Investigation of Femoropopliteal In Situ Valve Formation With the InterVene System
Phase: NA
Conditions: Chronic Venous Insufficiency
Sponsor: Intervene, Inc.

InterVene, Inc. 
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03 November 2021 
 
 
 
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CONFIDENTIAL 
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Investigation of Femoropopliteal In Situ Valve Formation 
with the InterVene System 
INFINITE-OUS 
 
 
Version: CLN 003 Rev 04 
03 November 2021 
 
Sponsor 
InterVene, Inc. 
415 Grand Ave, Ste. 302 
South San Francisco, CA 94080 
USA 
 
This Clinical Investigational Plan is the sole property of InterVene, Inc.  Any reproduction in part 
or whole without the written permission of InterVene, Inc. is prohibited.  
 
 

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TABLE OF CONTENTS 
PROTOCOL AGREEMENT............................................................................................................... 6 
CLINICAL STUDY SYNOPSIS.......................................................................................................... 7 
1 
INTRODUCTION AND BACKGROUND ............................................................................... 11 
1.1 
Pathophysiology of Chronic Venous Insufficiency .............................................................. 11 
1.2 
Clinical Need ........................................................................................................................ 13 
1.3 
Treatment Strategies for Venous Valvular Incompetence .................................................... 13 
2 
INTENDED USE AND DESCRIPTION OF THE STUDY DEVICE ................................... 13 
2.1 
Intended Use of the System .................................................................................................. 13 
2.2 
Device Description ................................................................................................................ 14 
2.3 
Device Traceability ............................................................................................................... 15 
3 
PRIOR INVESTIGATIONS ...................................................................................................... 15 
4 
STUDY OBJECTIVES ............................................................................................................... 15 
4.1 
Study Purpose ....................................................................................................................... 15 
4.2 
Scope and Duration of the Study .......................................................................................... 15 
4.3 
Iterative Evaluation Process for Device, Procedure, Protocol Modifications ....................... 16 
5 
CLINICAL STUDY DESIGN .................................................................................................... 16 
5.1 
Study Population ................................................................................................................... 16 
5.2 
Inclusion Criteria .................................................................................................................. 16 
5.3 
Exclusion Criteria ................................................................................................................. 17 
5.4 
Informed Consent .................................................................................................................. 19 
5.5 
Primary Safety Endpoint ....................................................................................................... 19 
5.6 
Primary Effectiveness Endpoint ............................................................................................ 19 
5.7 
Secondary Endpoints ............................................................................................................ 19 
5.8 
Study Assessments ................................................................................................................ 20 
Compression Therapy Use: ........................................................................................................... 20 
Wound Care Regimen: .................................................................................................................. 20 
Photography: ................................................................................................................................ 20 
Duplex Ultrasound: ...................................................................................................................... 21 
Venography: .................................................................................................................................. 21 
IVUS:............................................................................................................................................. 22 
Air plethysmography: .................................................................................................................... 23 
Revised Venous Clinical Severity Score: ...................................................................................... 23 
Pain VAS Score: ............................................................................................................................ 24 

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Patient Reported Outcome Survey: ............................................................................................... 24 
VEINES-QOL/Sym Questionnaire: ............................................................................................... 24 
6 
INVESTIGATIONAL PROCEDURE AND POST-PROCEDURAL CARE ....................... 25 
6.1 
Preparation of the Subject for the Procedure ........................................................................ 25 
6.2 
Periprocedural Medications .................................................................................................. 26 
Option 1: ....................................................................................................................................... 26 
Option 2: ....................................................................................................................................... 26 
6.3 
Diagnostic Venogram and IVUS .......................................................................................... 27 
6.4 
Formation of the Autogenous Valve Leaflets ....................................................................... 27 
6.5 
Completion Venography and IVUS ...................................................................................... 28 
6.6 
Sheath/Guide Removal ......................................................................................................... 28 
6.7 
Post-procedural Care Regimen ............................................................................................. 28 
7 
INVESTIGATIONAL DEVICE ACCOUNTABILITY .......................................................... 29 
7.1 
Accountability of Investigational Devices ............................................................................ 29 
7.2 
Other Devices and Equipment .............................................................................................. 29 
8 
STATISTICS AND DATA ANALYSIS .................................................................................... 30 
8.1 
Statistical Methodology ........................................................................................................ 30 
8.2 
Sample Size Calculation ....................................................................................................... 30 
8.3 
Study Visit Window .............................................................................................................. 30 
8.4 
Missing Data ......................................................................................................................... 30 
8.5 
Demographics and Baseline Characteristics ......................................................................... 30 
8.6 
Analysis of the Primary Safety Endpoint .............................................................................. 30 
8.7 
Analysis of the Primary Effectiveness Endpoint .................................................................. 30 
8.8 
Analysis of Follow-Up Observations .................................................................................... 30 
8.9 
Subgroup and Other Analyses ............................................................................................... 31 
8.10 
Interim Analyses ................................................................................................................... 31 
9 
ASSESSMENTS AND FOLLOW-UP SCHEDULE ................................................................ 31 
9.1 
Screening/Baseline Assessment ............................................................................................ 31 
9.2 
Point of Enrollment ............................................................................................................... 32 
9.3 
Treatment Assessment .......................................................................................................... 32 
9.4 
Follow-Up Assessments ........................................................................................................ 32 
9.5 
Unscheduled Follow-up Visits .............................................................................................. 33 
9.6 
Study Exit, Withdrawal and Lost to Follow-Up ................................................................... 33 
10 
STUDY MANAGEMENT CONSIDERATIONS................................................................. 34 

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10.1 
Data Management: Collection of Clinical Data .................................................................... 34 
10.2 
Publication ............................................................................................................................ 34 
10.3 
Protocol Modifications .......................................................................................................... 34 
10.4 
Protocol Deviations ............................................................................................................... 34 
10.5 
Information to Study Personnel ............................................................................................ 35 
11 
DEVICE DEFICIENCIES ..................................................................................................... 35 
11.1 
Defining Device Deficiency.................................................................................................. 35 
11.2 
Reporting of Device Deficiency ........................................................................................... 35 
12 
SAFETY ASSESSMENTS AND ADVERSE EVENT REPORTING ................................ 35 
12.1 
Clinical Observations ............................................................................................................ 35 
12.2 
Defining Adverse Events ...................................................................................................... 35 
12.3 
Reporting of Adverse Events ................................................................................................ 36 
12.4 
Classification and Reconciliation of Adverse Events ........................................................... 37 
13 
DEVICE ACCOUNTABILITY ............................................................................................. 37 
13.1 
Accountability and Procedures ............................................................................................. 37 
14 
STUDY ADMINISTRATION ................................................................................................ 38 
14.1 
Site Initiation ......................................................................................................................... 38 
14.2 
Study Monitoring .................................................................................................................. 39 
14.3 
Study Termination ................................................................................................................ 39 
14.4 
Data Handling and Recordkeeping ....................................................................................... 40 
Completing, Signing and Archiving Case Report Forms .............................................................. 40 
Data Management and Archiving ................................................................................................. 40 
Direct Access to Source Data/Documentation .............................................................................. 40 
15 
STATEMENTS OF COMPLIANCE .................................................................................... 41 
16 
ETHICS ................................................................................................................................... 41 
16.1 
Informed Consent .................................................................................................................. 41 
16.2 
Ethics Committee and Regulatory Authority ........................................................................ 41 
16.3 
Confidentiality Regarding Study Subjects ............................................................................ 42 
16.4 
Oversight Committees .......................................................................................................... 42 
16.5 
Core Reference Laboratories ................................................................................................ 42 
16.6 
Participating Institutions and Investigators ........................................................................... 43 
16.7 
Agreements ........................................................................................................................... 43 
16.8 
Responsibilities ..................................................................................................................... 43 
17 
DATA SECURITY AND SCIENTIFIC INTEGRITY ........................................................ 43 

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17.1 
Access to Data ....................................................................................................................... 43 
17.2 
Security and Confidentiality ................................................................................................. 44 
17.3 
Electronic Data ...................................................................................................................... 44 
18 
RISK ANALYSIS .................................................................................................................... 44 
18.1 
Risks to the Subjects ............................................................................................................. 44 
18.2 
General Venous Intervention Risks ...................................................................................... 45 
18.3 
BlueLeaf Device and Procedure Risks .................................................................................. 45 
18.4 
Concomitant Medication Risks ............................................................................................. 46 
18.5 
Risk Mitigation ..................................................................................................................... 47 
18.6 
Benefit to Subjects ................................................................................................................ 47 
18.7 
Study Justification ................................................................................................................. 47 
19 
ABBREVIATIONS ................................................................................................................. 47 
20 
REVISION HISTORY ........................................................................................................... 49 
21 
REFERENCES ........................................................................................................................ 53 
APPENDIX A ...................................................................................................................................... 56 
A1: revised Venous Clinical Severity Score (rVCSS)41 ............................................................... 56 
A2A: RAND SF-36 ....................................................................................................................... 56 
A2B: VAS PAIN QUESTIONNAIRE (METHODS)................................................................... 56 
A3: VEINES-QOL/Sym Information43  ........................................................................................ 56 
 
 
 

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PROTOCOL AGREEMENT 
 
Investigation of Femoropopliteal In Situ Valve Formation with the InterVene System 
 
 
Investigator Name 
 
 
 
 
 
 
Investigational Site Name 
 
Investigational Site Number 
 
I have read the protocol and agree that it contains all necessary details for carrying out this study. I will 
conduct the study as outlined therein.  
I will provide copies of the protocol and all information on the device relating to past non-clinical and 
clinical experience, which were furnished to me by the Sponsor, to all physicians and other study 
personnel responsible to me who participate in this study, and will discuss this material with them to 
ensure that they are fully informed regarding the device and the conduct of the study. 
I agree to keep records on all subject information (e.g., case report forms and informed consent 
statements), device shipments and return forms, and all other information collected during the study, in 
accordance with local and national regulations. 
 
 
 
 
Investigator’s Signature 
 
 
Date 
  
 
 

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CLINICAL STUDY SYNOPSIS  
Protocol Number 
CLN 003 Rev 04 
Investigational Device BlueLeaf®  Endovenous Valve Formation System (BlueLeaf System) 
Study Title 
Investigation of Femoropopliteal In Situ Valve Formation with the 
InterVene System (INFINITE-OUS) 
Sponsor 
InterVene, Inc. 
415 Grand Ave, Ste. 302 
South San Francisco, CA 94080 
USA 
Study Purpose 
To evaluate the safety and effectiveness of the BlueLeaf System for the 
restoration of deep venous competence for the treatment of symptomatic 
chronic venous insufficiency (CVI).  
Study Population 
Subjects with CVI and a Clinical Etiological Anatomical 
Pathophysiological (CEAP) classification of 3 – 6; up to 60 enrolled 
subjects  
Investigational Sites 
Up to 10 investigational sites outside the United States 
Study Design 
Prospective, non-randomized, multicenter pre-market feasibility study to 
evaluate subjects treated with the BlueLeaf System for the treatment of 
symptomatic CVI of the lower extremity. 
Primary Endpoint 
Primary Safety Endpoint:  
1 
Freedom from deep venous thrombosis (DVT) in the target vessel 
defined as:  
a. Thrombotic occlusion, or  
b. Stenosis due to thrombus accounting for > 50% diameter 
reduction through the 30-day follow-up;  
and/or 
2 
Freedom from symptomatic pulmonary embolism confirmed by 
contrast-enhanced pulmonary angiography through the 30-day 
follow-up. 
 Primary Effectiveness Endpoint:  
Acute procedural success is evidence of hemodynamic effect as 
demonstrated by Intravascular ultrasound (IVUS) and/or venographic 
based evidence of pocket filling accompanied by leaflet or pocket 
mobility, at any autogenous valve sites. 
 
NOTE: ‘Target vessel’ is defined as the common femoral, proximal 
femoral, distal femoral and popliteal vein segments, in continuity 
(including duplications), of the treatment limb. 
Inclusion Criteria 
Subjects must meet the following criteria to be included in the study:  
1. 18 years of age or older; 
2. Symptomatic CVI subjects, CEAP classification 3 to 6; 

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3. Failed at least 6 months of conservative therapy at some point during 
the course of their CVI management (symptoms not adequately 
resolved or patient non-compliant/unable to tolerate);  
4. Willing and able to sign the approved informed consent form (ICF); 
5. Willing to comply with follow-up evaluations and protocols; 
6. Deep system venous reflux characterized by >1 second reflux time in 
two vein segments (vein segments defined as: proximal femoral, 
distal femoral, and popliteal), as assessed by duplex ultrasound 
(DUS) with patient in the standing position; 
7. Presence of at least two potential target sites within the target vessel, 
which is defined as a segment within the femoral or popliteal vein 
that is: 
• not less than 7mm in luminal diameter, and 
• not more than 12mm in luminal diameter, and  
• is at least 3cm long (two target sites in a row must be spaced 
at least 1 cm apart), and  
• is absent severe obstructive features such as thrombus, 
synechiae, natural valves, major tributaries (valves can be 
formed opposite tributaries) or severe heterogeneous fibrotic 
changes of the vessel wall which, in the Investigator’s 
opinion, would preclude formation of a valve,  
as preliminarily assessed by DUS, and then by IVUS, while the vein 
is under physiologically appropriate hemodynamic pressure, with 
IVUS being the definitive modality. 
8. In the Investigator’s opinion, the subject is a good candidate for 
treatment with the BlueLeaf System based on their symptoms, quality 
of life, anatomy, and the likelihood of benefit from continued 
conservative therapy. 
Exclusion Criteria 
Subjects with any of the following criteria are ineligible for inclusion in 
the study:  
1. Untreated significant superficial venous incompetence which, in the 
opinion of the Investigator, may be the primary source of existing 
symptoms; 
2. Deep venous intervention (includes stenting) in the target limb or 
outflow vessels within 3 months of consent; 
3. Significant peripheral arterial disease with an ankle-brachial index of 
<0.70 or with incompressible vessels; 
4. Contraindications to all protocol specified anticoagulation options; 
5. Known and uncontrolled hypercoagulopathy (i.e. hypercoagulopathy 
that cannot be adequately managed/controlled with medication); 
6. Acute deep venous thrombosis (DVT) within 6 months of consent; 
7. Comorbidity risks or other concerns (e.g. recent cancer) which, in the 
opinion of the Investigator, limit longevity or likelihood of complying 
with the protocol and its prescribed follow up or would preclude the 

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patient from open surgery in the event of a complication requiring 
surgical intervention (e.g. severe vein laceration); 
8. General contraindications to local, regional or general anesthesia 
required for the index procedure; 
9. NYHA Class III or IV heart failure; 
10. Active systemic infection; 
11. Women on long-term oral contraceptives; 
12. Subject is enrolled in another clinical study that, in the opinion of the 
Investigator, may conflict with this study or compromise study 
results; 
13. Invasive surgical procedure within the last 90 days that in the 
Investigator’s opinion would interfere with the study procedure or 
results; 
14. History of stroke within the last 6 months; 
15. Subject is incarcerated or will be incarcerated during the course of the 
study; 
16. Flow-limiting venous outflow obstruction central to the intended 
target sites, defined by a common femoral vein duplex exam found to 
have a continuous waveform without respiratory variation or a 50% 
or greater reduction in luminal cross–sectional area on IVUS;  
17. Inadequate flow into or through the target vessel (Investigator’s 
opinion);  
18. Anatomy that does not support proper device access of the treatment 
vein through the ipsilateral common femoral or femoral vein; 
19. Luminal diameter <7 mm between the vein access site and the 
intended treatment site, as assessed by IVUS, while the vein is under 
physiologically appropriate hemodynamic pressure; 
20. A competent vein valve in any vein segment through which the 
device is likely to be inserted, as assessed by DUS (<1 second reflux 
time) or with contrast venography (Investigator’s opinion); 
21. Chronic renal insufficiency with creatinine level of ≥2mg/dL; 
22. Hemoglobin level <9.0 mg/dL; 
23. Platelet count <50,000 or >1,000,000 per mm3; 
24. Total white blood cell count <3,000/mm3; 
25. Pregnant or lactating female; positive pregnancy test, women of 
childbearing potential must be tested; 
26. Non-ambulatory patients; 
27. Patients with a history of right heart failure occurring as a 
consequence of, for example, biventricular failure, intrinsic 
pulmonary disease, chronic thromboembolic pulmonary 
hypertension, and other etiologies that result in elevated right-sided 
pressures. 
Follow-Up Schedule 
Subjects will be followed through 360 days with annual visits through 5 
years. (A total of 5 years of study participation.) 

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Medical Monitor 
An independent Medical Monitor will review all primary safety endpoint 
events, unanticipated adverse device effects, and other important safety 
occurrences. 
Data Safety 
Monitoring Board 
(DSMB) 
An independent Data Safety Monitoring Board (DSMB) will review 
safety data from the study at predetermined time points as detailed in the 
protocol and as deemed necessary by the Sponsor or the DSMB Chair. 
The DSMB will make recommendations on protocol modifications and 
continuation of the study. 
Core Laboratories 
Assessment of duplex ultrasound, venography, IVUS, optional APG (Air 
Plethysmography) and ulcer photography will be performed by 
independent Core Laboratories. 
 
 
 
  
 
 

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1 INTRODUCTION AND BACKGROUND 
Chronic venous insufficiency (CVI) with incompetence of the deep venous valves affects 20% of the 
adult population.1 It has been estimated that varicose veins, the most common manifestation of CVI, 
are present in 25-33% of female and 10-20% of male adults.2-9 The prevalence of CVI continues to rise 
as the population ages. Signs of CVI include edema, telangiectasia, reticular or varicose veins, and skin 
changes including ulceration.10 Symptoms caused by CVI include chronic pain, edema, skin 
hyperpigmentation, dermatoliposclerosis, and ultimately ulceration in some patients (Figure 1). The 
symptoms of CVI are the source of significant patient discomfort, lost productivity and economic costs 
to society at large.11-13 
The total cost of CVI is estimated to be approximately $1 billion in Germany, France, and the UK. 
Estimates of the total cost of CVI in the US exceed $ 1 billion.14, 15 It is likely that these costs are much 
greater today, as these estimates are from the 1990’s.  
 
1.1 Pathophysiology of Chronic Venous Insufficiency 
It is quite rare for CVI to result from congenital malformations.10 The most frequent causes of CVI are 
from primary abnormalities of the venous wall and vein valves, or secondary changes resulting from 
previous venous thrombosis.10 For many patients suffering from primary or secondary CVI, these 
painful symptoms are caused by failed venous valves in the legs (Figure 2).  
 
Figure 1. Stages of progression from edema to active ulceration in patients with chronic venous 
insufficiency. 

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Figure 2. Healthy and diseased veins in the human lower extremity with reversal of flow in the 
superficial and deep venous systems. 
 
When venous valves fail and blood is permitted to flow retrograde toward the feet (venous reflux), 
patients suffer from elevated venous pressures, which triggers an inflammatory cascade that leads to 
the edema, skin changes and ulceration previously described. In some cases, these changes in skin result 
from severe impairment of blood capillary circulation in the limbs of patients with CVI.16 While many 
patients develop symptoms due to diseased superficial veins, a significant number of patients suffer 
from severe venous symptoms due to incompetent venous valves in the deep vein system. 
Unfortunately, deep system valve failure currently results in lifelong, often incapacitating symptoms of 
leg edema, pain, difficulty walking, and psychological disorders that are exacerbated by a lack of 
definitive treatment options. The standard of care is palliative and includes compression therapy, leg 
elevation and regular wound care. Studies have shown that patients with chronic venous ulcers suffer a 
reduced quality of life similar to that of patients with malignancies, diabetes and congestive heart 
failure.12 
 
Various diagnostic measures have been used to identify the nature and extent of CVI. These measures 
are particularly valuable in light of the fact that the history and physical examination does not always 
accurately indicate the nature and extent of the underlying abnormality such as the anatomic extent, 
pathology, and cause.17-19 For this reason, it will be important to utilize multiple diagnostic and 
measurement modalities in this study to gain a more complete picture of a patient’s baseline disease 
state and to assess that patient’s improvement following a procedure. In the past, localizing venous 
obstruction required a phlebogram but that is no longer the case thanks to advances in duplex scanning, 
which is considered simpler and more accurate than venography.10 That said, ascending venography 
has maintained a role in demonstrating vein patency, defining anatomy, and distinguishing between 
primary and secondary disease. Ascending venography also plays a secondary role in detection of 
incompetent perforating veins.10  

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Descending venography is used to identify reflux (in the superficial or deep veins) and determine points 
of reflux from the pelvis to lower limbs and deep to superficial veins.10 Other methods used to obtain 
information relating to morphology include varicography and liquid crystal thermography, amongst 
others. A variety of techniques, including ambulatory venous pressure, arm/foot pressure differential, 
air plethysmography and others, are available to gather hemodynamic information.10 
 
1.2 Clinical Need 
CVI patients with extensive deep vein reflux who fail superficial therapy are numerous and suffer from 
poor quality of life.  The costs associated with palliative care is large, particularly if ulceration develops. 
The average direct cost of patients with venous ulcers has been estimated to be $15,700 over a median 
follow-up of one year, and this number is significantly higher for patients with untreatable disease and 
nonhealing ulcers.20 Interventional options for patients suffering from extensive deep vein reflux are 
limited, with only a few centers offering a few varieties of technically-challenging open surgical 
procedures. This leaves most patients with nothing but the burdensome palliative care options 
previously described, or costly wound care management if the disease progresses. A less invasive, and 
easy to perform deep vein valve intervention is sorely needed for this patient population.  
 
1.3 Treatment Strategies for Venous Valvular Incompetence 
Open surgical and, more recently, minimally invasive techniques have been used to restore valve 
competence in the deep veins.13, 21 Minimally invasive techniques have historically focused on valve 
implantation with a foreign body, but no clinically viable technologies have been proven out to date.22 
Unfortunately, open surgical techniques are invasive and can be technically challenging. For these 
reasons, open surgical venous procedures are performed in only a handful of highly specialized centers. 
However, their results support the hypothesis that restoration toward normal venous valve function in 
only one or two locations, without a significant foreign body implant, can relieve the symptoms of CVI. 
This observation is the basis of InterVene’s approach. The BlueLeaf System is designed to mirror the 
goals of open surgical valve formation, but with a less invasive, percutaneous procedure. The goal of 
the BlueLeaf System is to percutaneously form one or more functional, autogenous deep venous valves 
and restore venous competence. An autogenous valve will henceforth be defined as a non-natural, newly 
formed valve that is either monocuspid (one autogenous leaflet) or bicuspid (two autogenous leaflets at 
the same vein level). Refer to the Investigator’s Brochure (IB) for additional background information. 
 
2 INTENDED USE AND DESCRIPTION OF THE STUDY DEVICE 
2.1 Intended Use of the System 
The BlueLeaf System is designed to treat patients with symptomatic CVI with evidence of deep venous 
valvular incompetence in the femoral and popliteal veins. The device is intended to form autogenous 
tissue leaflets from vein walls without the use of a permanent vascular implant. 

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2.3 Device Traceability 
Lot numbers will be used to trace devices used in the study. 
 
3 PRIOR INVESTIGATIONS 
The first generation InterVene device was evaluated in two patients in New Zealand in a First-in-Human 
experience (described in the IB). The first-generation device was a larger-bore system (20Fr), and 
utilized a distinct approach for valve formation, with separate tools for valve pocket formation and 
intimal incision. 
 
This study is being performed to allow the Sponsor to collect safety and effectiveness on its BlueLeaf 
System in preparation for a larger Feasibility and/or Pivotal study. 
 
4 STUDY OBJECTIVES 
4.1 Study Purpose 
The purpose of this study is to provide information on the BlueLeaf System for the formation of one or 
more autogenous vein valves constructed from autogenous leaflets in the femoral and/or popliteal vein, 
in subjects with CVI and who meet the specified eligibility criteria. In particular, the safety and technical 
feasibility of the procedure will be validated in humans, including the procedural steps, operator 
technique, and subject characteristics. The study will assess the safety and effectiveness of the study 
device acutely and through 5 years. 
 
In addition, the study will capture information on the femoral and popliteal vein anatomic and 
physiologic characteristics before and after formation of the autogenous valves, with respect to imaging 
data from venography, IVUS and duplex ultrasound, and hemodynamic data generated from duplex 
ultrasound and quantitative air plethysmography (APG) (optional testing). This data will be used to 
determine the most appropriate imaging and physiologic measures for subsequent investigations. In 
addition, the study will assess changes in general patient reported outcome surveys such as SF-36, and 
venous quality of life indices including the rVCSS and VEINS-QOL/Sym as they relate to the study 
procedure. 
 
4.2 Scope and Duration of the Study 
The study commenced enrollment in November of 2017. Enrollment is expected to conclude 24 months 
later and subjects will be followed for 5 years after treatment.   
 
Up to 10 investigational sites Outside the United States (OUS) will enroll up to 60 subjects, with 
expectation that approximately 30 of those 60 subjects will meet all inclusion/exclusion criteria and be 
eligible for the study treatment.  
 
The study will provide initial insights into the following aspects of the study device and procedure: 
• 
whether the device can be successfully delivered to the intended locations in the target vessel; 

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• 
technical challenges with use of study device; 
• 
human factors related to the device and comprehension of the procedural steps; 
• 
clinical safety of the device-specific aspects of the autogenous valve formation procedure; 
• 
whether the device performs its intended purpose of forming functional autogenous valves 
that are durable over early (30-day) and long-term follow-up; 
• 
characterization of device failures and analysis of their causes; 
• 
anatomic and other patient-related characteristics that may impact device performance; 
• 
therapeutic parameters that may impact device use, including sizes and actuation scheme of 
the device components. 
 
4.3 Iterative Evaluation Process for Device, Procedure, Protocol Modifications 
The study will have periodic subject outcome assessments and analyses by the Data Safety Monitoring 
Board (DSMB) in addition to a review by the Sponsor. The DSMB met after 7-day follow-up data was 
complete on the first three subjects prior to continued enrollment. Subsequent DSMB assessments will 
occur if/when there are substantial changes to the device or procedure which could impact subject 
safety.  In this case, the DSMB will review the 7-day follow-up data of the first 3 subjects enrolled with 
the modified device.   
 
Additionally, the DSMB will remain apprised of data as it comes in and a formal review will take place 
at least every 3 months during enrollment and during the first year of all subject’s study follow-up.  
5 CLINICAL STUDY DESIGN 
This Study of the BlueLeaf System (INFINITE-OUS) is an interventional, non-randomized, 
multicenter, pre-market, single-arm prospective clinical trial. The analyses are descriptive in nature, 
with no planned statistical comparisons. The study is not hypothesis-driven and no formal hypotheses 
will be tested. For this reason, there is no sample size calculation but the total sample size is pre-
specified at 30 treated subjects with data analyzed in an iterative fashion.  
 
5.1 Study Population 
The study population will include up to 30 male and female subjects treated with symptomatic, non-
obstructive dominant, CVI who are candidates for lower extremity endovascular venous intervention to 
address incompetence of the femoropopliteal valves.  
 
5.2 Inclusion Criteria 
Subjects must meet the following criteria to be included in the study.   
1. 18 years of age or older; 
2. Symptomatic CVI subjects, Clinical Etiological Anatomical Pathophysiological (CEAP) 
classification 3 to 6; 
3. Failed at least 6 months of conservative therapy at some point during the course of their CVI 
management (symptoms not adequately resolved or patient non-compliant/unable to tolerate);  
4. Willing and able to sign the approved informed consent form (ICF); 

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5. Willing to comply with follow-up evaluations and protocols; 
6. Deep system venous reflux characterized by >1 second reflux time in two vein segments (vein 
segments defined as: proximal femoral, distal femoral, and popliteal), as assessed by DUS 
with patient in the standing position; 
7. Presence of at least two potential target sites within the target vessel, which is defined as a 
segment within the femoral or popliteal vein that is: 
• 
not less than 7mm in luminal diameter, and 
• 
not more than 12mm in luminal diameter, and  
• 
is at least 3cm long (two target sites in a row must be spaced at least 1cm apart), 
and  
• 
is absent severe obstructive features such as thrombus, synechiae, natural valves, 
major tributaries (valves can be formed opposite tributaries) or severe 
heterogeneous fibrotic changes of the vessel wall which, in the Investigator’s 
opinion, would preclude formation of a valve,  
8. as preliminary assessed by DUS, and then by IVUS, while the vein is under physiologically 
appropriate hemodynamic pressure, with IVUS being the definitive modality. 
9. In the Investigator’s opinion, the subject is a good candidate for treatment with the BlueLeaf 
System based on their symptoms, quality of life, anatomy, and the likelihood of benefit from 
continued conservative therapy. 
 
5.3 Exclusion Criteria 
Subjects with any of the following criteria are ineligible for inclusion in the study:  
1. 
Untreated significant superficial venous incompetence which, in the opinion of the 
Investigator, may be the primary source of existing symptoms; 
2. 
Deep venous intervention (includes stenting) in the target limb or outflow vessels within 3 
months of consent; 
3. 
Significant peripheral arterial disease with an ankle-brachial index of <0.70 or with 
incompressible vessels; 
4. 
Contraindications to all protocol specified anticoagulation options; 
5. 
Known and uncontrolled hypercoagulopathy (i.e. hypercoagulopathy that cannot be 
adequately managed/controlled with medication); 
6. 
Acute deep venous thrombosis (DVT) within 6 months of consent; 
7. 
Comorbidity risks or other concerns (e.g. recent cancer) which, in the opinion of the 
Investigator, limit longevity or likelihood of complying with the protocol and its prescribed 
follow up or would preclude the patient from open surgery in the event of a complication 
requiring surgical intervention (e.g. severe vein laceration); 

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8. 
General contraindications to local, regional or general anesthesia required for the index 
procedure; 
9. 
NYHA Class III or IV heart failure; 
10. Active systemic infection; 
11. Women on long-term oral contraceptives; 
12. Subject is enrolled in another clinical study that, in the opinion of the Investigator, may 
conflict with this study or compromise study results; 
13. Invasive surgical procedure within the last 90 days that in the Investigator’s opinion would 
interfere with the study procedure or results; 
14. History of stroke within the last 6 months; 
15. Subject is incarcerated or will be incarcerated during the course of the study; 
16. Flow-limiting venous outflow obstruction central to the intended target sites, defined by a 
common femoral vein duplex exam found to have a continuous waveform without 
respiratory variation, or a 50% or greater reduction in luminal cross–sectional area on IVUS;  
17. Inadequate flow into or through the target verssel  (Investigator’s opinion);  
18. Anatomy that does not support proper device access of the treatment vein through the 
ipsilateral common femoral or femoral vein; 
19. Luminal diameter <7 mm between the vein access site and the intended treatment site, as 
assessed by IVUS, while the vein is under physiologically appropriate hemodynamic 
pressure; 
20. procedure competent vein valve in any vein segment through which the device is likely to be 
inserted, as assessed by DUS (<1 second reflux time) or with contract venography 
(Investigator’s opinion); 
21. Chronic renal insufficiency with creatinine level of ≥2mg/dL; 
22. Hemoglobin level <9.0 mg/dL; 
23. Platelet count <50,000 or >1,000,000 per mm3; 
24. Total white blood cell count <3,000/mm3; 
25. Pregnant or lactating female; positive pregnancy test, women of childbearing potential must 
be tested; 
26. Non-ambulatory patients; 
27. Patient with a history of right heart failure occurring as a consequence of, for example, 
biventricular failure, intrinsic pulmonary disease, chronic thromboembolic pulmonary 
hypertension, and other etiologies that result in elevated right-sided pressures. 
 

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5.4 Informed Consent 
Written, study-specific Informed Consent will be obtained from each subject prior to treatment with the 
BlueLeaf System. The Investigator will keep the original ICF and a copy will be given to the subject. It 
will also be explained to the subjects that they are free to refuse entry into the study and free to withdraw 
from the study at any time without prejudice to future treatment. Subjects will be consented for a total 
of five years. 
 
5.5 Primary Safety Endpoint 
The primary safety endpoint is the: 
• 
Freedom from deep venous thrombosis (DVT) in the target vessel defined as:  
o Thrombotic occlusion, or  
o Stenosis due to thrombus accounting for > 50% diameter reduction through the 30-
day follow-up;  
and/or 
• 
Freedom from symptomatic pulmonary embolism confirmed by contrast-enhanced pulmonary 
angiography through the 30-day follow-up. 
 
NOTE: ‘Target vessel’ is defined as the common femoral, proximal femoral, distal femoral and 
popliteal vein segments, in continuity (including duplications), of the treatment limb. 
 
5.6 Primary Effectiveness Endpoint 
The primary acute procedural success endpoint is evidence of hemodynamic effect as demonstrated by 
Intravascular ultrasound (IVUS) and/or venographic based evidence of pocket filling accompanied by 
leaflet or pocket mobility, at any autogenous valve sites.  
  
5.7 Secondary Endpoints 
The following will be secondary endpoint measures: 
• 
Freedom from target vessel deep venous thrombosis (DVT) in the primary treated vein 
segment at 90, 210, and 360 day follow-up imaging study. 
• 
Additional Outcome Measures 
The following will be additional outcome measures: 
 
All-cause mortality; 
 
PE as defined above beyond 30-day follow-up; 
 
Major bleeding, defined as Type 3a or greater bleeding using the Bleeding Academic 
Research Consortium criteria; 
 
Mural thickening or thrombus deposition not qualifying as a target vessel DVT; 
 
For CEAP 6 subjects, progression/regression of venous ulcer area, as expressed by 
total area of ulceration in the target limb; 

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 
Post-procedural Reflux Time (RT) of each individual autogenous valve and volumetric 
flow rates within a target vessel by DUS as detailed in the Imaging Manual of 
Operations; 
 
APG indices for subjects evaluated with APG as measured with change from baseline, 
including Venous Volume (VV), Ejection Fraction (EF) and Residual Volume 
Fraction (RVF) and Venous Filling Index (VFI); 
 
Disease-specific Quality of life indices, including rVCSS and VEINES-QOL/Sym; 
 
General patient reported outcome survey such as the SF-36; 
 
Technical success, defined as delivery of the system to the target vessel and formation 
of at least one mobile autogenous valve (as measured with IVUS following valve 
formation) without target vessel occlusion at the conclusion of the index procedure. 
 
CVI symptom evaluation, including Visual Analog (VAS) pain score and calf swelling 
 
5.8 Study Assessments 
The following study procedures and assessments will be required as noted in Table 1. A more complete 
description of the imaging assessments are included in the Imaging Manual of Operations. In case of 
any discrepancies between this protocol and the Imaging Manual of Operations, the Imaging Manual of 
Operations will be followed.   
 
Compression Therapy Use:  
Baseline and study duration compression therapy use information will be collected for all subjects at 
each follow up visit.  The type (i.e. 20-30 mm HG below-knee compression hose) and frequency of use 
(i.e. daily use) should be documented.  
 
Recommended post-procedural compression use is described in section 6.7. 
 
Wound Care Regimen:  
Baseline and study duration wound care regimen information (frequency of visits to a wound clinic and 
note of type of treatments received) will be collected for subjects presenting with leg wounds upon 
enrollment. Wound care regimen information will continue to be collected for these subjects for the 
duration of their study follow up.  If a leg wound develops during the study for any subject, this same 
wound care regimen information will be collected upon first presentation of the wound and for the 
duration study participation.  
 
Recommended post-procedural wound care is described in section 6.7. 
 
Photography:  
Subjects with leg ulcers upon enrollment must have photography of the ulcers at each visit where at 
least one ulcer is present. If an ulcer is completely healed during the course of follow-up, photography 
will be completed at the first visit following ulcer healing, but not in subsequent visits, unless an ulcer 

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recurrence occurs. Ulcer healing will also be documented in the source documents and on the follow-
up case report form (CRF).  
 
When photography is conducted, at least two photos of each ulcer will be obtained with a ruler present 
in the field of view of each photo. If more than one ulcer is present, additional photos of the subject’s 
entire leg will be obtained to orient the reviewer to the individual ulcer photos.  Specific photography-
based ulcer tracking technologies may be used as long as the photography requirements described are 
met. A copy of each photo will be submitted to the Sponsor and each will be labeled by location. No 
photo will include the subject’s face or other personal identifiers in the frame. 
 
The Imaging Manual of Operations should be referred to for additional details. 
 
Duplex Ultrasound:  
In the screening phase, color-flow duplex ultrasound will be obtained to document target vessel patency, 
reflux and other relevant subject screening information, with subject in the supine and standing 
positions, per specific guidelines outlined in the Imaging Manual of Operations. Waveform analysis of 
the common femoral vein will be used to rule out subjects with obvious outflow obstructions. Baseline 
RT and volumetric measurements will be made in the femoral, and popliteal veins, with the subject in 
the standing position. 
 
In study follow-up visits, views of each formed autogenous valve will be obtained and quantitative and 
qualitative data will be taken. Qualitative assessments, such as leaflet mobility, and flow reversal will 
be taken for each treatment site. Baseline RT and volumetric measurements will be made in the femoral, 
and popliteal veins, with the subject in the standing position. 
 
Specific parameters for duplex procedures, such as use of an automated calf cuff, manual augmentation, 
and subject positioning will be provided in the Imaging Manual of Operations, and must be adhered to, 
in order to insure consistency between subjects and between visits. 
 
Volumetric measurements involve utilizing a volumetric measurement program that is included within 
all modern DUS machines to capture a time averaged value of reflux velocity, in addition to the duration 
of reflux captured in the RT measurement. Furthermore, the sonographer is instructed to measure the 
luminal diameter of the vessel at the measurement location, so that a volumetric reflux value can be 
calculated. Volumetric measurements are taken concurrently with the RT measurements, and require 
no additional equipment. 
Venography:  
Contrast venography will be performed prior to commencement of the index procedure. The access site 
may be chosen at the Investigator’s discretion. Access will be achieved percutaneously using ultrasound 
guidance or through an open surgical venous exposure. The venogram will be performed with a scale 
present in the field of view.  
 
The screening venogram should include views of the ipsilateral outflow vessels, including the femoral, 
common femoral, external iliac and common iliac veins to assess outflow obstruction, although 

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definitive exclusion for outflow obstruction is determined with intravascular ultrasound. The contrast 
will be injected into the femoral or more caudal vein to assess outflow from the femoral vein (common 
femoral vein, external iliac vein, and central iliac vein). Pre-procedurally, a controlled bolus contrast 
venography should be performed as specified in the Imaging Manual of Operations. Additionally, the 
extent of flow limiting post-thrombotic venous change in the femoropopliteal segment will be assessed. 
 
The status of femoropopliteal reflux must be subjectively classified by the Investigator as either present 
or absent to aid in assessment of deep vein reflux. Presence of any competent vein valves between the 
access site and the most proximal potential treatment site must be identified for subject exclusion. The 
pre-intervention diagnostic venogram will be recorded digitally using Digital Imaging and 
Communications in Medicine (DICOM) format and submitted to the core laboratory. 
 
Contrast venography will be performed following completion of each autogenous vein valve formed, 
assessing the amount of residual reflux and the extent of any vessel damage visualized, and the degree 
of vessel stenosis at the site of the target sites. The post-intervention venograms will be recorded 
digitally and submitted to the core laboratory. The last contrast venography performed, after the highest 
autogenous valve formed, should be initiated from the same location as the baseline contrast 
venography performed before the procedure, with the same controlled bolus, as specified in the Imaging 
Manual of Operations.  
 
IVUS:  
IVUS will be performed using machines and probes at the Investigation’s discretion, but with 
appropriate MHz frequency to adequately visualize the target sites. An initial, diagnostic IVUS will be 
performed to assess the presence and extent of any outflow obstruction central to the planned level of 
autogenous valve construction, to include the ipsilateral femoral vein, and the common femoral, 
external iliac and common iliac veins. The diameter, perimeters, and cross-sectional area and location 
of the target sites will be measured with IVUS, as will the presence of any webs, spurs or synechiae in 
the target vessel or ipsilateral central outflow vessels. These parameters will be entered into the 
procedure CRF and IVUS images will be recorded digitally and submitted to the core laboratory. 
Reference diameters, perimeters, and cross-sectional areas of the proximal femoral, distal femoral and 
popliteal veins will also be taken prior to any treatment. 
 
During the valve creation procedure, after the formation of each new autogenous leaflet, IVUS will be 
utilized to assess certain parameters such as leaflet length, leaflet width at body, leaflet width at opening, 
and leaflet thickness, as shown in Figure 5. Leaflet mobility and coaptation will be subjectively graded 
by the Investigator with IVUS.  Coaptation will be objectively assessed by the core laboratory from 
cine venography images. As well, the core laboratory will use IVUS images to assess the thickness of 
the newly formed autogenous leaflets and to assess the degree, if any, of venous wall injury at and 
central to the valves. 
 

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Figure 5. Leaflet dimension guide. Left: side view of critical dimensions for bicuspid 
valve. Right, top view of critical dimensions for bicuspid valve. Similar values are 
collected for monocuspid valves as well. 
 
Air plethysmography:  
APG is an optional test that a site may choose to perform. Sites performing APG will record the APG 
tracing and submit them to the Core Laboratory. VV, EF and RVF and VFI will be assessed by the Core 
Laboratory10, 23, 29-34. The method for performing APG can be seen in Figure 6 below and is detailed in 
the Imaging Manual of Operations. A normal VFI is < 2 mL/s, while VFI values in the 4 - 7 mL/s range 
or higher tend to correlate with an increased severity of CVI.35-38 APG appears to be a reliable predictor 
of venous reflux, providing an estimate of CVI severity and an objective measure of deep reflux and/or 
perforator reflux.34 When APG is performed at the baseline, the assessment must be conducted at 7-
day, 30-day, 12-week, 210 and 365-day follow-up visits and will be considered per protocol. 
 
Figure 6. Air plethysmography (APG) curve for testing of reﬂux and calf muscle function. A. After elevation of the leg, 
the patient will stand with the weight on the contralateral limb until maximum venous volume (VV) is reached. B. One 
tiptoe movement. C. Ten tiptoe movements. D. The patient returns to the supine position with the leg elevated. VFI is 
calculated by dividing 90% of the venous volume by the time needed to fill 90% of the venous volume after returning 
to an upright position. Ejection fraction (EF) equals ejection volume (EV)/VV x 100%. Residual volume fraction (RVF) 
equals residual volume (RV)/VV x 100%. Reproduced from Kurstjens, et al32 
 
Revised Venous Clinical Severity Score:  
The rVCSS will be determined for each subject by assigning a severity level (0, 1, 2 or 3) to each of the 
ten attributes of venous disease. The rVCSS is provided in Appendix A.   

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The rVCSS evaluation and CEAP classification must be completed within 14 days of the index 
procedure. 
 
Pain VAS Score:  
A pain VAS (visual analogue scale) is a unidimensional measure of pain intensity. Using a ruler, the 
score is determined by measuring the distance (mm) on the 10-cm line between the “no pain” anchor 
and the subject’s mark, providing a range of scores from 0–100, where a higher score indicates greater 
pain intensity.  
 
Patient Reported Outcome Survey: 
(such as the Short Form, SF-36) The short form survey, SF-36, or similar, will be completed to capture 
general patient reported health outcomes. The SF-36 is provided in Appendix A. 
 
VEINES-QOL/Sym Questionnaire:  
The VEINES-QOL/Sym is a patient-based questionnaire that is designed for self-completion. The 
questionnaire measures the impact of CVI-related symptoms and quality of life from the patient’s 
perspective. Questions cover symptoms, limitations in daily activities, time of day of greatest intensity, 
changes over time, and psychological impact. The questionnaire is provided in Appendix A. 
 

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6.2 Periprocedural Medications 
The anticoagulation/antithrombotic regimen is specified in Table 2. 
 
Subjects will be treated with antiplatelet agents beginning on the day of the procedure and continued 
for at least 90 days thereafter. Aspirin is required, and use of Clopidogrel or Prasugrel is optional per 
investigator preference.  
 
Once venous access has been safely obtained, the subject will be anticoagulated with unfractionated 
heparin to achieve an Activated Clotting Time (ACT) of at least 250 seconds or a level corresponding 
to the local standard of care. Heparinization should be continued with repeated boluses or a continuous 
intravenous infusion, at the operator’s discretion, to maintain an adequate ACT throughout the 
interventional procedure.  Unfractionated heparin anticoagulation will be discontinued at the conclusion 
of the procedure unless investigator(s) choose to maintain lower doses of unfractionated heparin up 
until discharge. The use of protamine sulfate is discouraged.  
 
Post-procedurally, investigators have two options for anticoagulation: 
Option 1: 
Enoxaparin (e.g. Lovinox or Clexane) is begun within 2 hours of index procedure, using a weight-based 
twice daily administration (1mg/kg q 12h). Subjects may be assisted with training and administration 
of Enoxaparin injections by healthcare personnel engaged by the study Sponsor. Enoxaparin is 
continued for at least 7 days at this dosage, and is not discontinued until INR ≥2.5.  Warfarin is begun 
day of index procedure or the day after, and is administered per local Standard of Care (SOC) for 
therapeutic dosage. Warfarin is continued for at least 168 days post-index procedure unless bleeding 
complications occur. 
Option 2: 
Enoxaparin (e.g. Lovinox or Clexane) is begun within 2 hours of index procedure, using a weight-based 
twice daily administration (1mg/kg q 12h). Subjects may be assisted with training and administration 
of Enoxaparin injections by healthcare personnel engaged by the study sponsor.  Enoxaparin is 
continued for at least 7 days at this dosage. Direct Oral Anticoagulant (DOAC) such as Rivaroxaban, 
Dabigatran, or Apixaban is begun no more than 12 hours following discontinuation of enoxaparin at a 
therapeutic dose as typical for acute DVT per local SOC, and is continued for at least 168 days post-
index procedure unless bleeding complications occur.  
 
As the initial 7 day twice daily administration of Enoxaparin is considered a key safety requirement, 
the time and date of each injection will be captured and recorded on paper daily for each subject through 
the 7 day post-procedure period.  It must be entered into the electronic data capture (EDC) system by 
at least the day 7 visit. If the 7-day visit occurs before 7 days have elapsed since the procedure, those 
times and dates of each injection up through 7 days that were not accounted for at the 7-day visit, will 
be input at the next visit. Longer use of Enoxaparin will be tracked with other concomitant medications 
without the daily time of administration required to be recorded. 
 
 

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6.5 Completion Venography and IVUS 
Following completion of each autogenous valve leaflet, IVUS will be used to assess leaflet mobility 
and coaptation. Following completion of each autogenous valve (at a particular vein level), contrast 
venography will also be performed according to standard of care.  IVUS will be used to capture study 
specific valve information as detailed in Figure 5.  
 
6.6 Sheath/Guide Removal 
It is important to refrain from occluding the femoral vein outflow when applying manual pressure after 
sheath/guide removal. Ultrasound may be used to assure continued flow through the femoral vein at 
this time, at the discretion of the operator. 
 
6.7 Post-procedural Care Regimen 
Following the procedure, and after the investigator has assured access site hemostasis, the subject 
should ambulate as often as feasible. The subject should wear medium-level (e.g. 15-20 mm Hg) below-
knee level compression hose when out of bed. The use of compression hose must continue for at least 
the first 30 days after the investigational procedure. The compression hose can be removed when in 
bed, at the subject’s discretion. Intermittent pneumatic compression (IPC) devices, if available, should 
be used for at least the 7 days after the procedure and the subject is encouraged to use the devices 
whenever they are non-mobile.  After the 30-day follow-up visit, the subject should return to his or her 
pre-procedure compression level both in type and frequency. For example, if the subject is regularly 
using 10-20 mm HG below-knee compression hose prior to the study procedure, the subject should 
continue on regular use of 10-20 mm HG compression hose after the 30-day follow-up visit is 
completed.  If the subject is not using any compression hose prior to the study procedure (but is still 
included in the study due to prior history of failed conservative therapy), the subject should discontinue 
compression after the 30-day follow-up visit is completed, unless otherwise specified by investigator. 
The use of compression hose and IPC devices is recommended but not mandatory; thus, the failure to 
comply will not be considered a protocol deviation but the reason for non-compliance is to be recorded.  
Compression therapy usage will be tracked at each study follow-up visit. 
 
Strict compliance with the post-procedural anticoagulation/antithrombotic regimens described in Table 
2 is required. Extended travel before the 7-day follow-up visit, including but not limited to air travel, is 
strongly discouraged, and the Sponsor is willing to offer reasonable accommodations local to the 
investigational site to accommodate non-local subjects between discharge and the 7-day follow-up visit. 
 
Reasonable measures may be undertaken to promote compliance with anticoagulation/antithrombotic 
regimens, compression therapy, and mobility. A log of enoxaparin injection times and dates for all post-
procedural days up to and including the day of the 7-day follow-up visit must be maintained and logged 
into the appropriate CRF. The log also includes information on subject compliance with compression 
and mobility. The exact mechanisms for promoting compliance will vary from site to site, but some 
examples of reasonable measures include but are not limited to: 
• 
at-home (or in-hotel) nursing services;  

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• 
third party nursing or research coordinator phone calls, or other communication efforts to 
track and promote compliance; 
• 
outpatient administration of enoxaparin shots by clinical site staff. 
The type and frequency of wound care for subjects with active venous ulcers is not explicitly defined, 
and should be per local standard of care. It is recommended that the subject receive the same type and 
frequency of wound care pre- and post-procedure, as long as that falls within the local standard of care. 
Subjects with active ulcers, not receiving sufficient wound care prior to study enrollment, should be 
further evaluated for ability to resolve symptoms with conservative measures prior to study enrollment 
in alignment with inclusion criteria #8. 
 
7 INVESTIGATIONAL DEVICE ACCOUNTABILITY 
It is expected that an average of approximately 1.5 BlueLeaf Systems per subject will be used. 
 
7.1 Accountability of Investigational Devices 
Each batch of devices will be assigned, at a minimum, a lot number which will be used for tracking 
purposes. Device inventory will be managed using the Device Accountability Log which will include 
details concerning device receipt and disposition.   
 
Access to device inventory will be controlled and devices will be housed in a secure location.  Records 
will be maintained to document the physical location of inventory from shipment/removal from Sponsor 
manufacturing facility through use and/or return or disposal. 
 
The investigational sites will be responsible for keeping records of receipt, use, return and disposal of 
the investigation device which shall include, at a minimum, date of receipt, device identification 
number, expiration date, date of use, subject identification code, and date of disposition. The Device 
Accountability Log is provided for this purpose.  
 
The disposable system components will be disposed of as per standard institutional practice.   
 
If the device is associated with a possible device-related adverse event or device deficiency, the device 
should be returned to InterVene, Inc. for evaluation.  
 
In the event of product return, InterVene, Inc. must be contacted prior to product return for handling 
instructions. 
 
7.2 Other Devices and Equipment 
In addition to the investigational device, a table mount interface system will be provided by Sponsor 
(Top Mount Single Arm with QC Fitting And Rail Clamp, Model 73000-TM from Mediflex or similar).   
The following supplies are also required and are the responsibility of the investigative site.  See the IFU 
for specific recommendations for each item.   
• 
Introducer Sheath 

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• 
Intravascular Imaging Catheter and Corresponding Imaging Capital Equipment 
• 
Inflation Device 
• 
0.035 guidewire (180cm length minimum) 
• 
Syringes, stopcocks, RHV, extension lines and other standard interventional accessories 
 
These items are available commercially for the indications for which they are proposed in this study 
and will not be tracked with the device accountability system and log. 
8 STATISTICS AND DATA ANALYSIS 
8.1 Statistical Methodology 
This is a descriptive study and, as such no performance goals have been defined for the primary safety 
or effectiveness endpoints. 
 
8.2 Sample Size Calculation 
There is no formal sample size calculation in this descriptive, non-hypothesis generating clinical study. 
 
8.3 Study Visit Window 
The follow-up visit windows that will be used for analysis are specified in Table 1.  
 
8.4 Missing Data 
Best efforts will be made to minimize the amount of missing data. Imputation of missing data will not 
be performed. 
 
8.5 Demographics and Baseline Characteristics 
The baseline demographics and anatomic characteristics of the treatment group will be presented with 
descriptive statistics. 
 
8.6 Analysis of the Primary Safety Endpoint 
Descriptive statistics (frequency and percentage) will be calculated for the primary safety endpoint. 
 
8.7 Analysis of the Primary Effectiveness Endpoint 
Descriptive statistics (frequency and percentage) will be calculated for the primary effectiveness 
endpoint. 
 
8.8 Analysis of Follow-Up Observations 
Descriptive statistics will be calculated for all secondary observations, with frequency and percentage 
for categorical variables and mean (or median) and standard deviation (or range) for continuous 
variables. 
 

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8.9 Subgroup and Other Analyses 
No subgroup analyses are planned for this study. 
 
8.10 Interim Analyses 
The DSMB will review safety data (including components of the primary effectiveness endpoint to the 
extent that safety is impacted) to ensure that it is ethical to continue the study, based on the absence of 
unacceptable risks to the subject. There will be no formal interim effectiveness analysis of the primary 
endpoints.  
9 ASSESSMENTS AND FOLLOW-UP SCHEDULE 
Subjects will undergo the assessments depicted in the Schedule of Assessments (Table 1.)  
 
9.1 Screening/Baseline Assessment 
An initial evaluation will be used to determine if a subject may be considered for enrollment. This 
evaluation includes an assessment of diagnostic testing that would have been done as part of a subject’s 
routine care. If the initial assessment shows that the subject may be potential study candidate, the subject 
may be approached for study participation and informed of the risks and benefits of the study. If the 
subject provides written informed consent, then all inclusion/exclusion criteria are to be evaluated. The 
final disposition (e.g., enrollment, ineligibility, or decision by the subject or physician not to enroll) 
must be noted.  
 
The data captured for the Screening Visit may be gathered over the course of more than one office visit; 
however, the data must have been obtained within 2 months of the scheduled procedure date. The 
following procedures will be performed at the Screening visit prior to the procedure and all data must 
be recorded in the subject’s CRF: 
• 
Demographic information 
• 
Medical history including risk factors 
• 
Physical examination with ankle-brachial index 
• 
Compression therapy utilization (last 3 months) 
• 
Ulcer and wound care history (i.e. onset date of longest current active ulcer and recent 
utilization of wound care, if applicable) 
• 
Ulcer photography (if applicable) 
• 
Screening laboratory values to include hemoglobin, platelet count, total white blood cell 
count, and serum creatinine.  
o Clinical laboratory tests are expected to be performed at this visit to establish baseline 
levels. It is recognized that specific panels may vary between institutions. Laboratory 
data will not be specially analyzed but will be used only to support adverse event 
evaluations. 
• 
Duplex ultrasound  
IMPORTANT: The DUS imaging must be submitted to independent medical reviewer to 
confirm anatomical eligibility prior to performing the procedure. 

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o The quality of the DUS must also be confirmed by the duplex imaging core lab prior 
to performing the procedure. 
• 
APG testing, if performed 
• 
Quality of life indices, general and disease-specific  
• 
Serum or urine pregnancy test for females of childbearing potential.  
o The test must be negative at baseline and subject must be using a medically 
acceptable method of birth control. Acceptable methods of birth control include: 
barrier method with spermicide, steroidal contraceptive, contraceptives in conjunction 
with a barrier method, intrauterine device, or abstinence.  No pregnancy test is 
required for post-menopausal women or women who are surgically sterile. 
The procedure will be scheduled to allow InterVene personnel attendance.   
 
9.2 Point of Enrollment 
A subject is considered enrolled in the study after he/she has provided written informed consent. 
 
9.3 Treatment Assessment 
The procedure is conducted under fluoroscopic/venographic and IVUS guidance. Refer to the IFU for 
techniques and methods for device use. 
 
Anticoagulation therapy to ensure an ACT of at least 250 seconds is recommended. Investigator 
discretion is advised regarding antiplatelet therapy and blood pressure adjustment.  
 
Subjects who require conversion to open surgery due to treatment failure with the device will be 
followed at each of the follow-up visits specified in Table 1. 
 
The following data are to be recorded on the subject’s Procedure CRF.  
• 
Venous access site 
• 
Number and location of created valves, including attempted but unsuccessful  
• 
Blood loss and replacement fluids (blood products) administered 
• 
Required unplanned additional/adjunctive procedures 
• 
Adverse events and device deficiencies that occur during the index procedure 
• 
Procedure time (access stick to last sheath/guide removed) 
• 
Device time (introduction of study device to removal of study device) 
 
9.4 Follow-Up Assessments 
Each follow-up assessment will include a duplex ultrasound study to evaluate target vessel patency and 
valvular function. An APG may also be obtained as specified in Table 1. Imaging studies and the APG 
do not need to be performed on the same day as the scheduled follow-up visit.  
 

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9.5 Unscheduled Follow-up Visits 
If a subject returns to the investigator for clinical follow-up visits or undergoes imaging studies not 
protocol-specified but for matters related to the study procedure, such visits will be considered 
unscheduled visits. The assessments completed at such visits will be performed at the discretion of the 
Investigator. CRF pages are provided for unscheduled visits and contain the same information as all the 
follow-up visits, in addition to the reason for the visit. 
 
9.6 Study Exit, Withdrawal and Lost to Follow-Up 
Participation is completely voluntary and each subject is free to withdraw from the study at any time. 
An investigator also has the right to withdraw the subject from the study in the event of illness, adverse 
events or other reasons concerning the health or well-being of the subject, or in the case of lack of 
cooperation. Should a subject decide to withdraw for any reason, or should the investigator decide to 
withdraw the subject, all efforts will be made to complete and report the observations up to the time of 
withdrawal as thoroughly as possible. A complete final evaluation at the time of the subject’s 
withdrawal must be made and an explanation given of why the subject is withdrawing or being 
withdrawn from the study. 
 
Subjects will be exited from the study by completing a Study Exit CRF at the time of study completion 
provided the subject has not experienced an adverse event that is ongoing and unexplained, or, in the 
opinion of the Investigator, requires continued monitoring.  Following study exit, the subject will 
undergo standard medical care for their condition as determined necessary and appropriate by their 
physician.   
 
Subjects may be prematurely terminated or withdrawn from the study for the following reasons: 
• 
Death 
• 
Voluntary withdrawal whereby the subject voluntarily chooses not to further participate in the 
study. In this case, the data collected up to the time of withdrawal will remain in the analytic 
dataset. 
• 
Lost to follow-up. The subject is more than one month late to a study visit and three 
documented attempts to contact the subject are unsuccessful. A subject who misses a study 
visit but attends a subsequent visit will no longer be considered lost to follow-up.  A missed 
visit will be considered a protocol deviation and the deviation will be documented and 
reported. 
• 
In the Investigator’s opinion, it is not in the best interest of the subject to continue study 
participation.  
Successful autogenous valve formation is defined as any % decrease in RT for any treated vein segment 
as compared to the corresponding baseline measurement for that vein segment, at the first post-
procedural imaging study. If it is determined that autogenous valves were never successfully formed; 
or if, at any point after the procedure, it is determined that:  
• 
all autogenous valves are confirmed to have re-adhered to the vein wall, or 
• 
no autogenous valves can be visualized in a duplex follow-up exam and, in the same exam, no 
autogenous valves continue to provide improvement in venous function (defined as having a % 

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decrease in RT for any treated vein segment as compared to the corresponding baseline 
measurement for that vein segment), or 
• 
the target vessel has had a DVT, 
subjects must be followed for at least 90 days post index procedure for safety and then may be exited 
from the study at the discretion of the Investigator or Subject. If any of these items are discovered after 
90 days post index procedure, the subject may be exited from the study at that time, provided there are 
no ongoing AEs or ongoing clinical questions related to the procedure that, in the opinion of the 
investigator, require continued monitoring.  Note that it is preferable to have the Subject remain in the 
study and complete any remaining follow-up visits per protocol. 
 
All subjects treated with the study device, including those withdrawn or lost to follow-up, shall be 
accounted for and documented. The reason for and date of withdrawal must be recorded on the subject’s 
End of Study CRF. If the reason for the withdrawal is a device-related or procedure related adverse 
event (AE), the event must be reported to the Sponsor and recorded in the CRF. If a subject is exited 
from the study before the last day of any window, any required visits or imaging studies within that 
window that were not performed will not be considered missed for the purposes of protocol compliance.  
10 STUDY MANAGEMENT CONSIDERATIONS 
10.1 Data Management: Collection of Clinical Data 
The Sponsor and/or assigned designee will be responsible for the processing and quality control of the 
data. Source data will be retained for at least 2 years after the termination/completion of the study or 
after the approval/withdrawal of the marketing application, whichever occurs later at detailed in section 
13.4.2. 
 
10.2 Publication 
The conditions under which an investigator may publish results from this clinical investigation in any 
form are defined in detail in the clinical trial agreement. 
 
10.3 Protocol Modifications 
No changes from the final approved (signed) protocol will be initiated without appropriate regulatory 
oversight including the regulatory body (including EC) review and approval as appropriate except when 
necessary to eliminate immediate hazards to the subjects or when the change involves only logistics or 
administration. The Principal Investigator will acknowledge the amendment by signing the Protocol 
Agreement. 
 
10.4 Protocol Deviations 
A protocol deviation is the non-adherence to or divergence from the protocol-specific study procedures 
or assessments.  For example, divergence from the specified inclusion and exclusion criteria, deviations 
from the schedule of required follow-up assessments, improper or lack of consent, and lack of EC 
approval, would all be considered protocol deviations. A protocol deviation undertaken to protect the 
life or physical well-being of the subject in an emergency is a special circumstance that must be reported 
to the Sponsor and the reviewing EC within 5 working days. No other type of prospective protocol 

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deviation is permitted without prior approval. A record of all protocol deviations will be maintained 
and reviewed throughout the conduct of the study. The Sponsor will address deviations and take 
appropriate corresponding action. Continued non-compliance with the study protocol may lead to 
termination of the Investigator’s participation in the study. 
 
10.5 Information to Study Personnel 
The Investigator is responsible for giving information about the study to all staff members involved in 
the study or in any element of subject management, both before starting the study procedures and during 
the course of the study (e.g., when new staff become involved). The Investigator must ensure that all 
study staff members are qualified by education, experience, and training to perform their specific 
responsibilities.  
11 DEVICE DEFICIENCIES 
11.1 Defining Device Deficiency 
A device deficiency is an inadequacy of a medical device with respect to its identity, quality, durability, 
reliability, safety or performance. 
 
11.2 Reporting of Device Deficiency 
All device deficiencies related to the identity, quality, durability, reliability, safety or performance of 
an investigational medical device shall be documented throughout the clinical investigation and 
appropriately managed by the Sponsor. 
 
12 SAFETY ASSESSMENTS AND ADVERSE EVENT REPORTING 
12.1 Clinical Observations 
A Clinical observation is defined as an event typically occurring in conjunction with study required 
procedures or medications which require no treatment or action or minor treatment or action by the 
patient or healthcare provider. This type of event will not be reported as an adverse event, but rather 
tracked as a “clinical observation” on a designated CRF.  Examples of a clinical observation may be 
bruising at the groin access site or nausea from the general anesthesia.  
 
If the clinical observation worsens and requires an atypical action or treatment (e.g. intervention is 
required when it is typically not warranted), the event’s status will be elevated from an observation to 
an adverse event and reported accordingly on an Adverse Event CRF. The Clinical Observation and 
Adverse Event forms will have unique identifiers assigned that will allow the event to be identified as 
related.  
 
12.2 Defining Adverse Events 
An adverse event is an untoward medical occurrence, unintended disease or injury, or untoward clinical 
sign (including abnormal laboratory findings) in subjects, users or other persons, whether or not related 

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to the investigational medical device. This includes an exacerbation of an existing medical condition 
subsequent to enrollment in a clinical study.   
 
Adverse events are rated in several ways: 
• 
Severity (mild, moderate, severe) 
• 
Anticipated (anticipated, not anticipated) 
• 
Device and procedure relationships (not related, unlikely, possible, probable, causal 
relationship or relationship unknown). 
 
Adverse events will be categorized as either serious or non-serious.  A Serious Adverse Event (SAE) is 
an adverse event that meets at least one of the following: 
• 
Led to death, 
• 
Led to serious deterioration in the health of the subject, that either:  
o resulted in a life-threatening illness or injury, or 
o resulted in a permanent impairment of a body structure or a body function, or 
o required in-patient hospitalization or prolonged hospitalization, or 
o resulted in medical or surgical intervention to prevent life threatening illness or 
injury or permanent impairment to a body structure or a body function, 
• 
Led to fetal distress, fetal death or a congenital abnormality or birth defect. 
 
NOTE: This includes device deficiencies that might have led to a serious adverse event if a) suitable 
action had not been taken or b) intervention had not been made or c) if circumstances had been less 
fortunate. These are handled under the SAE reporting system. 
 
In addition, SAEs for hospitalization or surgery to treat pre-existing conditions, without a serious 
deterioration in health, will also not be reported as SAEs. 
 
An adverse device effect is an adverse event related to the use of an investigational device. 
 
A serious adverse device effect (SADE) is an adverse device effect that has resulted in any of the 
consequences characteristic of a serious adverse event. 
  
An anticipated serious adverse device effect (ASADE) is an effect which by its nature, incidence, 
severity or outcome has been identified in the risk analysis report. 
 
An unanticipated serious adverse device effect (USADE) is a serious adverse device effect which by 
its nature, incidence, severity or outcome has not been identified in the current version of the risk 
analysis report. 
 
12.3 Reporting of Adverse Events 
Adverse event reporting will start at the initiation of the study procedure (i.e. active preparation of the 
subject, such as initiating hospital’s anesthesia protocol).  Adverse events and concomitant medication 
that occur between the signing of the informed consent and the initiation of the study procedure thus 
will not be reported on the AE CRFs.  

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All reportable adverse events must be captured on the Adverse Event CRF. The report should include, 
wherever possible, severity, duration, outcome, and the Investigator’s written medical judgment as to 
the relationship of the adverse event to the study device, procedure, or underlying disease.  
 
All SAEs and USADEs must be reported to the Sponsor or designee immediately, but no later than3 
calendar days of the Investigator’s knowledge of the event. The event is reported in the electronic data 
capture system. The Sponsor will ensure compliance with all country-specific reporting requirements 
to the appropriate Ethical Committees and Competent Authorities.   
 
Non-serious reportable adverse events are to be submitted via the electronic data capture system in a 
timely fashion. Certain reportable events may require adjudication; therefore, supporting 
documentation may be requested to be sent to the Sponsor or designee. 
 
12.4 Classification and Reconciliation of Adverse Events 
All adverse events will be reviewed by the study’s independent Medical Monitor. Certain categories of 
adverse events and all USADEs will be reviewed by the Medical Monitor. Where the classification of 
an adverse event related to seriousness, relatedness, or whether it meets the criteria for an SAE or 
USADE differs between the Investigator and the Medical Monitor, the classification by the Medical 
Monitor will be reconciled s the final classification for the analytic dataset. If an investigator or the 
Medical Monitor cannot assign a causality category to an event’s relatedness, the event will be 
considered possibly related for reporting and analysis. 
 
For events not meeting the criteria for adjudication by the Medical Monitor but where the Investigator 
and the Medical Monitor differ in one or more elements of event classification, the Medical Monitor’s 
classification will be reconciled as the final classification for the analytic dataset. 
 
13  DEVICE ACCOUNTABILITY 
13.1 Accountability and Procedures 
a) Each device shipment must be documented on the Device Accountability Log and include the 
receipt, dispensing, and return of investigational devices. 
b) When a shipment is received, the Investigator (or designee) must record on the Device 
Accountability Log the date received and the Catalog and Lot Number of each device. It is 
recommended that the Packing List also be signed and dated.  
c) Investigational devices must be kept in a secure, limited access storage area under 
recommended storage conditions (room temperature).  
d) During the course of the study, the following information must also be noted on the Device 
Accountability Log: 
e) Identification number of the subject for whom the device was intended 
f) Procedure date 

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g) The Device Accountability Log must be readily available for inspection by representatives from 
the Sponsor, the EC, and/or other relevant regulatory authorities at any time.   
h) The Device Accountability Log and device storage locations will be reviewed during 
monitoring visits. 
i) All unused investigational devices must be returned to the Sponsor once it is determined they 
will not be used. Upon completion of the study, all unused investigational devices must be 
returned to the Sponsor if any remain at the site. The monitor is to verify return. 
 
14 STUDY ADMINISTRATION 
14.1 Site Initiation 
A Site Initiation Visit (SIV) will be conducted by the Sponsor or other appropriate designee (e.g., a 
CRO) to ensure that all study supplies are present, to ensure proper training of the Investigator and 
study staff members in study-specific procedures, to ensure regulatory requirements are fulfilled prior 
to enrollment of the first study subject at a site, and to verify the site facilities and equipment are 
appropriate for conduct of the study.  
 
The following items will be reviewed at the SIV.  All training will be documented and must contain 
signatures of participants (refer to SIV Training Log in the Regulatory Binder). 
a) Introduction and overview of agenda 
b) Obligations of the Investigator, including his/her responsibilities to ensure only appropriately 
qualified staff participate in the study conduct, and notification to the Sponsor or its CRO of 
any change in staff listed on the Delegation of Authority (refer to the site’s Regulatory Binder) 
during the course of the study 
c) Protocol (overall review including, but not limited to, inclusion/exclusion criteria, 
recruitment/withdrawal of subjects, study restrictions); 
d) Completion and maintenance of the Delegation of Authority  
e) Adverse experience reporting and USADE reporting 
f) CRFs (procedures, corrections, timely completion, retention) 
g) Source document preparation and retention 
h) Role of the EC 
i) Informed Consent Process 
j) Study file documents and document retention (ensure all pertinent regulatory documents are 
collected prior to the site starting the study) 
k) Clinical supplies and device management (storage and accountability; device dispensing, 
labeling, and packaging) 
l) Device training 

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m) Core laboratory processes 
n) Requirements for reporting any clinical data back to the Sponsor. (e.g., annual and final reports) 
o) Monitoring schedule/plan 
p) Other items that may be discussed: background and purpose of the study, previous studies/data, 
regulatory requirements, policy for publishing trial results, special equipment (if necessary). 
 
14.2 Study Monitoring 
Interim monitoring visits will be conducted by InterVene, Inc. personnel or other appropriate designees 
(e.g., a CRO) to ensure compliance with standard operating procedures (SOPs), the protocol, and other 
written instructions and regulatory requirements. 
 
The study monitor is the primary liaison between the Sponsor and the Investigator.  The main 
responsibilities of the monitor are to visit the Investigator before, during, and after the study to ensure 
adherence to the protocol; to verify all data are correctly and completely recorded and reported; and 
confirm that informed consent is obtained and recorded for each subject before study participation. 
 
The study monitor will contact and visit the Investigator at regular intervals throughout the study.  The 
monitor will be allowed to check and verify the various records (CRFs and other pertinent source data 
records) relating to the study to verify adherence to the protocol and to ensure the completeness, 
consistency, and accuracy of the data being recorded. 
 
As part of the supervision of the study progress, other Sponsor personnel may accompany the study 
monitor on visits to the study center.  The Investigator and assisting staff must agree to cooperate with 
the study monitor to resolve any problems, errors, or possible misunderstandings concerning the 
findings detected in the course of these monitoring visits. 
 
14.3 Study Termination 
InterVene, Inc. may terminate this study at any time.  If the study is terminated prior to completion, all 
subjects currently enrolled will be followed through the study visits as detailed in this protocol.  
Regulatory authorities have the right to terminate the entire study or a particular study site at any time. 
Situations that could warrant study termination include, but are not limited to: 
a) Increased incidence of adverse experiences and/or the severity of such, suggestive of a 
potential, device-related health hazard 
b) Insufficient subject enrollment 
c) Recurrent protocol non-compliance, violations or deviations 
d) Inaccurate, incomplete, and/or untimely data recording (>2 business days) on a recurrent basis 
e) Lack of cooperation with monitoring visits (e.g., failure to adequately prepare for visits, address 
action items from one visit to the next, or provide access to medical records) 
 

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14.4 Data Handling and Recordkeeping 
Completing, Signing and Archiving Case Report Forms 
The Investigator must keep a separate subject identification list showing enrollment numbers, names, 
and dates of birth to allow unambiguous identification of each subject included in the study.  It is 
recommended a note be made in the medical record that the subject is participating in a clinical research 
study. 
 
The required data will be recorded on the CRFs.  Clinical study data will be collected using electronic 
case report forms (eCRFs). A web-based electronic data capture (EDC) database will be used to record 
and manage study data. eCRF completion guidelines, the instructions for electronic data-entry, will be 
developed in conjunction with the Sponsor, the CRO, and/or the EDC vendor.  
 
All eCRFs must be kept in good order and updated so they always reflect the latest observations on the 
subjects participating in the study. 
 
The Investigator will sign the appropriate pages of the eCRF and source documentation. An embedded 
audit trail will capture the date, time, and user making updates and changes to the electronic data. All 
data will be entered into the EDC in a timely fashion. 
Data Management and Archiving 
The Sponsor will be responsible for the processing and quality control of the data. Source data for safety 
will be retained for at least 2 years after the termination/completion of the study or after the 
approval/withdrawal of the marketing application, whichever occurs later.  All other source data, 
eCRFs, copies of protocols and protocol amendments, device accountability forms, correspondence, 
subject identification lists, ICFs, and other essential documents must be retained for a period of at least 
2 years after the last approval of the marketing application and until there are no pending or 
contemplated marketing applications, or at least 2 years have elapsed since the formal discontinuation 
of clinical development of the investigational device. Sponsor will inform the Investigator/institution 
when it is no longer necessary to retain these documents.  
 
No study document or image will be destroyed without prior written agreement between the Sponsor 
and the Investigator.  Should the Investigator wish to assign the study records to another party or move 
them to another location, advance written notice must be given to the Sponsor. 
Direct Access to Source Data/Documentation 
The Sponsor, auditors, and health authority inspectors (or their agents) will be given direct access to 
source data and documentation (e.g., medical charts/records, laboratory test results, printouts, 
videotapes) for source data verification, provided that subject confidentiality is maintained in 
accordance with local requirements. 
 
The Investigator must maintain, at all times, the primary records (i.e., source documents) of each 
subject’s data. Examples of source documents are hospital records, office visit records, examining 

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physician’s findings or progress notes, consultant’s written opinion or notes, laboratory reports, device 
inventory, device label records, and CRFs that are used as the source. 
 
The Investigator will maintain a confidential subject identification list that allows the unambiguous 
identification of each subject. All study-related documents must be kept until notification by Sponsor. 
15 STATEMENTS OF COMPLIANCE 
This clinical investigation will be conducted in compliance with the principles that have their origin in 
the Declaration of Helsinki, this clinical investigation plan, requirements of the approving Ethics 
Committee, Good Clinical Practices (GCP), ISO 14155 and other applicable regulatory requirements.  
 
This clinical investigation will not be initiated until approval has been obtained from the Ethics 
Committee and the regulating Competent Authority. Any additional requirements imposed by the Ethics 
Committee or regulatory authority will be followed. No deviation from the protocol will be 
implemented without the prior review and approval of the Ethics Committee except where it may be 
necessary to eliminate an immediate hazard to a subject. In such case, the deviation will be reported to 
the Ethics Committee as soon as possible.  
Clinical trial insurance will be secured prior to initiation of this clinical investigation.  
16 ETHICS 
16.1 Informed Consent 
Written informed consent must be obtained for each subject before any study-specific (non-standard of 
care) procedures or assessments are done and, specifically, prior to the subject being treated with the 
BlueLeaf System. Written informed consent will be obtained after the aims, methods, anticipated 
benefits, and potential hazards are explained.  
 
The subject’s willingness to participate in the study will be documented in writing in the study-specific 
ICF, which will be signed and dated by the subject or Legally Authorized Representative. The 
Investigator will keep the original ICF and a copy will be given to the subject.  It will be explained to 
the subjects that they are free to refuse entry into the study and free to withdraw from the study at any 
time without prejudice to future treatment. Subjects will be consented for five years to allow for the 
ability to collect additional data, in the event that initial study results indicate a need for additional long-
term information (i.e., during a post-approval phase). 
 
16.2 Ethics Committee and Regulatory Authority 
This study must be approved by an appropriate ethics committee (EC) at each investigational site and 
any other applicable regulatory authority (e.g. Competent Authority (CA)). Securing EC approval is the 
responsibility of the Investigator, as defined by ISO 14155-1 prior to starting the study. The Sponsor 
must receive a copy of the EC approval letter (or equivalent documentation) for the study protocol and 
ICF before the study can be started at that site or devices shipped to that Investigator.  
 
The EC and Sponsor must approve any significant changes to the protocol as well as a change of 
Principal Investigator.  Documentation of the EC approval must be provided to the Sponsor.  Records 

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of all study review and approval documents must be maintained by the Investigator in the Regulatory 
Binder and are subject to inspection by the Sponsor or regulatory authority during or after completion 
of the study.  Serious Adverse Events and deaths must also be reported to the EC and Sponsor (reference 
Section 12 for reporting requirements).  
 
The Investigator must notify the EC, and applicable regulatory authority, as per their reporting 
guidelines, and the Sponsor when he or she deviates from the protocol.  The Sponsor must be notified 
of all relevant action taken by the EC and must receive a copy of all study-related correspondence 
between the Investigator and the EC. 
 
At study completion or termination, the EC and applicable regulatory authority must receive notification 
and a final report is to be submitted in accordance with the applicable regulations. A copy of these 
reports must be provided to the Sponsor.  The Investigator must maintain an accurate and complete 
record of all submissions made to the EC.     
 
16.3 Confidentiality Regarding Study Subjects 
The Investigator must ensure that best efforts will be made to hold the privacy of all subjects, including 
their personal identity and all personal medical information.  In CRFs and other documents or image 
material submitted to the Sponsor, subjects will not be identified by their names, but by an individual 
identification code. 
 
Personal medical information may be reviewed for the purpose of verifying data recorded in the CRFs.  
The monitor may conduct source-document verification on behalf of the Sponsor, the quality assurance 
unit, or regulatory authorities.  Personal medical information will always be treated as confidential. 
 
16.4 Oversight Committees 
The DSMB will assure that the study is being conducted ethically. The DSMB membership is 
represented from the key medical disciplines involved with endovascular repair, and may include an 
external biostatistician. None of the members is directly involved with the clinical trial.  
 
The Medical Monitor is an individual who is not a direct participant in the study. At the onset of the 
study, the Medical Monitor will establish explicit rules outlining the minimum amount of data required, 
and the algorithm followed in order to classify a clinical event. The Medical Monitor will review and 
adjudicate appropriate clinical events, mainly related to the device and to the study endpoints. 
 
16.5 Core Reference Laboratories 
One or more central core reference laboratories will independently evaluate imaging data collected at 
participating institutions.  All imaging studies that are performed per the protocol must be sent to the 
Core Laboratory for evaluation. Refer to the Imaging Manual of Operations for details about the 
identified laboratory and instructions for submitting data. 
 

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16.6 Participating Institutions and Investigators 
Study sites and Investigators will be selected based on a variety of factors including, but not limited to, 
experience with endovascular techniques, access to required facilities and equipment, sufficient and 
adequately trained personnel, and availability of potential subjects. No other centers/institutions are 
intended to participate in this study without permission from the relevant regulatory authority. 
 
16.7 Agreements 
All Principal Investigators and their Sub-Investigators must sign an Investigator Agreement.  The 
Sponsor must receive a copy of the signed Investigator Agreement before the study may be started at 
that institution or devices shipped. Any Investigators joining the study after the site has been initiated 
may not receive devices or participate until an agreement is signed and received by the Sponsor. 
 
16.8 Responsibilities 
Investigator responsibilities include, but are not limited to, the following:   
1. Conducting the study in accordance with this investigational plan, signed agreement, and 
applicable regulations protecting the rights and safety of study subjects 
2. Informing all subjects that the device being utilized is for investigational purposes only, and 
ensuring that the requirements relating to obtaining informed consent and EC approvals are met 
3. Ensuring that informed consent is obtained for each study subject in accordance with applicable 
regulations (e.g., ISO 14155-1) 
4. Ensuring that EC approval is secured prior to starting the study and ensuring continuing review 
and approval as required throughout the investigation 
5. Ensuring all associates, colleagues, and employees assisting in the conduct of the study are 
informed about their obligations, are adequately qualified and trained, and meet their 
commitments 
6. Maintaining adequate and accurate records and ensuring those records are available for 
inspection at any time 
7. Ensuring that conducting the study does not give rise to conflict of interest (financial disclosure 
is required)  
8. Controlling of all investigational devices under investigation. 
 
17 DATA SECURITY AND SCIENTIFIC INTEGRITY 
17.1 Access to Data 
The Sponsor, auditors, and health authority inspectors (or their agents) will be given access to source 
data and documentation (e.g., medical charts/records, laboratory test results, printouts, videotapes, etc.) 

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for source data verification, provided that subject confidentiality is maintained in accordance with local 
requirements. 
 
The Investigator must maintain, at all times, the primary records (source documentations) of each 
subject’s data. Examples of source documents are hospital records, office visit records, examining 
physician’s finding or notes, consultant’s written opinion or notes, laboratory reports, device inventory, 
device label records, and CRFs that are used as the source. 
 
The Investigator will maintain a confidential subject identification list that allows the unambiguous 
identification of each subject. All study-related documents must be kept until notification by InterVene, 
Inc. 
 
17.2 Security and Confidentiality  
The Investigator must ensure that the privacy of all subjects, including their personal identity and all 
personal medical information, will be maintained at all times. In CRFs and other documents or image 
material submitted to the Sponsor, subjects will not be identified by their names, but by an identification 
code (i.e., subject number). 
 
Personal medical information may be reviewed for the purpose of verifying data recorded in the CRFs. 
The monitor may perform source data verification on behalf of the Sponsor or regulatory authorities. 
Personal medical information will always be treated as confidential. 
 
17.3 Electronic Data 
Electronic data will only be accessible to authorized personnel through the use of a unique user ID and 
password. Passwords are set to expire periodically. Access to electronic study data will be provided to 
research personnel upon completion of training. Read and write access will be provided to 
investigational sites but only for information and subject data at their own site. The CRO and the 
Sponsor will have read-only access and will have the ability to post queries for potential data-related 
discrepancies. 
18  RISK ANALYSIS 
18.1 Risks to the Subjects 
Treatment with the BlueLeaf System is a procedure that poses significant risks to the subject, although 
these risks are not expected to be greater than with other endovascular treatment or open surgery. A 
summary of some of the known risks are identified below however, there may be risks that are not 
known or are unforeseen at this time. The risks related to the device and to the procedure including 
those related to concomitant medications used periprocedurally and during follow-up are detailed 
below.  Risks associated with anesthetic methods are not detailed as those methods are site specific and 
are typically detailed in a separate pre-operative consent.   
 

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18.2 General Venous Intervention Risks 
Anticipated risks that are associated with general venous interventions, and thus may be encountered in 
this study but are not considered unique to the BlueLeaf device include but are not limited to: 
• 
Air or thrombotic emboli (venous or arterial) 
• 
Hypotension 
• 
Vascular injury 
• 
Access site complications  
o Bruising  
o Bleeding, hemorrhage 
o Pain 
o Hematoma 
o Infection 
o Wound dehiscence  
o Serous wound drainage 
o Lymphorrhea 
o Ecchymosis 
o False aneurysm due to inadvertent arterial puncture 
 
• 
Local 
o Leg edema 
o Leg pain 
o Back pain 
• 
Sepsis 
• 
Phlebitis  
• 
Retained foreign body  
• 
Recurrent or worsened venous disease, related to clinical symptoms or pathophysiology 
• 
Radiation exposure related complication 
• 
Reaction to contrast solution 
• 
Complication resulting in death 
 
18.3 BlueLeaf Device and Procedure Risks 
Potential risks of the BlueLeaf device and procedure are presented below as event categories, with 
specific events sub-listed when appropriate. Note that a sub-listed event may fit multiple categories. For 
example, a “venous perforation” may be a vascular injury during device introduction or positioning or 
a clinically significant vascular injury due to valve formation steps, depending on which action was 
being conducted at the time of its occurrence.  
• 
Vascular injury during device introduction or positioning, such as: 
o Venous perforation 
o Arterial perforation 
o Vascular dissection 
• 
Clinically significant vascular injury due to valve formation steps, such as: 
o False venous aneurysm formation 

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o False aneurysm formation 
o Vascular occlusion 
o Arteriovenous fistula 
• 
Deep Vein Thrombosis 
• 
Mural Thickening or Mural Thrombus Formation  
o At the autogenous valve site 
o Vascular (not near the autogenous valve site) 
• 
Embolism (thrombus or air), such as: 
o Pulmonary embolism 
o Paradoxical embolization 
o Superficial thrombophlebitis 
o Distal embolization 
• 
Device embolization 
• 
Allergic or adverse reaction to ingredient or agent of concomitant medications used peri-
procedurally and during follow-up, contrast or anesthetic 
• 
Allergic or adverse reaction to device materials 
• 
Unusually prolonged clinical procedure, resulting in complications of extended general 
anesthesia 
• 
Device cannot be removed safely using standard techniques, resulting in unanticipated 
surgical maneuvers to remove device  
• 
Unsuccessful formation of functional (i.e. hemodynamically active) valves 
• 
Valves are not durable over time and heal in non-functional position 
 
18.4 Concomitant Medication Risks 
Potential side effects of the protocol required concomitant medications are reflected in the below lists.  
Aspirin 
• 
Black, bloody, or tarry stools 
• 
Coughing up blood 
• 
Severe nausea, vomiting, stomach pain 
• 
Extended fever 
• 
Swelling, or extended pain 
• 
Hearing problems, ringing in ears 
Enoxaparin 
• 
Hemorrhage, bleeding 
• 
Anemia 
• 
Thrombocytopenia 
• 
Elevation of serum aminotransferase 
• 
Diarrhea 
• 
Nausea 
Warfarin 
• 
Tissue necrosis 
• 
Calciphylaxis 
• 
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Direct Oral AntiCoagulant (Apixaban, Dabigatran, Rivaroxaban)  
• 
Uncontrolled bleeding 
 
Further details of risks associated with a specific anesthesia and anticoagulation regimen should be 
detailed in a separate institution-specific pre-operative consent and/or may be cited from public domain 
information (e.g. drug manufacturer’s labeling). Externally referenced risks for the anesthesia and 
concomitant medications will be tracked as adverse events but not categorized as unanticipated. 
 
18.5 Risk Mitigation 
The Sponsor designed the BlueLeaf System to minimize risks to study participants and the risk 
management for the system was completed in accordance with ISO 14971.  
 
The clinical investigational protocol, which includes the study eligibility criteria, was also designed to 
minimize risks to study participants. The eligibility criteria were formulated to limit use of the study 
device to subjects and venous pathology that fit the device specifications. Subjects will be seen more 
regularly by study personnel than standard practice for CVI patients which allows more thorough 
oversight and clinical care. Evaluation of safety data by an independent Medical Monitor and DSMB 
and assessment of imaging studies by an external core laboratory will provide an ongoing assessment 
of safety-related events, both individually and in aggregate.    
 
18.6 Benefit to Subjects 
It is hoped that the BlueLeaf System will provide an additional treatment alternative for patients with 
CVI and incompetent deep venous valves. Currently there exist few definitive options for such patients. 
Conservative measures such as compression stockings and leg elevation treat the symptoms but do not 
address the underlying venous incompetence Open surgical interventions including venous valve 
transposition, valvuloplasty, and other surgical methods are invasive and have been associated with 
suboptimal outcomes. A minimally invasive modality such as endovascular valve construction, if 
durable, would hold the potential to alleviate the pain, edema, ulceration and other aspects of chronic 
venous incompetence; an entity that, in its severe form, afflicts up to 10% of the general population.10, 
13, 39, 40  
 
18.7 Study Justification 
This study is justified in light of previous work showing positive outcomes obtained with the use of the 
study device in peripheral veins. This study will attempt to build on past results and, potentially, identify 
additional benefits of the BlueLeaf System in patients with symptomatic CVI. 
19 ABBREVIATIONS 
The following abbreviations are used in this document: 
ACT 
Activated Clotting Time 
AE 
Adverse Event 
APG 
Air Plethysmography 

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CEAP 
Clinical Etiological Anatomical Pathophysiological 
CRO 
Contract Research Organization 
CRF 
Case Report Form 
CVI 
Chronic Venous Insufficiency 
DOAC 
Direct Oral Anti-Coagulant 
DSMB 
Data Safety Monitoring Board 
DUS 
Duplex Ultrasound 
DVT 
Deep Venous Thrombosis 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EF 
Ejection Fraction 
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
IFU 
Instructions for Use 
INR 
International normalized ratio 
IPC 
Intermittent Pneumatic Compression 
ISO 
International Standards Organization 
IVUS 
Intravascular Ultrasound 
NYHA 
New York Heart Association 
PE 
Pulmonary Embolism 
rVCSS 
revised Venous Clinical Severity Score 
RT 
Reflux Time 
RVF 
Residual Volume Fraction 
SAE 
Serious Adverse Event 
SIV 
Site Initiation Visit 
SOC 
Standard of Care 
USADE 
Unanticipated Serious Adverse Device Effect 
VFI 
Venous Filling Index 
VAS 
Visual Analog Scale 
VV 
Venous Volume 
  
 
 

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APPENDIX A 
  

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