A Prospective, Multicenter, Single Blind, Randomized, Controlled Trial Comparing the Lutonix Drug Coated Balloon Versus Standard Balloon Angioplasty for Treatment of Below-the-Knee (BTK) Arteries(Lutonix BTK Trial)
Phase: NA
Conditions: Critical Limb Ischemia
Sponsor: C. R. Bard

Lutonix BTK Investigational Plan 
Document: CL0005-01 
 
Revision: 12 
7 Sept 2017 
LUTONIX CONFIDENTIAL 
Page 1 of 89 
 
A Prospective, Multicenter, Single Blind, Randomized, 
Controlled Trial Comparing the Lutonix Drug Coated 
Balloon vs. Standard Balloon Angioplasty for Treatment 
of Below-the-Knee (BTK) Arteries 
(Lutonix BTK Trial) 
 
 
Investigational Plan  
 
Version 12.0 
 
Protocol #CL0005-01 
 
 
  Sponsor:  
  
9409 Science Center Drive 
New Hope, MN 55428 USA 
A subsidiary company of C.R. Bard 
 
 
Investigational Device: Lutonix® Drug Coated Balloon 
 
NCT Number: 01870401 (NCT number added post-approval 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 
The Lutonix BTK Trial Investigational Plan 
 A Prospective, Multicenter, Single Blind, Randomized, Controlled Trial Comparing the 
Lutonix Drug Coated Balloon vs. Standard Balloon Angioplasty for Treatment of Below-
the-Knee (BTK) arteries 
 
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/Ethics Committee.  I will discuss this material with them and 
ensure they are fully informed regarding the investigational device and the conduct of the study 
according to ICH Good Clinical Practice (GCP), ISO 14155, Declaration of Helsinki, 21CFR 50, 
56 and 812, and any local regulations. 
 
 
 
Clinical Site Name____________________________________ 
 
_______________________ 
 
_____________________________________ 
Site Principal Investigator 
 
Site Principal Investigator 
     Date 
(Print Name) 
 
 
 
(Signature) 
 
 
 
 
 
 
 
 
 
 
 

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The Lutonix BTK Trial Protocol Summary 
 
Title 
A Prospective, Multicenter, Single Blind, Randomized, Controlled Trial Comparing the 
Lutonix Drug Coated Balloon vs. Standard Balloon Angioplasty for Treatment of 
Below-the-Knee (BTK) arteries 
Test Device 
Lutonix® 0.014” OTW Drug Coated PTA Dilatation Catheter (Lutonix DCB Catheter) 
Control Device 
Non-coated standard percutaneous transluminal angioplasty balloon catheter (standard 
uncoated PTA catheter) 
Study Design 
Prospective, Multicenter, Single Blind, Randomized, Safety and Efficacy  
Overview 
The study will enroll patients presenting with below-the-knee disease (Rutherford 
Category 3, 4 or 5) and an angiographically significant (≥ 70%) native artery lesion 
appropriate for angioplasty that is below the tibial plateau and above the tibiotalar joint.  
After successful protocol-defined pre-dilatation, subjects that continue to meet lesion 
and outflow angiographic criteria are randomized 2:1 to treatment with either the 
Lutonix DCB (test) or standard uncoated PTA catheter (control). All target lesion(s) in 
up to two target vessels are treated with the as-randomized test DCB or control PTA.  
After the protocol-defined pre-dilatation with a standard uncoated PTA catheter step is 
completed and if randomized to control, treatment with an additional standard uncoated 
PTA catheter (control device) is at the discretion of the investigator as long as 0-30% 
residual stenosis is achieved.  Subjects with no target vessels that meet post-
predilatation entry criteria are excluded (and treated per standard practice) and 
followed for safety for 30 days. 
Primary endpoint assessment is performed at 30 days for safety and at 6 months for 
efficacy. Doppler is required for all subjects.  Clinical follow-up continues through 3 
years.   
Purpose 
To assess the safety and efficacy of the Lutonix DCB for treatment of stenosis or 
occlusion of native below-the-knee arteries.   
Objective 
To demonstrate the superior efficacy and non-inferior safety of the Lutonix DCB by 
direct comparison to standard PTA catheter for treatment of stenosis or occlusion of 
below-the-knee arteries. 
Randomization 
Subjects will be randomized 2:1 to Lutonix DCB or standard PTA catheter. 
Enrollment 
Enrollment will occur at up to 75 global centers. Up to 1000 subjects may be enrolled 
to obtain up to the maximum of 840 treated vessels for the primary analysis.  The study 
includes interim analyses that occur when 400, 500, 600, and 700 vessels are treated.  
A Bayesian decision making process will be utilized to determine the final sample size 

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for the study based on the predicted probability of study success in the primary 
effectiveness assessment.   
At least 50% of randomized enrollment will occur in the US. 
Randomized 
Subject Follow-
Up Schedule 
Clinical: 1, 6, 12, 24, 36 Months  
 
Primary 
Endpoints 
Safety: Freedom from BTK MALE+POD at 30-Days 
Freedom at 30-Days from the composite of all-cause death, above-ankle 
amputation or major reintervention (new bypass graft, jump/interposition graft 
revision, or thrombectomy/thrombolysis) of the index limb involving a below-
the-knee artery.  
Efficacy: Composite of Limb Salvage and Primary Patency at 6 Months 
Defined as freedom from the composite of above ankle amputation, target 
lesion occlusion, and clinically-driven target lesion reintervention.  
Secondary 
Endpoints  
• Device (able to deliver, inflate and retrieve), Technical (device success and 
< 30% residual stenosis) and Procedural Success (restoration of at least 1 
infrapopliteal artery with residual stenosis < 30% and inline outflow to the 
foot) 
•  Comparison of the BTK MALE+POD rate in the test arm to a performance 
goal at 30 Days  
• Change in quality of life at 6, 12, 24, and 36 months from baseline, as 
measured by EQ-5D survey 
• Late lumen loss at 12 months (cohort with angiography) 
 
The following endpoints will be assessed at 30 days and at 6, 12, 24, and 36 
months: 
• Wound healing (healed or not; if not, improving, stagnant, worsening) 
• New or recurrent lesion (target limb) 
• Change in Rutherford Class (target limb) 
• Composite of freedom from the following in the index limb: 
Above-ankle amputation, unhealed wound, ischemic rest pain, target 
vessel occlusion, and clinically-driven TVR  
• Primary Patency (freedom from occlusion without clinically-driven TLR)  
• Primary Patency with exclusion of early mechanical recoil (freedom from 
occlusion without clinically-driven TLR events > 30 days) 
• Secondary Patency (not occluded, irrespective of TLR) 

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• Composite of freedom from clinically-driven TLR and from 50% DS by 
angiography/DUS 
• Hemodynamic outcome (change in toe & ankle pressures)  
• Change in Walking Impairment Questionnaire (improvement from baseline) 
 
The following endpoints will be assessed at 30 days and at 6, 12, 24, and 36 
months: 
• Clinically-driven TLR (all randomized subjects and in AFS cohort) 
• Total TLR (all randomized subjects and in AFS cohort) 
• Clinically-driven TVR (all randomized subjects and in AFS cohort) 
• Total TVR (all randomized subjects and in AFS cohort) 
• Limb salvage in surviving subjects (target limb) 
• Unplanned below ankle amputation (including digit) of the target limb 
• Overall burden of BTK index-limb reinterventions (total number of index 
limb BTK interventions incurred, all randomized subjects and AFS cohort) 
• Composite of POD, index limb-related death, below-the-knee 
reinterventions or major amputation of the index-limb  
• SVS CLI Endpoint Definitions ( (3) Conte 2009 JVS 50:1462-73)  
▪ MALE: Major adverse Limb Event: Above ankle amputation of the 
index limb or major reintervention (new bypass graft, jump/interposition 
graft revision, or thrombectomy/thrombolysis) 
▪ MALE+POD: Perioperative death (30 days), or any MALE 
▪ MACE: Major Adverse Cardiovascular Event: MI, stroke or death (any 
cause) 
▪ Amputation (Major): Above ankle amputation of the index limb 
▪ AFS: Amputation free survival (freedom from above ankle amputation 
of the index limb or death (any cause)) 
▪ RAO: Any reintervention or above ankle amputation of the index limb. 
▪ RAS: Any reintervention, above ankle amputation of the index limb, or 
stenosis  
▪ DEATH: Death (any cause) 
 
Inclusion 
Criteria 
 
Clinical Criteria 
1. Male or non-pregnant, non-breastfeeding female ≥18 years of age; 
2. Rutherford Clinical Category 3, 4, or 5;  
NOTE:  Patients categorized as a Rutherford Clinical Category 3 must 
have failed medical management per physician discretion. 
3. Life expectancy ≥ 1 year;  

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4. Patient is willing to provide informed consent, is geographically stable, and 
is willing to comply with the protocol-required follow up visits, testing 
schedule and recommended medication regimen; 
5. No other prior surgical or vascular interventions within 2 weeks before 
and/or planned 30 days after the protocol treatment;  
NOTE:  The following are allowed within 2 weeks prior or within 30 days 
after the procedure: 
• Planned transmetatarsal or lower minor amputations 
• Index limb inflow-lesion treatment 
• Contralateral iliac treatment 
• Wound debridement 
NOTE:  Except for allowed iliac treatment (noted above), contralateral 
limb lesion(s) cannot be treated during the index procedure or within 2 
weeks before and/or planned 30 days after in order to avoid confounding 
complications; 
 
Angiographic Criteria  
6. Significant stenosis (≥70%) or occlusion of one or two native artery(s) 
below the tibial plateau and above the tibiotalar joint appropriate for 
angioplasty per operator visual assessment 
NOTE: One or two flow pathways are allowed as artery(s); i.e., peroneal or 
posterior tibial arteries may involve tibioperoneal trunk lesions and tibial 
arteries may involve popliteal lesions;  
7. Cumulative length of target lesion(s) ≤ 320 mm;  
NOTE: Maximum allowed cumulative length of all DCBs ≤ 360 mm; 
8. Target lesion(s) not previously stented and at least 20 mm from any 
previous stent; 
9. A patent inflow artery from the aorta to the target lesion free from 
significant (≥50%) stenosis as confirmed by angiography 
NOTE: concurrent or staged treatment of iliac/SFA/above-knee popliteal 
artery  is allowed if successfully performed (with residual diameter stenosis 
≤ 30% and reconstitution at least 30 mm proximal to tibial plateau) without 
major vascular complication; 
NOTE: If atherectomy is performed on the superficial femoral (SFA) or 
popliteal lesion(s), use of a distal embolic filter is required. 
NOTE: Treatment of the femoropopliteal with a DCB is not allowed during 
the index procedure. 
10. Target vessel(s) diameter between 2 and 4 mm and able to be treated with 
available device size matrix; 

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11. Successful antegrade pre-dilatation of the target lesion with standard PTA 
catheter appropriate size for the reference vessel diameter;  
NOTE:   Successful pre-dilatation defined by residual stenosis ≤ 50% and 
operator determination that procedural success may be achievable by 
angioplasty alone 
NOTE: Multiple lesions allowed, but ALL target lesions MUST be 
successfully pre-dilated prior to randomization  
NOTE: If the popliteal artery is pre-dilated, it MUST meet angiographic 
inclusion criteria 
NOTE: Retrograde access for initial wire crossing allowed, but pre-
dilatation and treatment must be performed over antegrade wire 
12. Target vessel(s) reconstitute(s) at or above the ankle with inline flow to at 
least one patent (<50% residual stenosis) inframalleolar outflow vessel 
(planned treatment below-the-ankle is not allowed) 
NOTE: Outflow must be assessed AFTER pre-dilatation 
NOTE: Two arteries allowed, but each target vessel MUST demonstrate 
inline inframalleolar outflow prior to randomization. 
Exclusion 
Criteria 
Patients will be excluded if ANY of the following conditions apply:  
1. Any severe medical comorbidities (untreated CAD/CHF, severe COPD, 
metastatic malignancy, etc.) that would preclude compliance with the study 
protocol or currently receiving immune-suppressive, chemotherapeutic, or 
radiation therapy; 
2. Patient is currently participating in an investigational drug or device study 
or previously randomized or a roll-in subject in this study 
NOTE: Enrollment in another 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 30 days of enrollment; 
5. 
Gangrene extending proximal to the digit-metatarsal skin crease (index 
limb); 
NOTE: Gangrene must be confined to the toe or toes  
6. 
Ischemic ulceration that extends more than 4 cm proximal to digit-
metatarsal skin crease (index limb); 
NOTE: If ulcers are confined to toe, involvement of tendon or bone is 
acceptable.  Ulcers proximal to digit-metatarsal skin crease must be 
superficial (not involving tendon or bone).   
7. Neurotropic ulcer or heel pressure ulcer or ulcer potentially involving 
calcaneus (index limb); 
8. Evidence of osteomyelitis in a bone not intended for resection (index limb);  

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9. Signs and symptoms of systemic infection ( temperature of  ≥ 38.0° Celsius 
and/ or WBC of ≥ 12,000 cells/ µL) at the time of assessment;   
NOTE: If infection is adequately treated and controlled (temperature < 
38.0° C and WBC < 12,000 cells/ µL) patient may be enrolled; 
10. Planned major amputation (of either leg); 
11. Prior major amputation if amputation occurred less than one year prior to 
enrollment and if patient is not independently ambulating; 
12. GFR ≤ 30 ml/min per 1.73m2; 
13. Allergy to contrast or known allergy to contrast, taxols or polysorbates that 
cannot be adequately managed with pre- and post-procedure medication; 
14. Hemodynamically significant aortic or CFA occlusive disease (concurrent 
aortic and common femoral artery treatment NOT allowed); 
15. Intended use of adjunctive primary treatment modalities (e.g., atherectomy, 
laser, cutting balloons, radiation therapy, stents) in below-the-knee vessels;  
16. Acute limb ischemia (symptom onset within 2 weeks); 
17. In-stent restenosis of target lesion; 
18. Presence of thrombus in the target vessel. 
Data Analysis 
The primary analysis will be based on the ITT dataset of all randomized 
subjects. Safety endpoints are assessed per subject and efficacy endpoints per 
target vessel.  
Principal 
Investigator(s) 
Dr. Patrick Geraghty (USA) 
Washington University, Department of Surgery,  
Section of Vascular Surgery, Campus Box 8109,  
600 S. Euclid Avenue, 5103 Queeny Tower,  
St. Louis, MO 63110 
Dr. Jihad Mustapha (USA) 
Metro Health Hospital 
5900 Byron Center Ave. SW,  
Wyoming, MI  49519 
616-252-5020 
 
Prof. Dr. Marianne Brodmann (EU) 
LKH Universitatsklinikum Graz 
Abteilung fur Angiolgie 
Auenbruggerplatz 15 
A-8036 Graz, Austria 
0316/385-80286 
Sponsor/ 
Contact: 
Lutonix, Inc., C.R. Bard, Inc. 
9409 Science Center Drive 
New Hope, MN 55428  USA 

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EU CRO 
genae associates nv 
Head office: Paleisstraat 24 
CRO: Lange Lozanastraat 112 
2018 Antwerp, Belgium 
+32 3 290 03 06   
EDC 
C. R. Bard, Inc. 
730 Central Avenue 
Murray Hill, NJ 07974 
908-277-8152 
Angiographic 
Core Lab 
SynvaCor 
319 N. 5th St. 
Springfield IL 62701 USA 
217-492-9132 
DUS Core Lab 
VasCore 
One Bowdoin Square 
Boston MA 02114 USA 
617-726-5552 
EU Authorized 
Rep: 
BARD Limited 
Crawley 
RH11 9BP 
United Kingdom 
Japan Sponsor 
Authorized Rep: 
Medicon, Inc. 
2-5-8, Hiranomachi, Chuo-Ku, Osaka city, Osaka, Japan 541-0046. 
Contact: Okada Makiko  
Division Name/ Title : CA Director  
TEL: 06 6203 6560 

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Table of Contents 
1 
INTRODUCTION ...................................................................................................................... 13 
1.1 
CLINICAL BACKGROUND ................................................................................................... 13 
1.2 
DEVICE AND STUDY RATIONALE ..................................................................................... 18 
2 
STUDY OBJECTIVES AND ENDPOINTS ............................................................................ 18 
2.1 
PRIMARY OBJECTIVE ........................................................................................................... 18 
2.2 
PRIMARY ENDPOINTS .......................................................................................................... 19 
2.3 
SECONDARY ENDPOINTS.................................................................................................... 20 
3 
DEVICE DESCRIPTION .......................................................................................................... 21 
3.1 
INTENDED USE / INDICATIONS FOR USE ........................................................................ 22 
3.2 
ACTIVE PHARMACEUTICAL INGREDIENT (API): PACLITAXEL ................................. 22 
3.3 
EXCIPIENT (Drug Carrier) ...................................................................................................... 23 
3.4 
DEVICE INSTRUCTIONS ....................................................................................................... 23 
3.5 
SUPPLY & SUPPORT OF INVESTIGATIONAL DEVICE ................................................... 23 
4 
RISK-BENEFIT ANALYSIS .................................................................................................... 23 
4.1 
POTENTIAL RISKS ................................................................................................................. 23 
4.2 
RISK MANAGEMENT PROCEDURES ................................................................................. 26 
4.3 
POTENTIAL BENEFITS.......................................................................................................... 26 
4.4 
EARLY TERMINATION ......................................................................................................... 26 
5 
CLINICAL STUDY DESIGN ................................................................................................... 27 
5.1 
SCREENING PROCEDURES .................................................................................................. 29 
5.2 
PATIENT SELECTION FOR ENROLLMENT ....................................................................... 29 
5.3 
SUBJECT INCLUSION AND EXCLUSION CRITERIA ....................................................... 30 
6 
STUDY/TREATMENT PROCEDURES ................................................................................. 33 
6.1 
ENROLLMENT ........................................................................................................................ 33 
6.2 
LUTONIX DCB CATHETER INSTRUCTIONS FOR USE (IFU) ......................................... 34 
6.3 
BASELINE ANGIOGRAM ...................................................................................................... 34 
6.4 
IN-FLOW LESION TREATMENT .......................................................................................... 34 
6.5 
PRE-DILATATION AND TARGET VESSEL ENTRY CRITERIA ...................................... 35 
6.6 
RANDOMIZATION ................................................................................................................. 40 
6.7 
POST-TREATMENT AND PROVISIONAL (BAILOUT) STENTING PROCEDURES ...... 41 
6.8 
UNSCHEDULED ANGIOGRAPHY/REVASCULARIZATION ........................................... 41 
7 
TREATMENT OF SUBJECT ................................................................................................... 42 
7.1 
BLINDING PLAN .................................................................................................................... 42 
7.2 
MEDICATIONS ........................................................................................................................ 43 
7.3 
STANDARD TESTS, PROCEDURES, AND FOLLOW-UP .................................................. 45 
8 
ADVERSE EVENTS .................................................................................................................. 47 

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8.1 
ADVERSE EVENT REPORTING ........................................................................................... 47 
9 
SUBJECT WITHDRAWAL CRITERIA ................................................................................ 48 
10 
DATA COLLECTION AND MONITORING ........................................................................ 48 
10.1 
DATA COLLECTION .............................................................................................................. 48 
10.2 
MONITORING ......................................................................................................................... 48 
10.3 
PROTOCOL DEVIATIONS ..................................................................................................... 49 
10.4 
SOURCE DOCUMENTATION ............................................................................................... 49 
10.5 
RECORD RETENTION............................................................................................................ 49 
10.6 
STUDY PROCESSING ............................................................................................................ 50 
11 
DEVICE ACCOUNTABILITY ................................................................................................ 50 
11.1 
SUPPLY AND SUPPORT OF INVESTIGATIONAL DEVICE ............................................. 51 
12 
STUDY MANAGEMENT ......................................................................................................... 51 
12.1 
Advisory COMMITTEE............................................................................................................ 51 
12.2 
DATA MONITORING COMMITTEE ..................................................................................... 51 
12.3 
CLINICAL EVENTS COMMITTEE ....................................................................................... 51 
13 
REGULATORY RESPONSIBILITIES ................................................................................... 52 
13.1 
IRB/EC APPROVAL ................................................................................................................ 52 
13.2 
REGULATORY APPROVAL .................................................................................................. 52 
13.3 
INFORMED CONSENT ........................................................................................................... 52 
13.4 
SELECTION OF CLINICAL SITES AND INVESTIGATORS .............................................. 53 
13.5 
INVESTIGATOR’S RESPONSIBILITIES .............................................................................. 53 
13.6 
LUTONIX RESPONSIBILITIES ............................................................................................. 54 
14 
PUBLICATIONS ....................................................................................................................... 55 
15 
STATISTICAL ANALYSIS PLAN .......................................................................................... 55 
15.1 
ASSESSMENT OF COMPARABILITY OF TREATMENT GROUPS AND POOLABILITY 
OF SITES AND SECONDARY ANALYSES ....................................................................................... 56 
15.2 
HANDLING OF MISSING DATA .......................................................................................... 57 
15.3 
PRIMARY ENDPOINTS .......................................................................................................... 58 
15.4 
Interim Analysis ........................................................................................................................ 62 
15.5 
ADDITIONAL ANALYSES .................................................................................................... 63 
15.6 
Other Secondary Endpoints with Hypothesis Testing ............................................................... 63 
15.7 
Secondary Endpoints with Descriptive Statistics ...................................................................... 66 
16 
APPENDIX A:  DEFINITIONS ................................................................................................ 68 
17 
APPENDIX B:  DRAFT CASE REPORT FORM ELEMENTS ........................................... 78 
18 
APPENDIX C:  SAMPLE WALKING IMPAIRMENT QUESTIONNAIRE ..................... 79 
19 
APPENDIX D:  SAMPLE EQ5D QUESTIONNAIRE ........................................................... 82 
20 
APPENDIX E:  SAMPLE INSTRUCTIONS FOR USE ........................................................ 84 

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21 
APPENDIX F: SAMPLE INFORMED CONSENT FORMS ................................................ 85 
22 
APPENDIX G:  ANGIOGRAPHIC ACQUISITION GUIDELINES ................................... 86 
23 
APPENDIX H: DUPLEX ULTRASOUND CORE LAB GUIDELINES .............................. 87 
24 
APPENDIX I: SPONSOR-QUALIFIED INVESTIGATIONAL SITES .............................. 88 
25 
APPENDIX J: INTERIM ANALYSIS PLAN (ADAPTIVE DESIGN) ................................ 89 
 
Tables 
Table 1: Post-Pre-Dilatation Angiographic Target Lesion and Outflow Criteria ....................................... 39 
Table 2 : Suggested Medication schedule ................................................................................................... 44 
Table 3: Follow-up Schedule and Testing Requirements for Randomized Subjects .................................. 45 
Table 4: Reports Required from Clinical Investigators .............................................................................. 54 
 
Figures 
Figure 1: Lutonix 0.014"  OTW Drug coated PTA Dilatation Catheter ..................................................... 22 
Figure 2 : Chemical Structure of Paclitaxel ................................................................................................ 23 
Figure 3: Study Flowchart .......................................................................................................................... 28 
Figure 4: Proximal (A) and Distal (B) Target Vessel Boundaries .............................................................. 36 
Figure 5 : One or Two Flow Pathways are Allowed as Target Vessels ...................................................... 36 
Figure 6. Proximal vessel Segment (Applicable For enrollment of Proximal vessels Only) ...................... 37 
  
 
 
 

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1 INTRODUCTION 
The purpose of this investigation is to assess the safety and efficacy of the Lutonix™ Drug 
Coated Balloon (DCB) for treatment of a stenosis or occlusion of below-the-knee (BTK) arteries. 
1.1 CLINICAL BACKGROUND 
Peripheral arterial disease (PAD) is estimated to be present in 3% of people in the age range of 
40-59 years and in 20% of people over 70 years1 of age.  Most common clinical presentation 
comprises intermittent claudication but about one third of patients will progress to critical limb 
ischemia characterized by rest pain and/or tissue loss, which is the most severe limb 
manifestation of PAD.  Intermittent claudication significantly affects quality of life and is 
associated with severe functional impairment.2 While revascularization should be attempted 
without delay in all patients presenting with critical limb ischemia, whenever technically 
possible, the management of intermittent claudication varies depending on the severity of 
walking impairment and the associated impact of functional disability on individual lifestyle with 
limb revascularization procedures being pursued when exercise and/or drug therapy fail to 
improve symptoms.3   
Revascularization for intermittent claudication is an appropriate therapy for selected patients 
with disabling symptoms, after a careful risk-benefit analysis and based on comorbid conditions, 
degree of functional impairment, and anatomical factors. 4 Successful revascularization of  lower 
extremity peripheral arterial disease in patients affected by intermittent claudication  in addition 
to improving functional status, reduces the occurrence of future major cardiovascular events 
(PTA compared to patients manage with conservative therapy 6.4% vs. 16.3%; p=0.003).5  The 
same result has been found in the diabetic patient affected with intermittent cludication there was 
improve walking performance, and an associated reduction in the incidence of future major 
 
 
1 Zeller, T.  Current state of endovascular treatmet of femoro-popliteal artery disease.  Vas Med 12 (2007): 223-234. 
2 McDermmott MM, Greenland P, Liu K, Guralnik JM, Criqui MH, Dolan NC, et al. Leg symptoms in peripheral arterial disease: 
associated clinical characteristics and functional impairment. JAMA 2001;286:1599-606. 
3 Tendera M, Aboyans V, Bartelink ML, Baumgartner I, Clement D, Collet JP, Cremonesi A, De Carlo M, Erbel R, Fowkes FG, 
et al: ESC Guidelines on the diagnosis and treatment of peripheral artery diseases: Document covering atherosclerotic disease of 
extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries: the Task Force on the Diagnosis and 
Treatment of Peripheral Artery Diseases of the European Society of Cardiology (ESC). European heart journal 2011, 32:2851-
2906. 
4 Society for Vascular Surgery Lower Extremity Guidelines Writing Group, Conte MS, Pomposelli FB, Clair DG, Geraghty PJ, 
McKinsey JF, Mills JL, Moneta GL, Murad MH, Powell RJ, Reed AB, Schanzer A, Sidawy AN; Society for Vascular Surgery. 
Society for Vascular Surgery practice guidelines for atherosclerotic occlusive disease of the lower extremities: management of 
asymptomatic disease and claudication. J Vasc Surg. 2015 Mar;61(3 Suppl):2S-41S. Erratum in: J Vasc Surg. 2015 
May;61(5):1382 
5 Giugliano G1, Di Serafino L, Perrino C, Schiano V, Laurenzano E, Cassese S, De Laurentis M, Schiattarella GG, Brevetti L, 
Sannino A, Gargiulo G, Franzone A, Indolfi C, Piscione F, Trimarco B, Esposito G. Effects of successful percutaneous lower 
extremity revascularization on cardiovascular outcome in patients with peripheral arterial disease. Int J Cardiol. 2013 Sep 
10;167(6):2566-71.  

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cardiovascular events with PTA over managed conservative therapy.6 A recent study evaluating 
infrapopliteal angioplasty was performed with a paclitaxel-eluting balloon in patients with tibial 
artery disease in 104 patients. Of the limbs treated 82.6% were critical limb ischemia (Rutherford 
category 4-6) and 17.4% severe claudication (Rutherford category 3) resulting in significantly 
lower early restenosis rate of long-segment infrapopliteal disease after treatment with DEBs 
compared with historical data using uncoated balloons.7  
While various endovascular treatment modalities have been developed for femoropopliteal 
lesions, standard percutaneous transluminal angioplasty (PTA) is still most commonly used for 
below-the-knee (BTK) interventions. The majority of patients undergoing BTK interventions 
suffer from critical limb ischemia (CLI) with high cardiovascular risk and often significant 
medical co-morbidities. CLI is typically defined as limb pain that occurs at rest (Rutherford 
Category 4, 5) 8, or impending limb loss that is caused by severely compromised blood flow to 
the affected extremity.  The principal threat to these patients is failure of the treatment to restore 
and maintain adequate blood flow to relieve ulceration, gangrene, or rest pain, leading to the 
need for a major amputation.   
CLI populations are difficult to study due to their very high intermediate-term morbidity and 
mortality9.  Most subjects die for reasons that cannot be affected by differences in outcomes of 
treatment modalities used during a single interventional revascularization procedure.  As a 
consequence less invasive endovascular revascularization has become the preferred first line 
treatment strategy in many centers due to lower peri-procedural morbidity and mortality as 
compared to surgical bypass. 
Two recent meta-analyses10,11studying BTK-PTA reported 1-year primary patency rates of 
46.5% to 58.1%, limb salvage rates of 86.0% to 88.9% and overall 1-year survival rates of 85.7% 
to 87.0%.  Another meta-analysis focused on ‘un-reconstructable’ CLI reported a 1-year 
 
 
6 Giugliano G1, Perrino C, Schiano V, Brevetti L, Sannino A, Schiattarella GG, Gargiulo G, Serino F, Ferrone M, Scudiero F, 
Carbone A, Bruno A, Amato B, Trimarco B, Esposito G. Endovascular treatment of lower extremity arteries is associated with 
an improved outcome in diabetic patients affected by intermittent claudication. BMC Surg. 2012;12 Suppl 1:S19. 
7 Schmidt A, Piorkowski M, Werner M, Ulrich M, Bausback Y, Bräunlich S, Ick H, Schuster J, Botsios S, Kruse HJ, Varcoe RL, 
Scheinert D. First experience with drug-eluting balloons in infrapopliteal arteries: restenosis rate and clinical outcome. J Am 
Coll Cardiol. 2011 Sep 6;58(11):1105-9.  
8 Rutherford RB, Baker JD, Ernst C, Johnston KW, Porter JM, Ahn S, et al. Recommended standards for reports dealing with 
lower extremity ischemia: revised version. J Vasc Surg 1997;26:517-38. 
9 Hirsch, AT, Haskal, ZJ, Hertzer, NR, Bakal, CW, Creager, MA, Halperin, JL, Hiratzka, LF, Murphy, WR, Olin, JW, Puschett, 
JB, Rosenfield, KA, Sacks, D, Stanley, JC, Taylor, LM Jr, White, CJ, White, J, White, RA, Antman, EM, Smith, SC Jr, Adams, 
CD, Anderson, JL, Faxon, DP, Fust. ACC/AHA 2005 guidelines for the management of patients with peripheral arterial disease 
(lower extremity, renal, mesenteric, and abdominal aortic): executive summary a collaborative report from the American 
Association for Vascular Surgery/Society for Vas. J Am Coll Cardiol (2006), 47:1239-1312. 
10 Romiti M, Albers M, Brochado-Neto FC, Durazzo AE, Pereira CA and De Luccia N. Meta-analysis of infrapopliteal 
angioplasty for chronic critical limb ischemia. J Vasc Surg. 2008;47:975-981. 
11 Conte MS, Geraghty PJ, Bradbury AW, Hevelone ND, Lipsitz SR, Moneta GL, Nehler MR, Powell RJ and Sidawy AN. 
Suggested objective performance goals and clinical trial design for evaluating catheter-based treatment of critical limb 
ischemia. J Vasc Surg. 2009;50:1462-73 

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amputation-free survival rate of only 55.1%12.  Two more recent studies, ACHILLES13 and 
DESTINY14, demonstrated improved patency from use of limus-derived DES in short isolated 
lesions.  However, these results are of questionable applicability to the broader CLI population 
where long lesions in multiple diseased vessels are common.   
A novel therapy that is commercially available in some countries and under investigation in 
others is the drug coated balloon (DCB), an otherwise standard PTA catheter with a drug coating 
on the balloon surface.  During angioplasty, DCBs are designed to deliver an anti-proliferative 
drug directly to tissues of the treated vessel wall, thus inhibiting neointimal hyperplasia and 
restenosis without the need for a permanent foreign body implant.  The investigational device of 
the present study, the Lutonix DCB, is one example.  
DCBs have the potential to provide a more durable treatment and also to improve clinical 
outcomes. Early data regarding treatment of BTK lesions with drug-coated balloons (DCB) have 
been positive. BTK treatment with a paclitaxel coated balloon catheter was reported from a 
single-center study investigating 104 patients (82.6 % of whom had CLI). One-year target lesion 
revascularization was 17.3% and limb salvage rates were 95.6 %. Clinical improvement and 
complete wound healing was 91.2 and 74.2 % respectively.15 Additionally, results from the 
single center DEBATE BTK trial showed superiority of DCB over PTA in tibial arteries.16 
Binary restenosis was 27% in the DCB and 74% in the PTA group (P < 0.001). Finally, target 
lesion revascularization (TLR) was lower in patients treated with DCB compared to those treated 
with PTA (18% versus 43%).  However, results from the a randomized trial which studied the 
Ampherion DCB (manufactured by Medtronic Inc, MN) for BTK treatment (IN.PACT DEEP) 
has raised concerns pertaining to the safety and efficacy of DCBs in infrapopliteal vessels due to 
a trend towards an increased major amputation and death rate in CLI patients through 12 months 
(DCB=8.8% vs. PTA= 3.6%, p=0.08).17,18     
 
 
12 Benoit, E, O'Donnell, TF Jr, Kitsios, GD, Iafrati, MD. Improved amputation-free survival in unreconstructable critical limb 
ischemia and its implications for clinical trial design and quality measurement. J Vasc Surg (2012), 55:781-789. 
13 Schmidt, A. ACHILLES-STUDY (DES for BTK). Seoul, Korea : Angioplasty Summit TCTAP 2012, 2012. 
14 Bosiers, M, Scheinert, D, Peeters, P, Torsello, G, Zeller, T, Deloos, K, Schmidt, A, Tessarek, J, Vinck, E, Schwartz, LB. 
Randomized comparison of everolimus-eluting versus bare-metal stents in patients with critical limb ischemia and 
infrapopliteal arterial occlusive disease. J Vasc Surg (2012), 55:390-398. 
15 Schmidt A, Piorkowski M, Werner M, Ulrich M, Bausback Y, Braunlich S, Ick H, Schuster J, Botsios S, Kruse HJ, Varcoe RL 
and Scheinert D. First experience with drug-eluting balloons in infrapopliteal arteries: restenosis rate and clinical outcome. 
Journal of the American College of Cardiology. 2011;58:1105-9. 
16 Liistro F, Porto I, Angioli P, Grotti S, Ricci L, Ducci K, Falsini G, Ventoruzzo G, Turini F, Bellandi G and Bolognese L. Drug-
eluting balloon in peripheral intervention for below the knee angioplasty evaluation (DEBATE-BTK): a randomized trial in 
diabetic patients with critical limb ischemia. Circulation. 2013;128:615-21. 
17 Zeller T, Baumgartner I, Scheinert D, Brodmann M, Bosiers M, Micari A, Peeters P, Vermassen F, Landini M, Snead DB, 
Kent KC and Rocha-Singh KJ. Drug-eluting balloon versus standard balloon angioplasty for infrapopliteal arterial 
revascularization in critical limb ischemia: 12-month results from the IN.PACT DEEP randomized trial. Journal of the 
American College of Cardiology. 2014;64:1568-76. 
18 Laird JR and Armstrong EJ. Drug-Coated Balloons for Infrapopliteal DiseaseDigging Deep to Understand the Impact of a 
Negative Trial∗. Journal of the American College of Cardiology. 2014;64:1577-1579. 

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Consecutive Leipzig registries19,20 demonstrate a similar benefit for single-arm, open-label DCB 
over historic PTA, with 3-month angiographic occlusion rate of 9.5% for DCB (n = 104) 
compared to 37.6% for control PTA (n = 50).  In the DCB registry, the 1-year TLR rate was 17% 
and limb salvage was 96%10, which is significantly better than the outcomes reported for 
currently-available treatment modalities in the meta-analyses discussed above.  DCB also 
performed better than control PTA in the subset with below-the-knee lesions treated in the 
“Drug-Eluting Balloon Evaluation for Lower Limb Multilevel Treatment” (DEBELLUM) 
study21.  These initial results for DCB are consistent and very promising, and larger randomized 
trials are warranted to establish the safety and efficacy of DCB used to treat below-the-knee 
lesions. 
1.1.1 THE LEVANT I FIRST-IN-MAN TRIAL SUMMARY 
Lutonix recently completed the LEVANT I clinical trial22 in which the Lutonix DCB Catheter 
was compared to a standard PTA catheter (with and without stenting) for treatment of stenotic 
femoropopliteal arteries.   The primary endpoint was angiographic late lumen loss at 6 months, 
as determined by an independent angiographic core lab analysis.  One hundred-one randomized 
subjects were enrolled at 9 European centers.  After a defined pre-dilatation, subjects were 
stratified to the balloon strata or stent strata and then randomized to treatment with the Lutonix 
DCB (n=49) or a standard PTA catheter (n=52, control group).   
The Lutonix DCB exhibited significantly less late lumen loss (0.46 ± 1.13 mm) compared to that 
observed for conventional angioplasty (1.09 ± 1.07 mm) at 6 months (p=0.016).  There were no 
unanticipated adverse device effects in the DCB arm, and overall adverse event rates were 
similar to conventional uncoated balloon angioplasty through 24 months.  Taken together, the 
primary objective of the trial was met, and the angiographic and clinical results of the LEVANT 
I trial demonstrated the feasibility, safety, and efficacy of use of the Lutonix DCB for treatment 
of femoropopliteal lesions. 
1.1.2 THE LEVANT 2 PIVOTAL IDE TRIAL 
The pivotal Levant 2 IDE trial (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 
 
 
19 Schmidt, A, Ulrich, M, Winkler, B, Klaeffling, C, Bausback, Y, Bräunlich, S, Botsios, S, Kruse, HJ, Varcoe, RL, Kum, S, 
Scheinert, D. Angiographic patency and clinical outcome after balloon-angioplasty for extensive  infrapopliteal arterial 
disease. Catheter Cardiovasc Interv (2010), 76:1047-1054. 
20 Schmidt, A, Piorkowski, M, Werner, M, Ulrich, M, Bausback, Y, Bräunlich, S, Ick, H, Schuster, J, Botsios, S, Kruse, HJ, 
Varcoe, RL, Scheinert, D. First experience with drug-eluting balloons in infrapopliteal arteries: restenosis rate and clinical 
outcome. J Am Coll Cardiol (2011), 58:1105-1109. 
21 Fanelli F, Cannavale A, Boatta E, Corona M, Lucatelli P, Wlderk A, Cirelli C, Salvatori FM. Lower limb multilevel treatment 
with drug-eluting balloons: 6-month results from the DEBELLUM randomized trial. J Endovasc Ther (2012), 19:571-580. 
22 ClinicalTrials.gov Identifier: NCT00930813 

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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 is ongoing through 5 years.  
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.  
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 

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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. 
1.2 DEVICE AND STUDY RATIONALE 
The Lutonix BTK DCB Catheter is intended for use as a percutaneous transluminal angioplasty 
(PTA) catheter for dilatation of obstructive de novo or non-stented restenotic lesions in native 
popliteal, tibial, and peroneal arteries ≥ 2.0 and ≤ 4.0mm in diameter.  The drug coating on the 
Lutonix DCB contains paclitaxel and excipients (polysorbate and sorbitol) with a history of 
human safety for intravenous use.  Each component has been safely used in other products.  PTA 
catheters have been in commercial use for over 25 years, and the Lutonix DCB Catheter meets 
international standards (e.g. ISO 10555) developed over time to validate the mechanical safety of 
dilation catheters.  The anti-proliferative drug paclitaxel is a well understood active 
pharmaceutical ingredient (API) with an extensive history of human use in oncology23 and drug-
eluting stents (DES)24.  The maximum total dose of 3.8 mg on the largest peripheral Lutonix 
DCB Catheter is less than 2% of the dose of approximately 300 mg infused during a single 
course of cancer therapy.  In addition, GLP animal Safety and 4x dose Safety Margin studies 
have been performed to confirm the safety of the Lutonix DCB Catheter. 
 
2 STUDY OBJECTIVES AND ENDPOINTS 
 
2.1 PRIMARY OBJECTIVE 
The primary objective of the Lutonix BTK study is to demonstrate the superior efficacy and non-
inferior safety of the Lutonix DCB Catheter by direct comparison to standard PTA catheter for 
treatment of stenosis or occlusion of below-the-knee arteries.   
Enrollment will occur at up to 75 global centers. Up to 1000 subjects may be enrolled to obtain 
up to the maximum of 840 treated vessels for the primary analysis.   
Clinical follow-up is scheduled at 30 days, 6, 12, 24 and 36 months.  
 
 
23 Pacific Yew: Draft Environmental Impact Statement. Appendices. U.S. Departments of Agriculture, Interior, and Health and 
Human Services. January 1993. 
24 Lasala J, et.al.  An Overview of the TAXUS® Express®, Paclitaxel-Eluting Stent Clinical Trial Program.  J Interv Cardiol 
(2006), 19:431-442. 

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2.2 PRIMARY ENDPOINTS 
 
2.2.1 SAFETY 
The primary safety endpoint is freedom from BTK MALE (major adverse limb event) + POD 
(peri-operative death) at 30 Days. This is strictly defined as the composite at 30 days of all-cause 
death, above-ankle amputation or major reintervention (new bypass graft, jump/interposition 
graft revision, or thrombectomy/thrombolysis) of the index limb involving a below-the-knee 
artery. 
Percutaneous vascular reintervention involving a BTK artery is considered less major (than 
death, amputation, bypass, or thrombolysis) and is not counted as a failure of the primary safety 
endpoint. Since percutaneous reintervention is captured as a failure of the primary efficacy 
endpoint, this serves to decrease endpoint concordance that would otherwise arise from having 
the most common serious adverse event in both co-primary endpoints. In addition, not counting 
percutaneous reintervention as a failure made it possible to determine an expected failure rate, 
which was necessary for study powering. Unlike at 12-months, from historical studies it is nearly 
impossible to tease out an expected 30-day rate of percutaneous reintervention with a mandatory 
30-day clinical visit. In contrast, there is very good data for MALE and POD. Two recent meta-
analyses10,11 report 30 day data for elements of the composite safety endpoint. 
Major but not minor amputations are considered safety failures. In the enrolled population with 
significant risk of limb loss, many minor toe amputations will have already been planned at the 
time of the index procedure and will not constitute major adverse safety events.  Pre-defined 
clinical events, including index limb-relatedness of death, will be adjudicated by the blinded 
CEC. 
Major reinterventions below-the-knee are considered a safety failure but reintervention above-
the-knee is not. Since about half of enrolled subjects are expected to also require inflow 
treatment, and this will be allowed prior to randomization, above-the-knee re-interventions 
reflect safety of a pre-randomization procedure and could only confound safety assessment of the 
device used for treatment below-the-knee. 
2.2.2 EFFICACY 
The primary efficacy endpoint is the composite of Limb Salvage and primary patency at 6 
months.  The primary efficacy endpoint is defined as freedom from the composite of above ankle 
amputation, target lesion occlusion, and clinically-driven target lesion reintervention.  
 
Clinically-driven is defined by stagnant or worsening wound healing, new or recurrent wound, or 
worsening of Rutherford Class in index limb. 
 
Freedom from occlusion must be established by angiography and/or Doppler. Angiography is the 
gold standard for target lesion assessment, and patency will be determined by angiography if 
performed.  Patency will be assessed by Doppler if angiography is not performed.  

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Although binary restenosis based on angiographic 50% diameter stenosis (%DS) became popular 
in the context of coronary stenting, clinical relevance with respect to its use in infrapopliteal 
artery assessments is uncertain, particularly if ischemic wounds and rest pain have healed and 
there is in-line flow.  A more clinically meaningful measure of target vessel patency in this 
population may be the original surgeon’s definition of patency, i.e. “open” or “closed” vessel.  
This definition of patency allows a less stringent requirement for angiography.  Therefore, the 
primary efficacy endpoint measure for this study is freedom-from-occlusion and not freedom-
from-binary restenosis (arbitrarily 50%DS), which is instead captured as a secondary endpoint.   
Doppler is required at all clinical visits.  Even in calcified tibial arteries, the presence of 
antegrade flow through the target vessel can usually be established by Doppler.   
2.3 SECONDARY ENDPOINTS 
• Device (able to deliver, inflate and retrieve), Technical (device success and < 30% residual 
stenosis) and Procedural Success (restoration of at least 1 infrapopliteal artery with residual 
stenosis < 30% and inline outflow to the foot) 
• Comparison of the BTK MALE+POD rate in the test arm to a performance goal at 30 Days  
• Change in quality of life at 6, 12, 24, and 36 months from baseline, as measured by EQ-5D 
survey 
• Late lumen loss at 12 months (cohort with angiography) 
 
• The following endpoints will be assessed at 30 days and at 6, 12, 24, and 36 months: 
• Wound healing (healed or not; if not, improving, stagnant, worsening) 
• New or recurrent lesion (target limb) 
• Change in Rutherford Class  (target limb) 
• Composite of freedom from the following in the index limb: 
Above-ankle amputation, unhealed wound, ischemic rest pain, target vessel occlusion, 
and clinically-driven TVR  
• Primary Patency (freedom from occlusion without clinically-driven TLR)  
• Primary Patency with exclusion of early mechanical recoil (freedom from occlusion 
without clinically-driven TLR events > 30 days) 
• Secondary Patency (not occluded, irrespective of TLR) 
• Composite of freedom from clinically-driven TLR and from 50% DS by 
angiography/DUS 
• Hemodynamic outcome (change in toe & ankle pressures of target limb)  
•  Change in Walking Impairment Questionnaire (improvement from baseline) 
 
The following endpoints will be assessed at 30 days and at 6, 12, 24, and 36 months: 
• Clinically-driven TLR (all randomized subjects and in AFS cohort) 
• Total TLR (all randomized subjects and in AFS cohort) 
• Clinically-driven TVR (all randomized subjects and in AFS cohort) 

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• Total TVR (all randomized subjects and in AFS cohort) 
• Limb salvage in surviving subjects  (target limb) 
• Unplanned minor below ankle amputation (including digit) of target limb 
• Overall burden of BTK index-limb reinterventions (total number of index limb BTK 
interventions incurred, all randomized subjects and AFS cohort) 
• Composite of POD, index limb-related death, below-the-knee reinterventions or major 
amputation of the index-limb  
• SVS CLI Endpoint Definitions ( (3) Conte 2009 JVS 50:1462-73)  
▪ MALE: Major adverse Limb Event: Above ankle amputation of the index limb or 
major reintervention (new bypass graft, jump/interposition graft revision, or 
thrombectomy/thrombolysis) 
▪ MALE+POD: Perioperative death (30 days), or any MALE 
▪ MACE: Major Adverse Cardiovascular Event: MI, stroke or death (any cause) 
▪ Amputation (Major): Above ankle amputation of the index limb 
▪ AFS: Amputation free survival (freedom from above ankle amputation of the index 
limb or death (any cause)) 
▪ RAO: Any reintervention or above ankle amputation of the index limb. 
▪ RAS: Any reintervention, above ankle amputation of the index limb, or stenosis 
▪ DEATH: Death (any cause) 
 
3 DEVICE DESCRIPTION  
The Lutonix DCB Catheter consists of an OTW catheter with a DCB fixed at the distal tip.  The 
uncoated portion of the device consists of a dual lumen shaft with a high pressure dilatation 
balloon mounted on the distal tip.  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 DCB during delivery and placement.  The balloon surface 
between the marker bands is coated with a specialized immediate release non-polymer based 
coating formulation that includes the anti-proliferative drug – paclitaxel - at a surface 
concentration of 2μg/mm2 and two well-known carriers polysorbate and sorbitol. 
The coaxial catheter includes a low profile, semi-compliant balloon formed to a low profile 
tapered tip to facilitate advancement of the catheter to and through the stenotic region of the 
vessel.  The proximal portion of the catheter includes a female luer lock hub connected to the 
inflation lumen used to inflate and deflate the balloon, and a female luer lock hub connected to 
the guidewire lumen.  The guidewire lumen ends at the tip of the catheter and permits the use of 
guidewires for advancement of the catheter through the stenotic lesion.   
A balloon Compliance Chart is included on each device product label. 
The Lutonix DCB Catheter is compatible with 0.014” (0.36mm) guidewires and is available in 
150cm lengths.  Each product has a peelable balloon protector that has been positioned over the 

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balloon for protection prior to use.  To prevent crushing of the Lutonix DCB Catheter wire 
lumen, a disposable stainless steel stylet resides in the lumen.  
The Lutonix DCB Catheter operates on the principle of hydraulic pressurization applied through 
an inflatable balloon attached to the distal end.  Upon inflation, the balloon expands to a 
specified diameter as defined per the Compliance Chart on the product label. 
The catheter is made of common materials typical of standard PTA catheters.  The investigator 
should verify device size availability before each procedure. Always follow the current 
Instructions for Use (IFU) for procedural information, preparation and use of the Lutonix DCB 
Catheter. 
All devices are provided sterile and are for single-use only.  Devices are clearly labeled for 
investigational use only.  
 
FIGURE 1: LUTONIX 0.014"  OTW DRUG COATED PTA DILATATION CATHETER 
 
3.1 INTENDED USE / INDICATIONS FOR USE 
The Lutonix DCB Catheter is intended for percutaneous transluminal angioplasty of obstructive 
de novo or non‐stented restenotic lesions in the native popliteal, tibial, and peroneal arteries ≥ 2.0 
and ≤ 4.0mm in diameter. 
 
3.2 ACTIVE PHARMACEUTICAL INGREDIENT (API): PACLITAXEL 
Paclitaxel, discovered in 1967 and commercially developed by Bristol-Myers Squibb, is a well 
known mitotic inhibitor indicated for use in the treatment of patients with lung, ovarian, breast, 
head and neck cancers and advanced forms of Kaposi’s sarcoma.  Paclitaxel is also approved for 
the prevention of restenosis.  Various dosages are used depending on target treatment and range 
from multiple 300 mg IV infusions for oncology therapy to a single maximal nominal dose of 
282 µg for devices that treat restenosis, such as coronary stents.  Please refer to  
Figure 2 and the Investigator’s Brochure for a more detailed review of paclitaxel. 

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FIGURE 2 : CHEMICAL STRUCTURE OF PACLITAXEL 
3.3 EXCIPIENT (DRUG CARRIER) 
The balloon coating includes small amounts of well-known excipients (polysorbate and sorbitol) 
that are approved by the Food and Drug Administration (FDA) as inactive ingredients in drug 
products for intravenous (IV) drug delivery.  
3.4 DEVICE INSTRUCTIONS 
A comprehensive set of Instructions for Use (IFU), including warnings and precautions, has been 
created.  Please refer to the most current IFU for complete details on preparation and procedural 
use of the device.  A sample IFU can be found in Appendix E.  
3.5 SUPPLY & SUPPORT OF INVESTIGATIONAL DEVICE  
An investigational device supply of the Lutonix DCB Catheter will be made available to all 
activated study sites.  The investigational device matrix that is currently available for this study 
is referenced in the current IFU.  Always confirm current site inventory supply prior to enrolling 
subjects into the study.   
Prior to start of study enrollment, Lutonix or their designee will perform device training for study 
site personnel and support staff.  Each study site will receive a supply of the Lutonix DCB 
Catheters upon completion of the protocol requirements for study initiation.  Additional training 
and support will be provided as needed on an ongoing basis.  Any unused devices must be 
returned to the sponsor at the time site enrollment stops or upon sponsor request.  After use, this 
product may be a potential biohazard.  Handle and dispose of in accordance with acceptable 
medical practices and applicable local, state and federal laws and regulations.  For quality control 
purposes, devices may be requested to be returned to the sponsor before or after use, in which 
case the site should return devices by requesting a Return Material Authorization (RMA) number 
from the Sponsor. 
4 RISK-BENEFIT ANALYSIS 
4.1 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.  The Lutonix DCB Catheter and standard 

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uncoated percutaneous angioplasty catheters are intended to be the only devices used for 
treatment of the target lesion.   
Due to the high similarity of the Lutonix DCB Catheter to other marketed balloon catheters, 
procedural use is not expected to significantly change or increase risks during the initial 
procedure.  However, it shares the risks of conventional balloon angioplasty treatment of patients 
with vascular disease in the lower extremities.  There may also be risks associated with the drug 
coating on the Lutonix DCB Catheter that are unknown at this time.  Please refer to the 
Investigator’s Brochure for more details on the development of the Lutonix DCB Catheter. 
4.1.1 RISKS FOR PERIPHERAL CATHETERIZATION PROCEDURE 
Potential adverse events which may be associated with a peripheral balloon dilatation 
catheterization procedure include, but are not limited to, the following: 
• abnormal heart rhythms 
• abrupt vessel closure 
• allergic reaction 
• aneurysm or rupture of the artery 
• AV fistula 
• bleeding 
• death 
• dissection 
• embolization 
• femoral nerve compression with associated neuropathy 
• groin area bruising and discomfort 
• hematoma 
• hypotension/hypertension 
• inflammation 
• kidney failure 
• low blood pressure 
• pain or tenderness 
• perforation 
• pseudoaneurysm 
• respiratory failure 
• sepsis/infection 
• shock 
• stroke 
• total occlusion or thrombosis 
• vessel dissection, perforation, rupture, or spasm that may require re-intervention or 
surgery 
• additional angiographic intervention, surgical intervention, or amputation 

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There may be other potential adverse events that are unforeseen at this time. 
Even if the balloon catheter procedure is deemed successful, it is associated with a meaningful 
risk of vessel narrowing within 12 months (depending on risk factors).  Additional therapy may 
be required within 12 months such as reintervention using angioplasty or surgery.   
Patients undergoing an interventional procedure are often treated with courses of thienopyridines 
such as clopidogrel or prasugrel, which may cause thrombocytopenic purpura and/or bleeding 
complications.  In rare cases, these drugs may cause a significant reduction in white blood cell 
count, which may in turn result in serious infections.  Aspirin is also a common drug used before 
and after such procedures.  Aspirin is known to contribute occasionally to causing 
gastrointestinal ulcers (bleeding or non-bleeding).  Aspirin may also affect platelet function to 
the extent of causing bleeding complications (which may be minor, major, or life threatening).  If 
such conditions occur, the patient may require surgery, blood transfusion, or platelet transfusion.   
Any of the above could cause prolonged illness, permanent impairment of daily function or, in 
rare cases, death. Possible treatments could include, but are not limited to emergency PTA and 
vascular surgery.  It is expected that the fluoroscopy time of the interventional procedure will be 
similar to the time required for conventional percutaneous lower extremity interventional 
procedures and not pose additional risks to the subject or lab personnel.  
4.1.2 ASSOCIATED RISKS FROM THE DRUG COATING 
The balloon coating includes the API paclitaxel and small amounts of well-known excipients 
(polysorbate and sorbitol) that are approved by the Food and Drug Administration (FDA) as 
inactive ingredients in drug products for intravenous (IV) drug delivery.  Additional adverse 
events that 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 
• peripheral neuropathy 
There may be other risks associated with the drug coating that are unknown at this time.   
There are no adequate and well-controlled studies published in pregnant women or men 
intending to father children who have received paclitaxel.  Studies performed in rats and rabbits 
receiving IV paclitaxel during organogenesis revealed evidence of maternal toxicity, 
embryotoxicity, and fetotoxicity at dosages of 1 and 3 mg/kg, respectively (approximately 3 and 

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16 times the dose provided by the largest femoropopliteal Lutonix DCB Catheter coated with 3.8 
mg of paclitaxel adjusted for body surface area). The drug resulted in increased resorptions and 
increased fetal deaths.  No teratogenicity was observed in gravid rats receiving daily IV 
paclitaxel doses of 1 mg/kg (a daily dose of approximately 3 times the dose of the largest 
Lutonix DCB Catheter, adjusted for body surface area). Enrollment of women who are of 
childbearing potential or in men intending to father children should therefore take reproductive 
risk into careful consideration. 
4.2 RISK MANAGEMENT PROCEDURES 
Eligibility criteria have been selected that exclude patients who are at a higher risk for 
experiencing an anticipated adverse event in order to reduce the risks to subjects who participate 
in this study.  In addition, subjects enrolled in this study should be receiving a defined anti-
platelet regimen.  In addition, follow-up duplex ultrasound will be performed to assess the target 
vessel patency. All adverse events are monitored and events will be adjudicated by the Clinical 
Events Committee per Section 12.3. 
Extensive reliability engineering testing has been performed on the Lutonix DCB Catheter to 
help mitigate any risks to the subjects due to product failure.  Additionally, animal studies using 
the Lutonix DCB Catheter have been conducted to ensure that the device performs as intended 
without introducing more risks during the interventional procedure.  
Investigational device training will be conducted at each initiated study center and appropriate 
training records will be maintained.  
4.3 POTENTIAL BENEFITS 
There are no guaranteed benefits from participation in this study; however, it is possible that 
treatment with the Lutonix DCB Catheter may reduce the potential for restenosis of the lesion(s), 
thereby reducing the need for repeat hospitalization and/or procedure(s).  
Additionally, information gained from the conduct of this study may be of benefit to others with 
the same medical condition. As with all investigational medical devices, the long-term results of 
using the Lutonix DCB Catheter are not known at the present time.  Alternatives to the use of the 
Lutonix DCB Catheter include standard or cutting balloon angioplasty, vascular stenting, 
atherectomy, cryoplasty, or vascular radiation and surgery (vessel bypass with native or synthetic 
vessel).  Lutonix believes that the risk for significant injury or death due to the Lutonix DCB 
Catheter is extremely low, and the potential benefits of decreased restenosis and decreased need 
for reintervention is likely, but these potential risks and benefits have yet to be quantified. 
4.4 EARLY TERMINATION 
Lutonix, Inc. (Sponsor) and the Data Monitoring Committee (DMC) 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 issues: 

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• Evidence of an Investigator’s failure to maintain adequate clinical standards  
• Evidence of an Investigator or staff’s failure to comply with the protocol 
• Inaccuracy or late submission of data forms and core lab images 
• Inability to meet enrollment targets (1 subject/month) 
• Conditions of approval imposed by the reviewing IRB/EC and/or regulatory agencies 
• Evidence of safety concerns or protocol non-compliance 
• Change of staff at site that adversely impacts trial conduct   
Any evident pattern of non-compliance with respect to these standards will be cause for the site 
to be put on probation.  If corrective actions are not subsequently undertaken, the clinical site 
will be asked to withdraw from the study and their site may be replaced. 
Notification of suspension or termination will occur no later than five (5) working days after the 
Sponsor makes the determination.  In the event of study suspension or termination, the Sponsor 
will send a report outlining the circumstances to the Institutional Review Board (IRB)/Ethics 
Committee (EC), and all Investigators and Regulatory Authorities as required by regulation.  A 
suspended or terminated study may not be re-initiated without approval of the reviewing IRB/EC 
and Regulatory Authorities, as required by regulation. 
The Investigator must notify the IRB/EC in writing as soon as possible but no later than within 
10 days if the premature termination is related to safety or compliance issues. 
5 CLINICAL STUDY DESIGN   
The study will enroll patients presenting with below-the-knee disease (Rutherford Category 3, 4, 
or 5) and an angiographically significant (≥ 70%) native artery lesion appropriate for angioplasty 
that is below the knee and above the ankle.  After successful protocol-defined pre-dilatation, 
subjects that continue to meet lesion and outflow angiographic criteria are stratified by 
Rutherford Category and randomized 2:1 to treatment with either the Lutonix DCB (test) or 
standard uncoated PTA catheter (control). All target lesion(s) in up to two target vessels are 
treated with the as-randomized (by subject) test DCB or control PTA devices.  After the 
protocol-defined pre-dilatation with a standard uncoated PTA catheter step is completed and if 
randomized to control, treatment with an additional standard uncoated PTA catheter (control 
device) is at the discretion of the investigator as long as 0-30% residual stenosis is achieved.  
Subjects with no target vessels that meet post-pre-dilatation entry criteria are excluded (and 
treated per standard practice) and followed for safety for 30 days. 
All subjects will have ultrasound and clinical follow-up through 36 months. There is no pre-set 
limit to site enrollment, however site enrollment will be tracked and managed to ensure 
approximately 50% of the overall randomized enrollment occurs at US sites.  
Primary efficacy endpoint assessment is performed at 6 months. Clinical follow-up continues 
through 36 months.  The study treatment algorithm flow-chart is shown below in Figure 3. Bail-

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out stenting is allowed only if necessary to avoid surgical bypass or amputation.  Proper surgical 
procedure may be performed whenever appropriate, in the investigator’s judgment. 
If a ‘proximal vessel only’ arm of the trial is required per the adaptive study design (see Section 
15 of this protocol for additional details), then an additional inclusion criterion which defines this 
patient population, will be implemented and followed.  There are no changes to the procedural 
steps listed in this section above, that is successful pre-dilatation, randomization 2:1 ratio, 36 
month follow-up with primary endpoint at 6 months, will still be followed. The schedule of 
events listed in Table 3 of this protocol will still also be followed for this study arm. 
 
Post-Pre-dilatation Angiographic Criteria
(All Target Lesion(s) in 1 or 2 Infrageniculate Vessels)
Successful Inflow Treatment (if 
necessary) and Baseline Angiogram
Test Arm
Dilatation of ALL Target 
Lesions with Drug 
Coated Balloon
Control Arm
Additional treatment  is at the discretion 
of the investigator as long as procedural 
success is achieved (0 - 30% residual 
stenosis)
Defined Pre-Dilatation
 Enrollment
Subject
Randomization
2:1
Standard Post dilatation per physician discretion
Subjects followed for 
Safety through 30 days 
and withdrawn
Recruitment
Residual Stenosis >50%
-OR-
Operator determination that procedural success is 
unlikely to be achieved by angioplasty alone
-OR-
Target vessel fails to reconstitute at or above the ankle 
with patent in-line flow from target lesion to below-ankle 
outflow
Residual Stenosis <50%
-AND-
Operator determination that procedural success may be 
achievable using angioplasty alone
-AND-
Reconstitution at or above the ankle with patent in-line 
flow from target lesion to below-ankle outflow
Treat per Standard Practice
 
FIGURE 3: STUDY FLOWCHART 
 

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5.1 SCREENING PROCEDURES 
All Rutherford 3, 4, and 5 patients presenting for a percutaneous revascularization of an artery(s) 
below the tibial plateau and above the tibiotalar joint should be screened for study eligibility.  
Patients categorized as a Rutherford Clinical Category 3 must have failed medical management 
per physician discretion.  Once the patient’s eligibility has been determined, the Investigator will 
discuss the study and ask the patient to participate.  Prior to enrollment, the patient must sign the 
Informed Consent Form (ICF) approved for use by the IRB/EC or other appropriate committee.  
A copy of the signed and dated ICF will be provided to the subject.  Subjects will be assured that 
they may withdraw from the study at any time and for any reason.  The background and purpose 
of the study, participation requirements, as well as the potential benefits and risks of the 
procedure(s) must be explained to the subject.   
The status of all patients screened, whether enrolled, withdrawn, etc., should be captured on the 
study Screening Log for tracking and reporting purposes.   
If not already performed as standard practice, the following clinical 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: 
• Physical examination (including blood pressure, heart rate, and temperature) 
• Relevant medical history 
• Rutherford Classification (index limb) 
• Pregnancy Test (blood or urine; if female of child bearing potential) 
• Resting TBI (if possible) and ABI (within 90 days) 
• Walking Impairment Questionnaire 
• EQ-5D Questionnaire 
• Wound Assessment (including collection of images)    
 
Information already in the patient’s medical record that has been collected as part of standard 
hospital practice (including, for example, medical history, physical examination, Rutherford 
Classification, ankle and toe pressures) may be used as baseline data even if collected before the 
Informed Consent Form was signed. 
5.2 PATIENT SELECTION FOR ENROLLMENT 
Subjects 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 
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5.3 SUBJECT INCLUSION AND EXCLUSION CRITERIA 
 
5.3.1 
 INCLUSION CRITERIA 
Subjects must meet all inclusion criteria, 1 - 12 as specified below, to be enrolled in the study.   

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Clinical Criteria 
1. Male or non-pregnant, non-breastfeeding female ≥18 years of age;  
2. Rutherford Clinical Category 3, 4 or 5  
NOTE:  Patients categorized as a Rutherford Clinical Category 3 must have failed medical 
management per physician discretion; 
3. Life expectancy ≥ 1 year;  
4. Patient is willing to provide informed consent, is geographically stable, and is willing to 
comply with the protocol-required follow up visits, testing schedule and medication regimen 
5. No other prior surgical or vascular interventions within 2 weeks before and/or planned 30 
days after the protocol treatment;  
NOTE:  The following are allowed within 2 weeks prior or within 30 days after the 
procedure: 
• Planned transmetatarsal or lower minor amputations 
• Index limb inflow-lesion treatment 
• Contralateral iliac treatment 
• Wound debridement 
NOTE:  Except for allowed iliac treatment (noted above), contralateral limb lesion(s) 
cannot be treated during the index procedure or within 2 weeks before and/or planned 30 
days after in order to avoid confounding complications; 
 
Angiographic Criteria  
6. Significant stenosis (≥70%) or occlusion of one or two native artery(s) below the tibial 
plateau and above the tibiotalar joint appropriate for angioplasty per operator visual 
assessment 
NOTE: One or two flow pathways are allowed as artery(s); i.e., peroneal or posterior tibial 
arteries may involve tibioperoneal trunk lesions and tibial arteries may involve popliteal 
lesions;  
7. Cumulative length of target lesion(s) ≤ 320 mm;  
NOTE: Maximum allowed cumulative length of all DCBs ≤ 360 mm; 
8. Target lesion(s) not previously stented and at least 20 mm from any previous stent; 
9. A patent inflow artery from the aorta to the target lesion free from significant (≥50%) 
stenosis as confirmed by angiography; 
NOTE: concurrent or staged treatment of iliac/SFA/above-knee popliteal artery is allowed if 
successfully performed (with residual diameter stenosis ≤ 30% and reconstitution at least 30 
mm proximal to tibial plateau) without major vascular complication; 
NOTE: If atherectomy is performed on the superficial femoral (SFA) or popliteal lesion(s), 
use of a distal embolic filter is required. 
NOTE: Treatment of the femoropopliteal with a DCB is not allowed during the index 
procedure. 

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10. Target vessel(s) diameter between 2 and 4 mm and able to be treated with available device 
size matrix; 
11. Successful antegrade pre-dilatation of the target lesion with standard PTA catheter 
appropriate size for the reference vessel diameter; 
NOTE:   Successful pre-dilatation defined by residual stenosis ≤ 50% and operator 
determination that procedural success may be achievable by angioplasty alone 
NOTE: Multiple lesions allowed, but ALL target lesions MUST be successfully pre-dilated 
prior to randomization;  
NOTE: If the popliteal artery is pre-dilated, it MUST meet angiographic inclusion criteria; 
NOTE: Retrograde access for initial wire crossing allowed, but pre-dilatation and treatment 
must be performed over antegrade wire. 
12. Target vessel(s) reconstitute(s) at or above the ankle with inline flow to at least one patent 
(<50%) inframalleolar outflow vessel (planned treatment below-the-ankle is not allowed); 
NOTE: Outflow must be assessed AFTER pre-dilatation 
NOTE: Two arteries allowed, but each target vessel MUST demonstrate inline 
inframalleolar outflow prior to randomization. 
 
Additional Inclusion Criteria (only applicable if continued enrollment of “proximal 
vessel only” arm is required per adaptive study design; see Section 15 of this protocol 
for details): 
13. Target lesion is located entirely within the proximal two-thirds of the leg between the tibial 
plateau and tibiotalar joint. 
 
5.3.2 EXCLUSION CRITERIA 
Patients will be excluded if ANY of the following conditions apply:  
1. Any severe medical comorbidities (untreated CAD/CHF, severe COPD, metastatic 
malignancy, etc.) that would preclude compliance with the study protocol or currently 
receiving immune-suppressive, chemotherapeutic, or radiation therapy; 
2. Patient is currently participating in an investigational drug or device study or previously 
randomized or a roll-in subject in this study 
NOTE: Enrollment in another 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 30 days of enrollment; 
5. Gangrene extending proximal to the digit-metatarsal skin crease (target limb); 
NOTE: Gangrene must be confined to the toe or toes  
6. Ischemic ulceration that extends more than 4 cm proximal to digit-metatarsal skin 
crease(target limb); 
NOTE: If ulcers are confined to toe, involvement of tendon or bone is acceptable.  Ulcers 
proximal to digit-metatarsal skin crease must be superficial (not involving tendon or bone).   

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7. Neurotropic ulcer or heel pressure ulcer or ulcer potentially involving calcaneus(target limb); 
8. Evidence of osteomyelitis in a bone not intended for resection(target limb); 
9. Signs and symptoms of systemic infection ( temperature of  ≥ 38.0° Celsius and/ or WBC of 
≥ 12,000 cells/ µL) at the time of assessment; 
NOTE: If infection is adequately treated and controlled (temperature < 38.0° C and WBC < 
12,000 cells/ µL) patient may be enrolled; 
10. Planned major amputation (of either leg); 
11. Prior major amputation if amputation occurred less than one year prior to enrollment and if 
patient is not independently ambulating; 
12. GFR ≤ 30 ml/min per 1.73m2; 
13. Allergy to contrast or known allergy to contrast, taxols or polysorbates that cannot be 
adequately managed with pre- and post-procedure medication; 
14. Hemodynamically significant aortic or CFA occlusive disease (concurrent aortic and 
common femoral artery treatment NOT allowed); 
15. Intended use of adjunctive primary treatment modalities (e.g., atherectomy, laser, cutting 
balloons, radiation therapy, stents) in below-the-knee vessels;  
16. Acute limb ischemia (symptom onset within 2 weeks); 
17. In-stent restenosis of target lesion; 
18. Presence of thrombus in the target vessel. 
 
6 
STUDY/TREATMENT PROCEDURES 
6.1 ENROLLMENT 
Informed consent must be obtained prior to study-specific testing (that would not have been 
performed per standard-of-care of non-study subjects). A subject is considered enrolled in the 
study after both of the following steps have occurred: 
• Baseline angiographic confirmation that the target lesion(s) meets all appropriate 
inclusion/exclusion criteria. 
• Defined pre-dilatation balloon inflation has begun. 
All subjects enrolled and randomized in the trial will be followed for the entire duration of the 
study and included in the primary and secondary analyses. Subjects that do not meet post-pre-
dilatation criteria are enrolled, but not randomized, and treated per standard practice and 
followed for safety for 30 days via telephone or clinical visit. Subjects with target lesion(s) that, 
after baseline angiography, do not meet all inclusion/exclusion criteria and are not pre-dilated per 
protocol are considered screen failures and will not be enrolled or randomized in the study. 
Subjects who undergo a major amputation of the target limb (includes amputation of the treated 
vessel / lesion) will continue being followed for the study.  The following are not required for 
these patients: 
• DUS 

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• TBI/ABI assessment 
• Rutherford Classification 
• Walking impairment questionnaire (WIQ) 
 
6.2 LUTONIX DCB CATHETER INSTRUCTIONS FOR USE (IFU) 
Always follow the current IFU for procedural information, preparation and use of the Lutonix 
DCB Catheter.  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 Malfunction Form must be 
completed.  A balloon compliance chart is included on each device product label. 
In order to achieve the best procedural outcomes, the following steps should be completed: 
• The Lutonix DCB catheter should be advanced to the target site as fast as possible (~ 30 
seconds). 
• The DCB should be immediately inflated when reaching the target site to appropriate 
pressure to ensure full wall apposition (balloon to artery ratio of ≥ 1:1).  
• Maintain the DCB inflation for a minimum of 2 minutes (120 seconds).  The balloon may 
remain inflated as long as is required by the standard of care to achieve a good 
angioplasty outcome. 
• For optimal results, the final percent stenosis should be 0-20%. 
If more than one Lutonix DCB Catheter will be needed to treat the entire pre-dilated 
segment(s)/lesion(s), the combination of lengths available should be carefully considered 
beforehand to ensure complete coverage of the target lesions (maximum allowed cumulative 
length of all DCBs ≤ 360 mm) and, at the same time, reduce unnecessary vessel dilatation.  The 
IFU also contains detailed information on lesion coverage.   
6.3 BASELINE ANGIOGRAM 
DSA- or Cine- angiograms should be obtained per core lab guideline.  Standard off-line 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 such a way that 
they are suited for off-line QVA.  For purposes of ensuring protocol compliance, all angiograms 
must be submitted to the core laboratory as soon after the case as possible. 
6.4 IN-FLOW LESION TREATMENT 
Absence of inflow disease (≥50% stenosis) as confirmed by angiography is required for 
enrollment in the study. Concurrent or staged treatment of iliac, SFA, and above-knee popliteal 
artery lesion is allowed if successfully performed (residual diameter stenosis ≤ 30%) without 
major vascular complication.  If atherectomy is performed on the superficial femoral or popliteal 
lesion(s), use of distal embolic filter is required.  Treatment of SFA/popliteal inflow lesions must 
terminate 30 mm above the tibial plateau (i.e., there must be a segment of healthy artery between 

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any treated inflow lesions and potential target vessel lesions below the knee). Treatment of aortic 
and common femoral lesions is not allowed. 
6.5 PRE-DILATATION AND TARGET VESSEL ENTRY CRITERIA 
 
NOTE: All angioplasty balloons used for vessel pre-dilation or treatment of control arm subjects 
must be uncoated, standard PTA balloons. Balloons that incorporate a contoured surface, 
external wire support, cutting/scoring component, or other similar modifications may NOT be 
used for pre-dilation or control arm treatment. 
 
Always refer to the current IFU for complete pre-dilatation requirements. The pre-dilatation 
balloon should be a standard PTA balloon appropriate size for the reference vessel diameter.  
Always limit the longitudinal length of the pre-dilatation balloon to avoid creating a region of 
vessel injury that is outside the boundaries of the area to be treated by the Lutonix DCB (i.e., to 
avoid geographic miss).  In order to reduce dissections and potential exclusion of target vessels 
after pre-dilatation, careful and controlled pre-dilatation(s) inflations should be performed and 
recorded (on film). 
 
When possible, it is strongly encouraged to attempt treatment of the vessel perfusing the 
ischemic tissue (the site of ulceration or gangrene) based on the angiosome concept. This may 
not always be possible, and treatment of other vessels is allowed to maximally perfuse the at-risk 
ischemic limb at the operator’s discretion. Ensure that all target lesion diameters can be treated 
with the Lutonix DCB device sizes available; e.g., do not include a popliteal lesion with RVD 
diameter greater than largest available Lutonix DCB device size of 4.0mm. 
 
Per protocol, target lesions must be located in one or two native artery(s) below the tibial plateau 
(proximal boundary) and above the tibiotalar joint (distal boundary) (Figure 4).  
 
 

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A 
 
 
 
 
      B 
 
 
 
FIGURE 4: PROXIMAL (A) AND DISTAL (B) TARGET VESSEL BOUNDARIES 
 
Retrograde access for initial wire crossing or use of crossing devices is allowed, but pre-
dilatation and treatment must be performed over an antegrade wire. Manual pressure hemostasis 
should be conducted on the retrograde access site (not balloon inflation). One or two flow 
pathways are allowed as target vessel(s); i.e., peroneal or posterior tibial arteries may involve 
tibioperoneal trunk lesions and tibial arteries may involve popliteal lesions, as illustrated below 
in Figure 5. Peroneal or posterior tibial artery lesions (diffuse or focal) that extend into the 
tibioperoneal trunk can be counted as one target artery (Figure 5A).  Similarly, lesions (diffuse or 
focal) in the anterior tibial artery that extend into the popliteal artery can be counted as one target 
artery (Figure 5B).  
 
A 
 
 
 
 
   B 
 
              
  
 
 
 
 
 
 
 
 
 
FIGURE 5 : ONE OR TWO FLOW PATHWAYS ARE ALLOWED AS TARGET VESSELS 
 
Tibial plateau: 
Proximal boundary 
of target vessel  
Tibiotalar joint:  
Distal boundary 
of target vessel  
Tibia 
Talus 
Peroneal 
artery 
Posterior 
tibial artery 
Tibioperoneal 
trunk 
Distal popliteal 
artery 
Anterior tibial 
artery 

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Only applicable if continued enrollment of “proximal vessel only” arm is required per 
adaptive study design; see Section 15 of this protocol for details.   
 
In this case, only the target lesions completely within the proximal 2/3rd segment (see Figure 6) 
will continue to be enrolled in this study. 
 
 
FIGURE 6. PROXIMAL VESSEL SEGMENT (APPLICABLE FOR ENROLLMENT OF PROXIMAL VESSELS 
ONLY) 
 
Antegrade pre-dilatation of target lesion(s) is performed with a standard PTA catheter 
appropriate size for the reference vessel diameter.  Successful pre-dilatation is defined as residual 
stenosis ≤ 50% and operator determination that procedural success may be achievable by 
angioplasty alone.  Multiple lesions, up to 320 mm in cumulative length, may be pre-dilated, but 
ALL target lesions MUST be successfully pre-dilated and assessed prior to randomization.  
Outflow must be assessed AFTER pre-dilatation. Each target vessel(s) (flow path) must 
reconstitute(s) at or above the ankle with inline flow to at least one patent (<50%) inframalleolar 
outflow vessel. Note that planned treatment below-the-ankle is not allowed, and lateral and tarsal 
branches of the peroneal artery can be considered to represent acceptable patent outflow post-
pre-dilatation. In addition, note that a subject with a pre-dilated popliteal artery that fails to meet 
angiographic inclusion criteria CANNOT be randomized, since the popliteal artery is upstream 
of all flow from the 3 crural run-off vessels to the foot. 

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Multiple lesions in two target vessels are allowed, but each target vessel flow path MUST 
demonstrate inline inframalleolar outflow prior to randomization. If pre-dilatation of one vessel 
is attempted but fails to meet criteria, it is not a target vessel and is instead treated per 
institutional standard practice.  Another vessel may be attempted.  If pre-dilatation of two vessels 
is attempted, and only one meets lesion and outflow criteria, then there is only one target vessel 
for that subject. The other vessel is treated per institutional standard of care and is not a target 
vessel. If, after pre-dilatation, no target lesions meet angiographic lesion and outflow criteria, the 
subject will not be randomized but will be instead treated per institutional standard practice.  
Non-randomized subjects excluded after pre-dilatation will be followed for 30 days for safety 
and then withdrawn from the study. 
 
See Table 1 for an overview of target vessel and outflow assessment and outcome. 
 
 

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TABLE 1: POST-PRE-DILATATION ANGIOGRAPHIC TARGET LESION AND OUTFLOW CRITERIA 
(ALL TARGET LESIONS IN 1 OR 2 INFRAGENICULATE VESSELS) 
Angiographic Criteria 
Vessel Outcome 
 
 
Subject Treatment 
Residual Stenosis > 50% 
-OR- 
Operator determination that procedural 
success is unlikely to be achieved by 
angioplasty alone 
-OR- 
Target vessel fails to reconstitute at or 
above the ankle with patent in-line flow 
from target lesion to below-ankle outflow 
Not a target vessel. 
Vessel is treated 
per standard of 
care.  
If this criteria applies to ALL 
potential target vessels, then subject 
is not randomized, but followed for 
safety through 30 days, i.e. 
“Standard Practice” 
Residual Stenosis ≤50% 
-AND- 
Operator determination that procedural 
success may be achievable using 
angioplasty alone 
-AND- 
Reconstitution at or above the ankle with 
patent in-line flow from target lesion to 
below-ankle outflow 
It is a target vessel 
and will be treated 
with the as-
randomized device 
after subject 
randomization  
 
Subject is randomized 2:1 to 
treatment with Lutonix DCB vs. 
Control PTA (if two target vessels 
meet this criteria, both are target 
vessels and treated as-randomized 
with Lutonix DCB or control PTA) 
 
NOTE: If the popliteal artery has been pre-dilated but failed to meet angiographic entry criteria, 
the subject cannot be randomized but is instead to be treated per investigator’s standard practice.  
NOTE: Whenever possible, it is preferable to complete all intended interventional procedures on 
non-target vessels prior to randomization. This is to ensure a balanced distribution between arms, 
and to allow for proper attribution of any complications prior to randomization. 
 
 

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Below are 3 possible treatment Scenarios for randomization: 
Scenario 1: One potential target vessel identified, pre-dilated and meets post-pre-dilatation 
criteria for randomization.  The subject has a single target vessel and is randomized to either the 
Lutonix DCB or Control PTA; the target vessel is treated with the as-randomized device, as in 
Figure 3. 
Scenario 2: Two potential target vessels are identified and pre-dilated, but only one vessel meets 
the post-pre-dilatation criteria for randomization.  The subject has a single target vessel and is 
randomized to either the Lutonix DCB or Control PTA, as in Figure 3. The target vessel meeting 
criteria is treated with the as-randomized DCB or control PTA. The pre-dilated vessel that did 
not meet post-pre-dilatation criteria is NOT a target vessel and is treated per Investigator’s 
standard practice and is NOT treated with the investigational device. Non-target vessels are 
excluded from all endpoint analyses.  
Scenario 3: Two potential target vessels are identified and pre-dilated, and both vessels meet the 
post-pre-dilatation criteria for randomization.  The subject has TWO target vessels and is 
randomized to either the Lutonix DCB or Control PTA, as in Figure 3. Both vessels MUST be 
treated with the as-randomized device (the same treatment, either Lutonix DCB or Control PTA, 
as randomized for that subject). Both target vessels are included in endpoint analyses. If two 
target vessel flow pathways are successfully identified, attempting treatment of a third is not 
allowed.  
6.6 RANDOMIZATION 
If after pre-dilatation(s), subjects are determined to meet the criteria for randomization, they will 
be stratified by Rutherford Class and randomized using a pre-specified site randomization 
system.  Subjects will be randomized in a 2:1 fashion in each strata to Test (Lutonix DCB 
Catheter) or Control (standard PTA catheter), and all target lesions in up to two target vessels 
(meeting entry criteria) are treated with the as-randomized device.   
 
Any pre-dilated vessel that did not meet angiographic lesion and outflow criteria is NOT a target 
vessel and is NOT treated with the investigational device. Any vessel failing to meet criteria after 
pre-dilatation is instead treated per Investigator’s standard practice. 
 
6.6.1 TREATMENT WITH STANDARD PTA CATHETER (CONTROL) 
For subjects randomized to the control arm, treatment with an additional standard uncoated PTA 
catheter (control device) is at the discretion of the investigator. Control PTA treatment should 
maintain balloon inflation for minimum of 2 minutes. 
 
NOTE: All angioplasty balloons used for vessel pre-dilation or treatment of control arm subjects 
must be uncoated, standard PTA balloons. Balloons that incorporate a contoured surface, 

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external wire support, cutting/scoring component, or other similar modifications may NOT be 
used for pre-dilation or control arm treatment. 
Multiple lesions may be treated independently in the one or two pre-specified target vessels with 
control PTA. The total length of treated lesions (in target vessels) should not exceed 320 mm (for 
consistency with the treatment length limitation in the test arm).  
Pre-dilated vessels that did not meet post-pre-dilatation criteria are not target vessels and are 
treated with PTA or per institutional standard practice and are excluded from endpoint analyses. 
 
6.6.2 TREATMENT WITH LUTONIX DCB (TEST) 
Please refer to the current Lutonix DCB IFU for detailed information on device use. 
The Lutonix DCB should extend at least 5 mm proximally and distally of the pre-dilated segment 
or the lesion (whichever is longer) in order to avoid geographic miss.  Care should be taken not 
to extend the entire injury segment unnecessarily. 
Multiple lesions may be treated independently in the one or two pre-specified target vessels with 
test devices.  Multiple DCBs may be used; each balloon may be used only once for adequate 
drug delivery to the vessel wall.  DCBs may be overlapped as necessary to ensure coverage of a 
pre-dilated injury segment or lesion without geographic miss.  The total length of the all DCBs 
used during the procedure is limited to 360 mm.  
 
6.7 POST-TREATMENT AND PROVISIONAL (BAILOUT) STENTING PROCEDURES 
The current trial design is intended to minimize the need for bailout stenting, and it is expected 
that stents will be used in < 5% of procedures.  Bailout stenting should only be performed if it is 
deemed that a stent is required in order to avoid surgical bypass or amputation after attempting 
prolonged balloon inflations and/or nitroglycerin.  
If bailout stenting is necessary, a bare metal (not drug eluting) stent must be used, since no data 
is available on potential drug interactions and the allowed treatments must be similar in both 
arms (the only difference being the as-randomized presence or absence of the drug coating). The 
physician should use the shortest stent possible to treat only the clinically necessary segment and 
not the entire target lesion.  Antiplatelet therapy should be prescribed per the stent 
manufacturer’s IFU.  
Data obtained from bailout stenting procedures will be analyzed as per the Statistical Analysis 
Plan. 
6.8 UNSCHEDULED ANGIOGRAPHY/REVASCULARIZATION 
A DUS should be performed prior to any subsequent angiography of the index limb below the 
knee vessels, and the images should be submitted to the DUS Core Lab.  Hemodynamic and 
clinical status should also be evaluated prior to angiography, including Rutherford classification, 
wound status (including collection of images, if applicable) and ABI and/or toe pressures. 
 

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All subsequent angiograms for the below the knee vessels (index limb only) should 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.  Treatment of any new non-target lesions is 
left to the discretion of the Investigator.  However, use of drug-device combination products (e.g. 
DES or DCB) is not recommended within 90 days of the index procedure.  
  
7 TREATMENT OF SUBJECT 
Lutonix (or its designee) reserves the right to attend index or follow-up procedures in order to 
ensure protocol compliance, proper device handling and adequate image capture.  
7.1 BLINDING PLAN 
In order to minimize the introduction of bias into the study, a pre-specified blinding plan has 
been developed.  The subject will remain blinded to the treatment until after completion of the 6 
month clinical visit. Members of the Clinical Events Committee (CEC) will be blinded to the 
subject’s treatment assignment.   
At scheduled follow-up visits or interim visits for evaluation of recurrent symptoms, the WIQ 
and EQ-5D should be completed by the Subject prior to the Investigator evaluation so as to 
provide the Investigator with patient input prior to the examination.  Blinding procedures will be 
reviewed at the time of each site initiation by a Sponsor representative.  Blinding procedures and 
instructions are as follows: 
 
 

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Time point 
Blinding Procedure 
Informed Consent/ 
Pre-Procedure 
During review of the study and the informed consent process with the 
patient, blinding procedures, timelines and rationale should be discussed 
with the subject and any care takers. 
Randomization 
Communication to the Investigator performing the procedure as to the 
randomized treatment should be done in such a way as to prevent the subject 
from overhearing which group they have been allocated to.  Hand signals, 
written codes, scripts or headphones can all be employed to ensure the 
subject remains blinded.  Each site must develop a system that best works 
with lab work flow.  
Post-Procedure 
It is important that recovery and hospital/clinic staff is educated to the 
protocol blinding requirements and that the subject and care taker are not 
inadvertently unblinded during the recovery period.  In addition, the medical 
record should clearly identify the subject as a study participant and the type 
of treatment should be kept confidential. 
Follow-up 
The WIQ and EQ-5D should be completed by the Subject prior to evaluation 
by the investigator.  The clinical status of the subject (for assessment of 
clinical and primary safety endpoints) should be established prior to 
performing the required DUS and angiography (for assessment of the 
primary efficacy endpoint). 
Unblinding 
A subject may not become unblinded prior to the completion of the 6 month 
follow up unless it should become medically necessary as determined by the 
investigator.   
7.2 MEDICATIONS 
Table 2 displays the suggested anticoagulation medication regimen for this study and is 
consistent with standard hospital practice for angioplasty procedures. All anti-platelet, anti-
coagulant, and cardiovascular related medications administered will be recorded in the subject’s 
medical record and the appropriate eCRF.  Anti-platelet therapy labeling and use vary by 
country; and approved treatments for the Investigational Sites’ geography should be followed. It 
is preferred that all subjects be treated with clopidogrel and aspirin for one month, followed by 
aspirin thereafter throughout the duration study. Prolonged dual antiplatelet therapy may be 
indicated for non-study reasons and is allowed at the investigators discretion.  For subjects on 
chronic Coumadin, it is not required for both aspirin and a P2Y12 inhibiter be continued for at 
least 1 month; per protocol and per standard of care, only a single agent (in addition to 
Coumadin) is sufficient once INR is therapeutic. In subjects ≥75 years of age and/or < 60kg, 
prasugrel is generally not recommended because of the increased risk of fatal and intracranial 
bleeding and uncertain benefit, except in high-risk situations (diabetes or history of prior MI) 
where its effect appears to be greater and its use may be considered.  Always refer to the current 
package insert. 
 

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TABLE 2 : SUGGESTED MEDICATION SCHEDULE 
Drug 
Pre-Procedure 
Procedure 
Post-Procedure* 
Aspirin 
75-325 mg/day 
NA 
75-100 mg/day indefinitely 
Clopidogrel 
OR 
 
Ticagrelor 
OR 
 
Prasugrel 
75 mg or 300 mg 
loading dose 
NA 
75 mg daily for at least 1 month 
180 mg loading 
dose 
NA 
90 mg BID 
10 mg/day or 
loading dose of 60 
mg 
NA 
for at least 1 month (discontinue with 
active bleeding) 
 >60 kg - 10 mg/day 
<60 kg - 5 mg/day** 
Anticoagulation 
Per Hospital Standard Practice 
     *For cases of provisional (bailout) stenting, refer to the Stent IFU for dosing instructions  
     **The effectiveness and safety of this dose has not been prospectively studied 
 
7.2.1 PRE-PROCEDURE 
If the subject is known to be receiving a stent for a non-target lesion (i.e. inflow lesion), it is 
suggested that 3 days before the intervention clopidogrel (75 mg per day) or prasugrel (10 mg 
per day) be prescribed.  The initial loading dose of clopidogrel or prasugrel should attempt to be 
started prior to the index procedure, but should occur no later than 2 hours after the completion 
of the index procedure. 
 
7.2.2 INTRA-PROCEDURE 
All subjects must receive adequate anticoagulation according to hospital standard practice.  
It is recommended that subjects that are already taking daily chronic aspirin therapy should 
receive a dose of 75-325 mg aspirin within 24 hours prior to the index procedure and those 
subjects not already taking daily chronic aspirin therapy should be given at least 300 mg aspirin 
at least 2 hours and preferably 24 hours before the procedure is performed. 
 
7.2.3 POST-PROCEDURE 
Approved vascular closure devices are allowed.  Dual anti-platelet medication should be 
prescribed for at least 1 month, unless a stent is placed, in which case anti-platelet therapy should 
be prescribed per the stent manufacturer’s IFU, or the subject is on chronic Coumadin, in which 
case one agent should be discontinued after the INR is therapeutic.  Updated guidelines will be 
implemented via note-to-file if changes in the recommended doses occur. 
 

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7.3 STANDARD TESTS, PROCEDURES, AND FOLLOW-UP 
Table 3 displays the required schedule for randomized subject treatment and evaluation.  This 
schedule is consistent with standard clinical care pre- and post-interventional procedures.  The 
times for each test are broad enough to fit into most hospital routine testing procedures.  
Subjects enrolled, but not randomized, and treated per standard practice will be followed for 
safety through 30 days. The 30 day follow-up visit can be performed as a telephone or clinical 
visit.  Duplex ultrasound imaging is not a protocol requirement for this group.  Details of each 
testing requirement can be found in the sections below.   
TABLE 3: FOLLOW-UP SCHEDULE AND TESTING REQUIREMENTS FOR RANDOMIZED SUBJECTS 
Event 
Screening 3 
/(pre-consent) 
Pre- 
Procedure 
Procedure 
Post- Procedure 
30 days 
6 Month 
12 Month 
24 Month 
36 Month 
Visit Window 
30 
days 
30 
days 
±2  
weeks 
±1  
month 
±1  
month 
±2  
month 
±2  
month 
Inclusion/Exclusion Criteria 
√ 
√ 
√ 
 
 
 
 
 
 
Informed Consent  
 
√ 
 
 
 
 
 
 
 
Medical History  
√ 
 
 
 
 
 
 
 
 
Physical Exam 
 
√ 
 
√ 
√ 
√ 
√ 
√ 
√ 
ABI-TBI1 
 
√ 
 
 
√ 
√ 
√ 
√ 
√ 
Rutherford Classification 
 
√ 
 
 
√ 
√ 
√ 
√ 
√ 
Pregnancy Test (blood or urine)2 
 
√ 
 
 
 
 
 
 
 
WIQ and EQ-5D  
Questionnaires 
 
√ 
 
 
√5 
√ 
√ 
√ 
√ 
Angiogram 
 
 
√ 
 
 
 
 
 
 
Adverse Event Monitoring 
 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Duplex Ultrasound (after clinical 
assessment) 
 
 
 
 
√ 
√ 
√ 
√ 
√ 
Wound Healing Assessment4 
 
√ 
 
 
√ 
√ 
√ 
√ 
√ 
1TBI in cohort where data is available. Resting ABI is required within 90 days of Index Procedure 
2Pre-procedure and females of childbearing potential only  
3Screening (pre-consent, to determine which patients to consent) must be based only on information available from 
the patient’s medical record or collected as part of standard hospital practice; any additional protocol-required 
assessments must be performed after signing Informed Consent Form. 
4Wound imaging (including collection of images, if applicable) 
5Only the WIQ is required at the 30 day time point 
 
At 6, 12, 24 and 36 month follow-up visits and interim visits, the clinical status of the subject 
(for assessment of clinical endpoints) should be established prior to performing the required 
DUS, and DUS should be performed prior to angiography. 

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7.3.1 TESTING 
7.3.1.1 PREGNANCY TEST 
A pregnancy test (blood or urine) must be done on females of child bearing potential pre-
procedure. 
7.3.1.2 ANKLE AND TOE SYSTOLIC PRESSURE AND BRACHIAL INDICES (ABI-TBI) 
Resting ABI/TBI measurements will be recorded on the appropriate study eCRF.  Resting ABI 
and TBI should be performed per local hospital standard, and consistently among subjects over 
the lifespan of the study.  Non-compressible vessel status will be recorded. PVR/Doppler 
waveforms or TcPO2 data may optionally be obtained.  Data will be recorded on the appropriate 
study eCRF.  If TBI cannot be conducted, it will not be considered a deviation. 
7.3.1.3 RUTHERFORD SCALE 
Rutherford classification can be measured with or without treadmill, but must be performed 
consistently among subjects over the lifespan of the study. Rutherford classification should be of 
the Index limb at baseline and follow-up procedures. 
7.3.1.4 WALKING IMPAIRMENT QUESTIONNAIRE 
The WIQ form will be completed at pre-procedure and at 30 days, 6, 12, 24 and 36 months. 
See Appendix C for the questionnaire form. 
7.3.1.5 QUALITY OF LIFE QUESTIONNAIRE 
The EQ-5D surveys will be completed at pre-procedure and at 6, 12, 24 and 36 months. 
See Appendix D for the questionnaire form. 
7.3.1.6 DUPLEX ULTRASOUND GUIDELINES 
The initial baseline DUS must be performed after the index procedure at the 30 day visit and 
again at 6, 12, 24 and 36 months.  Since DUS is critical to assessing study endpoints, the quality 
of this test is extremely important, and DUS should be performed prior to angiography (if 
necessary).  The Core Labs will be closely monitoring the quality of all incoming images for 
compliance.  Sites should ensure that only DUS operators who are trained on the DUS guidelines 
are performing these tests.  Refer to the Duplex Ultrasound Guidelines Manual of Operations for 
the most current version of the documentation requirements.  See Appendix H for detailed core 
lab guidelines. 
7.3.1.7 ANGIOGRAPHY GUIDELINES 
Initial baseline angiograms should be performed at the time of procedure.  All angiograms 
should be submitted to the core laboratory as soon after the case as possible.  Refer to the 
Angiography Guidelines Manual of Operations for the most current version of the documentation 
requirements.  See Appendix G for detailed core lab guidelines. 

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7.3.1.8 WOUND HEALING ASSESSMENT 
Wound healing assessments must be performed at the pre-procedure, 30 day, 6, 12, 24 and 36 
month clinical visits of the target limb.  Photographs of the wound must be taken to document 
wound healing progression at each clinical visit. 
Wound healing assessments will be recorded on the appropriate eCRF as healed (completely 
epithelialized), not healed, or amputated.  In addition, if the wound is not healed, wound 
progression will be recorded on the eCRF as improving, stagnant, or worsening and a photograph 
of any wounds must be taken and placed in the subject’s study chart for reference at each visit. 
Note: Sites must have a wound care process/program in place for patients participating in the 
study.  Follow-up wound care for patients can be conducted at the site’s affiliated wound care 
center or equivalent wound care facility.   
7.3.2 FOLLOW-UP PROCEDURES 
All randomized subjects will return for follow-up at 30 days, 6, 12, 24 and 36 months post-
procedure.  See Table 3 for required testing at each follow-up visit time point.  Refer to Section 
7.1 Blinding Plan for specifics on maintaining the blind during the follow-up visits.   
 
Subjects will be instructed to report adverse events to their study physician between evaluation 
visits. 
Anti-platelet, anti-coagulant, and cardiovascular medications will be recorded on the eCRF.  
Anti-platelet therapy compliance including dose, periods of interruption (and reason for 
interruption), and invasive procedures deterred due to the need to take anti-platelet therapy will 
also be recorded on the eCRF. 
 
8 ADVERSE EVENTS 
An adverse event (AE) is defined as any untoward medical occurrence in a subject.  This 
definition does not imply that there is a relationship between the adverse event and the device 
under investigation.  The following will be adjudicated by the CEC:   all stroke events, all Major 
Adverse Cardiovascular Events (MACE) which includes stroke, Myocardial Infarctions, and 
death (all cause), all target limb related events, and all device- and / or procedure-related AEs. 
See Appendix A for detailed AE definitions. 
8.1 ADVERSE EVENT REPORTING 
All adverse events occurring since the start of the study procedure must be recorded in the eCRF. 
All adverse events occurring in this study will be classified in accordance with the adverse event 
signs or symptoms.  Any Serious Adverse Event must be reported in the EDC within 5 working 
days of knowledge.  All adverse events must be reported to the IRB/EC per local requirements. 
 

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9 SUBJECT WITHDRAWAL CRITERIA 
Subjects can withdraw from the study at any time for any reason; the reason for withdrawal will 
be documented.  All data available at the time of withdrawal (if any) will be used for analysis. 
There will be no further follow-up (per this study protocol) on the subject who has withdrawn.  
Subjects who withdraw from the study will not be replaced, however loss-to-follow-up has been 
considered for sample size statistics. 
If a visit is missed, the site is required to document a minimum of three (3) attempts to contact 
the subject within the follow-up window.  If the subject only misses one protocol required visit, 
the site should repeat the three (3) attempts to contact the subject followed by a certified letter.  
When a subject misses two (2) consecutive follow-up visits with failure of all contact attempts, 
the subject may then be considered lost to follow up and exited from the study. 
 
10 DATA COLLECTION AND MONITORING 
10.1  DATA COLLECTION 
The Investigator (or designated hospital staff) will assure primary data collection based on 
source-documented hospital chart reviews.  These documents will be completed in an expedited 
fashion.  
 
10.1.1 ELECTRONIC CASE REPORT FORMS (ECRF) 
All required clinical data for this trial will be collected in web-based standardized eCRFs.  
Clinical trial data will be collected in accordance with the Guidance for Industry: Collection of 
Race and Ethnicity Data in Clinical Trials.  Subject personal information should be blinded.  Site 
numbers, subject numbers and initials (when allowed by local regulatory bodies) will be used to 
track subject information throughout the study. 
   
10.1.2 ANGIOGRAMS AND DUPLEX ULTRASOUNDS 
All core lab raw data will be sent to the independent Core Lab listed in the study summary.  This 
information will be documented on a study form and the data entered onto an eCRF.     
 
10.2  MONITORING 
A formal written Monitoring Plan will be developed in accordance to FDA guidelines 53 CFR 
4723 and the study protocol for this study.  Appropriately trained and qualified monitoring 
personnel will monitor the progress of this study.  Prior to protocol submission to the site, a 
formal Site Qualification Visit will be conducted by a Lutonix clinical employee or designee at 
sites who have not previously been involved in Lutonix-sponsored trials.  Visits are conducted to 
confirm the appropriate staff, experience, resources, equipment, and patient population exist for 
this protocol. 
Each site will have an initiation visit performed by a Study Monitor and a member of the Lutonix 
clinical staff.  This visit will ensure that the investigator understands his/her responsibility for 

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conducting this study at his/her center.  This includes, but is not limited to, device accountability, 
protocol compliance, informed consent process, enrolling appropriate subjects, and IRB/EC 
submissions, approvals, and continuing reviews. 
Sites will be monitored according to the approved Monitoring Plan.   
10.3  PROTOCOL DEVIATIONS 
The investigator will not deviate from the protocol without the prior written approval of the 
Sponsor except in medical emergencies or in unforeseen, isolated instances where minor changes 
are made that will not increase the patient’s risk or affect the validity of the trial. Continued 
deviations from the protocol could result in study termination.   
 
10.4  SOURCE DOCUMENTATION 
Medical IRB/ECs, the study Sponsor (Lutonix), the Sponsors designees (Clinical Research 
Organizations) and regulatory authorities may have access to the medical records related to this 
study.  Original or certified copies of all relevant clinical findings, observations, and other 
activities throughout the clinical investigation must be recorded and maintained in the medical 
file of each enrolled subject.  
The Investigator will permit study-related monitoring, audits, IRB/EC review and authority 
inspections by allowing direct access to the source data.  
 
10.5 RECORD RETENTION 
Lutonix and Investigator will maintain the following accurate, complete, and current records 
relating to the conduct of the investigation according to national requirements.  The data for 
some of these records may be available in computerized form from the CRO, but the final 
responsibility for maintaining study records remains with the Investigator.  These include: 
• 
All correspondence with another Investigator, an IRB/EC, a Core Laboratory, Lutonix, 
their designees, or regulatory agency, including required reports; 
• 
Records of receipt, use, or disposition of the investigational device, including receipt 
dates, serial and/or lot numbers, names of all persons who received or used the device, 
why and how many devices were returned to or otherwise disposed of.  Device 
reconciliation logs should be kept current and available to Lutonix and their designees 
upon request; 
• 
Records of each subject's case history, source documents, evidence of informed 
consent, all relevant observations of adverse study device effects, the condition of each 
subject upon entering and during the course of the investigation, relevant medical 
history, the results of all diagnostic testing, and the date of each study treatment; 
• 
Screening log and  study personnel visit log; 
• 
Any other records that the regulations require to be maintained. 

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10.6  STUDY PROCESSING 
10.6.1  COMMUNICATION 
During the course of the study, regular teleconference calls between Lutonix, the Study 
Monitor(s) and each clinical site (if necessary) may be conducted to resolve any problems 
concerning the protocol and data collection.  Every effort will be made to ensure compliance 
with the protocol.  
 
10.6.2 TRAINING 
The training of appropriate clinical site personnel and support staff will be the responsibility of 
Lutonix or their designee.  To ensure proper device usage, uniform data collection and protocol 
compliance, Lutonix or their designee will present a formal documented training session(s) to 
study site personnel which will include, but may not be limited to, the following: 
• Techniques for the identification of eligible subjects  
• Investigational Plan  
• Device Training 
• Core lab Instructions (angiographic and Doppler), as applicable  
• Instructions on study and adverse event data collection  
• Schedules for follow-up with the study site coordinators  
• Regulatory requirements  
Detailed feedback regarding completion of forms will be provided by Lutonix or designee, 
through regular site monitoring. 
 
11 DEVICE ACCOUNTABILITY 
All investigational Lutonix DCB Catheter must be stored in a locked storage facility to which 
only the Investigator and/or designated study staff will have access.  The Investigator is 
responsible for device accountability at the trial site.  The Investigator may assign the 
responsibility for the device accountability to an appropriate study staff member, but remains the 
final responsible person.  The Investigator must ensure that the device is used only in accordance 
with the protocol and current IFU.  The Investigator must maintain records that document device 
delivery to the trial site, the inventory at the site and administration to each subject.  These 
records must include dates, quantities, batch/serial numbers, expiration dates, and the unique 
code numbers assigned to the trial subjects.  The Investigator must maintain records that 
adequately document which device the subject received according to the protocol and the 
assigned randomization.  In the case where a device has failed, the Investigator must make every 
possible effort to return the device to Lutonix; Contact Lutonix for a return manufacturer 
authorization number (RMA #).   

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11.1 SUPPLY AND SUPPORT OF INVESTIGATIONAL DEVICE 
An investigational device supply will be made available to all study sites. The device matrix will 
include various diameter and lengths to accommodate the anatomy of the target population.  
Prior to the start of study enrollment, Lutonix or their designee will perform formal device 
training of study site personnel and support staff.  Each study site will receive a supply of the 
Lutonix DCB Catheters upon completion of the protocol requirements for study initiation.  
Additional training and support will be provided on an ongoing basis. 
For re-supply of Lutonix DCB Catheters, the site is to contact Lutonix or its designee. 
 
12 STUDY MANAGEMENT 
 
12.1 ADVISORY COMMITTEE 
The Advisory Committee (AC) will meet as needed by conference or teleconference to monitor 
enrollment, clinical site progress, and protocol compliance.  The specific tasks of the AC are to: 
• Act upon recommendations of the Data Monitoring Committee 
• Resolve problems in cooperation with the Clinical Trial Manager 
• Sole discretion for stopping or otherwise modifying the study based on clinical data 
collected 
• Provide publication policy 
The Advisory Committee may be comprised of representatives from Lutonix, the Principal 
Investigators, core lab directors and selected physicians representing Interventional Cardiology 
and Vascular Surgery specialties.   
12.2 DATA MONITORING COMMITTEE 
The Data Monitoring Committee (DMC) is responsible for the oversight and safety monitoring 
of the study.  The DMC advises the Sponsor regarding the continuing safety of the trial subjects 
and those yet to be recruited to the trial, as well as the continuing validity and scientific merit of 
the trial.  The DMC members are leading experts in peripheral vascular disease, cardiovascular 
medicine and biostatistics who are not participating in the trial and have no affiliation with 
Lutonix. 
During the enrollment phase of the trial, the DMC will review accumulating safety data to 
monitor for incidence of serious vascular events that would warrant modification or termination 
of the trial. 
The DMC will meet at regular intervals to review the safety data.  DMC responsibilities, 
membership, meeting frequencies, and procedures will be outlined in the DMC charter. 
12.3  CLINICAL EVENTS COMMITTEE 
The Clinical Events Committee (CEC) will consist of a minimum of three clinicians with 
expertise in vascular intervention and who are not participants in the study or members of the 

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SC.  The members of the CEC will be blinded to the subject’s treatment.  The CEC is charged 
with the development of specific criteria used for the categorization of clinical events and 
clinical endpoints in the study which are based on the protocol.  
At the onset of the trial, the CEC will establish explicit rules outlining the minimum amount of 
data required in order to classify a clinical event.  All members of the CEC will be blinded to the 
primary results of the trial.  The CEC will review and adjudicate the following events:  all stroke 
events, all Major Adverse Cardiovascular Events (MACE) which includes strokes, Myocardial 
Infarctions, and death (all cause), all target limb related events, , and all device- and / or procedure-
related AEs.  Reportable AEs do NOT include dissection (Grade A or B) which do not require 
intervention, because dissection is an expected outcome of the angioplasty procedure and will be 
reported by the angiography core lab based on the Grade A-F (National Heart, Lung, and Blood 
Institute Dissection Classification System).   
   
13 REGULATORY RESPONSIBILITIES 
13.1 IRB/EC APPROVAL 
Investigators must submit the study protocol to their IRB/EC and obtain written approval before 
being allowed to conduct and participate in the study.  Annual re-approval must also be obtained.  
The Investigator is also responsible for fulfilling any conditions of approval imposed by the 
IRB/EC, such as regular safety reporting, study timing, etc.  The Investigator will provide 
Lutonix or designee with copies of such approvals and reports. 
Any amendments to the protocol, as well as possible associated information and consent form 
changes, will be submitted to the IRB/EC and written approval obtained prior to implementation.  
13.2  REGULATORY APPROVAL 
In the USA an IDE application must be submitted to the FDA.  IDE approval must be received 
prior to the inclusion of the first US subject.  
In the EU, the study must be submitted to the Competent Authorities in each country in which 
the study is being conducted, according to the national requirements. Approval or a confirmation 
that the study may start from the applicable authority must be received prior to the inclusion of 
the first EU subject. In Japan, PMDA must review and approve the Clinical Trial Notification 
(CTN) prior to device shipment and enrollment of the first subject. 
13.3  INFORMED CONSENT 
Part of the IRB/EC approval must include approval of an Informed Consent Form (ICF) that is 
specific to the study and approved by the FDA and any other relevant regulatory bodies.  The 
Investigator must administer this approved ICF to each prospective study subject, and obtain the 
subject's signature on the ICF prior to enrollment in the study.  The ICF may be modified to suit 
the requirements of the individual site.  The Investigator will provide Lutonix or designee with a 

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copy of the approved ICF for his/her site.  Lutonix or designee must pre-approve each ICF prior 
to initial submission to the IRB/EC; major changes must be approved by the FDA. 
The study must be explained in a language that is understandable to the subject and he/she must 
be allowed sufficient time to decide whether to participate. All subjects will be assured that they 
have the right to withdraw from the study at any time during the course of the protocol and this 
decision will not influence his/her relationship with the Investigator (treating physician) and/or 
study staff.  
13.4  SELECTION OF CLINICAL SITES AND INVESTIGATORS 
Lutonix will select Investigators who are qualified and experienced to participate in the 
investigation of the study devices.  Sites will be selected based upon a review of a recent site 
assessment and the qualifications of the (primary) Investigator(s) at the site.  Investigators must 
submit a current curriculum vitae (CV) as part of the qualification process. 
All Investigators must be approved by the Sponsor prior to participation in the study. 
Any site that becomes deactivated by the Sponsor or by the individual site itself prior to first site 
enrollment will be replaced. 
Due to the potential for an imbalance in the randomization ratio from low enrolling sites, any site 
not able to enroll a subject within 2 months (60 days) of formal initiation may be replaced.  The 
Sponsor will proactively be tracking site-based enrollment throughout the study and may 
implement enrollment restrictions to assist in balanced enrollment across sites. 
13.5  INVESTIGATOR’S RESPONSIBILITIES 
Each Investigator is responsible for ensuring the investigation is conducted according to all 
signed agreements, the Investigational Plan and applicable laws and regulations.  The site 
Principal Investigator will select qualified co-investigators at each site and will maintain 
responsibility for oversight of all procedures and data collection.  All co-Investigators must be 
trained on all aspects of the protocol prior to enrolling and performing procedures.  All 
interventionalists performing procedures must be trained as co-investigators in the study. 
The Investigator may not begin enrollment or receive the initial shipment of the investigational 
devices until Lutonix or designee receives and approves (when necessary) the following 
minimum documents: 
• Complete Signed Investigator Agreement 
• Financial Disclosure Forms for all participating Investigators 
• IRB/EC Roster 
• IRB/EC Protocol and Informed Consent Approvals 
• Investigators’ and Co-Investigators' current curricula vitae (CV) 
• Laboratory Normal Values and Lab Certification 
• Site Signature and Responsibility Form 

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13.5.1 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. 
13.5.2 REPORTS 
Table 4 below displays a list of the reports that are the Investigator's responsibility to generate.  
The table also shows to whom the report is to be sent, and with what frequency or time 
constraints.  While some of these reports will be developed by or with the assistance of Lutonix 
or their designee, the final responsibility rests with the Investigator.  
 
TABLE 4: REPORTS REQUIRED FROM CLINICAL INVESTIGATORS 
Report Type 
Prepared  For: 
Time Constraints of Notification 
Subject death during 
investigation 
Lutonix/CRO/IRB/EC 
 
To Lutonix/CRO: in eCRF within 24 hours of 
knowledge. 
To IRB/EC: Written documentation of the event 
within 10 working days 
SAE 
Lutonix/CRO/IRB/EC Within 5 working days of knowledge and to 
IRB/EC per local reporting requirements 
UADE 
Lutonix/CRO/IRB/EC Within 24 hours 
Report of subject enrollment CRO 
By eCRF within 24 hours 
Subject withdrawal 
Lutonix/CRO 
 
By eCRF  within 5 working days 
Withdrawal of IRB/EC 
approval 
Lutonix/CRO 
Immediately by telephone followed by a copy of 
the notification within 5 working days 
Continuing IRB/EC re-
approval 
IRB/EC 
Prior to continuing review date. 
Progress report 
Lutonix/CRO/IRB/EC Submitted at regular intervals or annually 
Failure to obtain ICF 
Lutonix/CRO 
Within 5 working days 
Final summary report 
Lutonix/CRO 
Within 3 months 
    
13.6  LUTONIX RESPONSIBILITIES 
An Investigator Meeting and site initiation visit will occur with each study site in order to orient 
the Investigator and staff to information such as:  the investigational device, the Investigational 
Plan, applicable regulations and requirements, and expectations of the study, including the 
numbers and time frame for subject enrollment, subject selection, informed consent, required 
clinical data, and record keeping. 
Lutonix or designee (CRO) will maintain the following records: 
• All correspondence which pertains to the investigation 
• Signed Investigator Agreements/Compensation Agreements, and Curriculum Vitaes 
• Adverse effects and complaints 
• All Case Report Forms (signed by the Investigator) 

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• Investigational Plan 
• Qualification Visit Form 
• Monitoring Reports 
14 PUBLICATIONS 
The trial will be registered in the ClinicalTrials.gov website upon approval by a human subject 
review board of the appropriate national health authorities 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, approved by the Principal 
Investigator and the Steering Committee, will be submitted to a reputable scientific journal.   
Following the publication of the main manuscript, secondary analyses proposals will be 
considered for publication from either the Steering Committee members or individual 
Investigators.  No submissions may be made without the written approval from Lutonix.    
 
15 STATISTICAL ANALYSIS PLAN  
The Lutonix BTK Trial is a global, multi-center, randomized, controlled clinical trial comparing 
the Lutonix DCB Catheter to standard PTA for the treatment of stenosis or occlusion of below-
the-knee arteries.  The primary effectiveness will consider analyses of all vessels and proximal 
vessels only.  Up to 1000 subjects may be enrolled to obtain up to the maximum of 840 treated 
vessels at up to 75 global centers. The study sample size will be determined using a Bayesian 
decision making method that evaluates the predicted probability of a significant primary 
effectiveness result at the full planned sample size to assess futility and at the existing enrollment 
to assess if the current sample size provides sufficient power.  Assessment for predicted 
probability for futility and success will be performed when the 400 th, 500 th, 600 th, and 700 th 
vessels are treated.  If the study enrollment is not ended at the 700 vessel evaluation, the study 
will continue to enroll until 840 vessels are treated.  Subject randomization will be allocated 2:1 
Lutonix DCB (test arm) to standard PTA catheter (control arm) after successful pre-dilatation 
and all vessels within a subject will receive the same therapy.  US and non-US enrollment will be 
contemporaneously monitored throughout the study to ensure at least 50% of randomized 
subjects occur at US sites. 
Subjects are considered enrolled in the study after being consented and the defined pre-dilatation 
balloon inflation has begun.  Based on angiographic results after pre-dilatation, some subjects 
will not meet criteria for randomization, and these nonrandomized patients are followed only for 
safety and do not contribute to the required sample size of 840 treated vessels.  However, since 

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the patient underwent a protocol defined pre-dilatation, they are considered to be enrolled even 
though they are not randomized. 
Successful pre-dilatation is defined as operator determination that procedural success may be 
achievable using angioplasty alone, ≤50% residual stenosis of the target lesion, and 
reconstitution of the target vessel above the ankle with patent in-line flow from the target lesion 
to below-ankle outflow.  Subjects with a target vessel meeting these criteria are randomized.  
Subjects who do not meet post-pre-dilatation lesion success criteria are not randomized and are 
instead treated per hospital standard practice, followed for safety for 30 days, and then 
withdrawn.  Subjects who are enrolled and randomized will be followed clinically for 6 months 
to assess the primary efficacy endpoint with further follow-up extending out to 3 years. 
The primary analysis is based on a repeated-measures logistic model of vessel success that 
includes treatment and a subject random effect using available data from all randomized subjects 
on an intent-to-treat basis. Safety endpoints are assessed per subject and efficacy endpoints per 
target vessel. For the study to be considered successful, superiority of Lutonix DCB Catheter 
must be demonstrated for the primary efficacy endpoint, non-inferiority of the Lutonix DCB 
Catheter must be demonstrated for the primary safety endpoint, and Lutonix DCB Catheter must 
meet the performance goal of the powered secondary safety endpoint.  Secondary time-to-event 
analyses will also be conducted. 
As the study includes interim assessments of the sample size, the primary effectiveness analysis 
includes an adjustment to the significance level used in the final analysis in order to maintain the 
overall Type I error level of the study.  Section 15.3.2 provides details of the primary 
effectiveness analysis.  Appendix J provides complete details on the operating characteristics of 
the adaptive study design.   
 
15.1  ASSESSMENT OF COMPARABILITY OF TREATMENT GROUPS AND 
POOLABILITY OF SITES AND SECONDARY ANALYSES 
To demonstrate the comparability of the Control to Test subjects, the samples will be compared 
using t-tests or nonparametric Wilcoxon rank sum tests for means and X2-tests for proportions: 
age, gender, smoking, obesity, dyslipidemia, hypercholesterolemia, hypertension, diabetes 
mellitus, vessels treated, total target lesion length and maximum percent stenosis of the target 
lesion (via core lab analysis), previous target lesion intervention, target limb hemodynamics, and 
Rutherford grade.   
All primary endpoints will also be presented by site, and the sites will be tested for differences in 
the endpoints.  Sites with 3 or fewer randomized subjects will be combined for this purpose.     
An analysis will be performed to examine the potential for interaction of site and treatment 
group.  A mixed effects logistic regression model will be fit that includes a fixed effect for 
treatment group, and random effects for individual, site, and the interaction of treatment group 

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and site.  If the p-value for the interaction term variance component is <0.15, it will be 
considered evidence of a statistically significant interaction effect, and additional analyses will 
be performed to explore the differences between sites to assess their potential causes and whether 
or not they are clinically meaningful.  The random effect for individuals will accommodate the 
potential for correlation between observations for subjects with two treated pathways. 
All primary endpoints will also be presented by geography (US versus OUS).  An analysis will 
be performed to examine the potential for interaction of geography and treatment group.  A 
logistic regression model will be fit that includes fixed effects for treatment group, geography, 
and the interaction of treatment group and geography.  If the p-value for the interaction term is 
<0.15, it will be considered evidence of a statistically significant interaction effect, and 
additional analyses will be performed to explore the differences between geographies to assess 
their potential causes and whether or not they are clinically meaningful.  The model will also 
include a random effect for individual to accommodate the potential for correlation between 
observations for subjects with two treated pathways. 
In addition, a descriptive analysis that examines the impact of important covariates on study 
results will be performed. Baseline covariates include age, gender, smoking, obesity, 
dyslipidemia, hypertension, diabetes mellitus, vessels treated, total target lesion length, and 
maximum percent stenosis of the target lesion (via core lab analysis), previous target lesion 
intervention, target limb hemodynamics, and Rutherford grade.  A binary assessment of target 
limb hemodynamics will also include an evaluation of whether the subject had an ankle pressure 
≤ 70 mm Hg, toe pressure ≤ 50 mg, TCP02 ≤ 50, or non-pulsatile metatarsal/toe PVR are 
document.  These covariates at a minimum will be included along with treatment group in a 
logistic regression model in order to understand their potential impact on study results and to 
account for chance imbalances between the randomized groups. 
To assess the consistency of results under different analyses, secondary as-treated (AT) and per-
protocol (PP) analyses may be performed for the primary and secondary endpoints.  The AT 
dataset will include only those subjects treated with either an investigational or control device, 
and the comparison will be based on the actual device used, not randomized assignment.  The PP 
dataset will include all randomized subjects that are characterized by appropriate exposure to 
treatment (procedurally correct as pre-specified), and the absence of major protocol violations 
including violations of entry criteria.  An additional supportive analysis of patients with and 
without bailout stenting will also be performed based on descriptive statistics, and data will 
further be presented for PP analysis of subjects with and without bailout stenting. It is expected 
that 5% or less of randomized subjects will receive a bail-out stent. 
15.2   HANDLING OF MISSING DATA 
Endpoints may be missing because subjects have died, have un-interpretable imaging data or 
have withdrawn from the study prior to the time the endpoint is measured.  The reason for the 
censoring of all subjects with missing endpoints will be reported. A tipping-point analysis will be 

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performed for each primary endpoint, in addition to the standard analysis, in which assumptions 
about missing data are varied from worst-case to best-case to examine at what point the missing 
data would alter the results of the analysis.  In addition, a multiple imputation analysis will be 
performed using available results and baseline variables identified for the assessment of 
poolability in Section 15.1.  This set of analyses will constitute sensitivity analyses of the effect 
of missing data on the study results. 
Secondary analyses will also be conducted using survival analysis techniques (Kaplan-Meier 
estimates), wherein unobserved endpoints are a standard part of the analysis; they are known as 
“censored observations”.  As long as the censoring is unrelated to the treatment, this method of 
handling missing endpoints produces unbiased estimates of the freedom-from-event rates. 
15.3   PRIMARY ENDPOINTS 
Primary Safety Endpoint 
The primary safety endpoint is a composite of freedom from BTK MALE + POD at 30 Days. 
This is defined as freedom from the composite of all-cause death, above-ankle amputation or 
major reintervention (new bypass graft, jump/interposition graft revision, or 
thrombectomy/thrombolysis) of the index limb involving a below-the-knee artery. These events 
are called “safety events” in the following text.  
Primary Efficacy Endpoint 
The primary efficacy endpoint is a composite of limb salvage and primary patency at 6 Months. 
This is defined as freedom from the composite of above ankle amputation, target lesion 
occlusion, and clinically-driven target lesion reintervention. These events are called “efficacy 
events” in the following text. 
 
15.3.1   PRIMARY SAFETY ENDPOINT: BACKGROUND CONSIDERATIONS & OUTCOME 
EXPECTATIONS 
 
Standard of care is surgical bypass or percutaneous transluminal angioplasty (PTA), and a 
difference between arms cannot be expected at the early time point of 30 days.  
 
Two recent meta-analyses10,11 report 30 day data for elements of the composite safety endpoint 
(“safety events”).  Conte et al. reported 2.8% deaths and 6.1% MALE.  It is unknown how much 
subject overlap there may be in these endpoints (cumulatively 8.9%, if none). Similarly, Romiti 
et al. reported 6.6% amputations and 1.8% death within 30 days along with 37/1743 = 2.1% 
thromboses and 17/1743 = 0.98% emboli. It is unknown how much subject overlap there may be 
in these endpoints (cumulatively 11.5%, if none); also reported were 22/1743 = 1.3% non-
amputation surgeries. Both meta-analyses demonstrate a similar failure rate ≤ 9 to 11%. As an 
estimate accounting for subject overlap, a 9% incidence of safety events is assumed for the 
purpose of power calculations.  

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15.3.2 PRIMARY SAFETY ENDPOINT:  HYPOTHESES AND SAMPLE SIZE CALCULATION 
Objective:  To assess whether the proportion of subjects free from any safety event* in the Test 
group is inferior or not inferior to that of Control group through 30-days post-index procedure. 
H0: The proportion of subjects free from safety events in the Test group through 30-days 
post-index procedure is clinically inferior to that of the Control group.  
H1: The proportion of subjects free from safety events in the Test group through 30-days 
post-index procedure is clinically non-inferior to that of the Control group. 
H0: φCONTROL  – φTEST  ≥       vs.    H1: φCONTROL  – φTEST < ** 
*All-cause death, above-ankle amputation, or major reintervention (new bypass graft, 
jump/interposition graft revision, or thrombectomy/thrombolysis) of the index limb involving a 
below-the-knee artery are safety events. **δ is the margin of noninferiority. 
The statistical analysis will be a Farrington & Manning test for non-inferiority of proportions; the 
test will be a one-sided test at α=0.025.  The response variable in each subject will be the 
presence or absence of at least one safety event from the time following the index procedure 
through 30-days.  The primary analysis will be the dataset of all randomized subjects ITT based 
on either all subjects and subjects with one or more proximal vessel as indicated by the primary 
effectiveness analysis outcome (refer to Section 15.3.4), and a significant rejection of the null 
hypothesis with one-sided p-value less than 0.025 indicates success for this endpoint.  In addition 
to the primary analysis, secondary as-treated analyses and per-protocol analyses will also be 
reported. 
The proportions at 30-days post-index procedure, and the confidence intervals of these rates in 
each group, will also be reported. 
Sample Size Estimate:  The sample size estimate assumed the following: 
• The true 30-days proportion in the Test group is 100% - 9% = 91%.  The true 30-days 
proportion in the Control group is 100% - 9% = 91%. 
• A 2:1 randomization ratio. 
• Farrington & Manning test for non-inferiority of proportions. 
• The Type 1 error,  = 0.025 (one-sided). 
• The Type 2 error,  = 0.10 (Power = 1 -  = 90%). 
• The non-inferiority margin, δ= 0.12. 
• Subjects who are censored without having an event will be omitted from the analysis. 
 
According to PASS 2008 (using the Farrington and Manning test for non-inferiority of 
proportions), the evaluable sample size required for 90% power is 254 (85 Control plus 169 
Test).   

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Based on the minimum study sample size of 400 treated vessels and assuming 1.15 vessels per 
subject, the study should include approximately 350 subjects.   Allowing for 10% drop-out, the 
study is expected to provide at least 313 evaluable subjects and will provide more than 90% 
power.  Hence the safety endpoint is not a driver of the sample size of the study. 
 
15.3.3   PRIMARY EFFICACY ENDPOINT: BACKGROUND CONSIDERATIONS & OUTCOME 
EXPECTATIONS 
Although the unmet clinical need is significant, there is little data from well-designed, 
randomized, controlled studies that compare the outcomes of different treatment modalities. The 
primary efficacy endpoint is a composite of limb salvage and primary patency at 6 months, 
defined as freedom from the composite of above ankle amputation, target lesion occlusion, and 
clinically-driven target lesion reintervention.  
Standard of care is surgical bypass or PTA.  For PTA recent meta-analyses10 report 6 month limb 
salvage rates of 88.2% and overall 6 month survival rates of 92.3%. Since Rutherford Class 6 
patients are excluded in the present study, a slightly lower amputation rate of 10% is assumed for 
both arms. 
 
One or two flow pathways are allowed as target vessel(s); i.e., peroneal or posterior tibial arteries 
may involve tibioperoneal trunk lesions and tibial arteries may involve popliteal lesions. 
Multiple lesions in up to two target vessels may be treated. All target vessels are identified prior 
to randomization. Failure of efficacy requires amputation or total occlusion (no flow through the 
flow pathway), independent of the number of target lesions, and therefore the sample size for 
testing of the efficacy endpoint is the number of treated vessels. If an upstream treated segment 
included in two otherwise distinct flow pathways fails (e.g., the treated popliteal artery fails in a 
subject with both AT and PT as treated target vessels), then at least one target vessel fails. Both 
target vessels fail if neither of the two distal branches (e.g., the AT or PT) can be demonstrated 
to be open. However, if one or both distal branches are demonstrated to be open (e.g., the AT or 
PT are open, filled by collaterals around an occluded popliteal), then only a single target vessel 
(1 of 2) is considered to have failed for purposes of efficacy endpoint analyses.  Doppler-
demonstrated antegrade flow through the target vessel is considered a patency and primary 
efficacy endpoint success (in subjects without an amputation or clinically-driven TLR), even if 
angiography was refused.  
Preliminary randomized and registry data has been reported for another manufacturer’s DCB 
(Medtronic/Invatec’s Amphirion In.Pact). In the DEBATE BTK study, n = 92 subjects were 
randomized to DCB or PTA16. Multiple infrapopliteal vessels were treated in 28% (26/92) of 
subjects (118 infrapopliteal lesions in 92 subjects), with concomitant treatment of inflow vessels 
(SFA in 33% and popliteal in 18%).  After 12 months, there were no major amputations in either 
arm; deaths included 7% (3/44) for DCB vs. 10% (5/49) for control, and the re-occlusion rate 
was 16% for DCB vs. 52% for control PTA. Consecutive Leipzig registries19,20 demonstrate a 

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similar benefit for single-arm, open-label DCB over historic PTA, with 3 month angiographic 
occlusion rate of 9.5% for DCB (n = 104) compared to 37.6% for control PTA (n = 50).  
A beneficial treatment effect difference of 36% at 1 year was observed in the randomized study, 
and a difference of 28% at 3 months was observed in consecutive registries.  
In the LEVANT 2 randomized study (pivotal study for the Lutonix DCB in SFA), the observed 
primary patency rate was 81.2% (DCB test) vs. 64.8%% (PTA control) at 6 months for beneficial 
treatment effect difference of 16.4%. 
Given that the Lutonix DCB with the same Lutonix drug coating is used in this trial as was used 
in the LEVANT 2 study, the treatment effect of at least 15% benefit for test DCB is assumed for 
the difference in total occlusion rate for the purpose of power calculations. 
Together with the 10% expected amputation rate, the expected composite primary endpoint 
success rate 55% for test DCB and 40% for control is assumed for power calculations.  
15.3.4 PRIMARY EFFICACY ENDPOINT: HYPOTHESIS AND SAMPLE SIZE 
 
Objective:  To assess whether the proportion of target vessels free from any efficacy event* in the 
Control group is less than or not to that of the Test group through 6-months post-index procedure.   
The primary effectiveness analysis will be performed in a staged fashion by evaluating all vessels 
for significance and, if that does not reach significance, then the analysis will be completed for 
only proximal vessels.  The  levels for the overall and proximal vessels analyses have been 
adjusted to ensure the overall study preserves a one-sided Type I error rate of less than or equal to 
0.025.  The study will be considered to have demonstrated effectiveness for all subjects if the all 
vessels analysis reaches significance and for proximal vessels in the event only the proximal vessel 
analysis reaches the significance level.   
For each analysis, all vessels and proximal vessels, the treatment effect will be estimated via a 
repeated measures logistic regression model, with random effects to account for correlation 
within subjects. The logistic regression model takes the form:  
 
log (
𝑝𝑖𝑗
1−𝑝𝑖𝑗) = 𝛼+ 𝛾𝑖+ 𝛽𝑡𝑖𝑗 (1) 
 
𝑋𝑖𝑗~Bern(𝑝𝑖𝑗) 
 where 𝑋𝑖𝑗 is a Bernoulli random variable for 6-month success (1=success, 0=failure) for patient 
𝑖 and vessel 𝑗 (𝑗= 1,2); 𝑝𝑖𝑗 is the failure-free (success) rate for patient 𝑖 and vessel 𝑗; 𝛼 is the log 
odds of success (failure-free) for patients in the control group; 𝛽 is the increment in log odds of 
success for patients in the treatment group; 𝑡𝑖𝑗 is an indicator variable equal to 1 if in treatment 
group and 0 if in control group; and 𝛾𝑖~𝑁(0, 𝜏) is a random intercept for patient 𝑖 that follows a 

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normal distribution with mean 0 and variance 𝜏. The parameter 𝜏 represents the between-subject 
variance of response. The model is fitted using restricted maximum likelihood methods (REML); 
hence the primary analysis is not Bayesian and does not depend on any prior distributions.  
The hypothesis test for superiority is the following: 
 
𝐻0:  𝛽≤0 
(2) 
 
𝐻1:  𝛽> 0 
The experimental treatment will be determined superior to control if the one-sided p-value of the 
above hypothesis is less than or equal to 0.0085.  This cut-off will be applied to the all vessels 
analysis and, if that is not significant, the cut-off will be applied to the proximal vessel populatoin. 
The cut-off of 0.0085 is selected to control the overall Type I error of the adaptive design below 
0.025 under the trial’s design assumptions as well as planned sensitivities to those assumptions, as 
detailed in Appendix J. 
This analysis will be based on an ITT population with available results.  Sensitivity analyses are 
included in Section 15.2 above. 
In addition to the primary analysis, secondary as-treated analyses and per-protocol analyses will 
also be reported but may not be the basis of labeling claims. 
The proportions at 6-months post-index procedure, and the confidence intervals of these rates in 
each group, will also be reported. 
The sample size was selected based on simulation work that demonstrated that a maximum 
possible sample size of 840 treated vessels and prevalence rates of proximal vessels of 55%, 
70%, and 80%.  The analysis approach provides power of at least 0.902 at the assumed response 
rates of 40.0% in the PTA arm and 55% in the DCB arm allowing for 15% drop-out depending 
upon the rate of proximal vessels.  If the PTA and DCB rates are both 40%, then the design 
achieves a power of no more than 0.0236 and an average sample of no more than 542 vessels 
allowing for 15% drop-out depending upon the prevalence rate of proximal vessels.  Hence, the 
design preserves the study-wide 0.025 one-sided Type I error rate for the staged effectiveness 
analyses of all vessels and proximal vessels only. Additional calculations for power and Type I 
error for various scenarios are provided via simulation in Appendix J. 
15.4 INTERIM ANALYSIS 
Interim evaluations will be performed at the time 400, 500, 600, and 700 vessels have been 
treated.  A Bayesian decision process will be used to adjust the finalize sample size for the study.  
At each interim analysis, the study will either continue to enroll subjects or enrollment will be 
considered complete.    If the study is not complete at the 700 vessel interim analysis, the study 
will enroll the full 840 vessels.   The study analysis of results will be performed once the all of 
the enrolled subjects has completed their 6 month assessment.  The sole objective of the interim 
evaluation is to identify the study sample size.   
 

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Interim analyses will evaluate for predictive probability (based on current enrollment) and 
futility (based on full sample size enrollment of 840) for superiority for effectiveness in the 1) all 
vessels population or 2) subgroup of proximal vessel population (see Figure 6 for definition of 
proximal vessel).  Interim decision rules based on these analyses are the following: 
1. If predictive probability for success is shown to be greater than 0.9 for either the all 
vessels population or the proximal vessel subgroup, the accrual is stopped and full 
follow-up will be observed and final analysis for success will take place (all vessels 
analysis, followed by proximal vessels analysis if all vessels analysis does not meet success 
criteria). 
2. If futility (predictive probability < 0.01) is shown for both the all vessels population and 
the proximal vessel subgroup, then accrual is stopped for futility. 
3. If futility is shown for the all vessels population but not for the proximal vessel subgroup, 
enrollment continues for the proximal vessel population only for any future next interim 
analysis. This is referred to as the ‘proximal vessel only’ arm of the trial.  All subsequent 
interims and final analysis will only evaluate hypothesis corresponding to the proximal 
vessel population only. 
4. If none of the above criteria are met, the trial continues enrolling to the next interim 
analysis or the maximum sample size of 840.  If the maximum sample size of 840 vessels 
is enrolled then the defined primary analysis (all vessels analysis, followed by proximal 
vessels analysis if all vessels analysis does not meet success criteria) occurs 6 months 
after the 840th vessel is enrolled. 
 
This approach is detailed in Appendix J. 
 
15.5  ADDITIONAL ANALYSES 
To assess the consistency of results under different analyses, secondary as-treated (AT) and per-
protocol (PP) analyses will be performed for the primary and secondary endpoints.  The AT 
dataset will include only those subjects treated with either an investigational or control device, 
and the comparison will be based on the actual device used, not randomized assignment.  The PP 
dataset will include all subjects in the full analysis dataset that are characterized by appropriate 
exposure to treatment (procedurally correct as pre-specified), availability of measurements, and 
the absence of major protocol violations including violations of entry criteria.  An additional 
supportive analysis of patients with and without bailout stenting will also be performed based on 
descriptive statistics, and data will further be presented for PP analysis of subjects with and 
without bailout stenting. It is expected that 5% or less of randomized subjects will receive a bail-
out stent. 
In addition to the primary proportion based analyses, secondary time-to-event analyses will also be 
conducted. 
 
15.6   OTHER SECONDARY ENDPOINTS WITH HYPOTHESIS TESTING  
The following secondary endpoints will be evaluated with hypothesis tests.  To control for 
multiplicity, no secondary endpoints will be tested unless both primary objectives and the 
powered secondary performance goal objective are successful. The testing of the following 

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secondary objectives will be performed in a hierarchical fashion in the order in which they are 
listed below.  This means that as soon as a null hypothesis is not rejected, no further hypotheses 
will be tested.  This hierarchical testing scheme ensures that the study-wide Type 1 error rate is 
0.05 when all of the secondary endpoints are tested at α = 0.05.  The secondary analysis will only 
be tested in all vessels or all proximal vessels depending upon the outcome of the primary 
effectiveness analysis. 
 
15.6.1 SECONDARY ENDPOINT:  PRIMARY PATENCY WITH EXCLUSION OF EARLY MECHANICAL 
RECOIL AT 6 MONTHS 
Objective: To assess whether the Primary Patency rate with exclusion of early mechanical recoil 
(the proportion of target vessels free from both clinically-driven TLR and total occlusion by 
DUS events > 30 days) in the Test arm is greater than in the Control arm through 6 months post 
the index procedure. 
H0: The proportion of target vessels with primary patency with exclusion of early 
mechanical recoil in the Test group through 6-months post-index procedure is equal 
to or less than in the Test group. 
H1: The proportion of target vessels with primary patency with exclusion of early 
mechanical recoil in the Test group through 6-months post-index procedure is 
greater than in the Control group. 
H0: P1TEST ≤  P1CONTROL    vs.    H1: P1TEST > P1CONTROL 
The statistical analysis will be a repeated measures logistic model evaluating the treatment and 
included subject as a repeated effect with a compound symmetry covariance structure; the test 
will be a one-sided test at α=0.05.  The response variable for each target vessel will be the 
presence or absence of any clinically-driven TLR or total occlusion (or both) events > 30 days 
through 6 months.     
The proportions at 6-months post-index procedure, and the confidence intervals of these rates in 
each group, will be reported. 
 
15.6.2 SECONDARY ENDPOINT:  PRIMARY PATENCY AT 6 MONTHS 
Objective: To assess whether the Primary Patency rate (the proportion of target vessels free from 
both clinically-driven TLR and total occlusion by DUS) in the Test arm is greater than in the 
Control arm through 6 months post the index procedure. 
H0: The proportion of target vessels with primary patency in the Test group through 6-
months post-index procedure is equal to or less than in the Test group. 
H1: The proportion of target vessels with primary patency in the Test group through 6-
months post-index procedure is greater than in the Control group. 
H0: P2TEST ≤  P2CONTROL    vs.    H1: P2TEST > P2CONTROL 
The statistical analysis will be a repeated measures logistic model evaluating the treatment and 
included subject as a repeated effect with a compound symmetry covariance structure; the test 

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will be a one-sided test at α=0.05.  The response variable for each target vessel will be the 
presence or absence of any clinically-driven TLR or total occlusion (or both) through 6 months.     
The proportions at 6-months post-index procedure, and the confidence intervals of these rates in 
each group, will be reported. 
 
15.6.3 SECONDARY ENDPOINT:  CLINICALLY-DRIVEN TLR AT 6 MONTHS 
Objective:  To assess whether the proportion of target vessels with a clinically-driven TLR in the 
Control group is greater than that in the Test group through 6-months post-index procedure. 
H0: The proportion of target vessels with a clinically-driven TLR in the Control group 
through 6-months post-index procedure is less than or equal to that of the Test 
group. 
H1: The proportion of target vessels with a TLR in the Control group through 6-months 
post-index procedure is greater than that of the Test group. 
H0: P3CONTROL ≤ P3TEST       vs.    H1: P3CONTROL >  P3TEST 
The statistical analysis will be a repeated measures logistic model evaluating the treatment and 
included subject as a repeated effect with a compound symmetry covariance structure; the test 
will be a one-sided test at α=0.05.  The response variable for each target vessel will be the 
presence or absence of a clinically-driven TLR by 6 months.     
The proportions at 6-months post-index procedure, and the confidence intervals of these rates in 
each group, will be reported. 
 
15.6.4 SECONDARY ENDPOINT:  COMPOSITE EVENTS AT 6 MONTHS 
Objective:  To assess whether the proportion of subjects free from a “composite event” in the 
index limb is higher in the Test group than in the Control group at 6 months. A “composite 
event” is defined as an above-ankle amputation, unhealed wound, ischemic rest pain, target 
vessel occlusion, and clinically-driven TVR.   
H0: The proportion of subjects free from any “composite event” in the Test group at 6-
months is equal to or lower than that in the Control group.  
H1: The proportion of subjects free from any “composite event” in the Test group at 6-
months is higher than that in the Control group. 
H0: P4TEST ≤  P4CONTROL    vs.    H1: P4TEST > P4CONTROL 
The statistical analysis will be a Z-test for binomial proportions; the test will be a one-sided test 
at α=0.05.  The response variable for each target vessel will be the presence or absence of a 
“composite event” at 6 months.  
For clarity, any above-ankle amputation, target vessel occlusion, and clinically-driven TVR are 
counted as a “composite event” whether it occurred prior to or during the 6-month follow-up 

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window, while unhealed wound and ischemic rest pain are as-assessed at the 6 month clinical 
follow-up visit. I.e., an unhealed wound at a 1 month clinical follow-up visit that is healed 
(completely epithelialized) at 6 months is NOT counted as a “composite event” at 6 months. 
Subjects without 6-month clinical follow-up are censored.    
The proportions at 6-months post-index procedure, and the confidence intervals of these rates in 
each group, will be reported. 
 
15.7 SECONDARY ENDPOINTS WITH DESCRIPTIVE STATISTICS 
The following secondary endpoints will have descriptive statistics estimated.  For each endpoint, 
the estimated mean and standard deviation or proportion and sample size will be calculated and 
reported for the Control group and for the Test group.  Any target pathway or vessel based 
analysis will be completed with repeated measures models adjusted for the potential for repeated 
observations within a subject.  (NOTE:  Some of these endpoints are also tested endpoints; these 
were presented above).  In addition to the primary analysis based on all randomized subjects, 
descriptive statistics will also be estimated for the primary endpoints and for each of the 
following secondary endpoints based on as-treated (AT) and per-protocol (PP) analyses.  In 
addition, descriptive statistics will also be estimated for the subsets of subjects with and without 
bailout stenting and for patients in the PP dataset with and without bailout stenting. 
• Device (able to deliver, inflate and retrieve), Technical (device success and < 50% residual 
stenosis) and Procedural Success (restoration of at least 1 infrapopliteal artery with residual 
stenosis < 50% and inline outflow to the foot) 
• Comparison of the BTK MALE+POD rate in the test arm to a performance goal of 15% at 30 
Days (e.g. null hypothesis is that event rate is greater than or equal to 15%) 
• Change in quality of life at 6, 12, 24, and 36 months from baseline, as measured by EQ-5D 
survey 
Late lumen loss at 12 months (cohort with angiography) 
 
The following endpoints will be assessed at 30 days and at 6, 12, 24, and 36 months: 
• Wound healing (healed or not; if not, improving, stagnant, worsening)     
• New or recurrent lesion 
• Change in Rutherford Class  
• Composite of freedom from the following in the index limb: 
Above-ankle amputation, unhealed wound, ischemic rest pain, target vessel occlusion, 
and clinically-driven TVR  
• Primary Patency (freedom from occlusion without clinically-driven TLR)  
• Primary Patency with exclusion of early mechanical recoil (freedom from occlusion without 
clinically-driven TLR events > 30 days) 
• Secondary Patency (not occluded, irrespective of TLR) 
• Composite of freedom from clinically-driven TLR and from 50% DS by angiography/DUS 

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• Hemodynamic outcome (change in toe & ankle pressures)  
•   Change in Walking Impairment Questionnaire (improvement from baseline) 
 
The following endpoints will be assessed at 30 days and at 6, 12, 24, and 36 months: 
• Clinically-driven TLR (all randomized subjects and in AFS cohort) 
• Total TLR (all randomized subjects and in AFS cohort) 
• Clinically-driven TVR (all randomized subjects and in AFS cohort) 
• Total TVR (all randomized subjects and in AFS cohort) 
• Limb salvage in surviving subjects 
• Unplanned minor below ankle amputation (including digit)  
• Overall burden of BTK index-limb reinterventions (total number of index limb BTK 
interventions incurred, all randomized subjects and AFS cohort) 
• Composite of POD, index limb-related death, below-the-knee reinterventions or major 
amputation of the index-limb  
• SVS CLI Endpoint Definitions ( (3) Conte 2009 JVS 50:1462-73)  
▪ MALE: Major adverse Limb Event: Above ankle amputation of the index limb or 
major reintervention (new bypass graft, jump/interposition graft revision, or 
thrombectomy/thrombolysis) 
▪ MALE+POD: Perioperative death (30days), or any MALE 
▪ MACE: Major Adverse Cardiovascular Event: MI, stroke or death (any cause) 
▪ Amputation (Major): Above ankle amputation of the index limb 
▪ AFS: Amputation free survival (freedom from above ankle amputation of the index 
limb or death (any cause)) 
▪ RAO: Any reintervention or above ankle amputation of the index limb. 
▪ RAS: Any reintervention, above ankle amputation of the index limb, or stenosis 
▪ DEATH: Death (any cause) 
 
 

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16 APPENDIX A:  DEFINITIONS 
 
Adverse Event 
An adverse event (AE) is defined as any untoward medical occurrence in a subject.  This 
definition does not imply that there is a relationship between the adverse event and the device 
under investigation.   
Adverse Device Effect  
An adverse device effect is any untoward and unintended response to a medical device.  This 
definition includes any event resulting from insufficiencies or inadequacies in the instructions for 
use for preparation or deployment of the device.  It also includes any event that is a result of a 
user error. 
Anticipated Adverse Event  
Any undesirable health related experience occurring to a subject whether or not considered 
related to the investigational product(s) or drug regimen prescribed as part of the protocol, 
predefined in the protocol and/or Instructions For Use (IFU) that is identified or worsens during 
a clinical study. 
Serious Adverse Event (SAE)  
An SAE is an adverse event with one of the following outcomes:  
• Death 
• Life-threatening 
o The patient was at substantial risk of dying at the time of the adverse event. 
• Hospitalization (initial or prolonged) 
o Admission to the hospital or prolongation of hospitalization was a result of the 
adverse event. 
• Disability or Permanent Damage 
o The adverse event resulted in a significant, persistent or permanent change, 
impairment, damage or disruption in the patient's body function/structure, 
physical activities and/or quality of life. 
• Required Intervention to Prevent Permanent Impairment or Damage  
• Medical or surgical intervention was necessary to preclude permanent impairment of 
a body function, or prevent permanent damage to a body structure, either situation 
suspected to be due to the use of the Investigational Device 
 
Serious Adverse Device Effect (SADE) 
An untoward medical occurrence that happens in a subject, is related to the investigational 
device, and is serious, but is not unanticipated. Untoward medical occurrences that are not 

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unanticipated are identified in the Investigator’s Brochure, Protocol, and Informed Consent Form 
(ICF). 
 
Unanticipated Adverse Device Effect (UADE) 
An untoward medical occurrence that happens in a subject, is related to the investigational 
device, and is serious, and is not listed in the Investigator’s Brochure, Protocol and ICF. 
 
Adverse Event Severity Stratification 
The Investigator will use the following definitions to rate the severity 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 
The Investigator will use the following definitions to assess the relationship of the adverse event 
to the use of study device: 
 
Not Related 
 
The event is definitely not associated with study device.  The 
adverse event is due to an underlying or concurrent illness or 
effect of another device or drug. 
Unlikely 
 
An adverse event has little or no temporal relationship to the 
study device and/or a more likely alternative etiology exists. 
Possible 
 
 
The temporal sequence between device use and the event is 
such that the relationship is not unlikely or subject’s condition 
or concomitant therapy could have caused the AE. 
Probable 
 
The temporal sequence is relevant or the event abates upon 
device application completion/removal or the Event cannot be 
reasonably explained by the subject’s condition. 
Highly 
Probable 
The temporal sequence is relevant and the event abates upon 
device application completion/removal, or reappearance of the 
event on repeat device application (re-challenge).   
 
 
Relationship to study procedure 
The Investigator will use the following definitions to assess the relationship of the adverse event 
to the use of study procedure: 

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Not Related 
 
The event is definitely not associated with procedure.  The 
adverse event is due to an underlying or concurrent illness or 
effect of another procedure. 
Unlikely 
 
An adverse event has little or no temporal relationship to the 
procedure and/or a more likely alternative etiology exists. 
Possible 
 
 
The temporal sequence between the procedure and the event is 
such that the relationship is not unlikely or subject’s condition 
or concomitant therapy could have caused the AE. 
Probable 
 
The temporal sequence is relevant or the event abates upon 
procedure completion or the Event cannot be reasonably 
explained by the subject’s condition. 
Highly 
Probable 
The temporal sequence is relevant and the event abates upon 
procedure completion, or reappearance of the event on repeat 
procedure (re-challenge).  
  
 
Abrupt or Acute Closure 
Angiographic documentation of significantly reduced flow due to mechanical dissection, 
thrombus, or severe vessel spasm in the treatment area. 
 
Acute Limb Ischemia 
Acute limb ischemia is defined as a sudden decrease in limb perfusion that causes a potential 
threat to limb viability (manifested by ischemic rest pain, ischemic ulcers, and/or gangrene) in 
patients who present within two weeks of the acute event. 
 
Acute Technical Success 
Acute technical success is defined as the achievement of successful delivery and deployment of 
the study device(s) as intended at the intended target lesion with < 50% residual percent stenosis 
and a successful withdrawal of the catheter system. 
All Cause Perioperative Death (POD) 
All-cause Perioperative Death is defined as death within 30 days of the index procedure. 
Amputation of the Index Limb  
Amputation is categorized as Major (above the ankle) or Minor (transmetatarsal or lower, 
including digits). Minor amputations are categorized as Planned (intended prior to the index 
procedure) or Unplanned.  
Amputation-Free Survival (AFS) 
Freedom from above-ankle amputation of the index limb and death (any cause) 

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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. Non-compliant vessels complicate interpretation and are 
excluded from secondary endpoint analysis. 
As-Treated  
The As-Treated analysis is based only on those subjects (and target vessels) treated with either 
an investigational or control device, and the comparison is based on the actual device used, not 
randomized assignment.     
 
Binary Restenosis  
The presence of a hemodynamically significant restenosis (>50%) as determined by the 
independent core lab analysis by angiography (if performed) or by duplex ultrasound (based on 
study correlation of ultrasound core lab peak systolic velocity ratios with angiographic data in 
the cohort with both).  
Clinically Driven Target Lesion Revascularization 
Revascularization at the target lesion due to worsening of Rutherford Class of the index limb, 
stagnant or worsening wound healing, or a new or recurrent wound in the index limb.  
Clinically Driven Target Vessel Revascularization 
Revascularization at the target vessel due to worsening of Rutherford Class of the index limb, 
stagnant or worsening wound healing, or a new or recurrent wound in the index limb.  
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 labeling of the 
device. The intended performance of a device refers to the intended use for which the device is 
labeled or marketed. 
Device Success 
Acute device success is defined as, a per device basis, the achievement of successful delivery 
and deployment of the study device(s) as intended at the intended target lesion, without balloon 
rupture or inflation/deflation abnormalities and a successful withdrawal of the study system. If a 
device is inserted into the subject but not used due to user error (e.g. inappropriate balloon length 
or transit time too long), this device will not be included in the device success assessment. 
Discharge 
The time point at which the subject was released from the admitting hospital or transferred to 
another facility. 

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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. 
 
Enrollment 
Enrollment in the study occurs after both of the following steps have occurred: 
• Baseline angiographic confirmation that the target lesion(s) meets all appropriate 
inclusion/exclusion criteria. 
• Defined pre-dilatation balloon inflation has begun. 
Intent-To-Treat (ITT) 
The principle of including outcomes of all subjects in the analysis who are randomized into the 
study, regardless of the treatment actually received. 
Independently Ambulate 
To perform daily activities (walking, dressing, etc.) without assistance. 
 
Index Limb Related Death 
Any death adjudicated by the CEC as “likely related” to a complication of the index limb. 
Limb Salvage 
Freedom from above-ankle amputation of the index limb. 
 
Major Adverse Cardiovascular Event (MACE) 
MI, stroke or death (any cause) 
 
Major Bleeding Complications 
Bleeding will be considered major if:  
• It leads to death;  
• It leads to permanent disability; 
• It is clinically suspected or proven to be intracranial (see stroke)  

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• It produces a fall in hemoglobin of at least 3 mmol/l;  
• It leads to transfusion of 2 or more units of whole blood of packed cells;  
• Peripheral vascular surgery is necessary. 
• All other bleeding will be considered as minor. 
 
Major Vascular Complications (during Index procedure)  
Hemorrhagic vascular complications included the following: 
• Haematoma at access site >5 cm 
• False aneurysm 
• AV fistula 
• Retroperitoneal bleed 
• 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 
 
Major Adverse Limb Event (MALE) 
Above ankle amputation of the index limb or major reintervention (new bypass graft, 
jump/interposition graft revision, or thrombectomy/thrombolysis) 
 
MALE+POD (any MALE or Perioperative Death) 
Above ankle amputation of the index limb or major reintervention (new bypass graft, 
jump/interposition graft revision, or thrombectomy/thrombolysis) or death (all cause) within 30 
days of the index procedure.  
 
Patent Run-off (or Patent Outflow) 
Reconstitution of the target vessel at or above the ankle with inline flow to at least one patent 
(<50% diameter stenosis) inframalleolar outflow vessel that has not previously been 
revascularized. Patent lateral calcaneal and tarsal branches of the peroneal artery are considered 
patent outflow, in addition to the dorsalis pedis and posterior tibial arteries and their terminal 
branches. 
Per-Protocol (PP) 
The PP analysis is based on all subjects (and target vessels) that are characterized by appropriate 
exposure to treatment (procedurally correct as pre-specified), availability of measurements, and 
the absence of major protocol violations including violations of entry criteria. 
 
Primary Patency  
Primary Patency of the target lesion is defined as the absence of total occlusion (100% diameter 
stenosis) of the target lesion without prior target lesion revascularization. Occlusion is 

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determined by independent core lab analysis of angiographic data (if performed) or by 
ultrasound (if angiography not performed). [Freedom from Binary Restenosis (≥ 50% diameter 
stenosis) without reintervention is reported as an independent secondary endpoint.]  
 
Procedural success 
Restoration of at least 1 infrapopliteal artery with residual stenosis ≤ 30% by independent core 
lab analysis with inline outflow to the foot without major adverse events during the index 
procedure.  
 
Popliteal Artery 
The vessel located between Hunter’s canal and the trifurcation. 
PSVR 
Peak Systolic Velocity Ratio 
 
RAO 
Any reintervention or above ankle amputation of the index limb. 
 
RAS 
Any reintervention, above ankle amputation of the index limb, or restenosis 
 
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 
See Binary Restenosis. 
Restenotic Lesion 
A lesion in a vessel segment that had undergone a prior percutaneous treatment 
 
 

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Rutherford Categories  
Category 
Clinical Description 
0 
Asymptomatic, no hemodynamically significant occlusive disease 
1 
Mild Claudication 
2 
Moderate Claudication 
3 
Severe Claudication 
4 
Ischemic rest pain 
5 
Minor tissue loss, non-healing ulcer, or focal gangrene with diffuse pedal ischemia 
6 
Major tissue loss, extending above transmetatarsal level, functional foot no longer 
salvageable 
 
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. 
Secondary Patency 
Secondary Patency of the target lesion is defined as the absence of total occlusion (100% 
diameter stenosis) based on angiography (if performed) or ultrasound as analyzed by 
independent core lab, independent of whether or not patency is re-established via an 
endovascular procedure.   
Stroke 
Clinical signs/symptoms of focal neurological deficit lasting longer than 24 hours. 
Target Lesion 
Lesion(s) that are to be treated during the index procedure.  
The proximal margin of the target lesion must originate below the tibial plateau and terminate above 
the tibiotalar joint. Multiple target lesions (up to 320 mm in cumulative length) may be treated in up 
to two Target Vessels. All Target Lesion(s) must be successfully pre-dilated (successful pre-
dilatation defined by residual stenosis ≤ 50% and operator determination that procedural success 
may be achievable by angioplasty alone) and meet post-pre-dilatation lesion and outflow criteria. All 
Target Lesion(s) are to be treated with the as-randomized test or control device. 
Target Lesion Revascularization 
A repeat revascularization procedure (percutaneous or surgical) of the original target lesion site. 
Target Vessel Revascularization 
A repeat revascularization procedure (percutaneous or surgical) of a lesion in the target vessel. 
 

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Target Vessel   
The entire vessel in which the target lesion is located. One or two below-the-knee arterial flow 
pathways to the foot are allowed as Target Vessel(s); i.e., peroneal or posterior tibial arteries may 
involve tibioperoneal trunk lesions and tibial arteries may involve popliteal lesions. Each target 
vessel(s) (flow path) must reconstitute(s) at or above the ankle with inline flow to at least one 
patent (<50%) inframalleolar outflow vessel (planned treatment below-the-ankle is not allowed).  
Technical Success 
Acute technical success of the balloon procedure is defined as the achievement of successful 
delivery and deployment of the study device(s) as intended at the intended target lesion and a 
successful withdrawal of the study system with the achievement of < 30% residual percent 
stenosis without deployment of a bail-out stent. 
 
Thrombosis 
A total occlusion documented by duplex ultrasound and/or angiography at the treatment site 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. 
 
Toe Brachial Index Assessment   
Toe systolic pressure/brachial systolic pressure, measured by constructing a ratio from the peak 
systolic pressure measured during the deflation of the toe cuffs during Doppler detection to the 
systolic brachial pressure. Non-compliant vessels complicate interpretation and are excluded 
from secondary endpoint analysis. 
 
Transient Ischemic Attack (TIA) 
Clinical signs/symptoms of focal neurological deficit lasting up to 24 hours without evidence of 
infarct on imaging studies. 
 
Treatment Area 
The entire treated vessel segment(s) in which angioplasty balloons were inflated (the injury 
segment) in Target Vessel(s) including the Target Lesion(s). 
Walking Impairment Questionnaire (WIQ) 
A measure of subject-perceived walking performance for subjects with PAD and/or intermittent 
claudication. This questionnaire estimates walking distance, walking speed and stair climbing 
capacity. 
Worsening Rutherford Clinical Category 
A deterioration (an increase) in the Rutherford Category of the index limb by more than 1 
category from the earliest post-procedural measurement. 
 

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Wound 
Foot ulcer or gangrene. After debridement and/or minor amputation, a wound is characterized as 
a healed wound when it is completely epithelialized. 
 
 

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17 APPENDIX B:  DRAFT CASE REPORT FORM ELEMENTS 
 
 

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18 APPENDIX C:  SAMPLE WALKING IMPAIRMENT QUESTIONNAIRE 

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19 APPENDIX D:  SAMPLE EQ5D QUESTIONNAIRE 
 
By Placing a tick in one box in each group below, please indicate which statements best describe your 
own health state today 
 
Mobility 
 
I have no problems walking about 
 
 
 
 
 
 
I have some problems walking about 
 
 
 
 
 
 
I am confined to bed 
 
 
 
 
 
 
 
 
 
Self-Care 
 
I have no problems with self-care 
 
 
 
 
 
 
I have some problems with self-care 
 
 
 
 
 
 
I am unable to wash or dress myself 
 
 
 
 
 
 
 
Usual activities (e.g. work, study, housework, family or leisure activities) 
 
I have no problems with performing my usual activities  
 
 
 
I have some problems with performing my usual activities 
 
 
 
I am unable to perform my usual activities 
 
 
 
 
 
 
Pain/Discomfort 
 
I have no pain or discomfort 
 
 
 
 
 
 
 
I have moderate pain or discomfort 
 
 
 
 
 
 
I have extreme pain or discomfort 
 
 
 
 
 
 
 
Anxiety/Depression 
 
I am not anxious or depressed 
 
 
 
 
 
 
 
I am moderately anxious or depressed 
 
 
 
 
 
 
I am extremely anxious or depressed 
 
 
 
 
 
 
Patients own health state today  
 
 
 
 
 

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To help people say how good or bad a health state is, we  
Have drawn a scale (rather like a thermometer) on which 
The best state you can imagine is marked 100 and the worst 
State you can imagine is marked 0 
 
 
We would like you to indicate on this scale how good 
Or bad your own health is today, in your opinion.  Please 
Do this by drawing a line from the box below to whichever 
Point on the scale indicates how good or bad your health is  
today. 
 
 
 
 
 
 
Best 
imaginable 
health state 
100 
▬ 
9●0 
▬ 
8●0 
▬ 
7●0 
▬ 
6●0 
▬ 
5●0 
▬ 
4●0 
▬ 
3●0 
▬ 
2●0 
▬ 
1●0 
▬ 
0 
Worst 
imaginable 
health state 
 

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20 APPENDIX E:  SAMPLE INSTRUCTIONS FOR USE 

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21 APPENDIX F: SAMPLE INFORMED CONSENT FORMS 
 
 

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22 APPENDIX G:  ANGIOGRAPHIC ACQUISITION GUIDELINES 
 
 

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23 APPENDIX H: DUPLEX ULTRASOUND CORE LAB GUIDELINES 
 
 

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24 APPENDIX I: SPONSOR-QUALIFIED INVESTIGATIONAL SITES 
 
 

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25 APPENDIX J: INTERIM ANALYSIS PLAN (ADAPTIVE DESIGN)