplex response in both studies was the 
pooled Varithena™ groups versus the Varithena™ 0.125% (control) group. Results are shown 
in Table 4. 
Reference ID: 3412964 

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o Two compression pads. 
16.2 
Storage and Handling 
Do not shake Varithena™ canisters.  
Avoid contact with eyes.  
Store the Varithena™ convenience box at 68° to 77°F (15° to 25°C); excursions are permitted to  
between 59° to 86°F (15° and 30°C).  Do not refrigerate or freeze.  
Unused, non-activated Varithena™ canisters may be stored in the flat or upright position.   
Contains gas under pressure: May explode if heated.  Store in a well-ventilated place. Store the  
canisters away from sources of heat including strong light conditions.   
Pressurized Oxygen:  May cause or intensify fire; oxidizer.  Store away from combustible materials.  
Once activated, the canister of Varithena™ must be used within seven (7) days.   
Store activated canisters of Varithena™ upright, with the Varithena™ Transfer Unit attached, under the  
same temperature conditions as the Varithena™ convenience box. Use a new Varithena™ Transfer Unit  
for each treatment session.  
Discard aerosol canisters after use in accordance with state and local requirements.  
For more information, please refer to the IFU.  
17 
PATIENT COUNSELING INFORMATION     
Advise the patient to keep post-treatment bandages dry and in place for 48 hours and to wear 
compression stockings on the treated legs continuously for 2 weeks. Compression stockings should be 
thigh or knee high depending upon the area treated in order to provide adequate coverage. Advise the 
patient to walk for at least 10 minutes immediately after the procedure and daily for the next month. 
Following treatment, advise the patient to avoid heavy exercise for 1 week and extended periods of 
inactivity for 1 month. 
If you would like more information, please talk with your doctor. For more information about 
Varithena™ you can also call us at {1-855-971-VEIN} or go to www.varithena.com. 
Manufactured for Provensis Ltd by: 
Biocompatibles UK Ltd  
Chapman House, Weydon Lane, Farnham, UK, GU9 8QL.  
Distributed by: 
Biocompatibles, Inc.  
115 Hurley Road, Building 3, Oxford, CT 06478  
Reference ID: 3412964 

 
 
 
 
 
 
 
 
 
 
 
 
Provensis Ltd, Biocompatibles UK Ltd, and Biocompatibles, Inc. are BTG International group 
companies 
Varithena™ is a trademark of Provensis Ltd 
BTG and the BTG roundel logo are registered trademarks of BTG International Ltd 
Reference ID: 3412964 

Protocol BTG-001652-01 (VIEW-VLU) 
Version 1.1, 14Aug2017 
 
 
 
 
 
Page 44 of 50 
Provensis Ltd 
CONFIDENTIAL 
 
A BTG International group company 
 
13.4 Appendix D: Varithena® (polidocanol injectable foam) 1% Instructions for Use 
 
 
 
 

Varithena (polidocanol injectable foam) Delivery System IFU  
Page 1 of 17 
 
 
  Varithena Delivery System 
  Instructions for Use 
 
Please read all prescribing information before using the product. 
 
The Instructions for Use are for the entire Varithena system. There are 2 packaging configurations: 
Option A:  Bi-Canister box and Administration Pack* 
Option B: Convenience box (Bi-Canister Box + 3 Ancillary Packs + 3 Varithena transfer units)* 
*The components in each packaging configuration are to be used only in conjunction with each other 
for activation of Varithena. 
Administration Packs can be used for either configuration for further treatment sessions. 
 
Always write the activation date and time on the canister and verify the product has not expired prior 
to use. 
 
Once the Varithena canister has been activated, the shelf life for the product is thirty days. 
Rx Only 
A canister of Varithena generates 90mL of foam which, following purging instructions contained in this IFU, is 
sufficient to yield 45mL of usable foam for injection. The gas mix of the foam is 65:35 O2:CO2. 
 
WARNINGS: 
As the foam fills the syringe and before injecting, inspect the syringe full of foam for any visible bubbles. If 
there are any present, the foam should be emptied into the Varithena transfer unit waste chamber and the 
syringe refilled.  
 
Do not shake Varithena canisters.  
 
Always use a fresh pair of sterile gloves when handling the Bi-Canister and Varithena transfer unit. 
 
A new Varithena transfer unit must be used for each treatment session. 
 
Notes: Use a new sterile syringe after each injection. Never fill a syringe until just before the foam is required. 
The activated Varithena canister should always be stored with a Varithena transfer unit in place in the upright 
position at controlled room temperature in an appropriately controlled clean area to limit contamination. 
 
Use foam within 75 seconds of generation or discard and generate new foam. 
 

Varithena (polidocanol injectable foam) Delivery System IFU  
Page 2 of 17 
 
 
  Unpacking Varithena: 
Option A: Bi-Canister Box and Administration Pack 
 
Gather all the items needed for the generation of foam: the Varithena Bi-Canister box (Figure 1a), 
Administration Pack (including: Varithena transfer unit, manometer tube, compression pad and silicone-free 
syringes) (Figure 1b), and the following items that are not supplied: scissors, pen, sterile alcoholic wipes, timer 
and gloves (Figure 1c). 
 
Open the Varithena Bi-Canister box and remove the Varithena Bi-Canister pouch. Open the Administration 
Pack and remove the components. Inspect the pouch and components for damage (do not use product if there 
are any visible signs of damage to pouch or components). 
 
 
Figure 1a Varithena Bi-Canister 
 
Figure 1b Administration Pack 
 
Figure 1c Additional Procedure Items 
(not supplied) 
 

Varithena (polidocanol injectable foam) Delivery System IFU  
Page 3 of 17 
 
  Unpacking Varithena: 
Option B: Convenience Box (Bi-Canister Box + 3 Ancillary Packs + 3 Varithena 
transfer units) 
 
Gather all the items needed for the generation of foam: the Varithena Bi-Canister Box (Figure 2a), Ancillary 
Pack (including silicone-free syringes, manometer tubing, and compression pads and Varithena transfer unit 
(Figure 2b), and the following items that are not supplied: scissors, pen, sterile alcoholic wipes, timer and 
gloves (Figure 2c). 
 
Open the Varithena Convenience box and remove all the components. Open the Varithena Bi-Canister box 
and remove the Varithena Bi-Canister pouch. Open an Ancillary Pack and remove the components. Inspect the 
pouch and components for damage (do not use product if there are any visible signs of damage to pouch or 
components). 
 
 
Figure 2a – Varithena Bi-Canister 
 
Figure 2b – Three Ancillary Packs 
 
 
Figure 2c – Additional Procedure Items (not Supplied) 
 
 

Varithena (polidocanol injectable foam) Delivery System IFU  
Page 4 of 17 
 
  Preparing the Patient 
 
Preparations for treating the patient with Varithena should include the following steps: 
 
• Position the patient comfortably on the treatment table in a supine position 
with their hip externally rotated to facilitate access to the GSV. 
 
• Use ultrasound to find the best site for venous access. 
 
• Using an aseptic technique, infiltrate the skin over the venous access point 
with local anesthetic. 
 
• Obtain venous access under ultrasound guidance. 
 
• IV catheters that are 16 to 22 gauge and 40 - to 50 - mm long or 
micropuncture sets are recommended for venous access. 
 
• Prefill the manometer tube with sterile heparinized normal saline solution and 
connect to the IV catheter. 
 
• Confirm venous access by aspirating with a syringe, blood should be dark and 
under low pressure. 
 
• Flush the IV catheter and manometer tube with heparinized normal saline and 
secure it to the skin with adhesive tape, leave the saline syringe connected. 
 
• With the IV catheter in place and secure, place the patient supine and elevate 
the leg to approximately 45 degrees. 
 
Complete all preparation of the patient and preparations for Varithena injectable foam 
injection  before generation of the foam. 
 

Varithena (polidocanol injectable foam) Delivery System IFU  
Page 5 of 17 
 
 Varithena Preparation 
1 
2 
Wearing appropriate sterile gloves, open Bi-
Canister pouch using a pair of scissors. Place 
canisters upright on a cleaned (sterile wipes) 
stable surface with the white oxygen canister on 
top (Figure 3). Discard empty pouch. 
Remove the safety clip by lifting one corner of the 
clip out (Figure 4). Discard the safety clip. 
 
 
 
Figure 3 
 
Figure 4 
 
 
 
 
 
 
 

Varithena (polidocanol injectable foam) Delivery System IFU  
Page 6 of 17 
 
  Gas Activation of the Varithena Canister 
3 
To begin the gas transfer, twist the canisters together clockwise (Figure 5) until they come to a stop and the 
small indicators/marks on the collars are aligned (Figure 6). You may hear a bubbling sound. 
 
While the canisters are activating, keep them upright on the clean flat surface for 1 minute. Use a timing device 
to keep track of the 1 minute time. 
 
 
Figure 5 
 
Figure 6 
 
 
 
 
 
 
 

Varithena (polidocanol injectable foam) Delivery System IFU  
Page 7 of 17 
 
  Gas Activation of the Varithena Canister 
 
4 
Note: In order to maintain sterility of the Varithena transfer unit, the following steps must be followed.  While 
waiting 1 minute for the gas transfer, open a new Varithena transfer unit, blister pack, but leave the Varithena 
transfer unit in the package (Figure 7). 
The manometer tubing (20 inch) should have been previously filled with sterile heparinized normal saline 
solution. 
 
 
Figure 7 
 
 
 
 
 
 
 
 
 
 

Varithena (polidocanol injectable foam) Delivery System IFU  
Page 8 of 17 
 
  Gas Activation of the Varithena Canister 
5 
After 1 minute, 
• 
Twist the two canisters by turning them in the opposite direction (counterclockwise) as before 
(Figure 8). 
• 
Pull straight up to separate the oxygen canister from the Varithena canister, as shown (Figure 9). 
Do not separate canisters until you have a Varithena transfer unit ready to place onto the Varithena 
canister (See step 6). 
• 
Put the oxygen canister (with white collar) aside. 
• 
The Varithena canister (with blue collar) should remain on a clean flat surface, in the upright 
position. 
 
 
Figure 8 
 
Figure 9 
 
 
Figure 10 
Write today’s date and time in the “Date and 
Time of Activation” box on the Varithena 
canister (Figure 10) 
 
 

Varithena (polidocanol injectable foam) Delivery System IFU  
Page 9 of 17 
   Connecting a new Varithena transfer unit and syringe 
 
6 
Remove the Varithena transfer unit from the blister pack, wearing a fresh pair of sterile gloves. Make sure not 
to touch the sterile underside of the Varithena transfer unit, (discard Varithena transfer unit if contaminated). 
 
Immediately place the Varithena transfer unit on top of the blue Varithena canister. Gently rotate the Varithena 
transfer unit clockwise as indicated (Figure 11) until it drops into the collar threads then twist the Varithena 
transfer unit (clockwise) until it reaches a stop (Figure 12). 
 
 
Figure 11 
 
Figure 12 
 
 
 
 
 
 
The system is now activated and ready for use. 

Varithena (polidocanol injectable foam) Delivery System IFU  
Page 10 of 17 
 
  Connecting a new Varithena transfer unit and syringe 
7 
Change the Varithena transfer unit immediately before each new treatment session. 
 
Once all preparations for injection are complete, i.e., cannula in situ, patient’s leg elevated and a good 
ultrasound view of the saphenofemoral junction (SFJ) obtained, foam may be generated for immediate use. 
 
Open a sterile 10mL silicone-free syringe package and keep it in the package until needed. 
 
Remove the syringe from the package, and connect it to the Varithena transfer unit as shown (Figure 13). 
 
 
Figure 13 
 
 
  Priming a New Syringe 
 
8 
Gently press down the Varithena transfer unit to begin producing foam (Figure 14). 
 
Using continuous pressure, allow the silicone-free syringe to fill between 3mL and 5mL. 
 
Release the pressure on the Varithena transfer unit and leave the syringe connected. 
 
 
Figure 14 
 
 
  Priming a New Syringe 

Varithena (polidocanol injectable foam) Delivery System IFU  
Page 11 of 17 
 
9 
Push the silicone-free syringe plunger in fully to discard its contents (Figure 15). Do not disconnect the syringe. 
 
Note: The foam will automatically be diverted into the waste chamber within the Varithena transfer unit (Figure 
16). This process eliminates the small quantity of air in the syringe and Varithena transfer unit. 
 
 
Figure 15 
 
Figure 16 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Varithena (polidocanol injectable foam) Delivery System IFU  
Page 12 of 17 
 
  Generation of Foam 
 
 
10 
Foam Generation: The technique to produce usable foam requires a single purge cycle before filling the 
syringe, a process that takes less than 1 second. 
 
 
 
 
 
 
 
While holding the silicone-free syringe plunger in place, gently press down on the Varithena transfer unit to 
begin the purge cycle (Figure 17). 
 
Visually inspect the flowing foam inside the Varithena transfer unit to make sure the visible air bubbles have 
been expelled (less than 1 second) before releasing the syringe plunger and allowing it to fill to the desired 
volume (Figure 18). 
 
Draw up to 5mL of foam into the syringe. 
 
 
 
Figure 17 
 
Figure 18 
 
 
 
 
 
Important Note: Foam must be generated by pushing down on the Varithena transfer unit continuously 
without pulling back on the plunger of the syringe (aspirating). 

Varithena (polidocanol injectable foam) Delivery System IFU  
Page 13 of 17 
 
  Inspecting and Injecting Foam 
11 
Figure 19 
After the silicone-free syringe has filled to the desired volume, 
wait 10 seconds to allow the pressure to equalize before 
removing the syringe from the Varithena transfer unit (Figure 
19). 
WARNING: As the foam fills the syringe and before injecting, 
inspect the syringe full of foam for any visible bubbles 
(easily seen with the unaided eye at arm’s length). If there are 
any present, empty the foam into the Varithena transfer unit 
waste chamber and refill the syringe. 
12 
Remove the syringe from the Varithena transfer unit and 
inspect it for visible bubbles (Figure 20).  
If no visible bubbles are present then the foam is ready for use. 
Use the foam within 75 seconds of generation or discard 
and generate new foam. 
WARNING: The total amount of foam injected in any one 
treatment session must not exceed 15mL, comprised of 
individual injections of up to 5mL each. 
After each treatment session, mark-off on the canister label the 
number of aliquots of up to 5mL of usable foam drawn from the 
canister per step 11 (Figure 21). 
 
Figure 20 
 
Figure 21 
13 
Connect a syringe of freshly generated foam to the manometer 
tubing, which is already connected to the cannula, in 
preparation for the initial injection. The manometer tubing (20) 
inch should have been previously filled with sterile heparinized 
normal saline solution. 

Varithena (polidocanol injectable foam) Delivery System IFU  
Page 14 of 17 
 
  Inspecting and Injecting Foam 
 
14 
 
Inject the foam at approximately 0.5mL to 1.0mL per second through the manometer tubing. Five (5) mLs of 
foam should be injected in approximately 10 seconds. Always inspect the foam as it passes through the 
manometer tubing for visible bubbles (Figure 22). If any visible bubbles are seen (easily seen with the unaided 
eye at arm's length) they should be aspirated back into the silicone-free syringe and the syringe contents 
discarded back into the Varithena transfer unit waste chamber, and a fresh syringe of foam generated. 
Notes: Use a new sterile syringe after each injection. 
 
 
Figure 22 
 
 
WARNING: The total amount of foam injected in any one treatment session must not exceed 15mL, comprised 
of individual injections of up to 5mL each 
 
Do not remove Varithena transfer unit if the Varithena canister is to be stored (see Storage) 
 
Change sterile gloves appropriately, to limit any contamination of the Varithena transfer unit and Bi-
Canister. 
 
Compression Pads 
 
15 
Once treatment is complete, the Compression Pads should be used: 
 
The objective of the pads is to focus the compression forces on the treated vein to keep them as free from 
blood as possible, thus minimizing retained thrombus. 
 
The compression pads supplied should be placed along the course of the treated trunk vein in the thigh, and 
over raised treated varicose veins above and below the knee. The pads may be shaped to follow the course of 
the veins. The pads should be placed outside the first layer of limited stretch bandage and held in place by a 
second layer of bandage. 
 
The appropriate length compression stocking is then applied. 

Varithena (polidocanol injectable foam) Delivery System IFU  
Page 15 of 17 
 
  Replacing the Varithena transfer unit 
 
 
Important Note: Do not replace the Varithena transfer unit if the canister is to be stored for future use. The 
activated Varithena canister should always be stored in an appropriately cleaned area with a Varithena transfer 
unit in place in the upright position at controlled room temperature. Replace the Varithena transfer unit just 
prior to the next treatment session. 
 
16 
Wearing appropriate new sterile gloves, hold the 
Varithena canister, twist the Varithena transfer unit 
counterclockwise and then pull up to separate 
from the canister (Figure 23). 
17 
Discard the old Varithena transfer unit and open a 
new Varithena transfer unit. 
 
Make sure not to touch the sterile underside of the 
Varithena transfer unit. 
 
Figure 23 
 
 
 
 

Varithena (polidocanol injectable foam) Delivery System IFU  
Page 16 of 17 
 
  Replacing the Varithena transfer unit 
 
18 
 
Swab the uncovered shuttle with a fresh 
sterile alcohol wipe (Figure 24) and 
immediately place the Varithena transfer 
unit on top of the Varithena canister. 
 
Gently rotate the Varithena transfer unit 
clockwise until it drops into the collar 
threads (Figure 25), then twist the Varithena 
transfer unit (clockwise) until it reaches a 
stop (Figure 26). 
 
Figure 24 
 
Figure 25 
 
Figure 26 
 
 
The Varithena device now ready for use for a new treatment session, following the 
instructions in Steps 7 to 15. 

Varithena (polidocanol injectable foam) Delivery System IFU  
Page 17 of 17 
 
  Storage and Disposal 
 
 
Note: The activated Varithena canister should always be stored with a Varithena transfer unit in place in the 
upright position at controlled room temperature in an appropriately controlled clean area to limit contamination. 
 
Once the Varithena canister has been activated, the shelf life for the product is thirty (30) calendar days. 
 
Always write the activation date and time on the canister and verify the product has not expired prior to use. 
 
Dispose of Varithena and oxygen canisters following local and state regulations for aerosol disposal. 
 
The Varithena transfer unit can be disposed of as non-toxic non-clinical waste. 
 
Net Contents: 18ml 
 
One canister of Varithena contains: 
180mg Polidocanol, ethanol 756mg (96%), disodium hydrogen phosphate dihydrate 43.2mg, potassium 
dihydrogen phosphate 15.3mg, water for injection. 
 
One canister of Varithena generates 90mL of foam which, following purging instructions contained in this IFU, 
is sufficient to yield 45mL of usable foam for injection. 
The gas mix of the foam is 65:35 O2:CO2. 
NDC 60635-118-01 Varithena Bi-Canister 
Administration Pack 
NDC 60635-133-01 Varithena Convenience Pack 
 
 
Manufactured for Provensis Ltd by: 
 
Biocompatibles UK Ltd 
Chapman House, Weydon Lane, Farnham, Surrey, UK, GU9 8QL 
 
Distributed by: 
Biocompatibles Inc., Five Tower Bridge, Suite 810, 300 Barr Harbor Drive, West Conshohocken, PA, 19428-
2998, USA. 
 
Varithena is a registered trademark of Provensis Ltd 
 
BTG and the BTG roundel logo are registered trademarks of BTG International Ltd 
Provensis Ltd, and Biocompatibles UK Ltd, are BTG International group companies 
 
                              
 

Protocol BTG-001652-01 (VIEW-VLU) 
Version 1.1, 14Aug2017 
 
 
 
 
 
Page 45 of 50 
Provensis Ltd 
CONFIDENTIAL 
 
A BTG International group company 
 
13.5 Appendix E: Use of Varithena® to manage patients with GSV-derived venous 
hypertension and chronic venous leg ulcer 
 
 

Version 1.0, 05Jun2017 
Use of Varithena® to manage patients with GSV-derived venous hypertension and chronic 
venous leg ulcer 
 
Abstract: 
Venous leg ulceration (VLU) is increasingly prevalent with advancing age and places a large 
health care burden on western societies approximating to 1% of total health spending. 
Patients with VLU frequently suffer for months and years without adequate investigation or 
treatment of the underlying cause. This is in part a result of the view that ulcers should be 
healed first before intervention. Modern minimally invasive treatment can be delivered with 
little disruption to the patient and will contribute to ulcer healing and very significant reduction 
in risk of ulcer recurrence. Arguably chemical ablation of the trunk and tributary veins is most 
flexible and the least invasive of all technologies and so best suited to the elderly ulcer 
patient with complex vein disease. 
In this report the authors present their consensus opinion of the management of patients 
with great saphenous vein incompetence and varicose veins with VLU treated with 
polidocanol injectable foam 1% (Varithena®). 
 
Introduction: 
Venous leg ulcer (VLU) is the culmination of years of chronic venous insufficiency. In cases 
of severe venous obstruction this process can be reduced to a few years between the 
thrombotic incident and ulceration. In the majority, however, injury develops over decades 
with incremental damage to the skin until the point at which the skin can no longer be 
sustained and an ulcer develops. Chronic venous disease, whether due to superficial or 
deep system incompetence, is prevalent. In fact, some epidemiological reports suggest that 
up to 56% of men and 60% of women suffer from superficial venous disease and associated 
sequelae1. The prevalence of VLU is approximately 1-2% of the population, with reports of 
5% of older adults suffering from ulceration2. In Europe and North America venous disease 
has a substantial  healthcare burden in  excess of  $14Bn each year (not including out of 
pocket or indirect costs), and more than 1% of overall health care costs (Bergan JJ)3,4. 
Despite the economic impact and the severe reduction in Quality of Life (QoL) on the 
individual, in most countries a systematic approach to reduce the burden of VLU has not 
been adopted even though there is clear evidence that venous interventions designed to 
correct underlying venous insufficiency can significantly reduce the absolute number of 
ulcers and associated cost.5,6 The ESCHAR studies which evaluated the benefit of surgical 
intervention to correct the underlying superficial venous reflux, established that correction of 
reflux reduced 12-month ulcer recurrence.7 In the UK the National Institute for Health and 
Care Excellence reviewed the available data (2013) and concluded that patients with skin 

Version 1.0, 05Jun2017 
changes or active ulcerations should be referred to a venous specialists and to undergo 
correction of the underlying pathology where appropriate.8   
Although clinical guidelines and specialist societies have stressed the importance of treating 
the underlying venous insufficiency there is reticence to investigate at an early stage in 
patients with venous skin changes and ulcers. Most patients fail to receive appropriate 
investigation or if investigated they still fail to receive timely intervention. With the availability 
of modern, minimally-invasive ablative techniques the arguments for delaying intervention 
are misplaced. The use of foamed sclerosant to ablate distal tributaries feeding the ulcer bed 
offers simple, effective treatment at the bedside. Foam allows for a less invasive approach to 
treating venous hypertension above the knee, while ablating distal veins with reflux that lead 
to skin changes below the knee, which may lead to more rapid healing of VLUs.  The use of 
foams to treat patients with VLUs has increased with data to support the efficacy in 
expediting healing and reducing recurrence. 9,10 FDA-approved endovenous microfoam, 
Varithena®, offers improved safety profile and reduced risk of central complications such as 
neurological adverse events compared with air based physician compounded foam.11 In this 
report, the authors who have had empirical success in treating leg ulcer patients with 
superficial vein disease describe their technical approach to using Varithena® endovenous 
microfoam  to directly address the cause of the venous leg ulcer. 
 
Diagnosis: As with all vein disease, the primary mode of diagnosis is with duplex ultrasound 
and color flow mapping.  
1. Proximal incompetence in the saphenous system is identified and the relative 
contribution to overall incompetence is determined.  
2. It is important to develop a complete venous map down to the ulcer area, noting sources 
of retrograde flow and re-entry perforators.  
a. In instances of leg ulcer it is beneficial for the physician and Registered 
Vascular Technologist (RVT) to map the routes of incompetence together. 
Veins should be traced towards the ulcer with scanning performed through 
the ulcer bed to determine their termination.  
b. Incompetent and dilated perforators that do not connect to superficial veins 
and conduct blood towards the foot, are re-entry perforators and are not 
contributing to overall venous hypertension.(diagram)  
3. The majority of venous leg ulcers are caused by great saphenous incompetence and 
venous hypertension transmitted to the gaiter area by the incompetent tributaries. These 
are all within the label treatment for Varithena® chemical ablation. A small number of 
ulcers are caused by small saphenous incompetence, usually occupying the lateral 
aspect of the leg.  

Version 1.0, 05Jun2017 
4. It is important to inspect the deep veins that the perforators connect to for competence. 
The presence of deep vein incompetence is not an absolute contra-indication to 
superficial vein treatment. The relative importance of superficial to deep incompetence is 
based on the duplex findings. If the superficial incompetence is dominant then its 
elimination will still yield benefit and may result in correction of the deep vein 
incompetence when the physiological disturbance and pressure (or ‘overload’) is 
eliminated. Some superficial veins feeding the ulcer are very superficial and can be seen 
visually and palpated. For these veins, ultrasound examination should be conducted with 
ample gel and minimal pressure so as not to occlude the vein with the probe and yield a 
false negative result. 
 
Exclusion of other potential causes: The patient population with leg ulceration are 
predominantly older and have consequentially more co-morbidities. It is important to 
consider the comorbidities when making the diagnosis. Arterial disease is the most common 
co-existing disease. Ankle brachial pressure indices (ABI) should be measured in all cases 
and validated with Doppler pulse wave profiles or photoplethysmography (PPG) pulsatility, if 
available, beware of calcified vessels giving erroneously elevated ABI values. Reduced ABI 
may suggest the need for future arterial bypass; this should be considered before ablating 
the GSV. ABI as low as 0.8 can be treated normally but below 0.8, post treatment 
compression needs to be reduced. With an ABI below 0.6, it is necessary to investigate and 
treat the arterial disease first if appropriate. 
If arterial intervention is not indicated, treatment with Varithena can still be carried out, 
though being careful to reduce the post treatment compression to take into account the 
reduction in arterial function. 
 
Causes of immobility are common and significantly add to the impact of venous insufficiency 
since the calf pump is not engaged to facilitate emptying of the vessels. Patients with 
significant mobility restrictions should be monitored after treatment as per current practice 
since they are at an increased risk for deep vein thrombosis (DVT).   
Rarer causes of ulcer should be considered but not limited to vasculitis, rheumatoid arthritis 
and neoplasia.  
Morbid obesity and diabetes should be addressed and should be referred to a specialist 
physician or group for assistance.  
 
Treatment: Treatment of patients with VLU is similar to patients with saphenofemoral 
junction (SFJ) and trunk vein incompetence, with additional emphasis on following and 
ablating any incompetent tributary varicose veins towards the ulcer. Treatment should be 

Version 1.0, 05Jun2017 
performed with the leg elevated 30-45 degrees before treatment to empty the superficial 
veins.    
Pre-operative marking is important to trace the varicosities towards the site of the ulcer. 
Frequently there may be a single dilated vein which may communicate with a perforator 
under the ulcer bed. The course of the vein(s) is mapped and marked using duplex 
ultrasound with the patient standing immediately before starting the procedure.  The distal 
portion may be more easily mapped with the patient on the table in reverse Trendelenburg 
(foot down) in which case it is important to apply copious quantities of gel and apply little 
pressure with the probe. When multiple vessels have been identified, venous access should 
be obtained for each of the incompetent tributaries below the knee and towards the 
lipodermatosclerotic (LDS) skin or ulcer. If multiple incompetent vessels are identified they 
should be mapped and multiple venous access points planned. 
 
As with the normal Varithena® procedure, injection of distal varices is accomplished from the 
access point and with a finger applying gentle pressure proximal to the access site. The 
foam is then injected at a steady rate (0.5-1 ml/s) and will travel distally. It remains important 
to monitor the re-entry perforators and not to permit foam to flow freely into the deep system. 
At the moment the foam column reaches the immediate intersection of superficial vein and 
perforator, the skin over the perforator is compressed and pressure above the access point 
is released. If there is significant extension of the incompetent vein beyond this point 
additional access with a butterfly needle will permit more distal filling. Forced dorsiflexion of 
the ankle (e.g. tell the patient to act as if they were pressing a gas pedal) will limit flow into 
the perforators, and repeated pumping of the ankle will stimulate flow in the deep calf veins 
and should minimize risk of thrombosis in these veins. 
 
When all incompetent veins approaching or under the ulcer have been filled, or the 
maximum volume of Varithena® has been administered (15 ml/treatment) the procedure is 
complete. Secondary and additional treatments may be necessary if the condition is bilateral 
or if the varicosities are extensive and extremely tortuous. . As described in the Instructions 
For Use it is important to ensure that the treating physician is able to visualise the column of 
Varithena that is being injected. Varithena is relatively echogenic given the gas fraction and 
so this should be straightforward and this feature also allows close control of the foam 
column to ensure that it only passes along the target vessels. Digital compression or 
dorsiflexion of the ankle can be employed to minimise the risk of unintended passage of 
Varithena into the deep venous system via the perforators. 
 

Version 1.0, 05Jun2017 
Post treatment compression The wound needs routine care after it has been exposed for 
treatment and should be cleaned with simple non-allergenic fluids, covered by non-adherent 
dressings and finally, compression bandaging. The leg should not be lowered before 
application of compression has been completed. The pressure applied by the bandaging 
should be modified to account for the pressure of the elastic stocking.  The patient should be 
instructed to wear the compression bandaging for 48h. As for most leg ulcers, a once a week 
dressing change is sufficient.  Dressings combined with multi–layer bandage and 20-30 
mmHg thigh stocking will be adequate. 
 
Special considerations 
Incompetent perforators: Varithena® is not indicated for perforator treatment. However,  if 
the superficial vein above and below the perforator is ablated there should be no flow in the 
perforator. In the rare case where a functionally incompetent perforator persists and is 
contributing to venous hypertension, it may be ablated with other techniques. 
 
Preparation: Thorough skin prep of the leg and ulcer should take place using iodine, 
starting in the thigh and working distally towards, and including, the ulcer assuming there is 
no known allergy to iodine. Prophylactic antibiotics are not indicated. 
 
Venous access: Access of the feeding vein to the ulcer can be made using the device of 
choice. Butterfly needles (21 or 23 G) are preferred and they should have  a long extension 
tube. Alternatively, and when there is a straighter segment of vein, a venous access kit using 
the sleeve will provide secure access.  In some cases, simple IV catheters can be used. 
Small gauge needles (>25G) and catheters should be avoided as they are too flexible and 
result in high velocity jets of foam which encourage mixing of foam and blood. 
 
Follow-up: Routine follow-up should be provided with an assessment at 1 week post-
treatment when dressings should be changed. At this time, a duplex assessment for 
completeness of treatment should be conducted. Reflux time and vein patency should be 
documented. Additional Varithena® treatment may be provided at this time if needed. 
Because veins in the ulcerated limb are frequently larger and more extensive, additional 
treatments are more common than for routine varicose vein patients.  
 
 
 

Version 1.0, 05Jun2017 
References 
1. 
Robertson L, Evans C and Fowkes FG. Epidemiology of chronic venous disease. 
Phlebology. 2008; 23: 103-11. 
2. 
Margolis DJ, Bilker W, Santanna J, et al. Venous leg ulcer: incidence and 
prevalence in the elderly. J Am Acad Dermatol 2002;46(3):381-6. PMID: 
11862173. 
3. 
Rice JB1, Desai U, Cummings AK, Birnbaum HG, Skornicki M, Parsons NBurden 
of venous leg ulcers in the United States. J Med Econ. 2014 May;17(5):347-56. 
doi: 10.3111/13696998.2014.903258. Epub 2014 Mar 24. 
4. 
Bergan JJ, Schmid-Schonbein GW, Smith PD, et al. Chronic venous disease. 
Engl J Med 2006;355(5):488-98. PMID: 16885552. 
5. 
McGuckin M, Waterman R, Brooks J, Cherry G, Porten L, Hurley S, Kerstein M. 
Validation of venous leg ulcer guidelines in the United States and United 
Kingdom. Am J Surg  2002 Feb;183(2):132–7 
6. 
Forssgren A1, Nelzén O. A Repeat Validated Population Questionnaire of a 
Defined Swedish Population Verifies Reduction in Leg Ulcer Prevalence Over 
Time. Acta Derm Venereol. 2015 Jul;95(6):725-9. doi: 10.2340/00015555-2060. 
7. 
Barwell JR1, Davies CE, Deacon J, Harvey K, Minor J, Sassano A, Taylor M, 
Usher J, Wakely C, Earnshaw JJ, Heather BP, Mitchell DC, Whyman MR, Poskitt 
KR. Comparison of surgery and compression with compression alone in chronic 
venous ulceration (ESCHAR study): randomised controlled trial. Lancet. 2004 Jun 
5;363(9424):1854-9. 
8. 
Marsden G, Perry M, Kelley K, Davies AH and Guideline Development G. 
Diagnosis and management of varicose veins in the legs: summary of NICE 
guidance. BMJ. 2013; 347: f4279. 
9. 
Howard JK, Slim FJ, Wakely MC, et al. Recanalisation and ulcer recurrence rates 
following ultrasound-guided foam sclerotherapy. Phlebology. 2016; 31: 506-13. 
10. 
Lloret P, Redondo P, Cabrera J and Sierra A. Treatment of venous leg ulcers 
with ultrasound-guided foam sclerotherapy: Healing, long-term recurrence and 
quality of life evaluation. Wound Repair Regen. 2015; 23: 369-78. 
11. 
Todd KL, 3rd, Wright DI and Group V-I. The VANISH-2 study: a randomized, 
blinded, multicenter study to evaluate the efficacy and safety of polidocanol 
endovenous microfoam 0.5% and 1.0% compared with placebo for the treatment 
of saphenofemoral junction incompetence. Phlebology. 2014; 29: 608-18. 
 
 
 

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13.6 Appendix F: Venous Clinical Severity Score (VCSS) 
 
Instructions for using the Revised Venous Clinical Severity Score 
On a separate form, the clinician will be asked to: 
“Please check 1 box for each item (symptom and sign) that is listed below.”  
The VCSS should be completed for the leg to be treated/treated leg. 
 
Pain or other Discomfort (i.e., aching, heaviness, fatigue, soreness, burning) 
The clinician describes the 4 categories of leg pain or discomfort that are outlined below to the 
patient and asks the patient to choose the category that best describes the pain or discomfort 
the patient experiences. 
None = 0: None 
Mild = 1: Occasional pain or discomfort that does not restrict regular daily 
Moderate = 2: Daily pain or discomfort that interferes with, but does not prevent, regular daily   
activities 
Severe  = 3: Daily pain or discomfort that limits most regular daily activities 
 
Varicose Veins 
The clinician examines the patient’s leg and chooses the category that best describes the 
patient’s superficial veins. The standing position is used for varicose vein assessment. Veins 
must be ≥3 mm in diameter to qualify as “varicose veins”. 
None  = 0: None 
Mild = 1:Few, scattered, varicosities that are confined to branch veins or clusters. Includes 
“corona phlebectatica” (ankle flare), defined as >5 blue telangiectases at the inner or sometimes 
the outer edge of the foot 
Moderate = 2: Multiple varicosities that are confined to the calf or the thigh 
Severe = 3: Multiple varicosities that involve both the calf and the thigh 
 
Venous Edema 
The clinician examines the patient’s leg and chooses the category that best describes the 
patient’s pattern of leg edema. The clinician’s examination may be supplemented by asking the 
patient about the extent of leg edema that is experienced. 
None = 0: None 
Mild = 1: Edema that is limited to the foot and ankle 
Moderate = 2: Edema that extends above the ankle but below the knee 
Severe = 3: Edema that extends to the knee or above 
 
Skin Pigmentation 
The clinician examines the patient’s leg and chooses the category that best describes the 
patient’s skin pigmentation. Pigmentation refers to color changes of venous origin and not 
secondary to other chronic diseases (i.e., vasculitis purpura). 
None = 0: None, or focal pigmentation that is confined to the skin over varicose veins 
Mild = 1: Pigmentation that is limited to the perimalleolar area 
Moderate = 2: Diffuse pigmentation that involves the lower third of the calf 
Severe = 3: Diffuse pigmentation that involves more than the lower third of the calf 
 
Inflammation 
The clinician examines the patient’s leg and chooses the category that best describes the 
patient’s skin inflammation. Inflammation refers to erythema, cellulitis, venous eczema, or 
dermatitis, rather than just recent pigmentation. 

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None = 0:  None 
Mild = 1: Inflammation that is limited to the perimalleolar area 
Moderate = 2: Inflammation that involves the lower third of the calf 
Severe = 3: Inflammation that involves more than the lower third of the calf 
 
Induration 
The clinician examines the patient’s leg and chooses the category that best describes the 
patient’s skin induration. Induration refers to skin and subcutaneous changes such as chronic 
edema with fibrosis, hypodermitis, white atrophy, and lipodermatosclerosis. 
None = 0: None 
Mild = 1: Induration that is limited to the perimalleolar area 
Moderate = 2: Induration that involves the lower third of the calf 
Severe = 3: Induration that involves more than the lower third of the calf 
 
Active Ulcer Number 
The clinician examines the patient’s leg and chooses the category that best describes the 
number of active ulcers. 
None = 0: None 
Mild = 1: 1 Ulcer 
Moderate = 2: 2 Ulcers 
Severe = 3: ≥3 Ulcers 
 
Active Ulcer Duration 
If there is at least 1 active ulcer, the clinician describes the 4 categories of ulcer duration that 
are outlined below to the patient and asks the patient to choose, for the leg that was treated, the 
category that best describes the duration of the longest unhealed ulcer. 
None = 0: No active ulcers 
Mild = 1: Ulceration present for <3 mo 
Moderate = 2: Ulceration present for 3-12 mo 
Severe = 3: Ulceration present for >12 mo 
 
Active Ulcer Size 
If there is at least 1 active ulcer, the clinician examines the patient’s leg and chooses the 
category that best describes the size of the largest active ulcer. 
None = 0: No active ulcer 
Mild = 1: Ulcer <2 cm in diameter 
Moderate = 2: Ulcer 2-6 cm in diameter 
Severe = 3: Ulcer >6 cm in diameter 
 
Use of Compression Therapy 
Choose the level of compliance with medical compression therapy on the leg to be treated / 
treated leg. 
None = 0: Not used 
Mild = 1: Intermittent use 
Moderate = 2: Wears stockings most days 
Severe = 3: Full compliance: stocking 

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Revised Venous Clinical Severity Score (VCSS) 
 
Pain 
or other discomfort (i.e., 
aching, heaviness, fatigue, 
soreness, burning) 
Presumes venous origin 
None: 0 
Mild: 1 
Occasional pain or other 
discomfort 
(i.e., not restricting 
regular daily activity) 
Moderate: 2 
Daily pain or other 
discomfort 
(i.e., interfering with 
but not preventing 
regular daily 
activities) 
Severe: 3 
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 
 
None: 0 
Mild: 1 
Few: scattered 
(i.e., isolated branch 
varicosities or clusters) 
Also includes corona 
phlebectatica (ankle flare) 
Moderate: 2 
Confined to calf or 
thigh 
Severe: 3 
Involves calf and 
thigh 
Venous Edema 
Presumes venous origin 
None: 0 
Mild: 1 
Limited to foot and ankle 
area 
Moderate: 2 
Extends above ankle 
but below knee 
Severe: 3 
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: 0 
None or 
focal 
Mild: 1 
Limited to perimalleolar 
area 
Moderate: 2 
Diffuse over lower 
third of calf 
Severe: 3 
Wider distribution 
above lower third of 
calf 
Inflammation 
More than just recent 
pigmentation (i.e., erythema, 
cellulitis, venous eczema, 
dermatitis) 
None: 0 
Mild: 1 
Limited to perimalleolar 
area 
Moderate: 2 
Diffuse over lower 
third of calf 
Severe: 3 
Wider distribution 
above lower third of 
calf 
Induration 
Presumes venous origin of 
secondary skin and 
subcutaneous changes 
(i.e., chronic edema with 
fibrosis, hypodermitis) 
Includes white atrophy and 
lipodermatosclerosis 
None: 0 
Mild: 1 
Limited to perimalleolar 
area 
Moderate: 2 
Diffuse over lower 
third of calf 
Severe: 3 
Wider distribution 
above lower third of 
calf 
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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13.7 Appendix G: EQ-5D-5L 
 
 
 

 
© 1990 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group 
 
 
 
 
 
 
 
 
 
 
 
 
Health Questionnaire  
 
English version for the UK  
(validated for Ireland) 
 
 

 
 
© 1990 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group 
 
2
 
By placing a tick in one box in each group below, please indicate which statements 
best describe your own health state today. 
 
Mobility 
I have no problems in walking about 
 
I have some problems in walking about 
 
I am confined to bed 
 
 
Self-Care 
I have no problems with self-care 
 
I have some 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 with performing my usual activities 
 
I have some problems with performing my usual activities 
 
I am unable to perform my usual activities 
 
 
Pain/Discomfort 
I have no pain or discomfort 
 
I have moderate pain or discomfort 
 
I have extreme pain or discomfort 
 
 
Anxiety/Depression 
I am not anxious or depressed 
 
I am moderately anxious or depressed 
 
I am extremely anxious or depressed 
 

 
 
© 1990 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group 
 
3
 
 
To help people say how good or bad a health state is, we 
have drawn a scale (rather like a thermometer) on which 
the best state you can imagine is marked 100 and the 
worst state you can imagine is marked 0. 
 
We would like you to indicate on this scale how good 
or bad your own health is today, in your opinion. 
Please do this by drawing a line from the box below to 
whichever point on the scale indicates how good or 
bad your health state is today. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Your own 
health state 
today 
9 
0 
8 
0 
7 
0 
6 
0 
5 
0 
4 
0 
3 
0 
2 
0 
1 
0 
100 
   Worst 
    imaginable 
     health state 
0 
Best  
imaginable 
health state 

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13.8 Apendix H: Adverse Event Form 
 

Varithena® Venous Leg Ulcer Registry 
Adverse Event Reporting Form V01 
Please email the completed form to BTG Vigilance within 48hrs of awareness to   
 
Vigilance@btgplc.com                                                           1 
 
 
Please complete the following information:  
Section 1. Patient Demographics  
 
Age: 
__________years     Gender:  
 Male 
 Female 
 
Height: __________cm         Weight: _________kg 
Ethnic Origin:  
 Caucasian  
 
                          
 Hispanic/Latin American 
 
                          
 Black/African American  
                          
 Western Asian 
             
                          
 East/Southeast Asian 
      
                          
 Other or unknown 
 
 
Section 2. Varithena Administration  
 
Treatment: _________mL  
 
 
 
Batch Number: ________________ 
 
Date:  ___/____/_____ 
 
 
 
Expiry Date: 
________________ 
 
 
Section 4.  Any relevant medical history/concurrent conditions and clinical progression of the adverse 
event including labs, diagnostics, etc.?                                   
 Y       
N    (If yes, specify below)  
 
 
 
 
 
 
 
 
 
Section 3.  Adverse Events                                                                        Continued on a separate sheet?      
 Y 
Event 
No. 
Adverse Event Term 
Dates of Onset & Resolution 
(dd/mmm/yyyy) 
Outcome of 
Event1 
Causal 
Relationship2 
1   
 
Onset        /          / 
 
 
Resolution        /          / 
2   
 
Onset        /          / 
 
 
Resolution        /          / 
3   
 
Onset        /          / 
 
 
Resolution        /          / 
4   
 
Onset        /          / 
 
 
Resolution        /          / 
5   
 
Onset        /          / 
 
 
Resolution        /          / 
 
(1)  Outcome of Event (enter one code per event):  1 = Fatal    2 = Not Resolved    3 = Resolved    4 = Resolved with Sequelae    5 = Resolving 
(2)  Causal Relationship to Varithena (enter one code): 0 = “Not related (no reasonable possibility)” 1 =  “Related (reasonable possibility)”    

Varithena® Venous Leg Ulcer Registry 
Adverse Event Reporting Form V01 
Please email the completed form to BTG Vigilance within 48hrs of awareness to   
 
Vigilance@btgplc.com                                                           2 
 
Section 5.  Concomitant medications  
Only include drugs given within the 30 days prior to AE onset excluding treatment for AE  
Drug Name 
Brand 
Indication 
for use  
Total Daily 
Dose Prior to 
this AE 
(include units) 
Freq.  
Route of 
admin. 
Date of First Administration of Drug 
AND 
Date of Last Administration of Drug 
Prior to this SAE 
(dd/mmm/yyyy) 
 
 
 
 
 
First         /          / 
Last         /          / 
 
 
 
 
 
First         /          / 
Last         /          / 
 
 
 
 
 
First         /          / 
Last         /          / 
 
 
 
 
 
First         /          / 
Last         /          / 
 
 
 
 
 
First         /          / 
Last         /          / 
 
 
 
 
 
Section 6.  Reporter information  
 
HCP Name:   
 
 
 
Position:  
 
 
 
Hospital Name:   
 
 
 
 
Address:   
 
 
 
 
 
 
 
 
 
State:  
 
 
 
Contact details:  
 
 
 
Form(s) completed by: 
Print 
Name: _________________________________ 
Signature: __________________________________ 
Date of 
Completion: 
      /          /