Randomized Study of IN.PACT 014 Paclitaxel-Coated Percutaneous Transluminal Angioplasty Balloon Catheter vs. Optimal Percutaneous Transluminal Angioplasty for the Treatment of Chronic Total Occlusions in the Infrapopliteal Arteries
Phase: NA
Conditions: Critical Limb Ischemia, Peripheral Arterial Disease
Sponsor: Medtronic Endovascular

 
 
Cover page for Study Protocol 
 
Sponsor name: 
Medtronic Endovascular 
NCT number 
NCT02963649 
Sponsor trial ID: 
APV-IN.PACT BTK OUS 
Official title of study: 
Randomized Study of IN.PACT 014 
Paclitaxel-Coated Percutaneous 
Transluminal Angioplasty Balloon Catheter 
vs. Optimal 
Percutaneous Transluminal Angioplasty for 
the Treatment of Chronic Total Occlusions in 
the Infrapopliteal Arteries 
Document date 
11 June 2020 
 

 
 
 
 
 
 
 
 
IN.PACT BTK Study 
Randomized Study of IN.PACT 014 Paclitaxel-Coated 
Percutaneous Transluminal Angioplasty Balloon 
Catheter vs. Optimal Percutaneous Transluminal 
Angioplasty for the treatment of chronic total 
occlusions  in the infrapopliteal arteries 
 
 
 
 
Clinical Investigational Plan (CIP) 
 
CIP IDENTIFIER: APV-IN.PACT BTK OUS 
VERSION 7.0 
11/JUN/2020 
 
 
 
 
Confidentiality Statement 
The information contained in this document is confidential and the proprietary property of Medtronic. Any distribution, copying, or 
disclosure without the prior written authorization of Medtronic is strictly prohibited. Persons to whom the information is disclosed must know that 
it is confidential and that it may not be further disclosed by them. 
 

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Clinical Investigation Plan 
Clinical Investigation Plan/ Study Title  Randomized Study of IN.PACT 014 Paclitaxel-
Coated Percutaneous Transluminal Angioplasty 
(PTA) Balloon Catheter vs. Optimal 
Percutaneous Transluminal Angioplasty (PTA) 
for the treatment of chronic total occlusions 
(CTO) in the infrapopliteal arteries 
IN.PACT BTK 
Clinical Investigation Plan Identifier APV-IN.PACT BTK OUS 
EUDAMED generated unique identifier provided under separate cover (once available) 
Study Product Name Investigational Device: IN.PACT 014 Paclitaxel-
Coated Percutaneous Transluminal Angioplasty 
(PTA) Balloon Catheter (hereinafter referred as 
“IN.PACT 014”) 
Sponsor/ Local Sponsor Sponsor  
Medtronic Aortic and Peripheral Vascular 
3576 Unocal Place 
Santa Rosa, CA 85403 
United States 
 
Local Sponsor 
Medtronic Bakken Research Center B.V. 
Endepolsdomein 5 
6229 GW Maastricht 
The Netherlands 
Document Version 7.0 
Version Date 11/JUN/2020 
Lead Principal Investigator(s) Prof. Francesco Liistro 
Prof. Antonio Micari  
Italy 
Confidentiality Statement 
The information contained in this document is confidential and the proprietary property of 
Medtronic. Any distribution, copying, or disclosure without the prior written authorization of 
Medtronic is strictly prohibited. Persons to whom the information is disclosed must know that it is 
confidential and that it may not be further disclosed by them. 

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1. Version History 
See Appendices 18.3 Version History 
 

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2. Investigator Statement 
Study product Name 
IN.PACT 014 
Sponsor 
Medtronic Aortic and Peripheral Vascular 
3576 Unocal Place 
Santa Rosa, CA 85403 
United States 
 
Local Sponsor 
Medtronic Bakken Research Center B.V. 
Endepolsdomein 5 
6229 GW Maastricht 
The Netherlands 
Clinical Investigation Plan Identifier 
APV-IN.PACT BTK OUS 
Version Number/ Date  
7.0, 11/JUN/2020 
I have read the protocol, including all appendices, and I agree that it contains all necessary details 
for me and my staff to conduct this study as described. I will conduct this study as outlined herein 
and will make a reasonable effort to complete the study within the time designated. 
I agree to comply with all applicable regulatory guidelines, under which the study is being 
conducted, e.g., United Stated Food and Drug Administration regulations and the latest version of 
ISO 14155. I agree to ensure that the confidential information contained in this document will not 
be used for any purpose other than the evaluation and conduct of the clinical investigation without 
the prior written consent of Medtronic. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Medtronic. I will discuss this material with them to ensure that they are 
fully informed about the products and the study. 
Investigator’s Signature: 
 
Investigator’s Name: 
 
Institution: 
 
Date:  
 
 
 

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Table of Contents  
1. 
Version History ..................................................................................... 3 
2. 
Investigator Statement ........................................................................ 4 
Table of Contents .......................................................................................... 5 
3. 
Glossary ................................................................................................ 9 
4. 
Synopsis .............................................................................................. 12 
5. 
Introduction ........................................................................................ 21 
5.1. 
Background ..................................................................................... 21 
5.2. 
Purpose ........................................................................................... 24 
6. 
Objectives and Endpoints ................................................................... 25 
6.1. 
Objectives ....................................................................................... 25 
6.1.1. Primary Objective(s) ............................................................................ 25 
6.1.2. Secondary Objective(s) ......................................................................... 25 
6.2. 
Endpoints ........................................................................................ 25 
6.2.1. Primary Endpoint ................................................................................. 25 
6.2.2. Secondary Endpoint(s) ......................................................................... 26 
7. 
Study Design ....................................................................................... 26 
7.1. 
Duration .......................................................................................... 27 
7.2. 
Rationale ......................................................................................... 27 
8. 
Product Description ............................................................................ 28 
8.1. 
General ........................................................................................... 28 
8.2. 
Manufacturer ................................................................................... 31 
8.3. 
Packaging ....................................................................................... 31 
8.4. 
Intended Population ........................................................................ 31 
8.5. 
Equipment ....................................................................................... 32 
8.6. 
Product Training Requirements ........................................................ 32 
8.7. 
Product Receipt and Tracking ........................................................... 32 
8.8. 
Product Storage ............................................................................... 32 
8.9. 
Product Return ................................................................................ 32 
9. 
Selection of Subjects .......................................................................... 33 
9.1. 
Study Population ............................................................................. 33 
9.2. 
Subject Enrollment .......................................................................... 33 
9.3. 
Inclusion Criteria ............................................................................. 35 
9.4. 
Exclusion Criteria ............................................................................. 36 
10. Study Procedures ................................................................................ 38 
10.1. Schedule of Events ........................................................................... 38 
10.2. Subject Screening ............................................................................ 39 
10.3. Prior and Concomitant Medications ................................................... 39 
10.4. Subject Consent............................................................................... 40 
10.4.1. 
Consent Materials ............................................................................. 40 

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10.4.2. 
Informed Consent Process .................................................................. 41 
10.4.3. 
Special Circumstances for Informed Consent Process and Signature........... 41 
10.4.4. 
Subject Accountability for Follow-up Extension ....................................... 42 
10.5. Randomization and Treatment Assignment ....................................... 42 
10.6. Index Procedure .............................................................................. 42 
10.6.1. 
Vascular Access ................................................................................ 42 
10.6.2. 
Angiography .................................................................................... 42 
10.6.3. 
Treatment of Non-Target Lesions ........................................................ 43 
10.6.4. 
Target Vessel / Lesion pre-dilatation .................................................... 43 
10.6.5. 
Treatment of Target Vessels/Lesions .................................................... 44 
10.6.6. 
Adjunctive Therapies ......................................................................... 45 
10.7. Follow-Up Requirements .................................................................. 47 
10.7.1. 
Discharge Follow-Up Requirements ...................................................... 47 
10.7.2. 
Follow-up Visit Requirements .............................................................. 47 
10.7.3. 
Follow-up phone calls ........................................................................ 47 
10.7.4. 
Unscheduled visits ............................................................................ 47 
10.7.5. 
Follow up Duplex Ultrasound Examination ............................................. 47 
10.7.6. 
Follow up Angiography ...................................................................... 47 
10.7.7. 
Wound Care Follow-up Assessments .................................................... 48 
10.8. Medication Compliance .................................................................... 48 
10.9. Assessment of Efficacy ..................................................................... 49 
10.10. 
Assessment of Safety .................................................................... 49 
10.11. 
Recording Data ............................................................................. 49 
10.11.1. 
Investigator records ....................................................................... 49 
10.11.2. 
Investigator reporting responsibilities ................................................ 50 
10.11.3. 
Sponsor records............................................................................. 51 
10.11.4. 
Sponsor reporting responsibilities ...................................................... 51 
10.12. 
Deviation Handling ........................................................................ 53 
10.13. 
Subject Exit, Withdrawal or Discontinuation ................................... 54 
10.13.1. 
Missed follow-up ............................................................................ 54 
10.13.2. 
Upon Early Termination Phone Calls .................................................. 54 
10.13.3. 
Study Completed ........................................................................... 54 
10.13.4. 
Lost-to-follow-up ........................................................................... 54 
10.13.5. 
Medical care after study exit ............................................................ 55 
11. Risks and Benefits .............................................................................. 56 
11.1. Potential Risks ................................................................................. 56 
11.1.1. 
Risks associated with the use of the study product ................................. 56 
11.1.2. 
Risks related to the study procedures ................................................... 57 
11.2. Potential Benefits ............................................................................ 58 
11.3. Risk-Benefit Rationale ..................................................................... 59 
12. Adverse Event Assessments ............................................................... 60 
12.1. Definitions/Classifications ................................................................ 60 
12.1.1. 
Definitions / Classifications ................................................................. 61 
12.1.2. 
Recording and reporting of Adverse Events ........................................... 62 

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12.1.3. 
Recording and reporting of Device Deficiencies ...................................... 62 
12.1.4. 
Adverse Event and Device Deficiency review process .............................. 63 
12.2. Reporting of Adverse Events ............................................................. 63 
12.3. Subject Death .................................................................................. 63 
13. Data Review Committees ................................................................... 65 
13.1. Data Monitoring Committee ............................................................. 65 
13.2. Clinical Event Committee.................................................................. 65 
13.3. Core Laboratories ............................................................................ 65 
14. Statistical Design and Methods .......................................................... 66 
14.1. General Considerations .................................................................... 66 
14.2. Analysis Cohorts .............................................................................. 66 
14.3. Sample Size Consideration ............................................................... 66 
14.4. Primary Objective ............................................................................ 67 
14.4.1. 
Objective......................................................................................... 67 
14.4.2. 
Endpoint ......................................................................................... 67 
14.4.3. 
Analysis Method ............................................................................... 67 
14.5. Secondary Objectives ....................................................................... 68 
14.5.1. 
Composite Safety Endpoint ................................................................. 68 
14.5.2. 
MAE Endpoint .................................................................................. 68 
14.5.3. 
Functional flow assessment ................................................................ 68 
14.5.4. 
Mortality Rate .................................................................................. 69 
14.5.5. 
Major Target Limb Amputation ............................................................ 69 
14.5.6. 
Clinical-Driven Target Lesion Revascularization (CD-TLR) ......................... 70 
14.5.7. 
Mechanically-Driven Target Lesion Revascularization (MD-TLR) ................. 70 
14.5.8. 
Target Lesion Revascularization (TLR) .................................................. 70 
14.5.9. 
Clinical-Driven Target Vessel Revascularization (CD-TVR) ......................... 70 
14.5.10. 
Target Vessel Revascularization (TVR) ............................................... 71 
14.5.11. 
Status of Wound Healing ................................................................. 71 
14.5.12. 
Thrombosis ................................................................................... 71 
14.5.13. 
Device Success .............................................................................. 72 
14.5.14. 
Clinical Success ............................................................................. 72 
14.6. Missing Data .................................................................................... 72 
15. Ethics .................................................................................................. 73 
15.1. Statement(s) of Compliance ............................................................. 73 
16. Study Administration .......................................................................... 74 
16.1. Investigator / Investigational site selection ...................................... 74 
16.2. Clinical Trial Agreement ................................................................... 74 
16.3. Study Insurance /Subject Indemnification ........................................ 74 
16.4. Subject Compensation ..................................................................... 75 
16.5. Site Activation/Supply of Trial Materials ........................................... 75 
16.6. Monitoring ...................................................................................... 75 
16.7. Data Management ........................................................................... 76 
16.8. Direct Access to Source Data/Documents .......................................... 76 

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16.9. Confidentiality ................................................................................. 77 
16.10. 
CIP Amendments .......................................................................... 77 
16.11. 
Record Retention .......................................................................... 77 
16.12. 
Publication and Use of Information ................................................ 78 
16.13. 
Suspension or Early Termination .................................................... 78 
17. References .......................................................................................... 80 
18. Appendices .......................................................................................... 85 
18.1. IN.PACT 014 Device label ................................................................. 85 
18.2. Definitions ....................................................................................... 86 
18.3. Version History ................................................................................ 92 
 

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3. Glossary 
Term 
Definition 
ABI 
Ankle Brachial Index 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
ASA 
Aspirin 
AT 
As Treated 
BMS 
Bare Metal Stent 
BTK 
Below-The-Knee 
CA 
Competent Authority 
CBC 
Complete Blood Count 
CD 
Clinically Driven 
CEC 
Clinical Events Committee 
CLI 
Critical Limb Ischemia 
CRF 
Case Report Form 
DAPT 
Dual Anti-Platelet Therapy 
DCB 
Drug Coated Balloon 
DEB 
Drug Eluting Balloon 
DES 
Drug Eluting Stent 
DS 
Diameter Stenosis 
DMC 
Data Monitoring Committee 
DUS 
Duplex Ultrasound 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Form 

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Term 
Definition 
EDC 
Electronic Data Capture 
EQ-5D 
EuroQol Five Dimension Scale 
FU 
Follow Up 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
IFU 
Instruction For Use 
ISO 
International Organization for Standardization 
ITT 
Intention-to-Treat 
LLL 
Late Lumen Loss 
MAE 
Major Adverse Events 
MD-TLR 
Mechanically-Driven Target Lesion 
Revascularization 
NHLBI 
National Heart, Lung, and Blood Institute 
NOAC 
Novel Oral Anticoagulants 
P3 
3rd Segment of the Popliteal Artery 
PAD 
Peripheral Artery Disease 
PI 
Principal Investigator 
PTA 
Percutaneous Transluminal Angioplasty 
PTX 
Paclitaxel 
QVA 
Quantitative Vascular Angiography 
RBP 
Rated Burst Pressure 
RCC 
Rutherford Clinical Category 
RCT 
Randomized Controlled Trial 
RVD 
Reference Vessel Diameter 

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Term 
Definition 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SFA 
Superficial Femoral Artery 
SoC 
Standard of Care 
TL 
Target Lesion 
TLR 
Target Lesion Revascularization 
TV 
Target Vessel 
TVR 
Target Vessel Revascularization 
USADE 
Unanticipated Serious Adverse Device Effect 
WIfI 
Wound, Ischemia and foot Infection 
 
 

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4. Synopsis 
Title 
Randomized Study of IN.PACT 014 Paclitaxel-Coated Percutaneous 
Transluminal Angioplasty Balloon Catheter vs. Optimal Percutaneous 
Transluminal Angioplasty  for the treatment of chronic total 
occlusions in the infrapopliteal arteries 
[IN.PACT BTK] 
Clinical Study Type 
First In Human, Interventional, Pre-market 
Product Name 
Investigational Device: IN.PACT 014 Paclitaxel-Coated Percutaneous 
Transluminal Angioplasty (PTA) Balloon Catheter (hereinafter 
referred as “IN.PACT 014”)  
Sponsor  
Funding Source: 
Medtronic Aortic and Peripheral Vascular 
3576 Unocal Place 
Santa Rosa, CA 85403 
United States 
Local Sponsor 
Medtronic Bakken Research Center B.V. 
Endepolsdomein 5 
6229 GW Maastricht 
The Netherlands 
External Organizations 
Independent Angiographic Core Laboratory 
Beth Israel Deaconess Medical Center, Inc., 375 Longwood Ave., MA 
02215 Boston, USA 
Independent Duplex Ultrasound (DUS) Core Laboratory 
Vascore Ultrasound Core Laboratory, Bowdoin Square 10th Floor 
Boston, MA 02114, USA 
Clinical Event Committee (CEC) 
Syntactx Europe BVBA, independent CRO, Tolstraat 26, 9550 
Herzele, Belgium 
Data Monitoring Committee (DMC) 
Syntactx Europe BVBA, independent CRO, Tolstraat 26, 9550 
Herzele, Belgium 
 
 

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Imaging Contract Research Organization (CRO) 
Medidata Solutions, Inc., a Delaware corporation, 350 Hudson 
Street, 9th Floor, New York, New York 10014, USA 
Interactive Web Response System (web-based 
randomization system) 
Bracket, 303 Second Street, Suite 700, 7th Floor, South Tower, San 
Francisco, California 94107, USA 
Indication under 
investigation  
Treatment of chronic total occlusions (CTO) in the infrapopliteal 
arteries.    
Investigation Purpose 
To assess the safety and efficacy of the paclitaxel drug-eluting 
balloon IN.PACT 014 versus conventional, optimal percutaneous 
transluminal angioplasty (PTA) for the treatment of patients with 
chronic total occlusions in the infrapopliteal arteries. This 
information can be used for regulatory purposes. 
Product Status 
IN.PACT Paclitaxel-Eluting Percutaneous Transluminal Angioplasty 
(PTA) Balloon Catheter (IN.PACT 014) is the investigational 
combination product used in the study. 
Primary Objective(s) 
To assess the efficacy of the IN.PACT 014 by comparing the Late 
Lumen Loss (LLL) 9 months after the index procedure of the 
investigational product vs optimal (conventional) PTA 

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Secondary Objective(s) 
• 
Composite Safety Endpoint: A composite of freedom from 
device- and procedure-related mortality within 30 days, 
freedom from major target limb amputation and freedom 
from clinically-driven TLR within 9 months post-index 
procedure. 
• 
Major Adverse Event (MAE) rate, defined as a composite of 
all-cause mortality, target limb major amputation and 
clinically-driven TLR through 3, 6, 9, 12, 24, 36, 48 and 60 
months. 
• 
Functional flow assessment at 3, 6, 9, 12, 24 and 36 months, 
defined as absence of target lesion occlusion (no flow) 
assessed by duplex ultrasound.  
• 
Death of any cause and cardiovascular related deaths 
through 3, 6, 9, 12, 24, 36, 48 and 60 months. 
• 
Rate of major target limb amputation through 30 days, 3, 6, 
9 ,12, 24, 36,48 and 60 months. 
• 
Rate of CD-TLR through 3, 6, 9, 12, 24, 36, 48 and 60 
months. 
• 
Rate of Mechanically Driven TLR through 37 days. 
• 
Rate of TLR through 3, 6, 9, 12, 24, 36, 48 and 60 months. 
• 
Rate of CD-TVR through 3, 6, 9, 12, 24, 36, 48 and 60 
months. 
• 
Rate of TVR through 3, 6, 9, 12, 24, 36, 48 and 60 months. 
• 
Status of wound healing (completely healed - improvement 
– unchanged – worsened) at 30 days, 3, 6, 9, 12, 24 and 
36months. 
• 
Rate of thrombosis at the target lesion through 30 days, 3, 
6, 9, 12, 24, 36, 48 and 60 months. 
• 
Device success (for investigational device only) 
o 
Device success is defined as successful drug delivery, 
balloon inflation, deflation and retrieval of the intact 
study device without burst below the rated burst 
pressure (RBP). 
• 
Clinical success 
o 
Clinical success is defined as residual stenosis of ≤ 
30% without procedural complications (death, major 
target limb amputation, thrombosis of the target 
lesion, or TVR) prior to discharge. 
Study Design 
This is a prospective, multi-center, randomized (1:1) study to 
evaluate the efficacy and safety of the IN.PACT 014 in the 
treatment of CTOs in the infrapopliteal arteries.  
All subjects will be followed with baseline, procedure, discharge, 
and follow-up evaluations at 30 days, 3, 6, 9, 12, 24, 36, 48 and 60 
months post procedure.  
Randomization 
1:1 randomization of IN.PACT 014 and optimal PTA 

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Sample Size 
At a minimum 50 patients are planned for enrollment. 
Inclusion/ Exclusion 
Criteria 
Inclusion Criteria 
1. Age ≥18 years.  
2. Subject has been informed of the nature of the study, 
agrees to participate and has signed an Ethics Committee 
(EC) approved consent form. 
3. Female subjects of childbearing potential have a negative 
pregnancy test ≤7 days before the procedure and are 
willing to use a reliable method of birth control for the 
duration of study participation. Female subjects will be 
exempted from this requirement in case they are sterile, 
infertile, or have been post-menopausal for at least 12 
months (no menses). 
4. Subject has documented chronic Critical Limb Ischemia 
(CLI) in the target limb prior to the study procedure with 
Rutherford Clinical Category 4 or 5.  
5. Subjects with documented infection grade 0-2 and ischemia 
grade 2-3 according to the WIfI classification. 
6. Life expectancy >1 year in the Investigator’s opinion. 
7. Reference Vessel Diameter (RVD) 2 - 4 mm, and confirmed 
by DUS assessment. 
8. Total occlusions (100% stenosis) with total lesion length 
≥40mm (by visual estimate). 
9. The lesion must be located in the infrapopliteal arteries and 
above the ankle joint. Lesions may not extend above the 
tibioperoneal trunk (P3 segment of the popliteal artery) or 
below the ankle joint (arteries of the foot), nor can the 
treatment (investigational device or standard PTA, including 
pre-dilatation) extend beyond these indicated regions for 
more than 1 cm. 
 

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Note: 
• 
A target lesion can extend into the P3 segment in case it 
involves a straight lesion extending from the target vessel.  
• 
Non-significant stenosis below the ankle joint can be allowed 
in case this is not part of the target lesion and does not 
require treatment 
10. Multiple lesions can be treated if they are located in 
separate vessels but all lesions must meet the protocol 
specified criteria. 
11. Presence of documented run-off to the foot (clearly visible 
dorsalis pedis, pedal arch or plantar arteries by 
angiography). Target vessel should give direct or indirect 
run-off to the foot.  
12. Inflow free from flow-limiting lesion confirmed by 
angiography. Patients with flow-limiting inflow lesions (≥ 
50% stenosis) can be included if lesion(s) have been 
treated successfully before enrollment, with a maximum 
residual stenosis of ≤30% per visual assessment. If an 
inflow lesion must be treated within or above the P3 
segment of the popliteal artery, there must be a minimum 
of 3 cm healthy tissue between this (treated) lesion and the 
infrapopliteal target lesion. 
13. Successful pre-dilatation of the (entire) target lesion. 
Success being documented by angiographic visual estimate 
of ≤30% Residual diameter stenosis of the target lesion and 
by functional assessment of the distal flow by intra-
operative Doppler: recording of biphasic or triphasic wave 
signal with rapid take-off distal to the target lesion. 
Exclusion Criteria 
1. Subject unwilling or unlikely to comply to the appropriate 
follow-up times for the duration of the study. 
Note: the investigator should discuss the follow-up 
requirements extensively during the Informed consent 
process to ensure that the subject is fully aware about the 
expectations and is willing to comply with the follow-up 
schedule. 
2. Planned index limb amputation above the metatarsal level, 
or any other planned major surgery within 30 days pre or 
post-procedure. A planned amputation including and below 
the metatarsal level (1 or multiple rays) is accepted. 
3. Lesion and / or occlusions located or extending in the 
popliteal artery or below the ankle joint space.  
 

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Note:  
• 
A target lesion can extend into the P3 segment in case it 
involves a straight lesion extending from the target vessel.  
• 
Non-significant stenosis below the ankle joint can be allowed 
in case this is not part of the target lesion and does not 
require treatment.  
4. Significant (≥50% DS) inflow lesion or occlusion in the 
ipsilateral Iliac, SFA and popliteal arteries left untreated. 
5. Failure to obtain a ≤30% residual stenosis in pre-existing, 
hemodynamically significant (≥50% DS) inflow lesions in 
the ipsilateral iliac, SFA and popliteal artery. Inflow lesions 
should be treated per standard of care. 
6. Prior stent(s) or bypass surgery within the target vessel(s) 
(including stents placed within target vessels during the 
index procedure prior to randomization).  
7. Previous DCB procedure in the target vessel within 6 
months prior to index procedure. 
8. Aneurysm in the target vessel. 
9. Angiographic evidence of thrombus within target limb. 
10. Pre-dilation resulted in a major (≥ Grade D) flow-limiting 
dissection (observed on 2 orthogonal views) or residual 
stenosis >30%.   
11. Use of alternative therapy, e.g. atherectomy, cutting 
balloon, laser, radiation therapy, stents as part of target 
vessel treatment. Note: Use of stents is only allowed for 
bailout stenting.  
12. Recent MI or stroke <30 days prior to the index procedure. 
13. Heart failure with Ejection Fraction <30%. 
14. Known or suspected active infection at the time of the index 
procedure (abnormal white blood cell count, fever, sepsis or 
positive blood culture), excluding an infection of a lower 
extremity wound on the target limb (only WIfI infection 
grade 0-2 allowed). 
15. Subjects with infection grade 3 and ischemia grade 0 and 1 
according to WIfI classification.  
16. Subjects with neurotrophic ulcers, heel pressure ulcers or 
calcaneal ulcers with a risk for major amputation. 
17. Subjects with documented active osteomyelitis, excluding 
the phalanges, that is beyond cortical involvement of the 
bone per clinical judgement. 

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18. Impaired renal function (GFR <20 mL/min) or patients on 
dialysis. 
19. Subject with vasculitis, systemic Lupus Erythematosus or 
polymyalgia rheumatica on active treatment. 
20. Patient receiving systemic corticosteroid therapy (expected 
dosage exceeding 5 mg of prednisolone or equivalent, per 
day, during the initial 9 months after procedure). 
21. This criteria has been removed. 
22. Known allergies or sensitivities to heparin, aspirin (ASA), 
other anticoagulant/anti-platelet therapies which could not 
be substituted, and/or paclitaxel or an allergy to contrast 
media that cannot be adequately pre-treated prior to the 
index procedure. 
23. The patient is currently enrolled in another investigational 
device or drug trial that is interfering with the endpoints of 
this study. 
24. Female subjects who are breast-feeding at the time of 
enrollment. 
Study Procedures and 
Assessments 
Describe procedure schedule by visit 
Screening visit: 
• 
Screening Inclusion/Exclusion and consent 
• 
Physical Exam 
• 
Pregnancy test when applicable 
• 
Medical history and demographics 
• 
Baseline Medications 
• 
Rutherford Classification  
• 
WIfI assessment  
• 
EuroQol-5D questionnaire (EQ-5D) 
Procedure visit: 
• 
Angiographic inclusion/exclusion 
• 
DUS study specific procedure for RVD sizing 
• 
Successful pre-dilatation of the target lesions 
• 
Intra-operative Doppler examination 
• 
Randomization and enrollment 
• 
Medications  
• 
Adverse Events Assessment 
Discharge visit: 

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• 
Physical Exam 
• 
DUS if available 
• 
Medications 
• 
WIfI assessment  
• 
Wound assessment and wound care* 
• 
EuroQol-5D questionnaire (EQ-5D) 
• 
Adverse Events Assessment 
30 days and 3, 6 months visits: 
• 
Physical Exam 
• 
DUS study specific procedure 
• 
Rutherford Classification 
• 
Medications 
• 
WIfI assessment 
• 
Wound assessment and wound care* 
• 
EuroQol-5D questionnaire (EQ-5D) 
• 
Adverse Events Assessment 
9 months visit: 
• 
Physical Exam 
• 
DUS study specific procedure 
• 
Angiographic study specific procedure 
• 
Rutherford classification 
• 
Medications 
• 
WIfI assessment 
• 
Wound assessment and wound care* 
• 
EuroQol-5D questionnaire (EQ-5D) 
• 
Adverse Events Assessment 
12, 24 and 36 months visits:  
• 
Physical Exam 
• 
DUS study specific procedure 
• 
Rutherford Classification 
• 
Medications 
• 
WIfI assessment  
• 
Wound assessment and wound care* 
• 
EuroQol-5D questionnaire (EQ-5D) 
• 
Adverse Events Assessment 
48 and 60 months phone calls: 
• 
Adverse Events Assessment 
Unscheduled Visits:  
• 
Physical Exam 
• 
DUS study specific procedure 
• 
Angiography (if available) 
• 
Rutherford Classification 
• 
Medications 

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• 
WIfI assessment  
• 
Wound assessment and wound care* 
• 
EuroQol-5D questionnaire (EQ-5D) 
• 
Adverse Events Assessment 
Upon Early Termination Phone Calls: 
• 
(Vital) Health Status 
Safety Assessments 
Clinical Event Committee and Independent Data Monitoring 
Committee will supervise study conduct, subject safety and 
adjudicate clinical events related to both Primary and Secondary 
Endpoints. 
 Statistics 
The primary analysis for the study objectives will be Intention-to-
Treat (ITT) analysis. The ITT analysis cohort will include all 
randomized subjects in the groups to which they are randomized 
regardless of treatment received. Late Lumen loss in each arm and 
the difference between the two arms (with 95% 2-sided confidence 
intervals) will be presented at 9 months. Frequency and percentage 
will be calculated for endpoints that are categorical. Summary 
statistics (mean, standard deviation, median, min, max) will be 
presented for endpoints that are continuous. 
* Wound assessment and wound care is only applicable for subjects that present with (ischemic) 
wounds on the target limb at baseline or for subjects who develop new (ischemic) wounds on the target 
limb during the conduct of the study. In case of planned amputations (that meet the inclusion criteria 
for this study) the amputation wound(s) will be monitored throughout the study. 
 
 

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5. Introduction  
5.1. Background  
Peripheral arterial disease (PAD) is a commonly occurring medical condition that involves 
atherosclerosis in vessels located outside the heart and brain. PAD affects an estimated 27 million adults 
in Europe and North America.1 Patients suffering from PAD generally experience a significant reduction 
in health-related quality of life (QOL). In some cases, PAD can cause patients to suffer from debilitating 
symptoms including loss of limbs. Based on objective testing conducted across a variety of 
epidemiologic studies, the prevalence of PAD is estimated to be between 3% and 10%. In patients 
greater than 70 years of age, the estimated prevalence is much higher, at 15% to 20%.2 Despite the 
potentially devastating consequences of PAD, it is estimated that nearly 75% of patients suffering from 
PAD fail to undergo treatment for the condition.3 With respect to prognosis, one-fourth to one-third of 
all patients with PAD will experience disease progression, with one to five percent eventually needing 
amputation.4-6  
Patients with PAD tend to experience an increase in morbidity and a reduction in health status measures 
of health-related QOL. Potential consequences of lower extremity arterial disease include reduced 
mobility, limb pain, gangrene, and amputation, as well as increased mortality, amongst others.2,7,8 
Critical limb ischemia (CLI) refers to severe persistent rest pain requiring treatment with analgesics, 
ulceration or gangrene on the distal extremity.9 CLI is so severe that patients suffering from it 
experience physical function, pain, and general health perception that are similar to or worse than 
patients with congestive heart failure or recent myocardial infarction. Patients with PAD generally have 
a number of comorbidities including cardiovascular disease (CVD), which may explain the increased risk 
of mortality from myocardial infarction (MI) and stroke.7,10,11 Mortality rates at five years range from 
30% to 44% in patients with PAD.12,13  
PAD  located below-the-knee is more likely to be diffuse and progressive than above-the-knee PAD, 
which is often characterized by multilevel disease and heavily calcified lesions.9,14 Patients often present 
with symptoms of CLI as opposed to claudication. Comorbidities such as diabetes and renal failure 
occur rather frequently alongside PAD.9 The instruments used to treat PAD differ based on whether the 
location is above- or below-the-knee. Arteries below-the-knee are narrower than those above-the-knee. 
As such, below-the-knee arteries are appropriately managed with instruments of smaller sizes than the 
instruments used to treat above-the-knee diseases.  
Below-the-knee arteries are often treated with devices originally intended for use in coronary artery 
disease, such as 0.014” guidewires and PTA balloons less than 4 mm in diameter.9  
Open surgical interventions and endovascular techniques are available as treatment modalities for 
patients with PAD. Bypass surgery has been shown to be effective in treating PAD. However, it is 
associated with a number of serious risks including wound complications, death, myocardial infarction 
(MI), infection, and leg edema.15,16 Endovascular treatments for PAD include percutaneous angioplasty 
and stenting. These endovascular modalities are associated with decreased morbidity and faster 
recovery times than surgical bypass. The downside to endovascular treatment is decreased longevity, 
as shown by the high rates of restenosis following PTA and stent implantation.17 If stenting in the infra-
popliteal arteries proves to be unsuccessful, patients may be limited in terms of their ability to undergo 
surgical interventions moving forward. In light of these concerns, recommendations for below-the-knee 
stenting have been limited to stent placement following sub-optimal angioplasty results or severe 
dissection. 18,19  

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Outcomes of percutaneous angioplasty interventions and/or stenting for below-the-knee PAD are 
available throughout the literature. A meta-analysis of 30 studies conducted between 1990 and 2006 
of infra-popliteal PTA for chronic CLI reported a pooled estimate of 89% technical success with one-
year results of 58% primary patency, 86% limb salvage, and 87% patient survival.20 Schmidt et al. 
reported on 77 infra-popliteal arteries treated with angioplasty. Their results showed a 68.8% 
angiographic restenosis rate at 3 months and 50% reintervention rate.21 A randomized controlled trial 
(RCT) comparing stenting and PTA of the infra-popliteal arteries showed no advantage of stenting over 
PTA. The 1-year patency rate was 56% in patients that were stented vs. 66% in patients treated with 
PTA.18 A meta-analysis of bail-out stenting, including studies with bare-metal stents and drug-eluting 
stents, reported a pooled 1-year patency rate of 78.9%. The stent coated with sirolimus demonstrated 
the greatest benefit over bare-metal stents (93.1% vs. 73%). These findings suggest that use of stents 
that elute anti-proliferative agents may result in further benefit in terms of restenosis rates as compared 
to uncoated PTA and bare metal stents.22  
The local application of anti-proliferative drugs such as sirolimus and Zotarolimus via stent delivery 
system has been successful for prevention of restenosis in coronary arteries. Clinical studies have 
proven these agents successful in their attempts to inhibit or reduce restenosis.23-34 Preliminary study 
results were favorable towards increased use of drug-eluting stents (DES) in the superficial femoral and 
proximal popliteal arteries. Unfortunately, these promising early results have not been sustained over 
time.35,36 Several nonrandomized studies suggested promising results with use of DES in management 
of patients with below-the-knee PAD.37-41 RCTs have demonstrated the superiority of DES over bare 
metal stents (BMS) for below-the-knee disease. The YUKON-BTK study randomized 161 patients to DES 
or BMS. Results showed higher rates of event-free survival and freedom from target lesion 
revascularization at the 3-year follow-up in the DES group than the BMS group.42 The DESTINY trial 
randomized 140  patients with CLI to Everolimus-eluting stents or BMS. Results from the DESTINY trial 
demonstrated significantly higher primary patency and freedom from target lesion revascularization at 
12 months in the DES group.43 The ACHILLES study randomized patients with CLI to sirolimus-eluting 
stents (n=99) or PTA (n=101). The 1-year results showed significantly less restenosis for the DES group 
(22.4%) than the PTA group (41.9%; p=0.019).44 Despite the generally favorable results, there are 
outstanding concerns regarding use of below-the-knee stents. These concerns are centered around the 
potential for stent fractures, in-stent thrombosis, and reduction of future surgical options. 
Moreover, studies assessing the efficacy of DES in infrapopliteal lesions, included mostly short lesions: 
a metanalysis of DES for revascularization of infrapopliteal arteries showed that the median lesion 
length was only 26.8 mm which could be perceived as not representative for patients encountered in 
daily practice, which often present with very diffuse disease (> 10cm).45 
Paclitaxel-Coated Angioplasty Balloons 
Paclitaxel is an antineoplastic drug that has demonstrated sustained inhibition of smooth muscle cell 
proliferation in several pre-clinical studies.46-49 Publications assessing effectiveness of local 
administration of paclitaxel on restenosis via drug-coated balloons in the femoropopliteal artery have 
shown promising results, as seen by reduced neointimal proliferation in the peripheral arteries.50-56 
Recent publications have discussed outcomes regarding use of paclitaxel-coated balloons in patients 
with below-the-knee disease. 
The first assessment of paclitaxel-coated balloons in the infra-popliteal arteries was published by 
Schmidt et al. in 2011.57 A total of 109 long-segment infra-popliteal lesions in 104 patients were treated 
for CLI (82.6%) or severe claudication (17.4%) with the IN.PACT Amphirion Paclitaxel-coated balloon.  

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The vast majority of patients (77.1%) in the study suffered from occlusion of all three infra-popliteal 
arteries. A single infra-popliteal artery was treated in 104 of the 109 patients in the study. The mean 
lesion length for treated arteries was 176±88 mm. Clinical improvement, defined as reduction in ulcer 
size or depth of at least 50% or increase of at least one Rutherford-Becker clinical classification, was 
achieved in  75.8% of the treated limbs amongst the 94 patients available at 3-month follow-up. 
Angiographic evaluation was done at 3 months in 84 of the treated arteries. Amongst this group, 72.6% 
of arteries remained free of significant restenosis. Most of the 27.4% lesions with restenosis of more 
than 50% experienced restenosis as opposed to occlusion. Most of these arteries demonstrated 
restenosis that was focal in nature (<20% of length of initial treated lesion). At one year, 86 patients 
with 91 lesions were available for follow-up evaluation. Clinical improvement was achieved in 91.2% of 
limbs from this group. Target lesion revascularization occurred in 17.3% of lesions. There were no 
bypass surgeries performed during the follow-up period. The rate of limb salvage was 95.6% in patients 
with CLI patients. The vast majority of patients with CLI (74.2%) experienced complete wound healing. 
These early studies using paclitaxel-coated balloons to manage complex below-the-knee lesions have 
shown paclitaxel-coated balloons to be superior to uncoated balloons with regard to restenosis rates. 
The DEBATE-BTK study was a randomized trial designed to evaluate the use of drug-coated balloons 
for below-the-knee angioplasty in diabetic patients with CLI.58 A total of 132 patients with 158 infra-
popliteal lesions were enrolled. Sixty-five patients with 80 lesions in 71 limbs were randomized to 
angioplasty with a drug-eluting balloon (IN.PACT Amphirion), while 67 patients with 78 lesions in 72 
limbs were randomized to angioplasty with an uncoated balloon (Amphirion Deep). Patients presenting 
with occlusions at baseline (CTO) was similar in both groups (77.5% in the drug-eluting balloon group 
vs 82.1% in the PTA group). Binary restenosis, defined as reduction in luminal diameter greater than 
50%, at 12 months was significantly lower at 12 months in lesions treated with the drug-eluting balloon 
(DEB, 27%) than in lesions treated with an uncoated balloon (74%; p<0.001). Patients treated with 
DEB experienced occlusion of fewer target vessels and occlusion of shorter target vessels than those 
treated with uncoated balloons (17.6% vs. 55.4%; p<0.001). The freedom from TLR was significantly 
higher in the DEB group (85% vs. 63%; p=0.02). The DEB group also experienced a significantly lower 
major adverse event rate than the uncoated balloon group (31% vs. 51%; p=0.02). Complete ulcer 
healing was also higher at 12 months for the DEB group than the PTA group (86% vs. 67%; p=0.01). 
Longer-term results showed similar benefits of DEB over PTA extended out to at least 24 months.59  
The first multi-center, prospective, single-blinded RCT (randomized-controlled trial), IN.PACT DEEP,  
comparing DEB (IN.PACT Amphirion) to uncoated PTA consisted of a 2:1 randomization to either DEB 
(n=239) or PTA (n=119).59 The baseline patient characteristics were similar between groups. The only 
significant difference was a greater number of previous target limb revascularizations in the DEB arm 
than the PTA arm (32.2% vs. 21.8%). In both groups, a minority of patients presented at baseline with 
CTO-lesions (38.6% in the DEB group vs 45.9% in the PTA group. Lesion and procedural characteristics 
which differed between the groups included longer lesions in the PTA group, more pre-dilation in the 
DEB group (90.5% vs. 36.0%), more procedural complications in the DEB group (9.7% vs. 3.4%), and 
more post-procedural dissections in the PTA group (12.3% vs. 19.2%). At baseline, wounds were 
significantly deeper in the PTA group than the DEB group. The primary efficacy endpoints were 12-
month clinically-driven TLR as well as late lumen loss for the 167-patient subset with angiographic data 
at 12 months. Differences between the DEB and PTA groups were not significant with respect to either 
endpoint. The clinically-driven TLR rate was 9.2% for the DEB group and 13.1% for the PTA group 
(p=0.29). Late lumen loss was 0.61±0.78 for the DEB group and 0.62±0.78 for the PTA group (p=0.95).  

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The composite safety endpoint of all-cause death, major amputation, and clinically-driven TLR at 6 
months was also similar between arms, occurring at a rate of 17.7% in the DEB group and 15.8% in 
the PTA group.  
While the difference was not statistically significant, there was a higher rate of major amputations in 
the DEB group (8.8% vs. 3.6%; p=0.08). It is difficult to determine why the results obtained by the 
PTA arm were much better than one may have estimated using historical data. The binary restenosis 
rate (35%) and major amputation rate (3.6%) observed in the PTA arm were both much lower than 
expected based on the literature involving PTA in management of patients with CLI.20,21,44 To obtain a 
more thorough understanding of the risks and benefits associated with use of DEB in the management 
of patients with CIL, additional studies using a more controlled standardization of amputation definitions 
and wound management protocols are needed.  
It would also be necessary to obtain core laboratory adjudication as well as clinical event committee 
and data safety and monitoring board oversight.60-62  
The BIOLUX P-II trial investigated the efficacy and safety of the Passeo-18 LUX Paclitaxel coated 
balloon. In this prospective, multicentre randomized first-in-man study, 72 subjects were randomized 
1:1 to either a Passeo-18 Drug Eluting Balloon (DEB) (n = 36) or a non-coated Passeo-18 PTA (n = 
36). In order to be included, the lesions had to be occluded or show high-grade stenosis (≥ 70% 
diameter reduction). The primary safety endpoint (a composite of all-cause mortality, target extremity 
major amputation, target lesion thrombosis, and target vessel revascularization at 30 days) was 0% in 
the DEB group versus 8.3% in the PTA group (p = 0.239). The primary performance endpoint (patency 
loss at 6 months) was 17.1% in the DEB group versus 26.1% in the PTA group (p = 0.298), and major 
amputations of the target extremity occurred in 3.3% versus 5.6% of the patients at 12 months, 
respectively.63  
More recently, the results of a retrospective analysis of the Lutonix Paclitaxel coated balloon were 
published.64  Fifty-five patients with symptomatic PAD and Rutherford stage > 3 were treated with the 
Lutonix DCB in the BTK vessels and followed to assess safety and efficacy. 72.2% of patients were 
treated for CTO disease (total occlusion at baseline). Taking into consideration the inherent limitations 
of a retrospective analysis and a small sample size, the results were favourable for DCB treatment in 
the BTK vessels: TLR occurred in 21.8% of patients, two below-the-ankle amputations were performed 
and no patients died. Freedom from death or major amputation was 96.5% and wound healing was 
89.1%. This let the authors conclude that the Lutonix DCB showed safety and efficacy in BTK 
interventions in CLI patients.  
5.2. Purpose 
To assess the safety and efficacy of the paclitaxel drug-coated balloon IN.PACT 014 versus conventional 
percutaneous transluminal angioplasty (PTA) for the treatment of patients with chronic total occlusions 
in the infrapopliteal arteries. This information can be used for regulatory purposes. 
 
 

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6. Objectives and Endpoints 
6.1. Objectives 
6.1.1. 
Primary Objective(s) 
To assess the efficacy of the IN.PACT 014 by comparing the Late Lumen Loss (LLL) of the investigational 
product vs optimal (conventional) PTA.  
6.1.2. 
Secondary Objective(s)  
To assess the safety of the IN.PACT 014 by comparing pre-specified safety parameters of the 
investigational product vs optimal (conventional) PTA. Other pre-specified parameters assessing 
efficacy and safety and clinical utility measures will be evaluated and rates will be compared for the 
IN.PACT 014 vs optimal PTA. 
6.2. Endpoints 
6.2.1. 
Primary Endpoint 
The primary efficacy endpoint will be Late Lumen Loss (LLL) at 9 months post procedure for the IN.PACT 
014 Investigational device vs optimal PTA. LLL will be assessed by means of Quantitative Vascular 
Angiography (QVA) by an independent angiographic core lab at 9 months post procedure or at the time 
of TLR (prior to any intervention on the target lesion). 
Restenosis of the target lesion remains an important problem in the treatment of occlusive lesions in 
below the knee arteries. Neointimal proliferation is a major culprit leading to a decrease in the arterial 
luminal diameter and eventually (re)stenosis. As it is expected that paclitaxel will reduce this neointimal 
proliferation, LLL has been selected as primary endpoint. 

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6.2.2. 
Secondary Endpoint(s) 
• 
Composite Safety Endpoint: A composite of freedom from device- and procedure-related 
mortality within 30 days, freedom from major target limb amputation and freedom from 
clinically-driven TLR within 9 months post-index procedure. 
• 
Major Adverse Event (MAE) rate, defined as a composite of all-cause mortality, target limb 
major amputation and clinically-driven TLR through 3, 6, 9, 12, 24, 36, 48 and 60 months. 
• 
Functional flow assessment at 3, 6, 9, 12, 24 and 36 months, defined as absence of target 
lesion occlusion (no flow) assessed by duplex ultrasound.  
• 
Death of any cause and cardiovascular related deaths through 3, 6, 9, 12, 24, 36, 48 and 60 
months. 
• 
Rate of major target limb amputation through 1, 3, 6, 9 ,12, 24, 36, 48 and 60 months. 
• 
Rate of CD-TLR through 3, 6, 9, 12, 24, 36, 48 and 60 months. 
• 
Rate of Mechanically Driven TLR through 37 days. 
• 
Rate of TLR through 3, 6, 9, 12, 24, 36, 48 and 60 months. 
• 
Rate of CD-TVR through 3, 6, 9, 12, 24, 36, 48 and 60 months. 
• 
Rate of TVR through 3, 6, 9, 12, 24, 36, 48 and 60 months. 
• 
Status of wound healing (completely healed - improvement – unchanged – worsened) at 30 
days, 3, 6, 9, 12, 24 and 36 months. 
• 
Rate of thrombosis at the target lesion(s) through 30 days, 3, 6, 9, 12, 24, 36, 48 and 60 
months. 
• 
Device success (for investigational device only) 
Device success is defined as successful drug delivery, balloon inflation, deflation and retrieval 
of the intact study device without burst below the rated burst pressure (RBP). 
• 
Clinical success 
Clinical success is defined as residual stenosis of ≤ 30% without procedural complications 
(death, major target limb amputation, thrombosis of the target lesion, or TVR) prior to 
discharge. 
7. Study Design 
This is a prospective, multi-center, randomized (1:1) study to evaluate the efficacy and safety of the 
IN.PACT 014 in the treatment of CTOs in the infrapopliteal arteries. Enrollment per site should be limited 
around 30% of the total enrollment. 
The study will enroll at a minimum 50 subjects that will be randomized to the investigational product 
(IN.PACT 014) or a standard PTA balloon. Randomization will happen after screening of the subject, to 
assess the subject meets all the inclusion criteria and does not meet any of the exclusion criteria 
specified in this protocol; this includes meeting the criteria for successful pre-dilatation of the target 
lesion(s). Patient randomization will be determined centrally by means of a web-based system. 
In addition to the randomization outlined above, the following measures have been taken to avoid bias: 

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• 
A multi-center design is used to help ensure a representative sample of the physicians performing 
the procedure and to provide a reasonable enrollment period. 
• 
Enrollment per site should be limited around 30% of the total sample-size. 
• 
Clinical endpoints are reviewed and assessed by an independent Clinical Event Committee. 
• 
Endpoints that are based on imaging will be reviewed and assessed by  independent core labs. 
• 
Any known or foreseeable factors that may compromise the outcome of the clinical investigation or 
the interpretation of results are covered by the Inclusion and Exclusion criteria. 
• 
Preferably, one interventional operator per site will be identified to perform all procedures to 
minimize intra-operator induced bias. 
• 
A blinding plan will be implemented according to ‘Randomization and Blinding Plan’.   
7.1. Duration 
The estimated duration of the study is approximately 84 months from the time of first subject 
enrollment to the last study protocol-required follow-up contact. Each subject will be followed for 60 
months. 
7.2. Rationale  
The treatment of patients presenting with CLI by using standard PTA (without drug coating: Plain Old 
Balloon Angioplasty or POBA) is associated with a significant rate of restenosis (loss of patency).21 
Neointimal proliferation is expected to play an important role in the development of restenosis. The 
comparison of Late Lumen Loss (LLL) after treatment with the IN.PACT 014 (coated with  Paclitaxel) 
versus PTA (POBA) is intended to provide more information on the inhibitory effects of paclitaxel 
delivered  onto the vessel wall towards neointimal proliferation in subjects with below-the-knee arterial 
occlusive disease. For the design of this first-in-human study, randomization against POBA was selected, 
with the intention to show the effect of the addition of Paclitaxel. This will enable for the analysis to 
compare to a control group that was subjected to the same PTA during the index procedure. The 
endpoint of LLL at 9 months post index procedure was selected, as the available evidence (there is only 
limited evidence obtained from controlled randomized controlled trials) have shown a trend for 
reduction of CD-TLR at 12 month follow up in favor of the DCB (which was not statistically significant).62 
This trend in favor of DCB are suggestive to appear as of 6 months of follow up (careful interpretation 
of the Kaplan-Meier curve, Medtronic Data on File), and for this reason this study is intended to show 
any difference in the selected primary endpoint (LLL) at 9 month follow up. For the study population, 
patients with CTO were selected. These CTOs are typically difficult to treat, and because of complete 
stenosis (occlusion) at baseline, maintaining a sufficient luminal diameter is considered essential. For 
this reason, while assessing LLL as primary endpoint, subjects with CTO at baseline are at increased 
risk for “lumen loss”, and a potential benefit of the investigational device compared to PTA can be 
considered clinically significant in this subject population. This potential increased benefit of PTX coated 
balloons over PTA in CTO-lesions has previously been suggested by Liistro during an oral presentation65 
when comparing the rates of patients presenting with CTO-lesions at baseline in the DEBATE-BTK trial 
and in the IN.PACT DEEP trial: in the DEBATE-BTK trial this rate was approximately 80% in both groups, 
while only approximately 40% in both groups in the IN.PACT DEEP trial, and might have played a role 
in the outcomes of both trials. 

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8. Product Description 
8.1. General 
The IN.PACT 014 is a medical device that contains an ancillary medicinal substance. The product 
consists of an over-the-wire (OTW) balloon catheter with a drug-coated balloon at the distal tip. The 
product is indicated for percutaneous transluminal angioplasty in patients with obstructive disease of 
peripheral arteries. The IN.PACT 014, including its components, is considered an investigational 
product.  
The medicinal substance component, referred to as the Freepac™ drug coating, consists of the 
medicinal substance paclitaxel and the excipient urea provides a nominal drug dose density of 
3.5µg/mm2.  The device component physically dilates the vessel lumen by Percutaneous Transluminal 
Angioplasty (PTA) (primary mode of action), and the medicinal substance provides a pharmacological 
agent targeted towards reducing the injury response that leads to restenosis (secondary mode of 
action).    
 
Balloon coating 
The balloons are coated with the FreePac™ drug formulation which consists of a solvent mixture that 
is 9 parts tetrahydrofuran (THF) to 1 part water by volume, while the solute is 50 mg/mL of paclitaxel 
(drug) and 7 mg/mL urea (excipient) by weight. The FreePacTM coating is applied at a nominal drug 
dose density of 3.5 µg per mm2 to the balloon surface area. The drug coating consists of a single 
layer applied along the entire working length of the balloon. Paclitaxel was approved for use for the 
treatment of stenotic or obstructive vascular lesions in the lower extremities in various CE Marked 
commercial products such as disease of the peripheral arteries: IN.PACT Admiral (Medtronic), Lutonix 
® 014 (Bard), Ranger SL (Boston Scientific), and the Passeo-18 Lux (Biotronik).  
The IN.PACT 014 balloon components are made of polyamide (nylon [PA 12]). This material is utilized 
in the commercially available IN.PACT™ Admiral balloons. The IN.PACT 014 drug-coated balloon 
(DCB) design shown in Figure 1 is identical to all the other IN.PACT DCB family designs in formulation 
and target dose per surface area applied. Utilization of the existing FreePacTM coating and similar 
balloon material used on IN.PACT Admiral will allow this product to leverage the large pool of existing 
clinical data, which shows strong safety and efficacy in drug eluting balloons.  
 
Catheter design 
IN.PACT 014 is a dual lumen product (co-axial), available in two usable catheter lengths, 100 cm and 
150 cm, in a range of balloon sizes from 2.0 to 4.0 mm in cylindrical balloon diameter and 40 to 120 
mm in length. The guidewire lumen (central lumen) will permit the use of guidewires to facilitate 
advancement of the IN.PACT 014 catheter to and through the stenosis to be dilated. The catheter will 
be compatible with 0.014” diameter guidewires. In order to correctly position the balloon of either 
product under fluoroscopy, two Platinum-Iridium radio-opaque markers are swaged on the guidewire 
shaft under the balloon itself to define the dilatation area.  

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Figure 1: Engineering diagram of the IN.PACT 014 Balloon Catheter 
 
The IN.PACT 014 delivery catheter has an OTW construction consisting of a proximal luer, a coaxial 
dual lumen shaft, and a distal balloon. The tri-layer inner tubing with black colorant (guidewire tube) 
serves as guidewire lumen and is compatible with guidewires of 0.014” as maximum diameter. The 
annular space surrounding the guidewire tube and the outer polyamide tubing (shaft tube) is the balloon 
inflation/deflation lumen. The shaft tube is compatible with 4 Fr (1.33mm) introducer sheaths. Distally, 
the balloon is welded to the distal shaft portion and to the distal guidewire tube. The balloon design is 
a standard cylindrical balloon. Two radiopaque platinum-iridium markers, applied to the inner tubing 
by a swaging process, provide visual reference points to facilitate positioning of the balloon across the 
target lesion. Proximally, the shaft and guidewire tube are bonded by an ultraviolet (UV) adhesive 
process to the polycarbonate luer. The luer, compatible with monomeric syringes in conformity with 
ISO 594, EN1707, has a straight channel connected to the guidewire lumen to load the guidewire 
(guidewire port). The lateral luer channel is the balloon inflation port, which is used to inflate and 
deflate the balloon with a mixture of contrast medium and saline solution.  
The catheter construction and balloon are designed so that a specific balloon diameter can be reached, 
depending on the balloon size and defined pressure. 
There are two key differences in the design of the IN.PACT 014 catheter when compared to the CE-
marked IN.PACT Admiral.  First, the IN.PACT 014 utilizes a co-axial shaft design, whereas the IN.PACT 
Admiral utilizes a bi-lumen design. Second, the guidewire compatibility for the IN.PACT 014 is 0.014” 
whereas the Admiral is 0.035”.  
IN.PACT 014 is built on the platform of the CE marked Amphirion Plus catheter. Compared to the 
Amphirion Plus platform, the IN.PACT 014 will have: 
• 
The same balloon raw material (Polyamide 12) but medical grade. 
• 
No hydrophilic coating. 
• 
Fully automated coating process with FreePac paclitaxel solution. 
 
 
 
 
Figure 2: Example 2.0x40 mm IN.PACT 014 coated in open configuration 
 
 
 

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Sizing Matrix 
The IN.PACT 014 available matrix for this study is shown in Table 1. The entire IN.PACT 014 
investigational product matrix utilizes a 3-fold balloon wrap configuration. 
The nominal pressure for all sizes is 8 atm. while the rated burst pressure (RBP) is 14 atm. for all 
sizes. 
Table 1: Balloon Diameters and Lengths 
Diameter 
(mm) 
Balloon Length (mm) 
Fold Design 
 
40 
60 
80 
100 
120 
 
2.0 
 
 
 
 
 
 
3 folds 
 
2.5 
 
 
 
 
 
3.0 
 
 
 
 
 
3.5 
 
 
 
 
 
4.0 
 
 
 
 
 
 
Table 2: Model Numbers Mix of IN.PACT 014 
Reference Number  
Balloon 
Diameter 
(mm) 
Balloon 
Length 
(mm) 
Shaft 
Length    
(cm) 
BTK02004015P 
2.0 
40 
150 
BTK02006015P 
2.0 
60 
150 
BTK02008015P 
2.0 
80 
150 
BTK02010015P 
2.0 
100 
150 
BTK02012015P 
2.0 
120 
150 
BTK02504015P 
2.5 
40 
150 
BTK02506015P 
2.5 
60 
150 
BTK02508015P 
2.5 
80 
150 
BTK02510015P 
2.5 
100 
150 
BTK02512015P 
2.5 
120 
150 
BTK03004015P 
3.0 
40 
150 
BTK03006015P 
3.0 
60 
150 
BTK03008015P 
3.0 
80 
150 
BTK03010015P 
3.0 
100 
150 
BTK03012015P 
3.0 
120 
150 
BTK03504015P 
3.5 
40 
150 
BTK03506015P 
3.5 
60 
150 
BTK03508015P 
3.5 
80 
150 
BTK03510015P 
3.5 
100 
150 
BTK03512015P 
3.5 
120 
150 
BTK04004015P 
4.0 
40 
150 

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BTK04006015P 
4.0 
60 
150 
BTK04008015P 
4.0 
80 
150 
BTK04010015P 
4.0 
100 
150 
BTK04012015P 
4.0 
120 
150 
 
Biocompatibility testing has categorized the IN.PACT 014 Paclitaxel-eluting PTA catheter as an 
externally communicating device with limited (< 24 hours) exposure to circulating blood.  
Overall, no signs of delayed or systemic toxicity could be detected in the preclinical investigations or 
biocompatibility testing performed. 
8.2. Manufacturer 
The IN.PACT 014 drug-coated, peripheral balloon catheter is manufactured by Medtronic, Inc. 
Minneapolis, USA.  
8.3. Packaging 
As the IN.PACT 014 is non-CE marked in the regions involved in this study, this will be clearly indicated 
on the label by the following statement: “Exclusively for clinical investigations”. See Appendix A Device 
labeling for the specific device label.  
Inner packaging  
A protective stylette is inserted into the distal tip. The device is then loaded into a hoop, which locks 
onto the device luer and has a clip to hold the compliance chart. The hoop is inserted into a pouch and 
sealed. A label is placed on the pouch indicating the product name, size/diameter and lot number. The 
label also contains a serial number that can be used for tracking purpose. 
Outer packaging  
An identical product label from the pouch is placed on the shelf carton. The sealed pouch (containing 
the finished product and compliance chart) are inserted into the carton with both product labels facing 
the same direction. An instruction for use (IFU) booklet is inserted into the carton and closed. Stickers 
are placed on either end of the sample carton to maintain integrity of each unit. The IFU will be provided 
in English (unless otherwise required by local laws). 
Sterilization  
IN.PACT 014 product is sterilized by an Ethylene Oxide (EtO) sterilization cycle at Medistri SA, located 
in Switzerland. The sterilization cycle and provider are identical to the commercially available IN.PACT 
Family of products. 
8.4. Intended Population 
The intended population to be treated with the IN.PACT 014 device will be adult patients suffering from 
advanced peripheral arterial disease (PAD) located in the infrapopliteal arteries.  

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8.5. Equipment 
Any test equipment critical to be used for assessing endpoints (e.g., Duplex Ultrasound, Angiography) 
will be maintained/calibrated according to the site’s standard protocol. Maintenance and calibration 
reports will be monitored periodically. 
8.6. Product Training Requirements 
The implanting Investigator will be evaluated to ensure that he/she is qualified by training, education, 
and experience to perform DCB procedures in the infrapopliteal arteries.  
The implanting Investigator(s) will be trained on the Instructions for Use. Performed training will be 
documented prior to start of study activities. Medtronic and/or its designees are responsible for the 
training of appropriate clinical site Personnel. The overview of training requirements for clinical site 
Personnel is documented in the study training plan and based on a risk assessment. 
8.7. Product Receipt and Tracking 
All sites will be trained to proper product tracking processes to meet Medtronic policies and regulatory 
standards for Product Accountability, including the return of open or unopened products (for defect, 
damage, malfunction, expired inventory).  
Once the site has been activated, investigational products will be ordered and shipped to the site. 
Investigational products will be tracked during the clinical study by assigning unique identifiers to each 
product. The investigator or designee is responsible for maintenance of a Product Accountability Log in 
the investigator site file. On this log, the receipt, use, return, and disposal of the investigational 
devices/products shall be documented.  
The investigational products may only be used in the clinical study and must be used according to the 
clinical protocol and Instruction for Use. All unused product will be returned to Medtronic upon 
completion of study enrollment. 
8.8. Product Storage 
Investigational products must be stored in a secured area. The method of storage shall prevent the use 
of investigational devices/products for other applications than mentioned in this clinical investigation 
plan. In addition, all information for the use, storage, and handling of the investigational device/product 
as indicated in the Investigator’s Brochure and Instructions for Use must be taken into account. 
8.9. Product Return 
All non-functioning investigational products will be returned to Medtronic for analysis. Relevant 
information should also be recorded on associated case report forms. Detailed instructions for the return 
of non-functioning devices will be provided in the investigational site file. At the end of the study 
enrollment period, all remaining investigational devices must be returned to Medtronic. 

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9. Selection of Subjects 
9.1. Study Population 
The study population will be comprised of patients with symptomatic Chronic Critical Limb Ischemia 
(CLI) who are candidates for percutaneous endovascular intervention and who meet the 
Inclusion/Exclusion criteria.  
Subjects enrolled in this study will be comprised of adult male and female subjects derived from: 
• 
Individuals referred to a non-invasive vascular laboratory for assessment of the peripheral 
arterial disease. 
• 
Angiography suites 
• 
Clinical practice: subjects presenting to the investigator’s practice with chronic symptoms in the 
lower extremity(s), peripheral arterial disease are potential study candidates. 
The study will enroll at a minimum 50 subjects at approximately ten (10) European sites. 
9.2. Subject Enrollment 
Only subjects that meet all the study eligibility criteria and sign and date an Informed consent form will 
be eligible for enrollment. This includes intra-procedural anatomical eligibility criteria such as successful 
pre-dilatation of the target lesion(s). If the aforementioned criteria are fulfilled, the subject can be 
randomized to one of the treatment arms and at this point the patient is considered enrolled. The point 
of enrollment is only considered after successful pre-dilatation because until then only standard of care 
procedures are followed. Enrolled subjects will be documented on the Screening and Enrollment log. 
Subjects who are enrolled, but in whom the device does not cross the (target) lesion will be followed 
through the 1 month follow-up only. 
Subjects who do not qualify for enrollment will be documented as ineligible on the Screening and 
Enrollment log.  
 
 
 

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Figure 3: Subject Enrollment Flow 
 

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9.3. Inclusion Criteria 
1. Age ≥ 18 years.  
2. Subject has been informed of the nature of the study, agrees to participate and has signed an EC 
approved consent form. 
3. Female subjects of childbearing potential have a negative pregnancy test ≤7 days before the 
procedure and are willing to use a reliable method of birth control for the duration of study 
participation; Subjects will be exempted from this requirement in case they are sterile, infertile, or 
have been post-menopausal for at least 12 months (no menses). 
4. Subject has documented chronic Critical Limb Ischemia (CLI) in the target limb prior to the study 
procedure with Rutherford Clinical Category 4 or 5 . 
5. Subjects with documented infection grade 0-2 and ischemia grade 2-3 according to the WIfI 
classification. 
6. Life expectancy >1 year in the Investigator’s opinion. 
7. Reference Vessel Diameter (RVD) 2 - 4 mm, confirmed by DUS assessment. 
8. Total occlusions (100% stenosis) with total lesion length ≥40mm (by visual estimate). 
9. The lesion must be located in the infrapopliteal arteries and above the ankle joint. Lesions may not 
extend above the tibioperoneal trunk (P3 segment of the popliteal artery) or below the ankle joint 
(arteries of the foot), nor can the treatment (investigational device or standard PTA, including pre-
dilatation) extend beyond these indicated regions for more than 1 cm. 
Note:  
• 
A target lesion can extend into the P3 segment in case it involves a straight lesion extending 
from the target vessel.  
• 
Non-significant stenosis below the ankle joint can be allowed in case this is not part of the 
target lesion and does not require treatment 
10. Multiple lesions can be treated if they are located in separate vessels but all lesions must meet the 
protocol specified criteria. 
11. Presence of documented run-off to the foot (clearly visible dorsalis pedis, pedal arch or plantar 
arteries by angiography). Target vessel should give direct or indirect run-off to the foot. 
12. Inflow free from flow-limiting lesion confirmed by angiography. Patients with flow-limiting inflow 
lesions (≥50% stenosis) can be included if lesion(s) have been treated successfully before 
enrollment, with a maximum residual stenosis of ≤30% per visual assessment. If an inflow lesion 
must be treated within or above the P3 segment of the popliteal artery, there must be a minimum 
of 3 cm healthy tissue between this (treated) lesion and the infrapopliteal target lesion. 
13. Successful pre-dilatation of the (entire) target lesion. Success being documented by angiographic 
visual estimate of ≤30% Residual Stenosis of the target lesion and by functional assessment of the 
distal flow by intra-operative Doppler: recording of biphasic or triphasic signal with rapid take-off 
distal to the target lesion. 
 
 

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9.4. Exclusion Criteria 
1. Subject unwilling or unlikely to comply to the appropriate follow-up times for the duration of the 
study. 
Note: In case the subject lives far from the investigational site, the investigator should discuss 
the follow-up requirements extensively during the Informed consent process to ensure that the 
subject is fully aware about the expectations and is willing to comply with the follow-up schedule. 
2. Planned index limb amputation above the metatarsal level, or any other planned major surgery 
within 30 days pre or post-procedure. A planned amputation including and below the metatarsal 
level (1 or multiple rays) is accepted. 
3. Lesion and / or occlusions located or extending in the popliteal artery or below the ankle joint 
space. 
Note:  
• 
A target lesion can extend into the P3 segment in case it involves a straight lesion extending 
from the target vessel 
• 
Non-significant stenosis below the ankle joint can be allowed in case this is not part of the 
target lesion and does not require treatment. 
4. Significant (≥50% DS) inflow lesion or occlusion in the ipsilateral Iliac, SFA and popliteal arteries 
left untreated. 
5. Failure to obtain a ≤30% residual stenosis in pre-existing, hemodynamically significant (≥50% 
DS) inflow lesions in the ipsilateral iliac, SFA and popliteal artery. Inflow lesions should be treated 
as per standard of care. 
6. Prior stent(s) or bypass surgery within the target vessel(s) (including stents placed within target 
vessels during the index procedure prior to randomization. 
7. Previous DCB procedure in the target vessel within 6 months prior to index procedure. 
8. Aneurysm in the target vessel. 
9. Angiographic evidence of thrombus within target limb. 
10. Pre-dilation resulted in a major (≥ Grade D) flow-limiting dissection (observed on 2 orthogonal 
views) or residual stenosis > 30%.  
11. Use of alternative therapy, e.g. atherectomy, cutting balloon, laser, radiation therapy, stents as 
part of target vessel treatment. Note: Use of stents is only allowed for bailout stenting.  
12. Recent MI or stroke < 30 days prior to the index procedure. 
13. Heart failure with Ejection Fraction < 30%. 
14. Known or suspected active infection at the time of the index procedure (abnormal white blood 
cell count, fever, sepsis or positive blood culture), excluding an infection of a lower extremity 
wound on the target limb (only WIfI infection grade 0-2 allowed). 
15. Subjects with infection grade 3 and  ischemia grade 0 and 1 according to WIfI classification.  
16. Subjects with neurotrophic ulcers, heel pressure ulcers or calcaneal ulcers with a risk for major 
amputation.  
17. Subjects with documented active osteomyelitis, excluding the phalanges, that is beyond cortical 
involvement of the bone per clinical judgement. 
18. Impaired renal function (GFR < 20 mL/min) or patients on dialysis. 

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19. Subject with vasculitis, systemic Lupus Erythematosus or Polymyalgia Rheumatica on active 
treatment. 
20. Patient receiving systemic corticosteroid therapy (expected dosage exceeding 5mg of 
prednisolone or equivalent, per day during the initial 9 months after procedure). 
21. This criteria has been removed. 
22. Known allergies or sensitivities to heparin, aspirin (ASA), other anticoagulant/anti-platelet 
therapies which could not be substituted, and/or paclitaxel or an allergy to contrast media that 
cannot be adequately pre-treated prior to the index procedure. 
23. The patient is currently enrolled in another investigational device or drug trial that is interfering 
with the endpoints of this study. 
24.  Female subjects who are breast-feeding at the time of enrollment. 
 
 

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10. Study Procedures  
10.1. Schedule of Events 
The schedule of study procedures and assessments can be seen in Table 3. 
Table 3: Schedule of study procedures and assessments 
  
Screening 
Procedure 
Discharge 
30 days 
(± 7 days)  
3 months 
(±15 days) 
6 months 
(±30 days) 
9 months 
(±60 days) 
12 months 
(±30 days) 
24 months 
(±30 days) 
36 months 
(±30 days) 
48 months 
(±30 days) 
60 months 
(±30 days) 
Unscheduled 
Upon Early 
Termination 
 
Visits 
Phone Calls 
Visit 
Phone 
Calls 
Inclusion/Exclusion 
and consent 
X 
 
 
 
 
 
 
 
 
 
X6 
 
 
 
Physical Exam 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
Medical history and 
demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
DUS 
 
X3 
X4 
X 
X 
X 
X 
X 
X 
X 
 
 
X5 
 
ANGIOGRAPHY 
 
X 
 
 
 
 
X 
 
 
 
 
 
X5 
 
Rutherford 
Classification 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
WIfI assessment 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
Wound care  / 
Assessment1 
X2 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
EQ-5D 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
Adverse Events 
Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
X7 
1. For as long as applicable 
2. Includes WIfI classification at baseline visit 
3. Duplex Ultrasound for Reference Vessel Diameter measurements and Procedural Duplex Ultrasound Doppler Examination to determine 
successful pre-dilatation 
4. DUS assessment if available, should be prior to discharge,.  
5. In case an angiography / DUS of the study limb is done during an unscheduled visit it has to be provided to sponsor 
6.   
• 
Ensure subject is reconsented prior to conducting any study specific assessments after 36 months. 
• 
In case the subject exited the study at 36 months post procedure or before, ensure that the subject is picked up again in the study 
through reconsenting, prior to conducting any study-specific assessments after 36 months, if allowed by local regulations. 
7. Collection of information about (vital) health status for exited subjects, upon subject's consent until 60 months after index procedure 
 
 

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10.2. Subject Screening  
Subject eligibility to the study will be determined by the investigator or by a trained and delegated 
member of the investigational site’s research team according to the criteria listed in section 9 of this 
protocol. In case they fulfil the criteria, subjects will be informed about the IN.PACT BTK study and 
asked for their interest and willingness to participate via the Informed consent process. Failure to 
meet all inclusion and exclusion criteria results in a Screening Failure and such subjects must not be 
enrolled to the study.  A screening and enrollment log is provided to the site and should be completed 
by the site’s study staff to maintain a cumulative log of all screened and enrolled subjects. 
 
Screening/Baseline Assessments: 
After the subject voluntarily has signed and dated the Informed Consent Form, the subject will be 
considered a study candidate. If a subject does not sign the Informed Consent Form, then no further 
screening can occur.   
Collection of screening and baseline information will take place only after the subject has given 
voluntary, documented Informed consent and will include the following: 
• 
Screening Inclusion/Exclusion and consent 
• 
Physical Exam 
• 
Pregnancy test for applicable subjects 
• 
Medical history and demographics 
• 
Baseline Medications (see 10.3. Prior and Concomitant Medications) 
• 
Rutherford Classification  
• 
WIfI Classification 
• 
Wound assessment 
• 
EuroQol-5D questionnaire (EQ-5D)  
Subjects who do not qualify for enrollment will be documented as ineligible on the Screening and 
Enrollment log. 
10.3. Prior and Concomitant Medications 
Prior and concomitant medication schedules below are recommended but investigator’s discretion and 
institutional standard of care should be followed.  
Medication use: the subject’s anti-platelet and anti-coagulant medication use will be documented at 
baseline and follow-up visits (see also 10.8. Medication Compliance). 
 
 

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Prior to the index procedure: 
Administer dual antiplatelet therapy (aspirin and clopidogrel, ticlopidine or equivalent) before the 
procedure. 
Any loading dose can be given as per institutional standard of care; patients already receiving oral 
anticoagulants (warfarin or Novel Oral Anticoagulants (NOAC) should receive concomitant to their 
anticoagulant 1 or both antiplatelet drugs, per investigator’s discretion evaluating the risk of 
bleeding and thrombotic events. 
During the index procedure: 
Use of systemic heparinization as per institutional standard of care. 
Following the index procedure: 
Subjects should be prescribed daily acetyl-salicylic acid (ASA) and daily clopidogrel (ticlopidine, or 
equivalent if required) for at least 4 weeks following the procedure. For the purpose of the study 
recommended duration of DAPT within this study is 3 months.  
Prolonged antiplatelet therapy can be given at the discretion of the physician and should be 
considered after placement of stents. Patients already receiving oral anticoagulants (warfarin or 
Novel Oral Anticoagulants (NOAC) should receive concomitant to their anticoagulant 1 or both 
antiplatelet drugs, per investigator’s discretion evaluating the risk of bleeding and thrombotic 
events. 
 
10.4. Subject Consent 
10.4.1. 
Consent Materials 
Medtronic, the Competent Authorities (CA), and Ethics Committees (where applicable) shall approve all 
Informed consent documents prior to implementation in the study. Medtronic, Ethics Committees, and 
CAs, where applicable must pre-approve all language changes to the Informed consent throughout the 
course of the study prior to implementation; this includes initial submission, annual reviews (if 
applicable) and protocol amendment reviews. The original approved Informed consent must be retained 
at the investigational site.  
Any revisions required by the Ethics Committee must be forwarded to Medtronic for review and approval 
before the revised consent form is returned to the Ethics Committee for final review and full approval. 
Medtronic will provide any important new information that impacts the health, safety or welfare of study 
subjects, for inclusion in Informed consent updates as it becomes available. Sites should follow any 
Medtronic, CA or Ethics Committee requirements for disseminating new information and re-consenting 
subjects during the course of the study. 
The Informed consent form will be provided separate from this CIP. 
 
 

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10.4.2. 
Informed Consent Process 
The investigator (or authorized designee) must administer the approved Informed consent to each 
prospective study patient without coercion or undue improper influence on, or inducement of, the 
patient to participate.  During the consent discussion the investigator (or authorized designee) must 
fully inform the patient of all pertinent aspects of the study, using native non-technical language that 
is understandable to the patient. The patient must be informed about their right to withdraw from the 
study at any time and for any reason without sanction, penalty, or loss of benefits to which the patient 
is otherwise entitled, and also informed that withdrawal from the study will not jeopardize their future 
medical care. The patient must also be informed that by participating in the study, they are not waiving 
their legal rights. The patient must have ample time and opportunity to inquire about details of the 
study, and to decide whether or not to participate in the clinical study. All questions about the study 
should be answered to the satisfaction of the patient. All items discussed in the Informed consent must 
be explained. 
Informed consent will be obtained in writing from the patient. The date of consent and process by 
which the consent was obtained (including documentation of special circumstances, if applicable; see 
Section 10.2) will be documented in the patient’s medical record prior to any study-specific procedures. 
The Informed consent shall be documented before any procedure specific to the clinical investigation 
is applied to the subject except when special circumstances apply. Informed consent must be obtained 
in accordance with the national and local laws, regulations and guidelines of each site. The institutional 
standard procedure consent form does not replace the study Informed consent. 
The patient’s signature and date of consent serve to document that they understand the written and 
verbal information that the investigator (or designee) provides, and their agreement to participate and 
collect their medical data. The investigator (or designee) who conducted the Informed consent process 
must provide their handwritten signature and date the consent was completed on the Informed consent 
form. The original signed Informed consent will be retained in the patient’s study records. A copy of 
the signed Informed consent will be provided to the patient. 
10.4.3. 
Special Circumstances for Informed Consent Process and Signature 
If a patient cannot read or write, an impartial witness must be present during the entire Informed 
consent discussion. The written Informed consent (and any other information) shall be read aloud and 
explained to the patient and witness. The witness signs and personally dates the Informed consent 
attesting that the information was accurately explained and that consent was freely given. The patient 
will sign and date if possible.   
Given the investigational status of the IN.PACT 014, emergency cases are not allowed under this 
protocol. 
In case national or local legislation contains requirements on the Informed consent process that are 
in addition to or different from the requirements outlined in this CIP, then the national or local 
requirements should be complied to. 
 
 

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10.4.4. 
Subject Accountability for Follow-up Extension 
Subjects in follow-up and willing to extend their follow-up from 36 to 60 months are to be re-consented.  
Where locally allowed, study extension until 60 months can occur for subjects who exited the study at 
the 36-month follow-up visit or before, as soon as the required competent authorities and ethics 
commitees approve the required study documents.  
Subjects who already exited the study, are picked up again in the study through re-consenting prior to 
conducting any study-specific assessments. Exited subjects who refuse to participate in the extension 
beyond 36 months remain listed as exited. 
Subjects who are not willing to participate in the follow-up extension, may still give their consent for 
the collection of information around health (vital) status. Please refer to the inform consent form for 
detailed information. 
10.5. Randomization and Treatment Assignment 
Randomization will be 1:1 and be stratified by study site. Due to the nature of the procedure, it is not 
possible to blind the patient, implanting investigator or study site staff.   
Randomization will be performed after confirmation the subject meets all inclusion/exclusion criteria, 
including successful pre-dilatation of the target lesion(s). Randomization will be processed centrally by 
means of a web-based system that will provide the randomization treatment arm ( investigational device 
(IN.PACT 014) or optimal PTA).   
Once subjects are assigned a study group (DCB  or PTA) they are considered randomized. A deviation 
is required if a subject does not receive the study device per their randomized assignment. 
10.6. Index Procedure 
The following section describes the required assessments and activities during the index procedure. 
There should be preferably  one operator per site. 
10.6.1. 
Vascular Access 
Vascular access should be obtained as per site standard of care (depending on lesion location, patient 
factors or any other factors that would impact the choice of vascular access). 
10.6.2. 
Angiography 
Angiography must be conducted according to the Angiographic Corelab Protocol. The Angiographic 
Corelab Protocol will be available outside of this CIP. 
A radiopaque ruler will be placed on the subject prior to the start of the procedure and will be used to 
define anatomical measurement references and assess the lesion length. Detailed instructions for the 
placement of the ruler are specified in the Angiographic corelab protocol. As a next step, a compatible 
sheath should be inserted and anticoagulation should be administered as per the Investigators 
discretion to obtain or maintain appropriate clotting time (see 10.3. Prior and Concomitant Medications). 
In order to identify the anatomical characteristics of the vasculature and to visualize and define the 
lesion(s), a selective angiography of the index limb will be performed that must include: ipsilateral 
femoral, popliteal and tibioperoneal vessels (up and including the pedal level). 
 

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10.6.3. 
Treatment of Non-Target Lesions 
Significant (≥ 50% DS or occlusions) inflow lesions in the ipsilateral iliac, SFA and popliteal arteries, 
must be treated prior to enrollment of the subject, no other non-target lesions (including out-flow 
lesions) in the index limb may be treated during the index procedure. Any contralateral disease (that 
requires treatment) should be 30 days after the index procedure. 
The inflow lesions should be treated per institutions standard of care, and based on the relevant 
evidence with regards to the efficacy of these treatments. If an inflow lesion must be treated within 
or above  the P3 segment of the popliteal artery, there must be a minimum of 3 cm healthy tissue 
between this (treated) lesion and the infrapopliteal target lesion.If significant inflow lesions are 
present, successful treatment must be performed prior to the treatment of any target lesion(s). 
Successful treatment of inflow lesion(s) will be defined as: obtaining a residual diameter stenosis of 
≤30%. 
BTK vessels that have non-CTO lesions are considered as Non-Target Vessels / Lesions.  These lesions 
should be treated first per standard of care. 
10.6.4. 
Target Vessel / Lesion pre-dilatation 
1. Identify the target vessel(s) / lesion(s)  
2.  Perform digital substraction angiographic (DSA) images of the target lesion(s) that 
demonstrate the occlusion (in a view that minimizes the degree of vessel overlap)  
3.  Perform Duplex Ultrasound according to corelab guidelines for Reference Vessel Diameter 
measurements 
Perform pre-dilatation of the target lesion with a non-drug coated standard semi compliant balloon (no 
other devices, such as cutting/scoring balloons are allowed). In case there are multiple target lesions, 
the Investigator will select the first target lesion upon his discretion and proceed with pre-dilatation of 
this lesion. 
For the pre-dilatation, a non-drug coated standard semi compliant balloon must be 
selected with: 
• 
A diameter that will provide at least 1:1 ratio with the Reference Vessel Diameter (RVD) 
• 
A length that covers the entire length of the lesion  
Note that more than one pre-dilatation balloon may be used, and that this balloon may be 
inflated more than once. 
• 
Inflate the balloon for at least 3 minutes 
• 
Any CE-marked PTA balloon can be used 
 
4. Record an image of the target lesion post pre-dilatation. Ensure to perform an angiography 
distal to the target lesion (including run-off and visualize the entire vessel distally through the 
pedal arch). Assess the subject for any angiographic complications post pre-dilatation and 
confirm the angiographic inclusion and exclusion criteria. An intra-procedure Doppler 
examination distal of the target lesion must also be performed. 
 
 

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Successful pre-dilatation of the target lesion is defined as: 
• 
Residual stenosis of < 30% after pre-dilatation (per visual estimate) AND 
• 
Intra-procedure Doppler examination records a biphasic (with rapid take-off) or triphasic 
wave signal.  
• 
No major (> Grade D) flow-limiting dissection (observed on 2 orthogonal views). 
 
Enrollment: If the above criteria have been met, the subject can be randomized and will be 
considered enrolled (at the time the patient has been randomized). 
 
In case the subject does not meet the criteria above, the subject cannot be randomized and should be 
considered and documented as a screening failure, treated by standard of care.  
Subjects with multivessel disease are allowed and multiple target lesions can be treated during the 
index procedure. In case of subjects with multiple target lesions, the randomization is at “subject” 
level.  All lesions that meet the specifications detailed in the inclusion  and exclusion criteria (lesion 
anatomical characteristics) including the pre-dilatation criteria will be considered as target lesions. 
All target lesions must be treated with the assigned (randomized) treatment. Following the treatment 
of first target lesion per the randomization arm, the subsequent lesion(s) must receive the same 
treatment as the first treated target lesion. 
10.6.5. 
Treatment of Target Vessels/Lesions 
All vessels that have a CTO lesion and are intended for treatment at the time of the index procedure, 
meeting all inclusion criteria and none of the exclusion criteria will be considered the target vessels. 
The lesion(s) intended for treatment at the time of the index procedure that meet the inclusion criteria 
and none of the exclusion criteria will be considered the target lesion(s).  
Multiple lesions in one vessel should always be treated as one lesion, no gaps should be left untreated. 
In case the lesion has following characteristics: a CTO section and a section of stenosis that requires 
treatment, the entire lesion (occluded and stenosed section) must be treated as one lesion. 
In case the patient is randomized to the PTA arm, no further treatment of the target lesion(s) should 
be performed (a <30 % residual diameter stenosis has been obtained in the absence of flow limiting 
dissections).  
In case the patient is randomized to the IN.PACT 014 arm, an appropriate balloon must be selected. 
The diameter of the IN.PACT 014 balloon will be selected based on the reference vessel diameter 
(approximating 1:1 ratio).  
The length of the IN.PACT 014 balloon should be sized to ensure the balloon extends beyond the 
proximal and distal edges of the target lesion by 1 cm. In case the target lesion requires treatment with 
multiple IN.PACT 014 balloons, the Investigator must ensure an overlap of 1 cm to maintain continuous 
coverage of the target lesion. The IN.PACT 014 balloon catheters will be delivered and deployed per 
the Instructions for Use (IFU).  
 

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IN.PACT BTK Inflation Time: Maintaining balloon inflation for 3 minutes is strongly recommended.  
 
After the treatment of the target lesion(s) is considered complete by the Investigator, an angiographic 
image should be captured that visualizes the entire target lesion(s) treatment area. A final image should 
now be recorded that documents the target lesion treatment area(s) and includes run-off of all vessels 
distal to the treatment area including the dorsalis pedis, pedal arch or plantar arteries. 
In case multiple paclitaxel coated balloons are used (inflow treatment and index procedure), consider 
the total paclitaxel dosage from all devices. Medtronic has not evaluated systemic safety of implanting 
multiple IN.PACT DCBs with a total drug dosage exceeding 34,854 µg paclitaxel.  
To minimize risk of embolic events due to drug coating, when treating long lesions, maximize single 
balloon length. 
10.6.6. 
Adjunctive Therapies 
Adjunctive therapies should be avoided if possible. In case of suboptimal procedure result (>50 % 
residual stenosis, perforation, occlusive complication (recoil) or flow limiting dissection) prolonged 
balloon inflation should be attempted. If prolonged balloon inflation does not provide the expected 
result, bail-out stenting is allowed. All other adjunctive therapies (including but not limited to: laser, 
atherectomy, cryoplasty, cutting/scoring balloons or brachytherapy) are not allowed.  
Final angiographic images will be collected once treatment of the target lesion(s) is complete. This will 
include capturing images that demonstrate the residual stenosis post-treatment of the target lesion 
treatment area(s) and run-off of all vessels distal to the target lesion treatment area(s) including the 
dorsalis pedis, pedal arch or plantar arteries. 
Note: The end of the procedure is defined as the time after a complete final angiogram has been 
performed and the last guidewire and catheter have been removed. In case the subject needs to return 
to the procedure room and a guiding catheter is reinserted for dilatation, this is considered a 
reintervention. Removal of the sheath(s) may be done at the Investigators discretion. 
 

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Figure 4: Randomization and Treatment Assignment flow 
 
No
Subject Screening
Does the subjectt 
meet study eligibility 
criteria and signed 
Informed Consent 
Form?
Screening failure
Succesful 
pre-dilatation?
Yes
No
Yes
Randomization
Subject Enrollment
Optimal 
PTA
DCB
Treatment
Device crossed the 
target lesion
FU Visits at Discharge, 
1m, 3m, 6m, 9m, 12m, 
24m, 36m
Phone calls at 48m, and 
60m post-procedure
1 month 
follow-up 
No
Study Exit
Study Exit
FU Visits at Discharge, 1m, 
3m, 6m, 9m, 12m, 24m, 36m, 
Phone calls at 48m, and 60m 
post-procedure
Study Exit
Screening and 
Enrollment Log
Screening and 
Enrollment Log
Yes
Successful predilatation of the (entire) target lesion.
Success being documented by angiographic visual estimate of ≤30% 
Residual Stenosis of the target lesion and 
by functional assessment of the distal flow by intra-operative Doppler: 
recording of biphasic or triphasic signal with rapid take-off distal to the 
target lesion
Pre-dilatation
Standard Semi-Compliant PTA balloon at least 1:1 to RVD. 
Inflation time of approximately 3 minutes. 
DCB Treatment
Extend at least 10 mm each side of the lesion; if multiple 
treatment balloons, overlap each by at least 10 mm. 
Hold inflation for approximately 3 minutes. 
Treatment balloon(s) must match RVD distal to target 
lesion.
 
 
   
 

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10.7. Follow-Up Requirements 
10.7.1. 
Discharge Follow-Up Requirements 
All subjects are required to have a discharge assessment. 
Please refer to Table 3 (schedule of events) for the mandatory assessments during this follow up. 
10.7.2. 
Follow-up Visit Requirements 
Following hospital discharge, all subjects are required to have follow-up visits at predetermined time 
points during the study, as specified in table 3. If necessary, the follow-up assessments can take place 
outside of the investigational site, as long as the study protocol requirements and local regulations are 
met.  
10.7.3. 
Follow-up phone calls 
Subjects that consented for the study extension will be contacted by telephone at 48-months, and 60-
months post-procedure. At this time, an evaluation for AEs per protocol requirements will be completed 
and documented as specified in table 3.  
10.7.4. 
Unscheduled visits 
A subject who returns to the investigational site between protocol-required visits with an ischemic event 
of the target limb, is considered to have an unscheduled visit. The requirements for unscheduled visits 
must be followed as specified in table 3 and the data will be collected in the eCRF.  
10.7.5. 
Follow up Duplex Ultrasound Examination 
The DUS should be performed by an experienced DUS-operator that has been trained on the study 
protocol and should follow the DUS corelab protocol (refer to DUS corelab manual of operation). Since 
the DUS examination is operator dependent, all efforts should be made to have 1 dedicated operator 
performing all study required DUS examinations. 
10.7.6. 
Follow up Angiography 
At 9 months follow up, there will be a required angiographic follow up. These angiographic images will 
be reviewed by the angiographic corelab to assess the study’s primary efficacy endpoint of Late Lumen 
Loss (LLL). It is therefore required that this angiography will be performed per the standards provided 
by the angiographic corelab protocol (refer to angiographic corelab manual of operation). 
These images must be captured and labelled as such prior to any intervention on the target lesion (if 
applicable). If, per the Investigators discretion, any treatment deemed necessary on the target lesion 
during this 9 month follow up angiography, this should be documented at the applicable location in the 
eCRF. Specific attention should be given to document such intervention as being incidental (eg 
revascularization done because of incidental finding during follow up angiography) or if this  (re-) 
intervention was done for clinical symptoms (CD-TLR). 

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10.7.7. 
Wound Care Follow-up Assessments 
Required wound care and assessment follow up is provided in Table 3 (Section 10.1. Schedule of 
Events). This pertains to the follow up assessments for which the information on wounds needs to be 
provided to the sponsor in the eCRF. In addition to the before mentioned assessments, the following 
wound care will be mandatory as a minimum requirement:
 
* A minimal of 3 assessments between the study procedure and the 1 month visit inclusive (including 
visit windows), is required.  
These wound care follow up assessments should take place at a dedicated wound-care clinic (or foot 
clinic) by a wound care specialist who will also be part of the study team. 
Wound assessment and wound care is only applicable for subjects that present with (ischemic) wounds 
on the target limb at baseline or for subjects who develop new (ischemic) wounds on the target limb 
during the conduct of the study.  In case of planned  amputations (that meet the inclusion criteria for 
this study) the amputation wound(s) will be assessed throughout the study. 
 
During the protocol required follow up visits, data will be collected on: 
Wound status by visual estimation 
• 
Worsened 
• 
Unchanged 
• 
Improved 
• 
Completely healed 
• 
Amputation 
• 
Skin graft 
Identification of new wounds (if applicable)  
If any wound is assessed for planned amputation (below the metatarsal level), the amputation should 
only be performed once the necrotic tissue is clearly and completely demarked from the healthy tissue. 
It is recommended that assessment for major amputation is done in agreement with the 
interventionalist and wound care specialist.   
10.8. Medication Compliance 
Medication usage for antiplatelet and anticoagulant therapy will be assessed at appropriate time points 
in accordance with Table 3. The medication compliance will be documented in the Electronic Data 
Capture (EDC). 

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10.9. Assessment of Efficacy 
The primary efficacy endpoint is evaluation of the Late Lumen Loss (LLL) assessed by QVA and 
determined by independent angiographic core lab. 
10.10. Assessment of Safety 
There are multiple secondary endpoints that will assess safety of the IN.PACT 014 device. One of the 
secondary endpoint will provide significant information to assess the safety of the IN.PACT 014 device 
and is described in section 6.2.2. as composite safety endpoint: A composite of freedom from device- 
and procedure-related mortality within 30 days, freedom from major target limb amputation and 
freedom from clinically-driven TLR within 9 months post-index procedure. 
10.11. Recording Data 
The investigator must ensure accuracy, completeness and timeliness of the data reported in the eCRFs 
and in all other required reports. Data reported on the eCRFs which are derived from source documents 
must be consistent with the source documents and discrepancies need to be justified in a documented 
rationale, signed and dated by the principal investigator or co-investigator, and filed in the subject’s 
medical file. 
Only authorized persons can complete eCRFs. The investigator (physicians only) shall sign eCRFs as 
specified on the Delegated Tasks List included in the Investigator Site File. 
The Electronic Data Capture (EDC) system maintains an audit trail on entries, changes, or corrections 
in eCRFs. If a person is only authorized to complete eCRFs or to make changes to an already signed 
eCRF, the investigator shall re-sign this eCRF. 
Any source documentation as well as any imaging (e.g., procedure reports, imaging material, lab 
reports, death certificates, autopsy reports) that is sent to the sponsor should have all subject identifiers 
removed and replaced with the subject’s study ID. 
Where copies of the original source document as well as print outs of original electronic source 
documents are retained, these shall be signed and dated by a member of the investigation site team 
with a statement that it is a true reproduction of the original source document.  
The source documents must be made available for monitoring or auditing by the sponsor’s 
representative or representatives of the competent authorities and other applicable regulatory agencies.  
An electronic PDF version or paper copy of the eCRFs as well as access to the EDC system will be 
provided to the investigation site prior to subject enrollment.  
10.11.1.  Investigator records 
At a minimum, the following records must be kept by the investigator:  
 
• 
Clinical Investigation Plan and, if applicable, any amendments 
• 
Investigator’s Brochure and 1 copy of the Instructions for Use 
• 
Medtronic and EC approved Informed Consent Form and, if applicable, any amendments 
• 
Competent Authority approval or notification 
• 
Fully signed Clinical Trial Agreement and confidentiality agreement (if not included in the 
Clinical Trial Agreement) 

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• 
Financial disclosures; If the financial interests change during the course of the study or within 
1 year, the study is completed the investigator is obliged to inform the sponsor of such financial 
change 
• 
Insurance certificates 
• 
Completed Delegated Task List and Curriculum Vitae of all investigational site personnel 
• 
Training documentation of all investigation site personnel 
• 
Relevant communications 
• 
Subject screening log and/or subject identification log  
• 
Signed, dated, and fully executed Informed consent 
• 
The investigator will clearly mark clinical records to indicate that the subject is enrolled in this 
clinical investigation. 
• 
Fully executed eCRFs and corrections (in the EDC) 
• 
Reports of Adverse Events and Device Deficiencies  
• 
Device accountability records 
• 
EC correspondence 
10.11.2. Investigator reporting responsibilities  
 
Investigator reporting responsibilities 
 
Report 
Submitted to 
Description 
Adverse Events 
Sponsor, EC, and 
local Competent 
Authority, where 
applicable 
Refer to section 12.2 for reporting requirements. 
Progress Report 
Sponsor and EC  
Provide if required by local law or EC.  
(ISO 14155).  
Withdrawal of EC 
approval 
Sponsor 
Investigator will inform Medtronic in case EC 
approval is withdrawn. 
Final Report 
EC 
A copy of the Final Clinical Study Report will be 
provided to the EC. 
Deviations from Investigational Plan 
Planned deviation 
Sponsor, EC, 
Competent Authority, 
if applicable 
Prior approval from Medtronic must always be 
obtained from Medtronic. If the deviation affects 
scientific soundness of the clinical study or the 
rights, safety, or welfare of the subject and is not 
an emergency, prior approval must be obtained 
from the EC and Competent Authority. 
Other Deviations 
Sponsor, EC, 
Competent Authority, 
if applicable 
Deviations that are beyond the control of the 
investigator (such as subject who fails to return to 
follow-up visit) or deviations that do not affect the 
scientific soundness of the clinical study or the 
rights, safety, or welfare of the subject and are 
not an emergency, should be submitted as they 
are identified by the investigational site or 
Medtronic staff. 

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10.11.3. Sponsor records 
At a minimum, the sponsor will keep the following records: 
 
• 
All essential correspondence related to the clinical study 
• 
Signed Investigator Agreement 
• 
Signed and dated current curriculum vitae for each Investigator 
• 
Records of device shipment and disposition (shipping receipts, material destruct records, etc.) 
• 
Adverse event and device deficiency information  
• 
Device complaint documentation 
• 
All data forms, prepared and signed by the Investigators, and received source documentation 
and core lab reports 
• 
CIP, investigator brochure and subsequent amendments 
• 
Site monitoring reports 
• 
Financial disclosure information 
• 
Trial training records for site participants and internal trial staff members 
• 
Contact lists of all participating investigators/investigative sites, Ethics Committee information, 
trial monitors and Sponsor staff members; Sponsor will maintain these lists and provide updates 
to the necessary parties.  
• 
Sample of device labeling  
• 
Insurance certificates 
• 
Ethics Committee approval documentation and voting list 
• 
Competent Authority notification and approval documentation 
• 
Statistical analyses 
• 
Clinical investigation report 
10.11.4.  Sponsor reporting responsibilities  
Table 4: Sponsor records and reporting responsibilities  
Sponsor Reports for Europe 
Report 
Submit To 
Description/Constraints 
Unanticipated Serious 
Adverse Device 
Effects (USADE) 
Ethics Committee, 
Investigators, 
Competent 
Authorities 
Medtronic will notify investigators and Ethics Committee 
in all geographies as soon as possible.   
For reporting to Competent Authorities, all USADEs are 
classified as SADEs and should follow the applicable 
reporting requirements. (ISO 14155) and Note for 
Guidance on Clinical Safety Data Management: Definitions 
and Standards for Expedited Reporting 
(CPMP/ICH/377/95 3.A.1).  Reporting timeframe as per 
local competent authority. (ISO 14155) 

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Sponsor Reports for Europe 
Report 
Submit To 
Description/Constraints 
Serious Adverse 
Event (SAE)  
Serious Adverse 
Device Effects (SADE) 
Device Deficiency that 
might have led to an 
SAE 
Serious Health Threat 
Ethics Committee, 
Competent 
Authorities 
Submit to Ethics Committee and Competent Authority in 
compliance with local legislation.  
Premature 
termination or 
suspension of the 
clinical investigation 
Investigators, 
Ethics Committee, 
Competent 
Authorities 
Provide prompt notification of termination or suspension 
and reason(s). (ISO 14155)  
Withdrawal of Ethics 
Committee approval 
Investigators, 
Ethics Committee, 
Competent 
Authorities 
All applicable investigators will be notified only if required 
by local laws or by the Ethics Committee. 
Withdrawal of 
Competent Authority 
approval 
Investigators, 
Ethics Committee, 
and Competent 
Authorities 
Investigators and Ethics Committees will be notified only 
if required by local laws or by the Ethics Committee. 
Progress Reports 
Ethics Committee, 
Competent 
Authority (if 
required) 
This will be submitted to the Ethics Committee and/or 
Competent Authority as required per local regulations. .  
Final Report 
Investigators, 
Ethics Committee, 
and Competent 
Authority (if 
required) 
The investigator shall have the opportunity to review and 
comment on the final report.  If a clinical investigator 
does not agree with the final report, his/her comments 
shall be communicated to the other investigator(s). 
Where required by national regulations, the sponsor and 
coordinating investigator shall be asked to provide their 
signatures, indicating their agreement with the content of 
the clinical investigation report.  (ISO 14155) 
Deviation  
Investigators 
Ensure that all deviations from the CIP are reviewed with 
the appropriate clinical investigator(s), are reported on 
the case report forms and the final report of  the clinical 
investigation.   
Site specific deviations will be submitted to investigators 
on a regular basis. (ISO 14155) 

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Sponsor Reports for Europe 
Report 
Submit To 
Description/Constraints 
Significant new 
information 
Ethics Committee 
and Competent 
Authority 
Ensure that the Ethics Committees and Competent 
Authorities are informed of significant new information 
about the clinical investigation (ISO 14155) 
 
10.12. Deviation Handling 
A deviation is any event in which the study is not conducted according to the CIP and/or agreement. 
Deviations may include, but are not limited to the following: 
• 
Failure to obtain Ethics Committee approval before the start of enrolling subjects in the study 
• 
Required testing and/or measurements not done or incorrectly done 
• 
Subject did not attend follow-up visit  
• 
Follow-up visit was completed outside window 
• 
Unauthorized use of investigational device 
• 
Adverse events or device deficiencies not reported in the required timeframe by country 
regulation  
• 
Control of study devices not maintained 
• 
Source data permanently lost 
• 
Enrollment of subjects during lapse of Ethics Committee approval 
• 
Enrollment limits exceeded 
• 
Non-compliance to obtain subject’s Informed consent 
• 
Non-compliance to the inclusion/exclusion criteria 
• 
Failure to follow subjects per scheduled follow-ups 
• 
Failure to follow-up with findings on monitoring reports 
• 
EC approval expiration 
• 
EC suspension of the center 
Medtronic is responsible for analyzing deviations, assessing their significance, and identifying any 
additional corrective and/or preventive actions (e.g. amend the CIP, additional training, terminate the 
study), such as those included in, but not limited to, the list above. Repetitive or serious investigator 
compliance issues may result in the need to initiate a corrective action plan, and in some cases freeze 
enrollment or ultimately terminate the investigator’s participation in the clinical study.  
The investigator is not allowed to deviate from the CIP, except when necessary to protect the life or 
physical well-being of a subject in an emergency situation. Deviations must be reported to Medtronic 
on the Deviation eCRF. 
If a center is terminated or suspended, no additional enrollments will be allowed at the center. Unused 
investigational product allocated to the center will be returned to Medtronic. 
Medtronic will provide site-specific reports to the investigators on a periodic basis (minimally yearly) 
summarizing information on deviations that occurred at the investigational site.  
The investigator shall adhere to EC requirements and procedures for reporting study deviations. 
 

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10.13. Subject Exit, Withdrawal or Discontinuation  
Subjects are urged to remain in the study as long as possible but may withdraw from the clinical study 
at any time and for any reason. If a subject decides to withdraw from the clinical study and agrees to 
provide the reason for withdrawal, the investigator will document the reason and indicate any 
relationship of the withdrawal to the study or products being investigated in the subject’s hospital record 
in the subject’s file.  
If discontinuation is because of safety or lack of efficacy, the subject shall be asked to be followed as 
per their institution’s standard of care outside the clinical study. In addition, subject withdrawal and 
reason for withdrawal will be documented on the Study Exit eCRF. If the subject is unable to be 
followed, the investigator is to notify the sponsor in a timely manner. 
Information about subject’s (vital) health status will be collected until 60 months after index 
procedure, upon subject’s consent, for subjects who will terminate the study earlier. 
10.13.1. Missed follow-up 
A missed follow-up visit should be documented by the investigator and reported in the eCRF including 
the reason. If the date the subject is last known to be alive is obtained, this should be recorded on the 
Follow-up visit eCRF and the method of obtaining this date should be documented in the medical record. 
10.13.2. Upon Early Termination Phone Calls 
Information about subject’s (vital) health status will be collected until 60 months after index procedure, 
upon subject’s consent, for subjects who will terminate the study earlier. 
10.13.3. Study Completed 
At the completion of the 60-month follow-up period, the 60-month follow-up phone call and study exit 
should be combined, and both the 60-month follow-up phone call CRF and Study Exit CRF need to be 
completed.  
Images and data obtained from subjects, during enrollment, may be used for scientific purposes also 
after the subjects exit the clinical investigation. 
Where locally allowed, subjects who exited the study at the 36-month follow-up visit or before and who 
are willing to extend their follow-up period to 60 months, will be picked up in the study, through re-
consenting.  
After exiting, subjects will be followed-up by their physicians, per standard of care. 
10.13.4. Lost-to-follow-up  
A subject may be considered lost to follow-up once the investigator and/or research staff has made at 
a minimum three documented unsuccessful attempts to contact the subject.  
Subjects unable to complete the study follow-up period should agree with their general practitioner 
upon a plan for future health care follow-up, as reflected in the Informed consent form. 

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10.13.5. Medical care after study exit 
After study exit the subjects will be followed as per routine standard of care by the investigational site 
or a treating physician.  
Relevant medical records may be made available by the investigational sites for the treating physician 
per local laws and regulations if needed for further subject treatment. As per local law and regulation 
the trial investigator may be contacted by the treating physician in case of questions related to the 
study device and treatment. 
 
 

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11. Risks and Benefits 
11.1. Potential Risks 
The risk analysis process for the IN.PACT 014 DCB is being performed in accordance with ISO 14971, 
and will ensure that the level of risk is acceptable prior to starting the study. 
11.1.1. 
Risks associated with the use of the study product 
A peripheral balloon dilatation procedure may be associated with the following potential complications 
(but may not be limited to): 
• 
Abrupt vessel closure/thrombosis (acute total occlusion/reocclusion that may require surgical 
intervention) 
• 
Access site pain, hematoma, hemorrhage, and/or local infection (bleeding may require 
transfusions) 
• 
Allergic reaction to contrast medium, antiplatelet therapy, or catheter system components 
• 
Aneurysm, pseudoaneurysm, or arteriovenous (AV) fistula 
• 
Arrhythmias 
• 
Balloon rupture 
• 
Death 
• 
Detachment of a component of the balloon and/or catheter system 
• 
Dissection, perforation, or rupture of the artery 
• 
Drug reactions 
• 
Failure of the balloon to perform as intended (inflation/deflation/retrieval) 
• 
Failure to deliver the balloon as intended (may release drug into unintended arterial segment) 
• 
Hypotension/hypertension 
• 
Ischemia/infarction of tissue/organ (severe ischemic events in treated limb may require 
amputation) 
• 
Local or distal thromboembolic episodes 
• 
Pain and tenderness at puncture sites 
• 
Pyrogenic reaction 
• 
Renal insufficiency or failure 
• 
Restenosis of the dilated artery 
• 
Sepsis/infection 
• 
Short-term hemodynamic deterioration 
• 
Systemic embolization 
• 
Vessel spasms or recoil/prolonged arterial spasms 
Potential adverse events not captured above, that may be unique to the paclitaxel drug coating 
include, but are not limited to: 

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• 
Allergic/immunologic reaction 
• 
Alopecia 
• 
Anemia 
• 
Blood product transfusion 
• 
Gastrointestinal symptoms 
• 
Hematologic dyscrasia (including leucopenia, neutropenia, thrombocytopenia) 
• 
Hepatic enzyme changes 
• 
Histologic changes in vessel wall, including inflammation, cellular damage, or necrosis 
• 
Myalgia/arthralgia 
• 
Myelosuppression 
• 
Peripheral neuropathy 
There is one updated potential risk of long-term increased mortality associated with drug coated 
(paclitaxel coated) balloons. Drug coated balloons used to treat peripheral artery disease have been 
shown in an FDA analysis69 to have an increased relative risk of mortality compared to uncoated devices. 
These devices used in the legs are the same or similar to those used in PAD BTK. However, the 
association of paclitaxel coated device use in PAD BTK with increased mortality risk is unclear. The risk 
of long-term increased mortality is being evaluated by the FDA. 
Any device that requires mechanical deployment and retraction (such as the IN.PACT 014 product as 
well as the used standard PTA balloon) have an inherent risk of mechanical failure. This might result in 
a potential surgical intervention to remove the device. 
The fluoroscopy time of the index procedure is expected to be similar to that of procedures 
performed in a non-clinical study setting and will not pose an additional risk to the subject or the 
study personnel. 
11.1.2. 
Risks related to the study procedures 
The required follow up (as per the schedule of events, Section 10.1.) might be perceived as an 
inconvenience for the subject, as it might involve more frequent follow up visits compared to standard 
of care. The sponsor does not anticipate any additional risks related to the required follow up visits, 
other than the required visit at 9 months. This visit includes an angiographic assessment of the target 
lesion. Any angiography has inherent risks, such as (but not limited to): 

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• 
Abrupt vessel closure/thrombosis (acute total occlusion/reocclusion that may require surgical 
intervention) 
• 
Access site pain, hematoma, hemorrhage, and/or local infection (bleeding may require 
transfusions) 
• 
Allergic reaction to contrast medium 
• 
Aneurysm, pseudoaneurysm, or arteriovenous (AV) fistula 
• 
Arrhythmias 
• 
Death 
• 
Dissection, perforation, or rupture of the artery 
• 
Hypotension/hypertension 
• 
Ischemia/infarction of tissue/organ (severe ischemic events in treated limb may require 
amputation) 
• 
Local or distal thromboembolic episodes 
• 
Pain and tenderness at puncture sites 
• 
Pyrogenic reaction 
• 
Renal insufficiency or failure 
• 
Restenosis of the dilated artery 
• 
Sepsis/infection 
• 
Short-term hemodynamic deterioration 
• 
Systemic embolization 
• 
Vessel spasms or recoil/prolonged arterial spasms 
The fluoroscopy time of this angiographic follow up assessment is expected to be very limited and 
expected to be no longer than any routine diagnostic angiography. The sponsor considers that this 
assessment does not pose additional risks to the subject or laboratory personnel. 
11.2. Potential Benefits 
Subjects who undergo Percutaneous Transluminal Angioplasty (PTA) of the infrapopliteal arteries may 
benefit by the use of the paclitaxel coated IN.PACT 014 because paclitaxel is known to reduce restenosis 
after PTA.  
Subjects may benefit from this study because the use of IN.PACT 014 may eliminate, decrease and/or 
delay the chance of restenosis and re-occlusion in the treated arteries with expected subsequent clinical 
benefit in terms of symptoms relief. However, there are no guaranteed benefits from participation in 
the study. 
In addition, the information obtained during this study may be used scientifically. It can help physicians 
better understand the prevention of restenosis and re-occlusion in the infrapopliteal lesions related to 
the use of IN.PACT 014. Information collected in this study can support the improvement of the 
Medtronic DCBs and the development of new devices. 
 
 

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11.3. Risk-Benefit Rationale 
Based on our current knowledge, participation into the IN.PACT BTK Clinical Study does not impose 
significant additional risks to the subject comparing to existing treatment option (ie. PTA, stenting).  
There is a high probability that subjects benefit when using a DCB as  studies have shown clinical and 
angiographic superiority when compared to standard PTA in related treatment areas.  
It is anticipated that the potential benefits of the study outweigh the potential risks; therefore the 
investigation is considered justified. It is possible in any clinical trial that unanticipated effects can 
happen which are not yet known at this time.  
The study design will minimize the risk through observance of strict center and investigator selection 
criteria, careful subject selection and management, and rigorous adherence to a standardized schedule 
of evaluations. Risks may be further limited by providing medications (such as aspirin and/or 
clopidogrel) and continuing to monitor subjects following the index procedure. The investigator in 
addition performs  continuous monitoring, assessment and documentation of any risks. 
The design for the IN.PACT 014 balloon catheter underwent hazard analysis by industry standard 
methods including analysis of contributing factors, human factors/usability, failure modes, effects, and 
criticality analysis. The results of the assessment concluded that all potentially critical failure modes 
have been appropriately mitigated to an acceptable level based on the products intended use and the 
product is therefore suitable for clinical evaluation. 
Standard risks associated with the medical device used in this study and an analysis of Adverse Device 
Effects listed in the investigator’s brochure.  
 
 

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12. Adverse Event Assessments 
12.1. Definitions/Classifications 
For the purpose of this clinical investigation Medtronic will define and classify the following events per 
the latest version of ISO14155. In case country specific definitions and safety reporting regulations are 
stricter than mandated per the latest version of ISO14155, reporting will be done in compliance with 
the country specific safety regulations.  
All adverse events identified from the point of enrollment until patient’s exit from the study will be 
reported to the sponsor and documented on the Adverse Event eCRF and in the subject’s medical 
records.  
All assessments prior to subject enrollment are considered standard of care. 
Medical occurrences that are inherent to a surgical procedure and expected to occur in the majority of 
subjects for a projected duration may be considered unavoidable. Such events include, but are not 
limited to, those listed in Table 5. These medical occurrences should not be to be reported as adverse 
events during this study. 
 
Table 5: Expected and not to be reported adverse events related to a surgical procedure 
 
Event Description 
Timeframe (hours) from the procedure 
Anesthesia related nausea / vomiting 
(with or without treatment) 
24 
Low-grade fever (<100°F or 37.8°C)  
48 
Pain at access site  
(with or without standard treatment and patient not 
returning to clinic to have additional treatment) 
72 
Mild to moderate bruising / ecchymosis at access site(s) 
168 
Sleep problems (insomnia) 
(with or without treatment) 
72 
Back pain related to laying on table 
(with or without treatment) 
72 
Bleeding at access site 
(not requiring treatment) 
24 
 
 
 

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12.1.1. 
Definitions / Classifications 
Adverse Event (AE):  
Any untoward medical occurrence, unintended disease or injury, or untoward clinical signs (including 
abnormal laboratory findings) in subjects, users or other persons, whether or not related to the 
investigational medical device and whether anticipated or unanticipated. 
NOTE 1:  This definition includes events related to the investigational medical device or the comparator.  
NOTE 2:  This definition includes events related to the procedures involved. 
NOTE 3:  For users or other persons, this definition is restricted to events related to investigational 
medical devices. 
 
Adverse Device Effect (ADE):  
Adverse event related to the use of an investigational medical device. 
NOTE 1: This definition includes adverse events resulting from insufficient or inadequate instructions 
for use, deployment, implantation, installation, or operation, or any malfunction of the investigational 
medical device. 
NOTE 2: This definition includes any event resulting from use error or from intentional misuse of the 
investigational medical device. 
NOTE 3: this includes ‘comparator’ if the comparator is a medical device. 
 
Serious Adverse Event (SAE):  
Adverse event that led to any of the following: 
a) 
death, 
b) serious deterioration in the health of the subject, users or other persons as defined by one or 
more of the following:  
 1)      a life-threatening illness or injury, or  
2) 
a permanent impairment of a body structure or a body function, , including chronic 
disease ,or 
3) 
in-patient or prolonged hospitalization, or  
4) 
medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function, 
c) 
fetal distress, fetal death or a congenital abnormality or birth defect including physical or 
mental impairment.   
NOTE 1:  Planned hospitalization for a pre-existing condition, or a procedure required by the CIP, 
without serious deterioration in health, is not considered a serious adverse event. 
 
Serious Adverse Device Effect (SADE):  
Adverse device effect that has resulted in any of the consequences characteristic of a Serious Adverse 
Event.  
 
 

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Unanticipated Serious Adverse Device Effect (USADE):  
Serious adverse device effect which by its nature, incidence, severity or outcome has not been identified 
in the current risk assessment. 
NOTE 1:  Anticipated serious adverse device effect (ASADE) is an effect which by its nature, incidence, 
severity or outcome has been identified in the risk assessment. 
 
Serious Health Threat:  
Signal from any adverse event or device deficiency that indicates an imminent risk of death or a serious 
deterioration in the health in subjects, users or other persons, and that requires prompt remedial action 
for other subjects, users or other persons. 
NOTE 1: This would include events that are of significant and unexpected nature such that they become 
alarming as a potential serious health hazard or possibility of multiple deaths occurring at short intervals.  
 
Device deficiency: 
Inadequacy of a medical device with respect to its identity, quality, durability, reliability, usability, safety 
or performance. 
NOTE 1: Device deficiencies include malfunctions, use errors and inadequacy in the information 
supplied by the manufacturer including labelling. 
NOTE 2: This definition includes device deficiencies related to the investigational medical device or 
the comparator. 
12.1.2. 
 Recording and reporting of Adverse Events 
Adverse Event (AE) information will be collected throughout the study and reported to Medtronic on 
the Adverse Event eCRF. All Adverse Events (except unavoidable events listed in table 5), regardless of 
relatedness or outcome, must be reported. The investigator is responsible for reporting all AEs to 
Medtronic and for their follow-up. Collection of AEs and AEs-related information will include the date of 
the adverse event, treatment, resolution, assessment of seriousness and the relationship to the device 
and comparator, to Paclitaxel and to the related procedure.  
For Adverse Events that require immediate reporting (see table 4), initial reporting may be done by 
phone, e-mail (contact details will be provided in the investigational site file), or on the eCRF with as 
much information as is available. In case the investigator requires information from the Sponsor in an 
emergency situation, the contact details for emergency situations are given in the investigational site 
file. 
12.1.3. 
 Recording and reporting of Device Deficiencies 
Device Deficiency information will be collected throughout the study and reported to Medtronic. Device 
Deficiencies should be reported on a Device Deficiency Form in the eCRF. In case the eCRF is not 
available the Device Deficiency form needs to be completed manually and must be sent to Medtronic. 
Contact details are given in the investigational site file. The investigator is responsible for reporting all 
Device Deficiencies to Medtronic. 
 

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Device deficiencies that did not lead to an Adverse Event but could have led to an SAE 
a) if either suitable action had not been taken, 
b) if intervention had not been made, or 
c) if circumstances had been less fortunate, 
require immediate reporting. Initial reporting may be done by eCRF, phone or e-mail, with as much 
information as available.  
12.1.4. 
Adverse Event and Device Deficiency review process 
All Adverse Events and Device Deficiencies will be reviewed by Medtronic Study Management and/ or 
designee. This review will include the determination whether the Adverse Event/Device Deficiency 
meets regulatory reporting requirements. The sponsor will ensure timely Adverse Event/Device 
Deficiency reporting to meet global and country specific regulatory requirements. 
In case the Adverse Event/Device Deficiency is related to a Medtronic market released device used 
during the study, Medtronic Study Management and/ or designee will immediately report this device 
related Adverse Event/Device Deficiency to the Product Experience Management (PXM) group. The PXM 
group will ensure prompt review, and appropriate reporting. 
12.2. Reporting of Adverse Events 
Table 6: Adverse Event Reporting Requirements from Investigator to Medtronic 
 
Serious Adverse Device Effects (SADE) 
Immediately (but no later than 3 calendar days) 
after the investigator first learns of the event or of 
new information in relation with an already reported 
event.  
  
Serious Adverse Events (SAE) 
Adverse Device Effects (ADE) 
Device Deficiency (with SAE potential) 
All other AEs 
Submit in a timely manner after the investigator 
first learns of the event. 
All other Device Deficiencies 
Submit in a timely manner after the investigator 
first learns of the deficiency. 
 
In addition, Investigators are obligated to report AEs to their EC in accordance with the requirements 
and local regulations.  
For subjects who consented to extend their participation in the trial to 60 months, all adverse events 
and device deficiencies that retrospectively occurred are to be reported. 
12.3. Subject Death  
All subject deaths must be reported by the investigator to Medtronic on an AE form (AE with the 
outcome of death) as soon as possible after the investigator first learns of the death. In the case of 
death, there should be one AE with the outcome of death.  
Local laws and procedures must be followed where applicable. 
A copy of the death certificate, if available and allowed by state/local law, should be sent to the 
Medtronic clinical study team. When a death occurs in a hospital, a copy of the death summary report 
and all relevant hospital records, if available should be sent to the Medtronic clinical study team.  

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If an autopsy is conducted, a copy of the autopsy report should also be sent to the Medtronic clinical 
study team if available and allowed by state/local law. When a death occurs at a remote study site, it 
is the investigative study site’s responsibility to attempt the retrieval of information about the death.  
 
 

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13. Data Review Committees  
13.1. Data Monitoring Committee 
A Data Monitoring Committee (DMC) will be established. The DMC is composed of several members 
with pertinent expertise who are not directly involved in the conduct of the study. 
The responsibility of the DMC is to evaluate safety data during the course of the study and to advise 
Medtronic about the continuing of the study, in order to ensure the well-being of the current participants 
and those yet to be enrolled as well as the continuing validity and scientific merit of the study. DMC 
composition, duties, procedures, deliberation rules are detailed and documented in the DMC Charter. 
For DMC meeting schedule and Data Review please refer to the DMC Charter. 
Based on the safety data, the DMC may recommend that Medtronic modify or stop the study. DMC 
composition, duties, procedures, deliberation rules, are detailed and documented in the DMC Charter. 
13.2. Clinical Event Committee 
The Clinical Events Committee (CEC) is made up of clinicians (interventional and non-interventional) 
with pertinent expertise (i.e. vascular surgeon, interventional radiologist) who are not participants in 
the study and who do not have any other real or potential conflicts of interest. The CEC is charged with 
the development of specific criteria used for the categorization of adverse events and clinical endpoints 
in the study. Criteria will be established for selected complications and clinical events. At the onset of 
the study, the CEC will establish explicit rules outlining the minimum amount of data required and the 
algorithm followed in order to classify an event.   
Database triggers, Medtronic Safety and the medical monitor from an independent external vendor will 
identify clinical events requiring adjudication (per the CEC Manual of Operations) and provide this 
information to the CEC. The CEC will meet regularly to review and adjudicate all events as specified in 
the CEC Manual of Operations and as requested by Medtronic, for which the required minimum data 
are available.   
13.3. Core Laboratories 
The Duplex Ultrasonography Core Laboratory (Duplex Core Lab) is responsible for developing DUS and 
RVD protocol requirements, reviewing and interpreting DUS and Doppler exams, and providing 
feedback on the quality of the DUS exams to participating sites. The Duplex Core Lab will review, 
analyze, and record data on the Duplex Core Lab Assessment eCRF. The Duplex Core Lab’s 
interpretation of all DUS exams will be used for the data analyses. 
The Angiography Core Laboratory is responsible for developing protocol requirements, reviewing and 
interpreting angiographies, and providing feedback on the quality of the imaging studies to participating 
sites. The Core Lab will review, analyze, and record data on the applicable Core Lab assessment eCRF. 
The Core Lab’s interpretation of all images will be used for the data analyses. 

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14. Statistical Design and Methods 
14.1. General Considerations 
Medtronic employees or their designated representatives will perform all statistical analysis. An 
intention-to-treat (ITT) analysis will be performed and will serve as the primary analysis for all 
objectives in the study unless otherwise specified. The ITT analysis cohort will include all randomized 
subjects regardless of treatment received. Additionally, a separate Statistical Analysis Plan (SAP) will 
be developed to further describe statistical methods, pre-specified data handling rules, and pre-
specified analyses that will be included in the final study report and primary publication(s).  However, 
additional exploratory analyses of the data may be conducted as deemed appropriate. Any changes to 
planned statistical analyses determined necessary prior to performing the analyses will be documented 
in an amended Statistical Analysis Plan and approved prior to the analysis. Any other deviations or 
changes from the planned analyses deemed necessary due to violation of critical underlying statistical 
assumptions, data characteristics, or  missing data will be clearly described in the clinical study report 
with justification and rationale.  
14.2. Analysis Cohorts 
Intention-to-treat (ITT):  The ITT analysis cohort will include all randomized subjects in the groups to 
which they are randomized regardless of the treatment received and will serve as the primary analysis 
cohort for each objective unless otherwise specified. 
As Treated: The AT cohort includes randomized subjects but analyzes subjects using the treatment 
they actually received. The AT cohort excludes subjects that were randomized but never received a 
study device. Additionally, for example, if a subject were randomized to the DCB group, but received 
the PTA treatment the subject would be included in the PTA group for analysis purposes. 
14.3. Sample Size Consideration 
Limited studies in BTK reported LLL data. LLL results are displayed in the table below for four previous 
studies which reported LLL either at 6 or 12 months. Based on these previous studies,  standard 
deviation of LLL at 9 months is estimated to be ~0.60 mm for DCB and PTA group. Randomization will 
be done in a 1:1 fashion. Assuming 15% attrition due to death and lost- to-follow up, and multiple 
lesions (~1.1 on average) per subject being allowed in the study, it is expected to have 21 subjects 
with 23 evaluable LLL measurements at 9 months for each arm. The precision, or margin of error, of 
the estimated LLL can be assessed by calculating the distance from the upper limit of the 95% 
confidence interval to the mean.  With 23 lesions in each arm,  the precision (half of the width of the 
confidence interval) is calculated to be 0.25 mm.  The precision of the LLL difference between the two 
arms is calculated to be 0.35 mm.    
 
 

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 Table 7: LLL results are displayed in the table below for four previous studies  
Study Name 
Endpoint Time 
Drug Coated 
Balloon 
Percutaneous 
Transluminal 
Angioplasty  
Drug Eluting 
Stent 
IDEAS66 
6 months 
1.15±0.3 mm 
Not applicable 
1.35±0.2 mm 
DEBELLUM67 
12 months 
0.66±0.9 mm 
1.69±0.5 mm 
Not applicable 
BIOLUX PII 
6 months 
0.56±0.65 mm 
0.54±0.66 mm  
Not applicable 
IN.PACT DEEP 
12 months 
0.605±0.775 mm 
0.616±0.781 mm  
 
Not applicable 
No formal hypothesis test is specified for this study. A sample of 50 subjects (25 in each group) will 
provide good precision to quantify the target parameter of LLL.  Primary analysis will be performed 
when all subjects have completed 9-month visits. The study may be extended to a larger clinical study 
upon appropriate ethical and clinical justifications, to be included in the premarket clinical evaluation 
cohort in US . Statistical justifications including type I error control and power will be provided to retain 
a high level of scientific rigor. Additionally, an independent Data Monitoring Committee (DMC) will be 
appointed to closely monitor the study progress and make recommendations based on study outcomes. 
14.4. Primary Objective 
14.4.1. 
Objective 
To assess the efficacy of the IN.PACT 014 by comparing the Late Lumen Loss (LLL) of the investigational 
product vs standard (conventional) PTA. 
14.4.2. 
Endpoint 
The primary efficacy endpoint will be Late Lumen Loss (LLL) at 9 months post procedure for the IN.PACT 
014 Investigational device vs Standard PTA. LLL will be assessed by means of Quantitative Vascular 
Angiography (QVA) by an independent angiographic corelab at 9 months post procedure or at the time 
of TLR. 
14.4.3. 
Analysis Method 
Primary analysis will be performed by ITT principle, which constitutes all evaluable angiographic images 
at 9 months post procedure or at the time of revascularization, whichever comes first. The mean and 
standard deviation for LLL will be calculated for each randomized group.  The difference between the 
two groups and the 95% confidence interval will be presented.  
As treated analysis may be performed as sensitivity analysis if patient crossover occurs. 
Interim analyses will be conducted and reviewed by an unblinded predesignated group when 15, 30, 
45 and/or when all subjects enrolled are randomized and followed up for 9 months. After primary 
endpoint analysis, additional analysis may be performed upon discretion of the sponsor. A decision to 
stop, continue or extend the study can be made after each interim analysis has been reviewed.  

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As the study has no formal hypothesis testing at each of the interim analyses, no multiplicity adjustment 
is needed, and descriptive statistics will be reported. 
14.5.  Secondary Objectives 
14.5.1. 
Composite Safety Endpoint  
Endpoint 
The composite safety endpoint will be a composite of freedom from device- and procedure-related 
mortality within 30 days, freedom from major target limb amputation and freedom from clinically-driven 
TLR within  9 months post-index procedure. 
Analysis Method 
The success rate of safety endpoint will be defined as the number of subjects without any device and 
procedure-related death within 30 days, major target limb amputation and CD-TLR within 9 months  
post-index procedure divided by number of evaluable subjects at 9 months. 
Percentage and 95% confidence interval will be calculated for the safety endpoint success rate for each 
randomization arm respectively.  
14.5.2. 
MAE Endpoint  
Endpoint 
Major Adverse Event (MAE) rate, defined as a composite of all-cause mortality, target limb major 
amputation and clinically-driven TLR through 3, 6, 9, 12, 24, 36, 48 and 60 months . 
Analysis Method 
The MAE rate through 3 months will be calculated as the number of subjects who experience death, 
target limb major amputation or CD-TLR by 3 months post-index procedure divided by the number of 
evaluable subjects at 3 months.  Percentage and 95% confidence interval will be calculated for the MAE 
rate  through 3 months. 
Similar analysis will be performed  through 6, 9, 12, 24, 36, 48 and 60 months for each randomization 
arm respectively. 
14.5.3. 
Functional flow assessment 
Endpoint 
Functional flow assessment at 3, 6, 9, 12, 24 and 36 months, defined as absence of target lesion 
occlusion (no flow) assessed by duplex ultrasound.  
Analysis Method 
Summary statistics (frequency percentage etc.) for occlusion rate among lesions with evaluable 
duplex ultrasound data at each visit will be provided for each arm. 

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14.5.4. 
Mortality Rate 
Endpoint 
Death of any cause through 3, 6, 9, 12, 24, 36, 48 and 60 months. 
Analysis Method 
Death rate through 3 months will be calculated as number of subjects die within 3 months post-index 
procedure divided by number of subjects known to be alive by 3 months plus number of subjects die 
within 3 months post-index procedure.  Percentage and 95% confidence interval will be presented for 
each randomization arm respectively. 
Death rate  through 6, 9, 12, 24, 36, 48 and 60  months will be calculated  and  presented similarly. 
Endpoint 
Cardiovascular related death through 3, 6, 9, 12, 24, 36, 48 and 60 months. 
Analysis Method 
Cardiovascular related death rate through 3 months will be calculated as number of subjects with 
cardiovascular related deaths within 3 months post-index procedure divided by number of subjects 
known to be alive by 3 months plus number of subjects die within 3 months post-index procedure.  
Percentage and 95% confidence interval will be presented for each randomization arm respectively. 
Cardiovascular death rate through 6, 9, 12,  24, 36, 48 and 60 months will be calculated  and  presented 
similarly. 
14.5.5. 
Major Target Limb Amputation  
Endpoint 
Rate of major target limb amputation through 30 days, 3, 6, 9, 12, 24, 36, 48 and 60 months. 
Analysis Method 
Major target limb amputation rate through 3 months will be calculated as number of subjects undergo 
major target limb amputation within 3 months post-index procedure divided by the number of evaluable 
subjects through 3 months. Percentage and 95% confidence interval will be presented for each 
randomization arm respectively. 
Major target limb amputation rate through 30 days,  6, 9, 12, 24, 36, 48 and 60 months will be 
calculated  and  presented similarly. 
 
 

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14.5.6. 
Clinical-Driven Target Lesion Revascularization (CD-TLR)  
Endpoint 
Rate of CD-TLR through 3, 6, 9, 12, 24, 36, 48 and 60 months 
Analysis Method 
Rate of CD-TLR through 3 months will be calculated as number of subjects undergo CD-TLR within 3 
months post-index procedure divided by the number of evaluable subjects at 3 months. Percentage 
and 95% confidence interval will be presented for each randomization arm respectively. 
Rate of CD-TLR through 6, 9, 12, 24, 36, 48 and 60 months will be calculated and presented similarly. 
14.5.7. 
Mechanically-Driven Target Lesion Revascularization (MD-TLR)  
Endpoint 
Rate of MD-TLR through 37 days. 
Analysis Method 
Rate of MD-TLR through 37 days will be calculated as number of subjects undergo MD-TLR within 37 
days post-index procedure divided by the number of evaluable subjects at 37 days. Percentage and 
95% confidence interval will be presented for each randomization arm respectively. 
14.5.8. 
Target Lesion Revascularization (TLR)  
Endpoint 
Rate of  TLR through 3, 6, 9, 12, 24, 36, 48 and 60 months. 
Analysis Method 
Rate of TLR at 3 months will be calculated as number of subjects undergo TLR within 3 months post-
index procedure divided by number of subjects who either undergo TLR by 3 months or have been 
followed in the study for at least 3 months without TLR. Percentage and 95% confidence interval will 
be presented for each randomization arm respectively. 
Rate of TLR through 6, 9, 12, 24, 36, 48 and 60 months will be calculated and presented similarly. 
14.5.9. 
Clinical-Driven Target Vessel Revascularization (CD-TVR)  
Endpoint 
Rate of CD-TVR through 3, 6, 9, 12, 24, 36, 48 and 60 months. 
Analysis Method 
Rate of CD-TVR through 3 months will be calculated as number of subjects undergo CD-TVR within 3 
months post-index procedure divided by the number of evaluable subjects at 3 months. Percentage 
and 95% confidence interval will be presented for each randomization arm respectively. 
Rate of CD-TLR through 6, 9, 12, 24, 36, 48 and 60 months will be calculated and presented similarly. 

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14.5.10. Target Vessel Revascularization (TVR)  
Endpoint 
Rate of  TVR through 3, 6, 9, 12, 24, 36, 48 and 60 months. 
Analysis Method 
Rate of TVR through 3 months will be calculated as number of subjects undergo TVR within 3 months 
post-index procedure divided by the number of evaluable subjects at 3 months. Percentage and 95% 
confidence interval will be presented for each randomization arm respectively. 
Rate of TVR through 6, 9, 12, 24, 36, 48 and 60 months will be calculated and presented similarly. 
14.5.11. Status of Wound Healing  
Endpoint 
Status of wound healing  at 30 days, 3, 6, 9, 12, 24 and 36 months. 
Analysis Method 
Wound status will be assessed by visual estimation from the wound care specialist.  Wound status are 
classified as:  
• 
Worsened 
• 
Unchanged 
• 
Improved  
• 
Completely healed 
• 
Amputation 
• 
Skin graft 
Percentage of wounds in each category will be presented for each treatment arm at 30 days, 3, 6, 9, 
12, 24 and 36 months respectively. Number of new wounds will also be reported.   
14.5.12. Thrombosis  
Endpoint 
Rate of thrombosis at the target lesion through 30 days, 3, 6, 9,  12, 24, 36, 48 and 60 months. 
Analysis Method 
Rate of thrombosis through 3 months will be calculated as number of subjects with thrombosis at the 
target lesion within 3 months post-index procedure divided by the number of evaluable subjects at 3 
months. Percentage and 95% confidence interval will be presented for each randomization arm 
respectively. 
Rate of thrombosis at the target lesion through 30 days, 6, 9, 12, 24, 36, 48 and 60 months will be 
calculated  and presented similarly. 

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14.5.13. Device Success  
Endpoint 
Device success is defined as successful delivery, balloon inflation, deflation and retrieval of the intact 
study device without burst below the rated burst pressure (RBP).  
Analysis Method 
Device success rate will be calculated as the number of IN.PACT 014 Investigational devices with 
successful delivery, balloon inflation, deflation and retrieval of the intact study device without burst 
below the rated burst pressure (RBP), divided by the total number of IN.PACT 014 Investigational 
devices assessed in the study.  
14.5.14. Clinical Success  
Endpoint 
Clinical success is defined as residual stenosis of ≤ 30% without procedural complications (death, major 
target limb amputation, thrombosis of the target lesion, or TVR) prior to discharge. 
Analysis Method 
Clinical success rate will be calculated as the number of index procedures with residual stenosis of ≤ 
30% for all target lesions and without procedural complications (death, major target limb amputation, 
thrombosis of the target lesion, or TVR) prior to discharge, divided by the number of total index 
procedures performed.  
14.6. Missing Data  
In general, all analyses will be performed using the ITT analysis set, which constitutes all available (or 
observed) cases. As treated analysis may be performed for some objectives if requested. Imputation 
of missing data will not be performed. For example, to determine the rate of freedom from MAEs, all 
subjects with MAEs reported or no MAEs observed during the defined time period will be counted in the 
analysis.  
 
 

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15. Ethics 
15.1. Statement(s) of Compliance  
The IN.PACT BTK Study is designed to reflect the good clinical practice (GCP) principles outlined in the 
latest version of ISO 14155. These include the protection of the rights, safety and well-being of human 
subjects, controls to ensure the scientific conduct and credibility of the clinical investigation and the 
definition of responsibilities of the sponsor and investigators. 
The study will be conducted according to federal, national and local laws, regulations, standards, and 
requirements of the countries/geographies where the study is being conducted.  
The study will also be conducted in accordance with the Declaration of Helsinki. The principles of the 
Declaration of Helsinki are implemented in this study by means of the Informed consent process, Ethics 
Committee approval, study training, clinical study registration, pre-clinical testing, risk benefit 
assessment, and publication policy. 
In addition, the study will be conducted in compliance with 21 CFR Part 11 and 54, the latest version 
of ISO 14155, the Clinical Trial Agreement, and the procedures described within this CIP. 
MDD 93/42/EEC and MEDDEV 2.7/3 rev 3 (May 2015), will be followed until date of application (DoA) 
of EU MDR 2017/745. After this time point, the study will be compliant to EU MDR 2017/745. 
Competent Authority notification/approval to conduct the study is required in all participating 
geographies (where applicable). Investigational sites will be not be activated, nor begin enrolling 
subjects until the required approval/favorable opinion from the respective regulatory agency has been 
obtained (as appropriate). The clinical investigation shall not begin until the required approval/favorable 
opinion from the Ethics Committee (EC) or notification/approval from a Competent Authority have been 
obtained.  
Additionally, any requirements imposed by a local regulatory agency or Ethics Committee shall be 
followed, as appropriate. 
Each site must provide Medtronic with a copy of the investigational site’s Ethics Committee approval 
letter and the Ethics Committee-approved Informed Consent Form.  Ethics Committee approval letters 
must contain the following elements: 
• 
Study Title and the Medtronic Protocol Number; 
• 
Medtronic’s Protocol Version (revision letter and/or date of issue); 
• 
A list of the documents reviewed at the meeting covered by the approval letter; 
• 
If applicable, the required interval for the site’s Continuing Review by the Ethics Committee; 
and 
• 
Expiration date, if applicable and/or allowed by the site’s system, of the current approval. 
If applicable, approvals for the continuation of the study at each investigational site must be kept 
current in accordance with the Ethics Committee’s review schedule. All site communications to and from 
the Ethics Committee must be forwarded to Medtronic as they are sent/received. 
The Sponsor will be informed by the Ethics Committee and/or the investigator in case any action is 
taken by an Ethics Committee with respect to this investigation. 
This study will be publicly registered on www.clinicaltrials.gov prior to first enrollment. 

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16. Study Administration 
16.1. Investigator / Investigational site selection 
The role of the principal investigator is to implement and manage the day-to-day conduct of the clinical 
study as well as ensure data integrity and the rights, safety and well-being of the subjects involved in 
the clinical study. 
An investigator may be included in the clinical study if compliant with the following requirements:   
• 
Investigator is qualified, educated and has experience in the drug coated balloon treatment of 
the infrapopliteal arteries 
• 
Investigator is not debarred, disqualified, or working under sanctions in applicable regions.  
• 
Investigator/site expects to have adequate time and resources to conduct the study throughout 
the duration of the study. Each site should have a designated research coordinator assigned to 
the study.  
• 
Investigator/site has access to an adequate number of eligible subjects.  
• 
Investigator/site has the ability to comply with applicable Ethics Committee and regulatory 
requirements.  
• 
Lack of potential conflict(s) of interest  
• 
Anticipated study startup timeline, including contracting and Ethics Committee and regulatory 
submission and approval (if applicable) is acceptable.  
• 
Anticipated competition for same subject population from competitive ongoing studies is at an 
acceptable rate. 
A list of participating investigational sites and investigators will be available as a separate document.   
Prior to study start, a recent signed and dated CV shall be collected from each principal investigator 
and key members of the investigation site team participating in this study, evidencing the required 
qualifications, including the year and where obtained, and shall include their current position at the 
investigation site. The signature on the CV must be dated within 3 years prior to the date of activation 
of the site.  
16.2. Clinical Trial Agreement 
A clinical trial agreement shall be in place, signed by the participating investigational site and/or 
principal investigator of each investigational site, as per the local legal requirements, and returned to 
Medtronic prior to the commencement of any clinical study activities. The investigator is indicating 
approval of the clinical investigation plan and subsequent amendments, with a fully executed 
agreement. 
16.3. Study Insurance /Subject Indemnification 
Medtronic, Inc. (including all wholly owned subsidiaries) maintains appropriate clinical trial liability 
insurance coverage as required under applicable laws and regulations and will comply with applicable 
law and custom concerning specific insurance coverage. If required, a Clinical Trial Insurance 
statement/certificate will be provided to the Ethics Committee.  
Medtronic will provide subject indemnification according to local laws where this trial will be conducted. 

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16.4. Subject Compensation 
Subjects will not receive any compensation for their participation in this study (including follow up); 
however, Medtronic may, at its option, provide reimbursement for participants who will incur 
extraordinary travel costs related to their participation in the study, including airfare, mileage or hotel 
expenses, if locally allowed. Participating Institution will make such request(s) in writing to Medtronic 
(de-identified of participant information), detailing the unusual circumstances and the excessive costs 
that the participant will incur. Medtronic will evaluate requests on a case-by-case basis, and will notify 
the Participating Institution of its decision in writing. 
16.5. Site Activation/Supply of Trial Materials 
Investigational sites will receive a formal letter of site activation, upon receipt of or completion of the 
following: 
• 
Curriculum vitae of the principal and sub-investigators and all key site staff 
• 
A signed trial agreement 
• 
Financial disclosure from the investigators 
• 
Competent Authority approval (as applicable to the geography) 
• 
A copy of the Ethics Committee approval letter, along with the voting roster 
• 
The Ethics Committee approved patient information and Informed consent form 
• 
Documented training of the investigative team 
• 
Delegated Task List 
Medtronic will control the supply of devices and study materials, and will only ship investigational 
devices once the above activation criteria are met, and the site receives a formal activation letter from 
Medtronic. 
16.6. Monitoring  
Monitoring and monitoring oversight will be provided by Medtronic (Maastricht, the Netherlands) and 
detailed in a Monitoring Plan separate from this CIP.   
A site qualification visit may be conducted by Medtronic personnel (or designees) to review the clinical 
investigational plan and, regulatory and study requirements with the investigator and study personnel. 
A site initiation visit will be performed after it has been verified that the site is prepared for the study 
and that the site requirements for study participation are met.  
Monitoring visits will be conducted at the start, during and at the closure of the clinical study in 
accordance with Medtronic SOPs and the Monitoring Plan. Frequency and timing of monitoring visits 
shall be determined by the Sponsor for each site based on enrollment rate and volume, study 
compliance and findings from previous visits.  
It will be verified whether signed and dated Informed consent forms have been obtained from each 
subject before any clinical study related procedures are undertaken. Medtronic or designee will conduct 
site monitoring visits to monitor compliance with the protocol and adherence to the data collection 
procedures, to assess the accuracy and completeness of submitted clinical data, and to verify that 
records and documents are being properly maintained for the duration of the study. 

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16.7. Data Management 
Electronic Data Capture 
Medtronic will use the Oracle Clinical Remote Data Capture database system for data collection. The 
database is located on a secure server at a Medtronic facility located in the United States. All users will 
be trained on the use of the database prior to obtaining access. Once access is granted, users will have 
a unique User ID and will create their own password. Data stored electronically shall be maintained in 
compliance with 21CFR Part 11. The database for this study will be maintained according to corporate 
policy and record retention schedule. 
Data Collection 
It is the responsibility of the participating Investigator to ensure the quality of the data being collected. 
Required data will be recorded on electronic case report forms (eCRFs) by authorized site personnel as 
indicated on the Delegated Tasks List. The eCRFs must be completed and/or updated to reflect the 
latest observations on the subjects participating in the study.   
The investigator (or authorized sub-investigator) will electronically sign each eCRF. 
The EDC system maintains an audit trail on entries, changes or corrections in eCRFs, once the eCRF is 
saved as complete. If changes are made to an already signed eCRF, the investigator shall re-sign this 
eCRF. 
At the end of the study, the data will be frozen and will be stored for the period defined by the applicable 
laws. 
Data Validation 
The sponsor and/or assigned designee will be responsible for the processing and quality control of the 
data (data management) per the Data Management Plan, which describes the procedures for data 
review, database cleaning and issue/resolution of data queries. Data will be collected and stored in a 
validated, password protected database. Data analysis will be conducted utilizing validated software 
and analysis programs by qualified biostatisticians.  
Study data collected will be monitored and verified against source documents in accordance with the 
latest version of ISO14155guidelines and international standards. Any data discrepancies will be 
addressed through queries posted within the EDC system. 
Database storage 
Image data (DUS, Angio) collected at office visits will be sent to Medtronic and uploaded to secure 
servers. Upon receipt, data will be maintained with databases and retrieved for analysis and reporting. 
16.8. Direct Access to Source Data/Documents  
The principal investigator(s), his/her delegate(s), and the study coordinator(s) shall be accessible to 
Medtronic personnel or designee(s) and the Clinical Study Manager. This accessibility is of particular 
importance for reviewing data in the eCRF. Direct access to subject medical files for source data 
verification will need to be granted and prepared prior to any monitoring visits. If direct access cannot 
be provided per local laws and regulations, certified copies need to be made available or monitor needs 
to obtain access by reviewing alongside with study staff. Additional details on source data verification 
requirements and rationale are provided in the IN.PACT BTK Monitoring plan. 

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In addition to regular monitoring visits, Medtronic may conduct audits at participating investigational 
sites. The purpose of an audit is to verify the adequate performance of the clinical study related 
activities, independent of the employees involved in the clinical study. Regulatory bodies may also 
perform inspections at participating investigational sites. Any Competent Authority inspection 
announcements shall be forwarded immediately to the Clinical Study Manager.  
The investigator and/or institution shall permit Medtronic and regulatory bodies direct access to source 
data and documents, taking into account any restrictions due to local law, to perform clinical study-
related monitoring, audits, EC review, and regulatory inspections. 
16.9. Confidentiality 
Subject confidentiality will be maintained throughout the clinical study to the extent permitted by law. 
That is, every attempt will be made to remove subject identifiers from clinical study documents. For 
this purpose, a unique subject identification code (site number and subject number) will be assigned 
and used to allow identification of all data reported for each subject. This will also ensure that the 
information can be tracked back to the source data. 
Study data may be made available to third parties, e.g., in the case of an audit performed by regulatory 
authorities, provided the data are treated confidentially and that the subject’s privacy is guaranteed. 
The identity of a subject will never be disclosed in the event that study data are published. 
16.10. CIP Amendments 
The investigator can propose any appropriate modification(s) of the clinical investigation plan or 
investigational device or investigational device use. Medtronic will review this proposal and decide 
whether the modification(s) will be implemented.  
Medtronic will submit any significant amendment to the clinical investigation plan, including a 
justification for this amendment, to the appropriate regulatory authorities and to the investigators to 
obtain approval from their EC. The investigator will only implement the amendment after approval or 
notification of the EC, Competent Authority and Sponsor. Administrative amendments to the clinical 
investigation plan will be submitted to the EC for notification. Furthermore investigators shall sign any 
approved amendment of the clinical investigation plan, if required per local regulation. 
16.11. Record Retention 
All study-related documents must be retained for a period of at least 2 years after market-release in 
his/her region and after study closure (or longer if required by local law). Medtronic will inform the 
investigator/site when these documents are no longer required to be retained. 
No study document or image will be destroyed without prior written agreement between the Sponsor 
and the investigator. The investigator should take measures to prevent accidental or premature 
destruction of documents. The Sponsor has to be consulted if the investigator wishes to assign the files 
to someone else, remove them to another location, or is unable to retain them for the specified period. 
The sponsor will retain the study records for the life of Medtronic, according to Medtronic corporate 
policy and record retention schedule. 

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16.12. Publication and Use of Information 
Publications and presentations referring to this clinical study will be coordinated by Medtronic to allow 
the use of all available data. The following publication policy will have to be adhered to by all 
participating investigational sites: 
Medtronic may use the study data for Competent Authority submission results, may publish the results 
in peer reviewed scientific journal(s) and present the data at major congresses. Authorship on any 
publication(s) resulting from this clinical study will be assigned according to substantial contributions 
to conception and design, acquisition of data, or analysis and interpretation of data, drafting the article 
or revising it critically for important intellectual content, and final approval of the version to be 
published. This is in accordance with the Vancouver principles (The Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical Publication, ICMJE, 
October 2008), as agreed upon by the editors of all major medical journals.  
The number of authors will be dependent on the regulations of the concerning journal with a maximum 
of 10 authors. Names of all participating investigators will appear in the Acknowledgment of the paper. 
Based on the principle that Medtronic owns the data of this clinical study, a single investigational site 
may access and use the data provided by itself for scientific publications following prior approval by 
Medtronic. 
Pooling data from several investigational sites for publication purposes, national projects and 
international projects all require prior approval from Medtronic. 
Medtronic as the owner of the data can use the data and/or any results derived from the data or 
publications based on that data for marketing purposes, further research and development of devices 
or educational use. 
The clinical investigation will be registered in a publicly accessible database and the results will be 
made publicly available.  
The study sponsor will collect data in such way that no subject can be identified. Participating subjects 
will not be identified by name in any published reports about the clinical study. 
16.13. Suspension or Early Termination 
Early study suspension or termination 
Medtronic or Competent Authority may decide to suspend or early terminate the clinical study (e.g. if 
information becomes available that the risk to study subject is higher than initially indicated, if interim 
analysis indicates that the results significantly differ from the study objectives or statistical endpoints). 
At these interim time points an independent DMC will review the safety data and according to the DMC 
charter determine whether study continuations is advisable. If the clinical study is terminated early or 
suspended, Medtronic shall promptly inform the investigators and the regulatory bodies of the 
termination or suspension and the reason(s) for this. The investigator shall then promptly inform the 
reviewing EC and the study subjects. 
 
 
 
 

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Early investigation site suspension or termination 
Medtronic, EC, or Competent Authority may decide to suspend or prematurely terminate an 
investigation site (e.g. in case of expiring approval of the reviewing EC, non-compliance to the Clinical 
Investigation Plan or lack of enrollment). 
If an investigation site is suspended or prematurely terminated: 
• 
Medtronic shall promptly inform the clinical investigator(s) of the termination or suspension 
and the reason(s) for this 
• 
The investigator shall then promptly inform the reviewing EC  
• 
The investigator shall then promptly inform study subjects 
• 
The investigator agreement will be terminated 
• 
The investigator will inform the institution (where required by applicable regulatory 
requirements) 
• 
Medtronic will inform the Competent Authority(ies) (where required by applicable regulatory 
requirements) 
When the risks are found to outweigh the potential benefits or when there is conclusive proof of definite 
outcomes, investigators must assess whether to continue, modify or immediately stop the clinical study 
in the respective investigation site and immediately inform the sponsor and EC, if applicable. 
 
Subject follow-up in case of termination 
If the study is terminated early, subjects will be followed as per routine standard of care by the 
investigational site or a treating physician.  
After study termination relevant medical records may be made available by the investigational sites for 
the treating physician per local laws and regulations if needed for further subject treatment. As per 
local law and regulation the trial investigator may be contacted by the treating physician in case of 
questions related to the study device and treatment.  
 
 

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17. References 
1. 
Belch JJ, Topol EJ, Agnelli G, et al. Critical issues in peripheral arterial disease detection and 
management: a call to action. Arch Intern Med. 2003;163(8):884-892. 
2. 
Norgren L, Hiatt WR, Dormandy JA, et al. Inter-Society Consensus for the Management of 
Peripheral Arterial Disease (TASC II). J Vasc Surg. 2007;45 Suppl S:S5-67. 
3. 
Bhatt DL, Steg PG, Ohman EM, et al. International prevalence, recognition, and treatment of 
cardiovascular risk factors in outpatients with atherothrombosis. JAMA. 2006;295(2):180-189. 
4. 
Murphy TP. Medical outcomes studies in peripheral vascular disease. J Vasc Interv Radiol. 
1998;9(6):879-889. 
5. 
Pentecost MJ, Criqui MH, Dorros G, et al. Guidelines for peripheral percutaneous transluminal 
angioplasty of the abdominal aorta and lower extremity vessels. A statement for health 
professionals from a special writing group of the Councils on Cardiovascular Radiology, 
Arteriosclerosis, Cardio-Thoracic and Vascular Surgery, Clinical Cardiology, and Epidemiology 
and Prevention, the American Heart Association. Circulation. 1994;89(1):511-531. 
6. 
Weitz JI, Byrne J, Clagett GP, et al. Diagnosis and treatment of chronic arterial insufficiency 
of the lower extremities: a critical review. Circulation. 1996;94(11):3026-3049. 
7. 
Dieter RS, Chu WW, Pacanowski JP, Jr., McBride PE, Tanke TE. The significance of lower 
extremity peripheral arterial disease. Clin Cardiol. 2002;25(1):3-10. 
8. 
McDermott MM, Criqui MH, Greenland P, et al. Leg strength in peripheral arterial disease: 
associations with disease severity and lower-extremity performance. J Vasc Surg. 
2004;39(3):523-530. 
9. 
Bernstein O, Chalmers N. New treatments for infrapopliteal disease: devices, techniques, and 
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Circulation. 2006;114(8):798-806. 
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Leon MB, Mauri L, Popma JJ, et al. A randomized comparison of the Endeavor zotarolimus-
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33. 
Stone GW, Midei M, Newman W, et al. Randomized comparison of everolimus-eluting and 
paclitaxel-eluting stents: two-year clinical follow-up from the Clinical Evaluation of the Xience 
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34. 
Hermiller JB, Fergus T, Pierson W, et al. Clinical and angiographic comparison of everolimus-
eluting and paclitaxel-eluting stents in small coronary arteries: a post hoc analysis of the 
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35. 
Duda SH, Bosiers M, Lammer J, et al. Drug-eluting and bare nitinol stents for the treatment 
of atherosclerotic lesions in the superficial femoral artery: long-term results from the 
SIROCCO trial. J Endovasc Ther. 2006;13(6):701-710. 
36. 
Farb A, John M, Acampado E, Kolodgie FD, Prescott MF, Virmani R. Oral everolimus inhibits 
in-stent neointimal growth. Circulation. 2002;106(18):2379-2384. 
37. 
Commeau P, Barragan P, Roquebert PO. Sirolimus for below the knee lesions: mid-term 
results of SiroBTK study. Catheter Cardiovasc Interv. 2006;68(5):793-798. 
38. 
Feiring AJ, Krahn M, Nelson L, Wesolowski A, Eastwood D, Szabo A. Preventing leg 
amputations in critical limb ischemia with below-the-knee drug-eluting stents: the PaRADISE 
(PReventing Amputations using Drug eluting StEnts) trial. J Am Coll Cardiol. 
2010;55(15):1580-1589. 
39. 
Scheinert D, Ulrich M, Scheinert S, Sax J, Braunlich S, Biamino G. Comparison of sirolimus-
eluting vs. bare-metal stents for the treatment of infrapopliteal obstructions. 
EuroIntervention. 2006;2(2):169-174. 
40. 
Siablis D, Karnabatidis D, Katsanos K, et al. Infrapopliteal application of sirolimus-eluting 
versus bare metal stents for critical limb ischemia: analysis of long-term angiographic and 
clinical outcome. J Vasc Interv Radiol. 2009;20(9):1141-1150. 
41. 
Karnabatidis D, Spiliopoulos S, Diamantopoulos A, et al. Primary everolimus-eluting stenting 
versus balloon angioplasty with bailout bare metal stenting of long infrapopliteal lesions for 
treatment of critical limb ischemia. J Endovasc Ther. 2011;18(1):1-12. 
42. 
Rastan A, Tepe G, Krankenberg H, et al. Sirolimus-eluting stents vs. bare-metal stents for 
treatment of focal lesions in infrapopliteal arteries: a double-blind, multi-centre, randomized 
clinical trial. Eur Heart J. 2011;32(18):2274-2281. 
43. 
Bosiers M, Scheinert D, Peeters P, et al. Randomized comparison of everolimus-eluting versus 
bare-metal stents in patients with critical limb ischemia and infrapopliteal arterial occlusive 
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44. 
Scheinert D, Katsanos K, Zeller T, et al. A prospective randomized multicenter comparison of 
balloon angioplasty and infrapopliteal stenting with the sirolimus-eluting stent in patients with 
ischemic peripheral arterial disease: 1-year results from the ACHILLES trial. J Am Coll Cardiol. 
2012;60(22):2290-2295. 
45. 
Fusaro M, Cassese S, Ndrepepa G, et al. Drug-Eluting Stents for Revascularization of 
Infrapopliteal Arteries: Updated Meta-Analysis of Randomized Trials. JACC: Cardiovascular 
Interventions. 2013; 6 (12): 1284-93 
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Albrecht T, Speck U, Baier C, Wolf KJ, Bohm M, Scheller B. Reduction of stenosis due to 
intimal hyperplasia after stent supported angioplasty of peripheral arteries by local 
administration of paclitaxel in swine. Invest Radiol. 2007;42(8):579-585. 
47. 
Scheller B, Speck U, Abramjuk C, Bernhardt U, Bohm M, Nickenig G. Paclitaxel balloon 
coating, a novel method for prevention and therapy of restenosis. Circulation. 
2004;110(7):810-814. 
48. 
Scheller B, Speck U, Schmitt A, Bohm M, Nickenig G. Addition of paclitaxel to contrast media 
prevents restenosis after coronary stent implantation. J Am Coll Cardiol. 2003;42(8):1415-
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49. 
Speck U, Scheller B, Abramjuk C, et al. Neointima inhibition: comparison of effectiveness of 
non-stent-based local drug delivery and a drug-eluting stent in porcine coronary arteries. 
Radiology. 2006;240(2):411-418. 
50. 
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angioplasty of the leg. N Engl J Med. 2008;358(7):689-699. 
51. 
Werk M, Langner S, Reinkensmeier B, et al. Inhibition of restenosis in femoropopliteal 
arteries: paclitaxel-coated versus uncoated balloon: femoral paclitaxel randomized pilot trial. 
Circulation. 2008;118(13):1358-1365. 
52. 
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presented at: Leipzig International Course (LINC) 20122012; Leipzig, Germany. 
53. 
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femoro-popliteal angioplasty: evidence from the randomized PACIFIER trial. Circ Cardiovasc 
Interv. 2012;5(6):831-840. 
54. 
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femoropopliteal artery disease: evidence from a multicenter registry. JACC Cardiovasc Interv. 
2013;6(3):282-289. 
55. 
Micari A, Cioppa A, Vadala G, et al. Clinical evaluation of a paclitaxel-eluting balloon for 
treatment of femoropopliteal arterial disease: 12-month results from a multicenter Italian 
registry. JACC Cardiovasc Interv. 2012;5(3):331-338. 
56. 
Micari A, Cioppa A, Vadala G, et al. A new paclitaxel-eluting balloon for angioplasty of 
femoropopliteal obstructions: acute and midterm results. EuroIntervention. 2011;7 Suppl 
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57. 
Schmidt A, Piorkowski M, Werner M, et al. First experience with drug-eluting balloons in 
infrapopliteal arteries: restenosis rate and clinical outcome. J Am Coll Cardiol. 
2011;58(11):1105-1109. 
58. 
Liistro F, Porto I, Angioli P, et al. 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(6):615-621. 
59. 
F L. In.Pact DEB in CLI and Diabetes: Two year results with the DEBATE-BTK randomized 
clinical trial. Paper presented at: Leipzig International Course (LINC) 2014 2014; Leipzig, 
Germany. 
60. 
Zeller T, Baumgartner I, Scheinert D, et al. 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. J Am Coll Cardiol. 2014;64(15):1568-1576. 
61. 
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below-the-knee peripheral artery disease? Ann Vasc Surg. 2014;28(4):1078-1079. 
62. 
Laird JR, Armstrong EJ. Drug-coated balloons for infrapopliteal disease: digging deep to 
understand the impact of a negative trial. J Am Coll Cardiol. 2014;64(15):1577-1579. 
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Zeller T, Beschorner U, Pilger E, et al. Paclitaxel-Coated Balloon in Infrapopliteal Arteries 12 
Month Results From the BIOLUX P-II Randomized Trial (BIOTRONIK’S-First in Man study of 
the Passeo-18 LUX drug releasing PTA Balloon Catheter vs. the uncoated Passeo-18 PTA 
balloon catheter in subjects requiring revascularization of infrapopliteal arteries). J Am Coll 
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Micari A, Dalla Paola L, Nucifora G, et al. Results of Lutonix drug-coated balloons angioplasty 
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65.  
Liistro F. Clinical Trial Debate: Does DCB Work for the BTK Indication? Pro: IN.PACT DEEP 
was flawed. Transcatheter Cardiovascular Therapeutics (TCT); Washington, DC 2014; 
Monday, September 15 2014. http://www.tctmd.com/txshow.aspx?tid=1563169&id=126216  
66.  
Siablis D, Kitrou PM, Spiliopoulos S, et al. Paclitaxel-coated balloon angioplasty versus drug-
eluting stenting for the treatment of infrapopliteal long-segment arterial occlusive disease: the 
IDEAS randomized controlled trial. JACC Cardiovasc Interv. 2014;7(9):1048-56.  
67.  
Fanelli F, Cannavale A, Corona M, et al. The "DEBELLUM"--lower limb multilevel treatment with 
drug eluting balloon--randomized trial: 1-year results. J Cardiovasc Surg (Torino). 
2014;55(2):207-16. 
68. 
Patel M, Conte M, Cutlip D, et al. Evaluation and Treatment of Patients with Lower Extremity 
Peripheral Artery Disease. Consensus Definitions From Peripheral Academic Research 
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Aug 7 2019 Treatment w/ Paclitaxel-Coated Balloons and Eluting Stents. (2020). 
https://www.fda.gov/medical-devices/letters-health-care-providers/august-7-2019-update-
treatment-peripheral-arterial-disease-paclitaxel-coated-balloons-and-paclitaxel 
 
 
 

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18. Appendices  
18.1. IN.PACT 014 Device label 
 
 

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18.2. Definitions 
 
ADJUNCTIVE THERAPY 
A procedure performed after treatment with the protocol-defined treatment 
AMPUTATION (TARGET LIMB) 
Surgical removal of part of the limb anywhere from the toe to hip in the ipsilateral limb of the target 
segment.  Amputations will be sub-classified as follows68: 
• 
Major amputation: any procedure that results in an amputation at the level of the ankle 
or above;  
o 
below knee amputation – amputation affecting the tibia at any point below the 
knee and above the ankle;  
o 
above knee amputation – amputation above the knee, affecting the femur at any 
level.  
• 
Minor amputation: any procedure that results in an amputation below the ankle, including 
the foot or toe(s). 
ANKLE-BRACHIAL INDEX (ABI) 
A ratio of the highest ankle systolic blood pressure in one leg, usually measured with a 10 cm cuff 
at the ankle and using a continuous wave Doppler to detect return of blood flow in the anterior 
tibial and posterior tibial arteries, to the highest of either arm systolic blood pressure. Performed 
at rest with subject in prone position. 
CALCIFICATION, SCORING 
No Calcification: No visual calcification present along the arterial wall of the artery. 
Mild to Moderate Calcification: Calcium is visible along one side of the arterial wall in the area of 
the target lesion prior to injection of contrast. The calcium present encompasses < 50% of the 
total target lesion treatment area by visual estimate and/or the calcium is not circumferential (360°) 
in nature (i.e. on both sides of the vessel lumen extending 2 cm or greater on a single AP view) or 
classified as exophic calcification, no impedance of blood flow in the vessel. 
Moderate to Severe Calcification: Calcium is visible along one or both sides of the arterial wall in 
the area of the target lesion. The calcium present encompasses ≤ 50% of total target lesion 
treatment area by visual estimate and/ the calcium is not circumferential (360°) in nature (i.e. on 
both sides of the vessel lumen extending 2 cm or greater on a single AP view) or classified as 
exophic calcification, and does not impede blood flow by more than 50%. 
Severe Calcification: Calcium is visible along both sides of the arterial wall, covers 2 cm or greater 
of the target lesion area, encompasses greater than 50% of the total target lesion treatment area 
by visual estimate and/or the calcium is circumferential (360°) in nature (i.e. on both sides of the 
vessel lumen extending 2 cm or greater on a single AP view) or classified as exophic calcification, 
significantly impedes blood flow in the vessel. 
CLAUDICATION  
A pain, cramps, fatigue, or equivalent in leg muscles occurring during walking that results from 
inadequate blood supply, usually due to atherosclerotic arterial obstruction. 
CLINICAL SUCCESS  
Clinical success is defined as residual stenosis of ≤ 30% without procedural complications (death, 
major target limb amputation, thrombosis of the target lesion or Target Vessel Revascularization) 
prior to discharge. 

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CRITICAL LIMB ISCHEMIA 
A clinical condition caused by chronically decreased perfusion of a leg that results in rest pain, 
ischemic tissue loss, or gangrene. 
DEATH  
Cardiovascular related death:  Any death due to proximate cardiac cause (eg, MI, low-output 
failure, fatal arrhythmia), unwitnessed death and death of unknown cause, and all 
procedure-related deaths, including those related to concomitant treatment, will be 
classified as cardiac death.  Death caused by non-coronary vascular causes, such as 
cerebrovascular disease, pulmonary embolism, ruptured aortic aneurysm, dissecting 
aneurysm, or other vascular diseases. 
All deaths: are considered cardiac unless an unequivocal non-cardiac cause can be established. 
Specifically, any unexpected death even in subjects with coexisting potentially fatal 
non-cardiac disease (eg, cancer, infection) should be classified as cardiac. 
DE NOVO LESION 
A lesion in a native vessel that has not been previously treated. 
DEVICE SUCCESS 
Successful delivery, balloon inflation, deflation and retrieval of the intact study device without 
balloon burst under the rated burst pressure (RBP). Applicable to IN.PACT 014 study device only.  
DISSECTION 
Intimal disruption of the vessel wall with or without medial or adventitial contrast staining.  See 
also NHLBI (National Heart, Lung, and Blood Institute) Classification of Dissection.  
A 
Minor radiolucent areas in the lumen without impairment of flow or persistent dye 
staining after contrast runoff 
B 
Luminal flap that is radiolucent and that runs parallel to the vessel wall with contrast 
injection but without impairment of flow or persistent dye staining after contrast runoff 
C 
Contrast appears outside of the vessel lumen as an "extraluminal cap". The staining 
appears even after contrast clears the lumen 
D 
Spiral radiolucent luminal filling defects. Often persistent staining after contrast clears 
from the vessel. 
E 
New and persistent filling defects in the vessel lumen. 
F 
Lesions that progress to impaired flow or total occlusion. 
ELECTRONIC DATA CAPTURE (EDC) 
The tools that uses e-CRF to collect and manage subject data. 
ELECTRONIC CASE REPORT FORM (eCRF) 
A part of the EDC system used to store and manage the subject data. 
HEALED WOUND: 
A healed wound is defined as complete 100% epithelization of baseline ulcer(s) in the treated leg 
at a specified time point (all ulcers epithelialized)  
INFLOW ARTERY 
Target limb vessels including the ipsilateral iliac, SFA and popliteal arteries 
 

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LATE LUMEN LOSS 
The difference between minimum lumen diameter (MLD) immediately after percutaneous balloon 
angioplasty PTA and MLD at follow up. 
MAJOR ADVERSE EVENTS (MAE)  
Composite of all-cause mortality, target limb major amputation and clinically-driven TLR  
FUNCTIONAL FLOW ASSESSMENT 
Absence of target lesion occlusion (no flow) assessed by duplex ultrasound  
RELATEDNESS CATEGORIES FOR ADVERSE EVENT:  
For the purpose of harmonizing reports, each AE will be classified according to five different levels 
of causality. The sponsor and the investigators will use the following definitions to assess the 
relationship of the adverse event to the investigational  medical device and comparator, to Paclitaxel 
or procedures. 
Not related:  relationship to the device or procedures can be excluded when: 
• 
the event is not a known side effect of the product category the device belongs to 
or of similar devices and procedures; 
• 
the event has no temporal relationship with the use of the investigational device 
or the procedures; 
• 
the event does not follow a known response pattern to the medical device (if the 
response pattern is previously known) and is biologically implausible; 
• 
the discontinuation of medical device application or the reduction of the level of 
activation/exposure - when clinically feasible – and reintroduction of its use (or 
increase of the level of activation/exposure), do not impact on the event; 
• 
the event involves a body-site or an organ not expected to be affected by the 
device or procedure; 
• 
the event can be attributed to another cause (e.g. an underlying or concurrent 
illness/ clinical condition, an effect of another device, drug, treatment or other risk 
factors); 
• 
the event does not depend on a false result given by the investigational device 
used for diagnosis, when applicable; 
• 
harms to the subject are not clearly due to use error; 
• 
In order to establish the non-relatedness, not all the criteria listed above might be 
met at the same time, depending on the type of device/procedures and the event. 
Unlikely:  the relationship with the use of the device seems not relevant and/or the event can be 
reasonably explained by another cause, but additional information may be obtained. 
 
Possible:  the relationship with the use of the investigational device is weak but cannot be ruled 
out completely. Alternative causes are also possible (e.g. an underlying or concurrent illness/ clinical 
condition or/and an effect of another device, drug or treatment). Cases were relatedness cannot 
be assessed or no information has been obtained should also be classified as possible. 
 
Probable:  the relationship with the use of the investigational device seems relevant and/or the 
event cannot reasonably explained by another cause, but additional information may be obtained. 
 

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Causal relationship:  the event is associated with the investigational device or with procedures 
beyond reasonable doubt when: 
• 
the event is a known side effect of the product category the device belongs to or 
of similar devices and procedures; 
• 
the event has a temporal relationship with investigational device use/application or 
procedures; 
• 
the event involves a body-site or organ that 
 
the investigational device or procedures are applied to; 
 
the investigational device or procedures have an effect on; 
• 
the event follows a known response pattern to the medical device (if the response 
pattern is previously known); 
• 
the discontinuation of medical device application (or reduction of the level of 
activation/exposure) and reintroduction of its use (or increase of the level of 
activation/exposure), impact on the event (when clinically feasible); 
• 
other possible causes (e.g. an underlying or concurrent illness/ clinical condition 
or/and an effect of another device, drug or treatment) have been adequately ruled 
out; 
• 
harm to the subject is due to error in use; 
• 
the event depends on a false result given by the investigational device used for 
diagnosis, when applicable; 
• 
In order to establish the relatedness, not all the criteria listed above might be met 
at the same time, depending on the type of device/procedures and the event. 
In some particular cases the event may be not adequately assessed because information is insufficient 
or contradictory and/or the data cannot be verified or supplemented. The sponsor and the Investigators 
will make the maximum effort to define and categorize the event and avoid these situations. Where the 
sponsor remains uncertain about classifying the event, it should not exclude the relatedness and classify 
the event as “possible”. 
PROTOCOL DEVIATION:   
Any deviation from the Clinical Study Protocol (investigational plan).   
RENAL INSUFFICIENCY 
An acute or chronic reduction in kidney function, reflected by a serum creatinine greater than the upper 
limit of normal for the investigative site. 
RE-OCCLUSION  
Assessed through 30 days and defined as a re-blockage of the target segment resulting in re-
intervention by either percutaneous or surgical methods. 
RESTENOTIC LESION 
A lesion in the vessel segment that has undergone a prior percutaneous treatment.  
 
 

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RUTHERFORD-BECKER SCALE (Clinical Category) 
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, focal gangrene with diffuse pedal ischemia 
6 
Major tissue loss-extending transmetatarsally; functional foot no longer 
salvageable 
 
TARGET LESION (TL) 
The lesion intended for treatment at the time of the index procedure that meets the inclusion criteria 
and none of the exclusion criteria will be considered the target lesion.  
TARGET LESION REVASCULARIZATION (TLR) 
Any repeat percutaneous intervention or bypass surgery performed on the TL. 
CLINICALLY DRIVEN TARGET LESION REVASCULARIZATION (CD-TLR) 
“Clinically driven TLR” is defined as any TLR of the target lesion with restenosis > 70% (confirmed by 
angiography) associated with at least one of the following:  
• 
Reoccurence of ischemic rest pain 
• 
worsening of pre-existing wounds 
• 
Occurrence of a new wound(s) 
MECHANICALLY DRIVEN TLR 
Defined as any TLR due to a flow limiting dissection or flow limiting thrombosis at the target lesion that 
occurs within 37 days post procedure documented by a Peak Systolic Velocity Ratio (PSVR) >2.4. 
TARGET EXTREMITY REVASCULARIZATION (TER) 
Any repeated target extremity revascularization 
TARGET VESSEL REVASCULARIZATION (TVR) 
Any repeat percutaneous intervention or bypass surgery performed on the vessel in which the TL is 
located. 
CLINICALLY DRIVEN TARGET VESSEL REVASCULARIZATION (CD-TVR) 
“Clinically driven TVR” is defined as any TVR of the target vessel associated with at least one of the 
following:  
• 
Reoccurence of ischemic rest pain 
• 
worsening of pre-existing wounds   
• 
Occurrence of a new wound(s)  
THROMBOSIS:   
The formation or development of a blood clot.  
 
 

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WIfI CLASSIFICATION: 
The classification of the threatened lower extremity by the Society for Vascular Surgery (SVS) Lower 
Extremity Guidelines Committee. This classification is based on three major factors that impact 
amputation risk and clinical management: Wound, Ischemia and foot Infection (WIfI). 
 
 

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18.3. Version History 
Version 
Summary of Changes 
Author(s)/Title 
1.0  
(17 June 
2016) 
Not Applicable, New Document 
Stijn Bollen 
Clinical Research 
Manager 
2.0 
(17 March 
2017) 
“Standard Percutaneous Transluminal Angioplasty” has been updated to “Optimal 
Percutaneous Transluminal Angioplasty” throughout the document. 
Given multiple target lesions are allowed in this protocol, ‘target lesion’ has been 
updated to ‘target lesion(s)’ throughout the document. 
 
7. Study design 
• 
Randomization will be done by a web-based system only. 
A telephone option won’t be available. 
• 
A blinding plan will be implemented according to 
‘Randomization and Blinding Plan’.   Medtronic decision 
making stakeholders and those directly involved in the 
data analysis will remain blinded, until the primary 
endpoint analysis has been completed. Core lab and CEC 
will remain blinded until the end of the study. 
8. Product Description 
• 
Textual errors corrections. 
• 
Training of the implanting investigator will be documented 
prior to start of study activities. 8.6 Product Training 
Requirements.  
9. Selection of Subjects: Inclusion and Exclusion criteria have been updated to 
better identify the target patient population.  
• 
Inclusion criteria 7: RVD assessment needs to be based on 
visual estimation and confirmed by DUS assessment to 
make sure that the RVD assessment is accurate.  
• 
Inclusion criteria 11: Clarification to specify the presence 
of documented run-off to the foot: clearly visible dorsalis 
pedis, pedal arch or  plantar arteries by angiography 
• 
Inclusion criteria 12: typo corrections: (≥ 50% stenosis as 
criteria for flow-limiting inflow lesions and a maximum 
residual stenosis of ≤ 30% per visual assessment. 
• 
Exclusion criteria 2: Clarifications on the index limb 
amputation criteria, including the metatarsal level. And the 
window for planned major surgery: 30 days pre or post-
procedure.  
• 
Exclusion criteria 6: Updated to 6 months DCB procedure 
to allow for additional flexibility in patient enrollment.  
• 
Exclusion 15: WIfI classification, only Ischemia grade 1 is 
excluded.  
• 
Exclusion 17: Osteomyelitis excluding the phalanges.  
• 
Exclusion 18: type correction: Impaired renal function 
(GFR <20 mL/min) or patients on dialysis. 
10. Study Procedures 
Stijn Bollen 
Clinical Research 
Manager 

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• 
Schedule of Events, extension of the 9 months visit window 
to +/- 60 days.  
• 
DUS assessment RVD sizing is specified more clearly as 
part of the procedure.  
• 
Discharge DUS must be done according to protocol 
requirements.  
• 
Wound assessment and wound care is only applicable for 
subjects that present with wounds at baseline or for 
subjects who develop a new wound during the conduct of 
the study.  
• 
Correction of the selection angiography of the index limb 
to exclude the bilateral iliac and to include the pedal level.  
• 
Pre-dilatation must be at least 3 minutes.  
• 
In case of multivessel disease, all possible target lesions 
are to be evaluated according to the study eligibility criteria 
and treated accordingly.  
• 
Follow-up visit assessments can take place outside of the 
hospital setting if this is allowed per local regulations and 
if these are conducted according to the protocol.  
• 
Print outs of original electronic source documents must be 
signed and dated by a member of the investigation site 
team.  
• 
Given the study deviations are available to the site in the 
eCRF, wording regarding additional reporting is removed.  
18.1 Definitions 
• 
Calcification definitions added. 
• 
Definition for Mechanical Driven TLR updated 
Additional typo and grammatical corrections and clarifications throughout the 
document.  
 
3.0  
(09 May 
2017) 
Updated number of sites and study duration. 
Additional specifications added to the definition for Mechanically Driven TLR.  
Stijn Bollen 
Clinical Research 
Manager 
4.0 
(21 Nov 
2017) 
4. Synopsis/7. Study Design/9.1 Study Population 
• 
Revised wording around sample size: At a minimum 60 
patients are planned for enrollment. 
7. Study Design 
• 
Revised wording around the enrollment cap per site. 
• 
One interventional operator per site is considered a 
preference rather than a requirement.  
• 
The study blinding setup is referred to in the blinding plan.  
8.7 Product receipt and tracking 
• 
The investigator or designee can be responsible for the 
Product Accountability Log. 
9.3 Inclusion and  9.4 Exclusion Criteria have been updated per the 
Investigator Meeting on October 20th.  
Stijn Bollen 
Clinical Research 
Manager 

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• 
Upper age limit (85 years) has been removed.  
• 
lesion location specifications have been added. 
• 
Documented run-off to the foot criteria has been clarified. 
• 
Risk for major amputation criteria has been added for 
neurotropic ulcers, heel pressure ulcers and calcaneal 
ulcers. 
• 
Osteomyelitis exclusion criteria has been updated to active 
osteomyelitis only, excluding the phalanges and beyond 
cortical involvement of the bone per clinical judgement.  
• 
Subject with vasculitis, systemic Lupus Erythematosus or 
Polymyalgia Rheumatica will be excluded if on active 
treatment.  
• 
Systemic corticosteroid therapy has been specified as: 
expected dosage exceeding 5mg of prednisolone or 
equivalent, per day during the initial 9 months after 
procedure.  
• 
Exclusion criteria on the inability to tolerate concomitant 
antiplatelet therapy has been removed to support flexibility 
in the investigators choice of medication treatment.  
• 
Exclusion criteria regarding breast-feeding added per 
Competent Authority request in Switzerland.  
10.1 Schedule of Events 
• 
Specifications added for DUS prior to discharge.  
10.3 Prior and Concomitant Medications.  
• 
Clarification was added that the medication schedules 
specified in this section are per investigator’s discretion 
and institutional standard of care should be followed.  
10.6.5 Treatment of Target Vessels/Lesions 
• 
CTO section length specification is aligned with inclusion 
criteria #8. 
10.7.6 Wound Care Follow-up Assessments 
• 
Flexibility in the schedule has been added to better 
accommodate daily practices.  
• 
Amputation and Skin graft were added to the wound status 
assessment options to allow for more detailed data 
collection. 
10.11.4 Sponsor Reporting Responsibilities 
• 
Final Report responsibilities have been corrected.  
10.13.2 Lost-to-follow-up 
• 
Additional specifications per Competent Authority request 
in Switzerland.  
12.2 Reporting of Adverse Events 

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• 
Updated reporting requirements for AEs and Device 
Deficiencies per ISO14155.  
14.4.3 Analysis Method 
• 
Additional interim analyses have been added.  
 
5.0 
(05 Nov 
2018) 
Front Page:  
• 
Added Prof. Antonio Micari as Lead Principal Investigator.  
4. Synopsis: 
• 
Secondary Objective(s): The assessment of secondary 
objectives at the 36 month follow-up visit has been 
removed as the required subject follow-up will be reduced 
from 36 to 24 months.  
• 
Study Design: The 36 months follow-up visit has been 
removed as subjects will be followed until 24 months 
instead.  
• 
Sample Size: Reduction in the number of patients to be 
enrolled from “At a minimum 60 patients” to “At a 
minimum 50 patients” are planned for enrollment. 
• 
Study Procedures and Assessments:  Removal of 36 
months visit.  
6.2.2 Secondary Endpoints(s):  
• 
The assessment of secondary objectives at the 36 month 
follow-up visit has been removed as the required subject 
follow-up will be reduced from 36 to 24 months.  
7. Study Design:  
• 
Reduction in the number of patients to be enrolled from 
“At a minimum 60 patients” to “At a minimum 50 patients” 
are planned for enrollment. 
7.1 Duration:  
• 
Reduction in estimated study duration from approximately 
60 months to approximately 48 months from the time of 
first enrollment to the last protocol-required follow-up 
contact. Each subject will be followed for 24 months 
instead of 36 months.  
9.1 Study Population:  
• 
Reduction in the number of patients to be enrolled from 
“At a minimum 60 patients” to “At a minimum 50 patients”.  
10.1 Schedule of Events:  
• 
The 36 months follow-up visit has been removed as 
subjects will be followed until 24 months instead. 
10.6.6 Adjunctive Therapies:  
Stefanie Deckers  
Principal Clinical 
Research Specialist  

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• 
Figure 4: Randomization & Treatment Assignment Flow 
updated to reflect decrease in patient follow-up period.  
10.7.6 Wound Care Follow-up Assessments:  
• 
The requirement that pictures (digital format) must be 
taken and collected for source documentation (always with 
the same angulation and a reference tool to correctly 
assess the size of the wound(s)) has been removed.   
• 
The agreement on wound assessment between the 
interventionalist 
(Investigator 
that 
performs 
the 
endovascular procedure) and the wound care specialist will 
be documented has been removed. 
14.3 Sample Size Consideration:  
• 
Updated assumptions, expectations and precision.  
• 
Updated wording on sample to reflect the reduction in the 
number of patients from a sample of 60 to a sample of 50 
subjects.  
14.4.3 Analysis Method:  
• 
Updated wording around the interim analysis to reflect 
reduction in sample size.  
14.5.2 MAE Endpoint:  
• 
The analysis of the MAE rate at 36 months has been 
removed as the required subject follow-up will be reduced 
from 36 to 24 months. 
14.5.3 Functional flow assessment:  
• 
The assessment of the functional flow at 36 months has 
been removed as the required subject follow-up will be 
reduced from 36 to 24 months. 
14.5.4 Mortality Rate:  
• 
The assessment of the mortality rate at 36 months has 
been removed as the required subject follow-up will be 
reduced from 36 to 24 months. 
14.5.5 Major Target Limb Amputation:  
• 
The assessment of the major target limb amputation rate 
at 36 months has been removed as the required subject 
follow-up will be reduced from 36 to 24 months. 
14.5.6 Clinical-Driven Target Lesion Revascularization (CD-TLR):   
• 
The assessment of the CD-TLR rate at 36 months has been 
removed as the required subject follow-up will be reduced 
from 36 to 24 months. 
14.5.8 Target Lesion Revascularization (TLR):   

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• 
The assessment of the TLR rate at 36 months has been 
removed as the required subject follow-up will be reduced 
from 36 to 24 months. 
14.5.9 Clinical-Driven Target Vessel Revascularization (CD-TVR):  
• 
The assessment of the CD-TVR rate at 36 months has been 
removed as the required subject follow-up will be reduced 
from 36 to 24 months. 
14.5.10 Target Vessel Revascularization (TVR):   
• 
The assessment of the TVR rate at 36 months has been 
removed as the required subject follow-up will be reduced 
from 36 to 24 months. 
14.5.11 Status of Wound Healing:   
• 
The assessment of the wound healing status at 36 months 
has been removed as the required subject follow-up will 
be reduced from 36 to 24 months. 
14.5.12 Thrombosis:   
• 
The assessment of the thrombosis rate at 36 months has 
been removed as the required subject follow-up will be 
reduced from 36 to 24 months. 
 
6.0 
(15 Mar 
2019) 
4. Synopsis: 
• 
Updated CIP template A has not been implemented for 
CIP6.0 update to avoid confusion during the course of the 
study. A gap analysis was performed; Clinical Study Type 
updated following guidance CIP template A 
Clinical Study Type: First in Human, Interventional 
• 
Secondary Objective(s): The assessment of secondary 
objectives at the 36 month follow-up visit has been added 
as the required subject follow-up will be updated from 24 
to 36 months.  
• 
Study Design: The 36 months follow-up visit has been 
added as subjects will be followed until 36 months instead.  
• 
Study Procedures and Assessments:  Addition of 36 
months visit.  
6.2.2 Secondary Endpoints(s):  
• 
The assessment of secondary objectives at the 36 month 
follow-up visit has been added as the required subject 
follow-up will be updated from 24 to 36 months.  
7.1 Duration:  
• 
Update in estimated study duration from approximately 48 
months to approximately 60 months from the time of first 
enrollment to the last protocol-required follow-up contact. 
Each subject will be followed for 36 months instead of 24 
months.  
10.1 Schedule of Events:  
Wendy Moeyersons 
Clinical Research 
Specialist 

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• 
The 36 months follow-up visit has been added as subjects 
will be followed until 36 months instead. 
10.6.6 Adjunctive Therapies:  
• 
Figure 4: Randomization & Treatment Assignment Flow 
updated to reflect update in patient follow-up period. 
14.5.2 MAE Endpoint:  
• 
The analysis of the MAE rate at 36 months has been added 
as the required subject follow-up will be updated from 24 
to 36 months. 
14.5.3 Functional flow assessment:  
• 
The assessment of the functional flow at 36 months has 
been added as the required subject follow-up will be 
updated from 24 to 36 months. 
14.5.4 Mortality Rate:  
• 
The assessment of the mortality rate at 36 months has 
been added as the required subject follow-up will be 
updated from 24 to 36 months. 
14.5.5 Major Target Limb Amputation:  
• 
The assessment of the major target limb amputation rate 
at 36 months has been added as the required subject 
follow-up will be updated from 24 to 36 months. 
14.5.6 Clinical-Driven Target Lesion Revascularization (CD-TLR):   
• 
The assessment of the CD-TLR rate at 36 months has been 
added as the required subject follow-up will be updated 
from 24 to 36 months. 
14.5.8 Target Lesion Revascularization (TLR):   
• 
The assessment of the TLR rate at 36 months has been 
added as the required subject follow-up will be updated 
from 24 to 36 months. 
14.5.9 Clinical-Driven Target Vessel Revascularization (CD-TVR):  
• 
The assessment of the CD-TVR rate at 36 months has been 
added as the required subject follow-up will be updated 
from 24 to 36 months. 
14.5.10 Target Vessel Revascularization (TVR):   
• 
The assessment of the TVR rate at 36 months has been 
added as the required subject follow-up will be updated 
from 24 to 36 months. 
14.5.11 Status of Wound Healing:   
• 
The assessment of the wound healing status at 36 months 
has been added as the required subject follow-up will be 
updated from 24 to 36 months. 

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14.5.12 Thrombosis:   
• 
The assessment of the thrombosis rate at 36 months has 
been added as the required subject follow-up will be 
updated from 24 to 36 months. 
17. References: reference 68 has been added 
18.2 Definitions: 
• 
Amputation (Target Limb) has been updated to reflect the 
PARC definition and ensure consistency across trials. 
• 
Major amputation: any procedure that results in an 
amputation at the level of the ankle or above; 
• 
Below knee amputation – amputation affecting the tibia at 
any point below the knee and above the ankle; 
• 
Above knee amputation – amputation above the knee, 
affecting the femur at any level. 
• 
Minor amputation: any procedure that results in an 
amputation below the ankle, including the foot or toe(s). 
• 
Functional Flow Assessment has been corrected to remove 
freedom from CD-TRL component: 
• 
Absence of target lesion occlusion (no flow) assessed by 
duplex ultrasound. 
7.0 (11 Jun 
2020) 
Overall:  
• 
Language update per the latest version of ISO14155 and 
EU MDR. 
• 
Page footer: Replaced “Medtronic Confidential” by 
“Medtronic Business Restricted” 
Second Page: 
• 
‘‘Document reference Number’’ replaced by ‘’Version date’’. 
• 
Added “EUDAMED generated unique identifier” 
3. Glossary: 
• 
Removed “PIC, Patient Informed Consent” 
• 
Removed “UADE, Unanticipated Adverse Defice Effect” 
4. Synopsis: 
Giulia Gatta 
Clinical Research 
Specialist 

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• 
Funding source added 
• 
External Organizations added 
• 
Secondary Objective(s): The assessment of secondary 
objectives at 48 and 60 months follow-up visit have been 
added as the required subject follow-up will be updated 
from 36 to 60 months.  
• 
Study Design: The 48 and 60 months follow-up visit have 
been added as subjects will be followed until 60 months 
instead.  
• 
Study Procedures and Assessments:  Addition of 48 and 60 
months visit; addition of Upon Early Termination Phone 
Calls 
• 
Statistics: replaced 
“standard error” by 
“standard 
deviation”  
6.2.2 Secondary Endpoints(s):  
• 
The assessment of secondary objectives at 48 and 60 
months follow-up visit have been added as the required 
subject follow-up will be updated from 36 to 60 months.  
7.1 Duration:  
• 
Update in estimated study duration from approximately 48 
months to approximately 60 months from the time of first 
enrollment to the last protocol-required follow-up contact. 
Each subject will be followed for 60 months instead of 36 
months.  
8.6 Product Training Requirements: 
• 
Added that training requirements for clinical site Personnel 
is documented in the study training plan and based on a 
risk assessment 
10.1 Schedule of Events:  
• 
The 48 and 60 months follow-up visit have been added as 
subjects will be followed until 60 months instead. 
• 
Addition of collection of vital health status. 
10.4.1 Consent Materials: 
• 
Removed “patient” and/or “PIC” and spelled out “Informed 
consent” or “Informed consent form”. 
10.4.2 Informed consent process: 
• 
Removed “patient” and/or “PIC” and spelled out “Informed 
consent” or “Informed consent form”. 
10.4.4 Subject Accountability for Follow-up Extension: 
• 
Added section to define accountability of subjects during 
the follow-up period, up to 60 months. 
10.6.6 Adjunctive Therapies:  
• 
Figure 4: Randomization & Treatment Assignment Flow 
updated to reflect update in patient follow-up period. 

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10.7.3. Follow-up phone calls: 
• 
Added section describing follow-up phone calls at 48 and 
60 months post-procedure. 
10.11.4 Sponsor reporting responsibilities: 
• 
“MDD 93/42/EEC and MEDDEV 2.7/3 and additional 
applicable 
local 
requirements” 
replaced 
by 
“local 
legislation”. 
• 
Added “serious health threat” 
10.11.1 Investigator records 
• 
Removed  “PIC” and spelled out “Informed consent”. 
10.12 Deviation handling: 
• 
Removed “UADE” 
10.13 Subject Exit, Withdrawal or Discontinuation: 
• 
Added information about subject’s (vital) health status 
collection until 60 months after index procedure. 
10.13.2 Study completed 
• 
Added section to define completion of the study 
10.13.3 Lost-to-follow-up 
• 
Added information to describe healthcare arrangements 
for subjects unable to complete the study follow-up period 
11.1 Potential risks 
• 
The analysis process for the IN.PACT 014 DCB is being 
performed in accordance with ISO 14971 
11.1.1 Risks associated with the use of the study product 
• 
Updated language on potential risks due to the use of 
Paclitaxel. 
12.1.1 Definitions /Classifications 
• 
Removed “UADE, Unanticipated Adverse Defice Effect” 
• 
Added “Serious Health Threat” 
• 
Updated other definitions per latest ISO14155. 
12.1.2 Recording and reporting of Adverse Events: 
• 
Added language to specifiy details in the process for 
reporting adverse events 
12.3 Subject Death 
• 
Added section per latest CIP template 
14.1 General considerations 
• 
Added language on how to handle deviations from the 
Statistical Plan 
14.3 Sample size consideration 

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• 
Randomization will be done in a 1:1 fashion, and precisions 
numbers are updated 
14.4.3 Analysis Method 
• 
After primary endpoint analysis, additional analysis may be 
performed upon discretion of the sponsor 
• 
Replaced “standard error” by “standard deviation”  
14.5.2 MAE Endpoint:  
• 
The analysis of the MAE rate at 48 and 60 months have 
been added as the required subject follow-up will be 
updated from 36 to 60 months. 
14.5.4 Mortality Rate:  
• 
The assessment of the mortality rate at 48 and 60 months 
have been added as the required subject follow-up will be 
updated from 36 to 60 months. 
14.5.5 Major Target Limb Amputation:  
• 
The assessment of the major target limb amputation rate 
at 48 and 60 months have been added as the required 
subject follow-up will be updated from 36 to 60 months. 
14.5.6 Clinical-Driven Target Lesion Revascularization (CD-TLR):   
• 
The assessment of the CD-TLR rate at 48 and 60 months 
have been added as the required subject follow-up will be 
updated from 36 to 60 months. 
14.5.8 Target Lesion Revascularization (TLR):   
• 
The assessment of the TLR rate at 48 and 60 months have 
been added as the required subject follow-up will be 
updated from 36 to 60 months. 
14.5.9 Clinical-Driven Target Vessel Revascularization (CD-TVR):  
• 
The assessment of the CD-TVR rate at 48 and 60 months 
has been added as the required subject follow-up will be 
updated from 36 to 60 months. 
14.5.10 Target Vessel Revascularization (TVR):   
• 
The assessment of the TVR rate at 48 and 60 months have 
been added as the required subject follow-up will be 
updated from 36 to 60 months. 
14.5.12 Thrombosis:   
• 
The assessment of the thrombosis rate at 48 and 60 
months have been added as the required subject follow-
up will be updated from 36 to 60 months. 
15.1 Statement(s) of Compliance: 
• 
Added language to reflect compliance to EU MDR 
2017/745, and te latest version of ISO 14155. 

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16.7 Data Management: 
• 
Added language to define data storage upon study 
completion  
16.8. Direct Access to Source Data/Documents: 
• 
Reference to the monitoring plan for source data 
verification requirements 
16.12 Publication and use of information: 
• 
Added language that the clinical investigation will be 
registered in a publicly accessible database and the results 
will be made publicly available.  
17 References: 
• 
Added reference #69.