Percutaneous Deep Vein Arterialization Post-Market Study
Phase: NA
Conditions: Critical Limb Ischemia
Sponsor: LimFlow SA

 
Percutaneous Deep Vein Arterialization 
PROMISE UK 
Post-market study  
Clinical Investigation Plan 
Version 4.4-UK 
21 July 2022 

 
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PROTOCOL  SIGNATURE  PAGE  
Percutaneous Deep Vein Arterialization 
PROMISE UK 
Post-market study  
I have read and agree to the final version of the post-market study protocol (version 4.4-UK, dated 21 July 
2022).   
I am aware of my responsibilities as an investigator under the ISO 14155:2020 standard “Clinical investigation 
of medical devices for human subjects—Good clinical practice”, local regulations (as applicable), and the clinical 
investigation plan. 
I agree to conduct the study accordingly and to appropriately direct and assist the personnel under my control 
who will be involved in the study. 
Investigator name:  ___________________________________________________________________________  
Institution name:  ____________________________________________________________________________  
Date (dd/mm/yyyy): _____/_____/__________ 
Signature:  ____________________________________  

 
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0. Table of contents 
0. 
Table of contents .............................................................................................................................................................. 3 
1. 
General information ......................................................................................................................................................... 5 
1.1. 
Identification ........................................................................................................................................................... 5 
1.2. 
Sponsor .................................................................................................................................................................... 5 
1.3. 
Contract research organization ............................................................................................................................... 5 
1.4. 
Independent committee .......................................................................................................................................... 5 
1.5. 
Principal investigators and investigation sites ......................................................................................................... 5 
1.6. 
Overall synopsis of the clinical investigation ........................................................................................................... 6 
1.6.1. 
Objectives ....................................................................................................................................................... 6 
1.6.2. 
Design ............................................................................................................................................................. 6 
1.6.3. 
Endpoints ....................................................................................................................................................... 6 
Primary endpoint ..................................................................................................................................... 6 
Secondary endpoints ............................................................................................................................... 6 
1.6.4. 
Visits and exams ............................................................................................................................................. 6 
1.6.5. 
Inclusion criteria ............................................................................................................................................. 7 
1.6.6. 
Exclusion criteria ............................................................................................................................................ 7 
2. 
Identification and description of the medical device ........................................................................................................ 8 
2.1. 
Summary description and intended purpose .......................................................................................................... 8 
2.2. 
Populations and indications for which the device is intended ................................................................................ 8 
2.3. 
Device identification and materials used ................................................................................................................ 8 
2.4. 
Device manufacturer ............................................................................................................................................... 8 
2.5. 
Traceability .............................................................................................................................................................. 8 
2.6. 
Device description ................................................................................................................................................... 9 
2.7. 
Training and experience needed ........................................................................................................................... 10 
2.8. 
Medical procedures involved ................................................................................................................................ 10 
3. 
Justification for the design of the clinical investigation .................................................................................................. 10 
3.1. 
Results of the preclinical testing ............................................................................................................................ 10 
3.2. 
Clinical data ........................................................................................................................................................... 10 
4. 
Risks and benefits ........................................................................................................................................................... 11 
4.1. 
Anticipated clinical benefits .................................................................................................................................. 11 
4.2. 
Anticipated adverse device effects ........................................................................................................................ 11 
4.3. 
Residual risks associated with the device .............................................................................................................. 11 
4.4. 
Risks associated with participation in the clinical investigation ............................................................................ 11 
4.5. 
Possible interactions with concomitant medical treatments ................................................................................ 11 
4.6. 
Steps that will be taken to control or mitigate the risks ........................................................................................ 12 
4.7. 
Risk-to-benefit rationale ........................................................................................................................................ 12 
5. 
Objectives and hypotheses of the clinical investigation ................................................................................................. 12 
5.1. 
Objectives .............................................................................................................................................................. 12 
5.2. 
Hypotheses ............................................................................................................................................................ 12 
5.3. 
Claims and intended performance to be verified .................................................................................................. 12 
5.4. 
Risks and anticipated adverse effects to be assessed ........................................................................................... 13 
6. 
Design of the clinical investigation.................................................................................................................................. 13 
6.1. 
General .................................................................................................................................................................. 13 
6.1.1. 
Type of clinical investigation ........................................................................................................................ 13 
6.1.2. 
Measures to be taken to minimize or avoid bias ......................................................................................... 13 
6.1.3. 
Primary and secondary endpoints ................................................................................................................ 13 
Primary endpoint ................................................................................................................................... 13 
Secondary endpoints ............................................................................................................................. 13 
6.1.4. 
Methods and timing for assessing, recording, and analysing variables ....................................................... 14 

 
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6.1.5. 
Equipment to be used for assessing the clinical investigation variables ...................................................... 14 
6.1.6. 
Any procedures for the replacement of subjects ......................................................................................... 14 
6.2. 
Device(s) used and comparator(s) ......................................................................................................................... 14 
6.2.1. 
Description of the exposure to the device(s) ............................................................................................... 14 
6.2.2. 
Justification of the choice of comparator(s) ................................................................................................. 14 
6.2.3. 
List of any other medical device or medication to be used .......................................................................... 14 
6.2.4. 
Number of device(s) to be used ................................................................................................................... 14 
6.3. 
Subjects ................................................................................................................................................................. 15 
6.3.1. 
Inclusion criteria ........................................................................................................................................... 15 
6.3.2. 
Exclusion criteria .......................................................................................................................................... 15 
6.3.3. 
Point of enrolment ....................................................................................................................................... 15 
6.3.4. 
Criteria and procedures for subject withdrawal or discontinuation ............................................................ 15 
6.3.5. 
Number of subjects and expected duration ................................................................................................. 16 
6.4. 
Procedures ............................................................................................................................................................. 16 
6.4.1. 
Overview ...................................................................................................................................................... 16 
6.4.2. 
Screening and baseline ................................................................................................................................. 17 
6.4.3. 
Treatment and discharge ............................................................................................................................. 19 
6.4.4. 
Follow-up visits ............................................................................................................................................. 19 
Day 015: two weeks ............................................................................................................................... 19 
Day 030: one month............................................................................................................................... 19 
Day 060: two months ............................................................................................................................. 20 
Day 090: three months .......................................................................................................................... 20 
Day 180: six months ............................................................................................................................... 20 
Day 270: nine months ............................................................................................................................ 20 
Day 360: twelve months ........................................................................................................................ 21 
6.5. 
Monitoring plan ..................................................................................................................................................... 21 
7. 
Statistical considerations ................................................................................................................................................ 21 
7.1. 
Statistical design, method and analytical procedures ........................................................................................... 21 
7.2. 
Sample size ............................................................................................................................................................ 22 
7.3. 
Provision for an interim analysis............................................................................................................................ 22 
7.4. 
Specification of subgroups for analysis ................................................................................................................. 22 
7.5. 
Treatment of missing, unused, or spurious data ................................................................................................... 22 
8. 
Data management .......................................................................................................................................................... 22 
9. 
Amendments to the clinical investigation plan ............................................................................................................... 23 
10. 
Deviations from clinical investigation plan ..................................................................................................................... 23 
11. 
Device accountability ...................................................................................................................................................... 23 
12. 
Statements of compliance .............................................................................................................................................. 23 
13. 
Informed consent process .............................................................................................................................................. 23 
14. 
Adverse events, adverse device effects and device deficiencies .................................................................................... 24 
14.1. 
Definitions ............................................................................................................................................................. 24 
14.2. 
Reporting ............................................................................................................................................................... 24 
14.3. 
Foreseeable events ................................................................................................................................................ 24 
14.4. 
Management ......................................................................................................................................................... 25 
14.5. 
Emergency contact details..................................................................................................................................... 25 
15. 
Vulnerable population .................................................................................................................................................... 25 
16. 
Suspension or premature termination of the investigation ............................................................................................ 25 
17. 
Publication policy ............................................................................................................................................................ 25 
18. 
Definitions ....................................................................................................................................................................... 26 
19. 
Bibliography .................................................................................................................................................................... 27 
20. 
Annex A: list of investigators and investigational sites ................................................................................................... 28 
 

 
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1. General information 
1.1. Identification 
Title 
PROMISE UK 
Version 
Version 4.4-UK 
Date 
21 July 2022 
History 
Please refer to Table 1 below 
Table 1.  Revision history 
Version 
Date 
Changes 
Version 4-UK 
28 November 2018 
Initial version (adapted from PROMISE International version 4) 
Version 4.1-UK 
01 June 2020 
Update product reference numbers, device description, and manufacturer 
Refer to IFU for procedural steps 
Clarify reporting of planned interventions for pre-existing conditions 
Update clinical data section to reference latest published information 
Version 4.2-UK 
 31 May 2021 
Update to study anticipated enrolment and completion timelines due to delays 
experienced due to the coronavirus pandemic.  
Update to current standard: ISO 14155:2020 
Clarification on exiting of patients who met main study endpoint of 
amputation.   
Note that some patient follow-up imaging assessment may be unnecessary in 
cases where earlier occlusion endpoint had been reached, to be discussed with 
the study sponsor. 
Version 4.3-UK 
29 November 2021 
Update to study anticipated enrolment and completion timelines due to 
impacts due to the coronavirus pandemic. 
Version 4.4-UK 
21 July 2022 
Ongoing update to study anticipated enrolment and completion timelines due 
to impacts due to the coronavirus pandemic. 
1.2. Sponsor 
LimFlow SA 
95 bis, boulevard Pereire  
75017 Paris 
France 
1.3. Contract research organization 
MedPass International 
95 bis, boulevard Pereire  
75017 Paris 
France 
1.4. Independent committee 
Syntactx 
4 World Trade Center 
150 Greenwich Street, 44th Floor 
New York, New York 10007 
United States of America 
1.5. Principal investigators and investigation sites 
The list of principal investigators and investigation sites is provided in Annex A to this protocol. 

 
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1.6. Overall synopsis of the clinical investigation 
1.6.1. Objectives 
The objective of this post-market study is to collect “real-life” clinical data among a population of patients treated 
with the commercially-available LimFlow System in order to evaluate the safety and effectiveness of the LimFlow 
System in creating a below-the-knee arterio-venous fistula for venous arterialization in subjects with critical 
limb ischaemia. 
1.6.2. Design 
This study is a single-arm, open-label, prospective, post-market follow-up study to be conducted on up to 25 eligible 
patients (roll-in subjects plus 20 analysis subjects) with a twelve-month follow-up period.  This study was designed 
and is to be conducted in compliance with the ISO 14155 standard. 
1.6.3. Endpoints 
Primary endpoint 
• 
Amputation-free survival 
Secondary endpoints 
• 
Complete wound healing 
• 
Primary and secondary patency 
• 
Limb salvage 
• 
Technical and procedural success 
1.6.4. Visits and exams 
Patients should be followed at regular intervals during one year after the initial percutaneous deep vein 
arterialization procedure.  The protocol follow-up schedule is intended to align with the standard of care as seen 
with patients who are treated with surgical bypass or endovascular revascularization.  Visits and exams scheduled 
for this post-market study are presented in Table 2 below (keys: ◼ mandatory,  optional). 
Table 2.  Visits and exams 
Exams  
Baseline Treatment Week 02 
Month 01 Month 02 Month 03 Month 06 Month 09 Month 12 
Eligibility  
◼ 
 
 
 
 
 
 
 
 
Demographics 
◼ 
 
 
 
 
 
 
 
 
Infection status† 
◼ 
 
 
 
 
 
 
 
 
Venous mapping‡ 
◼ 
 
 
 
 
 
 
 
 
Angiogram 
◼ 
◼ 
 
 
 
 
 
 
 
Ultrasound 
Duplex 
 
Duplex 
Duplex 
Duplex 
Duplex 
Duplex 
Duplex 
Medication 
◼ 
◼ 
◼ 
◼ 
◼ 
◼ 
◼ 
◼ 
◼ 
Creatinine 
◼ 
 
 
 
 
 
 
 
 
Rutherford 
◼ 
 
◼ 
◼ 
◼ 
◼ 
◼ 
◼ 
WIfI 
◼ 
 
◼ 
◼ 
◼ 
◼ 
◼ 
◼ 
Wound pictures 
◼ 
◼ 
◼ 
◼ 
◼ 
◼ 
◼ 
◼ 
Pain 
◼ 
 
◼ 
◼ 
◼ 
◼ 
◼ 
◼ 
◼ 
Perfusion 
 
 
 
 
 
 
 
 
 
Quality of Life 
◼ 
 
 
 
◼ 
◼ 
◼ 
◼ 

 
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Adverse events 
 
◼ 
◼ 
◼ 
◼ 
◼ 
◼ 
◼ 
◼ 
†Wound culture and/or blood analysis (WBC, CRP, ESR) 
‡Phlebography, duplex ultrasound, MRV or CTV, depending on what is available 
1.6.5. Inclusion criteria 
I-1. 
Subject must be > 21 and < 95 years of age 
I-2. 
Clinical diagnosis of symptomatic critical limb ischaemia, defined as Rutherford category 5 or 6 
I-3. 
Assessment that no conventional surgical or endovascular treatment is possible 
I-4. 
Proximally, the target in-flow artery at the cross-over point must be treatable with a 3.5 – 4.0 mm stent 
after pre-treatment (by visual estimate), and be <50% stenosed 
I-5. 
Subject is willing and has adequate support to comply with protocol requirements, including medication 
regimen and follow-up visits 
1.6.6. Exclusion criteria 
E-1. 
Concomitant hepatic insufficiency, deep venous thrombus in target limb, uncorrected coagulation disorders, 
or current immunodeficiency disorder 
E-2. 
Life expectancy less than 12 months 
E-3. 
Patient currently taking coumarin/warfarin which, in the opinion of the attending physician, interferes with 
the patient’s treatment 
E-4. 
Any significant medical condition which, in the attending physician’s opinion, may interfere with the 
patient’s optimal treatment 
E-5. 
Patient currently participating in another investigational drug or device study that has not completed the 
primary endpoint or that clinically interferes with the endpoints of this treatment 
E-6. 
Patient unable to give consent 
E-7. 
Pregnant or breastfeeding women 
E-8. 
Documented myocardial infarction or stroke within previous 90 days 
E-9. 
Patients suffering from renal insufficiency (GFR value less than 30 ml/min/1.73 m²) who are not on 
haemodialysis 
E-10. 
Patients with vasculitis and/or untreated popliteal aneurysms 
E-11. 
Patients with acute limb ischaemia 
E-12. 
Prior peripheral arterial bypass procedure above or below the knee which could inhibit proximal inflow to 
the stent graft 
E-13. 
Lower extremity venous disease with significant oedema in the target limb that may inhibit the procedure 
and/or jeopardize wound healing, in the investigator’s opinion 
E-14. 
Known or suspected systemic or severe infection (e.g., WIfI foot Infection grade of 3) 
E-15. 
Known or suspected allergies or contraindications to stainless steel, nickel, or contrast agent that cannot be 
adequately pre-treated, or patients who cannot receive anticoagulation or antiplatelet aggregation therapy 
E-16. 
Severe heart failure, which in the opinion of the investigator may compromise subject’s ability to safely 
undergo a percutaneous procedure (e.g., known ejection fraction of < 40%, NYHA Classification III-IV) 

 
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2. Identification and description of the medical device 
2.1. Summary description and intended purpose 
The medical device is the LimFlow System, which is CE-marked and intended to treat critical limb ischaemia by 
minimally invasively creating an arterio-venous bypass graft to produce the venous arterialization procedure in the 
below-the-knee vasculature. 
2.2. Populations and indications for which the device is intended 
The LimFlow System is indicated for endovascular, minimally invasive procedures in patients who have a clinical 
diagnosis of symptomatic critical limb ischaemia, have been assessed by a vascular surgeon and interventionalist 
and it was determined that no surgical or endovascular treatment is possible, and are clearly indicated for major 
amputation—also referred as “no-option” patients. 
2.3. Device identification and materials used 
The LimFlow System consists of five (5) medical device components: the ultrasound system, the extension cable set, 
the arterial and venous catheter set, the valvulotome, and a series of stent grafts with delivery systems.  Below in 
Table 3 is a listing of all medical device components including whether or not the devices are sterile, reusable, or in 
contact with patient blood, along with device names and current identification numbers (subject to change). 
Table 3.  Device identification 
Catalogue Number 
Device 
Materials 
Sterile 
Reusable 
Blood  
contact 
LF-US-EU-XX 
Ultrasound system 
Aluminium (outside enclosure of 
transceiver box) plus computer 
notebook 
No 
Yes 
No 
LF-EX-EU-XX 
Extension cable set 
Plastic cable isolation 
Yes 
No 
No 
LF-XX-EU-XX 
Arterial and venous 
catheters 
Various plastics and metals 
(nitinol and stainless steel) 
Yes 
No 
Yes 
LF-VT-EU-XX 
Valvulotome 
Nitinol, stainless steel, and various 
plastics (polyimide, pebax, etc.) 
Yes 
No 
Yes 
LF-SG-DDDDLL-EU-XX 
Stent grafts in lengths 
60 – 200 mm 
Nitinol, PTFE, and various plastics 
(PEEK, polyimide, pebax, etc.) 
Yes 
No 
Yes 
The materials used to construct the LimFlow System including all components are well characterized with a long 
history of clinical use in, and similar in form to, approved and marketed medical devices.  The LimFlow System 
contains no medicinal products, human and/or animal tissues or their derivatives, or other biologically 
active substances. 
2.4. Device manufacturer 
LimFlow SA 
95 bis, boulevard Pereire  
75017 Paris 
France 
Contract Manufacturer:  
Contract Medical International GmbH 
Lauensteiner Strasse 37 
01277 Dresden 
Germany 
2.5. Traceability 
Traceability shall be achieved during the clinical investigation by assignment of lot or serial numbers on all LimFlow 
System components.  Catalogue numbers and lot or serial numbers of all devices used will be collected and 
recorded on the Case Report Forms (CRFs).  LimFlow SA will supply the device; any requests for additional materials, 

 
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equipment, service, or information shall be directed to LimFlow SA.  An inventory of materials will be taken at 
monitor site visits. 
2.6. Device description 
The LimFlow System comprises the following five (5) components: 
▪ 
Ultrasound system 
The LimFlow ultrasound system consists of a power supply, a laptop computer, and a transceiver box.  The 
system produces a short electrical pulse which is applied to the transmit catheter.  The signal received by the 
receive catheter is amplified, filtered, and digitized.  The received signal is then displayed on the laptop as a 
waveform, giving a visual display of the strength of the received pulse and hence permitting orientation of 
the two catheters.  Software running on the laptop permits the gain of the receiver and other parameters to 
be adjusted. 
▪ 
Extension cable set 
The LimFlow extension cables carry power between the LimFlow ultrasound system and the LimFlow arterial 
and venous catheters. 
▪ 
Arterial and venous catheter set 
The arterial catheter is placed over a standard 0.014” guide wire through a sheath in the femoral artery and 
advanced to the target artery up to the point of total arterial occlusion.  The arterial catheter allows for the 
following:  
1. Locating neighbouring veins via ultrasound (if applicable): a small single directed ultrasonic transmitter 
as its tip allows to detect the venous catheter in a neighbouring vein.  The handle design and the 
catheter body allow for an easy torque and push-pull to find the correct location.  
2. Connecting to a neighbouring vein by advancing a crossing-needle: the catheter has a handle which 
advances the crossing needle from artery to vein.  The catheter is placed into the artery with the needle 
retracted inside the catheter shaft.  A standard 0.014” guide wire can be placed through the advanced 
needle from the proximal hub (this wire is referred to as the “crossing wire”). 
The venous catheter acts as a target in the vein for aligning the needle of the arterial catheter via ultrasound 
or fluoroscopy. The catheter is placed over a standard 0.014” guide wire and is placed through a sheath in 
the corresponding target vein and advanced up to and parallel to the arterial catheter. The venous catheter 
is left in place and the arterial catheter is rotated and moved longitudinally to facilitate creation of the 
arterio-venous connection.  
Both arterial and venous catheters are intended to be used in a catheterization laboratory in consenting 
patients under fluoroscopy guidance. Both catheters are supplied sterile, removed at the end of the 
procedure, and intended for single use only. 
▪ 
Valvulotome 
The valvulotome is intended to make venous valves incompetent.  The valvulotome is a device that is 
inserted over the crossing wire, passing the crossing section into the venous vessel.  A push-pull deployment 
mechanism allows to deploy a nitinol cutting basket mounted at the distal tip.  This cutting element self-
centres in the venous vessel up to a maximum diameter of 4.5 mm.  The actual cutting blades are arranged at 
a lower diameter as the maximum diameter of the cutting element, this prevents cutting the venous vessel 
but allows cutting of the vein vales ones the cutting element is pushed through the valves.  The device 
(undeployed cutting element) has a total outside diameter of 4 Fr.  The valvulotome is supplied sterile and 
intended for single use only. 
▪ 
Stent grafts 
To facilitate constant blood flow through the newly-created crossing from artery to vein, a stent graft needs 
to be inserted.  The LimFlow stent grafts product line consists of different self-expanding stent graft sizes and 
shapes, in order to meet physiological variations in anatomy of patients, and one delivery system, which is 
compatible for each stent size.  The blank laser-cut nickel-titanium alloy (nitinol) stent serves as a base for 
additional forming and electro spun PTFE encapsulation procedures to obtain a final stent graft. 
The stent graft delivery system comprises of inner tubing, compatible with a 0.018” guide wire lumen and a 
flushing lumen, which is proximally accessible through a check valve.  Design input specifications require 7-Fr 
sheath compatibility for the delivery device.  In order to achieve excellent mechanical properties and 
functional pushability the outer shaft was designed with a special braid pattern.  Two radiopaque markers 
are attached to the distal end of the delivery device where the stent is crimped in between. Unintended 
stent movement during sheath retraction is restricted by the delivery device.  

 
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2.7. Training and experience needed 
The procedure itself should be performed by vascular surgeons and/or interventionalists experienced in 
interventional techniques such as complex percutaneous transluminal angioplasty and stenting in the lower limb.  
Study investigators will be selected based on their experience in performing below-the-knee interventions and duly 
trained by LimFlow SA on the percutaneous deep vein arterialization specific medical procedure.  In order to avoid a 
learning curve bias, each study investigator will be required to first perform at least one (1) successful 
revascularization in a “roll-in” subject.  “Roll-in” subjects will be included the study but excluded from the endpoint 
analysis.  In addition, a LimFlow SA representative will attend the treatments performed in each site in order to 
assist the physician on technical issues as well as to ensure that treatment characteristics and potential 
complications are duly recorded. 
2.8. Medical procedures involved 
For the LimFlow procedure, please refer to the product instructions for use (IFU). 
3. Justification for the design of the clinical investigation 
3.1. Results of the preclinical testing 
The LimFlow System has undergone extensive verification and validation testing.  This includes device and 
packaging specific performance specifications, as well as transit, sterility, pre-clinical, biocompatibility and 
accelerated aging testing.  Test samples were manufactured in accordance with a Device Master Record (DMR) 
using trained operators to nominal specifications and documented within a Design History Record (DHR). 
Extensive in vitro, in vivo, and ex vivo studies have been successfully performed with the LimFlow System and 
verification testing for the catheter has been completed.  Testing on the device included comprehensive design 
verification and validation testing.  The following testing was completed on the LimFlow System: 
▪ 
Biocompatibility testing 
▪ 
Mechanical testing 
▪ 
Packaging testing 
▪ 
Shelf-life testing 
▪ 
Sterilization validation 
▪ 
Preclinical animal and cadaver studies 
3.2. Clinical data 
In the absence of treatment, Peripheral Vascular Disease (PVD) may progress to critical limb ischaemia (CLI), which 
is characterized by profound chronic pain and extensive tissue loss that restricts revascularization options and 
frequently leads to amputation.  CLI is estimated to have an incidence of approximately 50 to 100 per 100 000 per 
year and is associated with mortality rates as high as 20% at 6 months after onset. 
Interventional radiologists have been aggressively trying to treat CLI by attempting to open up Chronic Total 
Occlusions (CTOs) or bypassing them in the sub-intimal space using such products as the Medtronic Pioneer 
catheter which tunnels a wire into the sub-intimal space at the CTO and then attempts to re-enter the vessel after 
the occlusion.  Once a wire is in place, one can place a stent to provide a bypass conduit passed the occlusion.  More 
conventional approaches to treating PVD are also used in CLI treatment once (if) a wire gets across the occlusion.  
These conventional methods include PTA, stenting, and, more recently, drug eluting balloons and stents. 
The LimFlow approach to treating CLI involves the concept of venous arterialization, which has been performed 
surgically for many years with first clinical surgical cases reported in the early 1900s.1,2  Numerous small series of 
clinical trials have been published using a surgical approach and recent publications summarized this work.3-5  In 
conclusion, venous arterialization was considered as a viable alternative before major amputation is undertaken in 
“no-option” patients with critical limb ischaemia. 
Several clinical studies have been conducted with the LimFlow System in Europe, Singapore, and the United States.6  
Results from these studies supported the CE-mark approval of the device in October 2016 and on-going 
investigation in the United States. The results from these studies have been presented at international congresses 
and published, demonstrating safety and feasibility of percutaneous deep vein arterialization. The most recent 
publication demonstrates the long-term viability of the therapy by presenting two year follow-up data.7  

 
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4. Risks and benefits 
4.1. Anticipated clinical benefits 
The patients designated for percutaneous deep vein arterialization have critical limb ischaemia with no treatment 
option other than major amputation.  These patients have had repeated percutaneous procedures to use 
angioplasty to open up the below-the-knee vessels, but the re-occlusion rate is high and once the foot is deserted 
(lack of blood circulation to the foot), ischaemia and necrosis quickly set in.  Necrotic tissue has to be cut away to 
allow healthy tissue a chance to heal.  Infection is a major complication that can rapidly become systemic leading to 
mortality.  Critical limb ischaemia patients are desperate as all medical experts have told them that there are no 
more possible treatments.  The lack of options highlights percutaneous deep vein arterialization is a last hope 
treatment for these patients, who have exhausted all other possibilities.  For this reason, the benefits of 
percutaneous deep vein arterialization with the LimFlow System far outweigh the known risks associated with this 
device and readily available percutaneous angioplasty equipment. 
4.2. Anticipated adverse device effects 
The following adverse events are considered to be anticipated when performing any percutaneous catheterization 
and will be assessed during the course of the study: 
▪ 
Allergic reaction, including anaphylactic shock and Quincke’s oedema 
▪ 
Vascular complications at access site, including bleeding events and hematoma 
▪ 
Arterial and venous thromboembolic events, including angina or myocardial infarction, stroke or transient 
ischaemic event, pulmonary embolism, deep vein thrombosis, and limb ischaemia 
▪ 
Contrast-induced nephropathy and renal failure 
▪ 
Local or systemic infection 
▪ 
Oedema 
▪ 
Pain 
4.3. Residual risks associated with the device 
The LimFlow System was reviewed in accordance with a risk management process that complies with the 
international standard on the application of risk management to medical devices EN ISO 14971:2012.  The risk 
management process entailed an analysis of potential risks and an evaluation of their acceptability in the light of 
the intended therapeutic use of the system. The purpose of the risk analysis was to identify and characterize 
undesirable events that could result in harm.  For each identified hazard the risks were estimated by factoring in the 
probability of occurrence and severity of the harm.  The design verification report was reviewed to verify that all 
risk control measures identified as necessary to reduce risk to acceptable levels had been implemented and that no 
risks would arise from the implementation of control measures.  It was concluded that all risks associated with the 
identified hazards had been reduced to acceptable levels and that the overall risk of the use of the LimFlow System 
was determined to be acceptable.  The LimFlow System received CE-mark in October 2016. 
4.4. Risks associated with participation in the clinical investigation 
In addition to the risks associated with the device, risks associated with participation in the clinical investigation are 
limited to the risks associated with the exams required for the clinical investigation.  Those have been reduced to 
minimal levels by complying with standard of care procedures and not requiring any invasive measurement 
or exam. 
4.5. Possible interactions with concomitant medical treatments 
Possible interactions with concomitant medical treatments have been reduced by excluding patients with medical 
conditions necessitating medical treatments that could potentially interfere with the percutaneous deep vein 
arterialization procedure.  Please refer to Section 6.3.2 “Exclusion criteria” on page 15. 

 
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4.6. Steps that will be taken to control or mitigate the risks 
The following steps have or will be taken by LimFlow SA to control or mitigate the risks during the course of this 
post-market study: 
▪ 
The use of standard medical grade materials that have been thoroughly characterized and tested to 
assure biocompatibility. 
▪ 
Extensive pre-clinical evaluation including in vitro bench testing, animal and cadaver study. 
▪ 
The well-established, standard nature of the endovascular procedures and techniques to be used. 
▪ 
The ability to quickly and safely remove the LimFlow System from the procedure; the physician may elect to 
discontinue the use of the device at any time in favour of alternate devices. 
▪ 
Frequent follow-up visits are conducted in the first year post-operatively to allow for systematic monitoring 
and surveillance of the index limb, allowing for early detection of hemodynamically significant stenoses in 
the graft that may occur in the absence of obvious symptoms. 
▪ 
Potential subjects will be screened by an independent committee to ensure that all subjects meet defined 
eligibility criteria. 
▪ 
Investigators will receive device training and will be proctored for their first case, and then for as many cases 
as they deem necessary to perform the procedure proficiently. 
4.7. Risk-to-benefit rationale 
The associated risks proposed in this study are similar to risks posed by other interventional and vascular surgery 
procedures.  The benefit to the subjects enrolled in this study is the potential for improved blood flow to the foot, 
reducing or eliminating the need for major amputation.  The potential benefit of reduced or no amputation of the 
foot greatly outweighs the standard endovascular/surgical risks associated with this procedure in this “no-option” 
patient population.  It is therefore concluded, from the information currently available, that the risks inherent in the 
use of the device are in line with the generally accepted state of the art, have been reduced to a level as low as 
reasonably practicable and are outweighed by the anticipated benefits.  The proposed clinical investigation is 
designed to gather evidence to support this preliminary risk assessment.  The subjects to be enrolled in the clinical 
investigation are thus not expected to be exposed to any undue risks. 
5. Objectives and hypotheses of the clinical investigation 
5.1. Objectives 
The objective of this post-market study is to collect “real-life” clinical data among a population of patients treated 
with the commercially-available LimFlow System in order to evaluate the safety and effectiveness of the LimFlow 
System in creating a below-the-knee arterio-venous fistula for venous arterialization in subjects with critical 
limb ischaemia. 
5.2. Hypotheses 
Results of the LimFlow System risk assessment indicated that device-related risks had been reduced to levels as low 
as reasonably practicable and comparable with the state of the art.  However, although the risks associated with the 
use of the LimFlow System were comparable with the state-of-the-art, the clinical experience was insufficient to 
completely characterize the nature and incidence of device-related procedural complications or late clinical 
complications.  Therefore, post-market clinical follow-up was indicated to more precisely assess the nature and 
incidence of potential risks or to confirm that their prevalence lied below the threshold of concern. 
5.3. Claims and intended performance to be verified 
The LimFlow System is intended to treat critical limb ischaemia by minimally invasively creating an arterio-venous 
bypass graft to achieve venous arterialization.  The objective of this post-market study is to evaluate the safety and 
effectiveness of the LimFlow System in creating a below-the-knee arterio-venous fistula for venous arterialization in 
subjects with critical limb ischaemia. 

 
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5.4. Risks and anticipated adverse effects to be assessed 
The following adverse events are considered to be anticipated when performing any percutaneous catheterization 
and will be assessed during the course of the study: 
▪ 
Allergic reaction, including anaphylactic shock and Quincke’s oedema 
▪ 
Vascular complications at access site, including bleeding events and hematoma 
▪ 
Arterial and venous thromboembolic events, including angina or myocardial infarction, stroke or transient 
ischaemic event, pulmonary embolism, deep vein thrombosis, and limb ischaemia 
▪ 
Contrast-induced nephropathy and renal failure 
▪ 
Local or systemic infection 
▪ 
Oedema 
▪ 
Pain 
6. Design of the clinical investigation 
6.1. General 
6.1.1. Type of clinical investigation 
This study is a single-arm, open-label, prospective, post-market follow-up study to be conducted on up to 25 eligible 
patients (roll-in subjects plus 20 analysis subjects) with a twelve-month follow-up period.  This study was designed 
and is to be conducted in compliance with the ISO 14155:2020 standard. 
6.1.2. Measures to be taken to minimize or avoid bias 
In addition to the screening and enrolment of consecutive patients, an independent committee will act as a medical 
monitor in order to minimize or avoid bias during the course of the study.  The independent committee will consist 
of at least two (2) physicians with experience in surgical and/or endovascular treatment of critical limb ischaemia 
patients, who are independent from LimFlow SA and are not investigators in the study.  Furthermore, members of 
the independent committee are neither past or current users of the LimFlow System nor involved with the 
manufacturer supplying the LimFlow System.  Specifically, the independent committee will be responsible for 
performing the following tasks: 
▪ 
Screening: review of all potential patients for compliance with key eligibility criteria I-2 and I-3 
▪ 
Endpoints: assessment of technical success, patency, and wound healing 
▪ 
Adverse events: two-step process involving (1) independent review of all adverse events by a medical 
monitor and (2) adjudication of relevant adverse events following a 2 + 1 algorithm 
6.1.3. Primary and secondary endpoints 
Primary endpoint 
• 
Amputation-free survival 
Secondary endpoints 
• 
Complete wound healing 
• 
Primary and secondary patency 
• 
Limb salvage 
• 
Technical and procedural success 

 
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6.1.4. Methods and timing for assessing, recording, and analysing variables 
Timing for performing visits and assessing variables during the study follow-up period are presented in Table 4 
below.  Additional post-treatment evaluations performed outside of the follow-up window will be 
considered “unscheduled”. 
Table 4.  Time windows 
Visit  
Target 
Interval 
Minimum 
Maximum 
Two (2) weeks 
15 days 
± 5 days 
10 days 
20 days 
One (1) month 
30 days 
± 7 days 
23 days 
37 days 
Two (2) months 
60 days 
± 10 days 
50 days 
70 days 
Three (3) months 
90 days 
± 14 days 
76 days 
104 days 
Six (6) months 
180 days 
± 14 days 
166 days 
194 days 
Nine (9) months 
270 days 
± 14 days 
256 days 
284 days 
Twelve (12) months 
360 days 
± 28 days 
332 days 
388 days 
All variables will be recorded on electronic Case Report Forms (eCRFs) specifically designed for the study and 
provided by LimFlow SA to the investigational centres.  Collected variables will be analysed using IBM SPSS statistics 
software, version 17 or later. 
6.1.5. Equipment to be used for assessing the clinical investigation variables 
Standard evaluation tools such as the Rutherford classification8 or the SVS WIfI (Wound – Ischaemia – foot 
Infection) classification system9 will be used for the overall assessment of critical limb ischaemia at baseline and 
follow-up visits. Pain will be evaluated using a numerical rating scale and the EuroQol (EQ-5D) questionnaire10 will 
be used to assess the patients Quality of Life. 
The eKare inSight digital wound management platform (eKare, Inc., Fairfax, Virginia, United States of America) will 
be used for photographing, scanning, and assessing wounds at screening and follow-up visits.  eKare inSight® is an 
FDA registered Class 1 medical device and is CE marked. Additionally, eKare is ISO 13485 certified and is fully 
compliant with FDA 21 CFR Part 820, Part 11.  One (1) eKare insight platform will be provided by LimFlow to each 
participating clinical site for the purpose of the study. 
6.1.6. Any procedures for the replacement of subjects 
Patients who have signed a consent form and have not undergone the procedure will be replaced; however, 
patients who drop-out during the trial or withdraw their consent after the procedure will not be replaced. 
6.2. Device(s) used and comparator(s) 
6.2.1. Description of the exposure to the device(s) 
Exposure to the medical devices is described in Section 2.8 “Medical procedures involved” on page 10 as well as in 
Section 6.4.3 “Treatment” on page 19. 
6.2.2. Justification of the choice of comparator(s) 
Not applicable as this post-market study is a single-arm study performed in a population of patients with no 
therapeutic option (other than amputation). 
6.2.3. List of any other medical device or medication to be used 
Other medical devices or medications to be used are similar to those used when performing a transcatheter, 
percutaneous intervention in the below-the-knee vasculature.  The treatment is to be delivered under general 
anaesthesia or conscious sedation with regional block, therefore anaesthetic medications will be administered to 
the patient prior to the intervention.  In addition, anticoagulant medication (heparin) will be administered in order 
to attain and maintain appropriate systemic anticoagulation as verified by ACT or other similar testing.  Iodine 
contrast media will also be injected intravascular to visualize the vasculature under fluoroscopy. 
6.2.4. Number of device(s) to be used 
The ultrasound system is a reusable device therefore one (1) unit can be used to perform several interventions.  The 
extension cable set, the arterial and venous catheter set, and the valvulotome are single-use devices; at least one 
(1) unit of each should be used for every patient treated.  Several stent grafts may be implanted in every patient 
depending on the vasculature—typically one (1) stent graft used as a “crossing stent” and at least one (1) stent graft 
used as an “extension stent”. 

 
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6.3. Subjects 
6.3.1. Inclusion criteria 
I-1. 
Subject must be > 21 and < 95 years of age 
I-2. 
Clinical diagnosis of symptomatic critical limb ischaemia, defined as Rutherford category 5 or 6 
I-3. 
Assessment that no conventional surgical or endovascular treatment is possible 
I-4. 
Proximally, the target in-flow artery at the cross-over point must be treatable with a 3.5 – 4.0 mm stent 
after pre-treatment (by visual estimate), and be <50% stenosed 
I-5. 
Subject is willing and has adequate support to comply with protocol requirements, including medication 
regimen and follow-up visits 
6.3.2. Exclusion criteria 
E-1. 
Concomitant hepatic insufficiency, deep venous thrombus in target limb, uncorrected coagulation disorders, 
or current immunodeficiency disorder 
E-2. 
Life expectancy less than 12 months 
E-3. 
Patient currently taking coumarin/warfarin which, in the opinion of the attending physician, interferes with 
the patient’s treatment 
E-4. 
Any significant medical condition which, in the attending physician’s opinion, may interfere with the 
patient’s optimal treatment 
E-5. 
Patient currently participating in another investigational drug or device study that has not completed the 
primary endpoint or that clinically interferes with the endpoints of this treatment 
E-6. 
Patient unable to give consent 
E-7. 
Pregnant or breastfeeding women 
E-8. 
Documented myocardial infarction or stroke within previous 90 days 
E-9. 
Patients suffering from renal insufficiency (GFR value less than 30 ml/min/1.73 m²) who are not on 
haemodialysis 
E-10. 
Patients with vasculitis and/or untreated popliteal aneurysms 
E-11. 
Patients with acute limb ischaemia 
E-12. 
Prior peripheral arterial bypass procedure above or below the knee which could inhibit proximal inflow to 
the stent graft 
E-13. 
Lower extremity venous disease with significant oedema in the target limb that may inhibit the procedure 
and/or jeopardize wound healing, in the investigator’s opinion 
E-14. 
Known or suspected systemic or severe infection (e.g., WIfI foot Infection grade of 3) 
E-15. 
Known or suspected allergies or contraindications to stainless steel, nickel, or contrast agent that cannot be 
adequately pre-treated, or patients who cannot receive anticoagulation or antiplatelet aggregation therapy 
E-16. 
Severe heart failure, which in the opinion of the investigator may compromise subject’s ability to safely 
undergo a percutaneous procedure (e.g., known ejection fraction of < 40%, NYHA Classification III-IV) 
6.3.3. Point of enrolment 
Once any component of the LimFlow System is introduced into the body, the subject will be considered to be 
enrolled in the study and subject to all follow-up requirements.  If the device is introduced but implantation is either 
not attempted or unsuccessful, subjects will be followed through 30 days for safety only, or through resolution or 
stabilization of any device- or procedure-related adverse events, whichever is longer; those subjects will then be 
exited from the study and will not be replaced.  In addition, “roll-in” subjects performed to avoid a learning curve 
bias will be included the study but excluded from the endpoint analysis.  In some instances, “roll-in” subjects within 
the study may not be required for any study site who has performed LimFlow System procedures outside the study 
in the commercial setting. 
6.3.4. Criteria and procedures for subject withdrawal or discontinuation 
Patients are withdrawn from study if signed informed consent is withdrawn or when lost to follow-up (if a patient is 
not able to be contacted within three phone calls, the site shall send a letter requesting response from the subject 
and contact the patient general practitioner in order to check on the patient’s condition; if the site or service 
receives no response, the patient may be considered lost-to follow-up at that time).  Early study exit will also occur 
if the patient reaches the primary study endpoint either in death, or major amputation of the treated limb.  Reason 
for the study discontinuation must be recorded in the source documentation and on the electronic Case Report 
Form (eCRF). 

 
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6.3.5. Number of subjects and expected duration 
The number of subjects required to be included in the clinical investigation was set to up to 25 eligible subjects, 
which includes any “roll-in” subjects and 20 subjects for analysis.  The time needed to select this number (i.e., the 
enrolment period) was initially estimated to be twelve (12) months, however due to the worldwide pandemic and 
impact it has had to study enrolment, the study recruitment and enrolment period will be extended.  The enrolment 
period is extended to allow the full cohort of subjects which is anticipated to be by the end of October 2022. 
Following enrolment in the clinical investigation, each subject’s participation to this post-market study is expected 
to last twelve (12) months. 
Therefore, this post-market clinical study is expected to last approximately four years, from the actual starting date 
in December 2019. 
6.4. Procedures 
6.4.1. Overview 
Patients should be followed at regular intervals during one year after the initial percutaneous deep vein 
arterialization procedure.  The protocol follow-up schedule is intended to align with the standard of care as seen 
with patients who are treated with surgical bypass or endovascular revascularization.  Visits and exams scheduled 
for this post-market study are presented in Table 5 below (keys: ◼ mandatory,  optional). 
Table 5.  Visits and exams 
Exams  
Baseline Treatment Week 02 
Month 01 Month 02 Month 03 Month 06 Month 09 Month 12 
Eligibility  
◼ 
 
 
 
 
 
 
 
 
Demographics 
◼ 
 
 
 
 
 
 
 
 
Infection status† 
◼ 
 
 
 
 
 
 
 
 
Venous mapping‡ 
◼ 
 
 
 
 
 
 
 
 
Angiogram 
◼ 
◼ 
 
 
 
 
 
 
 
Ultrasound 
Duplex 
 
Duplex 
Duplex 
Duplex 
Duplex 
Duplex 
Duplex 
Medication 
◼ 
◼ 
◼ 
◼ 
◼ 
◼ 
◼ 
◼ 
◼ 
Creatinine 
◼ 
 
 
 
 
 
Rutherford 
◼ 
 
◼ 
◼ 
◼ 
◼ 
◼ 
◼ 
WIfI 
◼ 
 
◼ 
◼ 
◼ 
◼ 
◼ 
◼ 
Wound pictures 
◼ 
◼ 
◼ 
◼ 
◼ 
◼ 
◼ 
◼ 
Pain 
◼ 
◼ 
◼ 
◼ 
◼ 
◼ 
◼ 
◼ 
Perfusion 
 
 
 
 
 
 
 
 
 
Quality of Life 
◼ 
 
 
 
◼ 
◼ 
◼ 
◼ 
Adverse events 
 
◼ 
◼ 
◼ 
◼ 
◼ 
◼ 
◼ 
◼ 
†Wound culture and/or blood analysis (WBC, CRP, ESR) 
‡Phlebography, duplex ultrasound, MRV or CTV, depending on what is available 

 
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6.4.2. Screening and baseline 
The subject screening and recruitment process will be performed by the site medical personnel and should follow 
the steps below: 
1. 
Critical limb ischaemia patients with no endovascular or surgical treatment options (inclusion/exclusion 
criteria are aligned with the CE-marked indications/contraindications, as per the IFU) are initially identified by 
the site investigators 
2. 
No-option patients meeting the LimFlow System indications and contraindications (as provided in the 
instructions for use since the LimFlow System is commercially available) can be scheduled for a percutaneous 
deep vein arterialization 
3. 
Patients scheduled for a LimFlow intervention are asked whether they would be willing to participate to the 
study (to collect the data associated to the surgical procedure and standard of care follow-up).  
4. 
Patients candidate to the study are subsequently enrolled, treated, and followed as per standard of care (the 
study protocol does not require more visits than what is considered standard of care) 
◆ ◆ ◆ 
Once the patients have agreed to participate to the study (i.e., once the informed consent has been obtained), the 
following exams will be collected: 
▪ 
Demographics, medical history, and peripheral assessment 
▪ 
Infectious status, i.e., wound culture and/or blood analysis (WBC, CRP, ESR) 
▪ 
Venous mapping of the foot, i.e., phlebography, duplex ultrasound, MRV, or CTV 
▪ 
Arterial angiogram from the common femoral artery to the foot (two views) 
▪ 
Serum creatinine level 
▪ 
Rutherford classification 
▪ 
WIfI (Wound – Ischaemia – foot Infection) classification 
▪ 
Wound pictures and assessment 
▪ 
Pain assessment 
▪ 
Perfusion assessment (TcPO2, ICG i.v. injection, white-light spectroscopy with laser Doppler, etc.—optional) 
▪ 
Quality of Life (EQ-5D) 
▪ 
Review of medications (antiplatelets/anticoagulants and antibiotics regimen) 
A dedicated website (decidemedical.com platform provided by ClinFlows) will be used during the screening process 
to assess the eligibility of the candidates identified by the investigators.  Baseline radiological images (e.g., arterial 
angiograms, phlebography, duplex ultrasound, MRV, or CTV) as well as wound pictures should be uploaded by the 
investigators in order for the patients’ eligibility to be confirmed.  The eligibility screening process that will be 
followed for this post-market study is presented in detail on Figure 1 below. 

 
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Figure 1.  Eligibility screening process for LimFlow cases 
Physician
Case 
owner
Wound care and
clinical specialists
Independent
committee
(Syntactx)
Case submission:
- One-page form
- Wound pictures
- Angiograms
- Venous mapping
Quality check 
(file review for 
completeness)
Medical assessment:
- Overall condition
- Technical feasibility
Suitable 
patient?
Do not treat
Considered 
for PMS?
Proceed
outside of study
Clinical/regulatory 
assessment:
- Rutherford 5 or 6
- "No-option"
Eligible 
patient?
Proceed
within study
No
Complete 
file?
Forward to both
wound care and
clinical specialists
Proctor 
needed?
Physician 
proctor
Medical assessment:
- Overall condition
- Technical feasibility
No
Yes
No
Yes
No
Yes
Yes
No
Yes
 

 
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6.4.3. Treatment and discharge 
A LimFlow representative will attend the interventions performed in order to assist the physician on technical issues 
as well as to ensure that treatment characteristics and potential complications are duly recorded. 
Primary steps of the percutaneous deep vein arterialization intervention are described in Section 2.8 “Medical 
procedures involved” on page 10.  Refer to the “Instructions for Use” for proper preparation and use of the devices. 
In addition to the procedure images (angiography and/or ultrasound), the following intra-procedure parameters will 
be specifically recorded: 
 
Target artery and target vein 
 
Procedural steps 
 
Technical success 
 
Medical devices used 
 
Total procedure time 
 
 Total fluoroscopy time 
 
Total volume of contrast media 
 
Any adverse event or device deficiency 
Patients should receive adequate antiplatelet and anticoagulation therapy for a minimum of three (3) months post-
procedure as per institution practice. 
6.4.4. Follow-up visits 
Sites shall maintain a contact log recording the attempted follow-up visits, scheduled at one month, three months, 
six months, nine months, and twelve months.  If a patient is not able to be contacted within three phone calls, the 
site shall send a letter requesting response from the subject and contact the patient general practitioner in order to 
check on the patient’s condition.  If the site or service receives no response, the patient may be considered lost-to 
follow-up at that time. 
Follow-up and wound care are to be performed on-site under direct supervision of a study investigator.  Patient 
wounds should be treated in accordance with the TIME guidelines or following similar recommendations.11-17  An 
arteriography should be performed in case of suspected stent graft occlusion, as per standard practice. 
Day 015: two weeks 
At 15 days post-treatment, subjects will be examined during a clinic visit and the following assessment will 
be performed: 
▪ 
Wound pictures and assessment 
▪ 
Pain assessment 
▪ 
Perfusion assessment (TcPO2, ICG i.v. injection, white-light spectroscopy with laser Doppler, etc.—optional) 
▪ 
Adverse events 
▪ 
Review of medications (antiplatelets/anticoagulants and antibiotics regimen) 
Day 030: one month 
At 30 days post-treatment, subjects will be examined during a clinic visit and the following assessment will 
be performed: 
▪ 
Rutherford classification 
▪ 
WIfI (Wound – Ischaemia – foot Infection) classification 
▪ 
Wound pictures and assessment 
▪ 
Pain assessment 
▪ 
Perfusion assessment (TcPO2, ICG i.v. injection, white-light spectroscopy with laser Doppler, etc.—optional) 
▪ 
Duplex ultrasound 
▪ 
Adverse events 
▪ 
Review of medications (antiplatelets/anticoagulants and antibiotics regimen) 

 
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Day 060: two months 
At 60 days post-treatment, subjects will be examined during a clinic visit and the following assessment will 
be performed: 
▪ 
Rutherford classification 
▪ 
WIfI (Wound – Ischaemia – foot Infection) classification 
▪ 
Wound pictures and assessment 
▪ 
Pain assessment 
▪ 
Perfusion assessment (TcPO2, ICG i.v. injection, white-light spectroscopy with laser Doppler, etc.—optional) 
▪ 
Duplex ultrasound 
▪ 
Adverse events 
▪ 
Review of medications (antiplatelets/anticoagulants and antibiotics regimen) 
Day 090: three months 
At 90 days post-treatment, subjects will be examined during a clinic visit and the following assessment will 
be performed: 
▪ 
Rutherford classification 
▪ 
WIfI (Wound – Ischaemia – foot Infection) classification 
▪ 
Wound pictures and assessment 
▪ 
Pain assessment 
▪ 
Perfusion assessment (TcPO2, ICG i.v. injection, white-light spectroscopy with laser Doppler, etc.—optional) 
▪ 
Quality of Life (EQ-5D) 
▪ 
Duplex ultrasound 
▪ 
Adverse events 
▪ 
Review of medications (antiplatelets/anticoagulants and antibiotics regimen) 
Day 180: six months 
At 180 days post-treatment, subjects will be examined during a clinic visit and the following assessment will 
be performed: 
▪ 
Rutherford classification 
▪ 
WIfI (Wound – Ischaemia – foot Infection) classification 
▪ 
Wound pictures and assessment 
▪ 
Pain assessment 
▪ 
Perfusion assessment (TcPO2, ICG i.v. injection, white-light spectroscopy with laser Doppler, etc.—optional) 
▪ 
Quality of Life (EQ-5D) 
▪ 
Duplex ultrasound 
▪ 
Adverse events 
▪ 
Review of medications (antiplatelets/anticoagulants and antibiotics regimen) 
Day 270: nine months 
At 270 days post-treatment, subjects will be examined during a clinic visit and the following assessment will 
be performed: 
▪ 
Rutherford classification 
▪ 
WIfI (Wound – Ischaemia – foot Infection) classification 
▪ 
Wound pictures and assessment 
▪ 
Pain assessment 

 
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▪ 
Perfusion assessment (TcPO2, ICG i.v. injection, white-light spectroscopy with laser Doppler, etc.—optional) 
▪ 
Quality of Life (EQ-5D) 
▪ 
Duplex ultrasound (Note: if previous ultrasound assessment revealed a total occlusion of the stent graft and 
no further intervention was performed or planned, duplex ultrasound assessment at this timepoint may be 
unnecessary.  This will be handled on a case-by-case basis and will be discussed between the site and 
Sponsor ahead of the follow-up and documented accordingly.) 
▪ 
Adverse events 
▪ 
Review of medications (antiplatelets/anticoagulants and antibiotics regimen) 
Day 360: twelve months 
Finally, at 360 days post-treatment, subjects will be examined during a clinic visit and the following assessment will 
be performed: 
▪ 
Rutherford classification 
▪ 
WIfI (Wound – Ischaemia – foot Infection) classification 
▪ 
Wound pictures and assessment 
▪ 
Pain assessment 
▪ 
Perfusion assessment (TcPO2, ICG i.v. injection, white-light spectroscopy with laser Doppler, etc.—optional) 
▪ 
Quality of Life (EQ-5D) 
▪ 
Duplex ultrasound(Note: if previous ultrasound assessment revealed a total occlusion of the stent graft and 
no further intervention was performed or planned, duplex ultrasound assessment at this timepoint may be 
unnecessary.  This will be handled on a case-by-case basis and will be discussed between the site and 
Sponsor ahead of the follow-up and documented accordingly.) 
▪ 
Adverse events 
▪ 
Review of medications (antiplatelets/anticoagulants and antibiotics regimen) 
6.5. Monitoring plan 
Under the supervision of LimFlow SA, monitors will conduct investigational site monitoring to ensure that all 
investigators are in compliance with the Declaration of Helsinki (“Ethical Principles for Medical Research Involving 
Human Subjects”, 18th World Medical Association General Assembly, Helsinki, Finland, June 1964), the standard 
ISO 14155:2020 (“Clinical investigation of medical devices for human subjects—Good clinical practice”), the Clinical 
Investigation Plan, and the Investigator’s Agreement.  Sites and source documents will be monitored to ensure that 
completed CRFs match medical records and to resolve any differences.  The monitors and LimFlow SA will evaluate 
circumstances where an investigator deviates from the Clinical Investigation Plan. 
The monitor’s responsibilities include: maintaining regular contact with each investigational site, through telephone 
contact and on-site visits, to ensure that the investigational plan is followed; ensure that complete, timely and 
accurate data are submitted; ensure that problems with inconsistent and incomplete data are addressed; and that 
the site facilities continue to be adequate. 
The monitor shall have access to the source documents and other information needed to ensure investigator 
compliance with the clinical investigation plan and applicable rules and regulations, and to assess the progress of 
the clinical investigation.  The clinical investigators shall allow auditing of their clinical investigation procedures. 
LimFlow SA will review significant new information and ensure that such information is provided to the 
investigators, and to the Ethics Committees and Competent Authorities, as appropriate. 
7. Statistical considerations 
7.1. Statistical design, method and analytical procedures 
Subject demographics, baseline characteristics and medical history will be summarized descriptively.  Mean and 
standard deviation will generally be reported for continuous variables; median and range may be reported instead if 
the data distribution is skewed.  Frequencies and proportions will be reported for categorical variables. 

 
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The design of this post-market study (PMS) is mirroring that of the early feasibility study (EFS) conducted in the 
United States of America, allowing for both datasets to be pooled in order to perform a statistical analysis on a 
larger cohort of patients. 
7.2. Sample size 
In the absence of formal statistical hypotheses for this single-arm, post-market study, the planned sample size could 
not be derived statistically.  It was however estimated that a cohort of approximately twenty (20) subjects would 
provide sufficient data in order to meet the objectives defined in the study. 
7.3. Provision for an interim analysis 
Interim analyses may be performed at any time if deemed necessary to fulfil the sponsor’s or manufacturer’s 
reporting requirements and/or update the evaluation of the side effects and of the acceptability of the benefit/risk 
ratio, as required in Council Directive 93/42/EEC of 14 June 1993 concerning medical devices. 
7.4. Specification of subgroups for analysis 
If relevant, subgroup analyses may be performed based on baseline or treatment parameters—Student’s (or 
Wilcoxon’s according to the normality of the distribution) and Chi-2 (or Fisher’s) between-group tests will then be 
used for quantitative and qualitative parameters, respectively. 
In particular, renal function characteristics at baseline (GFR value and/or dialysis status) may be used to define 
subgroups for the purpose of the analysis.  Specifically, patients on dialysis are excluded from the early feasibility 
study (EFS), which will be taken into consideration when pooling datasets from both cohorts.  Safety and 
effectiveness results from dialysis and non-dialysis patients will be compared. 
7.5. Treatment of missing, unused, or spurious data 
The number of missing data will be presented for each variable as part of the descriptive statistical analysis.  
Subjects withdrawn and/or lost to follow-up will be presented in a patient tree showing detailed patient 
accountability at each follow-up visit. 
8. Data management 
Electronic Case Report Forms (eCRFs) will be specifically developed on the IBM Clinical Development platform for 
the study.  The eCRFs will be used for data collection during the course of the study and must be completed for all 
patients enrolled into the study.  It is the responsibility of the investigator to ensure the quality of the data collected 
and recorded in the eCRFs.  The eCRFs will be reviewed for errors, omissions, internal consistency, and to ensure 
that the investigator has signed and dated the appropriate sections; entered data will be audited for verification 
and validation purposes. 
Data collection will include clinical data, as well as medical images based on the clinical endpoints outlined above.  
Images will be centrally analysed by the independent committee.  Specifically, the role of the core laboratory will be 
(1) to assess the anatomical eligibility of all candidates at baseline and (2) to assess the safety endpoint at follow-up 
timepoints. 
The eCRFs are compliant with FDA 21 CFR Part 11 requirements.  All information and data concerning patients or 
their participation in this study will be considered confidential.  Only authorized personnel will have access to this 
confidential information.  All data used in the analysis and reporting of this evaluation will be without identifiable 
reference to individual patients.  Patients will be identified using a six-character sequence (ISO 3166-1 α-2 country 
code; two-letter site code; two-digit patient number). 
The investigator must retain paper copies of study records.  LimFlow SA will maintain copies of correspondence, 
data, and other records related to the study.  LimFlow SA will maintain records related to the signed 
Investigator’s Agreements. 
LimFlow SA will provide devices only to participating investigators, obtain a signed Investigator’s Agreement, and 
provide the investigator with the information necessary to conduct the study.  The training of appropriate clinical 
site personnel will be the joint responsibility of the Sponsor and the Monitor.  To insure uniform data collection and 
Clinical Investigation Plan compliance, the Sponsor and/or the Monitor will present a formal educational session to 
study site personnel which will review the Clinical Investigational Plan, techniques for the identification of eligible 
patients, instructions on in hospital data collection, methods for soliciting data from alternative sources, schedules 
for follow-up with the study site coordinators, and regulatory requirements. 

 
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9. Amendments to the clinical investigation plan 
The investigator will not implement any changes without the prior agreement of LimFlow SA and review by the 
Ethics Committee with documented approval/favourable opinion, except when the change involves logistical or 
administrative aspects of the investigational site. 
10. Deviations from clinical investigation plan 
The investigator is not allowed to deviate from the clinical investigation plan, except under emergency 
circumstances to protect the rights, safety and well-being of a study subject.  Such deviations shall be documented 
and reported to LimFlow SA and the Ethics Committee as soon as possible depending on local 
regulatory requirements. 
11. Device accountability 
Each component of the LimFlow System will be traceable via lot and serial number.  Records of device shipments 
will be maintained at the LimFlow facility in accordance with LimFlow’s quality system and internal procedures.  
Product Details will be captured on the case report forms for each subject receiving treatment with the LimFlow 
System to provide traceability. 
LimFlow SA will supply the device; any requests for additional materials, equipment, service, or information shall be 
directed to LimFlow SA.  An inventory of materials will be taken at monitor site visits. 
12. Statements of compliance 
This post-market study shall be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki (“Ethical Principles for Medical Research Involving Human Subjects”, 18th World Medical 
Association General Assembly, Helsinki, Finland, June 1964) and in compliance with the standard ISO 14155:2020 
(“Clinical investigation of medical devices for human subjects—Good clinical practice”) as well as any regional or 
national regulations, as appropriate. 
This post-market study shall not begin until the required approval/favourable opinion from the Ethics Committee or 
regulatory authority have been obtained, if appropriate.  Any additional requirements imposed by the Ethics 
Committee or regulatory authority shall be followed, if appropriate 
LimFlow SA subscribed to an insurance that shall be provided for all study subjects, in accordance with regional or 
national regulations, as appropriate. 
13. Informed consent process 
The sponsor will provide centres with a sample informed consent document that the centre may modify to meet 
individual Ethics Committee requirements.  Any modifications of the informed consent document must be 
submitted to LimFlow SA for approval prior to submission to the Ethics Committee. 
An informed consent form must be signed by each patient prior to study enrolment and implant of the study device.  
Informed consent will be obtained according to the Declaration of Helsinki (“Ethical Principles for Medical Research 
Involving Human Subjects”, 18th World Medical Association General Assembly, Helsinki, Finland, June 1964), 
requirements of the standard ISO 14155:2020 (“Clinical investigation of medical devices for human subjects—Good 
clinical practice”), and individual institution guidelines.  Patient informed consents will be audited to ensure they 
have been signed prior to the treatment procedure and that the correct version was used. 
The subject screening and recruitment process will be performed by the site medical personnel and should follow 
the steps below: 
1. 
Critical limb ischaemia patients with no endovascular or surgical treatment options are initially identified by 
the site investigators 
2. 
No-option patients meeting the LimFlow System indications and contraindications (as provided in the 
instructions for use since the LimFlow System is commercially available) can be scheduled for a percutaneous 
deep vein arterialization 
3. 
Patients scheduled for a LimFlow intervention are asked whether they would be willing to participate to the 
study (inclusion/exclusion criteria are aligned with the CE-marked indications/contraindications) 
4. 
Patients candidate to the study are subsequently enrolled, treated, and followed as per standard of care (the 
study protocol does not require more visits than what is considered standard of care) 

 
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14. Adverse events, adverse device effects and device deficiencies 
14.1.Definitions 
The ISO 14155:2020 “Clinical investigation of medical devices for human subjects—Good clinical practice” 
definitions will be used for this post-market study and are provided in Table 6 below. 
Table 6.  Definitions of adverse events and adverse device effects 
Adverse event (AE) 
Adverse device effect (ADE) 
Any untoward medical occurrence, unintended 
disease or injury, or untoward clinical signs (including 
abnormal laboratory findings) in subjects, users or 
other persons, whether or not related to the 
investigational medical device 
Adverse event related to the use of an investigational 
medical device or procedure 
Serious adverse event (SAE) 
Serious adverse device effect (SADE) 
Adverse event that 
▪ led to death, 
▪ led to serious deterioration in the health of the 
subject, that either resulted in 
▪ a life-threatening illness or injury, or 
▪ a permanent impairment of a body structure 
or a body function, or 
▪ in-patient or prolonged hospitalisation, or 
▪ medical or surgical intervention to prevent 
life-threatening illness or injury or permanent 
impairment to a body structure or a body 
function 
▪ led to foetal distress, foetal death or a congenital 
abnormality or birth defect 
Adverse device effect that has resulted in any of the 
consequences characteristic of a serious adverse 
event 
▪ Anticipated serious adverse effect (ASADE): 
SADE which by its nature, incidence, severity or 
outcome has been identified in the risk analysis 
report 
▪ Unanticipated serious adverse effect (USADE): 
SADE which by its nature, incidence, severity or 
outcome has not been identified in the risk 
analysis report 
Note: a planned hospitalisation or intervention for a pre-existing condition without deterioration in health is not 
considered to be an adverse event. 
Device deficiency is defined as inadequacy of a medical device with respect to its identity, quality, durability, 
reliability, safety or performance, including malfunctions, use errors, and inadequate labelling. 
14.2.Reporting 
All adverse events will be documented in the case report forms, including date of onset, symptoms, treatment, 
duration (or the fact that it is still continuing), resolution, and assessment of both the seriousness and the 
relationship to the device.  Similarly, all device deficiencies will be documented in the case report forms.  In 
addition, all serious adverse events and serious adverse device effects must be reported immediately after 
discovery by any site member to LimFlow SA. 
LimFlow SA will report such an event and the results of an investigation to the appropriate regulatory authorities in 
compliance with applicable regulatory requirements.  If LimFlow SA and the investigator determine that the events 
present an unreasonable risk to the subjects, LimFlow SA will terminate all or parts of the study. 
The reporting of any serious adverse events and/or serious adverse device effects to the Ethics Committee is the 
sole responsibility of the site’s Principal Investigator. 
All adverse events will be adjudicated by the independent committee in order to assess the procedure or device 
relatedness as well as the event seriousness. 
14.3.Foreseeable events 
The following adverse events may occur when performing percutaneous deep venous arterialization and will be 
specifically assessed during the course of the study: 
▪ 
Allergic reaction, including anaphylactic shock and Quincke’s oedema 

 
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▪ 
Vascular complications at access site, including bleeding events and hematoma 
▪ 
Arterial and venous thromboembolic events, including angina or myocardial infarction, stroke or transient 
ischaemic event, pulmonary embolism, deep vein thrombosis, and limb ischaemia 
▪ 
Contrast-induced nephropathy and renal failure 
▪ 
Oedema 
▪ 
Local or systemic infection 
▪ 
Pain 
14.4.Management 
If the investigator determines that an adverse event occurs the investigator will manage the subject as he/she 
would if a similar event occurred during a standard interventional procedure.  The investigator will formulate an 
appropriate management plan for the subject using only conventional, non-investigational methods.  Medical 
management of the subject is the responsibility of the investigator and/or other trained, licensed medical 
personnel.  It is at the discretion of the investigator as to whether the percutaneous deep vein arterialization 
procedure should be continued. 
All subjects with adverse events will be followed with the appropriate treatment and medical supervision until 
either the end of the study (i.e., 12 months) or resolution of the adverse event (whenever possible), whichever is 
the longer follow-up. 
14.5.Emergency contact details 
Serious adverse events and serious adverse device effects must be reported to the sponsor LimFlow SA.  Contact 
details are as follows: 
LimFlow SA 
Vincent Cabane 
Director of European Clinical Affairs 
E-mail: vcabane@limflow.com 
Cell phone: +33 (0) 6 03 86 17 13 
15. Vulnerable population 
Not applicable for this post-market study. 
16. Suspension or premature termination of the investigation 
In the event of unforeseen or increased risks to subjects encountered during the course of the study, LimFlow SA, 
the Ethics Committee, the Competent Authority, or the Investigator may decide to suspend or terminate the clinical 
study.  Such decision would be made after discussion with all parties. 
If the investigator terminates or suspends the study without prior agreement with LimFlow SA, he/she will promptly 
provide all details to the institution, LimFlow SA, and the Ethics Committee.  If the investigation is terminated or 
suspended by LimFlow SA, the investigator will be promptly informed, who must then inform the Ethics Committee.  
If the Ethics Committee terminates or suspends the study, the investigator will promptly inform LimFlow SA with 
written explanation. 
Subjects will continue to be followed per the clinical investigational protocol unless it has been determined by the 
investigator that the continued follow-up may jeopardize the rights, safety, and/or welfare of the subject. 
17. Publication policy 
The data generated by this clinical study are the property of the sponsor, and should not be disclosed without their 
prior written permission.  These data may be used by the sponsor now and in the future for presentation or 
publication at sponsor’s discretion or for submission to governmental regulatory agencies.  The principal 
investigator may publish or present the study results with prior consent of the sponsor, but will not disclose 
confidential information.  Prior to submission by a principal investigator for publication or presentation, the sponsor 
will be provided with the opportunity to review the submission for confidential information and accuracy.  The 
possibility of a publication in a peer-reviewed journal will be sought. 

 
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18. Definitions 
Amputation 
Major amputation is defined as amputation of the index limb at the level above the ankle. 
Minor amputation is defined as amputation(s) of the index limb (including metatarsals) at 
the level below the ankle. 
Amputation-free 
survival 
Defined as the percentage of subjects with limb salvage and survival. 
Arteriovenous 
fistula 
An unplanned, anatomical connection between the access artery and the adjacent vein that 
is demonstrated by arteriography or ultrasound, most often characterized by a
continuous bruit. 
Clinically-driven 
major 
re-intervention 
Creation of a new surgical bypass, the use of thrombectomy or thrombolysis (i.e.,
procedures done in the setting of lost primary-assisted patency), or major surgical revision 
such as a jump graft or an interposition graft performed for occlusion of the stent graft. 
Deterioration in 
renal function 
Defined as a ≥ 25% increase in serum creatinine after using iodine contrast agents, without 
another clear cause for kidney injury. 
Embolism 
The sudden blocking of an artery by a clot or other material that has been brought to its site 
of lodgment by the blood current (embolus).  Potential sources of emboli include blood 
clots, fat globules, air bubbles, tissue, clumps of bacteria, thrombus or foreign material. 
Limb salvage 
Freedom form major amputation. 
Myocardial 
Infarction (MI) 
The term myocardial infarction should be used when there is evidence of myocardial 
necrosis in a clinical setting consistent with myocardial ischaemia.  Specifically, the criteria
provided by the universal definition of myocardial infarction will be used for
diagnostic purposes. 
Occlusion 
Absence of flow on colour Doppler ultrasound and/or absence of flow on angiographic 
images (conventional or CT-scan). 
Patency 
Primary patency is defined as the absence of occlusion of the stent graft without prior 
clinically-driven major re-intervention of the stent graft.  Secondary patency is defined as
the absence of occlusion of the stent graft with or without prior clinically-driven major
re-intervention of the stent graft. 
Pseudoaneurysm 
A blood vessel abnormality resembling an aneurysm (localized abnormal dilatation of a 
blood vessel) but consisting of a collection of blood with persistent flow outside an artery, 
contained by surrounding tissue and due to a leaking hole through all layers of the arterial 
wall.  The leaking hole is due to injury of (e.g., rupture of or trauma to) the arterial wall.  The 
pseudoaneurysm is usually identified by angiography or ultrasound. 
Retroperitoneal 
bleeding 
Bleeding from an injured vessel, with deposition of blood into the retroperitoneal space 
(between the peritoneum and the posterior abdominal wall). 
Stroke 
A stroke is any sudden development of neurological deficits, such as vertigo, numbness, 
aphasia, or dysarthria due to vascular lesions of the brain such as haemorrhage, embolism,
thrombosis, or rupturing aneurysm. 
Success 
Technical success is defined as completion of the endovascular procedure and immediate 
morphological success with successful placement of the arterial and venous catheters in the 
desired location in the limb, and ability to place the stent graft.  Procedural success is
defined as combination of technical success, and absence of all-cause death, above-ankle
amputation or clinically driven major re-intervention of the stent graft. 
Survival 
Freedom from all-cause mortality. 
Thrombosis 
Formation or development of a blood clot or thrombus, specifically in the arterial or venous 
system of the ipsilateral distal extremity. 
Transient Ischaemic 
Attack (TIA) 
Focal neurologic abnormalities of sudden onset and brief duration that reflect dysfunction in 
the distribution of the affected artery.  Transient ischaemic attack is characterized by fully
reversible symptoms of short duration. 

 
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19. Bibliography 
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20. Annex A: list of investigators and investigational sites