A Prospective, Multicenter, Single Arm, Post-Approval Study of the Lutonix Drug Coated Balloon for Treatment of Femoropopliteal Arteries in United States Females
Phase: NA
Conditions: Femoral Artery Stenosis, Popliteal Artery Stenosis, Femoral Artery Occlusion, Popliteal Artery Occlusion
Sponsor: C. R. Bard

CONFIRM Investigational Plan 
 
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LUTONIX CONFIDENTIAL 
Page 1 of 43 
 
 
    
A Prospective, Multicenter, Single Arm, Post-Approval Study 
of the Lutonix® Drug Coated Balloon for Treatment of 
Femoropopliteal Arteries in United States Females  
(CONFIRM Trial) 
 
Investigational Plan 
 
CL0025-01 
Version 3.0 
December 1, 2017 
 
 
Sponsor: 
 
 
 
9409 Science Center Drive 
New Hope, MN 55428 USA 
 
Study Device: Lutonix 035 Drug Coated Balloon PTA 
Catheter  
(Lutonix Catheter) 
 
NCT Number: 02813577 (Number added post approval as per CT.gov requirement) 
This study will be conducted in compliance with the protocol and all other applicable regulatory 
requirements including the archiving of essential documents. 
 
 
Confidential Information 
No use or disclosure of this document outside Lutonix, Inc. is permitted without prior written 
authorization from Lutonix. 
 
 
 

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PROTOCOL SIGNATURE PAGE 
 
A Prospective, Multicenter, Single Arm, Post-Approval Study ofthe Lutonix Drug Coated 
Balloon for Treatment of Femoropopliteal Arteries in United States Females  
(CONFIRM Trial) 
 
CL0025-01 
Version 3.0 
 
 
I have read this protocol and agree to adhere to the requirements.  I will provide copies of this 
protocol and all pertinent information to the study personnel under my supervision and my hospital 
Institutional Review Board.  I will discuss this material with them and ensure they are fully informed 
regarding the conduct of the study according to ICH Good Clinical Practice (GCP), Declaration of 
Helsinki, 21 CFR 812 and parts 50, 54, 56 and any local regulations. 
 
 
__________________________ ______________________________ 
Clinical Site Name 
 
 
 
__________________________ 
___________________________ 
 
______________ 
Site Principal Investigator 
 
Site Principal Investigator 
 
 
Date 
(Print Name) 
 
 
 
(Signature) 
 
 
 
 
 
 
 
 
 
 

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SUB-INVESTIGATOR PROTOCOL SIGNATURE PAGE 
 
A Prospective, Multicenter, Single Arm, Post-Approval Study of the Lutonix Drug Coated 
Balloon for Treatment of Femoropopliteal Arteries in United States Females  
(CONFIRM Trial) 
 
CL0025-01 
Version 3.0 
 
I have read this protocol and agree to adhere to the requirements.  I agree to conduct the study in 
accordance with the signed Clinical Study Agreement (CSA), ICH Good Clinical Practice (GCP), 
applicable privacy laws such as HIPAA, Declaration of Helsinki, 21CFR parts 50, 54, 56 and 812 
and any local regulations. 
 
 
 
 
______________________________________________________________________________ 
Clinical Site Name 
 
 
 
 
_______________________ 
 
_________________________       ____________________ 
Site Sub-Investigator 
 
 
Site Sub-Investigator 
 
 
 
  Date 
(Print Name) 
 
 
 
(Signature) 
 
 
 
 

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Protocol Synopsis 
Title 
A Prospective, Multicenter, Single Arm, Post-Approval Study of the Lutonix 
Drug Coated Balloon for Treatment of Femoropopliteal Arteries in United States 
Females (CONFIRM Trial) 
Test Device 
Lutonix 035 Drug Coated Balloon PTA Catheter  (Lutonix® Catheter, PMA 
P130024) 
Study Design 
Prospective, Multicenter, Single Arm, Safety and Effectiveness 
Overview 
The study will enroll US female patients presenting with claudication or 
ischemic rest pain and an angiographically significant lesion in the superficial 
femoral or popliteal artery.  Subjects are treated per IFU with the Lutonix 
Catheter.  Subjects will have a Duplex Ultrasound and clinical follow-up 
through two (2) years. 
Purpose 
To assess the safety and effectiveness of the Lutonix Catheter for treatment of 
stenosis or occlusion of the femoral and popliteal arteries in the US female 
population. 
Objective 
To evaluate the safety and effectiveness of the Lutonix Catheter for treatment of 
stenosis of the femoropopliteal arteries in the US female population. 
Enrollment 
Approximately 165 patients will be enrolled at a minimum of 10 US centers and 
a maximum of 25. 
Follow-Up 
Schedule 
Clinical and DUS: 1, 6, 12, and 24 Months  
Primary 
Endpoints 
Safety: Composite of freedom from all-cause peri-operative (≤30 day) death and 
freedom at 1 year from the following: index limb amputation (above or below 
the ankle), index limb re-intervention, and index-limb-related death.  
Effectiveness: Primary Patency of the target lesion at 12 months: Primary 
Patency is defined as Freedom from target lesion restenosis (TLR) and from 
Binary Restenosis. Binary Restenosis is adjudicated by the independent Core 
Laboratory based on Peak Systolic Velocity Ratio (PSVR) ≥ 2.5 and / or 
abnormal waveforms, or based on angiographic ≥ 50% diameter stenosis.  
Secondary 
Endpoints 
The following endpoints will be assessed at 1 month: 
• Composite of freedom from all-cause perioperative (≤ 30 day) death and 
freedom from the following: index limb amputation, index limb re-
intervention, and index-limb-related death. 
• Major Vascular Complications (<30 days) 

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The following endpoints will be assessed at 1, 6, 12 and 24 months: 
• All-cause death  
• Clinically Driven Target Lesion Revascularization (TLR)  
• Target Vessel Revascularization (TVR)  
• Reintervention for treatment of thrombosis of the target vessel or 
embolization to its distal vasculature  
•  Rate of unanticipated and anticipated device related serious adverse events  
• Amputation (above the ankle)-Free Survival (AFS)  
• Change of Rutherford classification from baseline 
• Sustained Clinical Benefit (improvement in Rutherford Class compared to 
baseline AND freedom from target vessel revascularization) 
• Change of resting Ankle Brachial Index (ABI) from baseline 
Inclusion 
Criteria 
Clinical Criteria 
1. Non-pregnant female ≥18 years of age;  
2. Rutherford Clinical Category 2-4;  
3. Patient is willing to provide informed consent, is geographically stable, 
comply with the required follow up visits and testing schedule; 
Angiographic Criteria  
4. De novo or restenotic lesion(s) in native superficial femoral or popliteal 
arteries; 
5. Lesion ≥70% stenosis by visual estimate;  
6. Target reference vessel diameter of 4-7 mm; 
7. A patent inflow artery free from significant lesion (≥50% stenosis) as 
confirmed by angiography. (Treatment of target lesion acceptable after 
successful treatment of inflow artery lesions. Successful inflow artery 
treatment is defined as attainment of residual diameter stenosis ≤30% 
without death or major vascular complication.) 
8. At least one patent native outflow artery to the ankle, free from significant 
(≥50%) stenosis as confirmed by angiography after successful vessel 
preparation; 
9. Successful antegrade wire crossing and vessel preparation (may include pre-
dilatation) of the target lesion. Successful vessel preparation is defined by 
residual stenosis ≤30% without any major vascular complications.     
10. No other prior vascular interventions within 2 weeks before and/or planned 
30 days after the protocol treatment except for remote common femoral 
patch angioplasty separated by at least 2 cm from the lesion(s). 
Exclusion 
Criteria 
1. Life expectancy of <2 years; 

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2. Subject is currently participating in an investigational drug or device study, 
or previously enrolled in this study. Enrollment in another investigational 
drug or device study during the follow up period is not allowed. 
3. History of stroke within 3 months; 
4. History of myocardial infarction (MI), thrombolysis or angina within 2 
weeks of index procedure; 
5. Renal failure or chronic kidney disease with serum creatinine ≥2.5 mg/L 
within 30 days of index procedure or treated with dialysis; 
6. Sudden symptom onset, acute vessel occlusion, or acute or sub-acute 
thrombus in target vessel. 
National 
Principal 
Investigator 
Chris Metzger, MD 
Wellmont CVA Heart Institute 
2050 Meadowview Parkway 
Kingsport, TN 37660 
Sponsor 
Contact: 
Lutonix, Inc., a subsidiary of CR Bard 
9409 Science Center Drive 
New Hope, MN 55428 USA 
Tel: 1-763-445-2352 
Angiographic 
Core Lab 
Yale Cardiovascular Research Group 
Yale School of Medicine 
1 Church Street, Suite 330 
New Haven, CT 06510 
Tel: 1- 203-737-2275 
DUS Core Lab 
VasCore 
1 Bowdoin Square 
10th Floor 
Boston, MA 02114 
Tel: 1- 617-726-5552 
 
 
 

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TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE ..................................................................................................... 2 
SUB-INVESTIGATOR PROTOCOL SIGNATURE PAGE ............................................................ 3 
1 
INTRODUCTION ........................................................................................................................ 9 
1.1 
CLINICAL BACKGROUND ........................................................................................................ 9 
1.2 
LUTONIX PRECLINICAL TESTING .......................................................................................... 9 
1.3 
CLINICAL STUDY BACKGROUND ........................................................................................ 10 
1.4 
LUTONIX POST APPROVAL STUDY RATIONALE ............................................................. 12 
2 
STUDY PURPOSE AND OBJECTIVE ................................................................................... 13 
2.2 
OBJECTIVE ................................................................................................................................. 13 
3 
ENDPOINTS .............................................................................................................................. 14 
3.1 
PRIMARY ENDPOINTS ............................................................................................................. 14 
3.2 
SECONDARY ENDPOINTS....................................................................................................... 14 
4 
DEVICE DESCRIPTION .......................................................................................................... 14 
4.1 
CATHETER DESCRIPTION ...................................................................................................... 14 
4.2 
INDICATIONS FOR USE ........................................................................................................... 15 
4.3 
CONTRAINDICATIONS ............................................................................................................ 15 
4.4 
DEVICE INSTRUCTIONS .......................................................................................................... 15 
5 
RISK-BENEFIT ANALYSIS .................................................................................................... 15 
5.1 
POTENTIAL RISKS .................................................................................................................... 15 
5.2 
RISK MANAGEMENT PROCEDURES .................................................................................... 17 
5.3 
POTENTIAL BENEFITS............................................................................................................. 17 
5.4 
EARLY TERMINATION ............................................................................................................ 17 
6 
CLINICAL STUDY DESIGN ................................................................................................... 18 
6.1 
SCREENING AND INFORMED CONSENT ............................................................................. 18 
6.2 
PATIENT SELECTION FOR ENROLLMENT .......................................................................... 19 
6.3 
INCLUSION AND EXCLUSION CRITERIA ............................................................................ 19 
7 
STUDY PARTICIPATION ....................................................................................................... 20 
7.1 
ENROLLMENT ........................................................................................................................... 20 
7.2 
BASELINE ANGIOGRAM ......................................................................................................... 20 
7.3 
IN-FLOW LESION TREATMENT ............................................................................................. 21 
7.4 
PRE-DILATATION / VESSEL PREPARATION ....................................................................... 21 
7.5 
TREATMENT WITH LUTONIX CATHETER .......................................................................... 21 
8 
TREATMENT OF SUBJECT ................................................................................................... 21 
8.1 
STANDARD TESTS, PROCEDURES, AND FOLLOW-UP ..................................................... 21 
8.2 
Unscheduled angiography/revascularization ................................................................................ 23 

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9 
ADVERSE EVENTS .................................................................................................................. 24 
9.1 
ADVERSE EVENT REPORTING .............................................................................................. 25 
10 
DATA COLLECTION AND MONITORING ........................................................................ 26 
10.1 
DATA COLLECTION ................................................................................................................. 26 
10.2 
MONITORING ............................................................................................................................ 26 
11 
DEVICE ACCOUNTABILITY ................................................................................................ 27 
12 
STUDY MANAGEMENT ......................................................................................................... 27 
12.1 
INDEPENDENT EVENT REVIEW ............................................................................................ 27 
13 
REGULATORY RESPONSIBILITIES ................................................................................... 27 
13.1 
ETHICS OVERSIGHT................................................................................................................. 27 
13.2 
investigational plan amendments .................................................................................................. 28 
14 
SELECTION OF CLINICAL SITES AND INVESTIGATORS ........................................... 28 
14.1 
investigator’s responsibilities ....................................................................................................... 28 
14.2 
records .......................................................................................................................................... 29 
14.3 
reports ........................................................................................................................................... 31 
15 
PUBLICATIONS ....................................................................................................................... 33 
16 
STATISTICAL ANALYSIS PLAN .......................................................................................... 33 
16.1 
OVERVIEW OF STUDY DESIGN ............................................................................................. 33 
16.2 
ANALYSIS CONVENTIONS ..................................................................................................... 33 
16.3 
ANALYSIS POPULATIONS ...................................................................................................... 33 
16.4 
HANDLING MISSING DATA .................................................................................................... 34 
16.5 
ASSESSMENT OF POOLABILITY OF SITES ......................................................................... 34 
16.6 
SECONDARY ENDPOINTS....................................................................................................... 35 
17 
REFERENCES ........................................................................................................................... 36 
APPENDIX B: INFORMED CONSENT FORM ............................................................................ 42 
APPENDIX C: DATA POINTS COLLECTED .............................................................................. 43 
Tables 
Table 1.  Follow-Up Schedule and Testing Requirements ............................................................................ 22 
Table 2.  Sponsor Reports .............................................................................................................................. 31 
Table 3.  Investigator Reports ........................................................................................................................ 32 
 
 
 

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1 INTRODUCTION 
The Lutonix® 035 Drug Coated Balloon PTA Catheter (LUTONIX® Catheter) has been approved by 
the Food and Drug Administration (P130024) for percutaneous transluminal angioplasty, after 
appropriate vessel preparation, of de novo, restenotic, or in-stent restenotic lesions up to 300 mm in 
length in native superficial femoral or popliteal arteries with reference vessel diameters of 4-7 mm. 
The purpose of this post-approval study is to assess the safety and effectiveness of the LUTONIX® 
Catheter in the US female population.  
1.1 
CLINICAL BACKGROUND 
Peripheral arterial disease (PAD) is highly prevalent in the general population in the US with an 
estimated 20% of those over the age of 70 having clinically significant vessel involvement [1].  It 
may present with intermittent claudication, resulting in reduced quality of life due to pain in the legs 
on exercise, or with more severe symptoms of critical limb ischemia, such as rest pain or ischemic 
wounds.  The restriction in blood flow that causes these symptoms may be related to disease at a 
variety of different sites in the legs, including the aortoiliac segments, the femoropopliteal segments, 
or the smaller infrapopliteal arteries.  The femoropopliteal artery, including the superficial femoral 
artery (SFA) and popliteal artery, is the most commonly involved vessel in the peripheral circulation 
and the most common site for lower limb interventions [2].  
Indications for surgical or endovascular intervention in PAD include claudication, rest pain, and 
ischemic skin ulceration or gangrene which may progress to ischemic limb loss.  Since 1997, a 
significant change in practice has occurred, with endovascular interventions replacing surgical 
bypass as the dominant revascularization therapy.  The most common intervention is percutaneous 
transluminal angioplasty (PTA), in which the stenotic artery is dilated with a balloon tipped catheter 
inserted under fluoroscopic guidance.   
A drug coated balloon (DCB) is a standard angioplasty balloon coated with an antiproliferative agent 
on the balloon surface.  Many DCBs have been approved for use in Europe since 2008, and since 
2014 LUTONIX® Catheter is also available in the US.  Compared with drug eluting stents (DES) and 
other existing therapeutic approaches, DCB offers local delivery of an antiproliferative agent to the 
vasculature without implantation of a stent. DCBs have the potential to benefit patients with 
femoropopliteal artery disease by providing more durable patency than PTA without requiring a 
permanent implant.  This allows a broader population to be treated and preserves flexibility of future 
therapeutic treatment options for patients with peripheral vascular disease and multiple co-
morbidities. 
1.2 
LUTONIX PRECLINICAL TESTING 
A thorough panel of biocompatibility, bench, and animal testing was performed based on 
international standards and Food and Drug Administration (FDA) guidance.  Results from these 
combined studies demonstrated functionality and provided reasonable assurance of device safety.  
Animal studies in porcine model included six-month histopathology studies examining local, 

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regional, and systemic effects of Lutonix DCB at 1x and 4x doses, and to evaluate pharmacokinetics.  
Results demonstrated complete endothelialization, vascular healing, no safety problems, and no 
systemic effects related to the paclitaxel coating [3].  In addition, paclitaxel levels in porcine arterial 
tissue at 30 days were sufficient to reduce smooth muscle cell proliferation [4].  Additionally, coating 
adhesion integrity was assessed during development to assure that the drug is applied uniformly on 
the balloon during the manufacturing process and does not flake off the balloon during handling in 
clinical environment.  Finally, each batch of finished Lutonix DCB devices undergoes release testing 
for appearance, identity, potency, content uniformity, impurities, in vitro release, particulate matter 
and endotoxins to help assure consistent safety and effectiveness for all devices.   
The Lutonix DCB received CE Mark approval in 2010 and PMA approval from FDA in 2014.  It is 
currently commercialized in over 20 countries. 
1.3 
CLINICAL STUDY BACKGROUND 
 
1.3.1 THE LEVANT 2 PIVOTAL IDE TRIAL 
The pivotal Levant 2 IDE study (NCT01412541) was designed in collaboration with physicians and 
FDA to demonstrate safety and efficacy of the Lutonix Catheter for treatment of femoropopliteal 
lesions in a larger population and to obtain US FDA approval. Levant 2 is a prospective, multicenter, 
single blind, 2:1 randomized, controlled trial, comparing outcomes after treatment of symptomatic 
femoropopliteal artery lesions with Lutonix Catheter vs. uncoated PTA.  
The trial pre-specified two primary endpoints that must both be met for trial success. The primary 
effectiveness endpoint is primary patency of the target lesion at 1 year. Primary patency is defined 
as the absence of target lesion restenosis and freedom from target lesion revascularization (TLR). 
The primary safety endpoint is freedom from all-cause perioperative (≤30 day) death and freedom 
at 1 year from the following: index limb amputation (above or below the ankle), index limb 
reintervention, and index-limb-related death. The tested hypothesis was that DCB would 
demonstrate superior effectiveness and non-inferior safety compared to PTA. 
The trial enrolled patients with symptomatic claudication or ischemic rest pain (Rutherford category 
2-4) and an angiographically significant atherosclerotic lesion (>70% diameter stenosis, ≤15 cm 
length) in the superficial femoral and/or popliteal arteries of diameter 4 to 6 mm with a patent 
outflow artery to the foot.  
Enrollment began in July 2011, and randomization of 476 patients (n = 316 DCB vs. N = 160 PTA) 
at 55 centers was completed in July 2012.  One year follow-up and primary endpoint analysis has 
been completed, and clinical follow-up was completed in October 2017.  
Baseline demographics, comorbidities, and lesion characteristics were well matched between 
groups; 43% of patients were diabetic, 35% were current smokers, and 8% had critical limb ischemia 
(CLI). The mean lesion length was 62.8 mm and the treated length was 108 mm.  

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Levant 2 met both pre-specified primary endpoints.  Primary patency for Lutonix Catheter (65.2%) 
was superior to control PTA (52.6%, p= 0.015) at 12 months, demonstrating superior efficacy.  The 
primary safety endpoint success rate for Lutonix DCB (83.9%) was non-inferior to control PTA 
(79.0%, p = 0.005).  Freedom from TLR was 87.7% for DCB compared to 83.2% for control PTA.  
Several secondary endpoints were also analysed but not hypothesis tested. Procedural success (< 
30% residual stenosis without SAE) was similar for Lutonix Catheter and control PTA (88.9% vs. 
86.8%), demonstrating effectiveness at acute restoration of patency. The Rutherford scores, walking 
impairment (WIQ) scores, ABI, six minute walk test, and quality of life questionnaires each showed 
improvements from before treatment through 12 months in both treatment groups. At 12 months, 
88.2% of Lutonix DCB patients and 82.4% of control PTA patients had improved Rutherford Class 
compared to baseline. Mean improvement in the WIQ total score was 23.9 ± 27.6% for Lutonix 
DCB compared to 19.2 ± 26.5% for control PTA, and improvement in WIQ walking distance was 
31.5 ± 37.0% vs. 22.2 ± 35.4%, respectively. Improvements in ABI, six minute walk test, EQ-5D, 
and SF-36v2 through 12 months were similar for both groups.  
Secondary safety endpoints were generally similar for Lutonix Catheter and control PTA. These 
included respectively, all-cause death (2.4% vs. 2.8%), amputation (0.3% vs. 0.0%), amputation-
free survival (97.6% vs. 97.2%), thrombosis (0.4% vs. 0.7%), target vessel revascularization (TVR, 
13.3% vs. 18.2%), cardiovascular hospitalization (9.1% vs. 7.1%), and major vascular complications 
(6.3% vs. 4.9%; defined as hematoma >5 cm, false aneurysm, AV fistula, retroperitoneal bleed, 
peripheral ischemia/nerve injury, transfusion). Adverse events were similar for both treatment 
groups and consistent with historic data for the enrolled population with symptomatic PAD.  
Levant 2 successfully demonstrated superior efficacy and non-inferior safety of Lutonix Catheter 
compared to control PTA. 
 
1.3.2 THE LEVANT 2 REGISTRY (CONTINUED ACCESS & SAFETY REGISTRIES)  
Levant 2 Continued Access (NCT01628159) and Safety (NCT01790243) registries were initiated 
for collection of additional safety data after completion of Levant 2 enrollment.  These studies 
followed the same Levant 2 clinical protocol for the test arm in every aspect of inclusion/exclusion 
criteria, follow-up schedule, and treatment procedure, but were not randomized. They were 
conducted using the same data collection practices, independent core labs, and CEC adjudication 
process for SAE’s.  Sites that had enrolled in the randomized Levant 2 trial enrolled in Continued 
Access, and new sites enrolled in the Safety Registry. Results were pre-specified to be reported side-
by-side and pooled with the roll-in and randomized DCB-treated cohorts of the Levant 2 randomized 
trial in order to provide a DCB-treated cohort of sufficient size to detect and describe the rate of 
unexpected rare (1-2%) drug- or device- related adverse events, the primary endpoint, with precision. 
Secondary endpoints include the primary endpoints and most of the secondary endpoints of the 
Levant 2 randomized trial. 

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Enrolment was completed on September 27, 2013.  A total of 657 subjects were enrolled at 63 sites 
across the United States (US) and Europe (EU).  Baseline characteristics and treated lesions were 
comparable to the randomized cohort. As of the August 4, 2014 database export, the 30-day follow-
up window has been completed (98.8% compliance), and 95.1% and 75.6% of registry subjects have 
completed 6-month and 12 month follow-up, respectively; mean follow-up is 325 days. Clinical 
follow-up, monitoring, and CEC adjudications are ongoing.  
Together with the randomized study, n = 1029 patients have been treated with Lutonix DCB and 
followed for a mean duration of 438 days. There are no unanticipated device- or drug-related adverse 
events, the primary endpoint, as of this reporting date. For an observed incidence rate of 0%, the 
upper bound of the one-sided 95% CI = 0.3% at 30 days, 0.3% at 6 months, and 0.4% at 12 months. 
Overall device and procedural success rates for all DCB were 99.9% and 87.8%, respectively, and 
similar for roll-in, randomized, and registry cohorts. For all DCB-treated patients, the proportion of 
subjects meeting the composite safety endpoint (freedom from all-cause perioperative death and 
index limb-related death, amputation, and reintervention) was 99.4% (1003/1009) at 1 month, 96.0% 
(906/944) at 6 months and 90.5% (708/782) at 12 months. The 12 month rate of all cause death 
(1.4%), amputation (0.1%), AFS (98.6%), TVR (8.3%), thrombosis (0.1%), cardiovascular 
hospitalizations (10.2%), and major vascular complications (3.6%) are comparable across cohorts 
and consistent with safety.  No additional safety risks have been identified to date.  
Overall freedom from TLR for the all DCB-treated patients was 97.0% (914/942) at 6 months and 
92.5% (719/777) at 12 months.  Rutherford Class was significantly improved at all time points 
compared to baseline; through 12 months, 87% of patients had an improvement in Rutherford Class, 
72% by 2 or more grades. Sustained improvement in Rutherford Class without TVR was observed 
in 79% of patients. These clinical endpoints compare favorably to historic results and provide further 
support for the clinical benefit of Lutonix DCB.  
Taken as a whole, the Levant 2 randomized and registry studies demonstrate that treatment of native 
femoropopliteal lesions with Lutonix DCB provides more durable patency than standard PTA 
through 12 months with comparable safety and provides a reasonable assurance of safety and 
effectiveness.  
1.4 
LUTONIX POST APPROVAL STUDY RATIONALE 
The Levant 2 trial provided the pivotal clinical evidence supporting the safety and effectiveness of 
Lutonix Catheter. Both primary endpoints (superior effectiveness and non-inferior safety) were met 
in the intent-to-treat (ITT) population by direct comparison to conventional balloon angioplasty. 
Levant 2 demonstrated that treatment of native femoropopliteal lesions with Lutonix Catheter 
provides more durable patency and safety comparable to standard PTA. FDA therefore approved 
Lutonix Catheter (P130024) for treatment of the entire population enrolled in the pivotal trial.  
As in most clinical trials, Levant 2 was not powered to statistically examine differences in results 
between subgroups.  Although the overall treatment effect was generally consistent across 

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subgroups, unexpected results were observed in a few subsets.  Given the multiplicity of subgroups 
and their limited sample sizes, chance is the most likely explanation for differences in subgroup 
results that are commonly observed in clinical trials [5]. 
Although the pivotal study was not powered for subgroup analyses, the primary effectiveness data 
suggested a reduced treatment effect in women, as compared with observed outcomes in men. 
Primary patency for females was 56.4% for DCB compared to 61.4% for PTA (difference -4.9%), 
while for males patency was 70.6% for DCB compared to 48.4% for PTA (difference 22.2%). In 
contrast, primary safety data suggested an enhanced treatment effect in women, as compared with 
observed outcomes in men. Primary safety for females was 80.4% for DCB compared to 67.4% for 
PTA (difference 13.0%), while for males primary safety was 86.2% vs. 84.5% (difference 1.7%).  
Possible drivers of this unexpected inverse endpoint correlation by gender, were investigated in 
depth, including potential differences in baseline covariates and effect modifiers. A series of 
exploratory statistical models consistently demonstrated smoking to be a better statistical predictor 
of effectiveness than gender. In addition, although randomization was successful at balancing 
baseline characteristics for the entire Levant 2 ITT population, within the US female subset there 
were significant differences between lesions allocated to DCB compared to PTA that would be 
expected to favour primary patency outcomes for lesions treated in the control PTA group. These 
observations support – but do not prove – the conclusion that the observed outcome differences by 
gender are due to chance.  
The observed results by gender therefore warrant further investigation. The aim of this post approval 
study is to provide additional clinical evidence of effectiveness and safety of the Lutonix Catheter 
in the US female population. 
2 STUDY PURPOSE AND OBJECTIVE 
2.1.1 PURPOSE 
The purpose of the study is to assess the safety and effectiveness of the Lutonix Catheter for 
treatment of stenosis or occlusion of the femoral and popliteal arteries in the US female population. 
2.2 
OBJECTIVE 
The objective of the study is to evaluate the safety and effectiveness of the Lutonix Catheter for 
treatment of stenosis of the femoropopliteal arteries in the US female population. 

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3 ENDPOINTS 
3.1 
PRIMARY ENDPOINTS 
3.1.1 SAFETY 
The primary safety endpoint is the composite of freedom from all-cause peri-operative (≤30 day) 
death and freedom at 1 year from the following: index limb amputation (above or below the ankle), 
index limb re-intervention, and index-limb-related death.  
3.1.2 EFFECTIVENESS 
The primary effectiveness endpoint is primary patency of the target lesion at 12 months. Primary 
Patency is defined as Freedom from TLR and from Binary Restenosis. Binary Restenosis is 
adjudicated by the independent Core Laboratory based on PSVR ≥ 2.5 and / or abnormal waveforms 
or based on angiographic ≥ 50% diameter stenosis.  
3.2 
SECONDARY ENDPOINTS 
The following endpoints will be assessed at 1 month: 
• Composite of freedom from all-cause perioperative (≤ 30 day) death and freedom from the 
following: index limb amputation, index limb re-intervention, and index-limb-related death. 
• Major Vascular Complications (<30 days) 
The following endpoints will be assessed at 1, 6, 12 and 24 months: 
• All-cause death  
• Clinically Driven Target Lesion Revascularization (TLR)  
• Target Vessel Revascularization (TVR)  
• Reintervention for treatment of thrombosis of the target vessel or embolization to its distal 
vasculature  
• Rate of unanticipated and anticipated device  related serious adverse events  
• Amputation (above the ankle)-Free Survival (AFS)  
• Change of Rutherford classification from baseline 
• Sustained Clinical Benefit (improvement in Rutherford Class compared to baseline AND 
freedom from target vessel revascularization) 
• Change of resting Ankle Brachial Index (ABI) from baseline 
4 DEVICE DESCRIPTION  
4.1 
CATHETER DESCRIPTION 
The LUTONIX® 035 Drug Coated Balloon PTA Catheter (LUTONIX® Catheter) consists of an over the 
wire catheter with a drug coated balloon fixed at the distal tip.  The balloon is coated with a 
specialized formulation that includes the drug paclitaxel.  The LUTONIX® Catheter is 0.035” 
guidewire compatible, with a low profile, semi-compliant balloon formed to a low profile tapered 

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tip to facilitate advancement of the catheter to and through the stenotic region of the vessel.  Two 
radiopaque marker bands delineate the working length of the balloon and are located under the 
proximal and distal ends of the balloon to facilitate fluoroscopic visualization of the balloon during 
delivery and placement.  The proximal portion of the catheter includes an inflation female Luer Lock 
hub and a guidewire female Luer Lock hub.  Each product is packaged with a balloon protector that 
has been positioned over the balloon and a disposable wire lumen stylet, both of which are to be 
removed prior to use.  Any commercially available balloon lengths may be used in this trial.  
4.2 
INDICATIONS FOR USE 
Always refer to the electronic instructions for use (IFU) available online for the current indications 
for use. As of the date of this protocol revision, the indication for use is as follows:   
The Lutonix® 035 Drug Coated Balloon PTA Catheter is indicated for percutaneous transluminal 
angioplasty, after appropriate vessel preparation, of de novo, restenotic, or in-stent restenotic lesions 
up to 300 mm in length in native superficial femoral or popliteal arteries with reference vessel 
diameters of 4-7 mm.   
4.3 
CONTRAINDICATIONS 
The LUTONIX® Catheter is contraindicated for use in: 
• 
Patients who cannot receive recommended anti-platelet and/or anticoagulant therapy. 
• 
Women who are breastfeeding, pregnant or are intending to become pregnant or men intending 
to father children.  It is unknown whether paclitaxel will be excreted in human milk and there is 
a potential for adverse reaction in nursing infants from paclitaxel exposure. 
• 
Patients judged to have a lesion that prevents complete inflation of an angioplasty balloon or 
proper placement of the delivery system. 
4.4 
DEVICE INSTRUCTIONS 
Please refer to the most current IFU available online for complete details.     
5 RISK-BENEFIT ANALYSIS 
5.1 
POTENTIAL RISKS 
The potential risks and benefits of participation in this study are clearly identified in the subject 
Informed Consent Form (ICF) and are to be explained to the subject and/or their legal representative 
prior to participating in the study.   
5.1.1 
RISKS FOR PERIPHERAL CATHETERIZATION PROCEDURE 
Due to the high similarity of the LUTONIX® Catheter to other marketed balloon catheters, procedural 
use is not expected to significantly change or increase risks during the index procedure.   
Complications and AEs associated with use of the LUTONIX® Catheter are listed in the IFU. 
Potential adverse events which may be associated with a peripheral balloon dilatation procedure 
include: 

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• Additional intervention 
• Allergic reaction to drugs, excipients or contrast medium 
• Amputation/loss of limb 
• Aneurysm or pseudoaneurysm 
• Arrhythmias 
• Embolization 
• Hematoma 
• Hemorrhage, including bleeding at the puncture site 
• Hypotension/hypertension 
• Inflammation 
• Occlusion 
• Pain or tenderness 
• Pneumothorax or hemothorax 
• Sepsis/infection 
• Shock 
• Stroke 
• Thrombosis 
• Vessel dissection, perforation, rupture, or spasm 
 
5.1.2 
ASSOCIATED RISKS FROM THE DRUG COATING 
The balloon coating on LUTONIX® Catheter includes the API paclitaxel and excipients sorbitol and 
polysorbate. The Levant 2 randomized and registry trials (section 1.3.1 and 1.3.2 above) demonstrate 
safety comparable to conventional uncoated angioplasty catheters, and no unexpected additional 
risks attributable to the drug coating have been observed to date.  Although systemic effects are not 
anticipated, refer to the Physicians’ Desk Reference for more information on the potential adverse 
events observed with paclitaxel.  
Potential adverse events which may be unique to the paclitaxel drug coating include:   
• Allergic/immunologic reaction  
• Alopecia 
• Anemia 
• Blood product transfusion 
• Gastrointestinal symptoms 
• Hematologic dyscrasia (including leukopenia, neutropenia, thrombocytopenia) 
• Hepatic enzyme changes 
• Histologic changes in vessel wall, including inflammation, cellular damage, or necrosis 
• Myalgia/Arthralgia 

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• Myelosuppression 
• Peripheral neuropathy 
5.2 
RISK MANAGEMENT PROCEDURES 
The investigational plan is specifically designed to manage and minimize risks through careful 
subject selection, thorough training of investigators, adherence to the pre-determined time points to 
assess subject clinical status and regular clinical monitoring visits by Sponsor appointed monitoring 
personnel. 
Follow-up exams including duplex ultrasound will be performed to assess the target vessel patency 
and assess overall subject status.   
5.3 
POTENTIAL BENEFITS 
There are no guaranteed benefits from participation in this study.  LUTONIX® Catheter is a currently 
available treatment option. Although the superior effectiveness of LUTONIX® Catheter over PTA was 
demonstrated for the general population, participation in this study will determine whether or not 
that is true for the subpopulation of US women. Information gained from the conduct of this study 
will therefore be of significant benefit to others with the same medical condition. 
5.4 
EARLY TERMINATION 
The Sponsor will monitor the progression of the study.  If warranted, the study may be suspended 
or discontinued early if there is an observation of serious adverse reactions presenting an 
unreasonable risk to the study population.   
The Sponsor may terminate Investigator and site participation in the study for issues including but 
not limited to the following: 
• Evidence of an Investigator’s failure to maintain adequate clinical standards  
• Evidence of an Investigator or staff’s failure to comply with the signed Clinical Trial  
• Agreement with Sponsor, protocol, regulations, or any conditions of approval imposed by the 
reviewing Institutional Review Board (IRB) or FDA (21 CFR 812.46(a)) 
• Inaccuracy or late submission of data forms and core lab images 
• Evidence of safety concerns  
• Change of staff at site that adversely impacts trial conduct   
• Failure to secure subject informed consent or HIPAA forms 
• Falsification of data, or any other breech of ethics or scientific principles 
Any evident pattern of non-compliance with respect to these standards will be cause for the site to 
be suspended and or terminated.  If corrective actions are not subsequently undertaken, the clinical 
site will be asked to withdraw from the study and their site may be replaced. 
In the event of study suspension or termination, the Sponsor will send a report outlining the 
circumstances to the IRB and all Investigators and FDA as required by regulation.  A suspended or 

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terminated study may not be reinitiated without approval of the reviewing IRB and FDA, as required 
by regulation. 
The Investigator must notify the IRB in writing as soon as possible but no later than within 10 days 
if the premature termination is related to safety or compliance issues.  
6 CLINICAL STUDY DESIGN   
The study is a prospective, multicenter, single-arm study.  The study will enroll approximately 165 
patients presenting with claudication or ischemic rest pain and an angiographically significant lesion 
in the superficial femoral or popliteal artery and a patent outflow artery to the foot.  Subjects will be 
treated with the LUTONIX® Catheter and followed with ultrasound and clinical visits through 2 years. 
Patients will be enrolled at a minimum of 10 US sites and a maximum of 25.  
6.1 
SCREENING AND INFORMED CONSENT 
All female patients admitted for a percutaneous revascularization of a femoropopliteal artery should 
be screened for study eligibility.  If inclusion criteria are met and no exclusion criteria are present at 
the time of screening, the Investigator or authorized delegate will discuss the study and ask the 
patient to participate. Prior to enrollment, the patient must be fully informed of the nature of the 
study, details of study procedures, anticipated benefits, and potential risks of participation as 
required by applicable law.  Provide the patient with a copy of the Informed Consent Form (ICF) 
and HIPAA authorization approved for use by the IRB and review its content, allowing adequate 
time for questions.  An ICF template is provided in Appendix B. All information pertinent to the 
clinical study shall be provided in writing and in native, non-technical language that is 
understandable to the patient.  Patients will be assured that they may withdraw from the study at any 
time and for any reason and this decision will not influence her relationship with the Investigator 
and/or study staff.  
The patient must be allowed sufficient time to decide whether to participate.  Once the patient has 
read and understands the ICF, she will indicate her willingness to participate in the study by signing 
and dating the ICF.  The ICF must also be signed and dated by the person obtaining informed 
consent.  The investigator or authorized delegate must document in the subject’s medical records 
that the patient was consented and the date of which informed consent was obtained.  The original 
signed ICF will be retained in the subject’s clinical study record.  A copy of the signed and dated 
ICF will be provided to the subject and a copy placed in the subject’s medical record.   
If not already performed as standard practice, the following assessments and tests must be performed 
after obtaining informed consent and prior to the index procedure (within 30 days unless otherwise 
noted) to verify and complete eligibility and for baseline data collection: 
• Physical examination including: 
• Heart rate, brachial blood pressure, and weight 
• Rutherford Classification 

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• Resting Ankle-Brachial Index (ABI) (within 90 days) 
• Relevant medical history 
• Pregnancy test (blood or urine; if female of child bearing potential) 
• Serum creatinine level (within 30 days) 
6.2 
PATIENT SELECTION FOR ENROLLMENT 
Patients must meet all the clinical eligibility criteria, agree to participate and comply with study 
protocol requirements and follow-up schedule, and provide informed consent. 
All subjects are expected to remain available (geographically stable) for the duration of the study 
follow-up period. If any subject moves away, every effort must be made to maintain the follow-up 
schedule including having an appropriate physician follow the subject.  The Investigator is 
responsible for ensuring that each follow-up visit occurs at the specified time and that all applicable 
data is reviewed and entered into the electronic case report form system (eCRF) in a timely fashion. 
6.3 
INCLUSION AND EXCLUSION CRITERIA 
6.3.1 
 INCLUSION CRITERIA 
Patients must meet all inclusion criteria to be enrolled in the study. 
Clinical Criteria 
1. Non-pregnant female ≥18 years of age;  
2. Rutherford Clinical Category 2-4;  
3. Patient is willing to provide informed consent, is geographically stable, comply with the required 
follow up visits and testing schedule; 
Angiographic Criteria  
4. De novo or restenotic lesion(s) in native superficial femoral or popliteal arteries; 
5. Lesion ≥70% stenosis by visual estimate; 
6. Target reference vessel diameter of 4-7 mm; 
7. A patent inflow artery free from significant lesion (≥50% stenosis) as confirmed by angiography. 
(Treatment of target lesion acceptable after successful treatment of inflow artery lesions. 
Successful inflow artery treatment is defined as attainment of residual diameter stenosis ≤30% 
without death or major vascular complication.) 
8. At least one patent native outflow artery to the ankle, free from significant (≥50%) stenosis as 
confirmed by angiography after successful vessel preparation; 
9. Successful antegrade wire crossing and vessel preparation (may include pre-dilation) of the 
target lesion.  Successful vessel preparation defined by residual stenosis ≤30% without any major 
vascular complications.    

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10. No other prior vascular interventions within 2 weeks before and/or planned 30 days after the 
protocol treatment except for remote common femoral patch angioplasty separated by at least 2 
cm from the lesion(s). 
6.3.2 EXCLUSION CRITERIA 
Patients will be excluded if ANY of the following conditions apply:  
1. Life expectancy of <2 years; 
2. Subject is currently participating in an investigational drug or device study or previously enrolled 
in this study. Enrollment in another investigational drug or device study during the follow up 
period is not allowed 
3. History of stroke within 3 months; 
4. History of MI, thrombolysis or angina within 2 weeks of index procedure; 
5. Renal failure or chronic kidney disease with serum creatinine ≥2.5 mg/L within 30 days of index 
procedure or treated with dialysis; 
6. Sudden symptom onset, acute vessel occlusion, or acute or sub-acute thrombus in target vessel; 
7 STUDY PARTICIPATION 
7.1 
ENROLLMENT 
After signing the informed consent document, a patient will be considered enrolled in the study 
after baseline angiographic results and after successful vessel preparation confirm that the target 
lesion meets all appropriate inclusion/exclusion criteria and the subject is treated with the 
LUTONIX® Catheter.  
Subjects that meet baseline angiographic criteria but do not meet post vessel preparation 
angiographic criteria will not be treated with the LUTONIX® Catheter or enrolled in the study. 
Subjects who are not treated with the LUTONIX® Catheter will be treated per standard of care and 
will not be enrolled in the study.  
7.2 
BASELINE ANGIOGRAM 
Digital Subtraction Angiography (DSA) should be obtained per Angiographic Core Lab Guidelines.  
Standard off-line Quantitative Vascular Angiography (QVA) acquisition procedures will be 
followed for analysis at the independent imaging core laboratory. All angiography procedures (both 
index and non-scheduled) must be recorded in DICOM format that are suited for QVA analysis.  For 
purposes of ensuring protocol compliance, all angiograms must be submitted to the Core Laboratory 
as soon after the case as possible. Please refer to the Angiographic Core Lab Guidelines for specific 
procedural imaging and submission instructions. 

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7.3 
IN-FLOW LESION TREATMENT 
A patent inflow artery free from significant lesion (≥50% stenosis) as confirmed by angiography is 
required.  Treatment of inflow artery lesions may be performed.  Successful inflow artery treatment 
is defined as attainment of residual diameter stenosis ≤30% without death or major vascular 
complication.   
7.4 
PRE-DILATATION / VESSEL PREPARATION 
Successful vessel preparation of the target lesion must be confirmed prior to treatment with the 
LUTONIX® Catheter. Successful vessel preparation is defined by residual stenosis ≤30% without 
any major vascular complications. Always limit the longitudinal length of the pre-dilatation 
balloon, or other appropriate vessel preparation modality, to avoid creating a region of vessel 
injury that is outside the boundaries of the area to be treated by the LUTONIX® Catheter.  
7.5 
TREATMENT WITH LUTONIX CATHETER 
Always follow the current IFU for procedural information and use of the LUTONIX® Catheter.  The 
Investigator should determine the appropriate size of the balloon to be used by online QVA (if 
possible) or by visual estimate.  A balloon compliance chart is included on each device product label.  
Any devices found to be defective or that do not perform as expected should be returned immediately 
to the Sponsor for evaluation and a Device Failures/Malfunctions/Defects Case Report Form must 
be completed.  
All Device Deficiencies occurring during the conduct of this study will be recorded in the eCRF 
system, and reported by the Investigator to the Sponsor in a timely manner.   
Deficient devices shall be returned to the Sponsor.  The further management of device deficiencies 
by the Investigator and the Sponsor/manufacturer will adhere to the appropriate national laws and 
regulations. 
8 TREATMENT OF SUBJECT 
Lutonix (or its designee) reserves the right to attend index or follow-up visits including DUS 
procedures in order to ensure protocol compliance, proper device handling and adequate image 
capture.  
8.1 
STANDARD TESTS, PROCEDURES, AND FOLLOW-UP 
Table 1 displays the required schedule for treatment and evaluation.  This schedule is consistent 
with most standard clinical care pre- and post-interventional procedures.  The times for each test 
are broad enough to fit into most routine testing procedures.  
All subjects treated with the LUTONIX® Catheter will return for follow-up at 1, 6, 12, and 24 
months post procedure.  
 

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TABLE 1.  FOLLOW-UP SCHEDULE AND TESTING REQUIREMENTS 
Event 
Pre- Procedure 
Procedure 
1 Month 
6 Month 
12 Month 
24 Month 
Unplanned 
Angio/Revasc 
Visit Window 
30 days 
7 days ±30 days ±60 days ±60 days 
 
Inclusion/Exclusion Criteria 
√ 
√ 
 
 
 
 
 
Informed Consent  
√ 
 
 
 
 
 
 
Medical History  
√ 
 
 
 
 
 
 
Physical Exam (HR , BP, and weight) 
√ 
 
√ 
√ 
√ 
√ 
√ 
Resting ABI 
√1 
 
√ 
√ 
√ 
√ 
√ 
Rutherford Classification 
√ 
 
√ 
√ 
√ 
√ 
√ 
Pregnancy Test 2 
√ 
 
 
 
 
 
 
Angiogram 
 
√ 
 
 
 
 
√ 
Adverse Event Monitoring 
 
√ 
√ 
√ 
√ 
√ 
 
Duplex Ultrasound (after clinical assessment) 
 
 
√ 
√ 
√ 
√ 
√ 
1Resting ABI is required within 90 days of index procedure 
2Females of childbearing potential only 
 
8.1.1 TESTING 
8.1.1.1  PREGNANCY TESTING   
For women of childbearing potential, a pre-procedure pregnancy test must be done (blood or urine). 
Pre-procedure samples may be taken up to 30 days prior to the index procedure. 
8.1.1.2 PHYSICAL EXAM 
Physical exam includes the items noted below and must be performed pre-procedure and at 1, 6, 12, 
and 24 months.   The physical exam should also be completed prior to any repeat angiogram or 
revascularization, if possible.   
• Heart Rate, Brachial Blood Pressure, and weight  
• Rutherford Classification 
Rutherford classification is required pre-procedure, 1 month, 6 months, 12 months, and 24 months.  
It should also be collected at any repeat angiogram or revascularization.  It can be measured with or 
without treadmill, but must be performed consistently among subjects over the lifespan of the study. 

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8.1.1.3 ANKLE-BRACHIAL INDEX (ABI)  
A resting ABI must be performed at each visit per local standard practice, and consistently among 
subjects over the lifespan of the study for the index limb.  The baseline ABI may be obtained within 
90 days prior to the index procedure.  Post procedure resting ABI must be collected at 1 month, 6 
months, 12 months, and 24 months and any revascularization.   
8.1.1.4 DUPLEX ULTRASOUND  
Duplex Ultrasound (DUS) must be performed after the index procedure at 1, 6, 12 and 24 months 
and any revascularization.  Since the DUS is critical to assessing study endpoints, the quality of this 
test is extremely important.  The core lab will be closely monitoring the quality of all incoming 
images for compliance.  Sites should ensure that only DUS operators who are trained on the trial 
specific DUS guidelines are performing these tests.  Refer to the Duplex Ultrasound Core Lab 
Guidelines. 
The primary responsibility of the core lab is to provide consistent interpretation of imaging data 
across all study sites.  Data obtained from the core lab readings will be used for study purposes only 
and not for clinical treatment of the subject.  It is the responsibility of each site to perform the local 
interpretation of the imaging for clinical assessment, and to maintain a copy of the DUS and 
angiography studies and report in the medical record.  The core lab will not be responsible to notify 
the site of any abnormal findings that are identified in the studies.   
Lutonix will use only the measurements from the core lab for analysis.  If the core lab determines 
the study is unreadable, the subject may be asked to return for another DUS.   
8.1.2 
FOLLOW-UP PROCEDURES 
All subjects will return for follow-up at 1, 6, 12 and 24 months post procedure for required testing 
at each follow-up visit time point.  All subjects are required to complete all assigned follow-up visits 
and procedures.  See Table 1 above for required testing at each follow-up visit time point.     
8.2 
UNSCHEDULED ANGIOGRAPHY/REVASCULARIZATION 
A duplex ultrasound (DUS) is required prior to an angiography of the index limb, and the image 
should be submitted to the DUS core lab.  In the event that a subject undergoes repeat angiography 
or reintervention of the target limb after the index procedure is complete, the angiogram must be 
forwarded to the angiographic core lab for review and analysis.  Attempts should be made to record 
the same views and angles as from the index procedure.  
Following submission of the angiographic images from the first target lesion reintervention after the 
index procedure, no subsequent angiographic images are required to be submitted to the core lab for 
evaluation unless requested by the sponsor.   

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8.2.1 
DISCONTINUATION 
Subjects can withdraw from the study at any time for any reason. The reason for withdrawal will be 
documented.  There will be no further follow-up (per this study protocol) on the subject who has 
withdrawn.  
If a subject is potentially lost to follow-up, a minimum of three (3) attempts to contact the subject will 
be recorded in source documentation, including date and name of site personnel trying to make 
contact. One of the three (3) attempts to contact the subject must be via a certified letter.   
9 ADVERSE EVENTS 
The Principal Investigator or designee is responsible for the detection, documentation and reporting 
to the Sponsor of events meeting the criteria and definitions of an Adverse Event (AE), as provided 
in this protocol.   
For purposes of this study, the following events are not considered adverse events because they are 
expected to occur in conjunction with endovascular procedures / post-procedure timeframe, or are 
associated with customary, standard care of subjects undergoing these procedures: 
• Early post-operative pain (within 24 hours post-index procedure) at the access site and/or 
related to position on procedure table 
• Minor, localized tenderness, swelling, induration, bruising, oozing, hematoma <5 cm at 
vascular access site  
• Post-anesthesia/conscious sedation emesis, nausea, or headache (within 24 hours post-index 
procedure) 
• Chest pain without associated ECG changes  
• Hematocrit decrease from baseline not associated with hemodynamic changes, remaining 
above 30% and not requiring transfusion 
• Electrolyte imbalance without clinical sequelae following PTA, even if requiring correction 
• Low grade fever (38C/101.4F)  
• Sinus bradycardia/tachycardia that does not require treatment or intervention 
• Systolic or diastolic blood pressure changes that do not require treatment or intervention 
• Dissection (Grade A and B) which occur during the index procedure 
 
This listing of events is intended to provide guidance to the investigational sites for purposes of 
adverse event reporting.  The Investigator at the investigational site should utilize his/her own 
clinical judgment in evaluating adverse experiences, and may decide that the above events should 
be reported as adverse events.  
Only the following types of endpoint related adverse events need to be reported: 
• Events leading to death 
• Target limb reintervention  
• Target limb amputation 
• Any event deemed to be device- or procedure-related 

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• Major vascular complication within 30 days of the index procedure  
• Any event involving the target limb that requires treatment 
AEs involving the target limb that are observational (do not require treatment) do not require 
reporting. The Investigator at the site should utilize his/her own clinical judgment in evaluating 
adverse events, and may decide to report events not noted on the list above. 
Adverse Event Severity  
The Investigator will use the following definitions to rate the severity or intensity of each adverse 
event: 
 
Mild 
 
Awareness of a sign or symptom that does not interfere with the 
subject’s usual activity or is transient, resolved without treatment 
and with no sequelae. 
Moderate 
 
Interferes with the subject’s usual activity and/or requires 
symptomatic treatment. 
Severe 
 
Symptom(s) causing severe discomfort and significant impact of 
the subject’s usual activity and requires treatment. 
 
Relationship to study device and procedure 
The Investigator will use the following definitions to assess the relationship of the adverse event to 
the use of study device or procedure: 
 
Not Related 
 
The event is definitely not associated with the study 
procedure/device.  The adverse event is due to an 
underlying or concurrent illness, concomitant medication 
or the effect of another procedure. 
 
Possibly 
Related 
 
The temporal sequence between the study 
procedure/device and the event is such that the relationship 
cannot be ruled out completely and the event cannot be 
attributed to the subject’s condition, concomitant therapy 
or the effect of another procedure. 
 
Definitely 
Related 
 
The temporal sequence between the study 
procedure/device and the event is such that the relationship 
is obvious, certain, or there is little doubt regarding the 
relationship. 
 
9.1 
ADVERSE EVENT REPORTING 
Adverse Events should be documented in the medical records and in the eCRF. AEs experienced by 
the subject which require reporting per this protocol will be collected from the time point of 

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enrollment (i.e. after successful vessel preparation is confirmed and the subject is treated with the 
LUTONIX® Catheter) until the subject’s end of study participation. Redacted source documentation 
for adjudication purposes will be submitted to Lutonix per request. Refer to Table 3.  Investigator 
Reports for reporting requirements. 
Event review and adjudications will be specified in the Safety Management Plan.   
10 DATA COLLECTION AND MONITORING 
10.1   DATA COLLECTION 
The Investigator (or designee) will assure primary data collection based on source-documented chart 
reviews. These documents will be completed in an expedited fashion.  
All subject information collected during the course of this study will be kept confidential according 
to applicable state and federal laws and regulations.  
 
10.1.1 ELECTRONIC CASE REPORT FORMS (ECRF) 
The Investigator is responsible for ensuring the accuracy and completeness of all study 
documentation. 
All required clinical data for this trial will be collected in web-based standardized electronic case 
report forms (eCRF).  FDA 21 CFR 11 will be followed as well as other applicable legislation on 
the handling of electronic data.  Subject personal information will be pseudonymized.  Site numbers 
and subject numbers will be used to track subject information throughout the study. 
The eCRF is designed to accommodate the specific features of the study design.  Modification of 
the eCRF will only be made if deemed necessary by the Sponsor and/or the appropriate regulatory 
body. 
10.2   MONITORING 
Monitoring is necessary to ensure adequate protection of the rights and safety of human subjects and 
the quality and integrity of the data obtained during the study.  It is the responsibility of Lutonix as 
the sponsor of the study to ensure proper monitoring of the investigation and to see that all the 
clinical requirements are met.   
Sites will be monitored according to the Investigational Plan, Clinical Trial Agreement, ICH GCP 
guidelines, FDA regulations and guidance relevant to this clinical study, and the approved 
monitoring plan.  The Investigator will make subject and study records available to the clinical 
monitor for periodic inspection.  Monitoring personnel will monitor for accuracy and timely 
submission of CRFs and core lab images, compliance with the investigational plan, meeting 
enrollment commitments, applicable regulations, the signed Investigator Agreement and any 
conditions of approval imposed by the reviewing IRB and/or regulatory agencies.  
The clinical monitors will maintain personal contact with the Investigator and staff throughout the 
study by phone, email, and on-site visits.  The monitors will compile and submit to Lutonix a 

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monitoring report after each visit that will include any findings, conclusions, and actions taken to 
correct deficiencies.  
At the close of the study at an investigational site, appropriately trained personnel appointed by 
Lutonix will make a final on-site or remote visit.  The purpose of this visit is to collect all outstanding 
study data documents, ensure that the Investigator's files are accurate and complete, review record 
retention requirements with the Investigator, make a final account of all study supplies shipped to 
the Investigator, provide for appropriate disposition of any remaining supplies, and ensure that all 
applicable requirements are met for the study.   
11 DEVICE ACCOUNTABILITY 
Commercially available LUTONIX® 035 Drug Coated Balloon PTA Catheters will be utilized for 
this study.  In the case where there is a device malfunction or deficiency, the Investigator must make 
every possible effort to return the device to Lutonix.   
12 STUDY MANAGEMENT 
12.1  INDEPENDENT EVENT REVIEW 
Select events will be reviewed and adjudicated as specified in the Safety Management Plan. 
13 REGULATORY RESPONSIBILITIES 
13.1  ETHICS OVERSIGHT 
13.1.1 INSTITUTIONAL REVIEW BOARD (IRB) RESPONSIBILITIES 
All IRBs must comply with applicable IRB regulations (21 CFR 50) in reviewing and approving 
device investigations.  An IRB shall safeguard the rights, safety, and well-being of all study subjects.  
The IRB shall be composed of members meeting the minimum requirements set forth in 21 CFR 
56.107.  
13.1.2 INITIAL APPROVAL 
Investigators must submit the study protocol to their IRB and obtain written approval before Lutonix 
will approve the site to conduct and participate in the study. The Investigator is also responsible for 
fulfilling any conditions of approval imposed by the IRB, such as regular safety reporting and study 
timelines.   
Part of the IRB approval must include approval of an Informed Consent Form (ICF) that is specific 
to the study.  The ICF may be modified to suit the requirements of the individual site; however, all 
required elements as required by FDA regulations (21 CFR 50.25) must remain.  Lutonix or designee 
must pre-approve each ICF prior to initial submission to the IRB.  
The Investigator will provide Lutonix or designee with copies of approval letters, reports, and 
approved ICF documents. 

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13.1.3 ANNUAL RENEWAL 
An IRB shall conduct continuing review of the clinical study at intervals appropriate to the degree 
of risk posed by the device, but not less than once per year (21 CFR 56.109). A copy of the IRB 
renewal and other applicable documents are required to be sent to Lutonix. 
Continuation of research after expiration of IRB approval is a violation of the regulations.   
13.2 INVESTIGATIONAL PLAN AMENDMENTS 
Investigational Plan amendments may occur during the course of the study and will be reviewed 
prior to implementation to determine if the changes affect the:  validity of the data; risk-to-benefit 
ratio; scientific soundness of the Investigational Plan; or the rights, safety, or welfare of the human 
subjects involved in the clinical study.  
Investigational Plan amendments that affect any of the above criteria will require FDA approval 
prior to implementation.  Amendments that do not meet the criteria above will be reported to the 
FDA according to 21 CFR 812.35.  Any amendments to the protocol, as well as possible associated 
information and ICF changes, will be submitted to the IRB and written approval obtained prior to 
implementation.    
14 SELECTION OF CLINICAL SITES AND INVESTIGATORS 
The Sponsor will select Investigators who are qualified and experienced to participate in this post 
approval study.  Sites will be selected based upon a review of a recent site assessment and the 
qualifications of the site.  Any site that becomes deactivated prior to initial enrollment, either by the 
Sponsor or by the individual site itself, may be replaced.  The curriculum vitae (CV) of the 
Investigator will be maintained in the Sponsor files as documentation of previous medical training, 
and federal databases will be searched to ensure that the Investigator is not prohibited from engaging 
in federally sponsored clinical research.   
14.1   INVESTIGATOR’S RESPONSIBILITIES 
Each Investigator is responsible for ensuring the investigation is conducted according to all signed 
agreements, the Clinical Investigational Plan (CIP) and applicable laws and regulations.  The site 
Principal Investigator may select qualified Sub-Investigators at their site and will maintain 
responsibility for oversight of all procedures and data collection.  All Sub-Investigators must be 
trained on all aspects of the protocol prior to enrolling or performing CIP required procedures.  All 
physicians performing the index procedure must be trained as Sub-Investigators in the study. 
The Investigator may not enroll until the Sponsor or designee receives and approves (when 
necessary) the following minimum documents: 
• Complete Signed Investigator Agreement 
• Financial Disclosure Forms for Investigator and all participating sub-Investigators 
• IRB Roster or General Assurance number 

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• IRB Protocol and Informed Consent Approvals 
• Current curricula vitae (CV) for Investigators and sub-Investigators 
• Site Delegation of Authority Log 
• Protocol Training of PI, sub-investigators who perform the index procedure, and primary 
study coordinator 
To ensure proper execution of the Investigational Plan, each Investigator must identify a Study 
Coordinator for the site.  Working with and under the authority of the Investigator, the Study 
Coordinator helps ensure that all study requirements are fulfilled, and is the contact person at the 
site for all aspects of study administration.  The Investigator has the ultimate responsibility of all 
study requirements. 
14.1.1 INVESTIGATOR AGREEMENT 
Each Principal Investigator must sign the Clinical Study Agreement prior to their participation in 
the study.  In addition, each Sub-Investigator must sign the Sub-Investigator Protocol Signature page 
prior to conducting study activities.  The Investigator’s signature signifies his/her agreement to 
follow the Investigational Plan and all regulations and reporting requirements. 
14.1.2 FINANCIAL DISCLOSURE 
Investigators will also be required to sign a Financial Disclosure prior to study participation, which 
documents the Investigator’s and his/her immediate family’s financial interest in the Sponsor and 
study outcomes.  Investigators must inform Lutonix of any changes to the information within the 
Financial Disclosure throughout the course of the study and for a period of one year following the 
completion of the study.   
14.2    RECORDS 
14.2.1 SPONSOR RECORDS 
The Sponsor will maintain without limitation the following records: 
• The Investigational Plan and all amendments 
• Revision controlled CRF templates, ICF templates, and research authorization templates 
• CRFs with audit trails completed by sites and applicable DCFs 
• Signed Clinical Trial Agreements and any amendments  
• Investigator Financial Disclosure information 
• IRB approval letters, including a copy of the approved ICF and research authorization form 
• IRB roster or Assurance number 
• All correspondences relating to the conduct of the study between Lutonix and the FDA, sites, 
IRBs, CEC, and core laboratories 

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• CVs for all Investigators 
• Investigational Plan related training records for all applicable study personnel 
• Any other FDA required records 
14.2.2 INVESTIGATOR RECORDS 
Records to be maintained by the Investigator in a designated site file include without limitation: 
• Sponsor and IRB approved Investigational Plan and all amendments 
• Signed Study Agreement and all amendments thereto 
• IRB approval letters, including a copy of the approved informed consent forms and research 
authorization form template, progress reports, AE reports 
• IRB roster or Assurance number 
• All correspondence relating to the conduct of this clinical study between the site and Lutonix, 
IRBs, and other Investigators 
• CVs and copies of  professional licenses for all Investigators, if applicable 
• Study personnel signatures and documentation of the Principal Investigator’s delegation of 
responsibilities 
• Sponsor Site Visit Log 
• Documentation of Lutonix and IRB approval of changes made to the informed consent and 
research authorization forms 
• Investigational Plan related training records for all applicable study personnel 
• Financial Disclosure documentation for the Principal Investigator and sub-Investigators 
• Any other FDA required records 
The following records must be maintained and be readily available for each subject enrolled:  
• Signed and dated informed consent and research authorization forms 
• Completed eCRFs and queries 
• Records pertaining to adverse events and subject’s death occurring during the study 
• Complete medical records including procedure reports, imaging reports, and all additional 
records required to verify entries on the eCRFs 

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14.2.2.1 RETENTION 
Records are subject to FDA inspection.  Subject study records, correspondence files, all supporting 
study documentation, and reports as described above must remain on file at the site for a minimum 
of two years after the latter of the following dates (21 CFR 812.140(d)): 
• The date on which the study is terminated or completed 
• The date the records are no longer required for purposes of supporting an application to the FDA 
to market the device  
Lutonix must be contacted if the Principal Investigator plans to leave the site to ensure that 
arrangements for a new Principal Investigator or records transfer are made prior to the Investigator’s 
departure.  The FDA will be notified of this transfer no later than 10 working days after the transfer 
occurs (812.140 (e)). 
All Investigators must contact Lutonix prior to destroying or archiving off-site any records and 
reports pertaining to this study to ensure that they no longer need to be retained on-site. 
14.2.3 IRB RECORDS 
Each reviewing IRB must maintain the following records (21 CFR 56.115): 
• All pertinent correspondence relating to the study 
• All records of membership and affiliations 
• Meeting minutes 
14.3 REPORTS 
14.3.1 SPONSOR REPORTS 
Sponsors are responsible for preparing and submitting the following complete, accurate, and timely 
reports (CFR 812.150(b)).  Refer to Table 2 for the types of reports to be submitted.   
TABLE 2.  SPONSOR REPORTS 
Report 
Submit To 
Timeframe 
Unanticipated Adverse 
Device Effects  
FDA, IRBs, and 
Investigators 
Ten (10) working days after 
receiving notice of the event 
Withdrawal of IRB 
Approval 
FDA, IRBs, and 
Investigators 
Five (5) working days 
Withdrawal of FDA 
approval 
IRBs and Investigators 
Five (5) working days 
Current Investigator List 
FDA 
Six (6) month intervals 
Progress reports  
FDA and IRBs 
Annually 
Final Reports  
 
FDA, IRBs, and 
Investigators 
Six (6) months after completion or 
termination 

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Report 
Submit To 
Timeframe 
Recall and device 
disposition 
(Request for Investigator 
to return, repair, or 
dispose of any device) 
FDA and IRBs 
Thirty (30) working days 
Failure to obtain informed 
consent 
FDA 
Five (5) working days 
 
In addition, Lutonix will provide accurate, complete, and current information about any aspect of 
the study upon request of the FDA or a reviewing IRB.   
14.3.2 INVESTIGATOR REPORTS 
Investigators are required to prepare and submit to Lutonix complete, accurate, and timely reports 
on this clinical study as required by regulations (CFR 812.150(a)).  Refer to Table 3 for the types of 
reports to be submitted.   
TABLE 3.  INVESTIGATOR REPORTS 
Report 
Submit To 
Timeframe 
Unanticipated Adverse 
Device Effects  
IRB and Lutonix 
As soon as possible but no later than 
ten (10) working days 
Subject death 
IRB and Lutonix 
Lutonix: within 24 hours of 
knowledge 
IRB: per local requirements 
SAE/SADE  
IRB and Lutonix 
Lutonix: Five (5) working days of 
knowledge 
IRB: per local requirements 
Failure to obtain 
informed consent 
IRB and Lutonix 
Five (5) working days 
Subject withdrawal 
Lutonix 
Five (5) working days 
Continuing IRB approval IRB 
Prior to continuing review date 
Withdrawal of IRB 
Approval 
Lutonix 
Five (5) working days 
Progress reports  
IRB and Lutonix 
Annually, at a minimum or as 
required by IRB 
Final Reports  
 
IRB and Lutonix 
Three (3) months after termination 
or completion of a study or the 
Investigator’s part in a study 
 
In addition, Investigators must provide accurate, complete, and current information about any aspect 
of the clinical study upon request of the Sponsor, IRB or FDA.   

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15 PUBLICATIONS 
The trial will be registered in the ClinicalTrials.gov website upon approval by a human subject 
review board in order to meet the criteria of the International Committee of Medical Journal Editors.  
All publications will follow the Uniform Requirements for Manuscripts Submitted to Biomedical 
Journals (www.icmje.org, October 2008). 
After the conclusion and final analysis of the trial results, a formal abstract presentation may be 
made at a major cardiovascular conference and the study results will be submitted to a reputable 
scientific journal.  All public reporting of the results of the study will eliminate identifiable 
references to the subjects. Following the publication of the main manuscript, secondary analyses 
proposals will be considered for publication from individual Investigators.  No submissions may be 
made without the written approval from Lutonix.   
16 STATISTICAL ANALYSIS PLAN  
16.1   OVERVIEW OF STUDY DESIGN 
This is a single-arm study design that will enroll approximately 165 US female subjects presenting 
with claudication or ischemic rest pain and an angiographically significant lesion in the superficial 
femoral or popliteal artery and a patent outflow artery to the foot.  Subjects will be followed for 24 
months.  Primary and secondary endpoints will be summarized descriptively as appropriate.. 
16.2 ANALYSIS CONVENTIONS 
General reporting will include descriptive summaries of baseline information, subject medical 
history, characteristics of the treated lesion, procedure information, effectiveness measures as 
outlined below, the composite safety information, target lesion revascularization information, and 
study accountability information.  Variables reported at multiple visits will also be summarized by 
visit if applicable.  Descriptive statistics of frequency data will be the count and percents calculated 
based on available data.  Numeric descriptive measures include the number of observations (n), 
mean, standard deviation (SD), median, minimum, and maximum statistics. Kaplan-Meier estimates 
of event rates or event-free survival will be provided for some endpoints.  Results at 24 months will 
only include descriptive summaries.  If confidence intervals are provided in support of specific 
analyses they will be two-sided 95% intervals.  No inferential testing is planned for the study and 
any testing performed will be identified as post-hoc. 
16.3 ANALYSIS POPULATIONS 
The Intent-to-Treat (ITT) Population will be based on all subjects enrolled in the study.  The primary 
effectiveness will be based on evaluable ITT subjects receiving treatment with a known outcome 
through 12 months.  A Safety Population will be used for all safety endpoints and only include 
subjects who are treated with the Lutonix DCB and have some evidence of follow-up as indicated 
by any reported adverse event, any post-procedure follow-up assessments, or a recorded discharge 

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date.   If the ITT and Safety Population are the same, then only the ITT population will be used in 
discussion of the study results. 
A Per-Protocol (PP) Population may be used to summarize the primary endpoints and selected 
secondary endpoints.  The PP population would include treated subjects without major protocol 
violations and the identification of major protocol violations would be completed before closure of 
the database.      
16.4    HANDLING MISSING DATA 
This protocol provides descriptive statistics only, hence no sensitivity analyses are planned to assess 
the impact of missing data on hypothesis testing.  The number of non-missing observations will be 
reported for all endpoint summaries to indicate the completeness of the data set.  Further, Kaplan-
Meier estimates of the success rate will also be provided for time dependent measures.  These 
estimates incorporate the censoring of events and will be unbiased if the reasons subjects are missing 
do not relate to their outcome at the point they are censored.  
16.5 ASSESSMENT OF POOLABILITY OF SITES 
The results for the primary endpoints will be summarized by study sites  descriptively in order to 
allow a review of the homogeneity of results by study site. Primary Endpoints 
16.5.1 EFFECTIVENESS ENDPOINT AND SAMPLE SIZE CALCULATION 
The primary effectiveness endpoint is primary patency at 12 months and it will be analysed on a per-
lesion basis. 
A sample size of 165 subjects was selected for this study in order to allow for 140 subjects with 12 
month outcomes assuming a 15% drop-out rate.   This sample size was selected based on precision 
(width of the confidence interval) for the primary endpoint.  Assuming a response rate of 65%, the 
primary patency success rate observed in the LEVANT 2 pivotal study for DCB subjects, the 
expected two-sided exact confidence interval is (56.5%, 72.9%) which provides less than +/- 10% 
around the estimate (91/140 = 65%).  Further, the lower expected bound is adequate as it will 
differentiate from the control PTA response in the LEVANT 2 study. 
16.5.2 SAFETY ENDPOINT AND SAMPLE SIZE CALCULATIONS  
The primary safety endpoint is the composite of freedom from all-cause peri-operative (≤30 day) 
death and freedom at 1 year from the following: index limb amputation (above or below the ankle), 
index limb re-intervention, and index-limb-related death.   
The sample size was considered adequate based on the expected 95% confidence interval for the 
primary safety endpoint success rate being less than plus or minus 10%.  Assuming a response rate 
of 84.3% (118/140) and 140 completer subjects, the two-sided 95% exact confidence interval is 
(77.2%, 89.9%).  

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16.6 SECONDARY ENDPOINTS 
The following effectiveness and safety endpoints will be summarized descriptively as appropriate.   
For selected endpoints 95% confidences for event or success rates will be calculated using exact 
binomial intervals or using Kaplan-Meier methodology.  Additional endpoints include: 
The following endpoints will be assessed at 1 month: 
• Composite of freedom from all-cause perioperative (≤ 30 day) death and freedom from the 
following: index limb amputation, index limb re-intervention, and index-limb-related death. 
• Major Vascular Complications (<30 days) 
The following endpoints will be assessed at 1, 6, 12 and 24 months: 
• All-cause death  
• Clinically Driven Target Lesion Revascularization (TLR)  
• Target Vessel Revascularization (TVR)  
• Reintervention for treatment of thrombosis of the target vessel or embolization to its distal 
vasculature  
•  Rate of unanticipated and anticipated device  related serious adverse events  
• Amputation (above the ankle)-Free Survival (AFS)  
• Change of Rutherford classification from baseline 
• Sustained Clinical Benefit (improvement in Rutherford Class compared to baseline AND 
freedom from target vessel revascularization) 
• Change of resting Ankle Brachial Index (ABI) from baseline 
 

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17 REFERENCES  
 
1. 
Newman AB, Shemanski L, Manolio TA et al. Ankle–arm index as a predictor of cardiovascular 
disease and mortality in the Cardiovascular Health Study Group. Arterioscler Thromb Vasc Biol 
1999; 19: 538–45. 
2. 
Levy, P.J., Epidemiology and pathophysiology of peripheral arterial disease. Clin Cornerstone, 
2002. 4(5): p. 1-15. 
3. 
Yazdani, S.K., et al., Vascular, downstream, and pharmacokinetic responses to treatment with a 
low dose drug-coated balloon in a swine femoral artery model. Catheter Cardiovasc Interv, 2013. 
4. 
Axel, D.I., et al., Paclitaxel inhibits arterial smooth muscle cell proliferation and migration in vitro 
and in vivo using local drug delivery. Circulation, 1997. 96(2): p. 636-45. 
5. 
Pocock, S., et al., International differences in treatment effect: do they really exist and why? Eur 
Heart J, 2013. 34(24): p. 1846-52. 
 
 
 
 

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APPENDIX A:  DEFINITIONS 
 
Abrupt or Acute Closure 
Angiographic documentation of significantly reduced flow due to mechanical dissection, thrombus 
or severe vessel spasm in the treatment area. 
 
Adverse Device Effect (ADE) 
An AE related to the use of the study device. 
Adverse Event (AE) 
Any unfavorable and unintended sign, symptom, or disease temporally associated with the use of 
an investigational product, whether or not related to the investigational product.  
All Cause Perioperative Death 
All-cause Perioperative Death is defined as death within 30 days of the index procedure. 
Amputation of the Index Limb 
Amputation includes all amputations including both Major Amputations and Minor Amputations. 
• Major Amputation - Amputation of the lower limb above the ankle  
 
• Minor Amputation - Amputation of a foot, or of a part thereof 
 
Ankle Brachial Index Assessment   
Ankle systolic pressure/brachial systolic pressure, measured by constructing a ratio from the peak 
systolic pressure measured during the deflation of the ankle cuffs during Doppler detection to the 
systolic brachial pressure. 
Anticipated Adverse Event  
Any AE whether or not considered related to the investigational product(s) or drug regimen 
prescribed as part of the CIP, predefined in the CIP and/or IFU. 
Clinically Driven Target Lesion Revascularization 
Revascularization at the target lesion with evidence of target lesion diameter stenosis >50% 
determined by duplex ultrasound or angiography and new distal ischemic signs (worsening ABI or 
worsening Rutherford Category associated with the target limb). 
Device Deficiency 
Inadequacy of a medical device with respect to its identity, quality, durability, reliability, safety or 
performance and may include malfunctions, use errors, and inadequate labeling. 
 

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Device Malfunction 
A malfunction is a failure of a device to meet its performance specifications or otherwise perform 
as intended. Performance specifications include all claims made in the labelling of the device. The 
intended performance of a device refers to the intended use for which the device is labelled or 
marketed. 
Discharge 
The time point at which the subject was released from the admitting hospital or transferred to another 
facility. 
Dissections 
National Heart, Lung, and Blood Institute (NHLBI) Dissection Classification System:  
0:   None 
A. Minor radiolucencies within the lumen during contrast injection with no persistence after dye 
clearance.  
B. Parallel tracts or double lumen separated by a radiolucent area during contrast injection with no 
persistence after dye clearance. 
C. Extraluminal cap with persistence of contrast after dye clearance from the lumen.  
D. Spiral luminal filling defects.  
E. New persistent filling defects.  
F. Non-A-E types that lead to impaired flow or total occlusion.  
Note: Type E and F dissections may represent thrombus. Type A and B dissections are not 
considered adverse events for reporting. 
Enrollment 
A patient is considered enrolled in the study after baseline angiographic results and after successful 
vessel preparation confirm that the target lesion meets all appropriate inclusion/exclusion criteria 
and is treated with the LUTONIX® Catheter. 
Index Limb Related Death 
Any death adjudicated during event review as “related” to a complication of the index limb. 
Major Vascular Complications (<30 days) 
Hemorrhagic vascular complications included the following: 
• Haematoma at access site >5 cm 
• False aneurysm 
• AV fistula 
• Retroperitoneal bleed 

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• Peripheral ischemia/nerve injury 
• Any transfusion required will be reported as a vascular complication unless clinical indication 
clearly other than catheterization complication 
• Vascular surgical repair 
Patent Run-off 
At least one patent native outflow artery from the popliteal to the ankle, free from significant (≥50%) 
stenosis as confirmed by angiography or ultrasound. 
Per-Protocol (PP) 
All as-treated subjects characterized by appropriate exposure to treatment (procedurally correct as 
pre-specified) and the absence of major protocol violations (including violations of entry criteria) 
that if not met for a given subject may obscure the evaluation of effectiveness in that subject. 
Primary Patency 
Primary Patency is defined as Freedom from TLR and from Binary Restenosis. Binary Restenosis 
is adjudicated by the independent Core Laboratory based on PSVR ≥ 2.5 and / or abnormal 
waveforms or based on angiographic ≥ 50% diameter stenosis . 
Popliteal Artery 
The vessel located between Hunter’s canal and the trifurcation. 
PSVR 
Peak Systolic Velocity Ratio 
Reference Vessel Diameter (RVD) 
The interpolated reference vessel diameter is based on a computed estimation of the original 
diameter of the artery at the level of the obstruction (minimal luminal diameter) 
Restenosis 
Either ≥50% restenosis of the diameter of the reference-vessel segment by QVA or peak systolic 
velocity ratio of ≥2.5 or as adjudicated by the DUS Core Lab. 
Restenotic Lesion 
A lesion in a vessel segment that had undergone a prior percutaneous treatment. 
 
 
 
 
 

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Rutherford Categories  
Categorical description of the symptoms associated with the obstruction of the lumen of the 
peripheral arteries (NCI C78533). 
0 
Asymptomatic: documented peripheral arterial disease, without 
symptoms of claudication or ischemic pain 
1 
Mild claudication: ischemic limb muscle pain that does not limit 
walking, or limits walking only after >2 blocks (>600 feet, or 2 
football fields) 
2 
Moderate claudication: ischemic limb muscle pain that limits 
walking to 1-2 blocks (300-600 feet, or 1-2 football fields) 
3 
Severe claudication: ischemic limb muscle pain that limits walking 
to <1 block (<300 feet, or 1 football field) 
4 
Ischemic rest pain: pain in the distal foot at rest felt to be due to 
limited arterial perfusion 
5 
Minor tissue loss: nonhealing ischemic ulcer(s) on distal leg, or 
focal gangrene with diffuse pedal ischemia 
6 
Major tissue loss: ischemic gangrene extending above TM level, 
functional foot no longer salvageable without extensive 
revascularization efforts 
Adapted from VQI PVI registry, Rutherford J Vasc Surg 1997;26:517-38, ACC/AHA PAD Data 
Standards Circulation 2012;125:395-467, and PARC J Am Coll Cardiol 2015. 
Screen Failures  
Subjects screened, but not meeting all study entry criteria and hence are not enrolled, are considered 
screening failures and will be documented as such on the Screening Logs. 
Serious Adverse Event (SAE)  
A SAE is an adverse event that:  
• Results in death, 
• Is life-threatening, 
• Requires inpatient hospitalization  or prolongation of existing hospitalization,  
• Results in persistent or significant disability/incapacity,  
• Required intervention to prevent permanent impairment or damage, or 
• Caused a congenital anomaly/birth defect 

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Stroke 
Clinical signs/symptoms of focal neurological deficit lasting longer than 24 hours. 
Target Lesion 
Lesion that is to be treated during the index procedure. 
Target Lesion Revascularization 
A repeat revascularization procedure (percutaneous or surgical) of the original target lesion treatment 
area. 
Target Vessel Revascularization 
A repeat revascularization procedure (percutaneous or surgical) of a lesion in the target vessel. 
Target Vessel   
The entire vessel in which the target lesion is located. 
 
Treatment Area 
The entire treated vessel segment in which angioplasty balloons were inflated (the injury segment) 
including the target lesion. 
 
Thrombosis 
A total occlusion documented by duplex ultrasound and/or angiography with or without symptoms 
Thrombosis may be categorized as acute (<1 day), subacute (1-30 days) and late (>30 days). The 
presence of thrombus at the target lesion must be noted as an adverse event in the eCRF. 
 
Transient Ischemic Attack (TIA) 
Clinical signs/symptoms of focal neurological deficit lasting up to 24 hours 
 
Unanticipated Adverse Device Effect (UADE) 
A UADE is an ADE which by its nature, incidence, severity or outcome has not been identified in 
the current version of the risk analysis report. 
 
Worsening of Ankle Brachial Index 
A deterioration in the Ankle Brachial Index (ABI) by more than 0.15 from the maximum early post-
procedural level. 
 
Worsening Rutherford Clinical Category 
A deterioration (an increase) in the Rutherford Category by more than 1 category compared to 
baseline. 
 
 

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APPENDIX B: INFORMED CONSENT FORM 
 
Provided separately.  
 
 
 

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APPENDIX C: DATA POINTS COLLECTED 
 
Provided separately.